The Most Commonly Used Drugs at the Primary Health Care Level in Palestine 2003

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Birzeit University

The Most Commonly Used Drugs at the Primary Health Care Level in Palestine

Training and Self Learning Manual 2003

Edited by: Rana A. Khatib, MS Pharm, PhD Amal R. Daoud, BPharm, MPH

Published by: The Institute of Community and Public Health Birzeit University Editors: Rana A. Khatib, MS Pharm, PhD Amal R. Daoud, BPharm, MPH

Assistant editors: Samia O. Halileh, MD, MRCP DCCH, PhD Nahed S. Mikki, MD Pediatrics Chiara Zanetti, MD Ob/Gyn

Contributing editors: Awad R. Matariya, BPharm Luma I. Aryan, BPharm Amin F. Masad, MD, MPH Gabriela G. Abu-Zanat, MD, MPH

We are greatful to the following individuals and organizations for their contributions in reviewing and advising: • Assad Ramlawi, MD, MPH • Abdul-Naser Daraghmeh, MD, Diploma-PHC • Bashir Tarazi, MD, Diabetology • Bassam Ashhab, MD, BCh DPM, MRCPsych • Denise Mcgrouen, MD, Ophtal. • Hisham Arda, MD, Skin and Venereal Disease • Muhammad al-Hmouz, MD • Muhammad al-Khalili, MD, MPH • Muhammad Tafakji, MD • Rashid Jarallah, MD, MBBS, MRCOC • Samer Ghazal, MD • Shukri Oudeh, MD, MRCOC • Wael Salhab, MR, ORL/ENT • Waleed Obeidallah, MSc Pharm.

Institute of Community and Public Health Birzeit University POB 154, Ramallah, Palestine Tel: + 9722 2988654/5 Fax: + 9722 2951181 E-mail: [email protected] Website: icph.birzeit.edu

ii Table of Contents

PREFACE ……………………………………………………………….... ix HOW TO USE THIS MANUAL …………………………….……..……… xi ABBREVIATIONS ……………………………………….………………. xiii PREGNANCY CATEGORIES ………………………………………..….. xv

CHAPTER 1: ANALGESICS, ANTIPYRETICS, ANTI- INFLAMMATORY AND ANTIGOUT DRUGS …………………………... 1 A) ANALGESICS, ANTIPYRETICS, AND ANTI-INFLAMMATORY AGENTS …. 2 1) Acetylsalicylic Acid WHO,P …………………………………………………… 4 2) Paracetamol WHO,P ………………………………………………….…….……….. 6 3) Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) …..…….………….………… 8 B) ANTIGOUT AGENTS……………………………………………………...………. 13 1) Allopurinol WHO,P ……..…………………..………………………………………. 13 2) Sulfinpyrazone …………………………...……………………………………….. 15 WHO,P 3) Colchicine …………………………………………………………………... 17

CHAPTER 2: CARDIOVASCULAR DRUGS ……………………………… 21 A) ANTIHYPERTENSIVES…………………………………………………………… 23 1) DIURETICS ………………………………………………………………..……... 26 a) Thiazide Diuretics: Hydrochlorothiazide WHO,P ………………………………… 26 b) Loop Diuretics: Furosemide WHO,P ………………………………………….. 27 c) Potassium Sparing Diuretics: Spironolactone WHO,P …………………………... 29 2) BETA – BLOCKERS ………………………………………..……………………. 31 a) Propranolol P ………………………………………………………………. 31 b) Atenolol WHO, P ………………………………………………………..…… 33 3) ANGIOTENSIN CONVERTING ENZYME INHIBITORS (ACEI) …………….. 34 WHO,P a) Captopril ………………………………………………………... 35 4) CA CHANNEL BLOCKERS ………………………………………………... 37 a) Nifedipine WHO,P ……………………………………………………………. 38 WHO,P b) Verapamil ………………………………………………………….. 39 B) ANTI-ARRHYTHMICS ….…………………………………………………. 41 1) Amiodarone ……………………………………………………………… 42 WHO,P 2) Lidocaine ………………………………………………………….. 44 WHO,P 3) Quinidine ………………………………………………………….. 44 C) ANTIANGINA ………………………………………………………………. 44 WHO,P 1) Isosorbide Dinitrate …………………………………………………. 45 D) ANTICOAGULANTS ……………………………………………………….. 46 WHO,P 1) Aspirin ………………………………………………………………. 47 WHO,P 2) Warfarin ……………………………………………………………. 47 E) CONGESTIVE HEART FAILURE DRUGS ………………………………….. 49 WHO,P 1) Digoxin ………………………………………………………….. 50

iii F) LIPID LOWERING DRUG ………………………………………………….. 52 1) Fibric Acids: Bezafibrate …………………………………………………. 53 2) Bile Acid Sequestrants: Cholestyramine …………………………………… 54 3) HMG-COA Reductase Inhibitors: Simvastatin ……………………………… 56

CHAPTER 3: GASTRO-INTESTINAL DRUGS ………………………….. 56B 9 A) ANTACIDS & ULCER HEALING MEDICATION ……..……………………. 61 WHO,P 1) Mg/Al Salt ………………………………………………………….. 63 WHO,P 2) Ranitidine ………………………………………………………….. 64 3) Omeprazole ………………………………………………………….. 65 B) ANTISPASMODICS/ ANTICHOLINERGICS ……………………………….. 66 P 1) Hyocine N-butyl Bromide ……………….…………………………….…. 67 C) ANTIEMETICS ………………………………………………………….. 68 1) Metoclopramide WHO,P …………………………………………………….. 68 2) Meclozine/Meclizine ………………………………………………………. 70 D) DRUGS USED IN DIARRHEA ……………………………………………… 70 WHO,P 1) Oral Rehydrating Salts ………………………………………………. 73 P 2) Antidiarrheal Agent: Loperamide ………………………………………… 74 E) LAXATIVES ……………………………………………………………… 75 1) Bisacodyl P ……………………………………………………………….. 77 2) Castor Oil ……………………………………………………………….. 70 P 3) Glycerin ………………………………………………………………... 77 4) Psyllium …………………………………………………………………... 78 F) ANTI-HEMORRHOIDAL …………………………………………………. 79 1) Anusol (or other equivalent preparation WHO,P) ……………………………… 80

CHAPTER 4: RESPIRATORY DRUGS …………………………………. 83 A) ANTIHISTAMINES ………………………………………………………… 86 WHO,P 1) Chlorpheniramine …………………………………………………. 86 2) Astemizole …….………………………………………………………….. 88 B) NASAL DECONGESTANTS ………………………………………………... 90 1) Oxymetazoline ………………………………………………………….. 91 2) Pseudoephedrine ………………………………………………………….. 92 C) EXPECTORANTS ………………………………………………………….. 93 1) Ammonium Chloride ………………………………………………………. 93 2) Guaifenesin ……………………………………………………………….. 93 D) ANTITUSSIVES/ COUGH SUPPRESSANTS ……………………………….. 94 1) Codeine ………………………………...………………………………… 94 WHO 2) Dextromethorphan HBr ………………………………………………. 96 E) MUCOLYTICS …………………………………………………………….. 97 1) Acetylcysteine ….………………………………………………………….. 97 2) Bromhexine …………………………………………………………….. 97 F) BRONCHODILATORS & ASTHMA MEDICATION ………………………. 97 WHO,P 1) Theophylline (or soluble salt derivatives) …………………………….. 100 WHO,P 2) Salbutamol / Albuterol ………………………………………………. 103 WHO,P 3) Cromolyn / Cromoglycate ……………………………………………. 104 WHO,P 4) Beclomethasone Dipropionate ……………………………………….. 106

iv 5) Prednisolone WHO,P ………..………………………………………………. 107

CHAPTER 5: ANTI-INFECTIVE DRUGS ……………………………….. 111 A) ANTI-BACTERIALS ……….………………………………………………. 115 1) Penicillins (β-Lactam) …………………………………………………. 115 WHO,P WHO,P a) Benzylpenicillin & Phenoxymethyl penicillin ……………………. 116 WHO,P b) Cloxacillin & flucloxacillin: (Penicillinase resistant penicillins) ……… 119 WHO,P WHO,P c) Ampicillin & Amoxicillin (aminopenicillins) ……………………. 120 WHO,P d) Amoxicillin with Clavulanic Acid (Co-amoxiclav) ……………………. 122 2) Cephalosporins: CephalexinP, Cefadroxil and Cefaclor …………………….. 124 3) Tetracyclines: Tetracycline …………………………………………………. 127 WHO,P 4) Macrolides: Erythromycin ………………………………………… 129 P 5) Sulphonamides and Trimethoprim ………………………………………… 131 WHO,P 6) Nitrofurantoin ……………………………………………………….. 133 WHO,P 7) Nalidixic Acid ……………………………………………………….. 135 WHO,P 8) Fluoroquinolones: Ciprofloxacin …………………………………….. 136 B) ANTI-TUBERCULOSIS …………………………………………………….. 137 1) Isoniazid WHO,P …..……………………………………………………….. 139 WHO,P 2) Rifampicin ………………………………………………………….. 140 WHO,P 3) Pyrazinamide ………………………………………………………... 142 WHO,P 4) Ethambutol ………………………………………………………….. 142 C) ANTI-PARASITICS …………………………………………………………. 143 WHO,P 1) Metronidazole ……………………………………………………….. 143 WHO 2) Diloxanide Furoate …………………………………………………… 146 WHO 3) Mebendazole ………………………………………………………….. 146 4) Niclosamide ………………………………………………………………. 147 WHO 5) Albendazole ………………………………………………………….. 148 D) ANTI-FUNGALS ………………………………………………………….. 148 WHO,P 1) Nystatin ………………………………………………………….. 148 WHO,P 2) Miconazole ………………………………………………………….. 149 WHO,P 3) Griseofulvin ………………………………………………………….. 150 E) ANTIVIRAL AGENTS ……………………………………………………… 151 1) Acyclovir ………………………………………………………………….. 151 CHAPTER 6: ENDOCRINE SYSTEM DRUGS 155 A) ANTIDIABETIC DRUGS …………………………………………………. 157 1) Insulin WHO,P ……………………………………………………………... 159 WHO,P 2) Glibenclamide /Glyburide ……………………………………………. 162 WHO,P 3) Metformin ………………………………………………………….. 164 B) THYROID DRUGS ………………………………………………………….. 166 WHO,P 1) Thyroxine ………………………………………………………….. 166 WHO,P 2) Propylthiouracil …………………………………………………….. 168 C) CORTICOSTEROIDAL DRUGS …………………………………………….. 169 WHO,P 1) Prednisone ………………………………………………………….. 171 CHAPTER 7: CONTRACEPTIVE PREPARATIONS 175 A) CONTRACEPTIVE DEVICES & BARRIERS ……………………………….. 177

v 1) Intra-Uterine Devices (IUDs) ……………………………………………… 177 2) Spermicides and Condoms …………………………………………………. 178 B) HORMONAL PREPARATIONS …….……………………………………… 179 WHO,P 1) Estrogenic and Combined Oral Contraceptives ………………………. 179 2) Progestin-Only Products …………………………………………………. 183 a) Oral Progestogen-only Preparations ………………………………………… 183 WHO,P b) Injectables: Medroxy-progesterone acetate …………………………... 184 c) Implants: Levonorgestrel …………………………………………………. 185 3) Emergency Pills ………………………………………………………….. 186

CHAPTER 8: PSYCHOTHERAPEUTIC DRUGS ………………………. 189 PSYCHOACTIVE DRUGS: ……..………………………………………………. 191 A) ANTIDEPRESSANTS ………………………………………………………. 191 1) Amitriptyline WHO,P …………………………………………………………. 192 P 2) Imipramine ……………………………………………………………… 194 3) Fluoxetine ………………………………………………………………… 195 B) HYPNOTICS AND ANXIOLYTICS ………………………………………… 197 1) Diazepam WHO,P ………………………………………………………….. 198 2) Lorazepam ………………………………………………………………. 199 C) NEUROLEPTICS ………………………………………………………….. 200 WHO,P 1) Chlorpromazine …………………………………………………….. 201 WHO,P 2) Haloperidol ………………………………………………………….. 203 ANTICONVULSANT / ANTIEPILEPTIC DRUGS: ……………………………….. 205 WHO,P 1) Carbamazepine …….………………………………………………. 207 WHO,P 2) Clonazepam …………………………………………………………. 209 WHO,P 3) Ethosuximide ………………………………………………………. 211 WHO,P 4) Phenobarbital ………………………………………………..…….. 212 WHO,P 5) Phenytoin …………………………………………………………… 214 WHO,P 6) Valproic Acid …………………….…………………………..…….. 215 WHO,P 7) Diazepam …..……………………………………………..………… 217 ANTIPARKINSONS DRUGS: …………………………………………………. 217 A) ANTICHOLINERGIC DRUGS ……………………………………………… 219 1) Benztropine Mesylate ………………………………………………..……. 219 P 2) Trihexyphenidyl ………………………………………………..………… 220 B) DOPAMINERGIC DRUGS …………………………………………………. 221 1) Amantadine ………………………………………………..…………….. 221 P 2) Bromocriptine ………………………………………………..………… 222 WHO,P 3) Carbidopa/Levodopa …………………………………………………. 224

CHAPTER 9: OPHTHALMIC PREPARATIONS …………………………. 227 A) ANTI-INFECTIVE PREPARATIONS ………………………………………. 229 1) Antibiotics: Tetracycline WHO,P Chloramphenicol WHO,P, Framycetin, 230 Gentamicin WHO,P, and Neomycin …..……………………………………… WHO 2) Antivirals: Idoxuridine ……………………………………………….. 232 B) ANTI-INFLAMMATORY PREPARATIONS ………………………………… 233 WHO,P 1) Corticosteroids: Betamethasone …………………………………….. 233 P 2) Other Anti-Inflammatory Preparations: Cromoglycate /Cromolyn ….……… 234

vi C) β-BLOCKERS ………………………………………………..……………. 235 WHO,P 1) Timolol ………………………………………………..…………… 236 D) MYDRIATICS & CYCLOPLEGICS ………………………………………… 238 WHO,P 1) Atropine Sulphate …………………………………………………. 238 E) MISCELLANEOUS OPHTHALMIC PREPARATIONS USED ………………. 239

CHAPTER 10: OTIC PREPARATIONS ……………………………….. 241 A) DRUGS USED FOR OTITS EXTERNA …………………………………….. 243 B) DRUGS USED FOR OTITIS MEDIA ………………………………………… 244 C) DRUGS USED FOR EAR WAX …………………………………………….. 246

CHAPTER 11: DERMATOLOGICALS ……………………………...…… 251 A) EMOLLIENTS & HUMECTANTS …..……………………………………… 253 1) Vaseline ………………………………………………..…………………. 254 2) Glycerin ………………………………………………..…………………. 254 B) ANTIPRURITICS, ANTIHISTAMINES & LOCAL ANESTHETICS …………. 255 WHO,P 1) Zinc Oxide / Calamine ………………………………………………. 255 2) Lignocaine / Benzocaine …………………………………………………… 255 C) ANTIFUNGALS ………………………………………………..………… 256 WHO,P 1) Miconazole ………………………………………………..………… 256 2) Ketoconazole …………………………………………………..………… 257 3) Tolnaftate ………………………………………………..………………. 258 D) ANTIBACTERIALS ………………………………………………..……… 259 1) Oxytetracycline ………………………………………………..………… 259 WHO,P 2) Neomycin or Gentamicin ……………………………………………. 259 E) ANTIVIRALS ………………………………………………..…………….. 260 1) Acyclovir ………………………………………………..…………………. 260 F) ANTISEPTICS/ DISINFECTANTS ………………………………………… 261 P 1) Ethyl Alcohol (Ethanol) …………………………………………………. 261 WHO,P 2) Povidone-Iodine ………………………………………………..…… 261 3) Cetrimide ………………………………………………..……………… 262 WHO,P 4) Chlorhexidine ………………………………………………..………. 262 G) ANTIPARASITICS ………………………………………………..………… 263 WHO,P 1) SCABICIDES: Benzyl Benzoate ,Crotamiton …………………………. 263 2) PEDICULICIDES: Malathion, Lindane …………………………………….. 265 H) KERATOLYTIC AGENTS …………………………………………………. 267 WHO 1) Salicylic Acid ………………………………………………..………... 267 2) Sulfur ………………………………………………..…………………... 268 I) MISCELLANEOUS ………………………………………………..……….. 268 1) TOPICAL CORTICOSTEROIDS: Betamethasone Valerate WHO,P ……………. 269 2) PREPARATIONS FOR ACNE: Retinoic Acid (Tretinoin) & Benzoyl Perxoide … 272 3) SUNSCREENS ………………………………………………..………….. 274

CHAPTER 12: VITAMINS AND MINERALS …………………………… 279 A) VITAMINS ………………………………………………..………………. 281 B) MINERALS ………………………………………………..………………. 287

vii CHAPTER 13: VACCINES …………………………………………………. 2937B VACCINATION AND IMMUNIZATION ………………………………………… 295 WHO,P 1) BCG ………………………………………………..……………… 303 WHO,P 2) OPV / IPV ………………………………………………..…………. 303 WHO,P 3) Tetanus Vaccine ………………………………………………..……. 304 WHO,P 4) DPT ……...……………………..………………………..………… 305 WHO,P 5) Measles Vaccine ………………………………………………..……. 306 WHO,P 6) MMR Vaccine …………………………..…………………..………. 306 WHO,P 7) Hepatitis B Vaccine ………………………………………………..… 307 WHO 8) Influenza Vaccine ………………………………………………..……. 308 9) Hib Vaccine ……………………………………..………..……………... 309

APPENDIX A – PRICE LIST …………………………………………………. A-01 • Analgesics, Antipyretics, Non-Steroidal, Anti-Inflammatory, and Antigout Drugs … A-03 • Cardiovascular Drugs ……………………………………………………………...… A-06 • Gastrointestinal Drugs ……………………………………………………………….. A-09 • Respiratory Drugs ………………………………………………………. …………... A-12 • Anti-Infectives ……………………………………………………………………….. A-17 • Endocrine Disorder Drugs …………………………………………………………… A-23 • Contraceptive Preparations …………………………………………………………... A-24 • Antiepileptics ………………………………………………………………………… A-26 • Antiparkinsonism …………………………………………………………………….. A-27 • Psychoactive Drugs ………………………………………………………………….. A-28 • Ophthalmic Preparations …………………………………………………………….. A-29 • Otic Preparations ……………………………………………………….……………. A-31 • Dermatologicals ……………………………………………………………………… A-32 • Vitamins and Minerals ………………………………………………………………. A-37 • Vaccines …………………………………………………………………………….. A-42

APPENDIX B – DEFINITIONS ………………………………………….... A-44 APPENDIX C – SUMMARY OF DRUGS USED FOR ALLERGIC

REACTION OR ANAPHYLACTIC SHOCK ………….. A8B -48

APPENDIX D – PHARMACEUTICAL COMPANIES AND DRUG STORES …………………………………………… A-50

REFERENCES …………………………………………………………….. A-52

GENERAL INDEX

viii Preface

The issue of drug availability and accessibility is a matter of immense concern for health services all over the world, especially in developing countries. Commonly, a large proportion of the health budget is spent on medications, often unnecessarily, and thus adding financial burdens on sometimes already over-burdened health care systems, and contributing to the problem of iatrogenic diseases as well. Over-prescribing, multi-drug prescribing, misuse of drugs, use of unnecessary expensive drugs and overuse of antibiotics and injections are cited in the literature as the most common problems of irrational use by prescribers as well as consumers.

Strategies aimed at improving the quality of primary health care services and reducing medical and health care costs are linked to the promotion of rational drug use. These considerations prompted the World Health Organization (WHO) to develop its policy for rational drug use, which by now is widely accepted as essential for improving health care quality and reducing health care costs at the same time. However, a rational drug policy is not merely the production of an Essential Drug list, although such a list is a step in the right direction, but only one of many. The essential drug concept entails series of orchestrated measures and steps encompassing the development of national drug policies, with selection, procurement, quantification, quality assurance, inventory control, distribution, financing, and rational drug use by prescribers supported by treatment guidelines, all integrated within an overall scheme. All these measures and steps entail a good amount of training/re-training, and effective supervision aimed at changing prescribing and dispensing practices at different levels.

Parallel to and in support of the initiative recently taken by the Palestine Ministry of Health in developing an Essential Drug List and Drug Formulary, the Institute of Community and Public Health embarked on field research to identify the most commonly used medications at the Primary Health Care level. The rationale for such an activity entailed the fact that drug misuse also takes place within the private sector which did not adopt the Palestine Ministry of Health Essential Drug List. The other rationale is that health professionals working in all health sub-sectors continue to need training and re-training in rational prescribing so that the old prescribing practices would diminish and new ones would replace them. While the List and the Formulary are very good steps taken in the right direction, they cannot solve the problem of antibiotic over-prescribing, for instance, nor the numerous other encountered problems engrained in local medical practices, and that to a large extent stem from insufficient knowledge of drugs and their appropriate use and lack of training in rational practices.

Thus combining many of the essential medications listed in the Palestinian Drug Formulary with selected others that were found to be very commonly used by private practitioners, this training aid and self/learning reference manual was compiled with the aim of providing the prescriber with essential information on the proper use of these commonly used medications. It specifically addresses the identified weaknesses in the current local prescribing and dispensing practices. Utilizing classical texts and references, including key WHO publications, the compilation led to the production of an initial draft. The initial draft was circulated for review and comments to about 20 local experts: physicians and pharmacists

ix specialized in particular fields, and working within the different sub-sectors of health services (governmental, UNRWA, NGO services and private practitioners). Much discussion, re-drafting and re-modification ensued, ending up with the production of the final version of this training/self-learning manual in 2003.

We hope that this initiative will contribute to improved practices by physicians, pharmacists and nurses in Palestine.

Rita Giacaman, PharmD, M.Phil. Director Institute of Community & Public Health, Birzeit University June 2003

x How to Use this Manual:

This manual is divided into 13 chapters organized according to therapeutic categories. Each of the chapters is divided into groups and subgroups to facilitate comparisons of drugs. Some drugs with multiple uses may be listed in more than one section of this manual.

Each chapter starts with an overview of the therapeutic category, then each drug is presented in the drug monographs that include: • Drug summary: A small description of the drug. • Indications: Approved indications, mainly on the primary care level. • Contraindications: Specific conditions in which the drug should not be used. • Dosage forms: Available dosage form on the primary health care level. • Recommended dosage: Recommended dosage regimens and directions for administration. • Use in special cases: Which includes use of these drugs in pregnancy, lactation, children, and patients who have any renal or liver disease. • Precautions and warning: This section lists conditions in which use of the drug may be hazardous, and the medical team may need to use alternative dose regimens or drugs. • Adverse drug reactions: Reported side effects of the drug. • Interactions: A summary of documented drug-drug interactions. • Overdosage: The clinical symptoms of toxicity or an accidental overdose, and initial method of treatment. • Brands: The known brand names of the drug in the Palestinian market, and the companies that manufacturers them.

One can find the abbreviations and pregnacy categories included in the chapters in the first few pages. The appendix at the end of the manual include the Price list, the definitions, and general index.

The Price List, listing medications by generic name, brand name, concentration, dosage form, packaging and price list based on 2002 lists obtained locally (needless to say, the price list needs to be updated regularly, and we are setting up the infrastructure for such a task). This list represent an attempt at introducing several elements in the prescribing process at once: The use or remembering of generic names - a gradual process of using generic names of prescription is ultimately desired - the use of the correct dose and dosing interval - as we know that this is also a local problem - as well as paying attention to the cost, given that particular attention should be paid to the unit cost given the same drug quality, when prescribing. Note that local drug companies and wholesalers do produce price lists of available drugs, but those include merely the brand name and not the generic name nor the strength of the medication. These lists are used for commercial reasons at the level of the pharmacy, and are usually not accessible to doctors.

The Reference List includes the detailed books, and articles or journals that have been used to obtain the information compiled for the monographs.

xi The Index at the end provides a list of all the drugs that have been listed or mentioned in this reference. Brand names are written in italic font, while the proprietary/generic name in small letters.

The drugs mentioned in the Palestinian MOH EDL (2000) are indicated by (P), while the drugs mentioned in the WHO EDL 1999 are identified as (WHO) after each drug name. It should be emphasized that the resemblance with the previously mentioned lists is by the generic name ONLY, and not the concentration or dosage form.

xii Abbreviations

G0B eneral Abbreviations G6PD Glucose-6-Phosphate ACE Angiotensin-Converting Dehydrogenase Enzyme GABA Gamma Aminobutyric Acid AIDS Acquired Immunodeficiency GH Growth Hormone Syndrome GI tract Gastrointestinal Tract AST Aspartate Amino- GU Genitourinary Transferase (a high blood GERD Gastro-Esophageal Reflux level of AST can occur with a Disease heart attack or liver disease...) GFR Glomerular Filtration Rate ALT Alanine Amino Transferase HDL High-Density AV Atrio-Ventricular Lipoprotein(s) BBB Blood Brain Barrier Hgb Hemoglobin B.P. British Pharmacopoeia Hib Haemophilus influenzae BNF British National Formulary type B BP Blood Pressure HPA Hypothalamic Pituitary BUN Blood Urea Nitrogen Adrenocortical CBC Complete Blood Count I.U. International Unit CDC Center for Disease Control ICD 10 The International Statistical cGMP cyclic Gaunine Mono- Classification of Diseases Phosphate and Related Health CHF Congestive Heart Failure Problems, tenth revision Cl cr Creatinine Clearance IOP Intra-Ocular Pressure CNS Central Nervous System IUD Intra-Uterine Device COPD Chronic Obstructive LDL Low-Density Lipoprotein Pulmonary Disease LVF Left Ventricular Failure CSF Cerebrospinal Fluid MAO Mono-Amine Oxidase CVA Cerebrovascular Accident MAOI Mono-Amino Oxidase (leads to a stroke) Inhibitor CVS Cerebrovascular System meq Milliequivalent e.g. for example MI Myocardial Infarction ECG Electrocardiogram: mg Milligram recording of the electrical NSAIDs Nonsteroidal Anti- activity of the heart Inflammatory Drugs EEG Electroencephalogram: OC/ OCs Oral Contraceptive/s measures the electrical Oint. Ointment current within the brain OTC Over the counter ENT Ear, Nose, and Throat PKU Phenylketonuria EPI Expanded Program on PT Prothrombin Time Immunization REM Rapid Eye Movement ERT Estrogen Replacement RTS Respiratory Tract System Therapy SA Sinoatrial FDA Food & Drug SLE Systemic Lupus Administration Erythematosus

xiii

S.O.B. Shortness of Breath Pharmacy2B Abbreviations SPF Sun Protection Factor a.c. before meals SSRI Selective Seretonin b.i.d. two times a day Reuptake Inhibitors d day SR Sustained Release STD Sexually Transmitted h., hrs. hour, hours Diseases h.s. at night, or at bedtime Supp. Suppository ID intradermal Susp. Suspention IM intramuscular Syr. Syrup IV intravenous t ½ Therapeutic half life min. minute Tab./tabs. Tablet, tablets TCA Tricyclic Antidepressants mon. month TIA Transient Ischemic Attack PO by mouth/ orally (Stroke) prn / p.r.n. when needed ug or mcg Microgram q.d. once every day U.S.P. United States q.i.d. four times daily Pharmacopoeia q.o.d. every other day UNRWA United Nations Relief and Works Agency q. 4 h. every four hours UNICEF United Nations Children’s q. 4 w. every four weeks Fund SC subcutaneous UTI Urinary Tract Infections SL sublingual Vit. Vitamin ® Brand name WHO World Health Organization Rx Prescription Company1B Name Abbreviations tbsp. tablespoonful BMS Bristol Meyer Squibb t.i.d. three times a day BPC Birzeit Palestine Company tsp. teaspoonful Eastern Eastern Chemical Company Chem. wk week GSK Glaxo Smith Kline y., yrs. year, years HMR Hoechst Marion Rousel JCL Jordan Chemical Laboratory./ Beit-Jala JePharm Jerusalem Pharmaceuticals Company Pharmacare Pharmacare Ltd. Company

xiv Pregnancy Categories

Category Explanation4B Controlled studies in women fail to demonstrate a risk to the fetus in

A3B the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote. Either animal reproduction studies have not demonstrated a fetal risk, but there are no controlled studies in pregnant women, or animal- reproduction studies have shown an adverse effect (other than a B decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters). Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryonic effects or other) and there are no controlled C studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus. There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g. if the D drug is needed in a life-threatening situation or for a serious disease for which safer drugs can not be used or are ineffective). There will be an appropriate statement in the “warnings” section of the labeling. Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk of using the drug in pregnant women X clearly outweighs any possible benefit. The dug is contraindicated in women who are or may become pregnant. There will be an appropriate statement the “contraindications” section of the labeling.

xvi

Chapter 1: ANALGESICS, ANTIPYRETICS, ANTI-INFLAMMATORY AND ANTIGOUT DRUGS

A) ANALGESIC, ANTIPYRETIC, AND ANTI-INFLAMMATORY AGENTS 1. ACETYLSALICYLIC Acid (Aspirin) 2. PARACETAMOL (Acetaminophen) 3. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (Ibuprofen, Diclofenac, Indomethacin, Piroxicam)

B) ANTIGOUT AGENTS 1. Allopurinol 2. Sulfinpyrazone 3. Colchicine

A) ANALGESICS, ANTIPYRETICS, AND ANTI-INFLAMMATORY AGENTS

In this section, drugs that have analgesic, measured. Body temperature may be anti-inflammatory and/or antipyretic action measured at rectal, axillary, oral, or will be discussed. These are heterogeneous tympanic (ear canal) sites. The method used compounds, often chemically unrelated to measure the temperature should be (although most of them are organic acids), indicated in the reported patient’s but nevertheless share certain therapeutic temperature. Paracetamol, aspirin, and actions and side effects. In many textbooks ibuprofen have similar antipyretic activity. Aspirin is the prototype of this group; Product selection should be based primarily hence these compounds are often referred on patient acceptance, the side effects of to as aspirin-like drugs. More frequently each agent, concurrent diseases that may they are known as non-steroidal anti- prohibit the use of each agent, convenience inflammatory drugs (NSAIDs). of administration, and cost of therapy. There is no internationally agreed upon Anti-inflammatory agents are drugs that classification of analgesics/antipyretics. alleviate symptoms of inflammation, but do Most textbooks classify them depending on not necessarily deal with the cause. their efficacy, dividing them into two NSAIDs have been shown to be as groups; Non-narcotic analgesics (for the effective as aspirin (ASA), but not superior. mild to moderate pain, some of which may Cross-sensitivity between aspirin and also have antipyretic actions), and NSAIDs is high (can be up to 97% with narcotic/opioid analgesics (which are ibuprofen). If a person is severely allergic principally used in the relief of severe pain, to ASA, avoid use of NSAIDs. and may produce dependence). Many Clinically, there are no clear guidelines analgesics also have marked anti- to assist in selecting the most appropriate inflammatory actions and therefore are used agent for a patient. Base for selection for the treatment of arthritis and other depends on clinical experience, patient inflammatory conditions. Most exhibit convenience, side effects and cost. their effect, at least in part, by the inhibition NSAIDs’ action is due to the inhibition of of prostaglandin synthesis. cyclo-oxygenase activity and prosta- At the primary health-care level, non- glandin synthesis (see table 1.1) for specific narcotic analgesics are of major concern indications). NSAIDs may mask usual because of their wide use. signs of infection, therefore, cautious use in Analgesics are drugs used to relieve pain- case there is an existing controlled “pain killers”. Pain is one of the most infection. Always take a detailed drug common symptoms, and one of the most history prior to starting therapy to avoid frequent reasons why people seek medical cross-sensitivity effects. Single ingredient care. preparations should be prescribed because Antipyretic activity results in lowering compound preparations rarely have any the temperature, and is considered to advantage, and have a higher incidence of involve the hypothalamus. Normal body side effects. temperature varies according to the Some current analgesic preparations individual’s age, sex, level of physical and contain medications that have been pulled emotional stress, the environmental off the market in developed countries, but temperature, time of the day, and the are still used inappropriately at the primary anatomical site at which the temperature is care level. One example of such are pyralozones or butazones (phenylbutazone,

2 Analgesics, Antipyretics, Anti-Inflammatory and Antigout Drugs

oxyphenbutazone). Dipyrone is a sodium • CONTRAINDICATIONS: sulphonate derivative of amidopyrine or In patients with history of hypersensitivity, aminopyrin, a member of the pyrazolone asthma, peptic ulcer/dyspepsia, those with group of chemicals, marked by different bleeding tendencies or disorders. generic and brand names: Analgin, • DOSAGE FORMS: Novalgin, Baralgan, Cibalgin, Metamizol . . . Tablets. and many more. No matter what it is • RECOMMENDED DOSAGE: called, it is no longer an accepted drug. Adult: This medication has a potentially fatal risk 350 - 650 mg q. 4 h. for minor aches and of agranulocytosis; a severe loss of white pain. blood cells, which leaves the victim 500 - 1000 mg q. 4-6 h.; max. 4 g/24 h., for susceptible to many diseases. Its use should moderate to severe pain. be justified only in serious or life- 75 - 325 mg/day q.d. continued indefinitely threatening situations where no alternative for: Ischemic stroke & TIA, and the anti-inflammatory medications have been prevention of recurrent MI, unstable angina effective. pectoris, chronic stable angina pectoris ______(FDA, 1998). Child: Use not recommended, unless for certain conditions. (Refer to special cases).

1) Acetylsalicylic Acid WHO,P Directions: Take with or after food to avoid GI disturbances (including ulcers).

*The drug is hydrolyzed in the stomach, • DRUG SUMMARY: and primarily absorbed in the stomach and Acetylsalicylic Acid (ASA), Aspirin, is a upper small intestine. Peak level is within salicylate that relieves headaches, muscular 15 minutes to 2 h., so patient should expect and joint pains, and reduces inflammation. the drug effect to be noticed within 15 ASA has been considered the drug of minutes from taking the medication. choice in the treatment of arthritis, but its *ASA should not be used for self- anti-inflammatory action occurs only medication of pain for longer than 10 days when given in large doses (3-4 g/day). At in adults or 5 days in children, unless these large doses, ASA produces adverse directed by a physician. effects that are the main disadvantage *ASA preparations should not be used if a when used for arthritis conditions. NSAIDs strong vinegar-like odor is present. tend to be more appropriate for arthritis • USE IN SPECIAL CASES: conditions. The mechanism of action of Pregnancy- Contraindicated at analgesic ASA is that it inactivates cyclooxygenase doses. ASA crosses the placenta, and may irreversibly, it inhibits prostaglandin harm the fetus (Category D). Paracetamol synthesis and inhibits platelet aggregation. may be a better choice for analgesia. ASA • INDICATIONS: may be used in low doses (100 mg) as Used for pain, fever, inflammatory anticoagulant and for prophylaxis of pre- conditions such as rheumatic fever, eclampsia in high-risk pregnant women. rheumatoid arthritis, osteoarthritis, dys- (Refer to the anticoagulants in cardio- manorrhea and symptomatic relief of the vascular chapter for further information common cold pain and fever. It is used for about use). reducing the risk of recurrent Transient Lactation- Salicylates are excreted in breast Ischemic Attacks (TIA/stroke), or milk in low concentrations, but no adverse Myocardial Infarctions (MI/heart attack) at effects on infants have been reported. Use low doses. caution.

Children- Use is not recommended specially • INTERACTIONS: for undiagnosed fever when influenza is Overview of ASA suspected, due to risk of Reye’s syndrome (a Drug-Drug Interaction rare disorder presented by symptoms of Drug Interaction encephalitis combined with evidence of ACE Hypotensive and vasodilator liver failure). This potentially fatal condition inhibitors effect of ACEI may be reduced occurs following certain viral infections like Monitor patients, and chickenpox, or those with minor febrile discontinue ASA if possible. illness. It is characterized by vomiting and Anti- Anticoagulant effect lethargy that may progress to delirium and coagulants enhanced. Effect of ASA on coma. Paracetamol should be used instead. gastric mucosa and platelet (see recommended doses). function may enhance [Some of the USES IN SPECIAL CASES in possibility of hemorrhage. Avoid concomitant use. children that ASA should be used in are β-blockers Their antihypertensive Juvenile Arthritis (60-110mg/kg/d q.6-8 h.), effectiveness may be Rheumatic Fever, and Kawasaki disease decreased. Use with caution. that are not usual cases seen at the primary Cortico- Corticosteroids will reduce health care level.] steroids serum salicylate levels and Renal Disease- Caution in these patients, decrease salicylate ASA may aggravate chronic kidney disease, effectiveness. fluid retention, increased risk of GI bleeding. Monitor plasma salicylate In severe cases avoid. In minor cases reduce concentration when adding or the dose. (50% of the dose is eliminated in withdrawing corticosteroids. the urine.) NSAIDs Pharmacological effects of Liver Disease- The drug is metabolized in the certain NSAIDs may be liver. Use caution in patients with impaired decreased. Increased risk of GI liver function, pre-existing hypopro- disturbances if used thrombinemia and vitamin K deficiency may concomitantly. increase risk of bleeding. Oral hypo- ASA increases hypoglycemia • PRECAUTIONS AND WARNINGS: glycemics effect of sulfonylureas. Monitor the patient’s blood -Not to be taken on an empty stomach. glucose, if hypoglycemia Prolonged use (see directrion) requires occurs, decrease sulfonylurea medical supervision. dose. -Avoid ASA for at least 1 week prior to • OVERDOSE: surgery. Patients should inform the dentist Can be fatal, particularly in children. Acute or doctor of taking this medication before lethal dose is approximately 10-30 g for doing any lab or dental work. adults, and 4 g in children. Requires -Avoid alcohol while taking this medication immediate referral to hospital. It presents since it increases the risk of GI ulceration with confusion, rapid deep breathing, and bleeding. sweating, tinnitis (noises in the ear), • ADVERSE EFFECTS: deafness followed in severe cases by Dizziness, cinchonism (ringing in the ear), unconsciousness. Induce vomiting if skin eruptions, epigastric discomfort, peptic possible (patient is conscious) with syrup of ulceration and bleeding, increase bleeding ipecac. Activated charcoal decreases tendency, hypersensitivity reactions. absorption if given within 2 hrs. after ingestion. Chronic Salicylate toxicity may occur when > 100 mg/kg/d is ingested for 2 or more

4 Analgesics, Antipyretics, Anti-Inflammatory and Antigout Drugs

days. It is more difficult to recognize and is Child: PO or PR: 10-15 mg/kg/dose. associated with increased morbidity and AGE DOSE * mortality. Compared to acute poisoning, 0-3 mon 10mg/kg (5mg/kg if jaundiced) hyperventilation, dehydration, systemic 3 mon-1 y 60-120 mg acidosis and severe CNS manifestations 1-5 y 120-250 mg occur more frequently. Treatment includes 6-12 y 250-500 mg supportive measures. * Martindale, 1996:82. • BRANDS: * The doses may be repeated q. 4-6 h. not to Acetosal (Rekah), Aspirin (Bayer), Aspro exceed 4 doses in 24 hours. (Nicholas), Alka Seltzer (Agis), Baby Aspirin (JCL), Buffered Aspirin (Pennex), Bufsa Directions: (GAMA), Cartia (Smith Kline). *Can be taken with fluids, but before meals ______or 2 hours after meal, 4 times daily for 2-3 days or as required. 2) Paracetamol WHO,P *The drug is completely absorbed from the GI tract, less complete absorption takes • DRUG SUMMARY: place from rectal suppository. Paracetamol or Acetaminophen (N-Acetyl-p- *Peak effect occurs within 0.5-2 h., and amino-phenol-APAP) is a non-narcotic CNS duration is 3-4 h. agent. It is equivalent to aspirin in relieving *If fever does not subside within 3 days, pain and reducing fever, but it has little patient has to contact the physician. effect on platelet function, does not affect • USE IN SPECIAL CASES: bleeding time and generally produces no Pregnancy- Safe if used as directed (Category gastric bleeding or ulcers. It has no anti- B). It is the drug of choice in pregnant women inflammatory action in usual doses. for aches and pains, or fever. It does cross the Paracetamol reduces fever by direct action placenta, but no reports of harmful effects on the hypothalamus heat-regulating center have been noted. with consequent peripheral vaso-dilatation, Lactation- APAP is excreted in low sweating and dissipation of heat. concentration in breast milk. No harm on infants has been noted. It is safe when used as • INDICATIONS: recommended. Used for pain and fever Good substitute . Children- Can be used prophylactically (30 for ASA, when ASA is not tolerated or is min. before) in children receiving DPT contraindicated. vaccination to decrease incidence of fever and • CONTRAINDICATIONS: injection site pain. Use caution and do not In patients with history of hypersensitivity. exceed the recommended doses. In patients with severe liver and kidney Renal Disease- Kidney tubular necrosis may damage. occur with chronic use of very high doses of • DOSAGE FORMS: the drug ( > 4 g/d). Tablets, capsules, suspension, Liver Disease- The drug is exclusively suppositories. metabolized in the liver. Hepatotoxicity and • RECOMMENDED DOSAGE: severe hepatic failure occurred in chronic alcoholics following therapeutic doses. Avoid Adult: PO: 325-650 mg q. 4-6 h. as large dose in liver cases. (< 2 g/d is needed; max. 4 g/24 hours. acceptable for these patients). • PRECAUTIONS AND WARNINGS: -Do not exceed recommended doses. Chronic excessive use (> 4 g/d) eventually may lead to transient hepatotoxicity.

-If pain or fever persists for more than 3 symptoms, careful monitoring of blood levels days consult a physician. is needed to estimate potential for -Use caution when patients are taking other hepatotoxicity. drugs that might affect the liver. Oral N-acetylcysteine is a specific antidote • ADVERSE EFFECTS: for APAP toxicity. Administration of If used as directed it rarely causes any side activated charcoal will adsorb effects. acetylcysteine, so avoid administration. Heavy alcoholics and smokers are more Follow special directions for administration susceptible to liver toxicity. Skin rashes and of N-acetylcysteine antidote and monitor neutropenia are very rare. the patient for several days. • INTERACTIONS: • BRANDS: Overview of APAP Abrol (Rekah), Abrolet, (Rekah), Dexamol Drug-Drug Interaction (Dexxon), Acamol (Teva), Acamoli (Teva), Drug Interaction Aldolor (CTI), Febramol (BPC), Panadol Alcohol, The potential hepatotoxicity (Whinthrop), Otamol (JePharm), Paracare Barbiturates, of APAP may be increased (Pharmacare), Pamol (Eastern Chem.), Paramol Carba- by large doses or long term (JCL), Paracetamol (Rekah), Paramolan mazepine, use of the these agents due (Trima), Razimol (Al-Razi), Tylenol (McNeil). and to hepatic microsomal ______Rifampin enzyme induction

• OVERDOSE: Symptoms: Acute poisoning symptoms include nausea, vomiting, drowsiness, confusion, liver tenderness, low blood pressure, cardiac arrhythmia, jaundice and acute hepatic and renal failure. Treatment: Refer to the emergency room as soon as possible. There are no early specific

6 Analgesics, Antipyretics, Anti-Inflammatory and Antigout Drugs

Table 1.1: NSAIDs of Summary of Indication # Naproxen / INDICATION Diclofenac Ibuprofen Indomethacin Piroxicam Naproxen Na Rheumatoid arthritis (RA) 9 9 9 9 9 Osteoarthritis (OA) 9 9 9 9 9 Ankylosing spondylitis 9 9 9 Mild to moderate pain 8 9 9 Primary dysmenorrhea 9 8 9 8 Juvenile rheumatoid

arthritis 8 8 9 8 Tendinitis, Bursitis

9 9 Acute gout

9 9 Acute painful shoulder 8 9

Pre-menstrual / Naproxen 8 8 syndrome Na Fever

9 8 Migraine/Cluster

headache 8 8 9- Labeled use (approved by FDA for this indication) 8 - Unlabeled use (not approved by FDA for this specific indication, but is used by doctors.) Blank - is not usually used. # Drug Facts and Comparisons. 2000: p. 836.

3) Non-Steroidal Anti- CNS, including respiratory depression and Inflammatory Drugs the development of physical dependence. (NSAIDs) In addition to sharing many therapeutic activities, current NSAIDs share several

unwanted effects. The most common is the All NSAIDs are antipyretic, analgesic, and tendency to induce gastric or intestinal anti-inflammatory, but there might be some ulceration that can sometimes be differences in their individual activities. accompanied by anemia from the resultant Thus a patient may do well on one blood loss. Other reported side effects propionic acid (i.e. Ibuprofen) derivative, include disturbances in platelet function, but not on another. The reasons for such water retention, increased blood pressure, differences are not fully understood, but the delayed onset and prolongation of differential sensitivity of enzymes in the gestation or labor, and changes in renal target tissues may be the reason. When function. employed as analgesics, these drugs are Newer agents of NSAIDs that are usually effective against pain of low-to- cyclooxygenase-2 (COX-2) inhibitors are moderate intensity. Although their maximal being produced and sold on the market, as effect is much lower than opioids, they lack having lower GI side effects. Until further the unwanted effects of the opioids on the safety reports through post marketing

surveillance are studied, cost-benefit Doses of IBP in Children decisions should be made before 1-12 y: give 5-10 mg/kg q. 4-6 h. recommending such agents. or In general, NSAIDs work only on 6 - 11 mon. 25-50 mg 6 - 8 y. 125-250 mg symptomatic relief of fever, pain and 12 - 23 mon 50-100 mg 9 - 10 y. 150-300 mg inflammation associated with the disease. 2 - 3 y. 75-150 mg 11 - 12 y. 200-400 mg 4 - 5 y. 100-200 mg (all given q . 4-6 h. prn)

a) Ibuprofen WHO Maximum daily dose is 40 mg/kg/d.

Directions: IBP should be taken with food • DRUG SUMMARY: or milk if GI disturbances occur. Ibuprofen (IBP) is a proprionic acid *80% of the drug is absorbed from the GI derivative. Comparable to aspirin (ASA) in tract. Peak effect is 1-2 h. its analgesic action, but higher doses are *Onset for analgesia is 0.5 h., and for anti- required for anti-inflammatory effect. It has rheumatic action is 7 days. been reported to have less GI symptoms *If patient misses a dose, take as soon as than aspirin in equi-effective doses. they remember unless it is too close to the Cross-sensitivity with ASA and other following dose, so they need to skip the NSAIDs has been reported. IBP inhibits following dose and continue with the usual platelet aggregation and prolongs bleeding schedule. Dose should not be doubled. time, but does not affect prothrombin or • USE IN SPECIAL CASES: whole blood clotting times. Pregnancy- Better to avoid use (Category B). • INDICATION: Paracetamol is a better choice for analgesia. Refer to table-1.1. Lactation- Safe. IBP has not been detected in • CONTRAINDICATIONS: breast milk in analgesic doses. In patients who are hypersensitive where Children- Safety and efficacy has not been urticaria, severe rhinitis, bronchospasm, established for children < 6 mon old. angioedema, are precipitated by ASA or Normally, not recommended for children < 1 other NSAIDs. Active peptic ulcer or year or less than 7 kg. bleeding abnormalities. Renal Disease- Use with caution. Reduce • DOSAGE FORMS: dose. NSAID metabolites are excreted by kidney into urine. Tablets, suspension (100 mg/5ml), gel 5%. • Liver Disease- Use with caution, and decrease RECOMMENDED DOSAGE: the dose. The drug is metabolized in the liver. Adult: 200-400 mg PO q. 4-6 h., There is an increased risk of GI bleeding or max. 1800 mg/24 hours for pain and fever. fluid retention. 400-800 mg t.i.d. or q.i.d.; max. 3200 mg/d • PRECAUTIONS AND WARNINGS: for inflammation. -Patients with history of cardiac Emulgel dose: A thin layer of the gel is decompensation should be observed closely applied to affected area as needed, up to for evidence of fluid retention and edema. three times daily. -Instruct patient to report immediately any Child: Use is not recommended for passage of dark tarry stool, coffee-ground children under 6 months; emesis, blood or protein in urine. This can be an indication for GI bleeding. Medication should be stopped and patient should be re-evaluated.

8 Analgesics, Antipyretics, Anti-Inflammatory and Antigout Drugs

-Caution if skin rash, itching, visual • BRANDS: disturbances or persistent headache should Adex 200 (Dexxon), Advil (Whitehall), Artofen occur. (Teva), Brufen 400 (Boots), Ibufen (Dexxon), -Caution in hypertension, chronic renal Isofen (BPC), Motrin (Upjohn), Nurofen failure and patients with SLE. Advise (Boots), Trufen (JePharm). patient not to drink alcohol, to avoid ______increased risk of GI ulceration and bleeding. b) Diclofenac P • ADVERSE EFFECTS: GI disturbances are most common; i.e. • DRUG SUMMARY: heartburn, nausea and dyspepsia, An acetic acid derivative. It has analgesic, abdominal distress, gastritis and ulceration. antipyretic, and anti-inflammatory proper- Also, dizziness, drowsiness, jaundice, and ties. At therapeutic doses it has little effect fatigue may occur. Side effects are dose on platelet aggregation. Patients not related. Incidence or aggravation of responding to IBP can be given diclofenac epilepsy and parkinsonism have been instead. Do not co-administer with other reported with use of NSAIDs. NSAIDs or salisylates. • INTERACTIONS: • INDICATION: Overview of Ibuprofen Refer to table-1.1. (It is also used as an Drug-Drug Interaction ophthalmic agent for cataract surgery). Drug Interaction • CONTRAINDICATION: Oral anti- May prolong bleeding time. Same as IBP. coagulants, Avoid concomitant use. • and DOSAGE FORMS: heparin Tablets, sustained release tablets, Lithium, Increased toxicity of these suppositories, emulgel and ampoules. digoxin drugs with concomitant • RECOMMENDED DOSAGE: and NSAIDs use. Monitor each Adult: 75-150 mg/24h given by mouth in methotrexate drug serum levels and adjust divided doses. Total daily dose should not dose as needed. exceed 150 mg/d, such doses have not been

• OVERDOSE: studied. Symptoms: May include drowsiness, Suppository form is given in a dose of 75- dizziness, mental confusion, lethargy, 100 mg each evening. vomiting, abdominal pain, tinnitus, The emulgel form 1% should be applied to convulsions, hypotension, tachycardia, and painful site, 2-4 gm, 3-4 times daily. metabolic acidosis. Therapy should be reviewed after 14 days. Treatment: Induce emesis or perform gastric Child: Not recommended for children < 1 lavage to recover undigested tablets, include y. unless JRA. supportive measures. Since NSAIDs are Child > 1 y. for RA: 1-3 mg/kg in divided doses by mouth or rectum. strongly bound to plasma, hemodialysis or peritoneal dialysis may be of little value. Directions: Diclofenac is readily absorbed Charcoal tends to reduce the absorption of the from the GI tract, and 50-60% reaches the drug. systemic circulation. Peak effect is within 2-3 h. *Absorption is delayed by food, take with a full glass of water. For chronic use take after food to avoid GI problems.

*Sustained release forms are given once or Rufenal (BPC), Voltin (Eastern Chem.), twice daily. Voltaren/ Voltaren S.R. (Ciba-Geigy). *If simple GI disturbances occur, an ______antacid may be used, but not administered at the same time of the drug intake. P *If patient misses a dose, this dose should c) Indomethacin be taken as soon as remembered, unless it is too close to the following dose, so skip and • DRUG SUMMARY: maintain schedule. Do not double the dose. A very potent arylacetic acid NSAID • USE IN SPECIAL CASES: derivative. Because of its high potential to Pregnancy- Should not be used unless there cause side effects when used in high doses, are compelling reasons for doing so, it should be carefully considered for active (Category B). disease unresponsive to adequate trials with Lactation- Do not use in nursing mothers salicylates. It has equal or a little superior because of possible effects on infant’s action than naproxen, but higher incidence cardiovascular system. of side effects. This medication will enable Children- Use in child < 1 year is not reduction of steroid doses in severe forms recommended. Safety and efficacy in children of Rheumatoid Arthritis. (In this case have not been established. reduce steroid dose slowly!). Renal Disease- NSAID metabolites are • INDICATION: eliminated by the kidneys, 50-60% excreted Refer to table-1.1 in the beginning of this in urine. Reduce dose to avoid accumulation. chapter. (Also used as IV for Patent Ductus Liver Disease- Effects are not known. Arteriosus in premature infants.) Metabolism of the drug occurs in liver. Use • CONTRAINDICATION: caution to avoid increased risk of GI bleed. Same as IBP. • PRECAUTIONS, WARNINGS & Also in patients with recent rectal bleeding OVERDOSE: or proctitis if using suppositories. Same as IBP. • DOSAGE FORMS: • ADVERSE EFFECTS: Capsules, suppositories, gel. Similar to IBP, but with higher incidence. • RECOMMENDED DOSAGE: • INTERACTIONS: Adult: Rheumatoid Arthritis: See overview table. 25-50 mg b.i.d. or t.i.d., or 75 mg sustained Overview of Diclofenac release 1-2 times a day; max. 200 mg/d. Drug-Drug Interaction Dysmenorhea: up to 75 mg daily. Drug Interaction Acute Gout: 50 mg t.i.d. until pain is Lithium, Increased toxicity of these tolerable (usually within 2-3 days), then digoxin drugs with concomitant taper off to 25 mg t.i.d. until total resolution and NSAIDs use. Monitor each of attack. drug serum levels and adjust methotrexate (If administering both PO and rectal dosage dose as needed. forms combined, dose should not exceed Diuretics May decrease blood pressure lowering effects of diuretics. 200 mg/d). May lead to an increase in Child: Not recommended due to effect on serum K+, if using K+ sparing liver function. diuretics. Directions: Administer immediately after

• meals, or with food, milk or antacid to BRANDS: minimize GI side effects. (Food or antacid Abitren (Abic), Betaren/Betaren S.R (Dexxon), may cause somewhat delayed and reduced Diclofen (JePharm), Rhumacare (Pharmacare),

10 Analgesics, Antipyretics, Anti-Inflammatory and Antigout Drugs

absorption, but advantage of safety vomit or unconscious, gastric lavage should outweighs risk of impaired absorption.) be performed. Once the stomach has been *If patient misses a dose, take as soon as emptied, 25-50 gm of charcoal may be remembered unless it is too close to the given. Follow patient for several days following dose, so skip and maintain because of GI ulceration and hemorrhage schedule. Never double doses. complications. • USE IN SPECIAL CASES: • BRANDS: Pregnancy- Category B in the 1st and 2nd Indocaps (JCL), Indocin (Merk), Indocin trimester, and D in 3rd trimester. (Eastern Chem.), Indolin (BPC), Indomed/ Lactation- Use not recommended. Indomed S.R. (Assia), Indopharm (JePharm), Children- Contraindicated for children < 14 Indotard (CTI), Indovis (CTI). yrs. Hepatotoxicity including fatalities has ______occurred in children with juvenile rheumatoid arthritis when taking this medicine. d) Piroxicam Renal Disease- Use caution. • Liver Disease- Use caution, better to use DRUG SUMMARY: lower doses, high risk of GI bleeding. An oxicam NSAID derivative. Is as • PRECAUTION AND WARNINGS: effective as naproxen, and has a prolonged Same as IBP. Indomethacin has been duration of action which permits once daily reported to aggravate depression or other administration. Use is not recommended psychiatric disturbances, epilepsy and unless other NSAIDs have failed or patient parkinsonism. Extreme caution should be compliance would be improved with once taken in susceptible patients. In case of daily dose. hemorrhoids, caution use or avoid rectal • INDICATION: administration. Refer to table-1.1, at the beginning of this • ADVERSE EFFECTS: chapter. Same as IBP, but with higher incidence. • CONTRAINDICATIONS: • INTERACTIONS: Same as IBP. *Same as IBP, as well as: • DOSAGE FORMS: Overview of Specific Indomethacin Capsules, suppositories. Drug-Drug Interaction • RECOMMENDED DOSAGE: Drug Interaction Adults: 10-20 mg PO 1-2 times/day. Probenecid Increases in plasma For acute gout, 40 mg initially, then 40 mg concentration of daily in single or divided doses for 2 days, indomethacin; enhancing the then 20 mg q. d. for 7-14 days. pain relief effect, but Child: Not to be used. increasing its adverse Directions: Take with or after food. Peak effects. Use caution. effect is 3-5 hrs. for analgesia, and 2-4 weeks Concomitant use may result Sympatho- for anti-rheumatic action. Onset is 1 h. for mimetics in increased blood pressure. Monitor patient. analgesia, and 7 days for anti-rheumatic action. Duration is 48-72 hrs. • OVERDOSE: *If patient misses dose, it should be taken as Treatment is symptomatic and supportive. soon as remembered unless it is too close to The stomach should be emptied as quickly the following dose, so skip and maintain a possible if the ingestion is recent. If schedule. Do not double dose. vomiting has not occurred spontaneously, the patient should be induced to vomit with syrup of ipecac. If the patient is unable to

• USE IN SPECIAL CASES: sulfinpyrazone), this may prolong the Pregnancy- Category B in 1st and 2nd attack indefinitely. Colchicine is an trimester, and Category D in 3rd trimester. alternative to NSAIDs in patients with heart Lactation + Children- Not established. failure. Renal Disease- Use with caution to avoid risk After the initial attack of acute gout, the of accumulation. interval between subsequent attacks varies Liver Disease- Use with caution to avoid risk from a few days to several years. Some of GI bleedings. patients may never experience another • PRECAUTIONS AND WARNINGS, acute attack. Antihyperuricemic ADVERSE EFFECTS, INTERACTIONS medications should be initiated only when AND OVERDOSE: All Similar to IBP. gouty patients have frequent acute attacks, • BRANDS: urate tophi, or evidence of renal damage. Felcol (Eastern Chem.), Feldene (Pfizer), Pirox Therapy starts when the acute attack (JePharm). completely subsides. Once started, such ______therapy usually is continued indefinitely.

Initiation of treatment may precipitate an B) ANTIGOUT AGENTS acute attack therefore the colchicine or an NSAID could be used prophylactically for Gout is a disorder of uric acid metabolism. at least one month after the hyperuricemia It is manifested by hyper-uricemia, acute or has been corrected. If an acute attack chronic recurrent arthritis, and deposits of develops while the patient is taking monosodium urates. Although hyper- treatment, the treatment should be uricemia is a precursor of gout, it is not a continued at the same dosage, and disease by itself, and not diagnostic of gout. treatment for the acute attack should be The diagnosis of acute gouty arthritis is initiated on its own. confirmed when large numbers of polymorphonuclear leukocytes and mono- 1) Allopurinol WHO,P sodium urate crystals are demonstrated in synovial fluid aspirated from the inflamed • DRUG SUMMARY: joint. Allopurinol is an agent that inhibits uric Most acute attacks have no obvious acid synthesis by inhibiting xanthine precipitating events, but trauma, excessive oxidase, the enzyme responsible for the alcohol intake, drug induced (in therapy of conversion of hypoxanthine (end product of diuretics, aspirin, anti-tuberculosis agents purine catabolism) to uric acid, so it like pyrazinamide or ethambutol), or reduces endogenous uric acid production. It initiation of a hyperuricemic agent may is used for patients who overproduce uric contribute to an acute attack. acid. It has no analgesic, anti-inflammatory, In an acute attack, the goals of treatment or uricosuric actions, therefore, it is not are to immediately relieve pain and useful for acute gouty attacks and may inflammation, and not to decrease the actually aggravate and prolong it. serum uric concentration. This can be • effectively treated by a NSAID; i.e. INDICATIONS: To control primary hyperuricemia that indomethacin or naproxen. (refer to individual drug monographs for more accompanies severe gout, and to prevent details). Aspirin should not be used, since possibility of flare-ups of acute gouty salicylates increase urate concentration. attack. To prevent recurrent calcium Acute attacks should never be treated with oxalate stones, prophylactically to reduce allopurinol or uricosurics (probenecid, severity of hyperuricemia associated with

12 Analgesics, Antipyretics, Anti-Inflammatory and Antigout Drugs

antineoplastic and radiation therapies, both Directions: Doses of > 300 mg/day should of which greatly increase plasma uric acid be divided, taken with food or milk. levels in the body. *Normal serum levels of uric acid are • CONTRAINDICATIONS: usually achieved in 1-3 weeks, with a Hypersensitivity, patients who have normal range being 3.6-8.5 mg/dl for men, developed a severe reaction should not be and 2.3-6.6 mg/dl for women. restarted on the drug. Discontinue *A sudden decrease in serum level can medication at first appearance of skin rash precipitate an acute gouty attack, start with or other signs of allergic reactions. low dose and increase by 100 mg/week. Contraindicated as initial treatment for *It is advisable to maintain sufficient fluid acute gouty attack, or for asymptomatic intake to yield a daily urinary output of at hyperuricemia. least 2 L. The patient needs to drink at least • DOSAGE FORMS: 10-12 glasses of water daily. Tablets. *Advise patient to contact health care • RECOMMENDED DOSAGE: provider if any of these symptoms occur; Adult: Hyperuricemia; skin rash, painful urination, blood in the 100 mg daily initially, may be increased by urine, irritation of the eyes, or swelling of 100 mg/wk; max. 800 mg daily. the lips and mouth occurs. Discontinuation Serum uric acid level of ≤ 6 mg/dl should of the medication may be recommended. be attained. *Advise patient to limit high-purine foods: Control of gout, and secondary kidney, liver, anchovies, sardines, salmon, hyperuricemia; meat soups, peanuts, dried peas and beans, 200-300 mg/day for mild gout, cauliflower, peppers and spinach. 400-600 mg/day for moderate to severe. *For oxalate stone treatment, need to avoid Initially 100 mg daily as a single dose, after foods such as tea, chocolate, spinach, nuts, food, gradually the dose is increased over beets, figs, and excessive Ca intake. Also 1-3 wks according to the plasma or urinary need to increase oral fluids and dietary fiber uric acid concentration to about 300 mg. intake. Usual maintenance dose is 200-600 mg/d.; • USE IN SPECIAL CASES: max. 800 mg daily. Pregnancy- Use only when clearly needed Recurrent calcium oxalate stones; (Category C). There are no adequate and 200-300 mg/day in single or divided doses, well-controlled studies in pregnant women. as well as modification in the diet. Lactation- Allopurinol and its metabolites have been detected in breast milk. No adverse Renal impairment: reactions have been reported, but use with Creatinine Recommended Dose caution. Clearance (Clcr) Children- Allopurinol is rarely indicated for Clcr 60 ml/min. 200 mg/day use in children, with the exception to those Clcr 40 ml/min. 150 mg/day with hyperuricemia secondary to malignancy Clcr 20 ml/min. 100 mg/day or certain rare inborn errors of purine Clcr 10 ml/min. 100 mg on alternate days metabolism. Clcr < 10 ml/min. 100 mg 3 times a week. Renal Disease- Need to reduce dosage for

Child: Secondary hyperuricemia patients with renal disease, to avoid (associated with malignancy or neoplastic accumulation of allopurinol and its therapy), metabolites. For moderate to severe renal (6-10 y): 100 mg PO t.i.d. impairment refer to recommended doses. Liver Disease- Use caution. Perform periodic (< 6 y): 50 mg PO t.i.d. or 10 mg/kg/day liver function tests during early stages of divided q. 6 h.

therapy, particularly in patients with Thiazides May increase the risk of preexisting liver disease. allopurinol toxicity and • PRECAUTIONS AND WARNINGS: hypersensitivity, (especially -Hypersensitivity; need to discontinue drug with impaired renal function); at first appearance of skin rash or other so use caution. signs of allergic reactions. In some cases, Warfarin Allopurinol may enhance anti-coagulant effect of rash may be followed by more severe warfarin, use with caution. reactions such as fever, exfoliative, Large doses May increase the possibility urticarial or purpuric lesions, irreversible of vitamin C of kidney stone formation due hepatotoxicity and rarely, death. to urinary acidification. -Need to emphasize the importance of increasing fluid intake to avoid the • OVERDOSE: theoretic possibility of formation of Symptoms may include headache, nausea, xanthine calculi under the influence of vomiting, epigastric pain, jaundice and allopurinol therapy. other adverse side effects. • ADVERSE EFFECTS: Treatment: Need to evaluate patient, and a Drowsiness, headache, nausea, vomiting, dose reduction may be necessary if not diarrhea, abdominal discomfort, photo- discontinuation of the medication. sensitivity, urticaria, pruritic maculo- In accidental overdose, need to induce papular rash, jaundice, increased alkaline vomiting if it has not occurred already. phosphatase, AST and ALT liver enzymes, Refer to hospital for supportive or hepatotoxicity, xanthine renal calculi, symptomatic care. agranulocytosis, aplastic anemia, bone • BRANDS: marrow depression have all been reported. Allopurinol (Abic), Alloril (Dexxon), Caplenal • INTERACTIONS: (Berk), Uricnase (BPC), Zylol (Teva), Zyloric (GlaxoWellcome). Overview of Allopurinol ______Drug-Drug Interaction Drug Interaction ACE Captopril co-administration 2) Sulfinpyrazone inhibitors may increase risk of toxicity; it is better to space-out time • DRUG SUMMARY: interval of drug administration. A potent pyrazolidine derivative, uricosuric Alcohol May inhibit renal excretions of agent for gout. At therapeutic doses uric acid; warn patient against promotes urinary secretion of uric acid and drinking alcohol. reduces serum urate levels by competitively Ampicillin Co-administration increases risk inhibiting renal tubular re-absorption of and of skin rash. Start allopurinol uric acid. It is used for patients who are amoxicillin therapy after antibiotic therapy under-excretors of uric acid. As it has no has been completed for a couple of weeks. apparent analgesic or anti-inflammatory Antacids; May inhibit the GI absorption activity, it is not used for relief of acute Aluminum of allopurinol. This effect can gout. hydroxide be avoided by administering • INDICATIONS: allopurinol 3 or more hours Maintenance therapy in chronic gouty before Aluminum hydroxide. arthritis and tophaceous gout. Unlabeled uses include; drug induced hyperuricemia, and to decrease platelet aggregation.

14 Analgesics, Antipyretics, Anti-Inflammatory and Antigout Drugs

• CONTRAINDICATIONS: -Sulfinpyrazone may increase the Hypersensitivity to butazones or other frequency of acute gouty attacks during the pyrazoles, active peptic ulcer, or symptoms first 6-12 months of therapy, even when of GI inflammation or ulceration, as well as serum urate levels appear to be controlled. blood dyscrasias. The physician may prescribe colchicine • DOSAGE FORMS: prophylactically, concurrently during the Tablets. first 3-6 months to decrease the severity of • RECOMMENDED DOSAGE: the acute attack. Adult: Use in gout; • ADVERSE EFFECTS: 100-200 mg 1-2 times a day, for 1 wk, then Most frequent include: upper GI increase to 200-400 mg twice a day disturbances, nausea, diarrhea, blood loss, increased over 1-3 wks. It may be reduced reactivation or aggravation of peptic ulcer, to 200 mg after serum urate levels are precipitation of acute gout attacks. Less controlled. Maximum dose is 600 mg/d, frequently: rash and jaundice. Rarely: blood rarely 800 mg/d. dyscrasias, i.e. anemia, agranulocytosis, Child: Use not commonly indicated for aplastic anemia, bronchoconstriction in children. patients with aspirin-induced asthma. Directions: May cause GI upset, take with • INTERACTIONS: food, milk, or an antacids if needed. Overview of Sulfinpyrazone *Patient needs to increase fluid intake to at Drug-Drug Interaction least 10-12 glasses (8 ounces each) daily if Drug Interaction possible. Salicylates These suppress/antagonize the *Sulfinpyrazone therapy should be uricosuric action of sulfinpyrazone. Do not continued without interruption even when administer aspirin or salicylates the patient has an acute gouty attack, which to patients. may be treated with full therapeutic doses (These do not antagonize of the appropriate anti-inflammatory agent. allopurinol, but are nevertheless • USE IN SPECIAL CASES: NOT indicated in gout.) Pregnancy- Use only when clearly needed Sulfonyl- May be displaced by sulfin- and when the potential benefits outweigh the ureas pyrazone, increasing risk of potential hazards to the fetus (Category C). hypoglycemia. Lactation- Avoid use, unless clearly needed Theophylline Theophylline plasma clearance and potential benefits outweigh potential may be increased, thus hazards to the nursing infant. lowering plasma levels. Children- Not commonly prescribed for Monitor patient closely to children. determine dosage adjustments Renal Disease- Use caution. Renal failure has if needed. occurred in predisposed patients. Assess renal Verapamil Increase in clearance and function periodically to avoid complications. decrease in bioavailability may occur. Use with caution. Liver Disease- Use caution. This drug is Anticoagulant activity of metabolized to active and inactive Warfarin warfarin will be enhanced. metabolites in the liver. Hemorrhage could occur. Use • PRECAUTIONS AND WARNINGS: extreme caution. -Use caution in patients who had a history of peptic ulcer, may reactivate or aggravate • OVERDOSE: peptic ulcer. Symptoms include: Nausea, vomiting, -Need blood cell counts, as well as renal diarrhea, epigastric pain. Labored function evaluation periodically. respiration, convulsion, and coma may

occur. Possible symptoms seen after over- 2-3 h. till relief of pain is obtained, or dosages may include anemia, jaundice or vomiting or diarrhea occur; max. 10 ulceration. There is no specific antidote for mg/day. treatment. Induce vomiting if possible. One should wait 3 days before initiating a Refer to a hospital emergency room for second course to minimize the possibility of general supportive care. cumulative toxicity. • BRANDS: Use as prophylaxis or maintenance of Anturane (Ciba), Pyrocard (Trima). recurrent gouty arthritis; ______0.5-1 mg PO once or 3 times daily. Use in Familial Mediterranean fever; 1-3 mg/day, to prevent frequency and 3) Colchicine WHO,P severity of acute febrile episodes and to prevent amyloidosis. • DRUG SUMMARY: Child: Not commonly prescribed for An antigout agent that is not an analgesic, children, unless under direct specialist not a uricosuric, and will not prevent supervision for rare cases. progression of gout to chronic gouty Directions: Treatment should be started at arthritis. Its exact mechanism of action is the first sign of an attack, and stopped as not clear, but it reduces inflammatory soon as pain is relieved or at the fist sign or response to the deposited crystals and also vomiting or diarrhea. diminishes phagocytosis. Its prophylactic, *Medication should be discontinued if the suppressive effect helps reduce the patient reports any of the following: rash, incidence of acute attack. It is a good sore throat, fever, unusual bleeding, alternative to NSAIDs, and probably as bruising, weakness, numbness or tingling. • effective. It is of value in patients with USE IN SPECIAL CASES: heart failure since unlike NSAIDs it does Pregnancy- Contraindicated use (oral: not induce fluid retention, also it can be Category C, parenteral: D). Colchicine can cause fetal harm, and should be avoided. given to patients receiving anticoagulants. • Lactation- Avoid use, unless clearly needed INDICATIONS: and potential benefits outweigh potential For pain relieve of acute attacks of gout. hazards to the nursing infant. It is not known Short term prophylaxis during initial if this drug is excreted in breast milk. therapy with allopurinol or uricosuric Children- Safety and efficacy not established. drugs. It is also used for amyloidosis, Renal + Liver Diseases- Use caution in mild Behcet’s syndrome, Familial Mediterranean cases, there is an increased risk of toxicity. fever, idiopathic thrombocytopenic Use is contraindicated in severe cases of purpura, primary biliary cirrhosis, and hepatic/renal dysfunction. various skin disorders. • PRECAUTIONS AND WARNINGS: • CONTRAINDICATIONS: For patients receiving long-term therapy, Hypersensitivity to colchicine, serious GI, periodic blood count should be performed. renal, hepatic or cardiac disorders, blood Hepatic and renal function impairment: dyscrasias, and pregnancy. increased colchicine toxicity. Myopathy • DOSAGE FORMS: and neuropathy have been noted in patients Tablets. with altered renal function. • RECOMMENDED DOSAGE: • ADVERSE EFFECTS: Adult: Use in gout; GI effects; vomiting, diarrhea, abdominal 1 mg PO initially, given at the first warning pain and nausea may occur, especially with of an acute attack, followed by 0.5-1 mg q. maximum doses, and particularly

16 Analgesics, Antipyretics, Anti-Inflammatory and Antigout Drugs

troublesome in the presence of peptic ulcer • OVERDOSE: or spastic colon. Bone marrow depression Symptoms: Usually there is a latent period with aplastic anemia, agranulocytosis, of several hours between overdosage and myopathy, loss of hair, reversible symptom onset. First symptoms to appear azospermia (fertility impairment), hyper- include nausea, vomiting abdominal pain sensitivity, and dermatoses have all been and diarrhea. Myocardial injury, profound reported. shock and respiratory failure, leukopenia, • INTERACTIONS: alopecia may also occur. Overview of Colchicine Treatment: Begin with gastric lavage (if not Drug-Drug Interaction too much time has passed), and measures to Drug Interaction prevent shock. Hemodialysis or peritoneal Cyclosporin Increased risk of dialysis may be used. Continue with nephrotoxicity and myotoxicity supportive measures. due to increased plasma • BRANDS: cyclosporin concen-tration. Colchicine (RAFA, Abbott). Observe patients closely for severe adverse effects if coadministration is necessary, and adjust the dose accordingly. Erythromycin May increase serum colchicine concentration; toxicity may occur. Use with caution.

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Chapter 2: CARDIOVASCULAR DRUGS

A) ANTIHYPERTENSIVES 1. Diuretics 2. Beta-Blockers 3. ACE Inhibitors 4. Calcium Channel Blockers

B) ANTI-ARRHYTHMICS 1. Amiodarone 2. Lidocaine 3. Quinidine

C) ANTIANGINA 1. Isosorbide Dinitrate

D) ANTICOAGULANTS 1. Aspirin 2. Warfarin

E) CONGESTIVE HEART FAILURE DRUGS 1. Digoxin (Digitalis Glycoside)

F) LIPID LOWERING DRUGS 1. Fibric Acids 2. Bile Acid Sequestrants 3. HMG-CoA Reductase Inhibitors

Cardiovascular Drugs

A) ANTIHYPERTENSIVES

The actual level of blood pressure that can limited alcohol intake and smoke be considered hypertensive is somewhat cessations. difficult to define; it depends on a number Periodic blood pressure measurements of factors, including the patient’s age, sex, should be done for patients after starting race, and life style. In general, hypertension with life style modifications, then the is defined as a systolic blood pressure initiation of antihypertensive therapy. (SBP) that is > 140 mmHg diastolic blood Drug therapy should be individualized, pressure (DBP) of > 90 mmHg. especially that there are several groups of Hypertension is classified into three pharmacological therapy as seen on table stages as indicated in table-2.1. Patients are 2.2. But in general, for uncomplicated divided into risk groups based on their hypertension a diuretic and/or a beta- blood pressure as well as to the presence or blocker are the first choice of treatment. absence of target organ disease and For patients with other health problems additional risk factors (for further such as diabetes mellitus or heart failure, information see: Report of the Joint National starting with Angiotensin converting Committee- JNC 6-1997, and the WHO-ISH enzyme (ACE) inhibitors might be more 1999 guidelines, note that the JNC 7-2003 appropriate. See table 2.3, as well as each report has changed the categories, but will drug monograph for specific indications. not be adopted in this chapter). The aim of antihypertensive therapy is to Life style modification is the first step in lower and maintain blood pressure to a therapy for most patients, this includes, level within the normal range of the weight reduction if overweight, regular patient’s age and sex. physical activity on regular bases, reduction of sodium intake, adequate intake In the following pages the most commonly of potassium, calcium and magnesium, prescribed categories will be discussed.

Table-2.1. Classification of Blood Pressure For Adults > 18 Years of Age SBP DBP

Category (mmHg) (mmHg) Optimal < 120 and < 80 Normal < 130 and < 85 High normal 130 - 139 or 85-89 Hypertension * Stage 1 (Mild) 140 - 159 or 90 - 99 Stage 2 (Moderate) 160 - 179 100 - 109 Stage 3 (Severe) > 180 or > 110

*Based on the average of > 2 readings taken at each of > 2 visits after an initial screening. *When systolic and diastolic blood pressures fall into different categories select the higher category to classify the individual’s blood pressure status. Reference: Drug Facts & Comparisons 2000, Treatment Guidelines, p. A-5.

There are three general approaches for hypertension. These approaches are the pharmacological treatment of primary summarized in table-2.2.

Table-2.2: Pharmacological Approaches to Treatment of Hypertension CATEGORIES EXAMPLE

I. Diuretics to reduce blood volume: A. Thiazide diuretics Hydrochlorothiazide B. Loop diuretic Furosemide C. Potassium sparing diuretics Spironolactone

II. Drugs that interfere with the renin-angiotensin system: A. Converting enzyme inhibitors Captopril B. Angiotensin-receptor antagonists Saralasin

III. Drugs that decrease peripheral vascular resistance and/or cardiac output: A. Direct vasodilators 1. Calcium channel blockers Nifedipine Verapamil Diltiazem 2. Potassium channel activators Minoxidil 3. Elevation of cGMP Nitroprusside 4. Others Hydralazine B. Sympathetic nervous system depressants 1. α-Blockers Prazosin 2. β-Blockers (Non-selective) Propranolol

(β1 selectivity) Atenolol 3. Norepinephrine synthesis inhibitors Metyrosine 4. Norepinephrine storage inhibitors Reserpine 5. Transmitter release inhibitors Guanethidine 6. Centrally acting (decrease sympathetic outflow) α-Methyldopa

20 Cardiovascular Drugs

Table-2.3: Comparison of the Clinical Effects of Antihypertensive Drugs β Thiazide ACE Ca α Feature - - Blockers Diuretics Inhibitors antagonists Blockers Efficacy in coexisting disease states -Angina pectoris 9 8 8 9 8 -CHF/LVF 8 9 a 9 9 -Supraventricular 9 8 8 9 b 8 arrhythmias -Raynaud’s 8 8 8 9 9 phenomenon -Asthma 8 9 9 9 9 Effect on the heart rate ↓ ↔ ↔ ↔↑ ↔ Effect on total peripheral ↑, ↓ c ↔ ↓ ↓ ↓ resistance Effect on left ventricular ↓ ↔ or ↑ ↓ ↓ ↓ hypertrophy Generally Neutral/ Effect on serum lipids d Adverse Favorable Favorable adverse favorable Effect on glycemic Generally Generally Adverse None None control adverse e none

a. A loop diuretic may be more suitable if CHF/LVF is predominant. b. Some agents only (verapamil) c. β-blockers initially cause a reflex increase in total peripheral resistance followed by a decrease towards or slightly below pretreatment levels with long term use. However, β-blockers with vasodilator activity (labetalol or celiprolol) cause a reduction in total peripheral resistance. d. Not all β-blockers have adverse effects on the serum lipid profile (carvediolol, labetalol, pindolol) have not shown any adverse effects. e. β-blockers may mask some of the warning signs of hypoglycemic episodes. f. Symbols: 9: indicated use, 8: not indicated, ↔: no significant effect, ↑: effect increased, ↓: decreased. * References: Speight & Holford. Avery’s Drug Treatment, 4th ed. Adis International, New Zealand,1997. Drug Facts & Comparisons, 2000, p. A9.

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1) DIURETICS *It acts within 1-2 h. of oral administration, and has a duration of 12-24 h. Diuretics are agents that increase the rate of *It is advisable to eat a banana or have a urine formation, as the term used “for glass of orange juice to prevent diuresis”. They are divided into Thiazide, hypokalemia. Loop and Potassium-sparing diuretics, each *It should be administered early in the working on a specific segment of the renal morning after eating. If it is to be given in system. One drug from each group will be two doses, schedule the second dose no discussed as the prototype. later than 3 pm., so diuresis does not interfere with sleep. a) Thiazide Diuretics: *100 mg PO doses for hypertension are rarely recommended. Doses > 25 mg/d in WHO,P Hydrochlorothiazide older patients, or > 50 mg in young patients do not increase blood pressure lowering • DRUG SUMMARY: effect of the medication (plateau effect). Hydrochlorothiazide is a very potent • USE IN SPECIAL CASES: thiazide diuretic, classified as a cardio- Pregnancy- Diuretics are not used to treat vascular, antihypertensive agent. It is the hypertension in pregnancy since they might drug of choice for primary hypertension. affect placental perfusion due to decreasing Thiazides mainly increase excretion of Na the extracellular volume. Thiazides may and Cl, by inhibiting their reabsorption cause neonatal thrombocytopenia (Category from the thick ascending limb of Loop of B). Henle and the early distal tubules. Lactation- The amount excreted in breast (Other drugs in this group include milk is too small to be harmful to nursing Benzthiazide, Chlorothiazide, Chlorthalidone, infant; large doses may suppress lactation. Indapamide, Metolazone, etc.). Children- Not established. • INDICATIONS: Renal Disease- If there is a moderate renal Thiazides are mainly used to relieve edema dysfunction, avoid thiazide diuretics. If the due to heart failure and, in lower doses, to GFR < 25 ml/min. one should use loop reduce blood pressure. diuretics (furosemide), which will be more • CONTRAINDICATIONS: effective. Thiazides are not effective in these Anuria, hypercalcemia, severe renal and cases. hepatic impairment, hepatic coma or Liver Disease- Use with caution since precoma, hypersensitivity to thiazides or hypokalemia may precipitate coma. Also other sulfonamides, Addison’s disease, there will be a risk of hypomagnesemia in the porphyria. case of alcoholic cirrhosis. • • DOSAGE FORMS: PRECAUTIONS AND WARNINGS: Tablets. -It may cause hypokalemia. Potassium • RECOMMENDED DOSAGE: supplements may be recommended in these Adult: For Edema; cases: symptomatic hypokalemia, patient Start with 50-100 mg PO daily. with an abnormal resting ECG, patient with Maintenance 25-50 mg on alternate days. history of arrhythmias, ischemic disease or For Hypertension; severe heart failure, during concomitant 25 mg PO daily, can be increased to 50-75 digitalis therapy, and with planned general mg if necessary. In elderly patients, an anesthesia. For prevention, potassium initial dose of 12.5 mg may be sufficient. chloride doses of 2-4 g (approx. 25-50 Directions: It can be taken with food or mmol) PO per day are suitable in patient milk to reduce GI upset. taking a normal diet. Smaller doses must

22 Cardiovascular Drugs

be used if there is renal insufficiency Sex Estrogens and combined OCs (common in elderly). If patient can’t hormones antagonize diuretic effect. tolerate side effects, do not use thiazide Counsel women on use of diuretics, and switch to a potassium sparing alternative method instead of hormonal therapy if needed. diuretic. -Aggravation of diabetes and gout may • OVERDOSE: occur. May raise LDL-cholesterol, and drop Symptoms: changes due to plasma volume HDL-cholesterol. Take caution in the case depletion (e.g. orthostatic hypotension, of bronchial asthma, hepatic cirrhosis, renal dizziness, drowsiness, etc.), and signs of K dysfunction, and history of SLE. deficiency (e.g. confusion, dizziness, • ADVERSE EFFECTS: muscular weakness, GI disturbances). Impotence (reversible on withdrawal of Treatment: Perform gastric lavage or treatment), hypokalemia, hypomagnesemia, induce emesis, give activated charcoal. hyponatremia, hypercalcemia, hypo- Avoid cathartics since they may enhance chloremic alkalosis, hyperuricemia, gout, electrolyte and fluid loss. Always refer the hyperglycemia, and increases in plasma patient for further investigations. cholesterol concentration. • BRANDS: • INTERACTIONS: Esidrex (Ciba-Geigy), Disothiazide (Dexxon). Overview of Thiazide ______Drug-Drug Interaction Drug Interaction Analgesics Diuretics increase the risk of b) Loop Diuretics

nephrotoxicity of NSAIDs. WHO,P Use with caution. Furosemide Anion- Cholestyramine reduces the exchange absorption of thiazide • DRUG SUMMARY: resins diuretics. Give them at least Loop diuretics are used in pulmonary two hours apart. edema due to left ventricular failure and in Anti- Toxicity of many patients with long standing heart failure arrhythmics antiarrhythmic drugs increased who no longer respond to thiazides. These if hypokalemia occurs. Use drugs inhibit the reabsorption of Na and Cl with caution. ions from the ascending Loop of Henle in Anti- Increased risk of postural the renal tubule, and are powerful diuretics. depressants hypotension with TCAs. Hypokalemia may develop, and care is Anti- Hypoglycemic effect is needed to avoid hypotension. It is a good diabetics antagonized by thiazide diuretics. Use with caution. choice for patients who do not respond to Anti- Hypokalemia increases the risk thiazide diuretics, or have impaired renal histamines of ventricular arrhythmia with function. astemizole & terfenadine. The most important example of these Calcium Risk of hypercalcemia. Avoid diuretics is furosemide/frusemide. It is a salts use concomitantly. powerful diuretic that acts within 1 hour of Cardiac Increased toxicity if oral administration and diuresis is complete glycosides hypokalemia occurs. within 6 hours. The degree of diuresis Cortico- Increased risk of hypokalemia; associated with these drugs is dose related. steroids antagonism of diuretic effect. (Other drugs in this group include Ethacrynic Use with caution. acid, Bumetanide and Torsemide). Lithium Lithium excretion reduced by thiazides. Monitor patients.

• INDICATIONS: • USE IN SPECIAL CASES: Edema, oliguria due to renal failure, and Pregnancy- Avoid use. Diuretics are not hypertension. usually used to treat hypertension during • CONTRAINDICATIONS: pregnancy, since it might affect placental Precomatose states associated with liver perfusion thus decreasing the extracellular cirrhosis; porphyria; history of volume (Category C). hypersensitivity to furosemide; anuria; Lactation- Furosemide is excreted in breast increasing oliguria; fluid and electrolyte milk. Because of the potential adverse depletion states; and hepatic coma. reactions in nursing infants, decide whether to discontinue breast-feeding or to discontinue • DOSAGE FORMS: the drug, taking into account the importance Tablets, injection. of the drug to the mother. • RECOMMENDED DOSAGE: Renal Disease- In case of moderate renal Adult: For Edema; impairment, higher doses of furosemide may Initially, start with 40 mg PO in the be needed. In renal failure, use is morning adjusted as necessary according to contraindicated. patient’s response. Liver Disease- Avoid use in severe cases of Maintenance for mild cases: 20 mg PO liver dysfunction. Hypokalemia may daily, or 40 mg on alternate days. precipitate coma; potassium-sparing diuretics Some patients may require doses of 80 mg should be used to prevent this; increased risk or more daily given in 1 or 2 doses. of hypomagnesemia in alcoholic cirrhosis. (Only in very severe cases dose may be • PRECAUTIONS AND WARNINGS: titrated up to a maximum of 600 mg/d; in -These agents are potent diuretics; excess such case a specialist in this field is needed). amounts can lead to profound diuresis with For Hypertension; water and electrolyte depletion. Careful 40-80 mg PO daily either alone or in medical supervision is required and dosage conjunction with other antihypertensives. should be individualized. Child: For Edema and Hypertension; -Caution use in case of infants, elderly 1-3 mg/kg PO daily may be increased patients, hepatic cirrhosis, nephrotic according to response but for a maximum syndrome, cardiogenic shock associated of 40 mg/24 h. Doses over 6 mg/kg are not with MI, history of SLE, history of gout, recommended. patients receiving digitalis glycosides or

Directions: Furosemide can be taken with potassium-depleting steroids. food or milk to reduce possibility of gastric • ADVERSE EFFECTS: irritation. Hyponatremia, hypokalemia, hypochlor- *Drug effects are evident within 30 min. to emic alkalosis, increased calcium excretion, 1 hr. after an oral dose, and lasts for about hypotension; less commonly nausea, GI 4-6 h. disturbances, hyperuricemia and gout may *Schedule doses to avoid nocturia and occur; and hyperglycemia (less common sleeping disturbance (example: when given than thiazides). once daily it should be administered in the morning; when given twice daily it should be given at 8 am. and 2 pm.).

24 Cardiovascular Drugs

• INTERACTIONS: levels. Always refer the patient for further Overview of Loop Diuretics investigations. Drug-Drug Interaction • BRANDS: Drug Interaction Diasix (JCL), Furovite (Vitamed), Fusid (Teva), Analgesics Diuretics may increase the risk Lasix (Hoechst), Miphar (Pharbita), Urix of nephrotoxicity of NSAIDs, (BPC). if used for long periods of ______time. Monitor patients, especially those at risk of c) Potassium Sparing kidney disease. Anti- Toxicity of many anti- Diuretics

arrhythmics arrhythmic drugs might increase if hypokalemia occurs. Use caution. Spironolactone WHO,P Anti- Increased risk of postural depressants hypotension with TCAs. Warn • DRUG SUMMARY: patients against suddenly Potassium-sparing diuretics are another changing posture to upright class of diuretics that have been used to position (when standing up) to avoid hypokalemia associated with thiazide avoid feeling dizzy and falling. and loop diuretics. Spironolactone is a Anti- Hypoglycemic effects of diabetics antidiabetic drugs may be potassium sparing-diuretic that acts by antagonized by furosemide. antagonizing aldosterone. It is of value in Use caution. the treatment of the edema of cirrhosis of Anti- Hypokalemia increases the risk the liver, and is effective in edema of heart histamines of ventricular arrhythmia with failure, particularly when congestion has astemizole and terfenadine. caused hepatic engorgement. It is also used Avoid use with such in Conn’s syndrome (primary hyper- antihistamines. aldosteronism). Good choice for patients Cardiac Increased toxicity if who are very susceptible to hypokalemia glycosides hypokalemia occurs. complications, or can not tolerate the other Cortico- Increased risk of hypokalemia; diuretic agents. antagonism of diuretic effect. steroids (Other agents in this group include Amiloride Lithium Loop diuretics reduce lithium and Triamterene). excretion, but they are safer • INDICATIONS: than thiazides. Edema and ascites in cirrhosis of the liver, Sex Estrogens and combined OCs hormones antagonize diuretic effect. malignant ascites, nephrotic syndrome, Counsel women on use of congestive heart failure; primary aldos- alternative method instead of teronism. hormonal therapy if needed. • CONTRAINDICATIONS: Hyperkalemia, severe renal impairment; • OVERDOSE: pregnancy and breast-feeding; Addison’s Symptoms: Acute profound water loss, disease; and porphyria. volume and electrolyte depletion, • DOSAGE FORMS: dehydration, reduction of blood volume, Tablets. and circulatory collapse with a possibility • RECOMMENDED DOSAGE: of vascular thrombosis and embolism. Adult: For Edema; Treatment: Replace fluid and electrolyte 25-200 mg/24 hrs. PO in divided doses; losses by careful monitoring of the urine continued for at least 5 days; dose adjusted and electrolyte output and serum electrolyte to optimal response; if no response, a

thiazide or a loop diuretic may be added • ADVERSE EFFECTS: without changing spironolactone dosage. GI disturbances, gynecomastia and hyper- For Hypertension; kalemia. 50-100 mg/24 hrs. PO in single or divided • INTERACTIONS: doses; continued for at least 2 wks.; dose Overview of Spironolactone adjusted to optimal response. Drug-Drug Interaction For Primary Aldosteronism; Drug Interaction 100-400 mg/day in divided doses. Ammonium Combination of spironolactone Child: For Edema; chloride and acidifying doses of 3.3 mg/kg/day PO in single or divided ammonium chloride may doses continued for at least 5 days; dose produce systemic acidosis. needs to be adjusted till optimal response. Avoid concomitant use. For Hypertension; Aspirin Diuretic effect of spironolactone may be antagonized by 1-2 mg/kg PO given twice daily. aspirin and other salicylates. Directions: Administer with food to Avoid concomitant use. enhance absorption. Potassium Hyperkalemia may result from *Tablets may be crushed (unless package supplements the use of spironolactone along advises against) before administration and with potassium supplements. taken with fluid of patient’s choice. Avoid concomitant use. *It may produce drowsiness and lack of ACE Both medications may cause coordination; observe caution while driving inhibitors hyperkalemia that might cause complete heart block. or performing other tasks requiring Do not use together. alertness, coordination or physical dexterity, until effects of the medication is • OVERDOSE: fully known. Symptoms: The most likely signs are • USE IN SPECIAL CASES: dehydration and electrolyte imbalances. Pregnancy- Do not use. Spironolactone or its Other symptoms may include GI cramping, metabolites may cross the placenta barrier. vomiting, diarrhea, headache, drowsiness, Feminization occurs in male rat fetuses. In and mental confusion. general diuretics are not used to treat Treatment: discontinue therapy and observe hypertension in pregnancy since it might patient closely. Induce emesis or perform affect placental perfusion due to decrease of gastric lavage. Treatment is symptomatic extracellular volume (Category D). and supportive. If hyperkalemia occurs, Lactation- One of the metabolites of emergency procedures are to be spironolactone appears in breast milk, an implemented. alternative method of infant feeding should be • BRANDS: instituted when using spironolactone. Aldactone (Searle), Aldosprine (Teva), Renal Disease- use with caution. Use of Sincomen (Schering). spironolactone may cause a transient ______elevation of BUN, especially in patients with preexisting renal impairment. The drug may cause mild acidosis. Liver Disease- use with caution, since it is metabolized in the liver. • PRECAUTIONS AND WARNINGS: -Use caution with patients with BUN of 40 mg/dl or greater and if there is a hepatic disease since it is metabolized in the liver.

26 Cardiovascular Drugs

2) BETA – BLOCKERS heart, the following effects will occur: reduction of the heart rate, reduction of β-adrenergic receptor blocking agents myocardial irritability (class II anti- competitively antagonize the responses to arrhythmic agents), and reduction of the catecholamines that are mediated by the β- force of myocardial contraction. receptors. Some agents are more selective Propranolol also blocks bronchodilator than others, and all have differences in their effect of catecholamines leading to pharmacokinetic profiles. β-blockers are bronchoconstriction. the drugs of choice in: youth, hyperkinetic • INDICATIONS: circulation, angina pectoris, post- Management of cardiac arrhythmias; myocardial infarction (cardioprotective myocardial infarction; tachyarrhythmias effect), migraine head-aches, senile tremor. associated with digitalis intoxication, for Table-2.4 gives an overview of drugs in anesthesia and thyrotoxicosis; angina this class and indicates the selectivity in pectoris due to coronary atherosclerosis; in their action the treatment of hypertension alone or in combination with other anti-hypertensive Table- 2.4: Summary of Available β-Blockers agents; and for migraine prophylaxis. • Adrenergic receptor CONTRAINDICATIONS: Drug blocking activity It is contraindicated in the following cases: 1. Greater than first-degree heart block. Acebutolol β1 (β2 at higher doses) (ISA* activity) 2. CHF or Cardiogenic shock. Atenolol β (β at higher doses) 3. Significant aortic or mitral valvular disease. 1 2 4. Bronchial asthma or bronchospasm. Bisoprolol β (β at higher doses) 1 2 5. Allergic rhinitis during pollen season. Esmolol β (β at higher doses) 1 2 6. Concurrent use of adrenergic β β Metoprolol 1 ( 2 at higher doses) augmenting psychotropic drugs or within β β Oxprenolol 1 2 (ISA activity) two weeks of MAO inhibitors therapy. β β Pindolol 1 2 (ISA activity) 7. Sick sinus syndrome. β β Propranolol 1 2 (non-selective) • DOSAGE FORMS: β β Timolol 1 2 (non-selective) Tablets Labetolol β1 β2 α1 • RECOMMENDED DOSAGE:

*ISA- Intrinsic Sympathomimetic Activity; Adult: For Hypertension; tend to cause less bradycardia than other β- Initially 40-80 mg PO b.i.d.; increased at blockers, and may cause less coldness of the weekly intervals to 160-320 mg/24hrs in extremities. divided doses; max. 640 mg/d. -Other drugs produced include: Carteolol, For Angina; Celiprolol, Nadolol, Penbutolol, Sotalol. 40 mg PO b.i.d. or t.i.d.; may need 120-320 Reference: Drug Facts & Comparisons, 2000, p. mg/24 h in divided doses; max. 320 mg/d. 468. For Arrhythmias; 10-30 mg PO, t.i.d. or q.i.d. up to 320 mg/d. a) Propranolol P For Acute MI; 40 mg 4 times a day for 2 to 3 days then 80 • DRUG SUMMARY: mg twice daily; max. 240 mg/d or Propranolol is a non-selective β-blocker of 180-240 mg/24 h. in divided doses. For Migraine Prophylaxis; both cardiac (β1) and bronchial (β2) adrenoreceptor blocking activity. As a 40-80 mg in divided doses daily; increased at weekly intervals; may require up to 160- result of blocking β1-receptors within the

240 mg/d. If there is no response after 4-6 -Diabetes mellitus, since β-blockers prevent weeks then therapy should be discontinued. premonitory signs of hypoglycemia in Child: For Hypertension; diabetics and may also augment hypo- 1 mg/kg/24h PO in 2 divided doses, glycemia by interfering with increased to 2 to 4 mg/kg/24hrs. catecholamine-induced glycogenolysis. On

Directions: It is recommended to be taken the other hand propranolol may block before meals and at bedtime. Food insulin release from the pancreas with enhances bioavailability of propranolol, so resulting hyperglycemia. Use caution in advise patients to be consistent with regard patients prone to hypoglycemia. to taking propranolol with food or on an -Avoid abrupt withdrawal in angina. empty stomach to minimize variations in • ADVERSE EFFECTS: absorption. Bradycardia, heart failure, bronchospasm, *If a dose is missed, take as soon as peripheral vasoconstriction, gastrointestinal remembered. If too close to next dose, disturbances, fatigue, sleep disturbances, ignore and continue with the regimen. The rare reports of rashes and dry eyes next dose should not be doubled. (reversible on withdrawal). • USE IN SPECIAL CASES: • INTERACTIONS: Pregnancy- If it is administered in the third Overview of β-Blockers trimester it may cause intra-uterine growth Drug-Drug Interaction retardation, neonatal hypoglycemia, and Drug Interaction bradycardia; risk greater in severe Alcohol & Enhance the hypotensive hypertension (Category C). anesthetics effect. Use with caution and Lactation- Propranolol is excreted in breast warn patient of this effect. milk but in concentrations too low to have NSAIDs Antagonize hypotensive effect. significant side effects on nursing child If the patient has to take an compared to other β-blockers. Peak NSAID, advise to use caution concentrations occur 2-3 hours after a dose. and move slowly when Although no reported toxicity effects have changing postural positions, to been noted with β-blockers, the child should decrease the chances of be observed specially if the drug is used for dizziness or falling. long term. The American Academy of Anti- Increased risk of myocardial Pediatrics considers propranolol to be arrhythmics depression and bradycardia and increased risk of lidocaine compatible with breast-feeding. toxicity. Do not administer Children- Safety is not established. concomitantly. Renal Disease- In severe cases, start with Rifampicin Accelerates the metabolism of small dose; higher plasma concentrations propranolol. Do not administer after oral administration; may reduce renal at the same time. blood flow and adversely affect renal Antidiabetics Enhances the hypoglycemic function in severe impairment. effect (masking of warning Liver Disease- Reduce oral dose. signs such as tremor). Use • PRECAUTIONS AND WARNINGS: caution. -Use caution in special risk patients with: Anti- Plasma concentration of peripheral arterial insufficiency, patients psychotics chlorpromazine is increased by propranolol. Dose adjustment prone to non-allergenic bronchospasm (e.g. is required if patient has chronic bronchitis, emphysema), major increased side effects. surgery, renal and hepatic impairment, Anxiolytics Enhance the hypotensive effect Myasthenia Gravis, Wolff-Parkinson-White & hypnotics of β-blockers. syndrome.

28 Cardiovascular Drugs

Cardiac Propranolol may potentiate b) Atenolol WHO, P glycosides bradycardia due to digoxin. Cortico- (Estrogens and combined OC). • DRUG SUMMARY: steroids & Antagonism of the In therapeutic doses atenolol selectively sex hypotensive effect of β hormones propranolol. blocks 1-adrenergic receptors located Muscle Propranolol enhances the chiefly in cardiac muscle. With large doses relaxants effect of muscle relaxant. preferential effect is lost and inhibition of Sympatho- Severe hypertension with β2-adrenergic receptors (especially in mimetics adrenaline and noradrenaline; bronchial and vascular musculature) may Severe hypertension is also lead to increased airway resistance, possible with especially in patients with asthma. It is less sympathomimetic anorectics lipophilic (lipid soluble) than propranolol and cough and cold remedies. thus it does not readily cross the blood- β Theophyl- -blockers should be avoided brain barrier, therefore it is not associated line on pharmacological grounds with mental depression. It is not as heavily (bronchospasm). metabolized in the liver. It has a longer Thyroxin Metabolism of propranolol is accelerated with thyroxin antihypertensive effect than propranolol (reduced effects). Dose thus permitting once-a-day dosing. adjustment of propranolol may • INDICATIONS: be needed. Used in the management of hypertension Cimetidine Plasma concentration of (1st choice drug) as a single agent or propranolol is increased by concomitantly with other antihypertensive cimetidine. Do not administer agent, especially a diuretic. As an anti- at the same time. arrhythmic agent and for thyrotoxicosis. Calcium- Increased risk of bradycardia Treatment of stable angina pectoris and MI. channel and AV block with diltiazem; • CONTRAINDICATIONS: blockers severe hypotension and heart failure occasionally with Atenolol is contraindicated in the following nifedipine; asystole, severe cases: hypotension, and heart failure 1. Sinus bradycardia. with verapamil. They should 2. Greater than first degree heart block. not be used together. 3. Uncontrolled cardiac failure. 4. Cardiogenic shock. • OVERDOSE: • DOSAGE FORMS: Therapeutic overdoses of β-blockers may Tablets. cause lightheadedness, dizziness, and • RECOMMENDED DOSAGE: possibly syncope due to impaired Adult: For Hypertension; circulation secondary to bradycardia and 50 mg PO once daily initially, used alone or hypotension; heart failure may be added to a diuretic, may be increased to 100 precipitated or exacerbated. mg/d. The full effect is seen within 1-2 Acute massive overdoses must be managed weeks. Doses over 100 mg/day are unlikely in hospital and expert advice should be to produce any further benefit. obtained. Maintenance of a clear airway For Angina; and adequate ventilation is mandatory. 50-100 mg PO daily in 1 or 2 doses. • BRANDS: For Arrhythmias; Blocardril 10 (BPC), Deralin (Abic), Slow Deraline (Abic), Prolol (Dexxon). 50-100 mg PO daily. ______

For MI; -Impairment of renal function. Patient would be under emergency • ADVERSE EFFECTS, INTER- treatment where IV doses would be ACTIONS, OVERDOSE: administered, then switched to PO as Refer to propranolol. needed. • BRANDS

Directions: If necessary, tablet may be Apo-atenol (Apotex), Ateni (Generics), crushed (unless manufacture’s package Normiten (Abic), Corotenol (JePharm), Normalol (Dexxon). strictly advises against that) before ______administration and taken with fluid of patient’s choice. *If patient misses a dose, it should be taken 3) ANGIOTENSIN CONVERTING as soon as remembered. If too close to next ENZYME INHIBITORS (ACEI) dosing time, just continue with the regimen.

The next dose should not be doubled. The essential effect of these agents on the • USE IN SPECIAL CASES: renin-angiotensin system is to inhibit Pregnancy- If atenolol is administered in the conversion of the relatively inactive 3rd trimester it may cause intra-uterine angiotensin I to the active angiotensin II by growth retardation, neonatal hypoglycemia, blocking the angiotensin converting and bradycardia; risk is greater in severe enzyme (ACE). The converting enzyme hypertension (Category C). Lactation- Monitor infant; possible toxicity inhibitors are highly specific drugs. due to β-blockade but amount of most beta- Although they inhibit the degradation of blockers excreted in milk is too small to Bradykinin and potentiate its hypotensive affect the infant. Atenolol is excreted in action, the principal pharmacological and higher amounts than propranolol. clinical effects of ACE inhibitors are quite Children- Not established. specific at the level of the enzyme. In Renal Disease- In the case of moderate renal addition, recent studies suggest that ACE impairment, one should reduce the dose of inhibitors may also affect other enzymes, atenolol, since atenolol is excreted unchanged including those involved in the generation in the urine. If it is severe (Clcr < 15), start of prostaglandins. with a small dose; higher plasma Many agents on the market are in this concentrations after oral administration; may group, which differ in their reduce renal blood flow and adversely affect pharmacokinetic profiles, but do not add renal function in severe impairment; max much benefit over each other. Table-2.5 dose is 25 mg/d. compares some of the locally available Liver Disease- It is not metabolized in the drugs. liver. So there is no need for dosage adjustment in the case of hepatic dysfunction. Captopril will be the prototype for • PRECAUTIONS AND WARNINGS: discussion on ACE inhibitors group. Use with caution in the following cases: -Hypertensive patient with CHF controlled by digitalis and diuretic. -Asthmatic patient. -Diabetic patient. (Refer to propranolol)

30 Cardiovascular Drugs

Table-2. 5: Available ACE Inhibitors Chart of Comparisons Pharmacokinetic Parametersa Principal

Drug Prodrug t max t 1/2 Vd PB route(s) of (h) (h) (L) (%) elimination Benazepril Yes 1.5 2-3 (22)b 8.4 > 95 Renal Captopril No 1.0 2.0 49 c 30 Renal Cilazapril Yes 3.0 2(40-50) 35 - Renal Enalapril Yes 3-4 5 (35)b - 50 Renal Lisinopril No 6.0 12 (30)b 124 < 1 Renal Quinapril Yes 2.0 2-3 - 97 Renal Ramipril Yes 3.0 3.0 (110)b 90 56 Renal/Hepatic

a Values shown are for active metabolite if compound is a prodrug. b Terminal phase elimination half-life. C At steady state.

Abbreviations: tmax = time to peak plasma concentration, t1/2 = elimination half-life, Vd = apparent volume of distribution, PB = protein binding. -Other produced drugs in this group include: Delapril, Fosinopril, Moexiprol, Perindopril, Spirapril, Trandolapril, Zofenopril. Reference: Speight & Holford. Avery’s Drug Treatment, 4th ed. Adis International, New Zealand 1997. a) Captopril WHO,P • CONTRAINDICATIONS: It is contraindicated in the following cases: • DRUG SUMMARY: Hypersensitivity to ACE inhibitors, known Captopril is an angiotensin-converting or suspected renovascular disease, aortic enzyme (ACE) inhibitor, cardiovascular, stenosis or outflow tract obstruction, antihypertensive, vasodilating agent. It porphyria, and pregnancy. lowers blood pressure by specific inhibition • DOSAGE FORMS: of the angiotensin-converting enzyme that Tablets. leads to the formation of angiotensin-II that • RECOMMENDED DOSAGE: is a vasoconstrictor. ACE inhibitors have Adult: For Hypertension; been considered for treatment of Initially, 12.5 mg b.i.d. would be started if hypertension when thiazides and beta- using it alone. blockers are contraindicated, not tolerated, Initially 6.25 mg b.i.d. if used in addition to or fail to control blood pressure. ACE a diuretic, in elderly, or in renal inhibitors are a good choice for impairment. hypertension in insulin-dependent diabetics Usual maintenance dose is 25 mg b.i.d.; max. and for patients with cardiac heart failure. 50 mg t.i.d. (rarely: 50 mg t.i.d. is used as in • INDICATIONS: severe hypertension). Used in mild to moderate essential For Heart Failure; hypertension alone or with thiazide Initially 6.25-12.5 mg t.i.d. therapy; severe hypertension resistant to Start as early as 3 days after infarction, then other treatment. increase over several weeks to 150 mg in divided doses; max. 450 mg/day. For congestive heart failure (CHF) in conjunction with digitalis and diuretics. Directions: Administration of first dose in Also in diabetic nephropathy in insulin- therapy should be started at night, at dependent diabetes. bedtime to avoid hypotensive side effects.

*Food decreases its absorption; so it should Liver Disease- Some hepatic metabolism be taken one hour before meals or 2 hours occurs, but it seems to be safe to be used in after meals. hepatic disease. *If a dose is missed, it should be taken as • PRECAUTIONS AND WARNINGS soon as remembered. If too close to second -Use caution if administered with diuretics. dosing time, it should be ignored and the -First dose may cause hypotension patient should continue with the usual especially in patients: taking diuretics, on a regimen. The next dose should not be low sodium diet, on dialysis, or dehydrated. doubled. -Monitor renal function before and during • USE IN SPECIAL CASES: treatment (refer to USE IN SPECIAL CASES). Pregnancy- The use of ACEIs during the 2nd -ACE inhibitors should be used with and 3rd trimesters has been associated with particular caution in patients with fetal and neonatal injury, including peripheral vascular disease or generalized hypotension, neonatal skull hypoplasia, renal atherosclerosis, as such patients may have failure and death. When pregnancy is clinically silent renovascular disease. detected, ACEIs should be discontinued as -White cell counts and urinary protein st soon as possible. (Category C in 1 trimester, estimations are needed. nd rd Category D in 2 & 3 trimesters). -In the case of patients on dialysis, avoid Lactation- Use with caution. It is excreted in the combination of ACEI therapy with the breast milk, but in amounts too small to be use of high flux polyacrylonitrile harmful to the nursing infant. Use the lowest membranes, since anaphylactic reactions possible dose of drug. Peak concentration have been reported. levels occur at 4 hrs, so nursing should be -Take caution in patients receiving avoid then. immunosuppressants or other drugs that Children- Safety of captopril in children has cause leukopenia or agranulocytosis, not been established. coronary or cerebrovascular disease. Renal Disease- ACE inhibitors are excreted • by the kidney, and occasionally cause ADVERSE EFFECTS: impairment of renal function which may Persistent dry cough, throat discomfort, progress and become severe. At particular voice changes are very common. Taste risk are those with pre-existing renal disease disturbances (loss of taste), sore mouth, or impairment, the elderly, those with abdominal pain, rash, angioedema, bilateral renal artery stenosis. hypotension; proteinureai, thrombo- Note:- cytopenia, neutropenia, agranulocytosis, Concomitant treatment with NSAIDs hyperkalemia (all are more common in increases the risk of renal damage, and renal impairment); increases in liver potassium-sparing diuretics or use of enzymes, liver damage, and cholestatic potassium-containing salt substitutes jaundice; renal impairment. increase the risk of hyperkalemia. Renal function and electrolytes should be checked before starting an ACE inhibitor, and monitored during treatment. -In general, with mild renal impairment, reduce dose and monitor response, but avoid if possible. In the case of renal impairment, even mild, hyperkalemia and other side effects are more common (but specialized role in some forms of renal disease).

32 Cardiovascular Drugs

• INTERACTIONS: Uricosurics Probenecid reduces excretion Overview of ACEI of captopril. Use with Drug-Drug Interaction caution.

Drug Interaction • OVERDOSE: Alcohol, Hypotension is the most common symptom anesthetics, Enhance the hypotensive of overdose. Systolic blood pressure of 95- anxiolytics, effect. Use with caution. hypnotics, 80 mmHg in hypertensive patients have muscle been reported. Treatment includes usual relaxants supportive measures, with correction of (baclofen), hypotension being the primary choice. corticosteroids, • BRANDS: & anti- Capoten (Squibb), Cardopril (BPC), Inhibace depressants (Pharmabest). β -blockers, ______Enhance the hypotensive Ca-channel blockers, effect. Use with caution. nitrates, & levodopa 4) CA CHANNEL BLOCKERS Analgesics Antagonize the hypotensive effect and increased risk of Calcium channel blockers (less correctly renal failure with NSAIDs; called Ca antagonist) interfere with the hyperkalemia with Indo- inward displacement of Ca ions through the methacin and possibly other slow channels of active cell membranes. NSAIDs. They influence the myocardial cells, the Anti- Severe postural hypotension walls within the specialized conduction psychotics with chlorpromazine and system of the heart, and the cells of the possibly other phenothiazines. Avoid concomitant use. vascular smooth muscle. Thus, myocardial Cardiac Plasma concentration of contractility may be reduced, the formation glycosides digoxin possibly increased by and propagation of electrical impulses with captopril. Monitor closely the heart may be depressed, and coronary when initiating captopril or systemic vascular tone may be therapy. May need to reduce diminished. They should be avoided in dose of glycoside. heart failure because they may further Diuretics Enhanced hypotensive effect depress cardiac function and cause (can be extreme); clinically significant deterioration. Ca hyperkalemia with channel blockers differ in their action, potassium-sparing diuretics. therefore their therapeutic effects are much Use with caution. variable within the group as compared to Lithium ACE inhibitors reduce excretion of lithium (increase the other classes of drugs. its plasma concentration). (Drugs in this category include: Nifedipine, Potassium Patients will be at increased Verapamil, Diltiazem, Isardipine, salts risk of hyperkalemia. Avoid Felodipine, Nicardipine, Nisoldipine, and concomitant use. Nimodipine). Sex hormones Estrogen and combined oral contraceptives antagonize The major agents that will be discussed hypotensive effect. Dose include nifedipine, verapamil and adjustment of ACE inhibitors diltiazem. may be needed if patient not responding to therapy.

a) Nifedipine WHO,P in premature labor under intensive observation). • DRUG SUMMARY: Lactation- Amount excreted in breast milk is Nifedipine relaxes vascular smooth muscle too small to be harmful, but manufacturers advise to avoid. Delay breast-feeding by 3-4 and dilates coronary and peripheral arteries hrs after a dose, to decrease the amount of (hypotensive effect), in greater effect than drug ingested by infant. that produced by verapamil or diltiazem Renal Disease- In the case of moderate renal and usually results in reflex tachycardia. It impairment, start with a small dose; has more influence on vessels and less on reversible deterioration in renal function has the myocardium than does verapamil, and been reported. unlike verapamil has no anti-arrhythmic Liver Disease- Reduce dose in case of hepatic activity. It rarely precipitates heart failure. impairment. • INDICATIONS: • PRECAUTIONS AND WARNINGS: Prophylaxis and treatment of angina; Withdraw medication if ischemic pain hypertension; Raynaud’s phenomenon. occurs or existing pain worsens shortly • CONTRAINDICATIONS: after initiating treatment; heart failure or Cardiogenic shock; advanced aortic significantly impaired left ventricular stenosis; and porphyria. function; severe hypotension; diabetes • DOSAGE FORMS: mellitus; may inhibit labor. Tablets, soft gelatin capsules. • ADVERSE EFFECTS: • RECOMMENDED DOSAGE: Adverse side effects that may occur: Adult: Use for Angina; headache, flushing, dizziness, lethargy; also 10-20 mg PO t.i.d. up to 180 mg/24 hrs. gravitational edema, rash, nausea, increased Use for Hypertension; frequency of micturition, eye pain, gum 10-20 mg t.i.d. up to 180 mg/24 hrs. or 30- hyperplasia, tachycardia and palpitation, 90 mg sustained release once/day. tremor, leg cramps; depression has been Use for Hypertensive Emergency; reported as well as teleangectasia. 10-20 mg PO q. 20-30 min. if necessary. • INTERACTIONS: Child: Safety and efficacy not established. Overview of Nifedipine

Directions: In a hypertensive emergency, Drug-Drug Interaction nifedipine capsule may be swallowed Drug Interaction whole or contents may be given SL. Anti- Increased risk of Puncture capsule with a pin and squeeze arrhythmics bradycardia, AV block, and myocardial depression. contents under the tongue (puncture about Nifedipine reduces plasma 10 times). The punctured capsule may also concentration of quinidine. be chewed. Anti- Rifampicin possibly *If a dose is missed, it should be taken as bacterials increases metabolism of soon as remembered. If too close to second nifedipine (reduce plasma dosing time, it should be ignored and the concentration). patient should continue with the usual Anti- Nifedipine may occasionally regimen. The next dose should not be diabetics impair glucose tolerance. doubled. Use with caution and warn • USE IN SPECIAL CASES: diabetic patients. Pregnancy- Avoid use during pregnancy Anti- Nifedipine increases plasma unless clearly indicated (Category C). May epileptics concentration of phenytoin. Effect of nifedipine reduced inhibit labor (and has been used for treatment by carbamazepine.

34 Cardiovascular Drugs

Antihyper- Enhanced hypotensive • INDICATIONS: tensives & effects. Warn patient. - Supraventricular arrhythmias. Anti- - Angina. psychotics - Hypertension. β-blockers Occasionally severe hypo- • CONTRAINDICATIONS: tension and heart failure with nifedipine. Safer to avoid use Hypotension, bradycardia, second- and concomitantly unless clearly third-degree heart block, sick sinus indicated. syndrome, cardiogenic shock, cardio- megaly, sino-atrial block; history of heart • OVERDOSE: failure or significantly impaired left Symptoms include nausea weakness, ventricular function, even if controlled by dizziness, drowsiness, confusion and therapy; Wolff-Parkinson-White syndrome slurred speech. Hypotension, bradycardia including atrial flutter or fibrillation; and AV block may occur. Death can occur. porphyria, digitalis toxicity. Treatment: If the patient is seen shortly • DOSAGE FORMS: after oral ingestion of nifedipine, employ Tablets. emetics or lavage and cathartics. Dialysis is • RECOMMENDED DOSAGE: not likely to help since these drugs are Adult: highly protein-bound. Treatment is For Supraventricular Arrhythmias; supportive. Refer the patient for further 40-120 mg PO, 3-4 times daily. control and investigation. For Angina; • BRANDS: 80-120 mg 3 times daily. Adalat (Bayer), Angilat (BPC), Aprical For Hypertension; (Rentshler), Corotrend (Siegfried), Osmo-Adala 240-480 mg PO daily in 2-3 divided doses. (Pharma-Clal), Pressolat (Agis), Megalat (Agis). ______Directions: Administer oral dose with food to reduce gastric irritation. b) Verapamil WHO,P *Sustained action dosage forms should not be opened, crushed or chewed. Capsule • DRUG SUMMARY: should be swallowed as a whole Verapamil inhibits the calcium ion influx *If a dose is missed, it should be taken as through slow channels into cells of soon as remembered. If too close to second myocardial and arterial smooth muscles dosing time, it should be ignored and the (both coronary and peripheral blood patient should continue with the usual vessels). It dilates coronary arteries and regimen. The next dose should not be arterioles and inhibits coronary artery doubled. • spasm; thus myocardial oxygen delivery is USE IN SPECIAL CASES: increased (antianginal effect). It decreases Refer to Nifedipine. Verapamil crosses the and slows SA and AV nodes conduction placenta. (antiarrhythmic effect) without effect on In lactation, verapamil or its metabolites normal arterial action potential or have not shown any adverse effects on intraventricular conduction. By vaso- nursing children. dilatation of peripheral arterioles, drug decreases peripheral vascular resistance and reduces arterial BP at rest. It reduces the cardiac output and it may slightly decrease the heart rate. It may precipitate heart failure and exacerbate conduction disorder.

• PRECAUTIONS AND WARNINGS: Cardiac Plasma concentration of -Caution use in the following cases: 1st glycosides digoxin may be increased by degree heart block; acute phase of verapamil, also there will be myocardial infarction (avoid if bradycardia, an increased risk in AV block hypotension, or left ventricular failure and bradycardia. Lithium Neurotoxicity may occur present); aortic stenosis, as well as in without any increase in plasma patients with hepatic and renal impairment. lithium concentration. Monitor • ADVERSE EFFECTS: patients taking Li. Constipation; less commonly nausea, Theophylline Verapamil enhances the effect vomiting, flushing, headache, dizziness, of theophylline. Use caution, fatigue, and ankle edema. Other reported monitor patient response effects include pruritis, AV block, closely when starting therapy. bradycardia, and rarely gynecomastia and • OVERDOSE: gingival hyperplasia after long term Refer to nifedipine. treatment. • BRANDS: • INTERACTIONS: Ikacor/Ikapress (Teva), Verac (Dexxon). Overview of Verapamil ______Drug-Drug Interaction

Drug Interaction

Anesthetics Verapamil increases hypotensive effect of general c) Diltiazem anesthetics and risk of AV delay. • DRUG SUMMARY: Anti- Increased risk of bradycardia, A slow calcium channel blocking, cardio- arrhythmics AV block, and myocardial vascular agent. It is effective in most forms depression. Verapamil raises of angina; the longer acting formulation is plasma concentration of also used for hypertension. It may be used quinidine (extreme in patients for whom beta-blockers are hypotension may occur). contraindicated or ineffective. It has a less Rifampicin increases Anti- negative inotropic effect than verapamil bacterials metabolism of verapamil (reduce plasma concentration). and significant myocardial depression Anti- It increases plasma occurs rarely. Nevertheless because of the depressants concentration of imipramine risk of bradycardia it should be used with and other tricyclics. caution in association with beta-blockers. It Anti- The effect of carbamazepine is does not alter total serum calcium levels. epileptics enhanced by verapamil; effect • INDICATIONS: of verapamil reduced by Prophylaxis and treatment of angina and phenobarbitone and phenytoin. hypertension (long acting formulations). Anti- Enhanced hypotensive effects. • CONTRAINDICATIONS: hypertensives Caution patients to slowly Severe bradycardia, left ventricular failure, change position when standing up or sitting down, so they second- or third-degree AV block (unless won’t feel dizzy. pacemaker fitted), sick sinus syndrome; Anti- Enhanced hypotensive effects. pregnancy; and porphyria. psychotics Use with caution. • DOSAGE FORMS: Beta- Asystole, severe hypotension, Tablets. blockers and heart failure. It should be usually avoided.

36 Cardiovascular Drugs

• RECOMMENDED DOSAGE: • ADVERSE EFFECTS: Adult: For Angina; Bradycardia, sino-atrial block, atrio- 30 mg PO q.i.d.; may increase q. 1-2 d. as ventricular block, hypotension, malaise, required; usual dose range 180-360 mg/day headache, flushing, gastrointestinal in 3-4 divided doses. Sustained release disturbances, constipation, ankle edema; doses: start with 120-180 mg once daily; rarely rashes (toxic erythema reported); then titration may be carried out over a 7- altered liver function tests; hepatitis, 14 day period to 360-480 mg/d. amnesia and depression have been reported. For Hypertension; • INTERACTIONS: 60-120 mg sustained-release b.i.d. (usual Same as nifedipine. [Refer to nifedipine.] range: 240-360 mg/d). • OVERDOSE: Child: No recommendations. Refer to verapamil.

Directions: Administer oral drug before • BRANDS: meals and at bedtime. Dilatam/Dilapress (Abic), Levozem (Dexxon). *If using sustained release forms, do not ______chew, open or crush the tablet. Swallow as whole. • USE IN SPECIAL CASES: B) ANTIARRHYTHMICS Pregnancy- May inhibit labor. Manufacturers advise that diltiazem is The exact mechanisms underlying rhythm teratogenic in animals, therefore should not disturbances are complex, and for the most be used in pregnant women (Category C). part, unknown. Arrhythmia may result from Lactation- Significant amount is excreted in abnormal impulse formation (automaticity), breast milk but not known to be harmful to abnormal impulse conduction, or a the nursing infant. Benefit-risk ratio should combination of both processes. be made on whether do discontinue the drug Accurate diagnosis and appropriate or stop breast-feeding. therapy of disturbances in cardiac rhythm Children- Diltiazem safety and efficacy not require gradual analysis of patient’s history established. (specially relating to new use of drugs Renal Disease- Start with smaller dose. affecting the heart), physical exam as well Liver Disease- Reduce dose in hepatic as laboratory and ECG results. Diagnosis of impairment. such cases is usually done by a cardiologist. • PRECAUTIONS AND WARNINGS: The most widely used classification of -Reduce dose of diltiazem in hepatic and antidysrhythmic drugs is based on the renal impairment; heart failure or electrophysiologic action, (refer to table 2.6 significantly impaired left ventricular on classification). function, mild bradycardia (avoid if At the primary level, physicians will not severe), first degree AV block, or prescribe such medications, but they may prolonged PR interval. see patients who are taking such drugs. Therefore, knowledge about these agents is needed.

Table- 2.6: Classification of Antiarrhythmic Drugs Drugs with local anesthetic effects and membrane stabilizing Class I properties. These are subdivided depending on the magnitude of their effects on the different cardiac phases. Affecting both atrial and ventricle muscle. Type IA Quinidine, Procainamide, Moricizine, Disopyramide. Usefulness is confined to ventricular rhythm disorders. Type IB Lidocaine, Tocainide, Mexiletine, Phenytoin. Indicated primarily in ventricular dysrhythmias, can be used in atrial Type IC arrhythmia. Encainide, Flecainide, Lorainide, Propafenone. β-adrenergic blocking agents, general myocardial depressants for both Class II supraventricular and ventricular rhythm disturbances. Propranolol, Esmolol, Acebutolol. No membrane stabilizing effects, selectively increases action potential Class III duration. Amiodarone, Bretylium, Sotalol. Calcium channel blockers, and others. Class IV Verapamil, Adenosine. # The drugs in bold have been discussed in this chapter.

1) Amiodarone • CONTRAINDICATIONS: Sinus bradycardia, SA heart block; unless • DRUG SUMMARY: pacemaker fitted; avoid in severe Amiodarone is an iodine-containing conduction disturbances or sinus node benzofuran derivative that possesses disease; avoid IV use in severe respiratory cardiac electrophysiological actions that failure, circulatory collapse, severe arterial differ fundamentally from those of hypotension, congestive heart failure; currently available antiarrhythmic agents. It thyroid dysfunction; pregnancy and breast is a Class III antiarrhythmic with a very feeding; iodine sensitivity; and porphyria. long half-life. • DOSAGE FORMS: Toxicity associated with amiodarone has Tablets. led the FDA to recommend that the drug • RECOMMENDED DOSAGE: be reserved for use in patients with life- Adult: For Arrhythmias; threatening arrhythmias. Loading dose (administered initially in • INDICATIONS: hospital): 800-1600 mg/d PO in 1-2 doses for 1- It is used for the treatment of both vent- 3 wks. Maintenance dose: 400-800 mg/d PO in ricular and supraventricular arrhythmias. 1-2 doses. Child: No recommendations. Mainly used for the treatment of tachycardia associated with the Wolff- Directions: GI symptoms occur commonly Parkinson-White syndrome. Also it can be during high-dose therapy, especially with used in the following arrhythmias when loading doses. Symptoms usually respond other drugs are ineffective or contra- to dose reduction or to administration in indicated; paroxysmal supraventricular, divided doses and with food, including nodal and ventricular tachycardias, atrial milk. fibrillation and flutter, and ventricular * Use the lowest effective dose to prevent fibrillation. the occurrence of side effects.

38 Cardiovascular Drugs

*Be alert to pulmonary toxicity presenting bronchospasm or apnea in respiratory with; progressive dyspnea, fatigue, cough, failure. pleuritic pain and fever. • INTERACTIONS: • USE IN SPECIAL CASES: Overview of Amiodarone Pregnancy- Use only if no alternative is Drug-Drug Interaction available (Category D). If it is given in the Drug Interaction second or third trimester there will be a Other anti- Increased myocardial depres- possibility of neonatal goiter. arrhythmics sion risks. Use with caution. Lactation- Avoid use even though no adverse Anti- Metabolism of nicoumalone effects were observed. Breast feeding should coagulants and warfarin inhibited be avoided in mothers currently taking the (enhanced anticoagulant drug or have taken it chronically within the effect). Monitor patient past several months. closely. Children- Safety and efficacy for use in Anti- Metabolism of phenytoin children have not been established, therefore epileptics inhibited (increased plasma concentration). Monitor amiodarone is not recommended for use. blood levels of patient Renal Disease- With moderate renal closely. impairment, Iodine will be accumulated and Anti- Increased risk of ventricular there will be a risk of thyroid dysfunction. histamines arrhythmias with astemizole Liver Disease- It is contraindicated in severe and terfenadine. Avoid use of hepatic impairment. these antihistamines while on • PRECAUTIONS AND WARNINGS: therapy. -Liver function and thyroid function tests β-blockers Increased risk of required in long-term therapy. Amiodarone bradycardia, AV block, and interferes with tests of thyroid function. myocardial depression. -Use caution in heart failure, renal Calcium- Diltiazem and verapamil impairment, elderly, severe bradycardia and channel increase risk of bradycardia, conduction disturbances in excessive blockers AV block, and myocardial dosage. depression. Use with caution. -IV use may cause moderate and transient Cardiac Increased plasma concent- fall in blood pressure (circulatory collapse glycosides ration of digoxin (half precipitated by rapid administration or digoxin maintenance dose). overdose). Diuretics Toxicity increased if -Also take caution in the case of congestive hypokalemia occurs. Monitor heart failure, electrolyte imbalance, and patient closely, especially preexisting lung disease. when starting them on the • ADVERSE EFFECTS: medication. Reversible corneal microdeposits Ulcer- Cimetidine increases plasma (sometimes with night glare); peripheral healing concentrations of neuropathy and myopathy (usually drugs amiodarone. Use with reversible on withdrawal), bradycardia and caution, do not administer at the same time-interval if conduction disturbances; phototoxicity; needed. Other ulcer healing blue-grey discoloration of the skin medication have not shown (specially nose and ears), hyper- or this interaction, but no hypothyroidism; diffused pulmonary sufficient data is available. alveolitis and fibrosis; hepatitis; anaphylaxis on rapid injection, also

• OVERDOSE: rhythm disorders, so it should be used on The most likely effects of amiodarone specialist advice only. overdose are: hypotension, cardiogenic ______shock, bradycardia, AV block, and hepatotoxicity. C) ANTIANGINA Treatment includes usual supportive measures. In addition, monitor the patient’s Angina pectoris is a symptom of cardiac rhythm and blood pressure; if myocardial ischemia, which is usually bradycardia occurs, a β-adrenergic agonist secondary to atherosclerosis of the coronary may be used. Always refer the patient. arteries. Although angina usually implies • BRANDS: severe chest pain or discomfort, its Amiodacore (CTI), Cordorone (Labaz/ C.T.S.), presentations are variable. Angina may Procar (Unipharm). occur predictably with strenuous exercise ______(stable angina), or at other times unexpectedly with little or no exercise 2) Lidocaine WHO,P (unstable angina). Both reflect underlying narrowing of coronary arteries. Classical • DRUG SUMMARY: Prinzmetal variant angina (vasospastic It was introduced as a local anesthetic and angina) occurs in patient without coronary is still used extensively for that purpose. In heart disease, and is due to a spasm of the contrast to quinidine and procainamide, coronary artery that decreases myocardial lidocaine acts primarily on disturbances of blood flow. ventricular origin and has a narrow Specific treatment of ischemic disease is spectrum of antiarrhythmic effects. Use is directed toward improving myocardial only in injection form, in clinical settings. oxygen supply, reducing myocardial Indicated for ventricular arrhythmias oxygen demand, and treating precipitating especially after an MI. No adequate and factors or concurrent disorders that may well controlled studies available on aggravate ischemia. The selection of an pregnancy (Category B), lactation or use in effective therapeutic regimen depends on children. the severity of symptoms, the presence of ______associated disease (e.g. pulmonary or renal disease) the patient’s age and activity level, 3) Quinidine WHO,P and the underlying pathophysiologic mechanism that is responsible for the • DRUG SUMMARY: ischemia. Nitrates remain important first-line Quinidine, a Cinchona derivative, is a class agents for the treatment of angina. They IA antiarrhythmic, cardiovascular agent. It have different mechanisms of action that acts as a depressant of myocardial result in vasodilatation action. Nitrate excitability, conduction velocity and tolerance and reduction in therapeutic contractility. There are differences in the response may occur with all the nitrate anhydrous quinidine alkaloid content preparations. To restore antianginal among the various salts. Make sure that the efficacy, nitrates need to be absent from the patient does not switch brands without your body for several hours, therefore, patients consultation. It should be prescribed only need a nitrate-free interval of at least 10-12 when other agents have failed or cannot be hours to enhance treatment efficacy. When available. Quinidine, may itself precipitate nitrates cannot be discontinued, even for a

40 Cardiovascular Drugs

short time, increased doses may be required • INDICATIONS: to overcome tolerance. Prophylaxis and treatment of angina; left Beta-adrenergic blockers (i.e. ventricular failure. propranolol, metoprolol) are also important • CONTRAINDICATIONS: in the management of stable angina. They Marked anemia, head trauma, cerebral reduce the frequency of anginal episodes by hemorrhage, closed angle glaucoma. reducing myocardial oxygen demand, and • DOSAGE FORMS: raise the anginal threshold. Choice of Tablets, skin patches. β β selective or non-selective 1- or 2 • RECOMMENDED DOSAGE: antagonists depends on individual patients; Adult: For Angina; type of angina, concurrent cardiac Sublingually: 5-10 mg. problems, side effects, etc. (refer to β- By mouth: 30-120 mg in divided doses. blockers in antihypertensive section). For Ventricular Failure; Calcium channel blockers (i.e. 40-160 mg PO, up to 240 mg if required. nifedipine, verapamil, diltiazem) are also Directions: Regular oral forms are best used as antiangina agents. The antianginal taken on an empty stomach (one h. before effects of these agents are due to direct meals or two hrs. after meals). coronary vasodilatation and an *Patient should not eat, drink, talk, or improvement in the efficiency of smoke while sublingual tablet is under myocardial performance. They are tongue. Sublingual tablet should be placed indicated in the management of stable and under the tongue at first sign of anginal unstable angina, and are the agents of attack. If pain is not relieved, repeat dose at β choice in patients unable to tolerate - 5 to 10 min. intervals to a maximum of 3 adrenergic antagonists and nitrates. Refer to doses. Beware of possible MI. individual monographs for each drug. *Patient should be sitting while taking (Refer to calcium channel blockers in rapid-acting forms of isosorbide dinitrate antihypertensive section.) (sublingual and chewable tablets) because ______of the possibility of fainting. *If tolerance should develop in treating WHO,P 1) Isosorbide Dinitrate angina, establish a short drug free period of 10-12 hrs. If the drug cannot be • DRUG SUMMARY: discontinued for a short period of time, Isosorbide dinitrate, a short-acting nitrate, reduce dosing intervals, i.e. if giving 3-4 is one of the most effective drugs for times/d, give 2-3 times/d. providing rapid symptomatic relief of *Patients using SL preparations should angina. It is active sublingually, and is always carry the pills with them. more stable than glyceryl trinitrate for those • USE IN SPECIAL CASES: who only require nitrates infrequently. It is Pregnancy- Safety for use during pregnancy also effective when given PO for has not been established. Use only when prophylaxis; although the effect is slower in clearly needed and when the potential onset, it may persist for several hours. benefits outweigh the potential hazards to the Duration of action up to 12 hrs is claimed fetus (Category C). for modified-release preparations. Lactation- Exercise caution when Isosorbide mononitrate is a major active administering to a nursing woman. It is not metabolite of the dinitrate that attributes to known whether nitrates are excreted in breast the activity, and is available in the market milk. No available data. as a separate preparation. Children- Safety and efficacy for use in children have not been established.

Renal + Liver Disease- Use caution. In case • OVERDOSE: of liver disease use of the mononitrate is Signs and symptoms result mainly from recommended instead of the dinitrate form. vasodilation and methemoglobinemia; also, • PRECAUTIONS AND WARNINGS: hypotension, tachycardia, flushing, -Take caution in the case of hypotensive perspiring skin, vertigo, syncope, vomiting conditions, with concomitant use of (possibly with colic and bloody diarrhea), medications that cause hypotension, and in dizziness, moderate fever and paralysis, as the case of hyperthyroidism. well as convulsions and death due to -In some patients there is a possibility of cardiovascular collapse. developing tolerance (reduced therapeutic If nitrates were ingested, induce emesis or effects). Refer to directions. perform gastric lavage followed by • ADVERSE EFFECTS: charcoal administration; however, nitrates Throbbing headache, flushing, dizziness, are usually rapidly and completely postural hypotension, and tachycardia. absorbed. Gastric lavage may be of use if These are more prominent at the beginning the medication has only recently been of treatment, and will be reduced with time. swallowed. Passive movement of the • INTERACTIONS: extremities may aid venous return. Refer to Overview of Isosorbide Dinitrate emergency room for symptomatic care. Drug-Drug Interaction • BRANDS: Drug Interaction Cordil (Dexxon), Isocardide (Sam-On), Isordil Alcohol, (Wyeth Ayerst), Isotard (CTI/C.T.S.). anesthetics, ______anxiolytics, hypnotics, β- All these drugs enhance the blockers, Ca- hypotensive effect. Need to D) ANTICOAGULANTS channel warn your patients if taking blockers, any of these during the time Blood coagulation resulting in the muscle of nitrate therapy. relaxants formation of a stable fibrin clot involves a (baclofen), cascade of proteolytic reactions involving cortico- the interaction of clotting factors, platelets steroids, and tissue materials. Although most cases dopa- of thromboembolic disease are idiopathic, minergics (levodopa), several clinical conditions have been anti- associated with and increased risk of psychotics, thrombosis. Such factors include: inherited diuretics, & deficiencies of factors like antithrombin III, anti- protein C, and protein S, and clinical depressants conditions that may predispose patients like Analgesics NSAIDs antagonize the pregnancy, malignancy, immobilization, hypotensive effect. Use congestive heart failure, cigarette smoking, with caution. Anti- Tricyclics may reduce effect or immunologic disorders. depressants of sublingual nitrates Prior to initiation of anti-coagulant (owing to dry mouth). therapy, patients must be screened for the Sex hormones Estrogen and combined OC presence of relative contraindications to antagonize hypotensive therapy (refer to table 2.7) because the effect. Use with caution. failure to detect such contraindications could result in fatal hemorrhage.

42 Cardiovascular Drugs

Aspirin and warfarin will be discussed (For other details on ASA, refer to analgesics in this section. chapter).

______Table- 2.7: Relative Contraindications to Anticoagulant Therapy WHO,P Active bleeding 2) Warfarin (e.g., active peptic ulcer disease). Bleeding tendency • DRUG SUMMARY: (e.g., hemophilia, thrombocytopenia). Warfarin, a coumarin derivative anti- Uncontrolled hypertension. coagulant, indirectly interferes with blood Cerebrovascular hemorrhage. clotting by depressing hepatic synthesis of Recent surgery or invasive procedures vitamin K-dependent coagulation factors. (e.g. arterial or lumbar puncture). Pericarditis or pericardial effusion. Has no effect on already synthesized Severe trauma. circulating coagulation factors or on Pregnancy (primarily related to warfarin). circulating thrombi. It does not reverse Patients prone to falling ischemic tissue damage, and has no effect (e.g., elderly or debilitated patients). on platelets. It takes 2-3 days for the Inadequate laboratory facilities. anticoagulant effect to develop fully. Unsatisfactory patient compliance. • INDICATIONS: Prophylaxis for embolization in patients 1) Aspirin WHO,P with rheumatic heart disease and atrial fibrillation; prophylaxis after insertion of • DRUG SUMMARY: prosthetic heart valve; prophylaxis and Aspirin is recommended in treatment of treatment of venous thrombosis and cardiovascular, cerebrovascular and pulmonary embolism; transient brain rheumatologic conditions. Studies have ischemic attacks. shown that it is effective in the treatment of • CONTRAINDICATIONS: TIA, ischemic stroke, angina, acute MI, Pregnancy, peptic ulcer, severe recurrent MI with low doses of 50-365 mg, hypertension, bacterial endocarditis, depending on case. hemorrhagic tendencies, vitamin C or K Low-dose aspirin may also help in deficiency, hemophilia, active bleeding, preventing pre-eclampsia/toxemia in open wounds, severe hepatic or renal pregnant women. The rationale for use of disease. ASA prophylaxis is the inhibition of Note: Oral anticoagulant should not be synthesis of prostaglandin thromboxane, used in cerebral thrombosis or peripheral which has been found to be elevated in arterial occlusion, but may be of value in severe pre-eclampsia. As of today, studies patients with transient brain ischemic attacks do not support the routine use of low-dose whether due to carotid or vertebrobasilar aspirin in pregnant women for prevention arterial disease. If these patients also have of pre-eclampsia or its complications. severe hypertension, anticoagulants are Further studies are needed. contraindicated, and antiplatelet drugs are an Doses: a single dose of ASA is given as alternative. soon as possible after an ischemic event: • DOSAGE FORMS: 150-300 mg after MI, and 300 mg after Tablets. TIA/stroke. After the initial dose, maintenance treatment with aspirin ranges from 75-325 mg daily, depending on case.

• RECOMMENDED DOSAGE: Lactation- Use caution. Warfarin appears in Adult: Whenever possible, the base-line breast milk in an inactive form. Infant nursed prothrombin time should be determined by warfarin-treated mothers had no changes before the initial dose is given. Treatment is in their PT. Warfarin has been considered very highly individualized. Control dosage safe for use. by periodic determination of Prothrombin Children- Safety and efficacy in children < Time (PT) or the International Normalized 18 years old have not been established. Ratio (INR). Heparin use might be safer. Use of oral anticoagulants in children is only indicated in Induction dose: The typical induction dose children with rare thromboembolic disorders is 10 mg daily for 2 days. On the other secondary to other diseases. hand, less than 10 mg should be given if Renal Disease- Use with caution. If there is base-line prothrombin time is prolonged, severe renal impairment this drug should be abnormal liver-function tests, patient in avoided. cardiac failure, parenteral feeding, less than Liver Disease- Use with caution. If there is average body weight, or over 80 years of severe hepatic impairment it should be age. avoided. Maintenance dose: It depends upon the • PRECAUTIONS AND WARNINGS: prothrombin time. The currently -Need to use caution in special risk patients recommended therapeutic ranges are: PT such as: hepatic and renal disease, recent ratio of 1.3 to 1.5; and INR of 2 to 3 except surgery, alcoholism, during menstruation, for cases of mechanical prosthetic valves and nursing mothers. and recurrent systemic embolism where -Table 2.8 is a list of endogenous factors therapeutic ranges are PT 1.5 to 2, and INR that may increase or decrease prothrombin 3 to 4.5 time response (enhance or decrease The daily maintenance dose of warfarin is anticoagulant effect respectively). usually 3 to 9 mg (taken at the same time • ADVERSE EFFECTS: each day or every other day). Hemorrhage from any tissue or organ. Directions: Tablet may be crushed before • INTERACTIONS: administration and taken with fluid of Note: Change in patient’s clinical patient’s choice. condition, particularly associated with liver *If a dose is missed, it should be taken as disease, intercurrent illness, or drug soon as remembered. Do not double the administration, necessitates more frequent dose on the next dosing scheduled time. testing. Major changes in diet (especially *It is essential that the PT or INR be involving green leafy vegetables; lettuce, determined: daily or on alternate days in cabbage, spinach, broccoli…) may also affect early days of treatment, then at longer warfarin control as well as herbal and intervals (depending on response) then up to botanical (ie. garlic, ginseng, licorice, every 8 weeks.

• capsicum) preparations. USE IN SPECIAL CASES: *Phenytoin and cholestyramine may Pregnancy- Oral anticoagulants are enhance or reduce warfarin anticoagulant teratogenic and should not be administered effect. Do not administer at the same time, specially in the first trimester of pregnancy (Category D). Women at risk of pregnancy and monitor patients blood levels closely. should be warned of this danger; difficult *Antiplatelet drugs: Aspirin increases risk decisions may have to be made, particularly of bleeding due to antiplatelet effect. Avoid in women with prosthetic heart valves or with use. Warn patient not to take OTC a history of recurrent venous thrombosis or medications containing aspirin. pulmonary embolism. See table on list of drugs-interactions.

44 Cardiovascular Drugs

Table 2.8 • OVERDOSE: Endogenous factors that may increase Early symptoms include: excessive prothrombin time response menstrual bleeding, melena, oozing from (enhance anticoagulant effect) superficial injuries, bleeding from gums Carcinoma. after brushing teeth, excessive bruising. Congestive heart failure. Collagen diseases. Hemorrhage is the principal adverse effect. Hepatic and renal insufficiency. Other symptoms may include nausea, Diarrhea. vomiting, headache, and malaise. Fever. Treatment includes discontinuation of Pancreatic disorders. therapy with the medication. If necessary Mal-nutrition. give small doses of oral phytomenadione Vitamin K deficiency. (Vit. K1) 2.5 to 10 mg. In persistent Alcoholism. bleeding or severe hemorrhage cases refer Endogenous factors that may decrease to emergency room for supportive care as prothrombin time response needed. (decrease anticoagulant response) • Edema. BRANDS: Hypothyroidism. Coumadin (Taro). Hyperlipidemia. ______Hypercholesterolemia. Chronic alcoholism. E) CONGESTIVE HEART Hereditary resistance to coumarin therapy. FAILURE DRUGS

The following is a list of drugs that exhibit hazardous interactions with warfarin and Heart failure is the inability of the heart to they should not be given concomitantly: maintain an adequate output to meet the metabolic demands of the body. Enhance Warfarin Effect The clinical manifestations of heart Alcohol. failure vary depending on the rapidity of Anabolic steroids. decompensation, underlying etiology, and Analgesics: e.g. aspirin increases risk of age of the patient. Signs and symptoms of bleeding due to antiplatelet effect. Antiarrhythmics: e.g. amiodarone, quinidine. low cardiac output include fatigue, exercise Antibacterials: e.g. chloramphenicol, intolerance, decreased peripheral perfusion cotrimoxazole, erythromycin, metronidazole, decreased urine output, confusion and sulfonamides. Others as tetracycline, lethargy, and ultimately shock. trimethoprim, and ampicillin may enhance Precipitating factors that cause heart warfarin effect. failure include: coronary artery disease, Antifungals: e.g. miconazole. hypertension, dilated cardiomyopathy (due Ulcer-healing drugs: e.g. cimetidine. to toxins like alcohol, viral or parasitic Influenza vaccine. infection or collagen vascular disease), Reduce Warfarin Effect valvular heart diseases, restrictive cardio- Antibacterials: e.g. Rifampicin. myopathy, constrictive cardiomyopathy, Antiepileptics: e.g. carbamazepine, phenobarbitone. and high-output heart failure due to chronic Antifungals: e.g. griseofulvin. anemia, atrioventricular shunts or thyrotoxicosis. Barbiturates. Oral contraceptives. Nonpharmacologic therapeutic measures Vitamin K: major changes in diet (especially are important to employ in conjunction involving vegetables). with the specific pharmacological measures. These include:

A) Restriction of physical activity and bed Since the Renin-angiotensin system rest to reduce myocardial workload. Simple becomes increasingly more active in exercise to improve functional capacity in cardiac failure, ACE inhibitors are being selected patients. Need to decrease promoted with a diuretic (thiazide or loop emotional stress. diuretics since they potentiate the blood B) Weight loss, specially in obese patients, pressure lowering effects of ACEI) to be C) Dietary sodium restriction (≤ 2.0 g first-line. The beneficial effects of these Na+/day), and fluid and water restriction (≤ drugs have been demonstrated in mild, 1.5 L/day). moderate and severe dysfunction. Since D) Discontinuation of negative inotropic they are less toxic and do not require as medications (e.g. beta-adrenergic much monitoring, their use has been antagonists, verapamil, diltiazem, type IA accepted widely. They have a particularly and IC antiarrhythmics) if possible. valuable role when cardiac failure develops E) Complete cessation of cigarette smoking during or after a myocardial infarction. is also important to optimize oxygen- carrying capacity and to reduce the risk of coronary disease. 1) Digoxin WHO,P

Pharmacological therapy principles include: control of sodium and fluid • DRUG SUMMARY: retention, vasodilator therapy and inotropic The most widely used glycoside of digitalis support, in conjunction with the non- lanata, acts by increasing the force and pharmacologic measures. velocity of myocardial systolic contraction; Diuretics are first line drugs. Their goal increases contractility (positive inotropic is to produce a maximum net loss of 0.5 to effect). Action is more prompt and less 1.0 liter of fluid per day to prevent prolonged than that of digitalis and intravascular volume depletion. Need to digitoxin. In patients with mild failure a monitor patients for complications of loading dose in not required, and a electrolyte imbalances and volume satisfactory plasma concentration can be depletion. Hypokalemia may be life achieved over a period of about a week. threatening in patients receiving digoxin or • INDICATIONS: predisposed to ventricular arrhythmias. Heart failure and supraventricular Digitalis glycosides are used to increase arrhythmias (particularly atrial fibrillation). myocardial contractility. The principal • CONTRAINDICATIONS: actions of the cardiac glycosides are: an Digitalis hypersensitivity, ventricular fib- increase in the force of the myocardial rillation, ventricular tachycardia unless due contraction and a reduction of the to congestive heart failure, supraventricular conductivity of the heart. Digoxin is most arrhythmias caused by Walff-Parkinson- efficacious in management of heart failure White syndrome. associated or caused by atrial fibrillation or Note: Full digitalizing dose is not given flutter (or other supraventricular tachycardias if the patient has received digoxin during that respond to digoxin), or in patients with the previous week, or if slowly excreted dilated left ventricles and impaired systolic cardiotonic glycoside has been given during function. Other cardiac agents may be used previous 2 weeks. depending on the patients’ condition. • DOSAGE FORMS: Always refer patients to a specialist for Tablets, elixir (0.05mg/ml). further management when patient is not responding to initial treatments.

46 Cardiovascular Drugs

• RECOMMENDED DOSAGE: • ADVERSE EFFECTS: Adult: Digitalizing Dose; Anorexia, nausea, vomiting, diarrhea, 10-15 µg/kg (1-1.5 mg) PO/IV in divided abdominal pain, visual disturbances, doses over 24-48 hrs. headache, fatigue, drowsiness, confusion, Maintenance dose; delirium, hallucination, arrhythmias, and 125-250 micrograms daily, (elderly 125 ug) heart block. Children: should be treated and monitored • INTERACTIONS: by a pediatrician/cardiologist. Premature Overview of Digoxin and newborn infants display considerable Drug-Drug Interaction variability in tolerance, and are very Drug Interaction sensitive; therefore doses are individualized Analgesics NSAIDs may exacerbate heart failure, reduce GFR and according to infant’s degree of maturity. increase plasma-cardiac Directions: Make sure that the patient will glycoside concentrations. not stop taking the medication without the Avoid concomitant use. doctor’s consultation. Anion- Digoxin absorption is reduced *If the patient misses a dose, it should be exchange by cholestyramine and taken as soon as remembered. If too close resins colestipol. Administer 2 hours to the next dose, it could be ignored and the after or before taking resins. Plasma concentration of required dosing schedule should be Anti- arrhythmic digoxin is increased by continued. drugs amiodarone, propafenone, and *Warn patient about the possible side quinidine (use half the effects. In case symptoms are severe or maintenance dose of digoxin). unmanageable, the patient should report to Anti- Erythromycins enhance the you as soon as possible, to manage the bacterials effect of digoxin. Use caution. toxicity effects. Anthyperten- Captopril possibly increases • USE IN SPECIAL CASES: sives plasma concentration of digoxin. Pregnancy- Use only when clearly indicated Anti- Quinine, chloroquine, and (Category C). It passes through the placenta malarials hydroxychloroquine raises and has been used to treat fetal tachycardia plasma concentration of and CHF. digoxin. Use half the Lactation- Use with caution. The amount maintenance dose of digoxin. appearing in breast milk is too small to be β-blockers Increased risk of AV block and harmful, and no data of adverse effects have bradycardia. been reported in nursing infant. Calcium- Plasma concentration of Renal Disease- Digoxin excretion is delayed channel digoxin increased by in renal insufficiency since it is eliminated by blockers diltiazem, nicardipine, and verapamil; increased AV block the kidneys. Doses will need adjustment and bradycardia with depending on Clcr and lean body weight, verapamil. maintenance dose will be lowered. Diuretics Increased toxicity occurs with Liver Disease- No dosage adjustment is acetazolamide, loop diuretics, required. and thiazides; effects of • PRECAUTIONS AND WARNINGS: digoxin enhanced by Cautious use in: renal insufficiency, spironolactone. hypokalemia, advanced heart disease, acute Muscle Arrhythmias with suxameth- MI, incomplete AV block, cor-pulmonale, relaxants onium. Avoid concomitant use. hypothyroidism, lung disease. Dose should be reduced in the case of elderly patients.

Potassium K antagonizes digitalis prep- medication intake that might contribute to arations. A decrease in K level elevating their cholesterol or triglycerides favors digoxin binding, (TGs) levels, such as: alcohol intake, OCs, increasing likelihood of corticosteroids, nicotinic acids, spirono- digitalis toxicity. Increased K lactone or thiazide diuretics. level decreases digitalis binding and decreases Table- 2.10: Cardiac Risk Factors digitoxin effect. Be very Male sex careful. Family history of CHD

• Cigarette smoking OVERDOSE: Hypertension Symptoms of toxicity include exaggerated HDL-cholesterol below 35 mg/dl (on side effects. more than one measurement) In the case of overdose one should Diabetes mellitus discontinue digoxin until all signs of Hypothyroidism toxicity are abolished. Always refer the Presence of cerebrovascular or peripheral patient for further medical investigation and vascular disease symptomatic care. Severe obesity (> 30 % over-weight)

• BRANDS: The rationale for therapy is to reduce the Digoxin-Zori (Teva), Lanoxin (Glaxo Wellcome). risk of atherosclerotic cardiovascular ______disease. Diet, weight loss and exercise are the

most important therapy to start with. Diet is F) LIPID LOWERING DRUGS the initial therapy, and in most cases, should be tried for several months before The relationship between the risk of drug therapy is considered. Cessation of atherosclerotic heart disease and serum smoking and reduction of blood pressure lipoprotein is well established. Elevated are also important. levels of total cholesterol and low-density Lipid lowering agents should be lipoprotein (LDL), and low levels of high- reserved for patients in whom severe density lipoprotein cholesterol (HDL) are hyperlipidemia is inadequately controlled associated with increased risk for cardiac by the modified fat diet. Choice of disease. See table-2.9 for classification of medication depends on the individual blood cholesterol levels. patient and type of disorder. Some drugs are used to lower cholesterol, others lower Table-2.9: Classification of both cholesterol and triglycerides. Blood Cholesterol Levels in Adults Classifi- Total LDL HDL TGs WHO recognizes the value of the lipid cation Chol. Chol. Chol. lowering drugs, but has not included any Desirable Male: specific agent on the EDL. blood 40-160 < 200 < 130 ≥ 35 Bile sequestrant resins (cholestyramine concentration and colestipol) are usually first-line choice, (mg/dl) Female: while HMG-CoA reductase inhibitors Borderline- 200- 130- 35-135

high (mg/dl) 239 159 (Fluvastatin, lovastatin, paravastatin, and High simvastatin) and fibric acid derivatives ≥ 240 ≥ 160 (mg/dl) (bezafibrate, clofibrate and gemfibrozil) are

Drug Facts and Comparisons, 2000, p. 532. second choice. (Long term safety and efficacy for second line agents have not Table 2.10 lists the common risk factors been established.) for heart disease. If no family history of high cholesterol levels, ask about any

48 Cardiovascular Drugs

Table- 2.11: Effects of Selected Antihyperlipidemic Drugs on Serum Lipids and Lipoproteins Lipids Lipoproteins Drug Cholesterol Triglycerides VLDL LDL HDL Cholestyramine Ð ÎÏ ÎÏ Ð ÎÏ Clofibrate Ð Ð Ð ÎÐ ÎÏ Gemfibrozil Ð Ð Ð ÎÐ ÎÐ Lovastatin Ð Ð Ð Ð Ï Nicotinic Acid Ð Ð Ð Ð Ï Probucol Ð Î Ð Ð Ï Simvastatin Ð Ð Ð Ð Ï Ð- decrease, Ï- increase, Î- unchanged. Adapted from Drugs Facts and Comparisons 2000, p. 532.

Measurement of LDL-cholesterol levels • INDICATIONS: should be at 4-6 wks, and at 3 mons. If the Hyperlipidemias types IIa, IIb, III, IV, and response is inadequate, refer this patient to V in patients who have not responded a lipid disorder specialist. Experience with adequately to diet and other appropriate combination therapy is limited. measures. For menopausal women with high serum • CONTRAINDICATIONS: cholesterol, estrogen replacement therapy Hypoalbuminemia, primary biliary can be considered as an alternative choice, cirrhosis, gall bladder disease, nephrotic since estrogen lowers LDL and raises HDL syndrome, pregnancy and breast feeding, cholesterol levels. and severe renal or hepatic impairment. Table 2.11 summarizes the effects of • DOSAGE FORMS: selected antihyperlipidemic drugs on serum Tablets lipids and lipoproteins. • RECOMMENDED DOSAGE: Adult: 200 mg PO t.i.d., may be reduced 1) Fibric Acids to 200 mg b.i.d. in hypertriglyceridemia. Directions: It may be taken with or after a) Bezafibrate food if GI upset occurs. • USE IN SPECIAL CASES: • DRUG SUMMARY: Pregnancy- Avoid in the case of pregnancy since there is a theoretical possibility of It belongs to a group known by the interference with embryonic growth and clofibrate group (refer to introduction). It development due to anticholesterol effect. can be regarded as broad-spectrum lipid- Strict birth control procedures must be modulating agent in that although their exercised by women of child-bearing main action is to decrease serum TGs they potential. Since no controlled studies on also tend to reduce LDL-cholesterol and to women have been performed, weigh the raise HDL-cholesterol. This group can possible benefits of the drug to the patient cause a myositis-like syndrome, especially against possible hazards to the fetus. in patients with impaired renal function. In Lactation- Avoid. No available data, but addition, clofibrate predisposes to animal studies suggest drug excretion into gallstones by increasing biliary cholesterol breast milk. excretion; it is therefore only indicated in Children- Safety and efficacy in children patients who have had a cholecystectomy. have not been established.

Renal Disease- If there is mild to moderate cholestrolemia (type IIa hyperlipidemia), renal impairment, reduce dose since it might with a significant risk of arthersclerotic cause further deterioration in renal function. heart disease and MI. Also has been used If there is severe renal impairment, avoid for relief of pruritus associated with partial bezafibrate. biliary obstruction, and to control diarrhea Liver Disease- Avoid in severe liver disease. caused by excess bile acids in colon for • PRECAUTIONS AND WARNINGS: hyperoxaluria. Some patients might not be responsive to • CONTRAINDICATIONS: clofibrate or its derivatives. Hypersensitivity to bile acid sequestering There has been no indication that these resins and in complete biliary obstruction. drugs cause a reduction in the incidence of • DOSAGE FORMS: fatal myocardial infarctions in patients. Be Tablets, powder. selective when choosing patients to start on • RECOMMENDED DOSAGE: therapy. Adult: For Hypercholesterolemia and • ADVERSE EFFECTS: Hyperlipoproteinemia; Nausea, abdominal discomfort; rarely 4-8 g PO b.i.d. to q.i.d., a.c. and h.s. myositis-like syndrome, pruritis, urticaria, May need up to 24 g/d; max. 32g/d). impotence; and headache reported. • INTERACTIONS: Directions: Medication is taken before Overview of Bezafebrate meals, and at bedtime. Drug-Drug Interaction *If using powder, dissolve one packet, or Drug Interaction one level scoop in at least 120-180 ml of Anti- Enhancement of effect of water or other preferred liquid. Permit drug coagulants nicoumalone and warfarin. to hydrate by standing without stirring 1-2 Anti- May improve glucose min., then stir until suspension is uniform. diabetics tolerance and have positive Rinse glass with small amount of liquid to additive effect. Monitor ensure entire dose is taken. glucose levels if therapy is *Determine cholesterol level frequently started. during the first few months of therapy.

• OVERDOSE: Serum levels are reduced within 24-48 hrs., Symptoms include excessive side effects. and continue to decline for a year. If Institute symptomatic supportive measures. response is unsatisfactory after 3 months of • BRANDS: treatment, the drug is usually withdrawn. Bezalip (Boehringer), Norlip (Unipharm). (See Precautions and Warnings). ______• USE IN SPECIAL CASES: Pregnancy- Use only when clearly needed, and the potential benefit outweighs the 2) Bile Acid Sequestrants potential hazards to the fetus (Category C). Safety for use during pregnancy has not been a) Cholestyramine established. Even though these agents do not get absorbed systematically, they interfere • DRUG SUMMARY: with fat-soluble vitamins that are essential to A quaternary ammonium anion exchange the growing fetus. resin (bile acid sequestrant) used for its Lactation- Exercise caution. The possible lack of proper fat-soluble vitamin absorption cholesterol-lowering effect. may have an effect on the nursing infant. • INDICATIONS: Children- Doses have not been established As adjunct to diet therapy in management in children. Safety and efficacy in children of patients with primary hyper- < 6 yrs old are not established.

Cardiovascular Drugs Renal Disease- Use with caution. • INTERACTIONS: Liver Disease- Use with caution. Cholesty- Note: ramine interferes with absorption of fat- Most medications should be taken soluble vitamins and may aggravate malabsorption in primary biliary cirrhosis. at least 1 hour before, or 4-6 hours after cholestyramine- • PRECAUTIONS AND WARNINGS: or colestipol- administration. -Carcinogenesis: The incidence of intestinal tumors in studies was greater in cholestyramine-treated rats than in controls. Overview of Cholestyramine Reported Drug-Drug Interaction Before instituting therapy, vigorously Drug Interaction attempt to control serum cholesterol by an Anti- The anticoagulant effect may appropriate dietary regimen and weight coagulants be decreased by cholestyramine. reduction. Digitalis Serum level of glycosides may -Resins may interfere with normal fat glycosides be reduced, reducing the absorption of digestion and may prevent therapeutic effect. absorption of fat-soluble vitamins A, D, E, Analgesics Piroxicam elimination is and K. Chronic use of resins may be enhanced, and paracetamol associated with increased bleeding time due absorption is reduced leading to vitamin K deficiency. Supplementation to subtherapeutic effects. with the vitamins may be given in a water Propranolol The plasma concentration of miscible form or administered parenterally propranolol and its metabolite if needed. is reduced. -Reduction of serum or red cell folate has Thiazide Absorption and serum level of diuretics thiazides may be decreased. been reported with chronic administration. Thyroid Loss of efficacy of thyroid and Consider supplementation with folic acid if Hormones potential hypothyroidism with needed. concurrent use of choles- -Use caution with patients with preexisting tyramine. constipation. Fecal impaction may occur, Vitamins Malabsorption may occur with and hemorrhoids may be aggravated. Need A, D, E, K chronic use of resins. to avoid constipation (causing strain on • OVERDOSE: defecation) in patients with symptomatic The chief potential harm would be GI tract coronary artery disease. Increased fluid obstruction. Location and degree of intake may be sufficient, if not, the patient obstruction and status of gut motility can use a laxative or stool softener. determine treatment. No ill effects have • ADVERSE EFFECTS: been reported. Most common are: constipation, and in • BRANDS: severe cases may be accompanied by fecal Chol-Less (Rafa), Questran (Bristol Labs/ Mead impaction and aggravation or bleeding of Johnson). hemorrhoids. Others may be, abdominal ______pain, flatulence, bloating sensation, nausea, indigestion, heartburn, belching, urticaria, asthma, and general backache or joint pains.

3) HMG-COA Reductase Renal Disease- Use with caution. Higher Inhibitors systemic exposure of simvastatin may occur in severe renal insufficiency. a) Simvastatin Liver Disease- Avoid use in patients who consume substantial quantities of alcohol or

who have a history of liver disease. • DRUG SUMMARY: • PRECAUTIONS AND WARNINGS: Simvastatin is an inhibitor of 3-hydroxy-3- -Use with caution in patients who consume methylglutaryl coenzyme A (HMG-CoA), substantial quantities of alcohol or who classified as a cardiovascular, lipid have a history of liver disease. Liver lowering agent. It is more potent than function tests should be performed in all lovastatin. A response is noted within 1-2 patients before initiating therapy. wks. Elevations of liver enzymes should be [Several statins have been shown to reduce monitored closely. If levels of transaminase fatal and myocardial infarction, stroke, the rise to 3 times the normal levels and are need for coronary by-pass surgery and all- persistent, discontinue the drug. cause mortality. (WHO EDL. 1997)]. • -Carcinogenesis/fertility impairments, have INDICATIONS: been noted in animal studies of these agents Hypercholesterolemia, familial hyper- at high doses. cholestrolemia. • • ADVERSE EFFECTS: CONTRAINDICATIONS: Angina, dizziness, headache, vertigo, Hypersensitivity to these agents, pregnancy insomnia, nausea, vomiting, diarrhea, and nursing mothers, active liver disease. flatulence, photosensitivity, transient • DOSAGE FORMS: elevations of liver transaminases, rhabdo- Tablets. myolysis, gynecomastia and erectile • RECOMMENDED DOSAGE: dysfunction, progression of cataracts. Adult: 5-40 mg q.d. • INTERACTIONS: Directions: Can be given without regard to Overview of Simvistatin meals. Better given in the evenings. Major Drug-Drug Interaction * Liver function tests should be performed Drug Interaction q. 4-6 wks. during the first 3 mons. of Warfarin The anticoagulant effect of therapy, then every 6-8 wks. for the next year. warfarin may be increased. (PT may be prolonged). Monitor prothrombin time. • USE IN SPECIAL CASES: Cyclosporin Increased risk of Myopathy Pregnancy- Contraindicated use (Category or rhabdomyolysis may X). Evidence in skeletal malformation in occur with concurrent animal studies has been reported. administration.

Lactation- It is not known if simvastatin is • OVERDOSE: excreted in human breast milk, but because Few cases of overdosage have occurred of the potential for serious adverse reaction with simvastatin, no patients had any in nursing infants it is inadvisable to use it. specific symptoms, and all recovered. Treat Children- Safety and efficacy in children symptomatically as required. < 18 years old have not been established. • BRANDS: Avoid use. Simovil (Assia/Riesel), Zocor (Merck).

______

Chapter 3: GASTRO-INTESTINAL DRUGS

A) ANTACIDS & ULCER-HEALING MEDICATION 1) Mg/Al Salts 2) Ranitidine 3) Omeprazole

B) ANTISPASMODICS/ANTICHOLINERGICS 1) Hyocine N-Butyl Bromide

C) ANTIEMETICS 1) Metaclopramide 2) Meclizine/Meclozine

D) DRUGS USED IN DIARRHEA 1) Oral Rehydration Salts 2) Anti-Diarrheal - Loperamide

E) LAXATIVES 1) Bisacodyl 2) Castor Oil 3) Glycerine 4) Psyllium

F) ANTI-HEMORRHOIDAL 1) Mentioned Formula - Anusol

A) ANTACIDS & ULCER HEALING MEDICATION

Gastro-intestinal tract (GIT) disorders are be promoted by minimizing these factors very common. Important clues to determine when possible. what type of problem is present can be The primary aim of pharmacological found by asking patients about time of therapy for such disorders has been either symptoms occurrence (in relation to meals to neutralize existing acid (using antacids), and night time), if pain is localized, if reduce the secretion of acid (using symptoms are acute or chronic . . . etc. anticholinergic agents, H2-antagonists or The following table shows some common proton pump inhibitors), or to eradicate H. GIT disorders with the associated pylori bacteria. Table-3.1 indicates a symptoms and characteristics: summary of the most common therapeutic classes, their mechanism of action and Summary of Selected GI Disorders some examples. Gastroesophageal Reflux Disease Antacids are useful for the short-term Heartburn/pain in lower chest. Pain is worse after meals & when lying down. relief of indigestion, heartburn and Pain may wake patient at night. excessive eating and drinking, as well as Pain is often relieved by antacids. for the long-term management of gastro- Pain may be worse after certain foods, esophageal reflux and peptic ulcer disease. smoking, alcohol, caffeine, and medications They give symptomatic relief, promote that reduce lower esophageal sphincter tone. healing and reduce reoccurrence. There are Gastric Ulcer 2 kinds of antacids. Absorbable antacids: Variable epigastric pain. these provide rapid, complete neutra- Unpredictable pattern. lization, but continuous use may cause Food may worsen pain. milk-alkali syndrome that can progress to Weight loss is common. irreversible kidney damage if unrecognized. May be relieved by antacids. History of chronic NSAID use. Examples include sodium bicarbonate, Duodenal Ulcer calcium carbonate. Non-absorbable Aching epigastric pain. antacids are relatively unsoluble salt of Well-localized, predictable pattern. weak bases and have fewer side effects. Begins 1-2 hrs. after eating, They interact with gastric HCL forming worse before next meal. non-absorbable salts thus increasing gastric Relieved by food or antacids. pH. Examples like Aluminium hydroxide Weight gain common. and Magnesium hydroxide. May wake patient at night. Dual and triple therapy regimens have History of smoking. been implemented to provide higher Acute Gastritis eradication rates. Dual therapy such as use Burning epigastric pain. of amoxicillin plus omeprazole, or Possible association with anorexia, clarithromycin plus omeprazole have an nausea, and vomiting. History of alcohol binge or NSAID use. overall lower efficacy rates compared to triple therapy. Also after treatment failure, There are many factors that disrupt the in patient who remain H. pylori positive gastric mucosal barrier, which lead to acid- resistance has developed. Therefore, peptic disorders. These factors include: experts no longer advocate dual therapy as Helicobacter pylori (H. pylori) bacteria, first-line treatment (Gitnick, 1997). The drugs, e.g. NSAIDs, corticosteroids, effectiveness of regimens may be due to alcohol, caffeine and smoking. Healing can antibiotic resistance. Therefore, the

54 Gastrointestinal Drugs

patients’ prior antibiotic exposure should be Examples of used regimens adopted considered when selecting a regimen. from Drug Facts and Comparisons are

shown in table-3.2.

Table-3.1: Summary of the Most Common Therapeutic Classes for Treatment of Ulcers Therapeutic Mechanism of Action Example Notes Class Neutralize existing acids, Na bicarbonate, These products differ in without affecting the amount Ca carbonate, potency, GI side effects, Antacids or rate of gastric secretion. Aluminium salts, systemic complications They react with acids to form Magnesium salts. and drug interactions. salt and water. Cimetidine, These products are Reduce acid secretion H - Ranitidine, almost equally effective 2 without enhancing mucosal Famotidine, with some differences in antagonists defenses. Nizatidine. side effects. These products are Omeprazole, comparable in effective- Proton pump Blocks the final step in acid Lansoprazole, ness with some inhibitors production. Pantoprazole, differences in drug-drug Rabeprazole. interactions.

Table-3.2: Regimens Used in the Eradication of H. Pylori Regimens Dosing Duration 1 Eradication Metronidazole 500 mg twice daily with meals 1 - 2 weeks 87% to > 91% Omeprazole 20 mg twice daily with meals Clarithromycin 500 mg twice daily with meals Amoxicillin 1 gram twice daily with meals 1 - 2 weeks 77% to 83% Omeprazole 20 mg twice daily with meals Clarithromycin 500 mg twice daily with meals

1 Extending therapy to 10-14 days in the above regimens may provide additional benefit. H2 blockers may be used with two antibiotics, but a longer treatment course (10-14 days), higher antibiotic doses and 3 times daily administration are required. Reference: Drug Facts and Comparisons, 2000; A-10,11.

1) Mg/Al Salt WHO,P disease, and they should stop these habits if possible to avoid such problems. • DRUG SUMMARY: *Warn patient of possible drug interactions. Many commercially available antacid (Refer to drug interactions). products contain a combination of • USE IN SPECIAL CASES: aluminium (Al) and magnesium (Mg) salts, Pregnancy- This type of antacid are generally hydroxide, trisilicate. Because constipation considered safe during pregnancy as long as from Al and diarrhea from Mg are dose chronic high doses are avoided. It is better to related, combining these two agents allow avoid use unless clearly needed. for a potent neutralizing capacity with Lactation- Safe if using in small dose, for a lower doses of each agent. The constipating very short period of time. Avoid use chronically, the cations are secreted in breast effect of Al should balance the diarrheal milk, and can cause side effects in the effect of Mg, and vice versa. These agents neonate such as hypermagnesemia. do not cause alkalosis or rebound Children- Such products are not intended for hyperacidity as NaHCO3. children < 6 yrs. old. • INDICATIONS: Renal Disease- Patient with renal disease are Hyperacidity; symptomatic relief of susceptible to toxicity of antacid (especially stomach upset, dyspepsia, heartburn, acid products containing Mg and Al) due to indigestion, GERD, and hyperacidity decreased clearance. Use caution, and reduce associated with peptic ulcer. doses. Avoid chronic use of such product. • CONTRAINDICATIONS: Liver Disease- Use caution. Known sensitivity to any of the • PRECAUTIONS AND WARNINGS: components of the products. -Prolonged use or aluminium-containing • DOSAGE FORMS: antacid may result in hypophosphatemia, Tablets, suspension. especially in patients with inadequate • RECOMMENDED DOSAGE: phosphate intake. Severe forms of this can Adult: For Indigestion and Heart Burn; lead to anorexia, malaise, muscle weakness, 1 or 2 tabs or 1 or 2 tbsp. when needed. and osteomalacia. For Ulcers; • ADVERSE EFFECTS: Take 1-2 tabs or 1-2 tbsp., one hour a.c. and Diarrhea (usually due to Al) or constipation at h.s. (due to Mg) may occur. Child: Use is not recommended. • INTERACTIONS: Directions: Antacids should be taken 1 h. Patient should space doses of antacids at after meals when needed, which will give a least 2 hrs apart from interacting drugs. duration of action for up to 3 hrs. Summary of Mg-Al Combination *If using the suspension, shake bottle well Drug Interactions before use. DRUG Effect DRUG Effect *Chewable tablets should be chewed well, Benzodiazepines ↓ Ketconazole ↓ and followed by a full glass of water. Captopril ↓ Levodopa ↑ *Advise patient to contact physician if relief Corticosteroids ↓ Phenothiazines ↓ of heartburn or indigestion is not obtained, Digoxin ↓ Quinidine ↑ or if any sign of bleeding such as black tarry Fluoroquinolones ↓ Salicylates ↓ stool or/and “coffee ground” vomitus occur. H2-antagonist ↓ Sulfonylureas ↑ This could be an indication of a serious Hydantoins ↓ Tetracyclines ↓ problem or GI bleed. Iron salts ↓ Valproic acid ↑ *Warn patient that smoking and alcohol ↓ Pharmacological effect decreased by antacid may increase their risk of peptic ulcer ↑ Pharmacological effect increased by antacid

56 Gastrointestinal Drugs

• OVERDOSE: *Patients should not use OTC remedies for No intentional overdose with antacids has gastric distress or pain without physician’s been reported. If a child took an overdose advice (e.g. antacids reduce ranitidine of antacid, take immediately to the absorption). If antacid is required in emergency room for supportive care. Do addition, administer the antacid 2 hrs. not induce vomiting at home. before or after ranitidine intake. • BRANDS: *Symptoms are usually relieved within 1 Maalox (Rorer), Magnagel (JePharm), Simigel week. Most patients have healed ulcers by (BPC), Stomagel (JCL). 4 weeks, however; if healing cannot be ______confirmed, treatment may be continued for up to 8 weeks. Advise patient to complete 2) Ranitidine WHO,P course of therapy as needed. *Smoking has been shown to decrease • DRUG SUMMARY: ranitidine efficacy and adversely affects An H2-receptor antagonist; antisecretory, ulcer healing. Urge patient to stop smoking. GI agent. It is a potent antiulcer drug that This is more important in preventing ulcer competitively and reversibly inhibits recurrence than the medication. • histamine action at the H2-receptor sites on USE IN SPECIAL CASES: parietal cells, thus reducing acid secretion. Pregnancy- Administer only when clearly Ranitidine has no analgesic effect, and needed and potential benefit outweighs should not be taken for relieve of potential risk. There are no well-controlled intermittent epigastric pain. studies in pregnant women (Category B). • INDICATIONS: Lactation- Ranitidine is excreted in breast milk. No reports of adverse effects Short-term treatment and maintenance documented, but use caution if need to therapy of active, benign gastric and administer to nursing mothers. duodenal ulcers. For hypersecretory Children- Not recommended. Safety and conditions (Zollinger-Ellison syndrome), and efficacy are not established. GERD. Renal Disease- May need to reduce dose. The • CONTRAINDICATIONS: drug is excreted primarily via the kidneys, Hypersensitivity to ranitidine, or other H2- and decreased creatinine clearance (CLcr) antagonists. may occur. CLcr is monitored if renal • DOSAGE FORMS: dysfunction is present. When less than 50 Tablets. ml/min, can reduce dose to 150 mg gradually • RECOMMENDED DOSAGE: to once every 24 hours. Adult: For Duodenal, Gastric Ulcers Liver Disease- Caution, the drug is and GERD: metabolized by the liver. 150 mg PO b.i.d. or 300 mg PO h.s. • PRECAUTIONS AND WARNINGS: Maintenance Therapy: -Symptomatic response to ranitidine 150 mg PO h.s. therapy does not preclude the presence of Zollinger-Ellison syndrome: gastric malignancy. 150 mg PO t.i.d. Doses up to 6 g daily in -Use caution in patients with hepatic and divided doses have been used. renal diseases. Child: Use is not recommended. • ADVERSE EFFECTS: Directions: Headache, malaise, dizziness, insomnia, *Food does not reduce oral ranitidine agitation, depression (mainly in the elderly) absorption or serum concentrations, so can may occur (due to penetration through the take medication without regard to food. BBB, but less than cimetidine).

Occasionally gynaecomastia has been 3) Omeprazole reported (with other H2 antagonists). Rarely constipation or diarrhea, nausea, abdominal • DRUG SUMMARY: pain, rash, thrombocytopenia, and Omeprazole is a substituted benzimidazole, hepatotoxicity or anaphylaxis have which does not exhibit anticholinergic or occurred. H2-antagnostic properties. It belongs to the • INTERACTIONS: class of antisecretory compounds: a gastric *Ranitidine weakly binds to cytochrome proton pump inhibitor. It blocks the final P450 (an enzyme responsible for oxidation step in acid production. Onset of action reactions in the mitochondria), therefore occurs within 1 hour. Omeprazole, as with serious drug interactions are less than other agents in this group, is a new drug cimetidine. Raise of aminotranferase may with limited use due to its high costs and be observed. lack of sufficient long-term studies. But it

Overview of Ranitidine can prevent NSAID-associated ulcers Drug-Drug Interaction specially in very elderly patients for whom Drug Interaction NSAIDs can’t be withdrawn. • Sulfonyl- H2-antagonists in general INDICATIONS: ureas- inhibit sulfonylurea hepatic Short-term use (4-8 weeks) for gastro- (glipizide) metabolism causing accum- esophageal reflux disease, gastric and ulation of sulfonylureas active duodenal ulcers, and erosive resulting in hypoglycemia but esophagitis. Used if there is a poor response this is mainly seen in to H -receptor antagonists in treating cimetidine. Ranitidine has 2 been reported to increase the GERD. Long-term use should be limited to hypoglycemic effect of conditions such as Zollinger-Ellison (ZE) glipizide. Monitor blood syndrome, multiple endocrine adenomas, glucose and adjust dosage of and systemic astocytosis. It is indicated sulfonylurea as necessary. with amoxycillin or clarithromycin to Warfarin Ranitidine may interfere with eradicates H. pylori (refer to introduction). warfarin clearance, increasing • CONTRAINDICATIONS: its effects. Do not administer Hypersensitivity to the drug. concomitantly. • DOSAGE FORMS: • OVERDOSE: Capsules. Symptoms: There is no experience with • RECOMMENDED DOSAGE: deliberate over-dose. In animals, toxic Adult: Duodenal ulcer & GERD (GERD doses caused rapid respiration, tachycardia, if poorly responsive to H2 antagonists): 20 muscle tremor, vomiting pallor of mucous mg PO q.d. for 4-8 wks. membranes or redness, miosis and diarrhea. Gastric ulcer: 40 mg q.d. for 4-8 wks. Treatment: Induce emesis and employ Hypersecretory conditions: the dose supportive therapy. should be individualized. Initial dose is 60 • BRANDS: mg/d. Doses up to 120 mg t.i.d. have been GI-Care (Pharmacare), Randin (JePharm), administered. Daily doses > 80 mg should Ratidine (BPC), Zantab (Teva), Zantac (Glaxo be divided. Some patients with Zollinger- Wellcome). Ellison syndrome have been treated ______continuously for > 5 yrs. Directions: Take one capsule before eating. Antacids may be used concomitantly.

58 Gastrointestinal Drugs

*Do not open, crush, or chew capsule. Take • INTERACTIONS: as whole with full glass of water. Overview of Omeprazole • USE IN SPECIAL CASES: Drug-Drug Interaction Pregnancy- Avoid use. Omeprazole passes Drug Interaction the blood-placenta barrier. In animal Diazepam, Increased plasma concen- studies, toxicity to the fetus has been noted. Phenytoin trations of these drugs when and used concomitantly with Use only when benefit justifies the risk to Warfarin omeprazole have been noted, the fetus (Category C). avoid administering any of Lactation- Avoid use. It is not known if these medications with omeprazole is excreted in breast milk. omeprazole. Lactating women should discontinue Drugs Omeprazole may interfere lactation prior to taking this drug. where with absorption of drugs Children- Avoid use. Safety and efficacy in gastric pH where gastric pH is important, children has not been established. is important because of its profound and Renal Disease- Use caution, even though no long lasting inhibition of dosage adjustment is necessary. 80% of drug gastric acid secretion (i.e. is excreted in urine. ketoconazole, ampicillin Liver Disease- The drug is metabolized in the esters, iron salts).

liver. In liver diseases, not more that 20 mg Propranolol or Theophylline: No reports of daily should be administered. interactions with these drugs. • PRECAUTIONS AND WARNINGS: • OVERDOSE: -Symptomatic response to therapy with Reports have been rare. omeprazole does not preclude gastric Symptoms: Confusion, drowsiness, blurred malignancy. vision, tachycardia, headache, dry mouth, -The safety and efficacy for treatment in and flushing. humans for more than 8 weeks is not Treatment: No specific antidote is known. established. Carcinogenesis; it has been Can administer syrup of ipecac to induce noted in animal studies that there is a vomiting before reaching the hospital. higher (increase of) incidence with long- Treatment should be symptomatic and term use (more than 2 years). supportive. Since omeprazole is extensively • ADVERSE EFFECTS: protein bound, it is not readily dialyzable. Omeprazole is generally well tolerated. • BRANDS: Most common side effects include Losec (Abic), Locid (JePharm), Mepral (BCP), headache, dizziness, fatigue, diarrhea, Prelosec (Astra Merk). abdominal pain, nausea, and rash. ______Erythema, fever, chest pain, pancreatitis, acute inerstitial nephritis, glucosuria, B) ANTISPASMODICS/ anemia, thrombocytopenia, hypoglycemia, ANTICHOLINERGICS bronchospasm, as well as testicular pain have been noted. Anticholinergic agents (agents that decrease/antagonize/prevent the effect of the neurotransmitter acetylcholine), also known as antimuscarinic drugs (i.e. atropine/hyoscyamine, scopolamine/ hyoscine, belladonna alkaloids, tridihexethyl, dicyclomine . . . etc.). These agents are used primarily as antispasmodics by decreasing smooth muscles tone

(motility) in the GI, biliary and urinary Children- Do not use in children less than 6 tracts. These antimuscarinc/antispasmodic years old. drugs may be useful as adjunctive treatment Renal Disease- Use with caution, drug is in non-ulcer dyspepsia, in the irritable excreted in urine, bile and feces unchanged. bowel syndrome, and in diverticular Liver Disease- Use with caution, drug disease. metabolized in the liver. • PRECAUTIONS AND WARNINGS: 1) Hyocine N-butyl Bromide P -Use in geriatrics: The elderly may respond to usual doses of the drug with excitement, • DRUG SUMMARY: agitation, drowsiness, or confusion. They A quaternary ammonium compound, are more susceptible to the antimuscarinic classified as an antimuscarinic/ anti- side effects. Also there is more incidence of cholinergic, antispasmodic agent. It is a glaucoma as well, so need to use caution more powerful suppressant of salivation when using this agent. than atropine, and usually slows rather than -Use caution in urinary retention, prostatic increases heart rate, especially in low enlargement, cardiac insufficiency, liver or doses. kidney dysfunction. • • INDICATIONS: ADVERSE EFFECTS: Antispasmodic for GIT and UT disorders Confusion, blurred vision, (avoid perform- characterized by smooth muscle spasm. ing hazardous activities until full effect of Also, can be used for motion sickness and the medication is known); depression, dysmenorrhea. psychotic reactions, constipation (patient should increase fluid intake), abdominal • CONTRAINDICATIONS: distension, urinary retention, dry skin, fever Hypersensitivity to the drug, narrow-angle (specially children), dry mouth, difficulty in glaucoma, prostatic hypertrophy, swallowing, palpitation, bradycardia. obstructive disease of the GI (i.e. paralytic • illues, severe ulcerative colitis, pyloric INTERACTIONS: obstruction), tachycardia, or myasthenia Overview of Hyocine N-butyl Bromide Drug-Drug Interaction gravis. • Drug Interaction DOSAGE FORMS: Alcohol and These have additive sedative Tablets, injection. other CNS effects if used with • RECOMMENDED DOSAGE: depressants antispasmodics. Caution use. Adult: Orally: 20 mg 4 times daily. Antacids These will decrease absorp- IM or IV (acute spasm): 20 mg, repeated tion from the GI tract; allow after 30 min. if necessary 2 h interval between the two Child (6-12 y): 10 mg PO t.i.d. medications. Anti- Concurrent use results in Directions: Taken 30 to 60 min. a.c. histamines, additive anticholinergic side • USE IN SPECIAL CASES: Anti- effects. Avoid concurrent Pregnancy- Avoid use. Safety for use has not cholinergics, administration. been established (Category C). Parenteral Pheno- administration before onset of labor has thiazine, caused CNS depression and hemorrhage in and TCAs the neonate. Digoxin Increased digoxin level and Lactation- Better to avoid in nursing mothers toxicity have been noted. Do as it is excreted in breast milk. Risk-benefit not administer together. decisions must be considered. • OVERDOSE: Symptoms are exaggerated adverse effects.

60 Gastrointestinal Drugs

Treatment includes inducing emesis or If nausea and/or vomiting continue performing gastric lavage. May administer despite such measures or are severe, then activated charcoal after emesis. Use an antihistamine like meclizine can be supportive and symptomatic therapy as prescribed. If symptoms have not settled in needed in hospital setting. 24 to 48 hours, then a specialist’s opinion • BRANDS: should be sought. Scobutyl (JePharm), Scopal (BPC). ______1) Metoclopramide WHO,P

C) ANTIEMETICS • DRUG SUMMARY: Metoclopramide (MTP) is a potent central Vomiting (emesis) is an important defense dopamine receptor antagonist, classified as mechanism by which the body attempts to an autonomic nervous system agent; direct- get rid of a variety of toxins and poisons. acting cholinergic, antiemetic and GI agent. Travelling (motion sickness) or pregnancy Exact mechanism of action is not clear. It can also cause vomiting. has a spectrum of activity similar to Antiemetics are useful in limited phenothiazines, but has less peripheral situations, but should always be used with action on the gut in addition to its central caution because of the potential danger of effect. Therefore, it may be superior to the masking the symptoms of more severe phenothiazines in the emesis associated disease; i.e. acute viral gastroenteritis, head with gastroduodenal, hepatic and biliary trauma, toxic ingestion, CNS infection, and disease. It does not stimulate gastric, or GI obstruction, specially in children. They pancreatic secretions. are also harmful in cases such as diabetic • INDICATIONS: ketoacidosis, or in excessive digoxin or Management of diabetic gastric stasis antiepileptic dosage. (gastroparesis), to prevent nausea and Therapy should start by identifying and vomiting due to different etiologies; removing the cause if possible, replacing mainly in cancer chemotherapy, and in fluids and electrolytes, counseling if there gastro-esophageal reflux, short term (4-12 is a problem like bulimia, then starting drug weeks). therapy. Some medications that can be used include: prochlorperazine and haloperidol [For patients under 20 years; use is in severe cases, lorazepam to relieve restricted to severe intractable vomiting of known cause, vomiting after radiotherapy anxiety related nausea and vomiting, and cytotoxics, and aid to gastrointestinal antihistamines like promethazine and intubation, pre-medication: BNF, 2001]. meclizine, and metoclopramide. The choice • CONTRAINDICATIONS: of which medication to use depends on the Sensitivity or intolerance to MTP, allergy cause and the patient's health. to sulfiting agents, history of seizure Nausea and vomiting in pregnancy are disorders (epilepsy), concurrent use of common in the first trimester. It is drugs that can cause extrapyramidal recommended to use non-pharmacological symptoms, mechanical GI obstruction or approaches to the pregnant women before perforation, history of breast cancer; pheo- starting any medication. Eating small, chromocytoma to avoid hypertensive crisis. frequent meals, lower the fat content of • DOSAGE FORMS: meals, ingesting crackers before arising in Tablets, syrup. the morning, lying down, can all help to alleviate symptoms.

• RECOMMENDED DOSAGE: extrapyramidal symptoms (especially in Adult: 10-15 mg PO q.i.d.; a.c. and h.s. children/young adults), hypotension, Young adult (15-19 yrs under 60 kg): nausea, diarrhea, sometimes constipation, 10 mg PO t.i.d., a.c. dry mouth, galactorrhea, amenorrhea, Child (6-14 y): 2.5-5 mg PO t.i.d., a.c.; impotence, methemoglobinemia, and max. dose for young adult and children 500 altered drug absorption have been reported. ug/kg/d. • INTERACTIONS: Directions: Take medication 30 min. a.c. Overview of Metoclopramide *Need to report any involuntary Drug-Drug Interaction movement of eyes, face or limbs. Might Drug Interaction need to discontinue MTP therapy. Alcohol Alcohol rate of absorption is • USE IN SPECIAL CASES: increased by MTP, increasing Pregnancy- Use only when clearly needed side effects. Discourage patient from alcohol intake. and benefit outweighs potential risk. MTP crosses the placenta, however there are no Analgesics, These may antagonize effect and of MTP on GI motility, and adequate studies in pregnant woman anti- enhance effect of aspirin and (Category B), and reports on safety are cholinergics paracetamol. conflicting. Cyclosporine An increase in the immuno- Lactation- Exercise caution. MTP is excreted suppressive and toxic effects into breast milk. There appears to be no may result. Avoid use of serious risk to the nursing infant, but side MTP. effects may include intestinal discomfort and Digoxin Plasma levels of digoxin may possible CNS effects. be decreased, decreasing its Children- Use caution, due to increased risk therapeutic effect. Monitor in children and young adults of extra- patients, the dose of digoxin pyramidal side effects (involuntary may need to be increased. movements of limbs or facial muscles). Limit Pheno- Extrapyramidal symptoms use to severe or persistent vomiting of known thiazines may occur. Do not administer etiology. concurrently. Renal Disease- Reduce dose, and use with • caution. MTP is excreted in urine mainly. OVERDOSE: Liver Disease- Use with caution. The drug is Symptoms: drowsiness, disorientation, and minimally metabolized in the liver. extrapyramidal reactions which are self • PRECAUTIONS AND WARNINGS: limiting and usually disappear within 24 h. -Depression has occurred in patients with Muscle hypertonia, irritability and agitation and without prior history of depression. Use are common. only if the expected benefits outweigh the Treatment: an anticholinergic or anti- potential risks. parkinson drug to help control -Carcinogenesis evidence has not been extrapyramidal reaction. Refer to hospital conclusive with MTP use. Elevated for management. prolactin levels persist during therapy, and • BRANDS: approximately 1/3 of human breast cancers Emestop (BPC), Novomit (JePharm), Pramin are prolactin-dependent. Evaluate patient (Rekah), Reglan (Robins). history carefully before prescribing. ______• ADVERSE EFFECTS: These are usually mild, transient and reversible upon drug withdrawal. Sedation, fatigue, restlessness, agitation, insomnia,

62 Gastrointestinal Drugs

2) Meclozine/Meclizine recommended for use in children < 12 years (Drug Facts & Comparisons, 2000). • DRUG SUMMARY: Renal + Liver Disease- Use with caution. A long-acting piperazine antihistamine. Safety has not been established. • PRECAUTIONS AND WARNINGS: Classified as a H1-receptor antagonist, GI agent, antihistamine and antiemetic agent. -Due to possible anticholinergic effects, use • INDICATIONS: caution in patients with glaucoma, Prevention and treatment of nausea, obstructive disease of the GI or GU, and in vomiting and dizziness (also in pregnancy) elderly males with possible prostatic and/or motion sickness. Can also be used hypertrophy. • for the management of vertigo associated ADVERSE EFFECTS: with diseases affecting the vestibular Drowsiness, dry mouth, blurred vision, and system. fatigue. (Warn patient against performing • CONTRAINDICATIONS: hazardous activities like driving or Hypersensitivity to the medication. operating machinery until the full effect of • DOSAGE FORMS: the medication is known.) • Tablets. INTERACTIONS: • RECOMMENDED DOSAGE: Alcohol and other CNS depressants will Adult: For Motion Sickness; enhance side effects. Avoid concomitant 25-50 mg PO 1 h. before travel, may repeat use. • q. 24 h. if necessary for duration of journey. OVERDOSE: For Vertigo Problems; Symptoms: Moderate overdose may cause 25-100 mg/d in divided doses (b.i.d.). hyperexcitability alternating with drowsi- Child: Not recommended for children ness. Massive overdose may cause under 12 years. convulsions, hallucinations and respiratory paralysis. Directions: Meclizine can be given without Treatment: Inducing emesis, and regard to meals. Onset of action takes 1 h., performing gastric lavage. Take to hospital, while duration is for 12-24 h. do not use morphine or other respiratory *Pyridoxine (vitamin B6) has been shown depressants. to be effective in treatment of nausea and • BRANDS: vomiting associated with pregnancy. So Ancozine (BPC), Antivert (Roerig), Bonine you might find it in some formulations as a (Leeming), Paravomine (JCL). combination with meclizine. ______• USE IN SPECIAL CASES: Pregnancy- Use only when clearly needed. Meclizine presents the lowest risk of D) DRUGS USED IN DIARRHEA teratogenicity, and is the drug of choice in treating nausea and vomiting during Diarrhea is a symptom that is characterized pregnancy (Category B). Large-scale human by an increased frequency or consistency of studies have not demonstrated teratogenic stools during a limited time period. effects. Epidemiological studies define it as the Lactation- Safety for use in nursing mothers has not been established. There is no passage of three or more loose or watery available data. stools in a 24 hour period, a loose stool Children- Safety and efficacy for use in being that would take the shape of a children have not been established. Not container. Variability in the causes of diarrhea makes identification of the pathophysiologic mechanism difficult. The

etiology may be psychogenic, neurogenic, seeds. Need to advise patient to monitor surgical, endocrine, irritant, dietary, allergic, the cause, and to avoid. Lactose deficiency malabsortpive, infectious or inflammatory. in infants or adults who develop intolerance Simple and effective treatment measures to whole milk or milk-based products, can are available that can markedly reduce the reduce/ eliminate their problem by intake of number of deaths caused by diarrhea, make lactase enzyme. admission to the hospital unnecessary in 4. Viral diarrhea is a common problem most cases and prevent the adverse effects in infants and young children. Children of diarrhea on nutritional status. Practical aged 6-24 months are most susceptible to preventive measures can also be taken that viral gastro-enteritis. Respiratory illness substantially reduce the incidence and such as otitis media or tonsillitis may occur severity of diarrheal episodes. concurrently. It is important to know that passing During the 12-24 hour incubation period several loose stools daily or with every vomiting, watery diarrhea and low-grade feeding in breast-fed infants is normal fever may occur. The illness tends to be provided that the infant is steadily gaining self-limiting, lasting 5-8 days, and weight. Mothers should be reassured that treatment should be restricted to the infant doesn’t need treatment, and symptomatic therapy, mainly to prevent should continue breast-feeding. dehydration complications. 5. Protozoal diarrhea, table-3.4 summa- Causes of Diarrhea: rizes the main protazoal organisms. 1. Food-borne diarrhea: Table-3.3 sum- Effective therapy consists of metronidazole, marizes the most common pathogenic after the confirmation of the causing agent bacteria. Infectious diarrhea may be treated by stool analysis. with fluid and electrolytes, since it is self- 6. Drug-induced diarrhea can occur limiting. Only in certain cases initiation of with administration of medication. antimicrobial therapy may be necessary; Commonly prescribed antibiotics that have i.e. doxycycline, trimethoprim/ sulfa- a broad spectrum of activity; i.e. ampicillin, methoxazole, or a fluoroquinolone. clindamycin, erythromycin, tetracycline, 2. Remember that antimicrobial drugs and fluoroquinolones can produce diarrhea are not indicated for the routine treatment as a side effect. Other drugs that may cause of acute diarrhea. Their indiscriminate use diarrhea and cramping include; stimulant must be discouraged, not only because they cathartics, anticancer agents, colchicine, are often of no therapeutic value, but also antacid containing magnesium, methyldopa they are needlessly expensive and can be and metoclopramide. If diarrhea does not harmful. subside within few days of starting any 3. Food intolerance: It may be caused medication, reduction of the dose might be by a food allergy, or by ingestion of foods necessary. that are excessively fatty or spicy that contain high amount of roughage or many

64 Gastrointestinal Drugs

Table- 3.3: Summary of the Most Common Pathogenic Bacteria # Type History Symptoms Treatment Prognosis Salmonella spp. Ingestion of Onset of 24-28 h, Fluid and electrolytes; Self- improperly cooked or diarrhea, fever, no antibiotics needed limiting refrigerated poultry and chills products, immunocompromised host. Shigella spp. Ingestion of Onset of 24-48 h, Fluid and electrolytes; Self- contaminated nausea, vomiting, antibiotics limiting vegetables or water, diarrhea (cotrimoxazole, immunocompromised ampicillin, host. ciprofloxacin) Enterotoxigenic Ingestion of Onset of 8-72 h, Fluid and electrolytes; Self- Escberichea contaminated food or watery diarrhea, in moderate or severe limiting coli (Travelers’ water, recent travel fever, abdominal cases, antibiotics; diarrhea) outside the country. cramps (fluoroquinolones) Campylobacter Ingestion of Nausea, Fluid and electrolytes; Self- jejuni contaminated water, vomiting, in severe or persistent limiting fecal-oral route, headache, diarrhea, antibiotics immunocompromised malaise, fever, (erythromycin, host. watery diarrhea fluoroquinolones) Clostridium Antibiotic-associated Watery or Water and electrolytes; Good, if difficile diarrhea. mucoid diarrhea, discontinuation of treated high fever, offending agent; oral cramping vancomycin, oral metronidazole, bacitracin, cholestyramine Staphylococcus Ingestion of Nausea, vomiting, Fluid and electrolyte; Self- aureus improperly cooked or watery diarrhea no antibiotics limiting stored food. # Handbook of Nonprescription Drugs, 10th ed., 1993: p. 204-5.

Table-3.4: Summary of Protozoa Organisms that Cause Diarrhoea # Type History Symptoms Treatment Prognosis Ingestion of water Chronic watery Metronidazole, Good, if treated Giardia contaminated with diarrhea, abdominal furazolidone human or animal distension lamblia feces, immunocompromised host Contaminated water, Chronic watery Fluid and Self-limiting, AIDS, diarrhea electrolytes except in AIDS Cryptosporidia immunocomp- or other romised host immunocompromised patients Fecal soiled food or Chronic watery Fluid and Need stool water, diarrhea, blood electrolytes; culture to Entamoeba immunocomp- mucous, abdominal metronidazole; confirm. Good, histolytica romised host cramps, maybe fever iodoquinol except for immunocompromised patients # Handbook of Nonprescription Drugs, 10th ed., 1993: p. 204-5.

1) Oral Rehydrating Salts WHO,P • DOSAGE FORMS: (ORS) Packages to be dissolved in certain amount of water as directed. • • DRUG SUMMARY: RECOMMENDED DOSAGE: Oral Rehydrating Salt (ORS) solutions are Mild/Moderate Diarrhea (not more than the first line treatment in acute diarrhea, one stool q. 2 h. or longer): especially in infants and in frail/elderly 100 ml/kg body weight per day until patients. They are a simple and effective diarrhea stops. way to markedly reduce the number of Severe Diarrhea (more than one stool deaths caused by diarrhea. ORS are q. 2 h.): 10-15 ml/kg body weight per hour, until diarrhea stops. balanced mixtures of glucose and electrolytes. Intestinal absorption of sodium Directions: Need to dissolve package in and water is enhanced by glucose, to required amount of water. Do not add sugar replace what has been lost through diarrhea, or boil after mixing. The prepared solution and restore acid-base balance. should be discarded after 24 hours, and The WHO criteria for an oral replacement replaced with a fresh one to avoid spoilage. fluid contains (per liter) *Drink slowly, small amount initially *Total substance concentration (including especially if vomiting is present. that contributed by glucose) should be *Administering fluid without electrolytes is within the range of 200-310 mmol/l. potentially dangerous because of the risk of * The individual substance concentration: inducing hyponatremia. - Glucose - should at least equal that of Na • USE IN SPECIAL CASES: but should not exceed 111 mmol/l Pregnancy- Use caution, might need to refer - Sodium - should be within the range of to hospital for monitoring. 60-90 mEq/l Lactation- Safe if taken for short period of - Potassium - should be within the range time as directed. of 15-25 mEq/l Children- Safe when used according to - Citrate - should be within the range of directions and under supervision as indicated 8-12 mmol/l for use. - Chloride - should be within the range of Renal Disease- Warning. Special care is 50-80 mEq/l. needed during usage because electrolyte or fluid imbalances might be aggravated if No commercial product currently available kidney is malfunctioning. strictly fulfils WHO recommendation. Still, Liver Disease- Use with caution. available products are more convenient and • PRECAUTIONS AND WARNINGS: seem to be potentially safer because they -Severe continuing diarrhea or other critical are premixed and there is less chance of fluid loss such as intractable vomiting, error in preparation. prolonged shock, should be referred to • INDICATIONS: hospital, and will require parenteral To prevent dehydration in cases of electro- therapy. lyte and water depletion as in diarrhea or -Use caution in patients with diabetes, vomiting. Severe cases need hospitalization cardiac failure, hypertension (specially and require parenteral therapy. patients on low sodium diet), impaired • CONTRAINDICATIONS: renal function and in peripheral or None; see warnings. pulmonary edema. Such solutions will aggravate their condition.

66 Gastrointestinal Drugs

• ADVERSE EFFECTS: acute diarrhea caused by broad spectrum Dizziness, nausea, or skin rash may occur. antibiotics or associated with micro- Vomiting may occur if the solution is given organisms, body temperature > 38.3 °C, too rapidly or forcefully to the infant. and bloody diarrhea, in children < 4 years. • INTERACTIONS: • DOSAGE FORMS: Electrolytes affect a lot of medications Capsules, drops. when given concomitantly. It is advisable • RECOMMENDED DOSAGE: not to take any medication the same time as Adult: For Acute Diarrhea; the preparation, unless clearly needed and 4 mg followed by 2 mg after each loose under direct supervision of doctor. stool, for not more than 5 days, • OVERDOSE: usual dose 6-8 mg/d, max. 16 mg daily. Serious electrolyte disturbances will occur For Chronic Diarrhea; if there is an ingestion of large amount of 4 mg PO followed by 2 mg after each loose preparation; due to the electrolytes (Na & stool until diarrhea is controlled. Continue K) included. Cardiac and respiratory administration if diarrhea cannot be functions could be serious. Refer to hospital controlled with diet or specific treatment. for symptomatic and supportive care. Child: Do not use for children < 4 y old. • BRANDS: If oral rehydration solutions fail, can Electrosubs (BPC), Hydran 60 (Teva), Orset administer 0.1 mg/kg after each loose stool, L.S. (Ciba), ORS (UNICEF), Rehidrat (Searle). usually 1 mg for acute diarrhea, for not ______more than 2 days. Directions: Loperamide is administered 2) Antidiarrheal Agent - after each unformed stool, up to a Loperamide P maximum of 16 mg/d for adults. *Include appropriate fluid and electrolyte

therapy to prevent dehydration and further • DRUG SUMMARY: complications. Advise patient to drink Loperamide is a synthetic piperidine plenty of fluids. derivative, chemically related to *In acute diarrhea, loperamide should be diphenoxylate and to meperidine, but discontinued if there is no improvement possesses a more favorable side effects after 48 hrs. of therapy. profile than the opiate and opiate-like *The doctor should be notified if agents. Classified as a GI, antidiarrheal abdominal pain or distention, or fever agent. It slows intestinal motility and occurs. Discontinuation of the medication affects water and electrolyte movement may be needed. through the bowel. It inhibits peristalsis, • USE IN SPECIAL CASES: prolongs transit time of intestinal contents, Pregnancy- Avoid use of Loperamide. No increases consistency of stools, and reduces available well controlled studies on pregnant fluid and electrolyte loss. Tolerance to the women. Safety has not been established antidiarrheal effect has not been observed. (Category B). • INDICATIONS: Lactation- It is not known if loperamide is Acute non-specific diarrhea, chronic excreted in breast milk. Safety has not been diarrhea associated with inflammatory established. bowel disease, and to reduce fecal volume Children- Not to be used in children < 4 yrs. from ileostomies. Use special care if you have to use for young • CONTRAINDICATIONS: children (6-12 yrs). Rehydration is usually Hypersensitivity to the drug, in patients sufficient. who must avoid constipation, severe colitis,

Renal Disease- The drug is primarily excreted E) LAXATIVES in feces. Small amounts are excreted by the kidneys, thus use caution. Constipation is generally defined as a Liver Disease- Warning. Patients with hepatic decrease in the frequency of fecal dysfunction have reported increased CNS elimination and is characterized by the toxicity because of large first-pass bio- difficult passage of hard, dry stools. (In transformation. Avoid use unless clearly other words incomplete evacuation or needed. • feeling of it.) It usually results from the PRECAUTIONS AND WARNINGS: abnormally slow movement of feces -Antiperistaltic agents should not be used in through the colon with a resultant acute diarrhea associated with organisms accumulation in the descending colon, and that penetrate the intestinal mucus (tissue increased water resorption. In elderly invasive); entroinvasive E-coli, salmonella, persons, constipation occurs due to or shigella; or in pseudomembranous colitis inappropriate diet, lack of exercise, associated with broad-spectrum antibiotics. medication use, or lack of muscle tone in -If clinical improvement of acute diarrhea the colon. Constipation in pregnancy is also is not observed in 48 hours, or abdominal common, due to increasing size of uterus, distension occurs, discontinue the or intake of mineral supplements that medication. Recommended dosage should contain iron and calcium that tend to be not be exceeded. constipating. • ADVERSE EFFECTS: Patients should be counseled about non- Adverse experiences are generally minor pharmacological methods before a drug is and self-limiting. Drowsiness, fatigue prescribed; proper diet, adequate fluid dizziness are reported, therefore; need to intake (6-8 glasses/day) and reasonable caution patient while driving or performing exercise to alleviate or prevent this hazardous jobs. Abdominal discomfort or problem. If the patient is still constipated, pain, bloating, constipation, nausea, and the constipation is not secondary to an anorexia, dry mouth can also occur; patient underlying undiagnosed complaint, a should drink plenty of fluids to help prevent laxative may be used. The laxative dehydration. May cause skin rash. In severe facilitates the passage and the elimination cases toxic megacolon (mainly in patients of feces from the colon and rectum. In with ulcerative colitis) may occur. children, the introduction of fruit and • INTERACTIONS: vegetable puree into the diet may be No major drug-drug interactions reported. sufficient to regulate bowel action. • OVERDOSE: Persistent constipation should be fully Symptoms: usually include constipation, investigated. CNS depression and GI irritation. Nausea Abuse of laxatives may lead to and vomiting may occur. hypokalemia and an atonic non-functioning Treatment: activated charcoal administered colon. It is important to recognize that the promptly after ingestion can reduce amount improved mobility and the provision of of drug absorbed into systemic circulation. time and privacy for going to the toilet may Take to hospital for supportive, be all that is required. symptomatic management. Laxatives are classified into different • BRANDS: categories. Table-3.5 indicates the Diacare (Pharmacare), Imodium (Janssen), properties of each type: Lipastop (Eastern Chem.), Loperid (Vitamid), Stopit (Rafa). ______

68 Gastrointestinal Drugs

1 Table-3.5: Classification and Properties of Laxatives Onset of Site of Systemic Laxatives Use in Pregnancy Action (hrs) Action Absorption Magnesium citrate 0.5 - 3 Small & large Avoid, possible Magnesium-OH intestine Yes 3 dangerous Magnesium SO4 2-4

Saline electrolyte ------imbalances. Na-biphosphate 0.03 - 0.25 2 Colon Cascara Senna Phenolphthalein 6 - 10 Colon Yes Avoid, unless under Biscodyl tabs. direct M.D. ------supervision. Biscodyl supp. 0.25 - 1 ------Irritant/stimulant Castor oil 2 - 6 Small Yes Avoid, premature intestines labor.

Bran 12-24 Small & large No Safe Methylcellulose (up to 72) intestine Polycarbophil Psyllium Bulk-forming

Yes, Do not use for long Mineral oil 6 - 8 Colon minimal time, loss of vitamin (Liquid parafin) amount absorption. Lubricant OK. Small & large Docusate 24 - 72 Yes Best in anorectal intestine painful-conditions. Surfactant Surfactant Glycerin supp. 0.25 - 0.5 ? ------Colon Caution use.

Misc. Lactulose 24 - 48 È amount

-1 Reference: Drug Facts and Comparisons. 2000, p. 1166. -2 2-15 minutes. 3 - Magnesium sulphate (Epsom salt) is available in packs. Dissolve in water and use before breakfast. -Stimulant laxatives should not be used regularly. If obstruction is suspected, do not use laxative.

1) Bisacodyl P • USE IN SPECIAL CASES: Pregnancy- Avoid use (Category C). Bulk • DRUG SUMMARY: forming or surfactant laxatives are a better A stimulant laxative, GI agent. Induces choice. peristaltic contractions by direct stimulation Lactation- Better to avoid. Excreted in small of sensory nerve endings in the colonic amounts in breast milk. walls. It also expands intraluminal fluid Children- Avoid use in children < 6 years old. Safety has not been established. Other volume by increasing epithelial agents may be safer for use. permeability. Renal Disease- Use with caution. Drug is • INDICATIONS: excreted in urine. Temporary relief of acute constipation and Liver Disease- Use with caution. Drug is for evacuation of colon before surgery, or metabolized in the liver. radiological examinations. Also used to • PRECAUTIONS AND WARNINGS: empty colon before delivery and to relieve -Abuse/dependency; chronic use of constipation in patients with spinal cord stimulant laxatives such as bisacodyl, may injury. lead to laxative dependence, which in turn • CONTRAINDICATIONS: may result in fluid and electrolyte Hypersensitivity to the drug. Acute surgical imbalances, osteomalacia, vitamin and abdomen, nausea, vomiting, abdominal mineral deficiencies. Use not recommended cramps, intestinal obstruction, fecal for long term ( > 1 week). impaction, ulcerative lesions of the colon. • ADVERSE EFFECTS: Use of rectal suppository in presence of Systemic effects not reported. Rarely: mild anal or rectal fissures, or ulcerated cramping, nausea, vertigo, diarrhea, fluid hemorrhoids. and electrolyte disturbances; especially • DOSAGE FORMS: potassium and calcium. Suppositories may Tablets, suppositories. cause proctitis (inflammation of rectum). • RECOMMENDED DOSAGE: • INTERACTIONS: Adult: 5-15 mg PO p.r.n. up to 30 mg for Milk and Antacids cause early dissolution special procedures. of enteric-coated tablets, resulting in 10 mg PR once daily p.r.n. abdominal cramping. Do not use within 1 h Child (6 to 12 y): 5 mg PO or PR p.r.n. of antacid intake. Directions: Administer PO drug in the • OVERDOSE: evening or before breakfast. Suppository There is no specific antidote, however, may be inserted at time bowel movement is supportive care may be required to prevent desired. dehydration or electrolyte imbalances. *Tablets are enteric coated, therefore, to • BRANDS: avoid gastric irritation, they should be Bisalax (JCL), Laxadin (Teva). swallowed whole, and not cut, crushed or ______chewed. They are preferably taken with a full glass of water or other liquid. 2) Castor Oil *Advise patient not to take medication within 1 hour of antacids or milk • DRUG SUMMARY: administration. These substances may cause Castor oil is also a stimulant laxative GI premature dissolution of the enteric coating, agent. Indicated for constipation; bowel resulting in gastric irritation. evacuation before radiological procedures, endoscopy or surgery. It is one of the

70 Gastrointestinal Drugs

widely abused laxatives, and should be • SPECIAL CASES: seldom used routinely for constipation. Pregnancy- Use with caution. Only use if It is contraindicated in abdominal pain, under medical supervision. It is safer to use intestinal obstruction, nausea or vomiting. bulk forming agents or surfactants when Should be avoided during pregnancy, since needed. it provokes premature labor. It should not Lactation- It is not known whether glycerin be used for more than one week of regular used rectally is excreted into breast milk. therapy. Chronic abuse may lead to Safety not established, since there is no “cathartic colon”, a poorly functioning available data. colon. Children- Glycerin suppositories are used in Misuse may lead to severe cramping, children and infants often to initiate enteric loss of protein, excess loss of fluid defecation. Adverse effects are minimal. • and electrolytes, and inhibition or PRECAUTIONS AND WARNINGS: absorption of fat-soluble vitamins. -Laxative use should only be used Dose ranges for adults: 15-60 ml/day. temporarily. • Children (2-12): 5-15 ml/day. ADVERSE EFFECTS: It is most effective when given on empty Abdominal cramps, rectal discomfort. • stomach, and produces evacuation within 2- INTERACTIONS: 6 hours after ingestion. It should not be No drug-drug interactions have been given at bedtime. Can be given with fruit reported. juice to mask the unpleasant taste. • BRANDS:

______Glycerol (various). ______3) Glycerin P 4) Psyllium • DRUG SUMMARY: • A GI agent; hyperosomotic laxative. It DRUG SUMMARY: produces an irritant effect, and by A bulk-forming laxative, GI agent. Usually absorbing water from tissues it creates seen as a highly refined colloid of blond more mass, therefore stimulates peristalsis. psyllium seed with equal amount of dextrose added as dispersing agent. On • INDICATIONS: To relieve constipation. contact with water, produces bland, lubricating gelatinous bulk that promotes • CONTRAINDICATIONS: peristalsis and natural elimination. Hypersensitivity to the drug. Reportedly, chronic use may reduce plasma • DOSAGE FORMS: cholesterol, possibly by interfering with Adult and pediatric suppositories. reabsorption of bile acids. • RECOMMENDED DOSAGE: • INDICATIONS: Adult: For Constipation; Orally as self-treatment of constipation. For 1 supp. when needed, inserted high into the atonic or spastic constipation and rectum. constipation associated with rectal Child: 1 supp. when needed. disorders of anorectal surgery, irritable Directions: Insert suppository high into the bowel disease and hemorrhoids. rectum and retain 15 minutes. Onset • CONTRAINDICATIONS: requires 15-30 minutes. In nausea, vomiting, undiagnosed *Store in cool place, preferably the abdominal pain, intestinal obstruction, refrigerator. appendicitis, ulceration or stenosis, and diarrhea.

• DOSAGE FORMS: • INTERACTIONS: Powder. None has been reported. • RECOMMENDED DOSAGE: • OVERDOSE: Adult: 1-2 rounded tsp. or 1 packet 1-3 No reported cases. Need supportive care to times/d. prevent obstruction or impaction. Child ( ≥ 6 y): 1 tsp. in water h.s. • BRANDS:

Directions: Need to stir dose into a full Metamucil (Searle). ______glass (240 ml) of water, fruit juice or other liquid, and drink. *Additional fluids should be taken during F) ANTI-HEMORRHOIDAL the day, fecal impaction can occur if fluid intake by mouth is insufficient. Hemorrhoids (also known as piles) are *Drug may reduce appetite if it is taken abnormally large bulging, symptomatic before meals. conglomerates of veins, supporting tissue, *Laxative effect generally occurs in 12-24 and overlying mucous membranes or skin hours, however some patients may require of the anorectal area. They are classified as 2-3 days of medication; inform patient. external (occur below the anorectal line) or *NOTE: if there is discomfort or abdominal internal (occur above the anorectal line). fullness, patients should take smaller doses. Many factors have been implicated in • USE IN SPECIAL CASES: the etiology of hemorrhoidal disease, such Pregnancy- Bulk-forming laxatives seem to as: heredity, erect posture, pregnancy, probe the safest laxatives to use during longed standing, lack of dietary bulk, heavy pregnancy. There are no well-controlled lifting, constipation, portal hypertension, studies in pregnant women. pelvic tumors and anal infections. Lactation- Generally safe. Symptoms include burning sensation, Children- Laxative use in children should not pain, itching, inflammation, irritation, be encouraged. Psyllium preparations might swelling in the anorectal region and general not be acceptable by children due to taste or discomfort. Some potentially serious form. Increasing both fluid and bulk contents anorectal disorders, including fissures, of the child’s diet are usually sufficient to fistulas, inflammatory bowel disease and improve bowel habits. High fiber cereal, tumors may present hemorrhoidal like vegetables and fruits should be enough. symptoms and should be taken seriously by Unbuttered popcorn is a good bulk-containing the physician. snack for children. Pharmacological agents recommended Renal or Liver Disease- Safe when used to relieve symptoms of anorectal disease properly without abuse. • include; PRECAUTIONS AND WARNINGS: 1) Local Anesthetics: Temporarily relieve -Impaction or obstruction may be caused by pain, burning, itching, and irritation by bulk-forming agents, if patient does not preventing transmission of nerve impulses. drink sufficient fluids, or has an obstructive Examples; Benzocaine 5-20 %, benzyl problem in the GI passage. alcohol 5-20 %, dibucaine 0.25-1 %, and -Rectal bleeding or failure to respond to lidocaine 2-5 %. therapy may indicate a serious condition that requires further medical attention. 2) Vasoconstrictors: They cause constric- • ADVERSE EFFECTS: tion of arterioles, shrink swollen hemor- Diarrhea, nausea, fecal impaction, rhoidal tissue a little, as well as relieve esophageal obstruction. some itching. [These need to be avoided in patients with diabetes, hyperthyroidism,

72 Gastrointestinal Drugs

hypertension, prostatic enlargement, anal hygiene should be emphasized as a cardiovascular disease, and patients taking way of preventing anorectal disease. MAO Inhibitors]. Examples; aqueous solution of ephedrine sulfate, epinephrine, phenylephrine and epinephrine base. 1) Anusol (or other equivalent preparation WHO,P) 3) Protectants: These prevent irritation of the anorectal area, and water loss from the • stratum corneum. Examples; Aluminium DRUG SUMMARY: hydroxide gel, cocoa butter, glycerine in This antihemorrhoidal preparation contains aqueous solution, mineral oil, white an astringent (Phenylephrine HCl 0.25%), a petrolatum. protector (vegetable oil base) in suppository form. Ointment contains; an anesthetic 4) Astringents: They provide relief from (pramoxine HCl 1%), astringents (zinc local anorectal irritation and inflammation. oxide 12.5% + balsam nicarague 3.0%), as Examples; Calamine and zinc oxide in well as mineral oil. Anusol helps to relieve concentrations of 5-25 %. pain, itching and discomfort arising from 5) Hydrocortisone: Reduce itching, irritated anorectal tissue. inflammation, and discomfort by producing • INDICATIONS: vasoconstriction, lysosomal membrane Hemorrhoids. stabilization and antimiotic activity. • CONTRAINDICATIONS: Topical hydrocortisone-containing products History of hypersensitivity to product. are indicated for temporary relief of minor • DOSAGE FORMS: external anal itching due to minor irritation Suppository, ointment. or rash. • RECOMMENDED DOSAGE: 6) Other agents that may be used include: Adults: Apply small amount of ointment counter irritants (camphor, menthol), at night and morning, and after defecation. wound healers (Peruvian balsam, vitamin Insert suppository up the anus after A, vitamin D), antiseptics (boric acid, defecation and at bedtime. phenol, sodium salicylic acid) and bulk Directions: For maximum effect, anorectal forming laxatives (to relief constipation products should be used after, rather than contributing to hemorrhoids). These agents before defecation. have not been proven to be safe or effective *Before the product is applied, the for hemorrhoidal preparations. anorectal area should be washed with mild For intra-rectal use, the only approved soap and warm water, rinsed thoroughly, ingredients are protectants, vaso- and gently dried by patting or blotting with constrictors, and astringents. toilet tissue or a soft cloth. Proper anal As a general rule, products containing hygiene is very important to emphasize to the least number of recommended patients. ingredients are the best, since you minimize *Suppository should be inserted into undesirable interactions and maximize rectum, while ointments should only be effectiveness. Scented or tinted products used externally and applied sparingly. used, (whether preparations or toilet paper) *If hypersensitivity reactions occur, should be avoided, since they can cause seepage, bleeding, severe pain resulting allergic reactions. from the medication, or symptoms worsen The importance of maintaining normal or do not improve after 7 days of treatment, bowel function by eating properly, drinking discontinue use. May need further adequate amount of fluids, avoiding evaluation or a different product. excessive laxative use, as well as proper

• USE IN SPECIAL CASES: Pregnant + Lactating women- only use products for external use. Children- Safety and efficacy has not been established. Children with hemorrhoids or other anorectal disease should be evaluated for cause, and treated accordingly. Use of local anesthetic should be only for short time (no longer than 3-4 days), since may cause sensitization of the anal skin. • PRECAUTIONS AND WARNINGS: -Approved ingredients for intra-rectal use are vasoconstrictors, protectant and astringents. Other ingredients might cause irritation to the inner mucosa. -Vasoconstrictors should be avoided in patients who have diabetes, hyperthyroidism, hypertension, difficulty in urination due to prostate enlargement, cardiovascular diseases, and in those patients who are taking monoamine oxidase inhibitors. Topical anorectal products containing ephedrine sulphate may cause nervousness, tremor, sleeplessness, nausea, and loss of appetite. -In case of local infection, treat with an appropriate antibiotic. • ADVERSE EFFECTS: Hypersensitivity reactions manifested by local redness, skin irritation, and rash. • BRANDS: Anusol (Park Davis), Hemoral H.C. (JCL), Procyoxylene (BCP).

Chapter 4: RESPIRATORY DRUGS

A) ANTIHISTAMINES 1. Chlorpheniramine Maleate 2. Astemizole

B) NASAL DECONGESTANTS 1. Oxymetazoline 2. Pseudoephedrine

C) EXPECTORANTS 1. Ammonium Chloride 2. Guaifenesin

D) ANTITUSSIVES/ COUGH DEPRESSANTS 1. Codeine 2. Dextromethorphan

E) MUCOLYTICS 1. Acetylcysteine 2. Bromhexine

F) BRONCHODILATORS AND ASTHMA MEDICATION 1. Theophylline 2. Salbutamol/ Albuterol 3. Cromolyn/ Cromoglycate 4. Beclomethasone Dipropionate 5. Prednisolone

RESPIRATORY DISORDERS Diseases of the respiratory tract may be due Single-agent therapy offers the ability to to viruses, bacterial infections, allergens … design a specific regimen directed at each etc. causing common cold, allergic rhinitis, symptom. However, many products contain upper respiratory tract infections and multiple medications. These combination asthma. For the proper diagnosis, the doctor products may be effective and provide a should be able to differentiate between convenient dosage form when the patient these disorders (bacterial vs. viral has multiple symptoms. However, com- infections, or allergy vs. asthma) so that the bination products are usually more minor self-limiting conditions can be expensive, are limited by fixed doses in the managed differently from the potentially preparation, and may have additive adverse serious ones that need immediate action. effects. The common cold is one of the most There is no evidence that show that common causes for which patient seek incorporating secondary agents or other medication. The course of the symptoms is ingredients of the same pharmacological 5-7 days, if no complications occur, and the classes in a sub-therapeutic dose provide disease is self-limiting since there are no more relief or even as much relief as one curative remedies. Influenza A may also agent at its full therapeutic dose. Two or mimic a cold and needs to be treated more antihistamines do not increase promptly. efficacy of product. A decongestant may be Whereas the common cold and influenza added to an antihistamine in a product for are caused by viruses, allergic rhinitis is allergic rhinitis, it may provide additional caused by pollen and mold spores. relief of symptoms, and counter act some Weather conditions as well as temperature drowsiness produced by the antihistamine. and rainfall cause the seasonal pattern of Combination products containing occurrence. Allergic rhinitis and asthmatic analgesic and antipyretics should not be attacks may be precipitated by the same generally recommended since they carry agents. If symptoms of allergic rhinitis are the risk of masking a fever that might indicate bacterial infections. prolonged, persistent cough, asthmatic wheezing or a feeling of constriction in the In this chapter, the most common agents chest may follow. These are dangerous used in the respiratory system are signals, or a warning of possible asthma discussed, noting some of the agents that onset. are misused as well. Patients with allergic rhinitis may develop complications of chronic nasal inflammation, including recurrent otitis Notes concerning certain agents: media with hearing loss, sinusitis, and loss 1) Sodium chloride 0.9% (normal saline) of epithelial cilia. These are more given as nasal drops may relieve nasal prominent in children. congestion by helping to liquefy mucous secretions. For the symptomatic treatment of the 2) Inhalations of warm moist air is useful in runny nose, cough, congestion and pain due the treatment of symptoms of acute infective to the mentioned disorders, there are conditions, and the use of compounds various OTC medications available. containing volatile substances such as Misuse or overuse of these products can menthol and eucalyptus may encourage their lead to complications. Anti-infective use. medications should be limited to the 3) There is no evidence that nasal bacterial infections. preparations containing antihistamines in

Respiratory Drugs combination with anti-infective agents have • INDICATIONS: any therapeutic effect. Symptomatic relief of various allergic 4) Douching the nose with salt and water is conditions, hay fever, urticaria, insect not recommended. stings, conjunctivitis, angioedema, as well 5) There is no evidence that topical anti- as adjunct in the emergency treatment of infective nasal preparations have any anaphylactic shock and severe angioedema. therapeutic value. Elimination of organisms • CONTRAINDICATIONS: such as staphylococci from the nasal Hypersensitivity to antihistamines, pre- vestibule can be achieved by the use of a mature or newborn infants, nursing cream containing chlorhexidine and neomycin, but re-colonization frequently mothers, narrow-angle glaucoma, occurs. A nasal ointment containing obstructive prostatic hypertrophy or other mupirocin is also available; but it should be bladder neck obstruction, GI kept in reserve for resistant cases. obstruction/stenosis, asthmatic attack, and 6) Chronic use of topical decongestants which during or within 14 days of MAO inhibitor produce after-congestion may aggravate therapy. chronic rhinitis (rhinitis medicamentose) if • DOSAGE FORMS: used continuously. Tablets, drops, syrups, capsules. 7) Sodium cromoglycate is the first choice in • RECOMMENDED DOSAGE: children with allergic rhinitis. Adult: 2-4 mg PO t.i.d. or q.i.d., or 8-12 mg b.i.d or t.i.d.; max. 24 mg/24 hrs. [For anaphylaxis: can be given by slow SC A) ANTIHISTAMINES or IM injection over 1 min., 10-20 mg repeated if required (max 40 mg/24hrs).] Antihistamines are chemical agents that Child (6-12 y): 2 mg q. 4-6 h., max. 12 mg/d. exert their effect in the body primarily by (2-6 y): 1 mg q. 4-6 h., max. 6 mg/d. competitively blocking the action of Directions: If GI upset occurs, can take histamine at H1-receptor sites. They do not with food and a full glass of water. prevent histamine release. These have no *Peak action occurs in 2-6 h., about 45% of therapeutic effect on the common cold. dose reaches systemic circulation. Their continued popularity stems from their *Driving and other potentially hazardous drying effect. Differences in antihistamines activities should be avoided until drug may be seen in table-4.1. response has been determined. *Antihistamines have additive effects with 1) Chlorpheniramine WHO,P alcohol or other CNS depressants. Caution your patient about this. • DRUG SUMMARY: • USE IN SPECIAL CASES: Chlorpheniramine maleate will be used as Pregnancy- Use chlorpheniramine only the prototype of commonly used anti- when clearly needed, and avoid during the histamines. It is a H1-receptor antagonist, third trimester (Category B). Safety during that generally produces less drowsiness pregnancy has not been established. Several than other antihistamines, but side effects associations with malformation have been involving CNS stimulation may be more found with the use of some antihistamines, common. It also has some antitussive, but significance is unknown.

anticholinergic and local anesthetic action, but no antiemetic properties.

Table – 4.1: Comparison of Selected Antihistamines Adult Dosing Anti- Anti- Sedative Antiemetic Antihistamine Single Dose Interval histaminic cholinergic Effects Effects (mg) (hour) Activity Activity Ethanolamines Clemastine 1 12 + + + to + + + + + ++ to +++ Diphenhydramine 25 - 50 6 - 8 + + + + to + + + + + ++ to +++ Ethylenediamines Pyrilamine 25 - 50 6 - 8 + + to + + + - Tripelennamine 25 - 50 4 - 6 + + + to + + + - Alkylamines Brompheniramine 4 4 - 6 + + + + + + - Chlorpheniramine 4 4 - 6 + + + + + - Dexchlorpheniramine 2 4 - 6 + + + + + + - Triprolidine 2.5 4 - 6 + ++ to +++ + + - Phenothiazines Promethazine 12.5 - 25 6 - 24 + + + + + + + + + + + + + Trimeprazine 2.5 6 + + ++ to +++ + + + + + + + Piperidines Azatadine 1 - 2 12 + + + + + + - Cyproheptadine 4 8 + + + + + + - Phenindamine 25 4 - 6 - + + + + - Miscellaneous Acrivistine 8 8 + ++ to +++ + - Astemizole # 10 24 + ++ to +++ + - Loratadine 10 24 + ++ to +++ + - Terfenadine § 60 12 + ++ to +++ + - ++++ = very high, +++ = high, ++ = moderate, + = low, + = low to none, - = none. * Drug Facts and Comparisons 1997; 1135. # Withdrawn from USA market 1999 voluntarily by the brand manufacturer Janssen since alternative available medications have less risk, § Withdrawn from USA and other European markets in 1998. ______

Lactation- Avoid use, unless clearly • PRECAUTIONS AND WARNINGS: needed. Antihistamines in general are -In elderly (> 60 yrs.), antihistamines are excreted in breast milk. Also can reduce more likely to cause dizziness, excessive milk flow. sedation, toxic confusional states and Children- Use of chlorpheniramine in hypotension. Dosage reduction may be children < 2 years should be avoided. Use required. caution in children, they may experience -Use caution in patients with convulsive paradoxical excitation. disorders, increased intraocular pressure, Renal Disease- Use caution in simple cases, hyperthyroidism, diabetes, cardiovascular reduce dose if patient can’t tolerate. Avoid disease, hypertension, G6PD deficiency. in patients with urinary retention or severe • ADVERSE EFFECTS: renal disease. Chlorpheniramine has a low incidence of Liver Disease- Avoid use. Some antihist- side effects. Possible side effects include: amines have been reported to precipitate Drowsiness, headache, tinnitus, disturbed coma in hepatic dysfunction. coordination, nervousness, restlessness, mild hypotension, tachycardia, dryness of

Respiratory Drugs mouth, nose and throat, blurred vision, 2) Astemizole diplopia, epigastric distress, nausea, constipation or diarrhea, or urinary • DRUG SUMMARY: retention. (Astemizole and Terfenadine have been • INTERACTIONS: withdrawn from some countries due to the Overview of Chlorpheniramine risks of death of irregular heart rhythms Drug-Drug Interaction when taken with certain other drugs and Drug Interaction when used at higher than recommended Alcohol and These potentiate the side doses). other CNS effects of the medication. Astemizole is a long acting selective depressants Caution patients. histamine H1-receptor antagonist. It binds MAO Intensify and prolong the preferentially to peripheral rather than inhibitors anticholinergic effects of the central H1-receptors. It does not block antihistamines. May cause histamine release, antibody production or severe hypotension and extra- antigen-antibody interactions. Has little or pyramidal reactions. Avoid no anticholinergic and sedative effects use of antihistamines within compared with diphenhyramine. 14 days of MAO inhibitor therapy. Astemizole has a slow onset of action and is more appropriate for use on a regular • OVERDOSE: basis than when symptoms occur. Symptoms may vary from mild CNS Good choice for people who cannot tolerate depression (sedation, diminished mental the sedative or anticholinergic effects of alertness, tinnitus) and cardiovascular other antihistamines that are indicated for collapse, to stimulation (insomnia, halluc- rhinitis, as well as having the benefit of inations, convulsions, severe hypotension) once a day dose. The downside to its use, is and respiratory depression leading to coma, the high cost, potential rare but possible especially in children and geriatric patients. adverse cardiac events including death, as Death may occur. well as the serious side effects that can Treatment: Induce emesis even if emesis has result from drug-drug interactions. occurred spontaneously, using syrup of • ipecac. Following emesis administer activated INDICATIONS: charcoal as a slurry with water and a cathartic Relief of symptoms associated with to minimize absorption. Do not induce emesis seasonal allergic rhinitis and chronic in unconscious patients. Continue with idiopathic urticaria. supportive and symptomatic treatments as • CONTRAINDICATIONS: needed. Same as chlorphineramine. • BRANDS: Also in patients with significant hepatic Ahiston (Teva), Allergon (JCL), Anaphyl (Sam- dysfunction, concomitant erythromycin, On), Artix (Megapharm) Cloroyate ketoconazole or itraconazole therapy, (Pharmacare), Disoramin (Dexxon). patients with hypokalemia and other ______electrolyte imbalances. • DOSAGE FORMS: Tablets, syrup. • RECOMMENDED DOSAGE: Adult and child > 12 yrs: 10 mg PO q.d. Child 6-12 yrs: 5 mg daily. Child < 6 yrs: Not recommended.

Directions: DO NOT EXCEED RECOM- • INTERACTIONS: MENDED DOSE. Overview of Astemizole *Should be taken on empty stomach, since Drug-Drug Interaction absorption is 60% decreased with food. Drug Interaction Take at least 2 hrs. after a meal. Have no Anti- Do not prescribe at the same food for 1 h. after taking the drug. arrhythmic time. Medication use *If syncope occurs, astemizole should be increases the risk of discontinued and patient evaluated for ventricular arrhythmias if potential arrhythmias. astemizole is added. Use is contraindicated. • USE IN SPECIAL CASES: Azole antifungals These increase astemizole Pregnancy- Safety and efficacy have not (Fluconazole, (and terfenadine) plasma established. Toxicity has been reported in itraconazole, levels, which may lead to animal studies, manufacturers advise that ketoconazole, & serious cardiovascular women of child-bearing potential should use miconazole) effects. [see warnings]. contraception while taking astemizole and for Fluvoxamine Use is contraindicated. several weeks after stopping (owing to its Increased concentration of long t½ ), to avoid any potential risks to the the astemizole/ terfenadine fetus (Category C). increasing its cardiotoxicity. Lactation- Avoid use, due to the increased Macrolide Use is contraindicated. risk or adverse effects in infants in general. antibiotics Erythromycin coadminis- Children- safety of use in children < 6 yrs. tration increases risk of old has not been established. cardiac toxicity. Renal Disease- Use caution, this drug has a Other macrolides may have long half-life, 20-24 hours, metabolites 12- the same risk. Loratidine 20 days, and is 25-50% excreted in urine. antihistamine may be a safe alternative. Liver Disease- Astemizole is contra- Increased antimuscarinic Tricyclic anti- indicated in patients with significant and ventricular arrhythmia depressants hepatic dysfunction or liver cirrhosis. risks. Avoid use if possible.

• PRECAUTIONS AND WARNINGS: -Cardiovascular effects; QT interval pro- • OVERDOSE: longation/ventricular arrhythmias, includ- Symptoms: Serious ventricular arrhythmias ing death, cardiac arrest, torsade de pointes have occurred following astemizole doses have all been observed in clinical setting. of > 200 mg, including severe forms of side -Severe arrhythmias have been preceded by effects. episodes of syncope. Syncope in patients Treatment: Need to induce emesis even if it receiving astemizole (or terfenadine) has occurred spontaneously, using syrup of should lead to discontinuation of treatment ipecac. Followed with activated charcoal as and evaluation of potential arrhythmias. a slurry with water, and a cathartic to • ADVERSE EFFECTS: minimize absorption. Follow with These may include; headaches, dizziness, supportive and symptomatic care. appetite increase, weight gain, nervousness, • BRANDS: depression, nausea, diarrhea, abdominal Hismanal (Janssen), Hismal (Eastern Chem.), pain, angioedema, arrhythmias, photo- Lahistan (BPC). sensitivity, or rash. ______

Respiratory Drugs

B) NASAL DECONGESTANTS Treatment of nasal congestion not only relieves the discomfort, but also prevents Decongestants are sympathomimetic excessive blowing, which may further amines administered directly to swollen irritate mucous membranes and nostrils. membranes (e.g. via spray or drops), or Topical decongestants are used to relieve systematically via the oral route. Oral nasal stuffiness in colds and allergies. It is agents are not as effective as topical very important to tell patient to strictly products especially on an immediate basis, follow the decongestant’s directions but generally have a longer duration of regarding the frequency and duration of action, cause less local irritation and are not use. When these agents are misused or associated with rebound congestion as do overused, a rebound phenomenon (rhinitis topical products (see table 4.2 & 4.3 for medicamentosa) may occur. The nasal summary of topical and oral nasal congestion mucosa agents). becomes more congested and edematous as the drugs vasoconstrictor effect subsides.

Table – 4.2: Topical Nasal Decongestant Dosages (Drops or Sprays) Concentration Adult dosage Children Children Drug (%) 6-12 y 2 to < 6 y Ephedrine 0.5 2-3 (≥ 4 h.) 1-2 (≥ 4 h.) - Not 0.05 2 (≥ 4-6 h.) - Naphazoline recommended Hydrochloride 0.025 - 1-2 (≥ 6 h.) - 2-3 (morning 0.05 Same as adult - Oxymetazoline and evening) Hydrochloride 2-3 (morning and 0.025 - - evening) Not recommended Not recommended 1.0, 0.5 1-2 (≥ 4 h.) (refer to 0.25%) (refer to 0.125%) Phenylephrine Not recommended Hydrochloride 0.25, 0.2 1-2 (≥ 4 h.) 1-2 (≥ 4 h.) (refer to 0.125%) 0.125 - - 1 drop (≥ 4 h.) Not recommended Not recommended Xylometazoline 0.1 2-3 (8-10 h.) (refer to 0.05) (refer to 0.05%) Hydrochloride 0.05 - 2-3 (8-10 h.) 2-3 (8-10 h.) (-): There is no recommended dosage for children, except under direct supervision of physician. Only drops should be used in children under 2 to 6 years of age.

Table – 4.3. Oral Nasal Decongestant Dosages (maximum/24 hours): Drug Adult Children 6 to 12 y Children 2 to < 6 y 10 mg q. 4 h. 5 g q. 4 h. 2.5 mg q. 4 h. Phenylephrine (60 mg) (30 mg) (15 mg) 25 mg q. 4 h. 12.5 mg q. 4 h. 6.25 mg q. 4 h. Phenylpropanolamine (150 mg) (75 mg) (37.5 mg) 60 mg q. 6 h. 30 mg q. 6 h. 15 mg q. 6 h. Pseudoephedrine (240 mg) (120 mg) (60 mg) There is no recommended dosage for children under 2 years old, unless under direct medical supervision.

1) Oxymetazoline develop anisocoria (inequality of pupil size and blurred vision). • DRUG SUMMARY: • USE IN SPECIAL CASES: Oxymetazoline is an imidazoline-derivative Pregnancy- Use oxymetazoline if clearly sympathomimetic agent, an autonomic needed (Category C). It is not known if nervous system, alpha-adrenergic agonist. topical agents cause fetal harm. Oxymetazoline is a longer acting topical Lactation- Exercise caution. It is not known nasal decongestant, with an effect that may if topical agents are secreted in breast milk. Children- Can use the 0.025% concentration last 5-6 hours or longer, with a gradual solution in children 2-6 yrs of age for not decline thereafter. It can be used twice a more than 3-5 days. There is no day. (Xylometazoline is a similar nasal recommended dosage for children ≤ 2 yrs. decongestant). • Direct supervision of a physician is required INDICATIONS: if it is decided that it is necessary to use this Relief of congestion of the upper medication, to monitor for any toxicity. respiratory tract. As adjunctive therapy of Renal + Liver Diseases- Use caution. There middle ear infections, to decrease should be no hazards, if used as directed in congestion around the Eustachian ostia. these patients. • CONTRAINDICATIONS: • PRECAUTIONS AND WARNINGS: Hypersensitivity, and use with MAO -Use caution with hypertensive patients as inhibitor therapy or within 14 days of they might experience a change in blood therapy. pressure because of the added • DOSAGE FORMS: vasoconstriction. Drops or sprays. -Use caution in special risk population, • RECOMMENDED DOSAGE: patients with hyperthyroidism, cardio- Adults and children > 6 yrs: 2-3 drops or vascular disease, coronary artery disease, 2-3 sprays of 0.05% solution into each increased intraocular pressure. Sympatho- nostril b.i.d. (q. 12 h.) for up to 3-5 days. mimetics may cause CNS stimulation or Children 2-5 yrs: 2-3 drops of 0.025% hypotension. solution into each nostril b.i.d. for up to 3-5 • ADVERSE EFFECTS: days. Burning, stinging, dryness of nasal mucosa,

Directions: Administer in the morning and and sneezing are common. With excessive at bedtime. Effects appear within 30 use: headaches, light-headedness, drow- minutes and last about 6-7 hours. siness, insomnia, palpitations, and rebound *Nasal spray is delivered with patient in congestion. Stop use of medication upright position. Instruct patient to place immediately if severe effects occur. spray nozzle in nostril without occluding it, • INTERACTIONS: and to bend head slightly forward and sniff Overview of Oxymetazoline briskly during administration. Drug-Drug Interaction *Lateral, head-low position is recom- Drug Interaction mended for instillation of nose drops. MAO Concurrent use may result in *Instruct patient to rinse dropper or spray inhibitors severe headache, hypertension, hyperpyrexia, and tip in hot water after each use to prevent possibly a hypertensive crisis. contamination of solution by nasal Avoid use concurrently or secretion. within 14 days of MAOI *Wash hands after use, and avoid rubbing therapy. eyes with contaminated fingers, can

Respiratory Drugs

• OVERDOSE: *Do not exceed recommended doses, Hypertension or rebound hypotension may higher doses may cause nervousness, occur, heart palpitations, headache and dizziness, and sleeplessness. dizziness. Treat symptomatically. *The drug acts as a stimulant, advise the • BRANDS: patient to avoid taking it within 2 hours of Alrin (Teva), Nasivin (Merck), Nosacare bedtime. (Pharmacare), Rhinoclir (Agis) • USE IN SPECIAL CASES: ______Pregnancy- Give only when clearly needed (Category C). It is not known whether these 2) Pseudoephedrine agents can cause fetal harm. Lactation- Oral pseudoephedrine has been • DRUG SUMMARY: detected in breast milk, avoid use to eliminate α possible side effects to the nursing infant. No An autonomic nervous system agent, - reports of side effects have been found. β adrenergic and -adrenergic agonist, sym- Children- Safe if used as recommended. pathomimetic decongestant amine. Unlike Renal + Liver Disease- Use with caution. ephedrine, it acts directly on smooth The medication is metabolized in the liver, muscle, has fewer side effects, less presser and excreted in the urine, but there have been action, and longer duration of action. It no reported risks when used as recommended. produces little, if any, rebound congestion • PRECAUTIONS AND WARNINGS: or irritation that occur with nasal sprays and -Special populations; administer with solutions. caution to patients with hyperthyroidism, • INDICATIONS: diabetes mellitus, cardiovascular disease, Symptomatic relief of nasal congestion coronary artery disease, ischemic heart associated with rhinitis, coryza, sinusitis disease, prostatic hypertrophy, and and Eustachian tube congestion. increased intraocular pressure. Sympatho- • CONTRAINDICATIONS: mimetics may cause CNS stimulation and Hypersensitivity to sympathomimetic convulsions or cardiovascular collapse amines, severe hypertension or coronary -Use caution with hypertensive patients as artery disease, use within 14 days of MAO they might experience a change in blood inhibitors, glaucoma, hyperthyroidism, pressure because of the added vaso- prostatic hypertrophy. The use of sustained constriction. release tablets in children < 12 years old is -Elderly (≥ 60 yrs) are more likely to also contraindicated. experience adverse reactions to • DOSAGE FORMS: sympathomimetics. Hallucinations, convul- Tablets, syrup (in combination with other sions, CNS depression and death have been agents). noted. Short acting sympathomimetics may • RECOMMENDED DOSAGE: be safer than the sustained release Adult: 60 mg PO q. 4-6 h. (or 120 mg SR formulation in this population. q. 12 h.); max. 240 mg/24h. • ADVERSE EFFECTS: Child (6-12y): 30 mg q. 4-6 h.; max. 120 Transient stimulation, tremors, anxiety, mg/24h. difficulty in voiding, arrhythmia, Child: (2-6y): 15 mg q. 4-6 h.; max. 60 palpitation, tachycardia, nervousness, mg/24h. headache, dizziness, insomnia, sweating,

Directions: May take with food if GI upset anorexia, dry mouth, nausea or vomiting, occurs. photophobia have all been reported.

• INTERACTIONS: renal, hepatic or chronic heart diseases, Same as oxymetazoline. Ammonium Cl doses of 5 gm have caused • OVERDOSE: severe poisoning. Symptoms of toxicity Symptoms include: somnolence, sedation including nausea, vomiting, thirst, rash, accompanied by profused sweating, headache, bradycardia, mental confusion, hypotension or shock. hyperventilation, hyper-reflexia and Treatment: For accidental overdose, refer electroencephalogram abnormalities. A to hospital for supportive and symptomatic relative contraindication for use in patients care. with hepatic, renal or pulmonary • BRANDS: insufficiency exists. Use in diabetics should Pseudoephedrine is mostly available in also be avoided. Doses larger than those combination with other antihistamines, recommended may predispose the patient to antitussives, analgesics or expectorants. hyperammonemia and metabolic acidosis. (Refer to price list in Appendix.) [Need to warn such patients who are ______predisposed to toxicity.] Since ammonium Cl acidifies the urine, it may also affect the excretion of other drugs when given in large C) EXPECTORANTS doses; (i.e. amphetamines, methadone, ephedrine, pseudoephedrine, sulfonylureas and salicylates). Expectorants are periphery-acting anti- The expectorant safe dosing recommen- tussives that produce their effect by dation to be used are; increasing the volume and reducing the Adults: 300 mg q. 2-4 h. viscosity of bronchial secretions, thus Child (6-12 y): 150 mg q. 2-4 h., facilitating their removal by productive Child (2 to < 6 y): 75 mg q. 2-4 h. cough. Use of expectorants in clinical Most companies include ammonium Cl in practice is controversial because of their cough products, and list it as a non- doubts regarding their therapeutic active ingredient. Use caution in efficacy. There is a lack of strong, susceptible patients. supportive, objective data showing that an ______expectorant truly decreases sputum viscosity or eases expectoration. Increasing fluid intake (6-8 glasses) and maintaining 2) Guaifenesin adequate humidity of the inspired air are important for the production and • DRUG SUMMARY: expectoration of respiratory tract fluid Guaifenesin (glyceryl guaiacolate) is mucus. claimed to enhance the output of respiratory tract fluid by reducing

1) Ammonium Chloride adhesiveness and surface tension facilitating the removal of viscous mucus.

As a result nonproductive cough becomes Ammonium chloride is primarily used as an more productive and less frequent. There is acidifying agent. Allegedly, it increases the a lack of convincing studies to document removal of respiratory tract secretions by efficacy just like any other expectorant. reflex stimulation of bronchial mucous • glands that result from irritation of the INDICATIONS: gastric mucosa, which makes it a common For the symptomatic relief of respiratory ingredient in cough mixtures. But it has conditions characterized by dry, non- questionable efficacy. In the presence of productive cough, and in the presence of mucus in the respiratory tract.

Respiratory Drugs

• CONTRAINDICATIONS: D) ANTITUSSIVES/ COUGH Hypersensitivity to the product, no other SUPPRESSANTS absolute contraindications to its use. • DOSAGE FORMS: Cough suppressants are centrally acting Syrup 100 mg/5 ml. antitussives, suppressing the medullary • RECOMMENDED DOSAGE: cough center. The drawbacks of prescribing Adults and children (≥ 12 y): 200-400 cough suppressants are really outweighed mg PO q. 4 h. by the benefits of treatments and only Do not exceed 2400 mg/24h. occasionally are useful, for example if sleep Child (6-12 y): 100-200 mg q. 4 h. Do not is disturbed by dry cough. Cough exceed 1200 mg/24h. suppressants may cause sputum retention Child (2-5 y): 50-100 mg q. 4 h. Do not and this may be harmful in patients with exceed 600 mg/24h. chronic bronchitis and bronchiectasis. The Directions: Drug is most effective if taken use of cough suppressants containing q. 4 h. around the clock or during waking codeine or similar opioid analgesics are not hours. May take dose with a full glass of generally recommended in children and water if needed. should be avoided altogether in those under • USE IN SPECIAL CASES: 1 year of age. Pregnancy- No sufficient data is available. Use if clearly needed (Category C). 1) Codeine Lactation- Exercise caution. Use only when clearly needed. • DRUG SUMMARY: • PRECAUTIONS AND WARNINGS: An opium derivative made by methylation -Do not use for persistent cough such as of morphine. It is classified as a CNS, cough that occurs with smoking, asthma or narcotic agent, analgesic, and antitussive. emphysema, or where cough is The dose required to suppress cough is accompanied by excessive secretions. lower than the doses required for analgesia. • ADVERSE EFFECTS: • INDICATIONS: These are uncommon, but may include: For suppression of cough induced by nausea, vomiting, headache, and rash. chemical or mechanical respiratory tract • INTERACTIONS: irritation. Also for relief mild to moderate Guaifenesin may increase risk of pain since it is a narcotic analgesic. hemorrhage in patients receiving heparin • CONTRAINDICATIONS: therapy. Hypersensitivity to the drug, acute asthma, • OVERDOSE: acute alcoholism, premature infants or Symptoms: Overdosage may cause nausea during labor when delivery of a premature and vomiting. infant is anticipated. Treatment: Induce vomiting if it has not • DOSAGE FORMS: occurred already. Use supportive and Tablets. Syrup in combination products. symptomatic care. • RECOMMENDED DOSAGE: • BRANDS: Adult: 10-20 mg PO q. 4-6 h.; max. 120 Resyl (Ciba-Geigy), Robutussin (Robins mg/24h. Consumer). Child (6-12 y): 5-10 mg q. 4-6 h.; max. 60 ______mg/24h. Child (2-6 y): 2.5-5 mg q. 4-6 h.; max. 30 mg/24h.

Not to be used in premature infants. Safety • PRECAUTIONS AND WARNINGS: and efficacy in newborn infants have not -Head injury and increased intracranial been established. pressure; the respiratory depressant effects

Directions: Take with food or milk to of codeine and their capacity to elevate reduce possibility of GI distress. cerebrospinal fluid pressure may be *Not to be administered to patients with markedly increased in the presence of such persistent or chronic cough; as occurs with cases. Exercise caution. smoking, asthma or emphysema, or where -Should not be given to patients with or at cough is accompanied by excessive risk of developing respiratory failure. secretion. -Drug abuse and dependence; potential of Treatment is directed toward decreasing abuse is less than that of heroin or frequency and intensity of cough, without morphine, but use caution in patients with a abolishing protective cough reflex that history of drug abuse. Psychological and serves the important function of removing physical dependence, and tolerance may bronchial secretions. occur. Be alert to over-prescribing. • USE IN SPECIAL CASES: • ADVERSE EFFECTS: Pregnancy- Avoid use (Category C). In usual oral antitussive doses, codeine has Dependence has been reported in newborns mild side effect. Nausea, vomiting, whose mothers took opiates during sedation, dizziness, constipation are most pregnancy. Signs such as irritability, common. Other effects may include: CNS excessive crying, tremors, fever, vomiting depression, respiratory depression, biliary and diarrhea, usually appear during the first tract spasms, tachycardia, palpitation, few days of life. Use only if potential faintness, orthostatic hypotension, urinary benefits outweigh the potential hazards to retention, antidiuretic effect, hallucination, the fetus. Also codeine may prolong labor; disorientation, lightheadedness, euphoria, avoid use especially if a premature infant is weakness, convulsions, as well as allergic anticipated. reactions have been reported. Lactation- Exercise caution. Use when Warn patients against performing tasks that clearly indicated. Studies have reported require full alertness and coordination (i.e. detectable amounts of codeine in breast driving or operating machines) until the full milk, but no adverse effects were reported effect of the medication is known. with the recommended doses for cough. Instruct patients to make position changes Children- Do not use opiates, including slowly, particularly from recumbent to codeine, in premature infants. Opiates cross upright posture, and to lie down immediately the immature BBB, producing respiratory if light-headedness/dizziness occur, especially depression. Codeine should be given to in elderly patients, to avoid falling down. infants and small children only with great • INTERACTIONS: caution since safety and efficacy have not Overview of Codeine been established. Drug-Drug Interaction Renal Disease- Use with caution. Drug Interaction Antitussive doses are not reported to be CNS Including other opiates, general hazardous. depressants, anesthetics, phenothiazines, Liver Disease- Use caution. The drug is and alcohol tricyclic anti-depressants, metabolized in the liver, may need to tranquilizers; all have additive effects when given reduce dose if patient can not tolerate the concomitantly with codeine. recommended dose. Avoid, or use extreme caution.

Respiratory Drugs

• OVERDOSE: Directions: Drink some water after The lethal oral dose of codeine in an adult administration. If GI upset occurs, the is in the range of 0.5 to 1 g. Infants, medicine may be taken with food. children, and elderly are more sensitive, *Unnecessary cough may be lessened by and comparatively intolerant. avoiding irritants such as smoking, dust, Symptoms include CNS depression, miosis, fumes, and other air pollutants. Humidi- and respiratory depression. fication of air may provide some relief. Treatment: Transfer immediately to the *Increasing the dose does not increase the emergency room for supportive and antitussive effect, but may extend its symptomatic care. Naloxone is the duration of action. antagonist of choice in narcotic agonist • USE IN SPECIAL CASES: overdoses. Pregnancy- Use if clearly needed (Category • BRANDS: C). No sufficient data is available. Codical (Sam-On), Codeine Phosphate (Trima). Lactation- It is advisable to avoid the ______medication, unless clearly needed. Children- Not recommended for children < 2 2) Dextromethorphan HBr WHO years of age, unless under direct medical supervision (administered in hospital or clinic). • DRUG SUMMARY: Renal Disease- Use with caution. Dextromethorphan is a non-narcotic Liver Disease- Use with caution. derivative of levorphanol classified as an • PRECAUTIONS AND WARNINGS: antitussive. Chemically related to morphine -Should not be used for persistent or but without the capacity to cause tolerance chronic cough, e.g. asthma, smoking or addiction. It controls cough spasms by emphysema, or where cough is depressing the cough center in the medulla. accompanied by excessive secretions, or to It does not depress respiration or inhibit patients with risk of developing respiratory cilliary action. Antitussive activity failure. comparable to that of codeine, but it is less -Cases of abuse of dextromethorphan- likely to cause constipation, drowsiness, or containing cough/cold products have been GI disturbances. reported, but there is no sufficient data to • INDICATIONS: prove potential dependency on this drug. Temporary relief of cough spasms in non- • ADVERSE EFFECTS: productive coughs due to colds, pertussis Side effects are rare, but may include; (whooping cough), and influenza. dizziness, drowsiness, CNS depression, GI • CONTRAINDICATIONS: upset, constipation and abdominal Hypersensitivity to dextromethorphan, or any discomfort. component of the product. • INTERACTIONS: • DOSAGE FORMS: Overview of Dextromethorphan Tablets, syrup. Drug-Drug Interaction • RECOMMENDED DOSAGE: Drug Interaction Adult: 10-20 mg PO q. 4 h. or 30 mg q. 6- MAO Dextromethorphan should not 8 h.; max. 120 mg/24h. inhibitors be given to patients taking Child (6 - 12 y); 5-10 mg q. 4 h. or 15 mg q. MAOI. Patient may develop 6-8 h.; max. 60 mg/24h. hypotension, nausea, myo- Child (2 - 6 y); 2.5 mg q. 4 h. or 7.5 mg q. 6- clonic leg jerks or coma 8 h.; max. 30 mg/24h. following co-administration. Do not co-administer.

• OVERDOSE: It can be administered by mouth or by Symptoms: Children may experience ataxia, inhalation. It should be avoided in patients respiratory depression and convulsion with with hypersensitivity, or risk of gastric accidental overdose. Adults symptoms hemorrhage. (No contraindications if used include altered sensory perception, ataxia, as an antidote for poisoning cases). Safe slurred speech, and dysphoria. use in pregnancy (Category B) and Treatment: There is rapid recovery after lactation is not established. Use extreme emesis with activated charcoal. caution in patients with asthma (if • BRANDS: bronchospasm progresses, the doctor needs Dextromethorphan is mostly available in to discontinue medication immediately). combination with other antihistamines, Most common side effects include nausea, decongestants, analgesics or expectorants. vomiting, bronchospasm, rhinorrhea, and Refer to price list for products. burning sensation when given as inhalation. ______

2) Bromhexine E) MUCOLYTICS • DRUG SUMMARY: Mucolytics are often prescribed to facilitate A mucolytic agent used in the treatment of expectoration, since they reduce the respiratory disorders associated with viscosity of the bronchial secretions by excessive mucus. It is usually given by breaking down their structure. They mouth in a dose of 4-16 mg three times a supposedly reduce sputum viscosity in day. Safety of use in pregnancy or lactation chronic asthma and bronchitis. Experts is not established. Do not administer to have suggested that “mucolytics are patients with history of peptic ulcer disease. probably no more effective than steam ______inhalation . . . A productive cough may be helped by a warm drink and/or steam inhalation” specially in the case of cough and cold medications. Available mucolytics F) BRONCHODILATORS & include: acetylcysteine, carbocysteine, ASTHMA MEDICATION methyl-cysteine, and bromhexine. There has been an increase in morbidity and mortality from asthma worldwide in 1) Acetylcysteine the last decade. This has been a major concern. Expert panels were established to • DRUG SUMMARY: provide guidelines for the diagnosis and Acetylcysteine is a derivative of the management of asthma. Asthma is defined naturally occurring amino acid L-cysteine. as an inflammatory airway obstruction It is used as adjunct therapy in patients with that is reversible (but not completely in abnormal viscid, or inspissated mucous some patients). It is a familial disease, secretions, and in pulmonary complications inherited like other allergic disorders. It is of cystic fibrosis, surgery, and atelectasis. episodic in nature, were an episode may Also used in acute paracetamol last from a few minutes to several days. (acetaminophen) overdoses or toxicity. It is Patients with chronic bronchitis and found in various cough/ expectorant emphysema are often described as having preparations. irreversible airway obstruction, and should be treated differently by a specialist.

Respiratory Drugs

Therapy is directed at preventing severe Pregnancy and Breast-Feeding: It is attacks and normalizing an asthma patient’s particularly important that asthma be well- lifestyle. Severe asthma can be fatal. It is controlled during pregnancy. Inhalation has characterized by persistent dyspnea poorly particular advantage as means of drug relieved by bronchodilators, exhaustion, a administration during pregnancy because high pulse rate (usually over 110/min.), and the therapeutic action can be achieved a very low forced expiratory volume (FEV1 without the need for plasma concentrations or PEF < 60% predicted, and PEF liable to have a pharmacological effect on variability > 30%). the fetus. Severe exacerbation of asthma The respiration is so shallow that can have adverse effects on pregnancy and wheezing may be absent. Such patients should be treated promptly with should be immediately taken to the conventional therapy, including oral or emergency rooms for prompt therapy with parenteral administration of corticosteroids oxygen and corticosteroids. (Prednisolone preferred) and a selective β2- Treatment of asthma has been agonist. Although theophylline has been undergoing major changes in recent years given without adverse effects during with the unrevealing of specific causes at pregnancy or breast-feeding, there have the cellular level, and production of new been occasional reports of toxicity in the classes of drugs such as the leukotriene fetus and neonate. modifiers. This chapter will discuss an overview of available products only at the primary level, and give summary of classification and updated treatment of asthma. National Asthma Education and Prevention program has adopted a classification of Asthma severity and treatment, this classification is as follows:

-Severe persistent: continual daytime symptoms, frequent night symptoms, FEV1/PEF<60%. -Moderate persistent: daily daytime symptoms, > 5 nights/month with symptoms, FEV1/PEF = 60-80%. -Mild persistent: 3-6 days/week with symptoms, 3-4 nights/month with symptoms, FEV1/PEF > 80%. -Mild intermittent: < 2 days/week with symptoms, < 2 nights/month with symptoms, FEV1/PEF > 80%.

Patient is classified according to the worst symptomatology that he has, and he can be moved from one scale to another depending on his symptomatology. A summary of classification of asthma is presented in table-4.4.

Table 4.4: Summary of Treatment of the Different Classes of Asthma in Adults Classification Long Term Control Quick Relief Mild No daily medication Inhaled β-2 intermittent agonist One daily medication Inhaled β-2 Mild • Either inhaled corticosteroids (low dose) or cromolyn agonist persistent • Sustained release theophylline: not a preferred alternative. Daily medication Inhaled β-2 • inhaled corticosteroid (medium dose) or agonist • inhaled corticosteroid (low-medium dose) and add Moderate either long acting inhaled β-2 agonist, sustained release persistent theophylline or long acting β-2 agonists tablets especially for nighttime symptoms if needed medium-high dose inhaled corticosteroids can be used Daily medication Inhaled β-2 • inhaled corticosteroids (high dose) and agonist Severe • either long acting inhaled β-2 agonist, sustained persistent release theophylline or long acting β-2 agonist tablets and • Corticosteroid tablets or syrup long term (2mg/kg/d) Summary of Treatment of the Different Classes of Asthma in Children Classification Long Term Control Quick Relief No daily medication is needed Bronchodilator either: -inhaled short acting β-2 agonist Mild by nebulizer or spacer or intermittent chamber -oral β-2 agonist -cromolyn (nebulizer is preferred or MDI) Bronchodilator as needed or nedocromil (MDI only) Mild (infants and young children usually begin with persistent cromolyn or nedocromil) or low dose inhaled corticosteroids with spacer or aerochamber. Moderate -medium dose inhaled corticosteroid with Bronchodilator as needed for persistent spacer or aerochamber. symptoms up to 3 times a day -high dose inhaled corticosteroid with spacer or Bronchodilator as needed for aerochamber symptoms up to 3 times a day Severe -if needed add systemic corticosteroids (2 persistent mg/kg/day) and reduce to the lowest daily or alternate–day dose. -Adapted from: National Asthma Education and Prevention Program, National Heart, Lung and Blood Institute, Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. NIH publication No. 97-4051, July 1997, updated 2002).

Respiratory Drugs

1) Theophylline WHO,P • RECOMMENDED DOSAGE: (or soluble salt derivatives) All doses are individualized, based on lean body weight. Dosages are based and • DRUG SUMMARY: adjusted on clinical response and Theophylline is a methyl-xanthine improvement in pulmonary function with derivative. It is classified as a broncho- careful monitoring of serum levels. dilator, respiratory and cerebral stimulant, Monitoring of serum levels should be done xanthine. Unlike sympathomimetic agents, during chronic therapy at 6-12 months tolerance to bronchodilator effects of intervals or when toxicity is suspected, it theophylline derivative rarely develops. should be measured 1-2 hours after Theophylline inhibits the enzyme phospho- administration of immediate release diesterase, resulting in the relaxation of the products and 5-9 hours after the morning smooth muscle of the bronchi that are dose for sustained release formulations. constricted, thus relieving the difficulty in Therapeutic range of 10-20 mcg/ml breathing. Because of differing (narrow therapeutic range) plasma theophylline content, the various salts and theophylline concentration should be derivatives are not equivalent on a weight maintained to avoid toxicity. basis (refer to dosage). Theophylline is (see table- 4.5,6,7 for equivalent doses, considered third line therapy because of its guidelines for dosing). *Better to take before meals, but if GI narrow therapeutic window. It is reserved upset occurs, can take with food, and full for patients who are unresponsive to β - 2 glass of water. Take at same time each day, agonists or steroids. • and adhere to the proper intervals between INDICATIONS: doses. Prophylaxis and symptomatic relief of *A low-carbohydrate, high-protein diet bronchial asthma, as well as bronchospasm increases theophylline elimination, and a associated with chronic bronchitis and high-carbohydrate, low-protein diet emphysema. (Also used for emergency decreases it. Charcoal-broiled foods may treatment of paroxysmal cardiac dyspnea increase elimination and reduce the half-life and edema of CHF.) as much as 50%. • CONTRAINDICATIONS: *Do not chew or crush enteric coated or Hypersensitivity to xanthines or any sustained release tablets or capsules, unless derivatives (caffeine), coronary artery specific product information identifies that disease or angina pectoris when myocardial capsule may be opened. stimulation might be harmful, severe renal *Avoid large amounts of caffeine- or liver impairment. containing beverages; i.e. tea, coffee, • DOSAGE FORMS: cocoa, cola or large amounts of chocolate, Tablets, syrup, capsules, suppository which may increase side effects. (adults and infants).

Table – 4.5: Theophylline Content and Equivalent Dose of Various Theophylline Salts Theophylline salt Theophylline % Equivalent Dose Theophylline anhydrous 100 100 mg Theophylline monohydrate 91 110 mg Aminophylline anhydrous 86 116 mg Aminophylline dihydrate 79 127 mg *Drug Facts & Comparisons 2000, p. 655.

Table – 4.6: Dosage Guidelines for Rapid Theophyllinization* (patients not receiving theophylline) Oral Loading Maintenance Maximum Daily Patient Group Dose Dose Dose Children 1 to 9 years 5 mg/kg 4 mg/kg q.6h. 24 mg/kg/d Children 9 to 16, and young adult 5 mg/kg 3 mg/kg q.6h. 20 mg/kg/d smokers Otherwise healthy non-smoking 5 mg/kg 3 mg/kg q.8h. adults 13 mg/kg/d Older patients, patients with 5 mg/kg 2 mg/kg q.8h. not to exceed corpulmonale dose, or 900 mg, Patients with congestive heart 5 mg/kg 1-2 mg/kg whichever less. failure q.12h. * Drug Facts & Comparisons 2000, p. 654. European countries may use different dosing regimens.

Table – 4.7: Dosage Adjustment After Serum Theophylline Measurement If serum theophylline is: Directions Increase dose by about 25% at 3 day intervals until Too low 5 to 10 mcg/ml either the desired clinical response or serum concentration is achieved. Within desired Maintain dosage if tolerated. Re-check serum 10 to 20 mcg/ml range concentration at 6-12 days. Decrease doses by about 10%. Re-check doses 20 to 25 mcg/ml after 3 days. Skip next dose and decrease subsequent doses by Too high 25 to 30 mcg/ml 25%. Recheck level after 3 days. Skip next 2 doses and decrease subsequent doses by > 30 mcg/ml 50%. Recheck levels after 3 days.

• USE IN SPECIAL CASES: other signs of toxicity in nursing infants. It Pregnancy- Risk-benefit evaluation, use only might be advisable to nurse the infant just if clearly needed (Category C). Theophylline before the mother takes the drug. If side seems to cross the placental barrier, but is not effects are apparent, a decision should be known if it can cause fetal harm. Neonatal made whether to discontinue nursing or irritability and apnea have been reported. discontinue the drug, taking into account the Lactation- Theophylline distributes readily importance of the drug to the mother. into breast milk. May cause irritability and

Respiratory Drugs

Children- Use only when necessary. Infants • INTERACTIONS: < 1 year of age have not been studied Drug effects on Theophylline levels; sufficiently, need to use extreme caution. Exercise caution in young children who Agents that Decrease Level cannot complain of minor side effects, and β-agonist sympathomimetics may experience toxicity. There has been Barbiturates Benzodiazepines some concern about the impact of Hydantoins Ketoconazole theophylline on learning, attention and Rifampin cognitive functions, but studies have not Smoking (cigarettes or marijuana) proven any real problems. May Increase or Decrease Renal Disease- Use with caution, drug Carbamazepine metabolites are excreted by the kidneys. Influenza virus vaccine Liver Disease- Need to use reduced doses for Isoniazid Loop diuretics hepatic disease. The drug is extensively Agents that Increase Level metabolized in the liver, and plasma Allopurinol Ca channel blockers clearance is reduced with hepatic function Cimetidine Corticosteroids impairments leading to toxicity. Macrolides • PRECAUTIONS AND WARNINGS: Non-selective β-blockers -Status asthmaticus is a medical emergency Oral contraceptives and is not rapidly responsive to usual doses Thyroid hormones of medication. Need intensive care setting. Caution should be used when using these -Cardiac effects: Theophylline may cause medications with theophylline, adjust dysrhythmias or worsen pre-existing dosage of theophylline accordingly. arrhythmias. Any significant changes in • OVERDOSE: cardiac rate or rhythm should be monitored. Symptoms include the adverse side effects, Use extreme caution in patients with mainly: anorexia, nausea, vomiting cardiac disease. nervousness, insomnia, irritability, tachy- -Use caution in patients with hypoxemia, cardia, tachypnea, tonic/clonic convulsions, hepatic disease, peptic ulcer disease, life-threatening ventricular arrhythmia, hypertension, alcoholism, heavy smokers, respiratory arrest. the elderly (particularly males) due to Overdose with sustained release prep- decreased plasma clearance of medication, arations may cause a dramatic increase in and neonates. All are candidates for toxicity serum theophylline concentrations with effects. time (≥ 12 hrs.). Early treatment will help • ADVERSE EFFECTS: but will not prevent these delayed elevated CNS stimulation; irritability, restlessness, levels. insomnia, headache, tremor, palpitations, Treatment: Transport to hospital as soon as tachycardia, flushing, hypotension, nausea, possible. If seizure has not occurred induce vomiting, anorexia, epigastric or abdominal vomiting, even if emesis has occurred pain, diarrhea, activation of peptic ulcer, spontaneously, ipecac syrup is preferred. transient urinary frequency, kidney Take precautions against aspirations irritation, fever, dehydration, and in severe especially in infants and children. If cases drug-induced seizures, circulatory vomiting is unsuccessful or contraindicated failure or respiratory arrest. (patient is unconscious), need to perform gastric lavage. If seizure occurs, establish an airway; administration of oxygen may be needed. Need to provide supportive measures as required and dialysis if needed.

• BRANDS: Directions: Give explicit directions for use Asthma ‘T’ (Sam-On), Glyphillin (Teva), of inhaler to the patient. Periodically check Somophyllin CRT (Fisons), Theo-dur (Key the adequacy of patient’s technique and Pharmaceuticals), Theopharm (JePharm) compliance, especially if no improvement Theotard (CTI), Theotrim (Trima). is observed. ______Proper nebulizer use: Dilute the dose of solution for nebulizer in sterile normal saline to a total volume of 3 ml and administer over WHO,P 2) Salbutamol / Albuterol 5-10 minutes period. Metered dose inhaler: shake the inhaler with • DRUG SUMMARY: canister in place for 5-10 seconds, breathe out Salbutamol, also called albuterol, is a to the end of a normal breath, hold the inhaler synthetic sympathomimetic amine and system upright, place the mouth piece into the moderately selective β2-adrenergic agonist mouth, close the lips tightly or position the with comparatively long action. Classified mouth piece 2-3 fingers width from the open as an autonomic nervous system agent, β- mouth and tilt head slightly backwards. While adrenergic agonist and a bronchodilator activating the inhaler, take a slow deep breath (respiratory smooth muscle relaxant). It has for 3-5 seconds, hold breath for 10 sec and α exhale slowly. Allow 1 min between minimal or no effects on -adrenergic inhalation. receptors. It is effective as isoproterenol and metaproterenol, but produces more *If the required effective dose fails to provide relief, it could be a sign for prolonged bronchodilation with little direct seriously worsening asthma, which requires cardiac stimulation. reassessment of therapy. Patient should not • INDICATIONS: increase the number or frequency of To relieve bronchospasm associated with inhalations without medical advice. acute bronchospasm or chronic asthma, *If the patient is to receive beclomethasone bronchitis, or other reversible obstructive inhalation treatment, salbutamol should be airway disease. Prophylaxis in exercise administered 20-30 minutes before. induced bronchospasm. For infants and young children, inhaled • CONTRAINDICATIONS: medications can be delivered through Hypersensitivity to any component (allergic aerochamber or babyhaler and to older reactions are rare), cardiac arrhythmias children through spacer. associated with tachycardia. • • DOSAGE FORMS: USE IN SPECIAL CASES: Pregnancy- There are no adequate studies in Tablets, syrup, aerosol, solution for nebulizer. pregnant women (Category C). Salbutamol • RECOMMENDED DOSAGE: ≥ may cross the placental barrier. Use if Adults 12 y: PO: 2-4 mg t.i.d. or q.i.d. potential benefit outweighs potential risk to May increase, max. 32 mg/24h. the fetus. Oral salbutamol has delayed pre- Inhaled: 1-2 inhalations q. 4-6 h. term labor, avoid use. Nebulized: 2.5-5mg q.i.d. Lactation- It is not known whether Children 6-12 y: PO: 2 mg t.i.d. or q.i.d., salbutamol is excreted in breast milk. Use may increase; max. 24 mg/24h. only when benefit outweighs the potential Inhaled: 1-2 inhalations q. 4-6 h. risk on the nursing infant. Nebulized: 2.5mg q.i.d Children- This drug has been used in young Children < 6 y: PO: 0.1 mg/kg t.i.d. may children even though its safety and efficacy be increased to 0.2 mg/kg t.i.d., has not been established for children < 2 yrs. max. 12 mg/24h. old for syrup and nebulizer, 6 yrs. for tablets. Nebulized: 0.15 mg/kg q.i.d. Note that children appear to be more

Respiratory Drugs susceptible to experience CNS stimulation; adverse effects. Seizures, hypokalemia and hyperactivity, excitement, and insomnia. hypertension may result. Renal Disease- Use with caution. The drug is Treatment includes general supportive eliminated in the urine in 3 days. measures. Sedatives (barbiturates) may be Liver Disease- Use with caution. Salbutamol given for restlessness. Use of a cardio- is metabolized in the liver. selective β-receptor blocker (i.e. • PRECAUTIONS AND WARNINGS: metoprolol) is suggested, bearing in mind -Special risk patients; use caution with the danger of inducing an asthmatic attack. patients with diabetes mellitus, hyper- Dialysis is not appropriate. thyroidism, and severe cardiovascular Symptoms due to oral absorption; disease. palpitation, tachycardia, heart block, -A common adverse effect associated with delirium, chills, nausea and vomiting, as the oral form of drug is fine tremor in well as the above symptoms can occur. fingers, which may interfere with precision Treatment: Emesis, gastric lavage or handwork. Keep informed of any unusual charcoal may be useful following overdose symptoms. with the oral agent. Need to use supportive • ADVERSE EFFECTS: measures. Tremor of the hands, anxiety, nervousness, • BRANDS: headache, palpitation, hypertension or Aerolin (3M), Asmalin (Agis), Fedral (Eastern hypotension, dilated pupils, hoarseness, Chem.), Salbuvent (Leiras), Ventocare nausea, muscle cramps, and possible (Pharmacare), Ventolin/ Volmax (Glaxo), hypersensitivity reactions such as rash Ventomin (Megapharm). (rarely with inhaled salbutamol). The ______patient should be warned about such things. In severe cases can cause convulsions and 3) Cromolyn WHO,P reflex tachycardia. (Cromoglycate) Sodium • INTERACTIONS: Overview of Salbutamol • DRUG SUMMARY: Drug-Drug Interaction Cromolyn sodium, also known as Drug Interaction cromoglycate, is a synthetic antiasthmatic, An additive effect when antiallergic, mast cell membrane stabilizer. Epinephrine, administered with these might It has no antichlolinergic, antiinflam- or other occur. Patients should be sympatho- matory, or vasoconstrictor activity. It is of advised to avoid OTC drugs, mimetic no value in the treatment of an acute such as cold remedies, broncho- attack/quick relief. Regular inhalation can dilators without consulting a doctor or pharmacist. reduce the incidence of asthma attacks, and Beta- These antagonize the effects allow dosage reduction of bronchodilators adrenergic of sympathomimetics. Do not and oral corticosteroids, and is best used for blockers administer both medications the prevention of exercise induced asthma together. especially in children. Tricyclic anti- May potentiate the action of • INDICATIONS: depressants sympathomimetics on the Primarily used for prophylaxis of mild to vascular system, use caution. moderate seasonal and perennial bronchial • OVERDOSE: asthma and allergic rhinitis. Also used for Symptoms due to inhalation include an prevention of exercise related broncho- exaggeration of the side effects listed in spasm (prevent bronchoconstriction), prevention of acute bronchospasm induced by known pollutants or antigens. Used as

ophthalmic preparations for allergic ocular disorders. *Advise patient to clear as much mucus as • CONTRAINDICATIONS: possible before inhalation treatments. Hypersensitivity to cromoyln or any of its *Inform patient that throat irritation, cough, components. hoarseness can be minimized by gargling • DOSAGE FORMS: with water. Drinking a few swallows of Inhalation, syrup. water will help. • RECOMMENDED DOSAGE: *Cromolyn does not eliminate the See table-4.8. continued need for therapy with bronchodilators, expectorants, antibiotics, Directions: It is important to inform the or corticosteroids, but the amount and patient that effectiveness of therapy frequency of use of these medications may depends upon administration at regular be reduced. time intervals.

*Onset of action requires 1 week for full effectiveness. Duration of effect lasts 4-6 hrs., and may last as long as 2 weeks. *A trial of 8-12 wks. should be conducted before determining that cromolyn is ineffective. *Treatment with cromolyn 15 minutes before doing protracted exercises, it reportedly blunts the effects of vigorous exercise as well as cold air.

Table - 4.8: Recommended Doses of Cromolyn (Aerosol inhaler) Asthma Bronchospasm‡ Adults and children 2 puffs inhaled, 4 times 2 sprays inhaled 10-15 min before ≥ 5 y a day exposure to the precipitating factor Children ≤ 4y Safety and efficacy has not been established (Ketotifen may be used under a specialist’s supervision) Nebulizer solution & Inhalation capsules via Asthma Bronchospasm‡ spinhaler Adults and children 20 mg (1 amp. or 1 cap.) 20 mg (1 amp. or 1 cap.) (> 5 y for capsules, and 4 times a day at regular No more than 1 hour before ≥ 2 y for nebulizer intervals exposure to the precipitating factor. solution) ‡ Bronchospasm due to exercise or environmental agents. * Drug Facts & Comparisons 2000, p. 681.

Respiratory Drugs

• USE IN SPECIAL CASES: suppress the hypothalamic-pituitary- Pregnancy- Use Cromolyn only when benefit adrenocortical function or produce other outweighs potential risk. Safe use during systemic effects. Because asthma is pregnancy has not been established. Animal predominantly an inflammatory disease, studies have demonstrated adverse fetal inhaled corticosteroids are becoming effects (Category B). important in chronic asthma therapy. They Lactation- Use caution. Safety for use in are not to be used during an acute asthma nursing mothers has not been established. attack because they don’t give fast relief Children- Safety and efficacy have not been like salbutamol. They are not to be used for established for aerosol in children < 5 y. and chronic bronchitis or emphysema either. for nebulizer in < 2 y. Oral use should be • INDICATIONS: cautiously used in children < 2 y. under direct Oral inhalation to treat chronic asthma pediatrician’s supervision. adjunctively with other therapy (sympatho- Renal + Liver Disease- Decrease of dose or discontinuation may be advisable in severe mimetics, xanthines), when these are cases of renal or hepatic impairment. insufficient in controlling asthma. Relief of • PRECAUTIONS AND WARNINGS: symptoms of seasonal or perennial rhinitis in those cases poorly responsive to -Cromolyn has no role in the treatment of acute asthma, make sure to inform the conventional treatment. Allergic and patient about this. vasomotor rhinitis. • • ADVERSE EFFECTS: CONTRAINDICATIONS: Dizziness, headache, lacrimation, rash, Hypersensitivity to the drug or any joint pain and swelling, nausea, nasal component of the product. itching or burning, sneezing, dry or irritated Untreated localized infections involving the throat, urinary frequency, and cough have nasal mucosa (i.e. fungal infections of all been reported. Candida albicans), and status asthmaticus. • • INTERACTIONS: DOSAGE FORMS: No interactions have been reported. Aerosol (50 mcg/metered dose: 1-inhalation), • OVERDOSE: nasal spray, inhalation caps. • Stop administration of medication. In RECOMMENDED DOSAGE: accidental overdose, no action other than Refer to table 4.4. medical observation should be necessary. For inhalation for asthma; • BRANDS: Adults: Cromunal Inhaler (Agis), Lomudal Spin Low dose: 200-500 mcg/day (4-10 puffs) in Capsules (Fison), Lomudal Nebuliser Solution 2-4 divided doses (Fisons), Nalcrom Oral Capsules (Fisons), Medium dose: 500-800 mcg/day (10-16 puff) in Vicrom Inhaler (Fisons). 2-4 divided doses ______High dose: > 800 mcg/day (16 puffs) in 2-4 divided doses Max. 20 inhalations/24 h. 4) Beclomethasone WHO,P Children (<12 yrs): Dipropionate Low dose: 100-300 mcg/day (2-6 puffs) in • DRUG SUMMARY: 2-4 divided doses. A synthetic corticosteroid structurally Medium dose: 300-600 mcg/day (6-12 related to hydrocortisone, with potent puffs) in 2-4 divided doses. glucocorticoid (anti-inflammatory) and High dose: > 600 mcg (> 12 puffs) weak mineralocorticoid activity. Unlike (200 mcg/dose is not indicated for children). hydrocortisone, therapeutic doses do not

For allergic Rhinitis; • ADVERSE EFFECTS: Adults: 1 spray in each nostril b.i.d. to q.i.d. Sneezing after administration; rarely Children (6-12 yrs): 1 spray in each nostril dryness and irritation of nose and throat, 3 times a day and epistaxis. Hoarseness and oral (< 6 yrs): no recommended dosage since no candidiasis may occur, these effects may be sufficient data is available. minimized by using a spacer device or by

Directions: Clear nasal passages of rinsing the mouth after each usage. secretions prior to use. If nasal passages are • INTERACTIONS: blocked, use a decongestant before No major interactions have been reported administration to ensure adequate when using the inhalation in the penetration of the spray. recommended doses. *Use the bronchodilator (salbutamol) • OVERDOSE: several minutes before inhaling the If recommended doses of intranasal corticosteroid, to enhance penetration of the beclomethasone are exceeded or if steroid into the bronchial tree. individuals are particularly sensitive or *Effects are not immediate and benefit predisposed by virtue of recent systemic requires regular use and usually occurs steroid therapy, symptoms of hyper- within 1-4 weeks. cortisolism may occur, including, very • USE IN SPECIAL CASES: rarely, menstrual irregularities, acneiform Pregnancy- Topical administration of lesions and cushingoid features. If such recommended dosage is unlikely to achieve changes occur, discontinue slowly, significant systemic levels; however, use consistent with accepted procedures for these agents during pregnancy only if the discontinuing oral steroids. potential benefits outweigh the potential • BRANDS: hazards to the fetus (Category C). Bacloforte Inhaler (Glaxo), Beconase Nasal Lactation- Use caution when administering to Aerosol (Glaxo), Becotide Inhaler (Glaxo), nursing women. It is not known whether Viarex Inhaler (Schering USA). these inhaled drugs are excreted in breast ______milk. Children- the most recent guidelines issued by the National Asthma Education & 5) Prednisolone WHO,P Prevention Program use this drug in children < 6 yrs., even though there is no safety and Refer to the Endocrine chapter under efficacy reports for use; therefore the drug prednisone for further details. should be used with caution. Growth Acute attack of asthma should be treated retardation does not seem to be a problem with short course of oral corticosteroid associated with inhalation administration in Dose in acute asthma: 1-2 mg/kg/day PO in recommended doses. Spacer devices may 2-3 divided doses for 5-7 days. No need to improved delivery in this age group, and taper it if it is used less than 1 week. Some reduce possible adverse effects of the inhaled schools recommend a short course of 3-5 corticosteroid. days, given once in the morning with no • PRECAUTIONS AND WARNINGS: tapering (Nelson, 2001). -Localized fungal infections with Candida Alternate day administration has not been albicans or Aspergillus niger have occurred successful in the management of asthma in mouth, pharynx and occasionally in the because control tends to diminish during larynx. Decrease or discontinue aerosol the second 24 hours. Dosage should always steroid treatment and use appropriate be titrated to the lowest dose that control antifungal therapy. symptoms.

Respiratory Drugs

Patients who have been taking long-term oral corticosteroids can be transferred to an inhaled product, but the transfer should be done slowly with gradual reduction in the oral dose, at a time when the asthma is well controlled.

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Chapter 5: ANTI-INFECTIVE DRUGS

A) ANTI-BACTERIALS 1. Penicillins 2. Cephalosporins 3. Tetracyclines 4. Macrolides 5. Sulphonamides and Trimethoprim 6. Nitrofurantoin (UTI) 7. Nalidixic Acid (UTI) 8. Fluoroquinolones (UTI)

B) ANTI-TUBERCULOSIS 1. Isoniazid 2. Rifampicin 3. Pyrazinamide 4. Ethambutol

C) ANTI-PARASITICS 1. Metronidazole 2. Diloxanide Furoate 3. Mebendazole 4. Niclosamide 5. Albendazole (hydatid disease)

D) ANTI-FUNGALS 1. Nystatin 2. Miconazole 3. Griseofulvin

C) ANTI-VIRALS 1. Acyclovir

ANTI-INFECTIVES

Anti-infectives are those agents that are spectrum antibiotics should be restricted to used for the treatment of infections by treatment of specific infections caused by a suppressing or destroying the causative few organisms or even a single species of microorganisms (bacteria, mycobacteria, organism. The property of broad specifica- fungi, protozoa, or viruses). tion should not be confused with a free license for broad-nonspecific use. Anti-infective agents should be used only ◊ Superinfection (suprainfection): Is the when: appearance of both microbiological and a. A significant infection has been clinical evidence of a new infection with diagnosed or is strongly suspected. pathogenic microorganisms or fungi not b. An established indication for prophy- sensitive to the used drugs during lactic therapy exists. antimicrobial treatment of a primary Abuse of these agents causes super- disease. The body's natural resistance is infections, cross-sensitivity and cross- compromised, making it more susceptible resistance, resulting in inappropriate to secondary infections by more dangerous treatment and in consequent advserve strains. reaction in adition to wastage of money. ◊ Auto-infection: Infection by an

DEFINITIONS: organism existing within the body or transferred from one part of the body to ◊ Bacteriostatic agents: Agents that another. inhibit the growth of the microorganisms by producing reversible changes. This ABUSE OF ANTIMICROBIAL AGENTS: delay in the growth will give the immune Antibacterials are valuable drugs if used system the chance to get rid of the appropriately. They are very effective in microorganism. treating infections if used in appropriate ◊ Bactericidal agents: Agents that kill the doses, at appropriate intervals and for the microorganism. appropriate period of time against sensitive (Being a bactericidal or a bacteriostatic microorganisms. agent depends on the mechanism of action They should not be used in the following of the antibacterial agent and on its cases: concentration.) 1. To treat all infections (e.g. viral infections ◊ Narrow spectrum: The range of activity or nonspecific inflammation). for agents that kill the micro-organism is 2. For minor infections (e.g. superficial small. It affects 1-2 classes of micro- bruises). organisms only. For example, Penicillin-G 3. Just because it is a new agent on the affects G+ve organisms and Neisseriae. market, while there is already another

◊ Broad spectrum: The range of activity effective and cheaper alternative in use. extends to many micro-organisms. For example, Tetracyclines depress G+ve, G- BACTERIAL RESISTANCE: ve, Rickettsiae and Chlamydiae. Antimicrobial agents are loosing their Separation between narrow and broad- effectiveness because of the spread of drug- spectrum activity is not clear due to the resistant strains. Therefore, there might emergence of many resistant strains due to come a time when such agents are no the overuse of these antibiotics. Broad- longer useful to combat diseases.

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Anti-Infectives The problem of microbial resistance is by carrying the susceptibility tests or by a global and is the result of widespread and good clinical experience in treating a given indiscriminate use of antimicrobial drugs in syndrome that will help in suggesting a man, animal and agriculture. Some bacteria potential effective agent. are naturally resistant to certain antibiotics b. Patient factors: These factors play a very (e.g. Staphylococcus), but often resistance important role in the selection of a specific is acquired. Bacteria can become resistant anti-infective agent, determination of the by incorporating a “resistance factor” into appropriate drug dosage and route of their genes to render the antibiotic administration,...etc. Those factors include: ineffective. This can pass quickly to other 1. History of drug allergy or adverse bacteria and this is called cross-resistance. reactions. Anaphylaxis or reactions due to Multiple resistance, where bacteria are immunoglobulin E (IgE) may be life resistant to several antibiotics, can also be threatening when taking penicillins. transferred from one species to another (i.e. 2. Age: A drug’s pharmacokinetic Mycobacteria). properties vary widely in patients of Emerging bacterial resistance is different age groups. increasing world wide. For example, 3. Underlying disease: methicillin resistant Staph. aureous -A pre-existing kidney and liver disease. (MRSA), vancomycine resistant staphylo- -CNS disorder. coccus, and Strep. pneumonia resistant to -Neuromuscular disorders. penicillins. Culture analysis is required to 4. Immunological status: Patients with identify proper treatment in these cases. impaired immune system require a Antibiotics given concurrently are bactericidal agent rather than a bacterio- useful in very specific circumstances (e.g., static one. as part of a mixed drug treatment in 5. Pregnancy and lactation. tuberculosis). Fixed-ratio combinations of 6. Genetic traits. antibiotics (other than co-trimoxazole) have 7. Presence of a foreign body: It has been few indications. The US FDA has found that the presence of prosthetic joints withdrawn almost all fixed dose or valves, cardiac pacemakers, and various combinations. There is only one drug kept internal shunts may reduce the (co-trimoxazole) on the WHO list of effectiveness of many anti-infective agents. essential drugs. According to the WHO, “Special mention must be made of the use DURATION OF ANTI-INFECTIVE of preparations containing two or more THERAPY: antibiotics in fixed ratio. Their spectrum of Acute cases: Treatment of acute activity is often so wide that they have uncomplicated infections generally should undesirable effects on the body, few of them continue until the patient has been afebrile have notable therapeutic advantages and and asymptomatic for at least 72 hours they are generally costly.” (minimum 5 days in most cases). Other cases as in Strep. throat (Streptococcal SELECTING AN ANTI-INFECTIVE pharyngitis) should be treated for 7-10 AGENT: days. Some infections require a proof of When you want to choose an anti-infective eradication by culture. agent, you should take into consideration Chronic cases: Treatment of chronic the following parameters: infections (e.g., endocarditis, osteomyelitis) a. The spectrum of activity of the anti- may require a longer duration (4 to 6 infective agent: It should be active against weeks), with a follow-up culture analysis the causative pathogen. This can be known afterwards.

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LACK OF THERAPEUTIC EFFECT- j. Unpleasant side effects that the patient IVENESS: cannot handle for example diarrhea, This problem arises due to one or more of constipation, stomach upset ...etc. the following reasons: STORAGE OF THE ANTI-INFECTIVE a. Misdiagnosis (inappropriate indication): AGENTS: Either a doctor’s or a lab’s error of identified Generally, antibiotics should be stored in a organism (the causative agent of the specific infection). cool dry place and protected from sunlight b. Improper drug regimen: Either the dose as they undergo degradation in high or the route of administration, or dosing temperatures. Most suspended forms should frequency, or the duration of therapy is be kept in the refrigerator after being mixed inappropriate. with water (check individual packages). c. Inappropriate choice of antibiotic agent: Occurs when the patient’s factors and the EXPIRATION DATE OF THE ANTI- agent’s spectrum, or the agent’s INFECTIVE AGENTS: pharmacological properties, are not taken into Tablets, capsules: As indicated on the box. consideration or when another agent might be Dry suspensions: The expiry date that is more suitable for the case. indicated on the box is for the dry powder d. Using a combination of bacteriostatic before suspending or diluting with purified and bactericidal agents: Each one will water. eliminate the effect of the other. Bactericidal After dilution: Normally, the bottle of agents need the microorganism to be active in medication should be used within 5-7 order to kill it while a bacteriostatic agent days. Refer to the label on the bottle. If inhibits the growth of the microorganisms. the diluted suspension lasted for more e. Microbial resistance. than the assigned time duration, this f. Unrealistic expectations: For example, might be an indication of misuse or wrong fever should not be treated by antibiotics dilution. The suspension left should not be since it may occur due to other non-infectious used after 7-14 days from the day of causes. In cases where surgical drainage is dilution (always check the manufactures required or renal calculi are present, antibiotic label). failure is expected. ______g. Infection by two or more microorganisms (mixed infection). h. Improper formulation of the final dosage A) ANTI-BACTERIALS form, the raw materials quality and storage, or improper manufacturing procedures; such Antibacterials are divided into subgroups, as compression and coating, that will interfere and are presented as such: Penicillins, with the bioavailability of the final product. cephalosporins, tetracyclines, macrolides, i. Patient compliance: Patients frequently sulphonamides and trimethoprim, and discontinue antibiotic therapy when they feel antibiotics used in urinary tract infection better. Unfortunately these individuals may (UTI). then self-prescribe the remaining antibiotic for themselves or for others at some other 1) Penicillins (β-Lactam) time. On the other hand patients might forget to take all of the scheduled doses or find it Agents of this group are characterized by difficult to wake up for a dose. All of these the presence of a β–lactam ring in their problems with patient compliance might lead structure. This ring is the one responsible to lack of therapeutic effectiveness. for their activity.

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Anti-Infectives Penicillins are the drugs of choice for the 24 hrs. It is the preferred choice for the treatment of a wide variety of infections treatment of syphilis, but neurosyphilis caused by various susceptible micro- requires special consideration. organisms. The three major groups of b- Benzathine penicillin: a benzylpenicillin penicillins are: salt with a very low solubility, giving a a. Benzylpenicillin & phenoxymethyl- prolonged action after intramuscular penicillin (natural penicillin) injection. Its duration of action is 20 days. b. Cloxacillin & flucloxacillin (penicillinase resistant penicillin) Phenoxymethyl penicillin (Pen. V) has c. Ampicillin & Amoxicillin (amino- a similar antibacterial spectrum as Pen. G, penicillin) but it is less active. It is gastric acid stable so it is suitable for oral administration. It Penicillins are bactericidal agents that should not be used for serious infections produce their antibacterial activity via because absorption can be unpredictable inhibiting the synthesis of the bacterial cell and plasma concentrations are variable. wall. • INDICATIONS:

WHO,P Benzylpenicillin is mainly indicated for the a) Benzylpenicillin & treatment of: throat infections, otitis media, Phenoxymethyl penicillin WHO,P streptococcal endocarditis, meningococcal and pneumococcal meningitis (if caused by • DRUG SUMMARY: susceptible microorganism), and as a These two are known as the natural prophylactic agent after limb amputation. penicillins. They are the first two Also it is used in combination with other penicillins that were discovered and are still agents if more than one organism are in use. Natural penicillins are narrow suspected. spectrum antibiotics and are only active Phenoxymethyl penicillin is indicated against facultative gram-positive cocci, principally for respiratory tract infections in rods and gram-negative cocci. Several children, for Streptococcal tonsillitis and for anaerobic gram-negative rods are sensitive continuing treatment after one or more to penicillin, with the notable exception of injections of Pen. G when clinical response has begun. It should not be used for Bacteroides fragilis. meningococcal or gonococcal infections. It is Benzylpenicillin (Pen. G) is the drug of used prophylactically against rheumatic fever choice in streptococcal, pneumococcal, following streptococcal infections. gonococcal, and meningococcal infections. • CONTRAINDICATIONS: It is also used in anthrax, diphtheria, gas- They are contraindicated in the case of gangrene, leptospirosis, syphilis, tetanus, hypersensitivity to any of the penicillins or yaws, and in the treatment of lyme disease cephalosporins. Procaine penicillin is also in children. It is inactivated by the gastric contraindicated in the case of hyper- fluids, and absorption from the gut is low; sensitivity to procaine or any other “caine- therefore it is best given by injection. In type” local anesthetic. addition to the use of Pen. G as sodium or • DOSAGE FORMS: potassium salts (soluble Pen. G), it is also Benzylpenicillin: vial. available in two other salts that are Phenoxymethyl penicillin: tablet, suspension. commonly used. They are: a- Procaine penicillin: a sparingly soluble Directions: It is recommended that salt of benzylpenicillin. It is used in intra- performance of a skin sensitivity test as well muscular depot preparations that provide as taking a good history, before giving therapeutic tissue concentrations for up to penicillins be done; adrenaline, dexamethasone and aminophylline injections

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should readily be available for treatment in • PRECAUTIONS AND WARNINGS: case of anaphylactic shock. (Reported Caution should be taken in case of: history incidence of anaphylactic shock is between of or suspected allergy (asthma, eczema, 0.015-0.04%.) hay fever, hives), myasthenia gravies, Food increases the breakdown of such epilepsy, neonates, young infants. penicillins in the stomach. These agents are If Pen. G Na is to be administered, take best taken on an empty stomach either one caution in patient with restricted Na intake. hour before meal or two hours after. Benzylpenicillins may cause convulsions • USE IN SPECIAL CASES: after high doses by IV or in renal failure. Pregnancy- Natural penicillins cross the • ADVERSE EFFECTS: placenta with low concentrations, and in For most people it is one of the safest general are safe during pregnancy drugs. (Category B). Nevertheless, these agents Some side effects that have been reported: should be used only when it is clearly in the case of parenteral penicillin, injection indicated. site reactions might occur. Electrolyte Lactation- Compatible. Penicillins are disturbances might occur with penicillin-G excreted in breast milk in low Na and K salts due to accumulation of these concentrations; use may cause diarrhea, salts in the body. candidiasis or allergic response in the In the case of phenoxymethyl penicillin one nursing infant. might suffer from the following side Liver diseases- Use with caution. effects: Nausea, vomiting, diarrhea, Kidney diseases- Cautious use, since the epigastric distress, hypersensitivity reactions kidney excretes penicillins. Avoid benzyl- (flushing, pruritus, urticaria or other skin penicillins in renal failure. eruptions, eosinophilia, anaphylaxis), hemolytic anemia, leukopenia, thrombocytopenia, neuropathy, superinfections.

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Anti-Infectives • RECOMMENDED DOSAGE:

Penicillin Route of Indication Age administ- Dose Derivative ration 1.2-2.4 million IU divided Adult IV/IM Benzyl- Moderate to severe q. 4-6 h. infections* 25,000-300,000 IU/kg penicillin Child IV/IM (Pen. G) divided q. 4 h. If meningococcal disease Adult IV/IM 1.2 g is suspected GP are > 10 y. IV/IM As for adults advised to give a single Child; injection of benzyl- IV/IM 600 mg penicillin before sending 1-10 y. the patient to the hospital Infants IV/IM 300 mg Adult IM 1,200,000 IU once/d Benzathine Mild to moderate Child IM > 27 kg: 900,000 IU once/d. penicillin infections * (including tonsillitis) < 27 kg, or < 5 yrs: 300,000- 600,000 IU single dose. Syphilis Adult IM < 1 y duration: 2,400,000 IU as single dose. > 1 y duration: 2,400,000 IU/wk for 3 wk. Congenital: 50,000 IU/kg as Child IM single dose. Prophylactic for Adult IM 1,200,000 IU every 4 weeks rheumatic fever Child IM 1,200,000 IU once for prevention, and every 3-4 weeks for prevention of recurrence. Moderate to severe 600,000-1,200,000 IU Adult IM Procaine infections * once/day for 10-14 days. penicillin Child IM 300,000 IU (0.3 g) once/day Pneumococcal Pneumonia Adult IM 600,000 IU q. 12 h. Uncomplicated Adult IM 4,800,000 IU divided Gonorrhea (if sensitive to between two different penicillins) injection sites at one visit, preceded by 1 g of probenecid 30 min. before inj. Syphilis Adult IM Primary, secondary, latent: 600,000 IU/day for 8 days. Late latent, tertiary, neurosyphilis: 600,000 IU /day for 10 to 15 days. Child IM 500,000-1,000,000 IU/m2, once/day.

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Adult PO 125-500 mg q. 6 h. Phenoxy- Mild to moderate infections * Child PO 15-50 mg/kg/d in 3-6 methyl < 12 y divided doses. penicillin Endocarditis Prophylactic Adult PO 2 g 30-60 min. before (Pen. V) surgical procedure; then 500 mg q. 6 h. for 8 doses. Child PO < 30 kg; 1 g 30-60 min. before procedure; then 250 mg q. 6 h. for 8 doses. * Moderate to severe infections include: Otitis media, Streptococcal throat infections, Meningococcal and Pneumococcal Meningitis, and Strep.Endocarditis.

• INTERACTIONS: to occur in patients with severe renal Overview of Penicillins impairment. Drug-Drug Interactions Symptoms may include: agitation, Drug Interaction confusion, hallucinations, stupor, coma, Erythro- Coadministration effect of a seizures, and encephalopathy. Hyper- mycin penicillin and erythromycin is kalemia is also possible. unpredictable. Some studies Management is by symptomatic treatment. have shown antagonist effect, Hemodialysis may be used in severe cases. while others showed a • synergistic effect when BRANDS: bactericidal effects are Bepen V.K. (BPC), Fenoxypen (Novo Nordisk), desirable. Mega (Rafa), Rafapen V-K (Rafa), Rafapen Use combination only when Oracillin (JePharm) either drug alone has failed. ______Oral contra- Pen. G decreases the efficacy of WHO,P ceptive these agents. Use additional b) Cloxacillin & flucloxacillin methods (e.g. condoms). (Penicillinase resistant penicillins) Potassium May cause hyperkalemia with sparing Pen. G potassium. Avoid • DRUG SUMMARY: diuretics concomitant use. Most staphylococci are now resistant to Probenecid It decreases renal elimination of benzylpenicillin because they produce penicillins producing higher and more prolonged plasma penicillinases. concentration. This is beneficial Cloxacillin and flucloxacillin are not in treatment of gonorrhea. affected by such enzymes, so they are effective in infections caused by penicillin Large doses of penicillin may cause false resistant staphylococci, but they are less positive test results with Benedict’s solution, potent than Pen. G against penicillin in urine glucose test; but not with glucose sensitive microorganisms, and generally oxidase method. ineffective against G-ve bacteria and • OVERDOSE: methicillin resistant staphylococci. The This may arise with the use of massive only difference between cloxacillin and doses of IV penicillin (40 to 100 million flucloxacillin is that flucloxacillin has a units/day). Penicillins overdose can lead to higher bioavailability than cloxacillin after neuromuscular hyper-excitability or oral administration. Another two examples convulsive seizures. It is more commonly of this group are Methicillin and

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Anti-Infectives Temocillin. However, only the first two • PRECAUTIONS AND WARNINGS: will be discussed. Cautious use in history of or suspected Notes: Sulbactam is another β-lactamase allergy (asthma, eczema, hives, hay-fever), inhibitor that is used in combination with renal or hepatic function impairment, ampicillin. Two commonly used history of allergy to cephalosporins. combinations in the market are ampicillin • ADVERSE EFFECTS: with flucloxacillin (Megacare, Magnicillin) and GI: Nausea, vomiting, flatulence, diarrhea. amoxicillin with cloxacillin (Clamoxin). Hematologic: Eosinophilia, leukopenia, • INDICATIONS: agranulocytosis. Cloxacillin and flucloxacillin are indicated Hypersensitivity: Pruritus, urticaria, rash, for the treatment of infections caused by wheezing, sneezing, chills, drug fever, penicillinase producing Staphylococci. anaphylaxis. • CONTRAINDICATIONS: Others: Super-infections. Hypersensitivity to penicillin. • INTERACTIONS: • DOSAGE FORMS: Refer to penicillin drug-drug interactions. Cloxacillin: Capsules and suspension. • OVERDOSE: Flucloxacillin: Not available in a separate Refer to penicillin G. formulation, but as combination with • BRANDS: ampicilin in Capsules. Cloxapen (Eastern Chem.), Loxavit (Vitamed), • RECOMMENDED DOSAGE: Orbenil (Teva). Mild to Moderate Upper Respiratory & ______Localized Skin and Soft Tissue Infections Adults and children 250 mg q. 6 h. WHO,P (> 20 kg) c) Ampicillin & 50 mg/kg/day in Amoxicillin WHO,P (aminopenicillins) Children equally divided (< 20 kg) doses q. 6 h. The commonly used penicillins are Severe Infections ampicillin and amoxicillin. In our (Lower Respiratory Tract or Disseminated community, amoxicillin is mostly used. An Infections) important drug in this group is Co- Adult and children 500 mg q. 6 h. (> 20 kg) amoxiclav (combination of amoxicillin and Children 100 mg/kg/day in clavulanate) which will be discussed later. (< 20 kg) equal doses q. 6 h. Other examples of this group are bacampicillin and pivampicillin, which Another suggested cloxacillin dosage for are esters of ampicillin. infants and children is 50 to 100 • DRUG SUMMARY: mg/kg/day, up to a maximum of 4 g/d, Aminopenicillins are active against some divided q. 6 h. G+ve and G-ve organisms but inactivated • USE IN SPECIAL CASES: by penicillinases, including those produced Pregnancy- Use only when clearly indicated by Staphylococcus aureus, and by common (Category B). G-ve bacilli such as Escherichia coli. Lactation- Use with caution; safety not International studies indicate that all established, but it is excreted in breast milk. Staphylococci, 50% of E. coli strains and Neonates- Safety not established. 15% of Haemophilus influenzae strains are Liver diseases- Use with caution since they now resistant. are metabolized in the liver. Amoxicillin is a derivative of ampicillin Kidney diseases- Use with caution since they that differs only by one hydroxyl group. are primarily excreted in the urine.

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Unlike ampicillin it can be given 3 times But this is not the case of amoxicillin that is daily without regard to food. not affected by the presence of food, so it • INDICATIONS: can be given without regard to food. They are principally indicated for the • USE IN SPECIAL CASES: treatment of chronic bronchitis and mild Pregnancy- Use if clearly needed, risk-benefit ear infections, both of which are usually must be considered (Category B). Animal due to Streptococcus pneumoniae and reproductive studies have failed to Haemophilus influenzae. They are also demonstrate a risk to the fetus and there are indicated for: urinary-tract infections, otitis no adequate and well-controlled studies in media, sinusitis, chronic bronchitis, pregnant women. Penicillins in general have invasive salmonellosis, and gonorrhea. been considered safer than other antibiotics in Amoxicillin is also used for typhoid fever pregnancy. Use lowest effective dose when and endocarditis prophylaxis. needed. Lactation- Compatible in general. They are • CONTRAINDICATIONS: excreted in breast milk, use may lead to They are contraindicated in the case of sensitization of infants; therefore, risk-benefit hypersensitivity to penicillins. must be considered. • DOSAGE FORMS: Liver disease- It can be given safely. Capsules, suspensions and injections. Kidney disease- Caution use in the case of • RECOMMENDED DOSAGE: severely impaired renal function. Increase These are shown in table-5.2. dosing interval to 12 hrs. if creatinine

Directions: Absorption of ampicillin is clearance < 10 ml/min. • affected by the presence of food in the PRECAUTIONS AND WARNINGS: stomach, so it should be taken one hour Avoid use in patients with a history of or before or two hours after the meal. suspected allergy (hives, eczema, hay fever, asthma), severely impaired renal function, and with history of cephalosporin allergy.

Table – 5.2: Recommended Doses of Ampicillin and Amoxicillin# Ampicillin Systemic infections Adult PO 250-500 mg q. 6 h. IM/IV 250 mg - 2 g q. 6 h. Child PO 25-50 mg/kg/d divided q. 6 h. IM/IV 25-100 mg/kg/d divided q. 6 h. Meningitis Adult IV 150-200 mg/kg/d divided q. 4-6 h. Child IV Same as for adult Gonorrhea Adult PO 3.5 g with 1 g probenecid x 1 IM/IV 500 mg q. 8-12 h. Amoxicillin Mild to moderate Adult PO 250-500 mg q. 8 h. infectionsM Child PO 20-40 mg/kg/d divided q. 8 h. Gonorrhea Adult PO 3 g as single dose with 1 g probenecid.

# Reference: Drug Facts & Comparisons 2000. M Including infections of ear, nose, throat, GU, and lower RTI caused by Strep., penicillinase & non-penicillinase producing Staph., and H. influenzae.

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Anti-Infectives

• ADVERSE EFFECTS: • BRANDS: Similar to other penicillins, including: Ampicillin: Ampicillin Balapharm (Ciba-Geigy), -GI: diarrhea, nausea, vomiting, pseudo- Ampitricine (JCL), Ampipharm (JePharm), membranous colitis (rare). Broadacillin (BPC), Penibrin (Teva), Pentrexyl -CNS: convulsive seizures. (Bristol), Vitapen (Vitamed). -Skin: pruritus, urticaria, or other skin Amoxicillin: Amoxi (Genmedics), Amoxicare eruptions. (Pharmacare), Amoxitid (BPC), Apomoxyn (Curex), -Hematological: hemolytic anemia, thrombo- Hiconcil (Mead Johnson), Moxypen (Teva), cytopenia, purpura, eosinophilia, leukopenia, Moxepharm (JePharm), Moxyvit (Vitamed). agranulocytosis. ______-Others: superinfections, cojunctival ecchymosis. d) Amoxicillin with Clavulanic • INTERACTIONS: Acid (Co-amoxiclav) WHO,P Overview of Aminopenicillins Drug-Drug Interactions • DRUG SUMMARY: Drug Interaction Co-amoxiclav consists of amoxicillin and May inhibit activity of Tetracyc- the β-lactamase inhibitor clavulanic acid. lines amoxicillin & ampicillin. Avoid concomitant Clavulanic acid itself has no significant administration. antibacterial activity, but by inactivating Probenecid Prolongs the activity of penicillinase, it makes the combination amoxicillin; may be beneficial active against penicillinase-producing in some cases. bacteria that are resistant to amoxicillin. Allopurinol Increases incidence of rash These include Staph. aureus, E. coli strains, with ampicillin. Avoid and of H. influenzae strains, as well as concomitant use. many Bacteroides and Klebsiella spp. Chloram- May reduce the bactericidal • INDICATIONS: phenicol, effects of ampicillin, this Infections caused by susceptible β- erythro- interaction is significant lactamase producing organisms: lower mycin primarily when low doses of ampicillin are used. respiratory tract infections, otitis media, Oral contra- Ampicillin reduces the oral sinusitis, skin and skin structure infections, ceptives contraceptive effectiveness. and UTI. Female patients should be • CONTRAINDICATIONS: advised to consider Hypersensitivity to penicillins. nonhormonal contraception Infectious mononucleosis. while on antibiotics. • DOSAGE FORMS: β- blockers Ampicillin may reduce the Tablets and suspension. bioavailability of atenolol. • RECOMENDED DOSAGE: Case reports indicate that β- See table-5.3. blockers may potentiate anaphylactic reactions of Directions: May be taken without regards penicillin. to meal. *Reconstituted suspension should be • OVERDOSE: refrigerated and discarded within 10 days. In the case of renal function impairment aminopenicillins can be removed by hemodialysis, but not peritoneal dialysis.

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Table – 5.3: Recommended Doses of Co-amoxiclav Patient Dosage Adult 250 mg or 500 mg tab. q. 8 h. Children's dose is based on the amoxicillin content. Usually 20 mg/kg/day, in divided doses q. 8 h. Children (< 40 kg) Because of the different amoxicillin to clavulanic acid ratios in the 250 mg (250/125) tabs. vs. 250 mg chewable tabs. (250/62.5), do not use 250 mg tab. until the child’s weight > 40 kg. Children (>40 kg) Dose according to the adult recommendations. Severe infections and respiratory One 875 mg tab. q. 12 h. or one 500 mg tab. q. 8 h. tract infections (adult) Otitis media*, sinusitis, lower respiratory infections and severe Children (< 40 kg): 40 mg/kg/day, in divided doses q. 8 h. infections

*Co-amoxiclav has been used for short-term treatment in otitis media, (400/75 mg suspension) twice daily for children 2 mon-12 yr. (BNF 2001 Sep., p. 261).

Note: Since both the 250 and the 500 mg Patients with GFR <10 ml/min should receive tablets contain the same amount of 500 or 250 mg tablet q. 24 h., depending on clavulanic acid (125 mg as potassium salt), the severity of infection. Hemodialysis two 250 mg tablets are not equivalent to one patients should receive 500 or 250 mg tablet 500 mg tablet. Tablets containing 875 mg q. 24 h., they should receive additional dose amoxicillin also contain 125 mg clavulanic both during and at the end of the dialysis. acid. • PRECAUTIONS AND WARNINGS: • USE IN SPECIAL CASES: Lactation and pregnancy. See amoxicillin. Pregnancy- Co-amoxiclav should be used • ADVERSE EFFECTS: only when clearly indicated (Category B). It GI: diarrhea, nausea, vomiting. crosses the placenta in very small amounts. Skin: rash, urticaria. Use of a single agent penicillin may be safer. Others: candidal vaginitis, moderate increase Lactation- Cautious use; it is excreted in the in serum ALT and AST, bone marrow breast milk in very small amounts. depression (rare), and glomerulonephritis. Liver diseases- Dose with caution and • monitor hepatic function at regular intervals, INTERACTIONS: since the drug is metabolized in the liver. Similar to those of amoxicillin. • Kidney diseases- Does not generally require a OVERDOSE: dose reduction unless impairment is severe. Refer to benzylpenicillin. Severely impaired patient with a GFR of < 30 • Brands: ml/min should not receive the 875 mg tablet. Augmentin (Smithkline Beecham), Curam Patients with GFR between 10-30 ml/min (Biochemi), Ogmin (BPC). should receive 500 or 250 mg tablet q. 12 h., ______depending on the severity of infection.

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Anti-Infectives 2) Cephalosporins . Cephalexin, Cefaclor, Cefadroxil are the (β - Lactam) three orally active ones & should be used as 2nd line therapy, due to the reasons

mentioned above. These are broad-spectrum antibiotics. There are many cephalosporins where individual agents have slightly different activities against certain organisms. They have a CephalexinP, Cefadroxil and similar mechanism of action as penicillins; Cefaclor they inhibit the bacterial cell wall synthesis, so they are bactericidal agents. • DRUG SUMMARY: Cephalosporins are not first-line drugs. Cephalexin and cefadroxil are orally active They should be used only to treat specific first generation cephalosporins while infections that are resistant to cefaclor is an orally active 2nd-generation antimicrobials of primary use. For this cephalosporin. For the spectrum of activity purpose, they would be considered refer to the previous table. Cefaclor has a essential. For example, some are suitable good activity against Hemophilus for the treatment of H. influenzae type b influenzae, but it is associated with meningitis where there is evidence that protracted skin reactions especially in strains are resistant to chloramphenicol and children. Cefadroxil has a longer duration benzyl penicillin. of action than other cephalosporins but Cephalosporins are divided into four poor activity against H. influenzae. groups called generations. This classification is based on the spectrum of Tables 5.4 & 5.5 give an overview and activity of these agents. Only the first three comparison of the three agents. generations will be discussed (See table- 5.4).

Note: Each generation of cephalosporins has shifted toward increased G-ve activity but has lost activity toward G+ve organisms.

Cephalosporins are not considered as the first line of treatment because they are: 1. Broad spectrum. 2. Expensive. 3. Resistance will develop easily and rapidly for such agents (since they are broad spectrum). Most are not active orally, instead IV or IM routes should be used (this is the case for all third generation cephalosporins and second generation ones; except cefaclor and many first generation agents).

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Table – 5.4: Summary of the Main Three Generations of Cephalosporins. Class First-generation Second-generation Third-generation Spectrum of 1. Most G+ve cocci 1. The same organisms 1. Wider activity against activity (exept enterococci) covered by 1st generation. G-ve bacteria as: Enterobacter, Citrobacter, 2. Enteric aerobic 2. Extended G-ve coverage Serratia, Providencia, G-ve bacilli (E. coli, K. (including β-lactamase- Neisseria and Hemophilus pneumoniae, and producing strains of spp. (including β-lactamase Proteus mirabilis). Hemophilus influenzae. producing organisms.) Examples Cefadroxil, cefazolin, Cefaclor, cefamandole, Cefoperazone, cefotaxime, cephalexin, cephalothin, ceforanid, cefonicid, cefotetan, ceftazidime, cephapirin, cephradine. cefoxitin, cefuroxime. ceftizoxime, ceftriaxone, moxalactam. Indications 1. Serious Klebsiella 1. Urinary tract infections 1. Since they penetrate the infections & G+ve & resulting from E. coli & blood brain barrier they some G-ve infections in gonococcal disease caused are used for the treatment patients with mild by organisms-resistant to of meningitis caused by penicillin allergy. other agents. microbes as Meningococci, 2. Preoperative 2. Cefaclor is useful in otitis Pneumococci, prophylaxis. media & sinusitis in patients H. influenzae, and enteric allergic to aminopenicillins. G-ve bacilli.

3. Cefoxitin can be used for 2. To treat sepsis of mixed aerobic-anaerobic unknown origin in infections as in intra- immunosuppressed abdominal infection. patients, or to treat fever in neutropenic immuno- 4. Cefamandole & suppressed patients cefuroxime used in (where it is used in community-acquired combination with pneumonia. aminoglycosides)

3. As empiric therapy* for life-threatening infection in which resistant organisms are the most likely cause.

4. Initial therapy of mixed bacterial infections (e.g., sepsis). * Empirical therapy: is the therapy given before the identification of the infecting organism in life- threatening conditions.

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Table – 5.5: Monograph Summary of Selected Oral Cephalosporins Drug Cephalexin Cefadroxil Cefaclor To treat infections caused Primarily in the treatment Treatment of otitis by susceptible pathogens of urinary tract infections media and infections of in the respiratory and caused by E. coli, Proteus upper and lower urinary tracts, middle ear, mirabilis, and Klebsiella respiratory tract, skin, soft tissue, and bone. spp.; infection of the skin urinary tract, and skin Indications and skin structures caused and skin structures by Staph. and Strepto- caused by ampicillin- cocci; and group A β- resistant H. influenzae, hemolytic Streptococcal acute uncomplicated pharyngitis and tonsillitis. UTI. Contra- Hypersensitivity to cephalosporins and related antibiotics (i.e. penicillins). indications Dosage forms Caps, susp. Use if clearly needed as no well-controlled studies have been established Pregnancy (Category B). They are used for the treatment of urinary tract infections. They are excreted in breast milk in small quantities, however, consider the following problems in the nursing infant: modification/alteration of bowel Lactation flora; pharmacological effects; interference with the interpretation of culture results if a fever/infection investigational testing is needed. Consider the relative benefit to risk before using the drug. In neonates, Children accumulation of cephalosporin antibiotics has occurred. Liver disease Safe in general. Cephalosporins may be nephrotoxic; use with caution in the presence of 2 markedly impaired renal function (Crcl < 50 ml/min/1.73 m ). In elderly and in patients with known or suspected renal impairment, monitor carefully prior Kidney disease to and during therapy. If renal impairment is severe the dose of cephalexin should not exceed 500 mg/day and if renal impairment is moderate the dose of cefadroxil should be reduced. Precautions Cautious use in history of hypersensitivity to penicillins or other drug allergy. and warnings Severely impaired renal function. Diarrhea (generally mild), nausea, vomiting, anorexia, abdominal pain, Possible dizziness, headache, fatigue, hypersensitivity reactions (rash, pruritis, . .), adverse effects interference with blood clotting factors leading to bleeding tendency. *Probenecid: decreases renal elimination of cephalexin. *Aminoglycosides: nephrotoxicity risk is increased when both drugs are used Interactions together. Avoid, or monitor renal function closely if needed. *Anticoagulants: Bleeding complications may occur. Use caution. It occurs mainly with parenteral administration of cephalosporins, particularly Overdose if the patient suffers from severe renal impairment. Seizures may occur. Treat accordingly.

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Table – 5.6: Recommended Doses of the Selected Cephalosporins Drug Indication Age Route Dosage Cephalexin Mild to moderate Adult PO 250-500 mg q. 6 h. infections Child PO 25-50 mg/kg/d in 4 divided doses Skin/skin structure Adult PO 500 mg q. 12 h. infections Otitis media Child PO 75-100 mg/kg/d in 4 divided doses Cefadroxil Uncomplicated UTI Adult PO 1-2 g/d in 1-2 divided doses Child PO 30 mg/kg/d in 2 divided doses Skin/skin structure Adult PO 1 g/d in 1-2 divided doses infections, Child PO 30 mg/kg/d in 2 divided doses Streptococcal pharyngitis, tonsillitis Renal impairment Adult PO 1 g q. 24 h. (Crcl < 25 ml/min) Child PO 15 mg/kg q. 24 h. Cefaclor Mild to moderate Adult PO 250-500 mg q. 8 h. infections Child PO 20-40 mg/kg/d divided q. 8 h. (max. 1 g/d) Acute bacterial Adult PO 500 mg q. 12 h. (for 7 days). exacerbation of chronic bronchitis

Direction: It is important to inform the similar antimicrobial spectra, and cross- patient that the full course of therapy resistance is common. Tetracycline will be should be completed. Duration of therapy used as the prototype for this group. should be for a minimum of 48-72 hours after evidence of bacterial eradication has Tetracycline (TC) been obtained. *If GI upset occurs, may take the oral • DRUG SUMMARY: preparation with food or milk. TC is a broad spectrum, bacteriostatic, • BRANDS: antibiotic. It acts by interfering with the Cephalexin: Cefacare (Pharmacare), Cefalex bacterial protein synthesis process. Its (BPC), Ceforal (Teva), Cefovit (Vitamed), usefulness has decreased due to the Keflex (Lilly), Jeflex (JePharm). widespread bacterial resistance. It remains Cefaclor: Ceclor (Lilly). however the drug of choice in some Cefadroxil: Biodroxil (Biochemi), Cefadrox infections (see indication below). TC is one (BPC), Duracef (Mead-Johnson). of the cheapest antibiotics. ______• INDICATIONS: 3) Tetracyclines It is the drug of choice in the treatment of infections caused by chlamydia (trachoma, Tetracyclines are broad-spectrum psittacosis, salpingitis, nongonococcal antibiotics whose values have decreased urethritis, inclusion conjunctivitis, and due to increasing bacterial resistance. There lymphogranuloma venereum), rickettsia is a large number of tetracyclines in the (including Q-fever, Rocky Mountain market (i.e. doxycyclineWHO,P minocycline, spotted fever, typhus), mycoplasma e.g. chlortetracycline). The tetracyclines have Mycoplasma pneumoniae (respiratory and genital infections).

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Anti-Infectives 1. Spirochetal infections (relapsing fever Direction: The drug may be taken with - Borrelia burgdorferi - Lyme disease), food if GI upset occurs, with a full glass of leptospirosis in penicillin hypersensitivity water. Do not take with dairy products. (as an alternative to erythromycin), (Doxycycline’s absorption is less likely to be Syphilis (in penicillin hypersensitivity affected by food or dairy products, but it has patients). to be taken with plenty of fluid and an hour 2. Amebiasis. before lying down to sleep.) 3. G-ve bacterial infections (e.g., • USE IN SPECIAL CASES: brucellosis, shigellosis, cholera, Pregnancy- Avoid use during pregnancy Gonorrhea [in penicillin hypersensitivity (Category D). It readily crosses the placenta patients], granuloma inguinale, tularemia). and can have toxic effects on the developing 4. G+ve infections (e.g. tetanus). fetus especially early in pregnancy 5. Used orally and topically (solution) (retardation of skeletal development). for inflammatory acne vulgaris. Lactation- It is excreted in breast milk. A 6. Topical ointment used for superficial dosage of 2 g/d for 3 days has achieved a skin infections. milk plasma ratio of 0.6 to 0.8. Because of 7. Ophthalmic use. the potential for serious adverse reactions, 8. Exacerbation of chronic bronchitis decide whether to discontinue nursing or to (because of their activity against discontinue the drug. Haemophilus influenzae). Children- It should not be used in children 9. As a sclerosing agent for pleural under 8 years of age, unless other drugs are effusions due to malignancy or cirrhosis. not likely to be effective, or are • CONTRAINDICATIONS: contraindicated. Hypersensitivity to tetracyclines or to any Teeth: The use of tetracycline during the ingredient in the formulation. period of tooth development (from the last Severe renal or hepatic impairment, half of pregnancy to the eighth year of life) common bile duct obstruction, use during may cause permanent discoloration (yellow- tooth development, during infancy and gray-brown) of deciduous and permanent children < 8 yrs., pregnant and nursing teeth. This adverse reaction is more common women. during long-term use of the drug, but has Safety of the use of tetracycline topically in been observed following repeated short-term children 8-11 yrs. has not been established. courses. Enamel hypoplasia has also been • DOSAGE FORMS: reported. Capsules, ointment. Bone: Tetracycline forms a stable calcium • RECOMMENDED DOSAGE: complex in any bone-forming tissue. A decrease in the fibula growth rate has been Dosage of Tetracycline observed in premature infants given oral

Systemic Infections tetracycline in doses of 25 mg/kg q 6 h. This Adult PO 250-500 mg b.i.d. to reaction was reversible when the drug was q.i.d. (1-2 g/d). discontinued. Child PO > 8 yrs: 25-50 Liver diseases- Avoid use. Dose related mg/kg/d in 2-4 toxicity especially with IV administration. divided doses. Kidney diseases- Avoid use. One can use doxycycline or minocycline. Acne Adult PO 500-1000 mg/d in 4 and divided doses. Child > Topical Apply to cleansed 8 yrs areas twice daily.

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• PRECAUTIONS AND WARNINGS: • BRANDS: Cautious use in the case of history of renal Brimocyclin (BCP), Tetrapharm (JePharm), or hepatic dysfunction, myasthenia gravis, Tevacycline (Teva). history of allergy, asthma, hay fever, ______urticaria, undernourished patients. • ADVERSE EFFECTS: 4) Macrolides Gastrointestinal upset, glossitis, stomatitis, rashes, proctitis, and infections due to Macrolide antibiotics include erythro- Candida albicans, Proteus, Pseudomonas, mycin, clarithromycin, azithromycin, or Staphylococci. It is deposited in dirithromycin and troleandomycin. These calcifying areas of bone, nails and teeth, may be bacteriostatic or bactericidal resulting in irreversible damage. depending on factors such as drug Photosensitization and hypersensitivity concentration. Macrolides are weak bases, reactions including anaphylactic shock can their activity increases in alkaline pH. This occur. May have hepatotoxic and is important when using for UTI. They nephrotoxic effects. Erythema (discontinue enter pleural fluid, ascitic fluid, middle ear treatment). Headache and visual disturbances exudates and sputum. Erythromycin is the that may indicate benign intracranial most commonly used macrolide. hypertension, and pseudo-membranous colitis. a) Erythromycin WHO,P • INTERACTIONS: Overview of Tetracyclines • DRUG SUMMARY: Drug-Drug Interactions Erythromycin has an antibacterial spectrum Drug Interaction that is similar but not identical to that of Antacids Calcium, magnesium bind to penicillin; it is thus a good alternative to tetracycline in the gut and penicillin, in penicillin-allergic patients. It decrease its absorption. can be a bactericidal or a bacteriostatic Anti- The ones with kaolin and diarrheal pectin may decrease TC agent depending on its concentration. It agents absorption. produces its antibacterial activity by Food Dairy products and iron inhibiting bacterial protein synthesis. supplements decrease Erythromycin is active against many G+ve tetracycline absorption. Space organisms, including streptococci (e.g., administration within 2 hrs. Streptococcus pneumoniae), Coryne- of tetracycline intake. bacterium and Neisseria species, some strains Meth- May produce fatal nephro- of Mycoplasma, Legionella, Treponema, and oxyflurane toxicity. Avoid concomitant Bordetella. Some S. aureus strains that use. resist penicillin G, are susceptible to Oral antico- Coadministration may erythromycin. agulants potentiate hypoprothrom- • INDICATIONS: binemia. a. Erythromycins are the preferred drugs for Oral contra- Effectiveness of OC the treatment of Mycoplasma pneumoniae ceptives decreases. Backup methods should be used. and Campylobacter infections, legionnaires disease, chlamydial infections, diphtheria, Penicillin Bacteriostatic drugs (e.g. tetracycline) may interfere and pertussis. It is also used for the treatment with the bactericidal action of of sinusitis, chronic prostatitis and acne penicillins; avoid vulgaris. concomitant administration. b. In patients with penicillin allergy, erythromycin is an important alternative in

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Anti-Infectives the treatment of pneumococcal pneumonia, S. *It should be given on an empty stomach aureus infections, syphilis, and gonorrhea. (1 hour before or 2 hours after meals). c. Erythromycin may be given prophy- *If GI upset occurs may administer with lactically before dental procedures to prevent food. bacterial endocarditis. *There is no interaction between milk and d. It has activity against gut anaerobes and erythromycin preparations. has been used with neomycin for prophylaxis • before bowel surgery. USE IN SPECIAL CASES: * (Clarithromycin is indicated as part of Pregnancy- Use only when clearly indicated therapy for eradication of Helicobacter pylori (Category B). Only small amounts cross the -peptic ulcer- with other agents). placental barrier of erythromycin base. Side • CONTRAINDICATIONS: effects have only been reported when using -Hypersensitivity to macrolide antibiotics. erythromycin estolate. Do not use erythromycin estolate in pregnant women. -Porphyria. Lactation- Only small amount is excreted in -Erythromycin estolate is contraindicated in breast milk and no infant adverse effects are liver disease. It produces cholestatic reported. But problems that may occur in jaundice. nursing infants include modification of bowel • DOSAGE FORMS: flora and interference with the interpretation Tablets and suspensions. of culture results if a fever work-up is • RECOMMENDED DOSAGE: required. The American Academy of Adult: 250-500 mg q. 6 h. or 0.5-1 g q. 12 Pediatrics considers erythromycin to be h. up to 4 g daily in severe infections. compatible with breast-feeding. Early syphilis: 500 mg q. 6 h. for 14 days. Renal Disease- If severe case, the maximum Children: Age, weight, and severity of the possible dose to be given is 1.5 g daily. infection are important factors in deter- Ototoxicity (hearing loss) or transient hearing mining the proper dosage. The usual loss has been reported in such cases. (Refer to dosage for children is 30-50 mg/kg/day in BNF42; 2001). equally divided doses q. 6 h. Liver Disease- Erythromycin is principally In mild to moderate infections the usual excreted by the liver. One must take caution dosage of erythromycin base is as table-5.7 during the administration of erythromycin to indicates. patients with impaired hepatic function. There have been reports of hepatic dysfunction with Table-5.7: Erythromycin Base or without jaundice. Erythromycin estolate is Dosages in Children contraindicated in liver disease. Body Total Daily • Weight Dose PRECAUTIONS AND WARNINGS: Under 4.5 kg 30-50 - Hepatic and renal impairment. (under 10 lb.) mg/kg/day - Superinfections might occur. 4.5 to 6.8 kg • ADVERSE EFFECTS: 200 mg (10-15 lb.) Nausea, vomiting, abdominal discomfort, 7.0 to 11.5 kg 400 mg diarrhea after large doses, reversible (16-25 lb.) hearing loss also reported after large doses. 11.6 to 22.7 kg 800 mg If given for more than 14 days it may (26-50 lb.) occasionally cause cholestatic jaundice. 22.8 to 45.5 kg 1200 mg (51-100 lb.) Over 45.5 kg 1600 mg (over 100 lb.)

Directions: Erythromycin dose is doubled in severe infections.

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• INTERACTIONS: • BRANDS: Overview of Erythromycin Bristamycin (Bristol), E-Mycin (Upjohn), Eryc Drug-Drug Interactions (Taro), Erytab (Abbot), Erythrocare (Pharmacare), Drug Interaction Erythrocin Filmtab (Abbot), Erythroped (Abbot), Astemazole Inhibit the metabolism of Erythrolet (BPC), Erythropharm (JePharm), and astemazole and terfenadine Erythroteva (Teva). terfenadine leading to cardiotoxicity. ______Contraindicated use.

Bromo- Serum level may be increased criptine due to erythromycin 5) Sulphonamides and P inhibiting hepatic Trimethoprim metabolism. Monitor patient, and adjust bromocriptine dose The importance of sulphonamides as accordingly. chemotherapeutic agents has decreased due Carba- Inhibit the metabolism of to the increase in bacterial resistance and mazepine carbamazepine, leading to an their replacement by antibiotics which are increase in its plasma level. generally more active and less toxic. Cyclosporins Inhibit the metabolism of Sulphamethoxazole is the most commonly cyclosporins. used sulphonamide, it is used in Digoxin Enhance the effect of digoxin. Use with caution. combination with trimethoprim (TMP) for Theophyline Inhibit the metabolism of the treatment of some infections. Increasing theophyline, leading to an bacterial resistance to sulphonamides and increase in its plasma level, the high incidence of sulphonamide-related use with caution. side effects, have limited the value of use of Warfarin Enhanced effect of warfarin. this drug alone. TMP has been used in Monitor prothrombin (PT) combination because of the synergistic levels and caution the patient. activity, leading to less bacterial resistance.

• OVERDOSE: The combination is indicated as first line Symptoms may include nausea, vomiting, treatment in many cases. This combination epigastric distress and diarrhea. Reversible is called co-trimoxazole (TMP-SMZ). • pancreatitis, hearing loss with or without DRUG SUMMARY: tinnitus and vertigo especially in patients Co-trimoxazole combination contains five with renal or hepatic insufficiency. parts of SMZ and one part of TMP. • Treatment includes usual supportive INDICATIONS: measures. GI decontamination is not 1. Urinary tract infections and prostatitis (if necessary unless five times the normal dose sensitive organisms). has been ingested. Hemodialysis and 2. Bone and joint infections due to peritoneal dialysis are not particularly Haemophilus influenzae. 3. Invasive salmonellosis and typhoid fever. effective. 4. Sinusitis and exacerbation of chronic bronchitis. 5. High doses of co-trimoxazole are used for Pneumocustis carinii infections. It is no longer recommended for the treatment of gonorrhea.

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Anti-Infectives

Table – 5.8: Dosage of Co-trimoxazole in Systemic Infections * Adult PO UTI, 160 mg TMP/800 mg SMZ (1 double Acute otitis media, strength [DS] tablet) q. 12 h. for 10-14 Acute exacerbation of days. chronic bronchitis Shigellosis 160 TMP/800 SMZ q. 12 h. for 5 days Travelers diarrhea 160 TMP/800 SMZ q. 12 h. for 5 days Child PO 8 mg/kg TMP/ 40 mg/kg SMZ > 2 month, less 40 kg divided q. 12 h. for 10 days > 40 kg 160 TMP/800 SMZ (1 DS tablet) q. 12 h. * Reference: Drug Facts & Comparisons, 2000, p 1352-54.

• CONTRAINDICATIONS: Lactation- Avoid use. Since there is a small 1. Hypersensitivity to TMP, SMZ, sulphon- risk of kernicterus in jaundiced infants and of amides, or bisulfites. hemolysis in G6PD deficient infants (due to

2. Jaundice, blood disorders, porphyria, the sulphamethoxazole ingredients). megaloblastic anemia (due to folate Children- It is contraindicated in children deficiency). under 2 months, since there is a risk of 3. Infants 2 mon. (except in treatment or kernicterus in these infants. prophylaxis of pneumocystis pneumonia). There is limited data on safety of repeated use for OM in children < 2 yrs; not indicated 4. Renal and hepatic failure. • for prophylactic use of prolonged DOSAGE FORMS: administration (Facts & Comparisons 2000; Tablets and suspension. 1352). • RECOMMENDED DOSAGE: Renal Disease- If there is a moderate renal See the table-5.8. impairment, one should reduce the dose (Clcr Directions: Take each oral dose with a full 15-30 ml/min: ½ dose). Rashes (including glass of water. If GI distress occurs when Stevens-Johnson syndrome) and blood taken on empty stomach, take with food or disorders may cause further deterioration of milk. renal function. In the case of renal failure (or *Advise patient to maintain adequate fluid Clcr < 15 ml/min) it is contraindicated. intake. Liver Disease- Use is contraindicated in the *Duration of therapy should be 7-10 days case of hepatic failure. for uncomplicated cases (i.e. acute cystitis). • PRECAUTIONS AND WARNINGS: For moderate infections (i.e. pyelonephritis, − Group A β-hemolytic Streptococcal bronchitis), duration should be 10-14 days. pharyngitis: Avoid use of this combination *3 day regimens may be used in; 1st for such cases, since there has been high episode of UTI, non-diabetic, young incidence of bacteriologic failure than with patients. But relapse or recurrence may penicillins. occur or an upper UTI may be missed. − Special care should be taken in patients Evaluate your patient. who may be folate deficient such as, old *Severe cases should be referred to hospital patients, chronic alcoholics, patients on for IV treatment. anticonvulsant therapy and ones receiving • USE IN SPECIAL CASES: prolonged treatment or high doses of the Pregnancy- Avoid use (Category C). drug. Cardiovascular defects have been reported − It should be used with care in the elderly when used in the first trimester. Use of and preferably only if there is no acceptable aminopenicillins or cephalosporins is safer. alternative. Since there has been recent

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reports of death in patients over 65 years • OVERDOSE: old using co-trimoxazole. Symptoms: − Special care should be taken in patients Acute: Signs and symptoms observed with with G6PD deficiency. either TMP or SMZ alone includes: − In patients receiving the drug for a long Anorexia, colic, nausea, vomiting, time, blood counts should be monitored dizziness, headache, drowsiness, − One should stop treatment if rashes unconsciousness, pyrexia, hematuria, appear. crystalluria, depression, and confusion. • ADVERSE EFFECTS: Chronic: High doses or use for extended Most common are GI disturbances. Other periods may cause bone marrow depression rare but possible effects include: rash, manifested as thrombocytopenia, leuko- Stevens-Johnson syndrome (erythema penia or megaloblastic anemia. Leucovorin multiforme), eosinophilia, agranulocytosis, (Ca-Folinate); 5 to 15 mg/day has been granulocytopenia, purpura, leucopenia, recommended to treat this case. thrombocytopenia, aplastic or mega- Treatment includes usual supportive loblastic anemia due to trimethoprim, measures. Perform gastric lavage or emesis, pseudomembranous colitis, jaundice and force oral fluids and administer IV fluids if hepatic necrosis (rare but have been urine output is low and renal function is reported). normal. Acidifying the urine will increase • INTERACTIONS: the renal elimination of TMP. Monitor Overview of Co-trimoxazole patient with blood counts and appropriate Drug-Drug Interactions blood chemistries, including electrolytes. Drug Interaction If significant blood dyscrasia or jaundice Cyclosporin The risk of nephrotoxicity occurs, institute specific therapy for these increases if co-trimoxazole is complications. Peritoneal dialysis is not given along with cyclosporin. effective and hemodialysis is only Phenytoin Co-trimoxazole has been moderately effective in eliminating co- found to cause an increase in trimoxazole. the plasma concentration of • phenytoin. This might lead to BRANDS: toxic effects because of the Bactrim (Roche), Diseptyl (Rekah), Pathoprim narrow therapeutic index. (BPC), Pharmaprim (Pharmacare), Resprim (Teva), Sulfatrim (Vitamed), Sulprim Sulphonyl- The effect of sulphonylurea (JePharm). urea has been found to be enhanced by co-trimoxazole, ______i.e. may cause

hypoglycemia. WHO,P Warfarin The effect of warfarin has 6) Nitrofurantoin been found to be enhanced by co-trimoxazole, i.e. increase • DRUG SUMMARY: the anticoagulant effect. Nitrofurantoin is a synthetic nitrofuran that Monitor Prothrombin time is bacteriostatic in low concentrations (5-10 (PT) and adjust dose mcg/ml) and bactericidal in higher accordingly. concentrations.

Most G-ve bacilli and G+ve cocci associated with urinary tract infections are susceptible. Some strains of Enterobacter and Klebsiella are resistant. Most strains of Proteus and Serratia species are resistant.

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Anti-Infectives It has no activity against Pseudomonous hemolytic anemia upon exposure. Safety for spp. Susceptible strains do not develop use in nursing mothers has not been resistance during therapy. established. • INDICATIONS: Children- Contraindicated in infants < 1 mon. Urinary tract infections due to susceptible (< 3 mon.: in BNF 2001), due to risk of strains of E. coli, Enterococci, S. aureus hemolytic anemia. (not for treatment of pyelonephritis or Renal Disease- Exercise caution. Refer to perinephric abscesses) and certain strains of contraindications. • Klebsiella and Enterobacter spp. PRECAUTIONS AND WARNINGS: • CONTRAINDICATIONS: -Culture and susceptibility testing should be -Renal function impairment if creatinine performed prior to and during treatment. clearance < 60 ml/min. Anuria or oliguria -Peripheral neuropathy may occur and as risk of toxicity might increase. become severe or irreversible. Pre- -Hypersensitivity to nitrofurantion. disposing factors like renal impairment, -Pregnant patients at term, during labor and anemia, diabetes, electrolyte imbalance, delivery, and in infants under 1 month. vitamin B deficiency and debilitating diseases may enhance these problems. • DOSAGE FORMS: -Overuse may result in bacterial and fungal Capsules. overgrowth and non-susceptibility that may • RECOMMENDED DOSAGE: cause super infections. Adult: 50-100 mg 4 times/day a.c. and h.s. -Pulmonary reactions, acute, sub-acute or For long-term suppressive therapy, reduce chronic, may occur (i.e. pulmonary fibrosis dosage: 50-100 mg at bedtime. like symptoms). Child: 5-7 mg/kg/24 hrs. given in 4 divided -Hematological disorders may occur such doses. For long term suppressive therapy, as hemolytic anemia. doses as low as 1 mg/kg/24 hrs., given in • ADVERSE EFFECTS: single or in 2 divided doses, may be GI, hepatic and pulmonary disturbances adequate. may occur. Some lab tests abnormalities Directions: Administration with food or may be found, such as increased AST, milk decreases GI disturbances and ALT, decreased hemoglobin, increased enhances bioavailability. serum phosphorus. *Duration: Continue for at least 1 week or • INTERACTIONS: 3 days after sterile urine analysis. *It may cause brown-orange discoloration Overview of Nitrofurantoin of the urine. Drug-Drug Interactions *There are no suspension preparations in Drug Interaction the local market, which requires pharmacist Anti- Nitrofurantoin bioavailability to specially prepare it. cholinergics will increase; clinical • interventions may not be USE IN SPECIAL CASES: necessary. Pregnancy- Safety for use in pregnant women Magnesium Nitrofurantoin absorption has not been established, Category B; low salts may be delayed or increased. incidence of minor malformation has been Avoid concomitant use. reported in mice. Contraindicated in pregnant Uricosurics Nitrofurantoin renal clearance women at term. Do not give to pregnant will decrease and serum level women with G6PD deficiency because of the increase- leading to toxic risk of hemolysis. effects. Lactation- It is excreted into milk in very low Drug/lab tests interactions: A false- concentrations. Infants with G6PD deficiency are adversely affected, and may develop positive glucose test in urine may occur

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with Benedict`s and Fehling`s but not with Child (3 mon. - 12 yrs. of age): the glucose enzymatic tests. Initial therapy: 55 mg/kg/d in 4 equally Drug/food interactions: food intake divided doses. increases the drug bioavailability. Prolonged therapy: may be reduced to 33 • OVERDOSE: mg/kg/day. Symptoms: no specific or serious Do not administer to infants < 3 months symptoms have been reported except for of age. vomiting. Directions: Should be taken with food to Treatment: Induction of emesis and prevent GI disturbances. increase fluid intake to enhance excretion. *May produce drowsiness or dizziness; The drug is dialyzable. caution the patient against hazardous • BRANDS: activities such as driving till full effect of Furadantin/Macrodantin (Proctor&Gamble), the medication is known. Macrofuran (BPC), Urantoin (Rafa). • USE IN SPECIAL CASES: ______Pregnancy- Not recommended, since safety for use during the first trimester has not been 7) Nalidixic Acid WHO,P established (Category B). No congenital defects have been reported. If benefit • DRUG SUMMARY: outweighs risks to the fetus, and the drug is Nalidixic acid is a bactericidal quinolone used, need to discontinue the drug prior to agent that interferes with DNA delivery because of the theoretical risk that polymerization. It is effective against G-ve exposure in utero may lead to significant bacteria, i.e. Proteus mirabilis, Proteus blood levels in the neonate immediately after morganii, Proteus vulgaris, Providencia birth. Lactation- Data is little on nalidixic acid. rettgeri, E. coli, Enterobacter and Milk to plasma ratios are 0.08 to 0.13. Klebsiella species. Pseudomonus strains are Although small amounts, but hemolytic generally resistant. • anemia was reported in one case. INDICATIONS: Children- Use care in prepubertal children; as Treatment of urinary tract infections caused erosions of the cartilage in weight bearing by susceptible G-ve microorganisms, joints in animals were reported. including the majority of Proteus strains, Renal Disease- Exercise caution if Clcr is 2-8 Klebsiella and Enterobacter spp. and E. ml/min. coli, if the patient did not respond to, or is Liver Disease- Exercise caution. not sensitive to co-trimoxazole. • PRECAUTIONS AND WARNINGS: • CONTRAINDICATIONS: -Periodic blood counts, renal and liver Hypersensitivity to nalidixic acid, history function tests should be performed if of convulsive disorders. treatment is continued for > 2 weeks. • DOSAGE FORMS: -Photosensitivity may occur, advise patient Tablets and suspension. against prolonged exposure to sunlight. • RECOMMENDED DOSAGE: -May produce drowsiness and dizziness; Adult: Initial therapy: 1.0 g 4 times daily exercise caution while driving or operating (total of 4 g/d) for 1 or 2 weeks. dangerous machines. Prolonged therapy: may be reduced to 2 -It might cause hemolytic anemia in patients g/day after the initial treatment period. with or without G6PD deficiency. *Under dosage (< 4 g/d) during initial • ADVERSE EFFECTS: therapy may predispose to emergence of CNS disturbances (i.e. drowsiness, bacterial resistance. headache) and ophthalmic disturbances

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Anti-Infectives might occur but are reversible upon as reserve agents when other agents have discontinuation. GI disturbances (i.e. failed. nausea, diarrhea) might occur. • INTERACTIONS: Ciprofloxacin WHO,P The effects of anticoagulants may be enhanced by nalidixic acid, hemorrhage • DRUG SUMMARY: could occur. A decrease in dose of warfarin A fluoroquinolone antibacterial agent with may be required. a wide spectrum of activity, mainly for Drug/Lab test interactions: The urinary G-ve bacteria (i.e. Salmonella spp., metabolites of nalidixic acid liberate Shigella spp., Brucella melitensis . . .), glucuronic acid and produce false-positive including Enterobacteriaceae, Pseudo- urinary glucose results with Benedict’s or monas aeruginosa, Heamophilus, Neisseria Fehling’s or Clinitest’s tests. spp., Staphylococci, and some other G+ve • OVERDOSE: bacteria. Most anaerobic organisms are not Symptoms: Toxic psychosis, convulsions, susceptible. (It may be used for infections increased intracranial pressure, metabolic that were resistant to other antibiotics acidosis, vomiting, nausea and lethargy including penicillins, cephalosporins and may occur in patients taking more than the aminoglycosides). recommended dosage. • INDICATIONS: Treatment: Reactions are short lived (2-3 Mainly used for urinary tract infections due hrs.) because the drug is rapidly excreted. to G-ve and some G+ve susceptible Gastric lavage is indicated if the bacteria. overdosage was noticed early. If absorption May be used for lower respiratory has occurred, increase fluid administration infections, gonorrhea and chancroid, and have supportive measures. Anti- typhoid fever, salmonella, severe convulsants may be indicated in severe shigellosis, and hospital-acquired infections cases. when other agents have failed. • BRANDS: • CONTRAINDICATIONS: Granexin (Dexxon), NegGram (Sterling- Hypersensitivity to ciprofloxacin or other winthrop), U-Gram (JePharm), Urigram quinolones. (Trima). • DOSAGE FORMS: ______Tablets. • RECOMMENDED DOSAGE: 8) Fluoroquinolones Adult (>18 yrs): 250-500 mg b.i.d. Child: Use not recommended in growing Fluoroquinolones are synthetic, broad- children < 18 yrs. (adolescents). spectrum antibacterial agents related to the Directions: Should be administered for at 1st generation quinolones; nalidixic acid least 3 days after signs and symptoms of and cinoxacin. Ciprofloxacin, is the main infection have disappeared. 2nd generation quinolone, others include *Ensure adequate fluid intake (advise enoxacin, lomefloxacin, norfloxacin, and patient to drink fluids) to prevent ofloxacin. Newer 3rd generation quinolones crystaluria. include levofloxacin and sparfloxacin. *Milk decreases the absorption of Fluoroquinolone agents are bactericidal. quinolones; space out interval between They may not be indicated as essential or milk-product ingestion and quinolones 1st line therapy drugs, but are of real value intake as much as possible.

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• USE IN SPECIAL CASES: • INTERACTIONS: Pregnancy- Not to be used in pregnant Overview of Fluoroquinolones women (Category C). Animal studies have Drug-Drug Interactions shown teratogenic effects. Drug Interaction Lactation- Use not recommended. It is Antacids Quinolones pharmacological excreted in milk, and the potential for effect is decreased due to arthropathy and other toxicities to occur in decreased absorption. If the nursing infant are high. Levels of this necessary antacids may be drug are undetectable after 36-48 hours, given at least 6 hrs. before or therefore if there is a clear indication for use, 2 hrs. after quinolone do not breast feed until 48 hours after the last administration. dose of a fluoroquinolone. Didanosine Quinolones effect may be Children- Avoid use in children < 18 yrs. and decreased. If concurrent use adolescents [Some references use 12 yrs.]. cannot be avoided, give Reports of bone disorders in animal studies didanosine at least 6 hrs. before or 2 hrs. after the have been established. quinolone. Renal Disease- Dose should be reduced if Iron & These reduce fluoro- creatinine clearance is < 20 ml/min. calcium quinolones absorption; thus, Liver Disease- Exercise caution. salts ciprofloxacin should not be • PRECAUTIONS AND WARNINGS: administered 4 hrs. within -Avoid use in pregnancy, lactation and taking these preparations. growing children. Sucralfate It decreased absorption of -Exercise caution in patients with G6PD quinolones. If needed, give deficiency. sucralfate at least 6 hrs. after -Should be used with caution in patients quinolone administration. with epilepsy or with history of CNS Warfarin Enhanced anticoagulant disturbances, and in patients with effect may occur. Use with caution. myasthenia gravis. Fluoroquinolones may induce convulsions in such patients. • BRANDS: -Rupture of the shoulder, hand and Achilles Ciprocare (Pharmacare), Ciprogis (Agis), tendons that required surgical repair have Ciproxin (Bayer), Floxin (JePharm). been reported with use of fluoroquinolones. ______Treatment should be discontinued if the patient experiences pain, inflammation or rupture of the tendon. B) ANTI-TUBERCULOSIS • ADVERSE EFFECTS: GI, CNS disturbances and some derma- Tuberculosis is one of the most serious tological reactions as well as photo- infections that are showing a comeback. sensitivity reactions. Superinfections with Control of this epidemic will require a organisms not very susceptible to number of initiatives on the part of ciprofloxacin may occur. clinicians and health care workers. Because of the slow growth rate of mycobacteria and their intracellular location, drugs must be administered for a longer period of time than in other infectious diseases. The risk of adverse reactions must be a major consideration in drug selection. Furthermore, to prevent the emergence of resistant strains that occur

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Anti-Infectives naturally at very low frequencies, it is vital necessary for bone and joint infections, for to employ combined therapy with at least meningitis, or for resistant organisms. two agents to which the organism is Pregnancy and breast feeding: susceptible. The standard regimen (table-5.9) may be Antituberculosis drugs are classified used during pregnancy and breast-feeding; into first-line and second-line drugs, on the pyridoxine supplements are advisable. basis of their efficacy, activity, and risk of Monitor infant for possible toxicity and adverse reactions. The four first-line drugs theoretical risk of convulsions and are: Isoniazid (INH), Rifampin/rifampicin, neuropathy. Prophylactic pyridoxine is Pyrazinamide (PZN) and Ethambutol (see advisable in mother and infant. table-5.9 for standard dosing regimens). Children: Second-line drugs are indicated only when As for adults, children are given INH, the Mycobacterium tuberculosis organisms rifampicin, and PZN for the first two are resistant to the first-line agents. In months followed by isoniazid and general the drugs with similar toxicities rifampicin during the next 4 months. If should not be used together. PZN is omitted from the initial phase, then treatment with isoniazid and rifampicin Table-5.9: Recommended dosage for should be given for 9 months. Except in standard unsupervised 6-month regimen exceptional circumstances (e.g. drug Isoniazid Adult: 300 mg/d resistance). Ethambutol should be avoided (INH) Child: 10 mg/kg/d in young children because of the difficulty (for 6 months) (max. 300 mg). in testing eyesight and in obtaining reports Rifampicin Adult < 50 kg: 450 mg/d of visual symptoms. (for 6 months) Adult ≥ 50 kg: 600 mg/d Child: 10 mg/kg/d Non-compliant patients: Treatment needs to be fully supervised in Pyrazinamide Adult < 50 kg: 1.5 g /d (PZN) (for first Adult ≥ 50 kg: 2 g /d patients who cannot be relied upon to 2 months only) Child: 35 mg/kg/d comply with the treatment regimen. These patients are given INH, rifampicin, and Tuberculosis is treated in two phases: an PZN three times a week under supervision initial phase using at least three drugs and a for the first two months followed by INH continuation phase using two drugs. and rifampicin three times a week for a Treatment requires specialized knowledge, further four months. particularly where the disease involves Immunonocompromised patients: resistant organisms or non-respiratory Immunocompromised patients may develop organs. tuberculosis owing to reactivation of Initial phase: The concurrent use of at previously latent disease or to new least three drugs during the initial phase is infection. Multi-resistant Mycobacterium designed to reduce the population of viable tuberculosis may be present or the infection bacteria as rapidly as possible and to may be caused by other mycobacteria. Here prevent the emergence of drug resistant a culture should be always carried out and bacteria. Treatment of choice for the initial the type of organism and its sensitivity phase is the daily use of INH, rifampicin, should be confirmed. A minimum duration and/or PZN; ethambutol is added if drug of treatment of 9 months is currently resistance is a problem. recommended. Continuation phase: After the initial phase, treatment is continued with INH and rifampicin; longer treatment may be

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1) Isoniazid (INH) WHO,P neuropathy. Prophylactic pyridoxine is advisable in mother and infant. Refer to the • DRUG SUMMARY: introduction of antituberculosis drugs. INH is a bactericidal agent that is cheap Children- Refer to the introduction of and highly effective. It should always be antituberculosis drugs. included in any antituberculosis regimen Renal Disease- If severe renal impairment is unless there is a specific contraindication. present, the maximum dose to be given is 200 Its only common side effect is peripheral mg daily; since increase risk of peripheral neuropathy. neuropathy which is more likely to occur Liver Disease- Avoid. Idiosyncratic hepato- where there are pre-existing risk factors, toxicity is more common. such as diabetes, alcoholism, chronic renal • PRECAUTIONS AND WARNINGS: failure, and malnutrition. In these circum- Caution should be taken in the case of: stances pyridoxine 10 mg daily should be impaired liver and kidney function, given prophylactically from the start of the epilepsy, history of psychosis, alcoholism, treatment. breast-feeding, and patients > 35 years old. • INDICATIONS: • ADVERSE EFFECTS: -Treatment of all forms of active TB caused Nausea, vomiting, hypersensitivity by susceptible organisms. reactions including rashes, peripheral -Preventive therapy in high-risk persons neuritis (with high doses), convulsions, (e.g., household members, persons with psychotic episodes, agranulocytosis; positive tuberculin skin test reactions). hepatitis (especially > 35 years); systemic • CONTRAINDICATIONS: lupus erythematosus-like syndrome. History of INH-associated hypersensitivity • INTERACTIONS: reactions including: hepatic injury, acute Overview of Isoniazid liver damage of any etiology, and Drug-Drug Interactions porphyria. Drug Interaction • DOSAGE FORMS: Alcohol Ingestion on a daily basis Tablets. increases risk of • RECOMMENDED DOSAGE: hepatotoxicity.

Treatment Antacids Those reduce absorption of and INH. INH should be Adult PO/IM 5 mg/kg up to 300 adsorbants administered 2 hrs. before mg/day. administration of these. Child PO/IM 10-20 mg/kg up to Anti- Metabolism of carbamaze- 300-500 mg/d. epileptics pine, ethosuximide, and Preventive Therapy phenytoin is inhibited leading Adult PO 300 mg/day to an increase in the plasma Child PO 10 mg/kg up to 300 concentrations of such agents. mg/day or 15 mg/kg Monitor liver functions with three times/wk. carbamazepine use. Use INH with caution. Directions: It should be taken 1 hour before Rifampicin Coadministration may result meals, since food decreases rate and extent in a higher rate of hepato- of isoniazid absorption. toxicity. If coadministration • USE IN SPECIAL CASES: is necessary, monitor liver Pregnancy- Category C. Refer to the function tests. If alterations introduction of antituberculosis drugs. occur, consider Lactation- Monitor infant for possible discontinuation of one or both toxicity, theoretical risk of convulsions and of the agents.

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Anti-Infectives Theophyl- INH possibly increases • INDICATIONS: line plasma theophylline 1. Tuberculosis. concentration. Use with 2. Leprosy. caution. 3. Brucellosis, legionnaires’ disease, and • OVERDOSE: serious staphylococcal infections. Symptoms of an overdosage occur within 4. Prophylaxis of Meningococcal 30 minutes to 3 hours. Nausea, vomiting, meningitis and Haemophilus influenzae dizziness, slurring of speech, blurring of (type B) infections. vision and visual hallucinations (including • CONTRAINDICATIONS: bright colors and strange designs) are Jaundice and other obstructive biliary among the early manifestations. With diseases. In patients with porphyria. marked overdosage, respiratory distress and • DOSAGE FORMS: CNS depression will occur along with Tablets. severe, intractable seizures. • RECOMMENDED DOSAGE:

Isoniazid overdosage can be fatal, but good response has been reported in most patients Pulmonary Tuberculosis adequately treated within the first few Adult PO 450 mg/day in < 50 kg conjunction with other hours after drug ingestion. antituberculous agents. Treatment: Secure the airway and establish Adult PO 600 mg/day in adequate respiratory exchange, gastric ≥ 50 kg conjunction with other lavage is advised within the first 2 to 3 hrs., antituberculous agents. but do not attempt it until convulsions are Child PO 10-20 mg/kg daily (max under control. Supportive and symptomatic 600 mg/day). care should be implemented as needed. Meningococcal Carriers • BRANDS: Adult PO 600 mg b.i.d. for 2 Isoniazid (Rekah). consecutive days. ______Child PO 10-20 mg/kg twice daily for 2 consecutive days 2) Rifampicin WHO,P (max. 600 mg/day).

Prophylaxis for H. influenzae type B • DRUG SUMMARY: Adult PO 600 mg/day for 4 days. Rifampicin, a bactericidal agent, is a key Child PO 10-20 mg/kg/day for 4 component of any antituberculosis regimen. days; max. 600 mg/day. Like isoniazid it should always be included Dapsone-Sensitive Multibacillary Leprosy unless there is a specific contraindication. During the first two months of rifampicin Adult PO 600 mg once/month with clofazimine and dapsone administration transient disturbance of liver for minimum of 2 years. function with elevated serum transaminases is common, but generally it does not Directions: It could be taken with food to require interruption of treatment. avoid gastric distress, but it is Occasionally more serious liver toxicity recommended to be taken 1 hour before or requires a change of treatment particularly 2 hours after meal. in those with pre-existing liver disease. Rifampicin is a potent hepatic enzyme inducer which accelerate the metabolism of several drugs.

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• USE IN SPECIAL CASES: Treatment: Gastric lavage is probably Pregnancy- There are evidences of preferable to induction of emesis. teratogenic effect, in animal studies, if it Activated charcoal slurry instilled into the has been used during the first trimester. stomach following evacuation of gastric The risk of neonatal bleeding may be contents can help absorb any remaining increased if rifampicin has been drug in the GI tract. Antiemetic medication administered during the third trimester. may be required to control severe nausea Lactation- Rifampicin is excreted in breast and vomiting. milk with a milk/plasma ratio of 0.2 to 0.6. • INTERACTIONS: Decide whether to discontinue nursing or Overview of Rifampicin to discontinue the drug, taking into account Drug-Drug Interactions the importance of the drug to the mother. Drug Interaction Children- Data is not available to determine Rifampicin induces hepatic enzymes which dosage for children < 5 yrs. of age. accelerate the metabolism of several drugs Renal Disease- No dosage adjustment is including: required in the case of renal failure. estrogens, corticosteroids, phenytoin, Liver Disease- Avoid use or do not exceed sulphonylurea, anticoagulants, 8 mg/kg daily because elimination might antiarrhythmics, chloramphenicol, antidepressants, antipsychotics, anxiolytics, be reduced and the risk of hepatotoxicity hypnotics, β-blockers, Ca-channel might be increased. blockers, cardiac glycosides, theophylline, • PRECAUTIONS AND WARNINGS: thyroxine and cimetidine. 1. Reduce dose in hepatic impairment- Monitor patients and plasma levels when look at special cases. applicable, and adjust dosage regimens as 2. Carry out liver function tests and blood needed. counts in the case of hepatic disorders and Oral contra- The effectiveness of OC is on prolonged therapy. ceptives reduced; alternative family 3. It discolors soft contact lenses. (OC) planning method should be 4. Cautious use in the case of alcoholism offered. or concomitant administration of another Antacids They reduce absorption of rifampicin. hepatotoxic agent. • Alcohol, Coadministration of any one ADVERSE EFFECTS: and of these increases the risk of Heartburn, anorexia, nausea, vomiting, isoniazid hepatotoxicity. Refer to INH. diarrhea, epigastric distress, flatulence, Para-amino- Effectiveness of rifampicin is cramps, transient elevation in liver function salicylic acid reduced. If necessary to tests (bilirubin, BSP, alkaline phosphatase, administer, give apart at an ALT, AST), thrombocytopenic purpura, interval of 8-12 hrs. flushing, urticaria and rashes, saliva and other • body secretions will be colored orange-red. BRANDS: • Mycobutin (Farmitalia/Agis), Rimactan (Ciba- OVERDOSE: Geigy). Signs and symptoms: Nausea, vomiting and ______increase lethargy will probably occur within a short time after ingestion; unconsciousness may occur with severe hepatic involvement. Brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears and feces is proportional to the amount ingested. Liver enlargement and jaundice may develop rapidly.

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Anti-Infectives 3) Pyrazinamide WHO,P nausea, vomiting, arthralgia, sideroblastic anemia, and urticaria. • DRUG SUMMARY: • INTERACTIONS: Pyrazinamide (PZN) is a bactericidal drug, It inhibits the renal secretion of urates. only active against intracellular dividing PZN antagonizes the effect of probenecid forms of Mycobacterium tuberculosis; it and sulphinpyrazone which are uricosuric exerts its main effect only in the first two to agents. three months. It is particularly useful in • OVERDOSE: tuberculous meningitis because of good Overdose experience is limited. meningeal penetration. It is not active • BRANDS: against M. bovis. No brand names available in our market. • INDICATIONS: ______Tuberculosis in combination with other drugs. WHO,P • CONTRAINDICATIONS: 4) Ethambutol Liver damage, porphyria. • • DOSAGE FORMS: DRUG SUMMARY: Tablets. Ethambutol, a bacteriostatic agent, is • RECOMMENDED DOSAGE: included in the treatment regimen of Adult tuberculosis when resistance to other agents PO 1.5 g daily < 50 kg is suspected. • Adult INDICATIONS: PO 2 g daily Tuberculosis in combination with other ≥ 50 kg drugs. Child PO 35 mg/kg daily. • CONTRAINDICATIONS: • USE IN SPECIAL CASES: - Renal function impairment. Pregnancy- Pyrazinamide should be used - Poor vision of optic neuritis. only if it is clearly indicated (Category C). - Children under 13 years old. Lactation- It is found in small amounts in • DOSAGE FORMS: breast milk, therefore, one should take the Tablets. risk-benefit ratio of this therapy into account. • RECOMMENDED DOSAGE: Children- PZN regimens employed in adults Directions: Absorption is not affected by are probably equally effective in children. food. Can be taken with food in order to PZN appears to be well tolerated in children. minimize stomach upset. Renal Disease- No dosage adjustment is required. Unsupervised Treatment with Ethambutol Liver Disease- Patients with preexisting liver 25 mg/kg daily in the initial phase followed disease should be followed up closely, and by 15 mg/kg daily in the continuation phase one should discontinue PZN if signs of (or 15 mg/kg daily throughout). hepatocellular damage appear. Fully Supervised Intermittent Treatment • PRECAUTIONS AND WARNINGS: 30 mg/kg three times a week or 45 mg/kg One should take caution in the case of: twice a week impaired renal function, diabetes, gout, or history of peptic ulcer. • USE IN SPECIAL CASES: • ADVERSE EFFECTS: Pregnancy- It should be used only when Hepatotoxicity including: fever, anorexia, clearly indicated (Category B). hepatomegaly, jaundice, or liver failure;

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Lactation- The amount excreted in breast agents that act either locally to expel worms milk is too small to be harmful to the nursing from the GI tract or systemically to baby. eradicate species and developmental forms Children- It is contraindicated in children less of helminths that invade organs and tissues. than 13 years old. The common antiparasitic drugs used in Renal Disease- Dose should be reduced if the our community are discussed in this degree of impairment is mild. section. Liver Disease- No dosage adjustment is required in the case of hepatic dysfunction. • PRECAUTIONS AND WARNINGS: 1) Metronidazole WHO,P -Reduce dose in the case of renal impairment. • DRUG SUMMARY: -Cautious use in the case of: gout, cataract, Metronidazole is an antimicrobial drug with recurrent ocular inflammatory conditions, a high activity against anaerobic bacteria diabetic retinopathy, and the elderly. and protozoa. It is the drug of choice for • ADVERSE EFFECTS: acute invasive amoebic dysentery, since it -Visual disturbances. is very effective against vegetative -Optic neuritis, red/green color blindness, amoebae in ulcers at a dosage of: 800 mg peripheral neuritis. every eight hours for five days. It is also • INTERACTIONS: effective against amoebae which may have Aluminum salts may delay and reduce the migrated to the liver. absorption of ethambutol, so separate their • INDICATIONS: administration by several hours. -Anaerobic infections (including brain • OVERDOSE: abscess). Experience with overdose is limited. -Protozoal infections including: • BRANDS: a: Trichomoniasis. Myambutol (Lederle). b: Amoebiasis (not for cystic form). ______c: Gardiasis (not for cystic form). -Bacterial vaginosis (as Gardnerella vaginalis infections and Trichomonas C) ANTI-PARASITICS vaginalis). -Surgical and gynecological sepsis in which Parasitic infections are a major world wide its activity against colonic anaerobes, health problem, particularly in less especially Bacteroid fragilis, is important. developed countries (i.e., malaria, schis- -Treatment of pseudomembranous colitis tomsomes, amoebiasis . . . etc.). Different (in a dose of 400 mg by mouth three factors contribute to this increase such as times/day). population crowding, poor sanitation and -Topical metronidazole reduces the odor lack of health education, inadequate control produced by anaerobic bacteria in fungating of parasite vectors, contaminated water tumors. • supplies, increased world travel, population CONTRAINDICATIONS: migrations, as well as development of Blood dyscrasias, active CNS disease, first resistance to agents used to treat these trimester of pregnancy, nursing mothers. infections. • DOSAGE FORMS: Antiparasitics or anthelmintics are drugs Tablets, suspension, gel or cream. used to rid the body of worms known as • RECOMMENDED DOSAGE: helminths. The term anthelminitc applies to See table-5.10.

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Anti-Infectives Directions: Administer oral preparations • ADVERSE EFFECTS: immediately before, with, or immediately Nausea, vomiting, unpleasant taste, GI after meals. If GI distress occurs, one can disturbances, rashes, urticaria and angio- take the drug with food or with milk. edema, drowsiness (rare), headache, • USE IN SPECIAL CASES: dizziness, ataxia, and darkening of urine. Pregnancy- Metronidazole is contraindicated • INTERACTIONS: in first trimester. It should be used only when Overview of Metronidazole it is clearly indicated. If benefit outweighs Drug-Drug Interactions risk for use, avoid high-doses regimens, or Drug Interaction single doses (Category B). Alcohol Disulfiram-like reaction. Lactation- Stop lactation during treatment as Warn patient against alcohol significant amount of the administered drug or alcohol containing product appears in the breast milk and it may give a intake. bitter taste to the milk. A nursing mother Disulfiram Concomitant administration should discard any breast milk produced will cause acute psychosis while she is on the drug, and resume nursing Phenobar- These inhibit the metabolism 24 to 48 hours after the drug is discontinued. bitone and of metronidazole. Children- Safety and efficacy in children cimetidine have not been established, except for the Phenytoin Metronidazole inhibits the treatment of amebiasis. There is a decrease in metabolism of phenytoin, this elimination in newborns. might lead to toxic effects. Renal Disease- No dosage adjustment is Warfarin Metronidazole enhances the required in the case of renal impairment. anticoagulant effect. Use with Liver Disease- Reduce the dose in the case of caution. severe liver dysfunction. • OVERDOSE: • PRECAUTIONS AND WARNINGS: Symptoms: Nausea, vomiting, ataxia, and -Metronidazole is carcinogenic in rodents neurotoxic effects. after long term use; avoid unnecessary use. Treatment: No specific antidote for metro- -It causes disulfiram-like reaction if it is nidazole is available. Treatment consists of administered with alcohol. usual supportive measures. -Cautious use in the case of liver • BRANDS: impairment. Entogyl (JePharm), Flagy (Specia), Metrocare -Cautious use in the case of alcoholism and (Pharmacare), Metrogyl (Teva), Metrozole coexistent candidiasis. (BPC), Trichonazole (Vitamed), Zadstat (Lederle).

______

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Table – 5.10: Recommended Doses of Metronidazole * Disease Age Route Dosage Anaerobic Adult PO An initial dose of 800 mg followed by infections 400 mg q. 8 h. for 7 days. Child PO 7.5 mg/kg q. 8 h. for 7 days. Leg ulcers and Adult PO 400 mg q. 8 h. for 7 days. pressure sores Bacterial Adult PO 400-500 mg twice daily for 7 days or vaginosis 2 g as a single dose. Acute Adult PO 200 mg q. 8 h. for 3–7 days. ulcerative Child (1- < 3 y) PO 50 mg q. 8 h. for three days. gingivitis Child (3- < 7 y) PO 100 mg q 12 h for three days. Child (7- 10 y) PO 100 mg q. 8 h. for three days. Acute dental Adult PO 200 mg q. 8 h. for 3-7 days. infections Invasive Adult PO 800 mg q. 8 h. for 5 days. intestinal Child (1- < 3 y) PO 200 mg q. 8 h. for 5 days. amoebiasis Child (3- < 7 y) PO 200 mg q. 6 h. for 5 days. Child (7- 10 y) PO 400 mg q. 8 h. for 5 days. Amoebiasis Adult PO 800 mg q. 8 h. for 7-10 days (including Child PO 35-50 mg/kg/d given in 3 divided doses, liver abscess) q. 8 h. for 7-10 days. Urogenital Adult PO 400-500 mg q. 12 h. for 5-7 days trichomoniasis Child PO 15mg/kg/d given in 3 divided doses for 7 days. Giardiasis Adult PO 2 g daily for 3 days and a further 2 g dose may be given if no clinical improvement, or 400 mg q. 8 h. for 5 days, or 500 mg q. 12 h. for 7-10 days. Child PO 35-50 mg/kg/d given in 3 divided doses, q. 8 h. for 7-10 days. *Reference: BNF 2001 (Sept), pp. 286,316.

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Anti-Infectives

2) Diloxanide Furoate WHO . • ADVERSE EFFECTS: Mild GI tract symptoms, particularly • DRUG SUMMARY: flatulence, may be troublesome. Vomiting, Diloxanide furoate, a dichloroacetamide pruritus and urticaria have been reported. derivative, is a luminal amoebicide acting • INTERACTIONS: principally in the bowel lumen and is used None reported. in the treatment of intestinal amoebiasis. It • OVERDOSE: is given alone in the treatment of Symptoms: Nausea and vomiting. asymptomatic cyst-passers, and in Treatment: Induces emesis if not already conjunction with an amoebicide that acts in occurred. Gastric lavage may be used. Use the tissues, in patients with invasive supportive symptomatic care. amoebiasis. Good choice for recurrent or • BRANDS: chronic amoebae. Furamide (Knoll). • INDICATIONS: ______Treatment of asymptomatic carriers (E. histolytica cyst-passers) in nonendemic 3) Mebendazole WHO areas (metronidazole and tinidazole are relatively ineffective for such cases. Refer • DRUG SUMMARY: to BNF 2001:316). Eradication of residual Mebendazole is effective in threadworm amoebae in the colonic lumen following infections (the commonest one is the treatment of invasive disease with pinworm “Enterobius vermicularis”), but metronidazole or other amoebicides. its use needs to be combined with hygienic • CONTRAINDICATIONS: measures to break the cycle of auto- Hypersensitivity to diloxanide. infection. All members of the family • DOSAGE FORMS: require treatment. Mebendazole is the drug Tablets. of choice for patients of all ages over two • RECOMMENDED DOSAGE: years. It is given as a single dose; as Adult: 500 mg 3 times daily for 10 days. reinfection is very common, a second dose Child: 20 mg/kg daily in 3 divided doses may be given after 2-3 weeks. Also, it is for 10 days. used in the treatment of infection caused by Directions: If necessary a second course other types of helminths as roundworm may be given immediately following the (Ascaris), whipworm, and hookworm first. infections. *May be taken without regard to meals. • INDICATIONS: • SPECIAL CASES: Treatment of infections caused by Pregnancy- Use only if clearly indicated. threadworm, roundworm, whipworm, and Treatment is best deferred until after the hookworm. first trimester. • CONTRAINDICATIONS: Lactation- Use with caution. Safety has not Hypersensitivity to mebendazole. been reported. • DOSAGE FORMS: Children- It has been used safely in children. Tablets and suspension. Renal + Liver Disease- Use with caution. No • RECOMMENDED DOSAGE: special adjustments reported. Doses are summarized in the table below. • PRECAUTIONS AND WARNINGS: Directions: It may be given without regard It is not effective against hepatic to food. The tablet may be chewed, amoebiasis. crushed, or swallowed.

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Recommended Doses of Mebendazole 4) Niclosamide Threadworms’ infection (Enterobius vermicularis) • DRUG SUMMARY: Adult & PO 100 mg as a single Niclosamide is a halogenated salicylanilide children dose; if reinfection derivative anthelminitic. It is the most over 2 years occurs a second widely used drug for tapeworm infections. dose may be It is not effective against larval worms, and needed after 2-3 it affects the cestodes of the intestine only. weeks. The fact that fasting is not necessary, Other infestations makes it more preferred by patients Adult & PO 100 mg twice particularly in the treatment of children. children daily for 3 days. • over 2 years If no cure, INDICATIONS: another course Intestinal tapeworm (cestode) infections, may be given. example Taenia saginata (beef tapeworm), Diphyllobothrium latum (fish tapeworm), • USE IN SPECIAL CASES: Hymenolepis nana (dwarf tapeworm), Pregnancy- Use not recommended for Hymenolepis diminuta (rat tapeworm), pregnant women (Category C); benefit-risk Dipylidium caninum (dog or cat tape- issue. worm). Lactation- Use not recommended. Safety in • nursing mother has not been established. CONTRAINDICATIONS: Children- Not recommended for children Hypersensitivity to niclosamide or any of under 2 years. its components. Renal Disease- Minimally absorbed from the • DOSAGE FORMS: GI tract, safely used in the case of renal Tablets. disease, when used as directed. • RECOMMENDED DOSAGE:

Liver Disease- Minimally absorbed from the Beef and Fish Tapeworm GI tract, can be used in the case of liver disease. Adult PO 2 g as a single dose • ADVERSE EFFECTS: Child PO 1.5 g as a single Abdominal pain and diarrhea which are (> 34 kg) dose rare. Child PO 1 g as a single dose • INTERACTIONS: (11-34 kg) *Carbamazepine and hydantoins may Dwarf Tapeworm reduce the plasma level of mebendazole, Adult PO 2 g/d as a single leading to a decrease in its therapeutic dose for 7 days effectiveness. Child PO 1.5 g/d as a single (>34 kg) dose for 6 days • OVERDOSE: Child 1 g as a single dose GI complaints lasting to a few hours may PO (11-34 kg) on day 1, then 500 occur. Induce vomiting and purging. mg once/d for next • BRANDS: 6 days. Vermacare (Pharmacare), Vermazol (JePharm), Vermox (Abic), Wormex (Megapharm). Directions: It should be taken after a light ______meal. Instruct the patient to chew tablet thoroughly, then swallow with a little water. *For young children, tablet may be crushed to a fine powder and mixed with sufficient water to form a paste for ease of ingestion.

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Anti-Infectives • USE IN SPECIAL CASES: D) ANTI-FUNGALS Pregnancy- Use during pregnancy only when it is clearly indicated (Category B). Fungal infections are frequently associated Lactation- Its use during lactation has not with a defect in host resistance which been established. should, if possible, be corrected; otherwise Children- Its use in children less than 2 years drug therapy may fail. Treatment of has not been established. dermatophyte infections may be Renal Disease- Minimally absorbed from the unsuccessful until the animal source has GI tract, therefore, safely used in the case of been removed or controlled. Fungal renal disease. infections are traditionally divided into two Liver Disease- Minimally absorbed from the classes; superficial and systemic. The most GI tract, may be used in the case of liver common fungal infections are superficial disease. and are treated with topical agents or with • ADVERSE EFFECTS: oral agents. Most current drugs (i.e. Occasional GI upset, light-headedness, and imidazoles and triazoles) may be used pruritus. • systemically or topically. Systemic mycotic OVERDOSE: infections are often found in debilitated or In the events of the overdose, do not induce immunosuppressed patients. vomiting. Refer to the hospital and give a fast-acting laxative and enema. (For topical use of antifungal agents refer • BRANDS: to the dermatological section). Yomesan (Bayer). ______1) Nystatin WHO,P WHO 5) Albendazole (hydatid disease) • DRUG SUMMARY: It is not absorbed when it is given by mouth Cysts caused by Echinococcus granulosus and is too toxic for parenteral use. It is grow slowly and asymptomatic patients do active against a number of yeast and fungi not always require treatment. Surgical but is principally used for Candida albicans treatment remains the method of choice in infections of skin and mucous membranes. many situations. Albendazole is used in It is also used in the treatment of intestinal conjunction with surgery to reduce the risk candidiasis. of recurrence or as primary treatment in • INDICATIONS: inoperable cases. Candidiasis. Alveolar echinococcosis due to E. • multilocularis is usually fatal if untreated. CONTRAINDICATIONS: Surgical removal with albendazole use is It is contraindicated in the case of hypersensitivity to nystatin, and in the case of the treatment of choice, when effective vaginal infections caused by Gardnerella surgery is impossible, repeated cycles of vaginalis or Trichomonas spp. albendazole (for a year or more) may help. • DOSAGE FORMS: Careful monitoring of liver function is Tablets, suspension, vaginal tablets. particularly important during drug • RECOMMENDED DOSAGE: treatment. Refer to the following table: ______

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Recommended Doses of Nystatin 2) Miconazole WHO,P Candida Infections Adult PO 50,000-1,000,000 IU • DRUG SUMMMARY: three times daily. Miconazole is mainly used for local 1-4 troches 4-5 times/d. treatment and can be given by mouth for Suspension: 400,000- oral and intestinal infection; it can also be 600,000 IU 4 times daily. given parentally for systemic infections Vagi- 1-2 tablets daily for 2 including aspergillosis, candidiasis, and nal weeks. Child PO Suspension: 400,000- cryptococcosis but the injection contains 600,000 IU 4 times daily. polyethoxylated caster oil which may give Infants PO 100,000-200,000 IU 4 rise to hypersensitivity reactions. times daily. • INDICATIONS:

Directions: In the case of oral suspension: Mainly used to treat severe systemic fungal rinse the mouth with 1-2 tsp of nystatin oral infections. • susp., keep it in the mouth as long as CONTRAINDICATIONS: possible then expectorate or swallow Hypersensitivity to miconazole. • (better for children and infants). Avoid DOSAGE FORMS: food and drink for at least 30 min. after Tablets. • RECOMMENDED DOSAGE: administration. *Avoid the direct contact of the drug with hands. Oral and Intestinal Fungal Infections 250 mg q. 6 h. for 10 days or up *Store vaginal suppositories in refrigerator By mouth to two days after symptoms below 15° C. as tablets clear. *Treatment of candidiasis should be By mouth Adult 5-10 ml in the mouth continued for at least 48 hours after the as oral after food q. 6 h.; disappearance of symptoms. gel retain near lesions • USE IN SPECIAL CASES: before swallowing. Child Pregnancy- Category A. No adverse effects 2.5 ml b.i.d. or complications have been attributed to < 2 yrs. Child nystatin in infants born to women treated 5 ml b.i.d. 2-6 yrs. by nystatin. Child 5 ml 4 times daily. Lactation- It is poorly absorbed from the GI > 6 yrs. tract, therefore it should not have any adverse effects on the nursing infant. Vaginal Infections Renal and liver Diseases- It is poorly Intra- Vaginal 1 applicator full of absorbed from the GI tract, and passes vaginal cream cream or one 100 mg or unchaged in the stool, therefore no special supp. at bedtime for 7 vaginal days or one 200 mg precautions are recorded. supp. • supp. at h.s. for 3 ADVERSE EFFECTS: days. Nausea, vomiting, diarrhea at high doses. • BRANDS: Directions: Oral preparations should be Nystatin (Taro), Candistan (BPC). taken after food. In the case of oral gel, ______smear the affected area with a clean finger and hold it in the mouth for a while before swallowing.

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Anti-Infectives • USE IN SPECIAL CASES: • INDICATIONS: Pregnancy- Category B after the first Dermatophyte infections of the skin, scalp, trimester. It should be used only when hair and nails, where topical therapy has clearly indicated. failed or is inappropriate. It is effective Lactation- No available data on use. Avoid against various species of Epidermophyton, use, unless clearly indicated. Microsporum, and Trichophyton (has no Children- Safety in children under 1 year of effect on other fungi, including Candida age has not been established. spp., bacteria, and yeast). Renal Disease- Cautious use in the case of • CONTRAINDICATIONS: renal impairment. In porphyria, hepatic failure, and systemic Liver Disease- Cautious use in the case of lupus erythematosus. hepatic impairment. • DOSAGE FORMS: • PRECAUTIONS AND WARNINGS: Tablets Hepatic and renal impairment. • RECOMMENDED DOSAGE: • ADVERSE EFFECTS: Nausea, vomiting, pruritus, and rashes. Tinea Corporis, Tinea Cruris, and • INTERACTIONS: Tinea Capitis 500 mg microsize or 330- Overview of Miconazole Adult PO 375 mg ultramicrosize Drug-Drug Interactions daily in single or divided Drug Interaction doses. Warfarin, Miconazole enhances the Tinea Pedis, Tinea Unguium sulphonyl- effect of these. Monitor ureas and patients and adjust their doses Adult PO 0.75-1 g microsize or 660- phenytoin as needed. 750 mg ultramicrosize daily in single or divided Ampho- Miconazole antagonizes its doses; microsize dose tericin effect. Use with caution. should be decreased to • BRANDS: 500 mg/d after response is Dakatrin Oral Gel (Abic), Daktazol Oral Gel noted. (JePharm), Gyno-Daktarin (Abic), Gyno- Child PO 11 mg/kg/d microsize or Daktazol (JePharm), Gyno-Daktazol Ovules 7.3 mg/kg/d ultramicrosize (JePharm). in single or divided doses.

______Directions: It should be taken with or after the meal. Continue taking the medication for entire course of therapy even if WHO,P 3) Griseofulvin beneficial effects may not be noticeable. *Duration of treatment depends on the • DRUG SUMMARY: thickness of the keratin layer: 2-6 wks. for May be produced by the growth of certain hair and skin, up to 6 mon. for fingernails, strains of Penicillium griseofulvum or by and 12 mon. or more for infections of the other means. It is selectively concentrated toenails. in keratin and is the drug of choice for • USE IN SPECIAL CASES: widespread or intractable dermatophyte Pregnancy- Use it only when it is clearly infections. It is well absorbed from the gut indicated (Category C). Griseofulvin was but is inactive when applied topically. It is embryotoxic and teratogenic rates. Cases of more effective in skin than in nail conjoined twins have been reported in infections and treatment must be continued patients taking griseofulvin during the first for several weeks or even months. Side trimester of pregnancy. effects are uncommon. Lactation- Use caution. No available data.

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Children- Safety not established in children With the increased number of HIV less than two years old. infected people world wide, there are many Liver Disease- It is contraindicated in the antiviral drugs that are specific for this case of hepatic failure. causative agent of AIDS. AIDS • PRECAUTIONS AND WARNINGS: medications will not be discussed in our -Use caution in the case of penicillin- book at this time, since AIDS patients in sensitive patients since there is a possibility our community seek special medical of the presence of cross-sensitivity between supervision, and will rarely be treated at the penicillin and griseofulvin. primary healthcare level. -It may impair performance of skilled tasks This section will discuss the antiviral (e.g. driving). agent Acyclovir. -It enhances the effect of alcohol. • ADVERSE EFFECTS: Headache, nausea, vomiting, rashes, 1) Acyclovir photosensitivity, dizziness, fatigue, agranulcytopenia and leucopenia have been • DRUG SUMMARY: reported; lupus erythematosus, erythema Acyclovir, written as aciclovir in British multiforme, peripheral neuropathy, English, is an antiviral agent (a synthetic confusion, and impaired co-ordination. purine nucleoside derivative) that inhibits • INTERACTIONS: the viral replication by inhibiting DNA Overview of Griseofulvin synthesis. It is active against Herpes Drug-Drug Interactions simplex virus 1&2, Varicella zoster, Drug Interaction Epstein-Barr and Cytomegalovirus. Anti- Griseofulvin increases the • INDICATIONS: coagulant metabolism of nicoumalone For the treatment of initial episodes and and warfarin leading to a management of recurrent genital herpes in decrease in their certain patients. It is also used for the acute anticoagulant activity. treatment of Herpes zoster (shingles) and Oral contra- Griseofulvin increases the Varicella (chickenpox). ceptives metabolism of OCs. • CONTRAINDICATIONS: Pheno- It increases the metabolism of Hypersensitivity to acyclovir or any of its barbitone griseofulvin, leading to a decrease in its anti-fungal components. activity. • DOSAGE FORMS: Tablets, capsules, suspension, ointment. • BRANDS: • RECOMMENDED DOSAGE: Grifulin Forte (Teva), Sporofulvin (JCL). Adult: *Herpes simplex: ______Initial genital herpes: 200 mg PO q. 4 h.; 5

times a day for 10 days. C) ANTIVIRAL AGENTS Chronic/recurrent disease: 400 mg b.i.d. for up to 12 months followed by Specific therapy of viral infections is reevaluation of the case. Reevaluation will generally unsatisfactory, and treatment is determine if there is a need to continue or primarily symptomatic. Most agents are discontinue the medication. active against the virus, but do not Intermittent therapy: 200 mg q. 4 h.; 5 eradicate them. Infections that do not times a day for 5 days. Therapy should start respond to antivirals include mumps, as soon as the first symptom of recurrence poliomyelitis, rabies and rubella. occurs.

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Anti-Infectives *Herpes zoster, acute treatment: 800 mg an extensive period of time. Another type q. 4 h.; 5 times a day for 7 to 10 days. of antiviral should be used in this case. Child: *Chicken pox: -Dosage depends on the estimated 20 mg/kg (not > 800 mg) q. 6 h. for 5 days. Creatinine clearance (CLcr). Continuous Therapy should be started at the earliest checking of CLcr is recommended for sign or symptom. patients using acyclovir for long periods of • USE IN SPECIAL CASES: time. Pregnancy- There are no adequate studies in • ADVERSE EFFECTS: pregnant women (Category C). Use during Several adverse effects may occur such as: pregnancy only if the potential benefit nausea, vomiting, diarrhea, headache, skin outweighs the potential risk to the fetus. rash, dizziness, edema, leg pain, sore Lactation- Acyclovir is excreted in the breast throat, flatulence, constipation, and milk, but there have been no reports of malaise. adverse effects. Exercise caution when • INTERACTIONS: administering to a nursing woman. Overview of Acyclovir Children- Safety and efficacy of oral Drug-Drug Interactions acyclovir in children < 2 years of age have Drug Interaction not been established. Probenecid Acyclovir may increase its Renal Disease- Dosage adjustment is required effect. with renal function impairment depending on Zidovudine Acyclovir interacts with the creatinine clearance as indicated in the zidovudine and causes severe table below: drowsiness and lethargy. Use Oral Acyclovir Dosage with caution.

In Renal Function Impairment • Normal OVERDOSE: CL Adjusted dosage cr Overdose may be treated with hemo- (ml/min/ dosage regimen dialysis. Renal failure might result from 1.73 m2) regimen (5 x daily) the overdose. In such cases, hemodialysis > 10 200 mg q.4 h., 200 mg should continue until renal function is 5 x dly q. 4 h. restored. 0-10 200 mg q.12 h. • BRANDS: 400 mg > 10 400 mg q. 12 h. Zovirax (Wellcome). q. 12.h. 0-10 200 mg q. 12 h. ______> 25 800 mg q. 4 h., 800 mg 5 x daily q. 4 h. 10-25 800 mg q. 8 h. 0-10 800 mg q. 12 h.

• PRECAUTIONS AND WARNINGS: -In the case of genital herpes, the patient should avoid sexual intercourse when visible lesions are present because of risk of infecting the other partner. -Acyclovir does not eliminate latent herpes simplex virus and is not a cure. It only decreases the frequency and the severity of recurrences. Resistance might develop when acyclovir is used continuously over

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Chapter 6: Endocrine System Drugs

A) ANTI-DIABETIC DRUGS 1. Insulin 2. Glibenclamide (Glyburide) 3. Metformin

B) THYROID DRUGS 1. Thyroxine 2. Propylthiouracil

C) CORTICOSTEROIDAL DRUGS 1. Prednisone

A) ANTIDIABETIC DRUGS

Diabetes Mellitus (DM) is a complex drug include cost, contraindications, side disease characterized by symptoms of effects, amount of glycemic-lowering glucose intolerance, as well as changes in needed to get the patient to the desired lipid and protein metabolism. Over the glucose range, ability for compliance, the long term, these metabolic abnormalities, patient’s weight and ideal weight, and the particularly hyperglycemia, contribute to lipid profile (White, 1998). the development of complications such as retinopathy, nephropathy and neuropathy. Table 6.1: Antidiabetic Drugs The Expert Committee on the Diagnosis Category Examples and Classification of Diabetes Mellitus has Insulins Regular insulin developed new criteria for the diagnosis of Lispro insulin DM [Diabetes Care, 1997(Jul); 20(7)]. Isophane insulin There are two major types of diabetes: Sulfonylurea 1st generation: Acetohexamide Type 1 previously known as insulin Chlorpropamide dependent diabetes mellitus (IDDM) or Tolazamide juvenile form, and Type 2 previously Tolbutamide known as non-insulin dependant diabetes 2nd generation: Glipizide mellitus (NIDDM) or adult/maturity onset Glibenclamide form. (glyburide) There are three major components for Gliclazide the treatment of DM; diet, exercise, and Liquidone drugs. Each of these components interacts Glimepiride with the other to the extent that no Thiazolidinediones Pioglitazone assessment and modification of one can be Rosiglitazone Troglitazone* made without knowledge of the other two. Repaglinide The goal of therapy is to keep the patient Meglitinides Nateglinide free of symptoms associated with hyperglycemia or hypoglycemia, to prevent Biguanides Metformin glucose toxicity, to eliminate or minimize Alpha-Glucosidase Acarbose Inhibitors Miglitol all other cardiovascular risk factors and further macrovascular and microvascular (*removed from market due to reports of serious hepatic injury.) diseases, and to maintain normal growth and development in children. The 1st generation sulfonylureas are Diet, exercise, and insulin must be considered equally effective, but differ with delicately balanced in type 1. If diet and respect to their pharmacokinetic properties weight loss have failed in type 2 patients, and adverse effects profile. The 2nd an oral hypoglycemic agent can be used. If generation agents are approximately 100 drugs are used properly they can be both times more potent than the first generation safe and effective. drugs on a mg-to-mg basis, and have a There are six categories of drugs lower profile of side effects and drug-drug approved for the management of diabetes interactions. For this reason, a second- mellitus (see table-6.1). Some of these generation agent (glibenclamide) was agents maybe used as single therapy or in recommended over first generation agents combination. The proper choice between to be discussed in this chapter. A them is not completely clear. The factors comparison between sulfonylureas and the that should be considered when choosing a

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Endocrine System Drugs biguanide Metformin can be seen in table- person. Warn your patients of symptoms of 6.2. hypoglycemia and hyperglycemia as noted The newer agents, thiazolidinediones, in table-6.3. meglitinides, and alpha-glucosidase inhibitors differ in their mode of action and Various medications may cause effects. Even within a class, there are symptoms of hyperglycemia or hypo- differences in terms of toxicities and effect glycemia, or clinically significant drug on lipid profiles. It is important to note that interactions (use caution in such cases) as not all these agents have long-term data and noted in table-6.4. comparative studies yet. One should emphasize to the patient the Table – 6.3: Symptoms of importance of testing and recording urine Hyperglycemia vs Hypoglycemia and blood glucose levels, as well as Hyperglycemia Hypoglycemia keeping records of medications, doses, diet -Flushed, dry skin -Fatigue and exercise for unstable patients to -Excessive thirst -Headache/Dizziness improve their diabetic control. Proper urine -Excessive urination -Excessive hunger or blood testing for glucose and ketones are -Low blood pressure -Profuse sweating important for them to know their blood -Drowsiness -Numbness of glucose levels and to prevent any diabetic -Lethargy extremities or mouth -Urinary glucose -Visual disturbances ketoacidosis. ketones -Delirium Also, note the importance of general -Coma hygiene, foot, dental and eye care since DM patients are more susceptible to have problems in these areas than the average

Table – 6.2: Summary of Oral Sulfonylureas vs. Metformin CHARACTERISTIC ORAL SULFONYLUREA METFORMIN Indication NIDDM not controlled NIDDM, mostly obese patients Diet and Exercise extremely important extremely important Dosing Intervals q.d. or b.i.d. b.i.d. or t.i.d. Adverse Side Effects - Lactic acidosis none possible - Hypoglycemia very common uncommon - Cardiovascular mortality decrease mortality no record, but possible - Weight reduction might cause weight gain help decrease weight - GI disturbances mild-moderate moderate- severe Pregnancy category B + C category B (avoid both if possible) Lactation excreted, discontinue drug excreted, not recommended Children not used not used Renal Disease use caution and monitor contraindicated Hepatic Disease use caution and monitor use not recommended Alcohol Intake disulfiram reaction lactic acidosis Administration with Insulin possible possible

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Table –6.4: Clinically Significant Drug Interactions in DM Patients (1)

Drug-Induced Hyperglycemia Drug-Induced Hypoglycemia - Glucocorticoids - Ethanol (Alcohol) - Diuretics - High dose salicylates - Pentamidine* - Pentamidine* - High dose phenytoin in NIDDM - Propranolol* - Oral contraceptives - Disopyramide - β-Adrenergic Blockers - Phenobarbital - Nicotinic acid/ Niacin - Sulfonamide antibiotics - Sympathomimietics (epinephrine)

* can cause either hyperglycemia or hypoglycemia. (1) Adapted from: Herfindal G, eds. Clinical Pharmacy and Therapeutics, 5th ed. Williams and Wilkins, Baltimore. 1992.

Table 6.5: Pharmacokinetics and Compatibility of Various Insulins Onset Peak Duration Compatibly Type Insulin -preps. (hr) (hr) (hr) mixed with Regular (clear soln.) 0.5-1.0 3-4 6-8 All Rapid-acting Semilente 1.0-1.5 6-10 12-15 Lente Lispro 0.25 0.5-1.5 6-8 Ultralente+ NPH Isophane- NPH 1.0-1.5 6-12 18-24 Regular

Intermediate Insulin Zinc-Lente 1.0-2.5 8-14 18-24 Regular + semilente PZI 4.0-8.0 12-24 36 Regular

Long-acting Ultralente 4.0-8.0 12-30 36-42 Regular + semilente

1) Insulin WHO,P • CONTRAINDICATIONS: Hypersensitivity to insulin animal proteins • DRUG SUMMARY: or preservatives. Insulin is a hormone that is secreted by • DOSAGE FORMS: islets of Langerhans by the beta-cells of the Injection: 100 units/ml, in 10 ml vials. pancreas. It is the principal polypeptide • RECOMMENDED DOSAGE: hormone required for proper glucose use in The type of insulin used and its dose and normal metabolic processes. It plays an frequency of administration depends on the important role in the metabolism of particular needs of each individual patient. carbohydrate, fat and protein. Insulin is Table-6.6 lists different regimens that are biosynthetically prepared by recombinant commonly recommended. Any of them can DNA technology using E. coli. be used depending on the patient’s needs. • INDICATIONS: Individualize dosing regimens.

Type 1 DM, and Type 2 DM that cannot be Dose guidelines for adult and children 0.5-1 properly controlled by diet, exercise and unit/kg/24 h. weight reduction. In hyperkalemic emergencies to produce a shift of potassium Adjust dose to achieve pre-meal and into cells and lower serum potassium levels. bedtime blood glucose levels of 80-140 Only the regular insulin can be given IV or mg/dl, and for children < 5 yrs. levels of IM in severe ketoacidosis or diabetic coma. 100-200 mg/dl. Also, for administration to pregnant and Insulin requirements may be increased by nursing diabetics, as well as during stressful infection, stress, accidental or surgical conditions or severe infections. trauma, puberty, and during pregnancy.

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Endocrine System Drugs Requirements may be decreased in patients *Rotate administration/injection sites to with renal or hepatic impairment and in prevent lipodystrophy. those with some endocrine disorders or *Insulin requirements may change in celiac disease. patients who become ill, especially with

Table-6.6: Some Examples of Common vomiting or fever. Also there is a need to Recommended Insulin Regimens* reduce the dose when caloric intake is Insulin Regimen reduced, or abnormally high physical 1. Short-acting mixed - twice daily (15- activity is undertaken, to avoid hypo- with intermediate- 30 min. a.c.). glycemia. acting insulin: *Need to emphasize to the patient the 2. Short-acting mixed - before breakfast importance of properly monitoring their with intermediate- only, will be blood glucose levels, and maintaining acting insulin: sufficient in some proper diet and exercise. patients. *Occasionally, redness, swelling and 3. a) Short-acting - before breakfast. itching at the injection site may develop. mixed with intermediate- acting This could occur if injection is not properly insulin: made; the skin may be sensitive to the b) Short-acting: - before evening antiseptic solution, or if the patient is meal. allergic to insulin or insulin additives c) Intermediate acting - bedtime (onset of (preservative). This condition usually action is 1-2 hrs.). resolves in a few days. If not, may need to 4. a) Short-acting - t.i.d. (15-30 min. switch type of antiseptic or insulin. insulin: before breakfast, • USE IN SPECIAL CASES: midday and Pregnancy- Pregnancy may make the evening meals). management of diabetes more difficult. - at bedtime. b) Intermediate Insulin is the drug of choice for controlling acting insulin: glucose levels during pregnancy; even in type * BNF 2001(Sep); (42): 323. 2 DM. Requirements may increase during the nd rd Directions: Patients should be given the 2 or 3 trimester of pregnancy. The patient should be kept under experienced medical following advice about the uses and supervision. Following delivery, insulin administration of insulin: requirements may drop for 24 to 72 hrs., *Patients should use the same type and rising towards the normal pre-pregnancy dose brand of insulin and syringe unit to avoid during the next 6 weeks. any dosage errors. Lactation- Insulin does not pass into breast *Store vials in refrigerator if not in use. Do milk. Breast-feeding may decrease insulin not freeze. requirements despite the increase in necessary *Do not inject cold insulin, it can lead to caloric intake. lipodystrophy, reduced rate of absorption Children- Safe when following the correct and local irritation. dosage and use. Can keep the vial in use at room Renal Disease- In severe cases, doses should temperature (up to 30 days), away from be reduced. Insulin requirements fall, since direct sunlight or temperature extremes. the compensatory response to hypoglycemia *Agitate vial by rolling between palm of is impaired. hands, do not shake vial vigorously. Liver Disease- Use caution, the drug is *If mixing insulin, always measure Regular metabolized primarily in the liver. (clear) before NPH (cloudy)! • PRECAUTIONS AND WARNINGS: -Lipodystrophy is the breakdown of adipose tissue at the insulin injection site,

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causing a depression in the skin. This may • ADVERSE EFFECTS: be the result of an immune response. -Hypersensitivity; usually occurs when Advise patient to rotate the injection site. insulin is at peak action, localized allergic -Diabetic ketoacidoses (DKA) is a reactions at the injection site, general potentially life-threatening condition, uricaria and rash. requiring immediate treatment. May result -Hypoglycemia / hyperinsulinism (refer to from stress, illness, insulin omission, or introduction of this chapter for symptoms). may develop slowly after a long period of -Post-hypoglycemia or rebound hyper- poor insulin control. Treatment involves glycemia may occur: administration of fluids, correction of ♦ Somogyi Effect, a morning (3-7 am), acidosis and hypotension, and low dose phenomenon caused by counter- regular insulin IM or IV in an emergency regulatory hormone release. This can be room. avoided by decreasing insulin dosage for -Hypoglycemia may result from excess critical time period, reduce insulin dose insulin dose, or: increased work load or for the overnight, or increase pre-bedtime exercise without eating, food not being snack. absorbed because of skipping a meal or in ♦ Dawn Phenomenon, an early morning illness with vomiting, fever or diarrhea. rise in plasma glucose due to greater Insulin requirements decline. surge of growth hormones in diabetics Refer to table-6.7 for summary of predisposing patient to development of difference between Ketoacidosis and hyperglycemia. Need to increase the Hypoglycemia. overnight insulin coverage.

(Test blood glucose levels at 3 am to differentiate between the two phenomenon.)

Table – 6.7. Summary of Hypoglycemia vs. Ketoacidosis Reaction Hypoglycemia (insulin reaction) DKA (diabetic coma) Onset sudden gradual, hours or days Urine glucose/acetone 0/0 * +/+ CNS symptoms fatigue, weakness, confusion, headache, drowsiness, dim vision diplopia, convulsions, dizziness, unconsciousness Respiration rapid, shallow air hunger Mouth /GI numb, tingling, hunger, nausea thirst, acetone breath, nausea, vomiting, loss of appetite Skin pallor, moist, shallow or dry dry, flushed Miscellaneous normal pulse, eyeball normal rapid pulse, soft eyeballs * 0/ 0 not found. +/+ found Professional Guide to Patient Drug Facts &Comparisons. St. Loius :Facts and Comparisons 2000.

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Endocrine System Drugs

• INTERACTIONS: lowering effect persists despite a gradual Decrease Hypoglycemic decline in the insulin secretory response to Effect of Insulin the drug. Extrapancreatic effects may play a Corticosteroids Oral contraceptives part in the mechanism of action of oral Dextrothyroxine Smoking sulfonylurea drugs. In addition to the Diltiazem Thiazide diuretics blood-glucose lowering action, this drug Epinephrine Thyroid hormone produces mild diuresis by the enhancement Increase Hypoglycemic of free water renal clearance. Effect of Insulin • INDICATIONS: Alcohol MAO inhibitors Anabolic steroids Phenylbutazone Glibenclamide is indicated as an adjunct to Colifibrate Salicylates diet to lower blood glucose in patients with Non-selective β- Tetracyclines type 2 DM when diet and weight reduction blockers alone fail to control their hyperglycemia. • CONTRAINDICATIONS: • OVERDOSE: Known hypersensitivity to the drug. As Symptoms: Insulin overdose causes single therapy in type 1, uncontrolled hypoglycemic symptoms; refer to adverse patients complicated by ketoacidoses; with effects. or without coma. Diabetes when Treatment: Eating sugar or sugar- complicated by pregnancy. sweetened product will correct simple • DOSAGE FORMS: conditions and prevent serious symptoms. Tablets 5 mg. Refer to emergency room if it cannot be • RECOMMENDED DOSAGE: controlled. Glucose and dextrose Adult: 2.5-5 mg daily with breakfast or administration, or glucagon, may be first main meal (for patients very sensitive necessary. to the agent start with 1.25), increase by 2.5 • BRANDS: mg every 1-2 weeks if needed. Doses of 15 Humulin-N, Humulin-R, Humulin-U, Humulin mg in 2 divided doses can be given, but 70/30 (Lilly), unlikely to produce additional effects. Novolin-N, Novolin R, Insulin Actrapid HM, Do not exceed 20 mg/24 hours. Insulin Mixtard ... (Novo Nordisk) See price list for other preparations. Child: Not to be used for children. ______Directions: To be taken 30 minutes before meals provided that the patient has no GI 2) Glibenclamide disorders, if so can give with food. Onset of action is about 1.5 hrs. (Glyburide) WHO,P *Advise patients not to discontinue

• medication abruptly, not to take any OTC DRUG SUMMARY: medications without consulting a health Glibenclamide is one of the most potent care professional, and to monitor their sulfonylurea, hypoglycemic agents. It is a nd blood or urine glucose levels. 2 generation sulfonylurea with a potency *Diet and weight control should be of more than a 100-fold over first emphasized as the primary form of generation agents. Glibenclamide appears treatment for all patients. to lower the blood glucose acutely by *Use of this medication is by no means a stimulating the release of insulin from the substitution for diet control or avoidance of pancreas, an effect dependent upon physical activity. functioning beta cells in the pancreatic islets. With chronic use, the blood glucose

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• USE IN SPECIAL CASES: treatment with diet plus insulin. The Pregnancy- Use of insulin is recommended patients have to be informed of potential during pregnancy. Sulfonylureas have been risk. teratogenic in animals (except glyburide), -Patients needs to contact the physician if no studies have been done on pregnant any side effects such as fever, sore throat, women. Use only if clearly needed. rash, unusual bruising or bleeding occurs, If used, it should be stopped at least 2 days as well as frequent episodes of – 4 weeks before expected delivery date to Hypoglycemia or Hyperglycemia (refer to prevent severe hypoglycemia in newborn introduction of this chapter for symptoms). (Category B). • ADVERSE EFFECTS: Lactation- Avoid. It is not known whether Hypoglycemia: all sulfonylureas may glibenclamide is excreted in human milk. produce severe hypoglycemia, more likely Some sulfonylureas are excreted, and had to occur when caloric intake is deficient, potential for hypoglycemia in nursing after severe or prolonged exercise, when infants. If the drug is discontinued and diet alcohol is ingested. Administer a simple alone is inadequate for controlling blood sugar as soon as possible if patient feels glucose, insulin therapy should be dizzy and ready to faint. considered. Other symptoms: GI disturbances; epigastic Children- Safety and efficacy haven’t been fullness, weight gain, heartburn, nausea, established. Use is not recommended. jaundice; pruritis, erythema, skin eruptions Renal Disease- Avoid use in severe cases. (if skin reactions persist, discontinue the Need dosage adjustments Clcr is < 30 drug), photosensitivity, joint pain, leg ml/min. Renal impairment may cause cramps, elevated liver function tests, and decreased elimination of the drug leading to blood dyscraisis. hypoglycemia. [Can use tolbutamide • INTERACTIONS: ® (Orinase, Tolanase ), or glipizide (Glucotrol, Overview of Glibenclamide Glibenese®); they are a better choice in renal Drug-Drug Interaction failure.] Drug Interaction Liver Disease- Drug is metabolized Alcohol It causes disulfiram-like extensively in the liver. Increased risk of reaction; facial flushing, hypoglycemia in severe liver disease, so occasional breathlessness, avoid use or use small doses. Can produce sometimes nausea and jaundice. vomiting. Avoid drinking • alcohol or eating foods that PRECAUTIONS AND WARNINGS: contain it, while taking this -Use caution in renal or hepatic medication. insufficiency, elderly (more susceptible to β-blockers, These may diminish the side effects), malnourished patients, adrenal hydantoins, hypoglycemic effect. or pituitary insufficiency. rifampin, Monitor blood glucose of -Diet and exercise remain the primary thiazide patients closely and adjust consideration in NIDDM patient diuretics, the sulfonylurea dosage management. and accordingly. Drugs are an adjunct to, not a substitute for steroids them. Dietary regulations should be taught to patients, as well as monitoring methods to keep patients well controlled. -The administration of oral hypoglycemic drugs has been associated with increased cardiovascular mortality as compared to

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Endocrine System Drugs Chloram- These increase the insulin secretion remains unchanged while phenicol, hypoglycemic effect of the fasting insulin levels and daylong plasma Co-trimox- medication. Monitor blood response may actually decrease. In clinical azole, glucose concentrations and studies, the drug has shown a favorable tetracyclines, observe for symptoms of effect on serum lipids, which are often butazones, hypoglycemia. Use with abnormal in type 2. salicylates, caution, if needed adjust and dose of sulfonylurea Metformin has a different mode of sulfonamides accordingly. action than the sulfonylureas. It is also used Digitalis Concurrent administration for type 2 patients in adjunction to diet glycosides increases digitalis serum when all methods of glycemic control have levels, caution use. For failed. Metformin has been associated with patients who start therapy, weight loss, which seems to be the only monitor serum digitalis advantage over the sulfonylurea agents, levels carefully until levels which has made it the drug of choice in are stabilized. obese (≥ 20% ideal body weight) diabetic Oral anti- Metabolic degradation of patients. Cases of lactic acidosis, which can coagulants sulfonylurea is slowed by dicumarol, leading to a be fatal, is its major hazard, especially in greater risk of renal disease patients. Metformin costs hypoglycemia. more than sulfonylureas, and has a more serious adverse effects profile. It may be • OVERDOSE: best used in obese patients, or in cases Symptoms: An acute overdose may produce when an oral sulfonylurea alone is hypoglycemia as well as tingling of the lips ineffective. It could then be used alone or in and tongue, nausea, diminished cerebral combination with a sulfonylurea (refer to function (lethargy, confusion, agitation, table-6.2). nervousness), increased sympathetic • INDICATIONS: activity (tachycardia, sweating, tremor, In type 2 DM. Metformin is used in the hunger) convulsions, stupor and coma. treatment when strict dieting and sulfonyl- Treatment: Treat mild hypoglycemia with ureas have failed to control patients, oral glucose and adjustment in drug dosage especially in overweight patients, in whom or meal patterns. Severe cases require it may if necessary, be used first. immediate hospitalization, administration It could be used concomitantly with a of dextrose IV, and close monitoring. sulfonylurea when diet and metformin or • BRANDS: sulfonylureas alone do not give control. Daonil (Hoechst), Declamide (JCL), Diabeta • CONTRAINDICATIONS: (Hoechst-Roussel), Glibetic (Teva), Gluben Renal disease or dysfunction, or abnormal (Dexxon), Glucocare (Pharmacare), Gluconil (JePharm). Clcr which may result from conditions such ______as cardiovascular collapse, acute MI and septicemia. 3) Metformin WHO,P Hypersensitivity to metformin. Acute or chronic metabolic acidosis.

Temporarily withhold metformin in • DRUG SUMMARY: patients undergoing radiological studies Metformin is a biguanide oral antihyper- involving parenteral administration of glycemic drug used in the management of iodinated contrast materials because these type 2, NIDDM. It is not chemically or may result in acute changes in renal pharmacologically related to the oral function. sulfonylureas. With metformin therapy,

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• DOSAGE FORMS: fatal. It is characterized by elevated blood Tablets. lactate levels (> 5 mmol/L), decreased • RECOMMENDED DOSAGE: blood pH, electrolyte disturbances with an Adult: 500 mg PO t.i.d., or 850 mg b.i.d.; increased anion gap. The risk of LA max. 3000 mg/day. increases with the degree of renal Child: Do not use in children. dysfunction and the patient’s age. Onset is Directions: Dosage should be often difficult to detect, and accompanied individualized on basis of both only by nonspecific symptoms such as effectiveness and tolerance. Give in divided malaise, respiratory distress, abdominal doses with or after meals. distress and hypotension. *Start with low dose 500 mg b.i.d., and -There is an increased risk or cardio- gradually increase to identify the minimum vascular mortality with administration of dose required for adequate glycemic oral anti-diabetic drugs. This warning may control. also apply to metformin although no *Use fasting plasma glucose to determine sufficient data is available. therapeutic response to metformin. -Hypoglycemia does not usually occur Thereafter, measure glycosylated hemo- under usual circumstances, but could occur globin at intervals of ∼ 3 months. with deficient caloric intake, excessive *Short-term administration may be exercise not compensated by caloric sufficient during periods of transient loss of supplementation, or during concomitant use control on diet alone. with other glucose lowering agents or *Inform the patient about the importance of ethanol. • adherence to dietary instructions, regular ADVERSE EFFECTS: exercise, regular blood glucose testing, GI side effects are very common, and are renal function and hematological tests. mainly dose related; diarrhea, nausea, • USE IN SPECIAL CASES: vomiting, abdominal bloating, flatulence Pregnancy- Avoid use. Safety has not been and anorexia. Temporary reduction in dose established (Category B). Use of insulin is may be useful, until the symptoms are recommended instead. controlled. Some patients may experience Lactation- Studies in rats show that it is metallic taste, this may resolve excreted in milk. Safety in humans has not spontaneously. Vitamin B12 absorption been established, exercise caution, and take may be impaired, administration of supple- into account the importance of the drug to the mentation may be done if necessary. Test mother when discontinuing use. Use of levels every 2-3 years to prevent any insulin may be safer. anemia complications. Children- Use not recommended. Safety and • INTERACTIONS: efficacy have not been established. Overview of Metformin Renal Disease- Contraindicated. Do not use Drug-Drug Interaction even in mild conditions due to the increased Drug Interaction risk of lactic acidosis. The drug is excreted Alcohol It enhances the effect of primarily unchanged in the urine. metformin on lactate Liver Disease- Avoid use due to increased metabolism; advise patients risk of lactic acidosis. against excess intake whether • PRECAUTIONS AND WARNINGS: acute or chronic use, to avoid -Lactic Acidosis: LA is a rare, but serious, precipitation of lactic acidosis. metabolic complication that can occur due to metformin accumulation during treatment. When it occurs, 50% of cases are

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Endocrine System Drugs Cationic Such as: levothyroxine (T4). The majority of patients drugs amiloride, digoxin, morphine, require lifelong replacement therapy. quinidine, ranitidine, Hyperthyroidism requires anti-thyroid trimethoprim, vancomycin, agents; such as propylthiouracil and which are eliminated by renal methimazole. Generally after 1-2 years of tubular secretion, have a control, medication can be stopped. potential for increasing levels of metformin. Use with caution. 1) Thyroxine WHO,P Cimetidine Caused a 60% increase in peak metformin plasma level. • Do not administer DRUG SUMMARY: concomitantly. Thyroxine sodium (the levothyroxine-T4 Furosemide It increases level of isomer) is the treatment of choice for metformin, while the half-life maintenance therapy in hypothyroidism. of furosemide was decreased. Administration of levothyroxine alone may Use with caution. produce normal levels of both T4 and T3, since it is converted to T3 naturally in the • OVERDOSE: body. Drug action is not clearly understood, No hypoglycemia has been seen even with but is known to increase the metabolic rate ingestion of up to 85 g of metformin. of all body tissues. Lactic acidosis has occurred. If suspected, • INDICATIONS: refer to hospital, hemodialysis is indicated. Hypothyroidism, as replacement therapy of • BRANDS: any etiology, including: cretinism, Glucomet (BPC), Glucomin (Dexxon), myxedema, non-toxic goiter, total or partial Glucophage (Bristol-Myers Squibb). absence of thyroid gland, or the effects of ______surgery, radiation or drugs. May be also used with anti-thyroid drugs to treat thyrotoxicosis. B) THYROID DRUGS • CONTRAINDICATIONS: Hypersensitivity to active or extraneous The hormones synthesized and released by constituents. Acute myocardial infarction, the thyroid gland affect such basic and adrenal insufficiency. processes as oxygen consumption, heat • DOSAGE FORMS: production and metabolism of Tablets. carbohydrates, fats and protein. Thyroid • RECOMMENDED DOSAGE: hormones are recognized as the regulators Adult: Doses are usually individualized of the metabolic level in most tissues, and depending on the basis of clinical response are required for normal growth and and biochemical tests. However the starting differentiation. They are required for the dose is 25-50 ug/24h (0.025-0.050 mg/24h) functioning of other hormones such as increased by 50-100 ug/24h every 3-4 catecholamines, corticosteroids and anti- weeks till response (usual recommended diuretic hormone. dose 100-200 ug/24h). Inadequate or excessive secretions of Patients > 50 yrs or with cardiac disease these hormones result in the clinical start with the lower dose (25 ug/24h) and conditions called hypothyroidism and titrated up more slowly. hyperthyroidism respectively. Hypothyroidism requires thyroid replacement therapy; using thyroxine and

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Child: Recommended Pediatric Dosages Renal Disease- Use with caution. for Congenital Hypothyroidism: Liver Disease- Use with caution.

Dose/day Daily dose/ • PRECAUTIONS AND WARNINGS: Age (mcg) kg (mcg) -Use caution in cardiovascular disease, 0 - 6 mon. 25 - 50 8 - 10 angina pectoris, hypertension, and in 6 - 12 mon. 50 - 75 6 - 8 impaired renal function. 1 - 5 yrs 75 - 100 5 - 6 -In endocrine disorders, thyroid hormone 6 - 12 yrs 100 - 150 4 - 5 therapy in patients with concomitant > 12 yrs > 150 2 - 3 diabetes mellitus or insipides or adrenal insufficiency (Addison’s disease) Directions: Administer as a single dose, exacerbates the intensity or their symptoms. preferably before breakfast to prevent Appropriate adjustments in therapy in these insomnia. Food interferes with absorption. cases are required. *Onset of actin requires 3-5 days. -Long-term levothyroxine therapy has been *If a dose is missed, tell the patient to take associated with decreased bone density in it as soon as remembered, then to continue the hip and spine in pre- and post- with the regular schedule. Do not menopausal women. These effects may be administer a double dose. avoided by using minimal dose required *For children who can’t swallow; tablets and periodically monitoring the patient. It can be crushed and suspended in a small may be beneficial to obtain a basal bone amount of water, then administered by density measurement, and monitor closely spoon or dropper. The prepared suspension for osteoporosis development. should not be stored for any period of time. • ADVERSE EFFECTS: Crushed tablets may also be sprinkled over Adverse side effects other than those a small amount of food such as apple- indicating hyperthyroidism due to sauce. therapeutic overdosage, either initially or *Inform the patient to report any signs of during maintenance period are rare. toxicity. • INTERACTIONS: *Patient should be advised not to change Overview of Thyroxin brands of medications, due to the a narrow Drug-Drug Interaction therapeutic window of thyroid hormone Drug Interaction therapy, since there may be differences in Choles- These decrease efficacy of bioequivalence between products. tyramine & thyroid hormone and cause *Caution patient to avoid OTC medications colestipol potential hypothyroidism. unless approved by the physician. Administer 4-6 hrs. apart. • USE IN SPECIAL CASES: Estrogen May decrease response to Pregnancy- Compatible (Category A). therapy in patients with non- Thyroid hormones do not readily cross the functioning thyroid gland. placenta. Do not discontinue medication in Use with caution. hypothyroid women during pregnancy. Anti- Thyroid hormones increase coagulants action of anticoagulants, Lactation- Use caution. Minimal amounts of there might be a need to thyroid hormones are excreted in breast milk. decrease the anticoagulant They are not associated with serious adverse dose if necessary. reactions. Digitalis Serum level of digoxin may Children- Partial loss of hair may be glycosides be reduced. Monitor levels. experienced in the first few months of Epinephrine Increase risk of cardiac therapy, it is a usual transient phenomenon & norepi- insufficiency. Avoid that later is recovered. nephrine concomitant use.

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Endocrine System Drugs Directions: Administer 3 equal doses at • OVERDOSE: approximately 8 hrs. intervals, with food or Symptoms are those of hyperthyroidism and milk to reduce stomach upset. may include: palpitations, tachycardia, *Advise patient not to change time angina, tremors, nervousness, insomnia, intervals throughout therapy. diarrhea, vomiting, weight loss, sweating, Most patients achieve euthyroid state heat intolerance and fever. within 6-12 wks, depending on severity of These agents rarely result in clinical the disease state. toxicity. *Clinical response is monitored through Treatment is aimed at reducing GI changes in weight and pulse. Advise absorption of the drug, and controlling side patient to chart weight 2-3 times weekly. effects that arise, cardiac, fluid loss, fever, Teach them to take pulse accurately. and hypoglycemia. • *They should report any signs of tremor, BRANDS: tachycardia, increased pulse rate, fever, Eltroxine (Glaxo). diarrhea, vomiting, weight loss and anxiety ______states, which may be due to inadequate therapy. Adjust dosage accordingly. WHO,P 2) Propylthiouracil *Caution use of iodized salt or of seafood in the diet. • DRUG SUMMARY: • USE IN SPECIAL CASES: Propylthiouracil (PTU) is a synthetic, Pregnancy- Can use when clearly needed. thioamide derivative, anti-thyroid agent. It The potential benefit for the mother is more interferes with iodine and blocks synthesis than the potential risk. It readily crosses the of thyroxin; T3 and T4. placenta and can induce goiter in developing • INDICATIONS: fetus. Still these agents are effective drugs in Hyperthyroidism. hyperthyroidism complicated by pregnancy, • CONTRAINDICATIONS: and should be used if the problem arises Hypersensitivity to anti-thyroid drugs, and (Category D). The thyroid dysfunction nursing mothers. diminishes as the pregnancy proceeds, thus • DOSAGE FORMS: making a reduction of dose possible. Tablets Lactation- Post-partum patient receiving anti- thyroid preparations should not nurse their • RECOMMENDED DOSAGE: babies. But if necessary, it is acceptable to Adult: Initially 300-600 mg/24h. in divided use PTU after a month or two. doses, depending on the severity of the Children- PTU has caused hepatotoxicity in disease, then the dose is reduced after pediatric patients. Discontinue the drug euthyroid state to maintenance dose. immediately if signs and symptoms of hepatic May need to increase 600-900 mg/day in dysfunction develop. some patients. Renal Disease- Use with caution; need to Maintenance- usually 100-150 mg/day in monitor patients. Cases of nephritis have been three equally divided doses. Max. 1200 reported. The drug is excreted in the urine. mg/d. Liver Disease- Use with caution. The drug is Child: > 10 years; initial dose 150-300 rapidly metabolized and inactivated in the mg/24h. liver. Can cause jaundice. 6-10 years; 50-150 mg/24h. • PRECAUTIONS AND WARNINGS: neonates; 5-10 mg/kg/24h. -Agranulocytosis is potentially the most Maintenance- determined by patients’ serious side effect of therapy that may response. occur (rarely) in the first few months of treatment if at all. Instruct patient to report

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any symptoms such as: hay fever, sore adrenocortical steroids, both naturally throat, skin eruptions, fever, consistent occurring or synthetic, and cause profound headaches or general malaise. The drug and varied metabolic effects. In addition, should be discontinued in such case, and a they modify the body’s immune responses WBC count and differential should be to diverse stimuli. Due to their made. glucocorticoid character, they are widely -Hemorrhagic effects: PTU may cause used in inflammatory conditions. hypoprothrombinemia and bleeding. Hydrocortisone (cortisol) and cortisone, Monitoring of prothrombin time during are used as replacement therapy in therapy is advised. adrenocortical insufficiency states and may -Treatment generally lasts 1-2 years. After be used for their anti-inflammatory effects control, medication can be stopped in severe cases. The synthetic steroid gradually. Relapse after one course of anti- compounds prednisone, prednisolone and thyroid drug therapy usually indicates the fludrocortisone also have both gluco- need for another form of treatment. corticoid and mineralocorticoid activity, • ADVERSE EFFECTS: and are used primarily for their gluco- Occur in < 1 % of patients. Agranulo- corticoid effects. The rest of the synthetic cytosis is the most serious effect. compounds are distinguished by the Possible side effects: headache, vertigo, absence of any significant salt-retaining CNS stimulation, nausea and vomiting, activity, and are very potent anti- epigastric distress, loss of taste, skin rash, inflammatory agents. exfoliative dermatitis, aplastic anemia, As can be seen from table-6.8, the major jaundice, nephritis, abnormal hair loss, differences among the corticosteroids are edema, or drug fever. potency of medication and variation in some • INTERACTIONS: secondary effects. If a patient is allergic to None reported. one corticosteroid, chances are they are • OVERDOSE: allergic to all, and the use of such Symptoms include: nausea, vomiting, medication should be avoided. epigastric distress, fever, headache, pruritis, Corticosteroids are prescribed for a wide edema, possible; agranulocytosis, hepatitis, variety of disorders from skin rash to CNS stimulation or depression. cancer. If patients are not producing enough Treatment: need to protect patient’s airway adrenal hormones, corticosteroids may be and support ventilation and perfusion till used as replacement therapy. They may reach emergency room where general also be prescribed to treat the following: management of acute overdose is applied. bursitis, arthritis; severe skin reactions • BRANDS: (such as psoriasis), severe respiratory Propylthiocil (Teva). diseases, blood disorders, gastrointestinal

______diseases (including ulcerative colitis), and inflammation of the nerves, heart and other organs. C) CORTICOSTEROIDAL DRUGS In this section Prednisone will be considered the prototype drug of the The naturally occurring adrenal cortical corticosteroids. For other corticosteroids steroids have both anti-inflammatory used in asthma, dermatology or ophthalmic (glucocorticoid) and salt retaining (mineral- preparations refer to individual chapters. ocorticoid) properties. Glucocorticoids are

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Endocrine System Drugs

Table 6-8. Glucocorticoid Equivalencies § + Approximate Relative anti- Relative Na Plasma equivalence inflammatory retaining half-life Glucocorticoid dose (mg) (Glucocorticoid) (mineralocorticoid) [Potency] potency potency (min.) Short-acting Cortisone 25 0.8 2 30 Hydrocortisone 20 1 2 80-118 Intermediate-acting Prednisone 5 4 1 60 Prednisolone 5 4 1 115-212 Triamcinolone 4 5 0 200 Methylprednisolone 4 5 0 78-188 Long-acting Dexamethasone 0.75 20-30 0 110-210 Betamethasone. 0.6-0.75 20-30 0 300 § Drug Facts & Comparisons, 2000; p. 321.

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1) Prednisone WHO,P . 8. Hematological disorders: Idiopathic thrombocytopenic purpura in adults, • DRUG SUMMARY: acquired autoimmune hemolytic anemia, Prednisone is an intermediate acting erythroblasopenia, congenital hypoplastic adrenal corticosteroid, a synthetic analog of anemia. hydrocortisone. Prednisone is inactive and 9. Gastrointestinal disease: Ulcerative is metabolized to prednisolone WHO,P in the colitis, Crohn’s disease, regional enteritis. body. 10. Renal disease: glomerulonephritis • INDICATIONS: (minimal lesion). Prednisone (or other intermediate acting 11. Other: Only under specialists corticosteroids) is indicated in the supervision: i.e., multiple sclerosis, following conditions; neoplastic disease, edematous states, 1. Endocrine disorders: primary or tuberculous meningitis, trichinosis with secondary adrenocortical insufficiency, neurologic or myocardial involvement. • congenital adrenal hyperplasia, hyper- CONTRAINDICATIONS: calcemia associated with cancer, Known hypersensitivity to the drug and autoimmune thyroiditis. systemic fungal infections. 2. Rheumatic disorders: As adjunctive • DOSAGE FORMS: therapy for short term administration, Tablets. psoriatic arthritis, rheumatoid arthritis, • RECOMMENDED DOSAGE: ankylosing spondylitis, acute and subacute Adult: 5 - 60 mg/d PO in single or divided bursitis, acute and nonspecific doses, depending on the disease being tenosynovitis [post traumatic osteoarthritis]. treated. [When administered on alternate 3. Collagen disease: systemic lupus days; twice the usual daily dose is given erythematosus, systemic dermato- every other day.] myosisitis, cranial arteritis, acute rheumatic Child: 0.1 - 0.15 mg/kg/d in single or carditis. divided doses.

4. Dermatologic diseases: Pemphigus, Directions: Oral medication is administered bullous dermatitis herpetiformis, severe at meal times or with a snack to reduce erythema multiform, exfoliative dermatitis, gastric irritation. mycosis fungoides, severe psoriasis, severe *Inform the patient to take the drug as seborrheic dermatitis prescribed and not to alter dosing regimens 5. Allergic states: seasonal or perennial or stop medication without consultation allergic rhinitis, bronchial asthma, contact with the treating physician. dermatitis, atopic dermatitis, drug *Single doses or alternate day doses should anaphylactic and hypersensitivity reactions. be taken in the morning prior to 9 am. 6. Respiratory diseases: symptomatic Multiple doses should be evenly spaced at sarcoidosis, Loeffler’s syndrome not intervals throughout the day. manageable by other means, berylliosis, *Inform your patient of signs of adrenal aspiration pneumonitis. insufficiency: fatigue, anorexia, vomiting, 7. Opthalmic disease: Severe acute and diarrhea, weight loss, dizziness and low chronic allergic and inflammatory process blood sugar. Dosage reduction or with- involving the eye, allergic corneal marginal drawal of therapy may be needed. ulcers, anterior segment inflammation, *For high doses or long-term therapy, avoid allergic conjunctivitis, keratitis, optic abrupt withdrawal of therapy, which may neuritis, iritis and iridocyclitis. result in withdrawal symptoms. Withdrawal symptoms include myalgia, fever, malaise,

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Endocrine System Drugs fatigue, dizziness, hypotension, and since complications of treatment, and side hypoglycemia. It is important to taper the effects are dependent on these factors. dose over several days to weeks to prevent -Corticosteroid products often contain withdrawal symptoms. tartrazine dyes (color) and sulfites *Small doses of corticosteroids or use for a (preservatives) that many people are short period (< wk.) may not produce allergic to. If the coloring and the withdrawal symptoms when the drug is preservatives are not indicated on the box, discontinued, still, tapering the dose is the patient or doctor can ask the advisable. manufacture of the product for this • USE IN SPECIAL CASES: information. Pregnancy- Pregnant women should not • ADVERSE EFFECTS: take corticosteroids unless the benefits Most common possible side effects may outweigh the potential risks. Prednisone has include: nausea, vomiting, stomach upset, the poorest transport in crossing the may lead to peptic or duodenal ulcers. placenta compared to the other Other common side effects: edema, heart corticosteroids (Category C) and may be failure, fluid and electrolyte disturbances, used in such cases. Chronic use of potassium loss, muscle weakness, loss of corticosteroids during the first trimester can muscle mass, calcium loss (osteoporosis in lead to birth defects (i.e., hypoadrenalism, severe cases), growth suppression in cleft palate). When using, the dose should children, slow wound healing, allergic skin be tapered of as for any other patient. rash, convulsions, headache, insomnia, and Lactation- Corticosteroids appear in breast dizziness. milk, but small doses (< 20 mg/d) for a short Less common side effects: irregular period of time (< 10 days) may not harm the menstrual cycles, adrenal and/or pituitary infant. Advise mother to wait 3-4 hours after gland suppression (specially following the dose before breast-feeding. If larger doses chronic doses > 7.5 mg/d), cushinioid state, are needed, advise mother against breast- hirsutism, hyperglycemia, precipitation of feeding. diabetes mellitus, cataracts, leukocytosis, Children- Growth and development of infants increased appetite, euphoria, mood swings, and children on prolonged corticosteroid personality changes, depression in patients therapy, should be carefully observed. with existing psychological problems. Renal Disease- Use with caution. Edema may occur in the presence of renal disease with a fixed or decreased glomerular filtration rate. Liver Disease- Use with caution. Use smaller doses in patients with liver problems. • PRECAUTIONS AND WARNINGS: -Infections: Corticosteroids may mask the signs of infection, and new infections may appear during their use. If an infection occurs during therapy, it should be promptly controlled by suitable antimicrobial therapy. -Use the lowest possible dose. Make a benefit/risk decision in each individual case as to the size of dose, duration of treatment and the use of daily or intermittent therapy,

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• INTERACTIONS: Overview of Prednisone Drug-Drug Interaction Drug Interaction Anti- Rifampin accelerates the tubercular metabolism of medications corticosteroids reducing their effect. Isoniazid serum concentrations may be decreased with corticosteroid use. Use caution and do not administer concomitantly. Barbiturates These decrease the and pharmacological effect of antiepileptics the corticosteroids. Use with caution. Digitalis Co-administration may glycosides enhance the possibility of digitalis toxicity associated with hypokalemia. Diuretics; Patients who are on these Potassium agents and are depleting administered cortico- agents steroids should be monitored for hypokalemia. Use with caution.

• OVERDOSE: Symptoms of overdosage may include anxiety, depression and/or stimulation, stomach bleeding, increased blood sugar, high blood pressure, and water retention. Treatment: Patient should be taken to a hospital for supportive and symptomatic care. Gastric lavage or emesis can be applied. Prolonged use of large doses will results in Cushinoid symptoms (moonface, central obesity, hirsutism, acne, etc.). Gradually taper of the medication, to the lowest dose that will control of the original disease symptoms. • BRANDS: Deltasone (Upjohn), Prednisone (Vitamed), Prednitab (BPC).

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Chapter 7: Contraceptive Preparations

A) CONTRACEPTIVE DEVICES AND BARRIERS 1. Intra-Uterine Devices (IUDs) 2. Spermicides and Condoms

B) HORMONAL PREPARATIONS 1. Estrogenic and Combined Oral Contraceptives: (Ethinylestradiol, Norethindrone and Desogestrel) 2. Progestin-Only Products: (including oral, injectables and implants) (Norethindrone, Levonorgestrel, Medroxyprogestogene acetate) 3. Emergency Pills

CONTRACEPTIVES

Several contraceptive methods are IUDs interfere with the implantation of available. In order to decide which is the the fertilized ovum. It is known that IUDs most appropriate method to choose, the are most commonly used and are suitable following factors should be considered: for parous women (who have had at least age, general health, frequency of one child). intercourse, whether the reason for use is to The IUDs that contain progestogene, prevent or to postpone pregnancy, personal which should be changed every year, have preference, medical contraindication, lower risk of ectopic pregnancy and the expected efficacy, safety, and if the method pre-existing heavy menses may be provides protection against STD and HIV. alleviated. The progestogene that is The ideal contraceptive should be highly released close to the site of action (on effective, safe, well tolerated, easily cervical mucus and endometrium) will accessible, fully reversible and cheap. decrease the progestinic side effects and The available methods and their interactions, in particular, the enzyme- effectiveness, risk of side effects, and inducing drugs are unlikely to have much protection against STD and HIV can be influence on the contraceptive effect. seen in the table-7.1. (Effectiveness IUDs are contraindicated in cases of depends mostly on the degree of history of ectopic pregnancy, abnormalities compliance and user reliability). of the uterine cavity, vaginal or cervical Other methods like douching are not infections, acute pelvic inflammatory effective. The postcoital contraception used diseases (PID), genital malignancy, for emergencies has a failure rate of about abnormal vaginal bleeding, previous tubal 1%. surgery, immunosupressive therapy and in Natural family planning methods as women who are allergic to copper. calendar, basal body temperature, cervical The most common side effects are mucus and sympatothermal, each requires menstrual irregularities with discharge and keeping detailed records of women’s discomfort. One of the primary concerns is menstrual cycle and other symptoms related the relation between IUDs and PIDs. to cyclic hormonal levels. The effectiveness Recent studies have shown that increased of these methods depends on several incidence of PID occurs almost exclusively unreliable factors like the presence of mild in the first 4 months after insertion (others cold, infections or cycle irregularities. mentioned after the first 20 days of

insertion) and among women who are A) CONTRACEPTIVE DEVICES & exposed to STDs. Some explains that this might be due to the septic techniques used BARRIERS during the insertion or to the pre-existing

reproductive tract infections. Careful 1) Intra-Uterine Devices (IUDs) screening of potential IUD users can This category is the most commonly used minimize complications related to PID. method. Copper IUDs are all effective in Moreover, education about the symptoms preventing pregnancy for up to 5 years, but of PID can also help in reducing the can not provide full protection (refer to the complications after seeking early treatment. table-7.1).

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Contraceptive Preparations

1 Table – 7.1: Pregnancy Rates for Various Means of Contraception (%)

Lowest 3 Risk of Protect against Method of Contraception # expected2 Typical side effects # STD/HIV Oral contraceptives (in general) 3 Combined 0.1 nd medium no Progestin-only 0.5 nd medium no Mechanical/Chemical Levonorgestrel implant 0.2 0.2 medium/high no Medroxyprogesterone injection 0.3 0.3 medium/high no IUD high no Progesterone 2 nd Copper T 380A 0.8 nd Condom low yes Without spermicide 2 12 4 With spermicide 1.8 4-6 Spermicide alone 3 21 low yes/no Diaphragm (with spermicide 6 18 low yes/no cream or gel) low yes/no Vaginal sponge 6 18 Nulliparous 9 28 Multiparous 2-4 12-25 low yes/no Female condom Periodic abstinence* 1-9 20 - no Sterility Vasectomy 0.1 0.15 low no Tubal ligation 0.2 0.4 medium no No contraception 85 85 - - nd= No data available. 1 During first year of continuous use. 2 Best guess of percentage expected to experience an accidental pregnancy among couples who initiate a method and use it consistently and correctly. 3 A typical couple who initiate a method and experience an accidental pregnancy. 4 Used as a separate product (not in condom package). * Includes rhythm and sympatothermal methods. Source: Health Action International, 1993. Drugs Facts & Comparisons, 2000.

2) Spermicides and Condoms vehicle which itself may have some Barriers (e.g. diaphragm, condom) may be inhibiting effect on sperm activity. preferred for older women who continue to Moreover, spermicides may provide smoke in whom there is a greater risk of protection against STD. side effects from OCs. The most commonly used products are Spermicides kill sperms and have an Nonoxinol ‘9’ and Benzylkonium chloride. antiseptic effect. They are considered as an Both can be used alone or with barrier additional safeguard but do not give methods like a condom. adequate protection if used alone. They Nonoxinol‘9’ is available in different have 2 components: spermicide and a dosage forms (foam, pessaries, gel, jelly,

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cream). When used alone, it should be estrogen and the estrogenic/ antiestrogenic/ applied high in the vagina. It is androgenic effect of the progestin. contraindicated in people who are allergic The main advantages of OCs include: to it. The main side effects are sensitization effectiveness, avoidance of dysmenorrhea, and irritation to mucous membranes. less iron deficiency anemia for women with Products like petrolatum jelly, baby oil heavy menstruation, avoidance of pre- and oil based vaginal and rectal menstrual tension, less benign breast preparations are likely to damage condom disease, decrease the risk against pelvic and diaphragms made from latex rubber, inflammatory disease, provides protection thus less protection even from STD. against endometrial and ovarian cancer, and possible decreased risk of Alzheimer’s. B) HORMONAL PREPARATIONS Note: • Estrogens have been reported to increase In this section, hormonal contraceptives the risk of endometrial carcinoma. will be discussed: combined oral However, the risk appears to be decreased contraceptives (OCs) and progestin-only in OC users due to progestin component. In products. Generally healthy women take fact it has a protective effect, where users these products, therefore, they should be appear about half as likely to develop extremely safe as well as effective. ovarian and endometrial cancers as women who have never used OCs. 1) Estrogenic and Combined • In spite of many studies, the relationship OCs WHO,P between OCs use and breast and cervical cancers, a cause and effect relationship has • DRUG SUMMARY: not been established. The combined OCs contain different There are 3 types of combined OC: estrogen-progestin combinations. They monophasic, biphasic and triphasic. suppress ovulation by imitating the Monophasic: Fixed dosage of estrogen to feedback effects of the woman’s own progesterone throughout the cycle. estrogens and progesterones on the pituitary Biphasic: The amount of estrogen is fixed and the hypothalamus, thus inhibiting the for the first 21 days of the cycle. Progestin: secretions of FSH and LH. Additionally, estrogen ration is decreased in the first half these agents cause changes in the genital of the cycle allowing endometrial tract. The cervical mucous becomes thick proliferation. The ration is increased in the (which inhibits sperm penetration) and the second half to provide adequate secretory endometrium becomes thin and hypoplastic development. (which reduces the likelihood of Triphasic: Estrogen amount remains the implantation). The effect and the relative same or varies throughout the cycle. potency of these combined agents depend Progestin amount varies. on the type and the relative combination of The biphasic and triphasic OCs are estrogenic and proges-tational activity. intended to deliver hormones in a similar The addition of progestins in a preparation way as the physiological process. may modify the effects of estrogens. These The most commonly used estrogens are changes depend on the type or amount of ethinylestradiol and mestranol. Pills progestin present and the ratio of progestin containing > 50 mcg of estrogens are not to estrogen. currently used as their use is associated The total estrogenic potency of OCs is with an unacceptable incidence of venous based on the combined effects of the thromboembolism.

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Contraceptive Preparations

Different progestinic derivatives are bleeding stopped or not, start a new course used. The progestogens desogestrel, of 21 days. Withdrawal flow will normally gestodene and norgestimate in combination occur about 3 days after the last pill is with ethinylestradiol have been reported to taken. have less adverse effects on lipids than - 28-Day regimen: To eliminate the need to ethynodiol, levonorgestrel and norethisterone count the days between cycles, some in combination with ethinylestradiol. products contain 7 inert or iron-containing However, desogestrel, gestodene have also tablets (21+7) to permit continuous daily been associated with an increased risk of dosage during the entire 28-day cycle. Take venous thrombo-embolism. the 7- tablets on the last 7 days of the cycle. • INDICATIONS: - Biphasic and triphasic OCs: One tablet is -As contraceptive agents. taken daily; as the color of the tablet -Some products might be used in changes, the strength changes too (i.e., the emergency contraception in high doses as a estrogen/progestin ratio changes). Usually, postcoital contraceptive or “morning after” it is clearly indicated on the package where pill, but they are not licensed or packed for to start and in what order to take the pills postcoital contraceptives (more details can (marked with arrows), along with the be found under emergency pill in this appropriate week numbers. chapter). - Missed pills: There is little likelihood of • CONTRAINDICATIONS: ovulation and consequent pregnancy Absolute: Pregnancy, thromboembolic occurring if only 1 tablet is missed, but the disease, certain cardiac abnormalities, possibility of spotting and bleeding is thalassemia major, porphyria, familial increased. If 2 consecutive tablets are hyperlipidemia, carcinoma of breast, missed, the possibility of ovulation idiopathic jaundice of pregnancy, liver increases. In general, other contraception diseases. precautions should be taken for the balance Relative: Diabetes mellitus, hypertension, of the cycle until tablets have been taken for 7 osteosclerosis, secondary amenorrhea, consecutive days. undiagnosed vaginal bleeding, sickle cell ∗ If one tablet is missed: take as soon as disease, lactation, multiple sclerosis, you remember, and the next one is at your obesity, depression, migraine, epilepsy, normal time. varicose vein, and in smokers > 35 yrs. old. If you are late by 12 hours or more • DOSAGE FORMS: (especially if it is the first in the package) Tablets in different strengths depending on the pill may not work for this cycle. the estrogenic/ progestinic derivative used. However, continue your normal pill taking • RECOMMENDED DOSAGE: whenever you remember and other safety Start new patients with preparations precautions should be taken into account containing ≤ 35 mcg estrogens. especially in the next 7 days. If these 7

Directions for use: days run beyond the end of the packet, start - One tablet should be taken at the same the second one immediately after finishing time every day with a meal or at bed time. the present one without any lag period, this Efficacy depends on strict adherence to the means that you will not have a period until dosage schedule. after the 2 packets, but this would not be a - 21-Day regimen: Day 1 of the cycle is the problem. Nor does it matter if you see some first day of bleeding. Take one pill daily for bleeding during taking the tablets. If you 21 days starting on day 5 of the cycle. No are using every day pills, miss out the 7 tablets are taken for 7 days; whether inactive ones.

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∗ If 2 consecutive tablets are missed: Take c) Diarrhea and vomiting: may interfere 2 tablets as soon as remembered with the with the absorption and limit the next pill at the usual time, or take 2 tablets effectiveness. Additional precautions daily for the next 2 days, then resume the should be used during and for 7 days after regular schedule. recovery. If this happens during the last 7 ∗ If 3 consecutive tablets are missed: begin tablets, the next pill free interval should be a new packet of tablets starting day 1 of the omitted. cycle after the last pill was taken or starting d) The administration of OC should be 7 days after the last pill was taken. stopped if any of the following symptoms occur: sudden severe pain in the chest, - Switching brands: wait 7 days before sudden breathlessness or cough with blood- starting the new pack (after the 21-day stained sputum. Severe pain in calf of the regimen) or start the next pack on the day leg or in the stomach. Unusual severe, after the last “reminder” pill (after the 28- prolonged headache (especially if it day regimen). happens for the first time or if it increases - Postpartum administration in non-nursing gradually), diplopia, dysphasia, vertigo, bad mothers: it may begin at the first fainting attack or collapse, weakness, postpartum examination (4-6 weeks), numbness, motor disturbances. regardless to whether spontaneous e) Bleeding that resembles menstruation menstruation has occurred. Also, start no occurs rarely. Persistent bleeding requires earlier than 4-6 weeks after a mid-trimester patient’s re-examination; consider non- pregnancy termination. Immediate hormonal causes. If pathology has been postpartum use is associated with increased excluded, time or changing the formulation risk of thromboembolism. may solve the problem. - Changing from progestogen-only tablet: f) Missed menstrual period: start on first day of menstruation or any day ∗ If one period is missed (patient did not if amenorrhea present and pregnancy has adhere to prescribed regimen): consider been excluded. possible pregnancy, withhold OCs until - After abortion or miscarriage: start on the ruling out pregnancy. same day. ∗ If two consecutive periods are missed • USES IN SPECIAL CASES: (patient adhered to the prescribed regimen): Lactation- Not recommended. Oral pro- rule out pregnancy before continuing the gestogen-only contraceptives are preferred. contraceptive regimen. Liver Disease- Exercise caution as steroids ∗ If menstrual bleeding is minimized: this metabolism decreases in liver impairment might be due to long usage of medication conditions. for several months and not due to • PRECAUTIONS AND WARNINGS: pregnancy. A complete, detailed and clear medical and g) Surgery: estrogen-containing OC should family history prior to initiation of therapy be stopped 4 weeks before major elective should be done. surgery and all leg surgeries. They are a) Smoking: The risk of cardiovascular side recommended again after the first menses effects increases with OCs in heavy occurring at least 2 weeks after smokers ( > 15 cigarette/d) who are > 35 mobilization. When discontinuation is not yrs. old. Women who use OCs should not possible (i.e., after trauma) then sub- smoke. cutaneous heparin should be given b) Missed pill: see “RECOMMENDED prophylactically. DOSAGE”. h) Contact-lens wearers who develop changes in vision or lens tolerance should

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Contraceptive Preparations be assessed by an ophthalmologist; contraceptive precautions (e.g. IUD) consider permanent or temporary cessation should be continued for at least 4 of wear. weeks after stopping it. Changes in the i) OCs do not protect against HIV infection strength or the regimen of the pills or other STDs (inform patients). may be done. • ADVERSE EFFECTS: c) Antibiotics such as penicillins, The aim of the prescriber should be to keep tetracylines and griseofulvin. the level of both the estrogenic and the (2) Allopurinol, cimetidine, chloram- progestinic derivative as low as possible phinicol, isoniazid and the phenothiazines consistent with maximal effectiveness and may potentiate the actions and adverse minimal discomfort for the patient. Side effects of oral contraceptives. effects that have been reported include: (3) Coadministration of OCs with the -CVS (Serious): Thrombophlebitis and following drugs will result in: venous thrombosis with and without a) Anticoagulants effect would decrease. embolism; pulmonary embolism; coronary b) Antidepressants (TCA), β-blockers, thrombosis; MI; cerebral thrombosis or caffeine, corticosteroids, theophylline hemorrhage; hypertension; mesentric effects or toxicity may be increased. thrombosis. c) Benzodiazepines effect or toxicity -GU: breakthrough bleeding, spotting; may be increased for some derivatives change in menstrual flow; amenorrhea; and decreased for lorazepam, change in cervical erosion and cervical oxazepam and temazepam. secretions; invasive cervical cancer; vaginal d) Clofibrate effect may be decreased as candidiasis. its elimination is increased. -Breast changes: tenderness; enlargement; e) Salicylate effect may be decreased. secretion; diminution in lactation when given immediately postpartum. Drug /lab test interactions: -GI: Nausea; vomiting; abdominal cramps; Estrogen-containing OCs may cause cholestatic jaundice. alterations in serum, blood or plasma -CNS: migraine; mental depression. concentrations of some hormones or -Ophthalmic: changes in corneal curvature; clotting factors, etc. This means that contact lens intolerance; neurocular lesions. continuous monitoring is needed, which -Miscellaneous: photosensitivity may may require a specialist clinic and not the occur; edema; weight changes; reduced general primary health care facility. carbohydrate tolerance; prevalence of • OVERDOSE: cervical clamydia trichomatis may be Serious events have not been reported increased; gallbladder disease; hepatic following acute overdosage. In case of adenoma. overdose, one might get nausea. • INTERACTIONS: Withdrawal bleeding may occur in female (1) The following drugs will decrease OCs children after accidental ingestion. effectiveness, which means that pregnancy • BRANDS: may occur. (Another contraceptive method Gynera (Schering/Agis), Microdiol (Organon), should be used during treatment.) Nordette (Wyeth Ayerst). a) Hepatic enzymes inducers such as ______barbiturates, hydantoin, rifampicin, carbamazepine. b) Note: Rifampicin is a potent enzyme inducer, that even if a course lasts for less than 7 days, the additional

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2) Progestin-Only Products a) Oral Progestogen-only Preparations Progesterone is the primary principle of corpous luteum. It causes the • DRUG SUMMARY: transformation of the proliferative These products are suitable for use as an endometrium into secretory endometrium. alternative to combined oral contraceptives Synthetic exogenous progesterone inhibits if estrogens are contraindicated and before gonadotropines secretion, thus prevents major elective surgery. maturation of the follicle and ovulation and • INDICATIONS: results in endometrial thinning. Thus, To prevent pregnancy. exerting its contraceptive action. (Refer to the introduction.) These products are more suitable in the • CONTRAINDICATIONS: following cases: Pregnancy, thrombophlebitis, thrombo- • When estrogens are contraindicated. embolic disorders, undiagnosed vaginal • For women over the age of 40 years in bleeding, liver diseases, breast and genital whom fertility has declined so that the small risk of pregnancy is reduced even tract carcinoma. • further. DOSAGE FORM: • For patients with diabetes mellitus and Tablets. migraine. • RECOMMENDED DOSAGE: • Women with a history of thrombo- Directions: embolism and valvular heart disease. - Daily administration: starting on the first • Women who have previously developed day of menstruation. Take one tablet at the hypertension with combined pills. same time each day, every day of the year. • Breast feeding mothers. And preferably, few hours before • Women over 35 who smoke. intercourse to obtain full effectiveness. -Postpartum administration: may be The dose of the progestin derivative in initiated no earlier than 4 weeks progesterone-only products is very much postpartum. The risk of thromboembolic lower than the daily dose of progesterone in disease that is associated with the combined pills. Therefore, progestin-only postpartum period should be considered. products have a higher failure rate than Moreover, heavy and irregular postpartum combined preparations (refer to table-7.1). bleeding may occur. However, side effects are considered to be -Missed dose: less. They are more likely to cause ∗One tablet: take as soon as remembered alteration in the menstrual patterns: (within 3-4 hrs), then take next tablet at Amount and duration of the flow, cycle regular time. Extra precautions should be length, BTB, spotting and amenorrhea taken for the next 48 hrs. varies. Although menstrual irregularities ∗ are more common than with OCs; but tend Two consecutive tablets: DO NOT take to resolve on long term treatment. the missed tablets; discard and take the next Another advantage is that a decline in tablet at the regular time, or take one of the serum HDL has occurred with progestins. missed tablets, discard the other and take The progestin-only products are divided daily tablet at usual time. ∗ into oral (e.g. levonorgestrel, ethynodiol Three consecutive tablets: discontinue acetate), injections (medroxyprogesterone immediately. acetate), implants (levonorgestrel), and are Use additional protection methods of added to IUD (levonorgestrel). contraception if 2 or more tablets are

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Contraceptive Preparations missed until menstruation appears or b) Injectables: Medroxy- pregnancy is ruled out. If menses does not progesterone acetate WHO,P occur within 45 days, regardless of circumstances, discontinue the drug, rule • DRUG SUMMARY: out pregnancy and use a non-hormonal It is a long acting progestogene given IM. It method of contraception. is useful for short-term interim contra- Because of the slightly higher failure of ception (e.g. before vasectomy becomes the progestin-only products, a more effective). For long-term contraceptive for conservative approach is to discontinue the women who have been appropriately regimen if only one tablet is missed and use counseled concerning the likelihood of other non-hormonal contraceptive methods menstrual disturbances (amenorrhea, heavy until menses occurs or pregnancy is ruled uterine bleeding) and the potential for a out. delay in return to full fertility, which is • PRECAUTIONS AND WARNINGS: unrelated to the duration of use, but there is Pretreatment physical examinations, which no evidence of permanent infertility. include breast and pelvic organs, should be • INDICATIONS: performed. Prevention of pregnancy. It is a long-term Women using progestin-only pills should contraceptive injection in women when be monitored for any manifestations or for administered at 3 months interval. Cautious the onset of any of the following use as severe side effects may persist symptoms: thrombotic disorders, fluid during and longer than 3 months. It should retention, depression, photosensitivity and be clear to the woman that these effects are ophthalmologic disorders. irreversible once it is administered for at • ADVERSE EFFECTS: least 3 months. Menstrual irregularities, nausea, vomiting, • CONTRAINDICATIONS: headache, breast discomfort and weight As for oral progestogene. changes. • • DOSAGE FORMS: INTERACTIONS: Injections of 150 mg/3 months. Effectiveness of oral progestogen-only • RECOMMENDED DOSAGE: products is not affected by broad-spectrum Directions: antibiotics but is reduced by enzyme- -The woman should fill and sign the inducing drugs: Barbiturates, phenytoin, informed consent first. carbamazepine, ethosuximide, rifampicin, -The first injection should be given only chlorpromazine, and griseofulvin. • during the first 5 days after the onset of OVERDOSE: normal menstrual period, within 5 days Refer to OCs. postpartum (this might affect bleeding • BRANDS: pattern) if not breast feeding and at sixth Femulen (Searle). week postpartum if breast feeding. ______-Shake well before use to ensure

homogenous dose. The recommended dose is 150 mg/3 months administered deep IM in the gluteal or deltoid muscle (do not massage). -If the period between injections is > 14 weeks, rule out pregnancy before new administrations.

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• USES IN SPECIAL CASES: • INDICATIONS: Lactation- It is detected in milk. Milk Prevention of pregnancy, up to 5 years. It is composition, quality and amount are not a reversible contraceptive system. The adversely affected. No adverse effects on capsules should be removed by the end of breast-fed infants. the 5th year. New capsules may be inserted Children- Children exposed to medroxy- at that time if continuing contraceptive progesterone acetate in utero and followed to protection is desired. adolescence did not show any abnormal • CONTRAINDICATIONS: physical, intellectual, sexual or social As for oral progestins. development. • DOSAGE FORMS: Liver Disease- Steroids metabolism may be affected in liver impairment cases. Implants; the package consists of a set of six flexible closed capsules made of silastic, each • PRECAUTIONS AND WARNINGS: containing 36 mg of the progestin -Diabetic patients should be observed levonorgestrel contained in an insertion kit to carefully as the therapy might result in a facilitate implantation. These capsules are decrease in glucose tolerance. sealed and sterilized. -Blood pressure should be checked before • RECOMMENDED DOSAGE: each injection. • The initial released dose from the inserted ADVERSE EFFECTS: implant is about 85 mcg/day, followed by a The most common side effect is menstrual decline to about a 50 mcg/day and to about irregularities (amenorrhea, bleeding) as 35 mcg/day by 18 months, with a further well as delay of return to fertility. decline thereafter to about 30 mcg/day. • INTERACTIONS: Directions: Insertion and removal: As for oral progesterones. Moreover, * A specific training should be conducted aminoglutethimide decreases the efficacy for health workers who are involved in this of medroxyprogesterone. procedure. • OVERDOSE: − An informed consent should be obtained Refer to OCs. before insertion. The capsules are inserted • BRANDS: during the first 7 days of the cycle or Depo-Provera (Upjohn). immediately following an abortion. Before ______insertion, pregnancy should be ruled out. Insertion is not recommended before 6 c) Implants: Levonorgestrel weeks postpartum in breast feeding women. − Healthcare professionals should provide • DRUG SUMMARY: proper insertion that will also provide Levonorgestrel is a synthetic and proper and easy removal. Sterility is the biologically active progestin that exhibits major concern during this process. no significant estrogenic activity and is − Proper insertion and removal should highly progestational. Unlike injectables, result in minimal scaring. If all capsules implants are almost reversible upon cannot be removed at the first time, try removal. The efficacy of the implant does removal later when the site has healed. not depend on the patient compliance. Bruising may occur at the implant site The main disadvantages of the implants are insertion or removal. In some women, the cost and the fact that the woman is hyper-pigmentation occurs over the dependent on the health professional for implantation site but is usually reversible insertion and removal. following removal. − Aseptic techniques should be followed during insertion to prevent infections. Use

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Contraceptive Preparations proper medication to treat infections but if cause fluid retention and uterine bleeding it persists, capsules should be removed. irregularities. − Expulsion of capsules is uncommon. • BRANDS: − Provisions for removal: women should Norplant (Discotrade). be advised that the capsules might be ______removed upon request at any time or at the end of the 5 years. • USES IN SPECIAL CASES: 3) Emergency Pills Lactation- Levonorgestrel has been identified in breast milk. No significant effects were Today, emergency contraception (EC) is observed on those infants whose mothers the most commonly used term to describe used the implants beginning 6 weeks after the post-coital use of levonorgestrel alone parturition in comparative studies with or the combination of ethinyl estradiol and mothers using IUDs or barrier methods. levonorgestrel within 72 hrs of unprotected Liver Disease- Steroid hormones metabolism sexual intercourse to prevent pregnancy. It may be decreased in liver impairment should not be confused with other agents conditions. such as mifepristone (also known as RU- • PRECAUTIONS AND WARNINGS: 486 or the "French abortion pill") that, -A full medical examination and follow up unlike emergency contracption pills, can be should be performed before insertion and at used to terminate an existing pregnancy. least annually during its use. Just as with the daily use of oral -Women with strong family history of contraceptives, EC pills prevent pregnancy breast cancer or who have breast nodules primarily due to inhibition or delay of should be carefully monitored. ovulation, and possibly by inhibition of -There may be an affect on carbohydrate fertilization or implantation. Once and lipid metabolism. Women with hyper- endometrial implantation has occurred, lipidemia should be carefully monitored pregnancy is initiated and EC has no effect. since the level of LDL may be altered. A combined tablet of 50 mcg ethinyl • ADVERSE EFFECTS: estradiol and 500 mcg norgestrel, or 50 The most common side effect is menstrual mcg ethinyl estradiol and 250 mcg irregularities: Irregular, frequent bleeding, levonorgestrel is to be taken 2 tablets spotting, amenorrhea. immediately, followed after 12 hours by Other side effects are breast discharge, another 2 tabs. This method is considered cervicitis, vaginitis, musculoskeletal pain, effective if taken within 72 hrs after abdominal discomfort, pain, itching, intercourse but it is less effective than infection at the implant sight. insertion of an IUD. • INTERACTIONS: These tablets should not be -Carbamazepine and phenytoin (hepatic administered if menstrual bleeding is enzyme inducers) will reduce the efficacy overdue or if protected intercourse occurred of levonorgestrel, thus pregnancy may more than 72 hours previously. occur. • -Lab/Drug test interactions: certain These tablets are contraindicated in endocrine tests may be affected, e.g. pregnancy, women with a history of thyroxine concentration may be decreased. thrombosis or who have focal migraine at • OVERDOSE: that time. • It can happen if > 6 implants are in situ. If vomiting occurs during 2-3 hrs after All implanted capsules should be removed taking the tablets, 2 other tablets should be before new insertion. Overdosage may taken instead with antiemetic.

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• The patient should be informed that pain or heavy bleeding or any menstrual there might be early or delayed period, also irregularities. to use barrier methods till the next period. The doctor should ask about any abdominal ______

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Chapter 8: PSYCHOTHERAPUTIC DRUGS

PSYCHOACTIVE DRUGS: A) ANTIDEPRESSANTS 1. Amitriptyline 2. Imipramine 3. Fluoxetine

B) HYPNOTICS AND ANXIOLYTICS 1. Diazepam 2. Lorazepam

C) NEUROLEPTICS 1. Chlorpromazine 2. Haloperidol

ANTICONVULSANT / ANTIEPILEPTIC DRUGS: 1. Carbamazepine 2. Clonazepam 3. Ethosuximide 4. Phenobarbital 5. Phenytoin 6. Valproic Acid 7. Diazepam

ANTIPARKINSONISM DRUGS: A) ANTICHOLINERGIC DRUGS 1. Benztropine Mesylate 2. Trihexyphenidyl (Benzhexol)

B) DOPAMINERGIC DRUGS: 1. Amantadine 2. Bromocriptine 3. Carbidopa / Levodopa

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Psychoactive drugs: include the tricyclic antidepressants A) ANTIDEPRESSANTS (TCAs), the selective serotonin reuptake inhibitors (SSRIs), and the mono-amine Depressive illnesses should not be confused oxidase inhibitors (MAOIs), as well as with the transient feelings of unhappiness others included at the end in table-8.1. that everyone experiences; the periods of The TCAs and the SSRIs are preferred sadness associated with unhappy events and over the MAOIs because they are more failures, or the emotional letdown that effective and do not show the dangerous occur. Suicide is the most serious interactions with some foods (that contain complication of depressive illnesses. tyramine) and fewer major drug-drug Depression can be a symptom secondary interactions. to organic brain syndrome, schizophrenia, The SSRIs also have fewer antianxiety disorders, obsessive compulsive muscarinic side-effects than the older disorders, hyperthyroidism, drug tricyclics, and they are less cardiotoxic in dependence, mental disorders, anemia, overdose. Although they are not more cardiovascular problems, or use of effective, they may be preferred where depressant drugs. there is a major risk of overdose. The American Psychiatric Association Each drug group has similar uses criteria for mood disorders (DSM-R), characteristics, contraindications, and side while the European community use the effects, but their pharmacokinetics profiles (ICD10), that permit clinicians to may differ, resulting in one drug having consistently distinguish between more or less side effects or indication for pathological states and normal changes in use than the other. emotion in everyday life. The most Drug selection is based on side effect common mood disorders are major profile, concomitant disease state (i.e. depression (unipolar disorders) and manic- benign prostatic hypertrophy, insomnia, MI, depressive illness (bipolar disorder). arrhythmias, obesity, glaucoma, hypertension, Psychotherapy (talk therapy) has sexual dysfunction, suicide potential, etc.), resulted in very positive outcomes in drug-drug interaction, cost, ease of use, and combination with pharmacotherapy. Drugs previous therapy. with clinically useful antidepressant effect

Table-8.1: Examples of Antidepressant Drugs TCAs TCAs Miscellaneous Tertiary Secondary SSRIs MAOIs Agents Amines Amines Amitriptyline --→ *Nortriptyline Citalopram Isocarboxide Bupropion Clomipramine Amoxapine Fluoxetine Moclobemide Maprotiline Doxepin Protriptyline Fluvoxamine Phenelzine Nefazodone Imipramine ---→ *Desipramine Paroxetine Tranylcypromine Trazodone Trimpramine Lofepramine Sertraline Venlafaxine Amitriptyline → metabolized to * Nortriptyline. Imipramine → metabolized to * Desipramine.

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Psychoactive Drugs Lithium salts are used in the treatment of 1) Amitriptyline WHO,P mania, affective disorders, and the prevention of recurrent attacks of manic- • DRUG SUMMARY: depressive illness. Lithium is not a Amitriptyline is a CNS agent, psycho- sedative, nor a depressant or euphoriant. therapeutic, tricyclic (tertiary amine) Lithium prescribing requires a specialist’s antidepressant. Among the most active advise, and should not be prescribed unless TCAs in inhibition of serotonin uptake, also facilities for monitoring serum inhibits nor-epinephrine reuptake to a concentration levels are available. Abrupt moderate degree. TCAs could occasionally withdrawal increases risk of relapse, and if be used as hypnotic because of their there is a need for discontinuation, the dose sedative property; this effect may be useful should be reduced gradually over a period in the initial therapy of a depressed patient of a few weeks with caution. A specialist who is not sleeping well. subscribes it to patients with normal • INDICATIONS: sodium intake, and with normal cardiac and Depressive illness, particularly where renal functions. Lithium is not suitable for sedation is required. children. Lithium will not be discussed in Has been used for enuresis, but there is this chapter. more experience with imipramine (refer to Prescribing more than one anti-depressant special cases for children, under at the same time is not recommended. imipramine). Compound preparations of an • CONTRAINDICATIONS: antidepressant and an anxiolytic are not Hypersensitivity to any tricyclic drug. Use recommended because the individual following a recent MI or arrhythmias, component should be adjusted separately. concomitant use of a MAOI s (may Where as antidepressants are given precipitate hyperpyrexic crisis), history of continuously over several months, seizure disorders. anxiolytics are prescribed on a short-term • DOSAGE FORMS: basis. Tablets. Patients who are suicidal or potentially • RECOMMENDED DOSAGE: suicidal are prescribed only small quantities Adult: 50-75 mg/day PO in divided doses of medication to avoid possible overdose, or as a single dose at bedtime, may increase until the patient is stabilized. to 150 mg/day. Treatment should be continued for 2 weeks (Elderly and adolescents start 25-50 before suppression of symptoms can be mg/day: 10 mg t.i.d. and 20 mg h.s.). expected, and should be maintained at the Child: Not recommended for children < 12 optimum level for at least another month years. before the attempt is made for dose reduction. Treatment may last between 3 Directions: When increasing the dose, start months to a year or more. Some patients with the night dose. Therapeutic appear to benefit from maintenance therapy antidepressant effect may take as long as 30 with about half the therapeutic dosage for days to develop. several months to prevent relapse. *Drug may be taken with or immediately Besides depression, many of these agents after food to reduce possibility of GI have other uses, which will be mentioned irritations. Tablets may be crushed if as each drug is discussed. patient is able to swallow. ______*Advise patient not to discontinue therapy, or take other drugs or OTCs that may interact with the medication. Abrupt

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discontinuation may cause nausea, angle-closure glaucoma or increased headache and malaise. The dosage should intraocular pressure, in patients receiving be diminished slowly over 2 weeks. anticholinergic medications (antiparkinson *Maintenance regimen is usually continued agents), patient with cardiovascular for at least 3 months to prevent relapse. disorders (since TCAs may produce Therapy typically lasts 6 months to 1 year. arrhythmia, and increase frequencies and *Advise patient to stop taking this severity of angina and other problems). medication and get emergency help if any -Psychiatric patients with schizophrenic or of the following occur: Seizures, difficult or paranoid cases may exhibit a worsening of fast breathing, fever with increased psychosis with TCA therapy. The sweating, high or low blood pressure, loss possibility of suicide in depressed patients of bladder control, severe muscle stiffness remains during treatment until significant and unusual weakness. remission occurs. Monitor patients. Patient *Elderly patients maybe more susceptible should not have easy access to large to the anticholinergic, antihistaminic and quantities of drug, prescribe small quantity cardiovascular side-effects of amitryptyline each time (one month supply at a time until and imipramine. If the patient can’t tolerate patient is stabilized). these, desipramine and nortiptlyine are used -Sexual dysfunction in males, and weight for such patients. gain may be the major side effects that • USE IN SPECIAL CASES: cause non-compliance. Warn patients. Pregnancy- Use only if potential benefits • ADVERSE EFFECTS: outweigh the hazards to the fetus (Catgegory Drowsiness, sedation, dizziness, restless- D). Even though clinical experience is ness; need to warn patient against limited; amitriptyline has been reported to hazardous activities like driving or cause limb reduction anomalies in fetus (Drug operating machinery till response to the Facts & Comparisons. 2000). drug is known. Orthostatic hypotension; Lactation- TCAs are excreted in breast milk advise patient to change position slowly, in low concentrations. Clinical effects of tachycardia, ECG changes, blurred vision, exposure to infant are not known. Use is not dry mouth; increased fluid intake, increased recommended, unless clearly indicated. appetite (especially to sweets) leading to Children- Not recommended for children less than 12 yrs old. Although some prescribe weight gain, constipation, urinary retention, amitriptyline to children for enurisis, urine discoloration, interference with sexual imipramine is more commonly used function, interference with blood sugar worldwide. (Refer to imipramine.) levels; elevation or lowering has occurred, Renal Disease- Use caution, the drug is need to warn diabetic patients. Occasional excreted primarily in urine. Need to reduce reports or photosensitivity, metallic taste of doses in patients with significantly impaired the mouth, and convulsions have been renal functions. noted. Liver Disease- Avoid drug in severe liver • INTERACTIONS: disease. Use with caution and reduce doses in Overview of Amitriptyline patients with hepatic impairment. Metabolism Drug-Drug Interaction of the drug may be impaired leading to drug Drug Interaction accumulation. It is metabolized to the active Alcohol Will enhance the sedative metabolite nortriptyline. effect. Advise patient not to • PRECAUTIONS AND WARNINGS: drink or eat foods/ medicines -Due to the high incidence of that contain it while on this anticholinergic side effects, use caution in medication. patients with a history of urinary retention,

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Psychoactive Drugs Anti- Has antagonistic effect, 2) Imipramine P epileptics lowered seizure threshold, and (phenytoin) reduced antidepressant effect. • DRUG SUMMARY: Do not administer concomitantly Imipramine is a CNS psychotherapeutic, Anti- Increased hypotensive effect. tricyclic (tertiary amine) antidepressant; hypertensives Do not administer at the same TCA. It has the same mechanism of action and diuretics time; use caution. as amitriptyline, but somewhat has less Cimetidine Increases serum level of TCAs, sedative properties. increasing anti-cholinergic • INDICATIONS: symptoms. Avoid use, Depressive illness, treatment of panic ranitidine might be a better attacks. Nocturnal enuresis in children. alternative. • CONTRAINDICATIONS: MAO Concomitant use is Same as Amitriptyline. Inhibitors contraindicated. It has been • reported to cause hyperpyretic DOSAGE FORMS: crisis, severe convulsions and Tablets. death. Do not administer TCAs • RECOMMENDED DOSAGE: with or within 2 weeks of Adult: Start with 75 mg/day PO h.s. or in MAO Inhibitors use. divided doses, increased if needed to 150 Oral contra- Inhibit the hepatic metabolism mg/d in divided doses; max. 200 mg/d. ceptives of TCAs and may increase Adolescents and elderly: initially 30-40 (OCs) their plasma levels, especially mg/d, not to exceed 100 mg/d. estrogen. Also steroids have Child: For childhood enuresis: 25 mg PO same effect. Use caution. h.s. Thyroid Patients on these need close < 12 years may increase to 50 mg nightly; medication supervision because of possibility of cardiovascular max. dose is 2.5 mg/kg/d. toxicity, including arrhythmia. > 12 years may increase to 75 mg nightly; max. dose is 2.5 mg/kg/d. • OVERDOSE: Directions: For children treated for Children are reportedly more sensitive than enuresis; institute a drug free period adults to acute overdose. Consider any following an adequate therapeutic trial with overdose in infants or young children as a favorable response. Gradually tapering serious and potentially fatal. dosage may reduce tendency to relapse. Symptoms include confusion, agitation and Children who relapse after drug hallucinations. Seizures are common. discontinuation do not always respond to a Flushing, dry mouth, dilated pupils, cardiac subsequent course. arrhythmia, depressed myocardial *Follow same directions as amitriptyline. contractility, heart rate and coronary blood • USE IN SPECIAL CASES: flow. Pregnancy- Avoid use unless potential Treatment; Hospitalize and closely observe benefit outweighs the potential hazard to the with ECG monitoring, even when the fetus (Category D). There have been clinical amount ingested is thought to be small. reports of congenital malformation associated • BRANDS: with imipramine. Amyvil (JePharm), Elavil (Stuart), Endep Lactation- Caution should be exercised. (Roche), Elatrol/Elatrolet (Assia/Riesesl), TCAs are excreted in breast milk. Tryptal/ Tryptalette (Unipharm). Children- TCAs are used (mainly imipramine ______but amitriptyline can be used) to treat

enuresis in children ≥ 6 years, mainly on

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special occasion such as sleeping away from obsessive compulsive disorder (OCD). home or patients not responding to non- • CONTRAINDICATIONS: pharmacologic therapy. Hypersensitivity to SSRIs. In combination Non-pharmacological approaches such as to a MAO inhibitor or within 14 days or bladder retention training, motivational discontinuing a MAO inhibitor. therapy and behavior modification are • DOSAGE FORMS: preferred and have a lower relapse rate. But Tablets. many physicians and patients’ families prefer • drug therapy for fast response. Do not exceed RECOMMENDED DOSAGE: 2.5 mg/kg/d. Adult: 20 mg/d PO in the morning time. Proper follow-up of such cases is important to May increase to a max. 80 mg/d in 2 prevent relapse, and long-term therapy is divided doses; morning and noon. Child: Not used in children. controversial. Effectiveness of imipramine in children for conditions other than nocturnal Directions: While patients may notice an enuresis has not been established. improvement with therapy in 1-4 weeks, Renal Disease- Use with caution especially in advise patients to continue therapy as patients with significantly impaired renal directed. Approximately 2-3 weeks are function. required for SSRI therapeutic effects. Liver Disease- Use with caution and reduce *Food does not affect systemic dose to avoid accumulation of the drug. It is bioavailability of fluoxetine, so it may be metabolized to desipramine (an active given with or without food. metabolite) by the liver. • *If patient missed a dose, take as soon as PRECAUTIONS AND WARNINGS, remember, unless too close to the next INTERACTIONS, OVERDOSE: dosing interval. Do not double the dose. Same as amitriptyline. *Provide suicidal or potentially suicidal • ADVERSE EFFECTS: patients with small quantities of the Same as amitriptyline, with less sedation. prescribed medication to avoid possible • BRANDS: overdose, especially when starting therapy. Tofranil (Ciba-Geigy), Primonil (Teva). • USE IN SPECIAL CASES: ______Pregnancy- Avoid unless potential of benefit outweighs potential hazards. There are no 3) Fluoxetine adequate and well-controlled studies in pregnant women; but it was reported that • DRUG SUMMARY: 5.5% of 228 women who took fluoxetine the st Fluoxetine is a selective serotonin reuptake 1 trimester delivered infants with structural inhibitor (SSRI) antidepressant. A anomalities (Category C). phenylpropylamine derivative chemically Lactation- Exercise caution. Fluoxetine is unrelated to the TCAs, with a very long excreted in breast milk. One case only half-life compared with other anti- reported indicated that infant showed depressants. Antidepressant effect is increased irritability. Children- Safety and efficacy of SSRIs in presumed to be linked to its inhibition of children < 18 yrs. old have not been CNS presynaptic neuronal uptake of established. serotonin. SSRIs are less sedating than Renal Disease- Use with caution. Additional TCAs, with few antimuscarinic effects and accumulation of drug or metabolite has with low cardiotoxicity. occurred with severely impaired renal • INDICATIONS: function, with chronic use. Use a lower or Primary indication is for depression. Other less frequent dose. uses include obesity, bulimia nervosa, and Liver Disease- Use with caution in severe

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Psychoactive Drugs liver impairment. SSRIs are extensively ventilation, pneumonia, acne, alopecia, dry metabolized in the liver, (fluoxetine to active skin, urticaria, eye pain, mydriasis, metabolite norfluoxetine), elimination is abnormal ejaculation, amenorrhea, urinary prolonged. Reduce initial dose with less incontinence/ retention/ urgency, anemia, frequent dosing intervals. Alternate-day hypoglycemia and hypothyroidism. dosing has been recommended for patients • INTERACTIONS: with significant hepatic impairment. Overview of Fluoxetine • PRECAUTIONS AND WARNINGS: Drug-Drug Interaction -In patients receiving MAOIs in Drug Interaction combination with SSRIs, serious sometimes MAO Use is contraindicated. If fatal, reactions have occurred including Inhibitors patient was placed on an hyperthermia, rigidity, seizures, extreme SSRI serious, sometimes fatal agitation progressing to delirium and coma. reactions, may occur. -Rash and accompanying events; instruct TCAs, anti- All enhance toxicity and side patient that a rash could be a sign of a histamines effects of SSRIs. Do not use serious group of adverse effects, and should and concurrently. notify physician if noted. Most patients carbamazepine improved after discontinuation of Tryptrophan May produce symptoms medication. (L-trypto- related to both central and -Significant weight loss, especially in phan) peripheral toxicity. Do not underweight depressed patients, has use concurrently. occurred. Monitor weight loss particularly • in elderly or nutritionally compromised OVERDOSE: patients. Symptoms: Nausea and vomiting are -Observe and report increased anxiety, prominent, also agitation, restlessness, nervousness or insomnia, modification of hypomania and other signs of CNS drug dose may be needed. Warn patients excitation. with a history of seizures to use appropriate Treatment: There is no specific antidote. safety precautions if taking this medication. Activated charcoal with sorbitol may be as • ADVERSE EFFECTS: or more effective than emesis or lavage. Commonly observed: nervousness, Refer to emergency room for management. • insomnia, drowsiness confusion, and BRANDS: fatigue, anxiety, anorexia, nausea, dry Affectine (Taro), Flutine (Teva), Fluoxicare mouth, diarrhea/loose stools, and excessive (Pharmacare), Prizma (Unipharm), Prozac (Dista/Eli Lilly). sweating. ______Other less common: palpitations, angina, postural hypotension, tachycardia, delusions, neck pain, bone pain, hyper-

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B) HYPNOTICS AND ANXIOLYTICS

The primary use of drugs classified in this • Substance abuse; alcohol, cocaine, group is to encourage calmness (anxiolytics amphetamines, and narcotics. or sedative), or to produce sleep (sedative • Medical conditions; sleep apnea, hypnotics). When symptoms become hyperthyroidism, gastroesophogeal reflux or intolerable or interfere with the treatment of CHF. the underlying disease and counseling is Benzodiazepines are closest to the ideal not sufficiently effective, drug treatment hypnotics, and are the most commonly used can be considered as a means of helping group. Alternative drugs such as patients. Specific cases such as phobias, barbiturates (e.g. phenobarbitol) or panic disorder, obsessive-compulsive meprobamate, have a high risk of abuse disorders (OCD) need further evaluation potential as well as producing a number of and specific drug regimens. serious and potentially lethal interactions Patients with insomnia should be with other drugs. They are not counseled about non-pharmacological recommended unless there is no other measures before starting a drug regimen, choice. They do not induce liver enzymes, such as: and their effectiveness may be reduced by • Avoidance of stimulants before retiring. smoking tobacco. When used for insomnia, • Maintenance of a proper diet. may cause early morning awakening and • Initiation of an exercise program. next day restlessness. • Avoidance of stressful or anxiety The main differences within the family provoking situations. relate to potency and duration. Table-8.2 • Maintaining a stable schedule; time of gives some examples of available drugs and going to bed, avoiding mid-day naps. compares them. • Not eating heavy meals before going to Diazepam and Lorazepam will be discussed bed. as the prototypes of this group of drugs. When evaluating a patient with a sleeping Other drugs in this group include: disorder, cases that need to be ruled out Chlordiazepoxide, Clonazepam, Clorazepate, include: Halazepam, Prazepam, and Nitrazepam. • Medication induced insomnia: use of sympathomimetics such as pseudoephedrine, or other medication like fluoxetine, or methylphenidate.

Table – 8.2: Some Examples of Benzodiazepines Drug Potency Onset Duration Route of elimination Alprazolam High Fast Short Hepatic metabolism with some active metabolites Clobazam Low Moderate Short Hepatic metabolism with active metabolites Diazepam Low Very Fast Intermediate Hepatic metabolism with active metabolites Lorazepam High Fast Short Hepatic metabolism with inactive metabolites Oxazepam Low Slow Short Hepatic metabolism with inactive metabolites Triazolam Low Fast Short Hepatic metabolism with small amounts excreted unchanged in urine)

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Psychoactive Drugs

1) Diazepam WHO,P . Directions: May be taken with food or water if stomach upset occurs. • DRUG SUMMARY: *Concomitant ingestion of diazepam with Diazepam is a CNS agent, very fast acting antacid may alter the rate of absorption. If benzodiazepine, anticonvulsant, anxiolytic- antacid is to be taken it should be 1 h. hypnotic. It appears to act at both the limbic before or 2 hrs. after diazepam. and subcortical levels of the CNS. administration. • INDICATIONS: *Durg should not be discontinued abruptly, Used for management of anxiety disorders this might cause withdrawal syndrome. If a or for short-term relief of the symptoms of dose is missed, it should be taken as soon anxiety. as remembered, unless too close to next Also used as adjunct for the relief of dose. The next dose should be taken only. skeletal muscle spasms (muscle relaxant), Do not double the dose. and in status epilepticus and severe *Maximum effect requires 1-2 weeks; recurrent seizures. patient tolerance to therapeutic effects may • CONTRAINDICATIONS: develop after 4 weeks. Hypersensitivity to benzodiazepines, • USE IN SPECIAL CASES: psychoses, oral dose in children < 6 Pregnancy- Risk-benefit issue (Category D). months, acute narrow-angle glaucoma, Benzodiazepines freely cross the placenta and respiratory depression, during or within 14 accumulate in fetal circulation. If patient days of a MAO inhibitor therapy. becomes pregnant during therapy, discuss • DOSAGE FORMS: possibility of discontinuing the drug. Tablets, injection. Neonatal withdrawal has been reported as well as prolonged CNS depression. • RECOMMENDED DOSAGE: Lactation- Avoid use during breast-feeding. Adult: Dose should be individualized for Benzodiazepines are excreted in breast milk. each person, and be increased cautiously to Chronic diazepam use in nursing mothers avoid adverse effects. reportedly caused infant to become lethargic Recommended doses for anxiety disorders/ and lose weight. depending on severity: 2-10 mg PO b.i.d. to Children- Oral dose is contraindicated in < 6 q.i.d. months. > 6 months: the initial dose should

Elderly or presence of debilitating be small, increased gradually as tolerated. disease: 2-2.5 mg q.i.d. or b.i.d., increased Hypotension is rare, however cardiac gradually if needed and tolerated. complications have been noted, use caution. Child: > 6 yrs. old; 1 - 2.5 mg PO b.i.d. or Safety of injectable not established in t.i.d., or not to exceed 0.12-0.8 mg/kg/d neonates < 30 days of age. given 3-4 times a day. Renal + Liver Disease- Use with caution, decrease dose to avoid accumulation. The In status epilepticus or severe convulsive drug is metabolized in the liver to active seizures, diazepam is given initially metabolite, and excreted primarily in the intravenously, where facilities of urine. resuscitations are not immediately • PRECAUTIONS AND WARNINGS: available, with caution because of the risk -Caution in epilepsy, psychoses, mental of respiratory depression. Small doses are depression, drug abuse, impaired hepatic or given: Adults: 5-10 m initially, may be renal function, and addiction-prone repeated at 10-15 min. to a max. of 30 mg individuals. Use extreme caution in elderly, if necessary. Therapy may be repeated in 2- and patient with chronic obstructive > 4 hrs. Children 5 yrs: 1 mg every 2-5 pulmonary disease (COPD). minutes up to max. 10 mg.

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-Long term use (> 4 months); effectiveness Oral May result in prolongation of has not been assessed, need to periodically contraceptive benzodiazepines t1/2; a evaluate your patient. reduction in benzodiazepine -Dependence and withdrawal: Prolonged may be needed. use of therapeutic doses can be habit- Digoxin Digoxin serum concentration forming, tolerance or psychological and may increase, need to monitor digoxin levels. physical dependence may occur. Ranitidine May reduce GI absorption of Withdrawal syndrome has occurred after as diazepines, do not use little as 4-6 weeks of treatment. Symptoms concomitantly. may appear 8-12 hours after the last dose; • and can range from dysphoria to muscle OVERDOSE: twitch and sweating, to tremor and Symptoms: mild; including drowsiness, convulsions. When discontinuing the drug, confusion, impaired co-ordination, especially for long-term therapy patients, diminished reflexes and lethargy. Serious; decrease the dose gradually over 4-8 weeks. include ataxia, hypotonia, hypotension, -Paradoxical reactions, i.e. excitement, hypnosis, coma, and rarely death. aggression, stimulation of acute rage have Treatment: Induce vomiting if it has not occurred in psychiatric patients and occurred. Refer to hospital as soon as hyperactive aggressive children. possible. Ipecac and gastric lavage are • ADVERSE EFFECTS: needed with the general supportive Drowsiness, sedation, confusion, dizziness, measures. • vertigo, headache (warn patient not to BRANDS: perform hazardous activity like driving or Assival (Teva), Disopam (Dexxon), Harmonal (JCL), Serepam (Birzeit), Valium (Roche). operating machinery until full effect of the ______drug is known). Benzodiazepines can cause vivid nightmare or sleep terrors. Also, hypotension, blurred vision, diplopia, 2) Lorazepam constipation, dry mouth, nausea, menstrual • irregularities, tachycardia, and edema are DRUG SUMMARY: possible. Lorazepam is an intermediate-acting • INTERACTIONS: benzodiazepine, anxiolytic and sedative- hypnotic. Overview of • Drug-Drug Interaction INDICATIONS: Elimination of benzodiazepines may be Labeled use: management of anxiety decreased by the following drugs due to the disorders and short-term use to relief inhibition of hepatic metabolism, need to use symptoms of anxiety associated with caution: depressive symptoms. Preanesthetic -Cimetidine -Oral Contraceptives medication, to reduce anxiety and recall of -Isoniazid -Fluoxetine events related to day of surgery. -Ketoconazole -Metoprolol Other uses: antiepileptic, chemotherapy- -Propoxyphene -Valproic acid induced nausea and vomiting, chronic Drug Interaction insomnia, alcohol withdrawal. Alcohol & Increase CNS depression. • anti- Avoid alcohol use with this CONTRAINDICATIONS: depressants medication. Hypersensitivity to benzodiazepines, (barbiturate, psychoses, acute narrow-angle glaucoma, narcotics) during or within 14 days of a MAOI therapy, PO use for children <12 years, and in shock and coma cases.

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Psychoactive Drugs • DOSAGE FORMS: Smoking and caffeine decrease sedative Tablets, injection. and antianxiety effects. • RECOMMENDED DOSAGE: • OVERDOSE: Adult: Antianxiety: Same as diazepam. 2-6 mg/day PO in divided doses, take largest • BRANDS: dose at bedtime; max. 10 mg/day. Ativan (Wyeth-Ayerst), Lorivan (Dexxon), Insomnia: Lorocare (Pharmacare). 2-4 mg PO at bedtime. ______Child: Use is not recommended.

Directions: May take with food or water if C) NEUROLEPTICS GI upset occurs. *Do not increase dose without consulting Antipsychotic drugs are also known as doctor. If need to increase dosage, increase neuroleptics and as major tranquilizers. the nighttime dose before the daytime. They generally tranquilize without *If patient can sleep without this impairing consciousness and without medication, discuss discontinuing the drug. causing paradoxical excitement, but they Do not stop taking the medication abruptly, should not be regarded merely as taper off over a few weeks if patient has tranquilizers. They can be used for short been using it for prolonged therapy. term to calm down disturbed patients *Advise your patients to avoid large whatever the underlying psychopathology, volume intake of coffee. Anxiolytic effects which may be brain damage, mania, toxic of lorazepam can be altered even by 500 delirium, agitation, depression, or anxiety. mg caffeine (1 cup = 125-250 mg). Specialists, according to certain criteria, • USE IN SPECIAL CASES: diagnose psychotic conditions. Symptoms Pregnancy- Risk benefit issue (Category D). must be present for 6 months or more for Benzodiazepines freely cross the placenta and the diagnosis to be made. Anti-psychotic accumulate in fetal circulation. If patient drugs relieve Ford-psychotic symptoms, becomes pregnant during therapy, discuss and prevent relapse. possibility of discontinuing the drug. Extrapyramidal symptoms are the most Neonatal withdrawal has been reported as troublesome side effects of antipsychotic well as prolonged CNS depression. agents. They depend partly on the dose, Lactation- Use is not recommended. It is not partly on the type of drugs, and on the known whether it is excreted in breast milk as patients susceptibility. They consist of: with other benzodiazepines. • Parkinsonian symptoms (including Children- < 18 yrs. old do not use injection, rigidity and tremor), which may occur Safety and efficacy for use in < 12 yrs. orally gradually and are reversible. has not been established. • Dystonia (abnormal spasms of the face, Renal + Liver Disease- Use with caution. The tongue, and body movement) which may drug is not metabolized to active metabolites, appear after only a few doses. it is safer to use than other benzodiazepines in • patient with mild liver disease. It is excreted Akathisia (restlessness) may resemble in the urine. an exacerbation of the condition being • PRECAUTIONS AND WARNINGS: treated. • Same as diazepam. Tardive Dyskinesia: involuntary oral- • ADVERSE EFFECTS: facial movements, choreiform movement of Same as diazepam. the extremities, which is the most serious. Medication should be discontinued if such • INTERACTIONS: symptoms occur. Same as diazepam.

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Table-8.3 lists examples of available • RECOMMENDED DOSAGE: antipsychotic drugs. In this section Adult: Psychotic disorders, agitation; chlorpromazine and haloperidol will be PO: 25-100 mg t.i.d. or q.i.d., discussed as the main drugs used. Usual dose 75-300 mg/day, but may need

Table- 8.3: Available Antipsychotic Drugs up to 1000 mg/day for psychosis. Phenothiazines- Aliphatic Thioxanthenes IV/IM: 25-50 mg up to 600 mg q. 4-6 h. Chlorpromazine Chlorprothixene Nausea and vomiting, intractable Promazine Thiothixene hiccups; Triuoperazine Butyrophenone PO: 25-50 mg t.i.d. or q.i.d. prn. Phenothiazines- Piperidines Haloperidol Elderly or debilitated need third to half Thioridazine Dihydroindolone adult dose. Mesoridazine Molindone Child ( > 6 mon.): Phenothiazines- Piperazines Dibenzodiazepine Psychotic disorders, agitation; Acetophenazine Clozapine PO: 0.5 mg/kg q. 4-6 h. prn., up to 500 Perphenazine Benzisoxazole Prochlorperazine Resperidone mg/day. Fluphenazine Benzamide IV: 0.5 mg/kg q. 6-8 h. prn. Trifluoperazine Sulpiride Nausea and vomiting; PO: 0.5 mg/kg q. 4-6 h. IV/IM: 0.5 mg/kg q. 6-8 h. prn., up to 40 1) Chlorpromazine WHO,P mg/day.

Directions: Chlorpromazine should be • DRUG SUMMARY: taken with food or a full glass of water or Chlorpromazine (CPZ) is a CNS agent, milk (240 ml), to reduce possibility of antipsychotic (neuroleptic/tranquilizer) gastric irritation. agent, belonging to the aliphatic pheno- *Some patients may fail to experience thiazine derivatives. Mechanism of action improvement until 7-8 weeks into therapy, is not clearly understood, but is believed to therefore may not be compliant. Stress be due to the blocking of dopamine necessity of keeping appointments for receptors within the CNS. follow up, and maintaining dose regimens. • INDICATIONS: Do not increase dose more than once To control the manic phase of manic- weekly if needed, the drug needs 4-7 days depressive illness, for symptomatic to reach steady state levels. management of psychotic disorders *When deciding to discontinue medication including schizophrenia. Also indicated for after prolonged therapy, taper off dose over the control of nausea and vomiting, and several weeks to avoid onset of relief of intractable hiccups. extrapyramidal symptoms. • CONTRAINDICATIONS: *CPZ may cause urine discoloration, Do not use CPZ in comatose or severely caution patient. depressed states. Hypersensitivity, cross *Avoid prolonged exposure to sunlight or sensitivity between phenothiazines may use sunscreens, since photosensitivity occur. Bone marrow depression, blood reactions may occur, as well as increased dyscrasias, liver damage, withdrawal from susceptibility to heat stroke. alcohol, severe hypotension or hyper- *Need to discontinue medication if any of tension, and closed-angle glaucoma. the following occur: sore throat, fever, skin • DOSAGE FORMS: rashes, tremor, impaired vision or jaundice. Tablets, injection. *Smoking increases metabolism of phenothiazines resulting in more rapid

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Psychoactive Drugs clearance of the drug. Higher dosage in neuroleptics in a way to minimize smokers may be required. Advise patient occurrence of NMS. In patients who require to stop or at least reduce smoking if chronic treatment, use the smallest- possible. effective dose and the shortest duration of • USE IN SPECIAL CASES: treatment producing satisfactory clinical Pregnancy- Use CPZ only when potential response. Periodically re-evaluate the need benefits outweigh potential hazards to the for continued treatment. If signs and fetus (Category C). Safety for use during symptoms appear, consider drug pregnancy has not been established. discontinuation. Lactation- CPZ has been detected in breast -Various blood dyscrasias have occurred. milk. Safety for use in nursing mothers has If sore throat or other signs of infection not been established. Infant should be occur, or if white cell and differential count observed for sedation. indicate cellular depression, stop treatment Children- In general phenothiazines are not and institute an antibiotic and other suitable recommend for children < 6 months of age therapy. except when potentially lifesaving. -Use caution in patients with cardiovascular Renal Disease- Administer cautiously to those disease, worsening of angina patients has with diminished renal function. Monitor been noted, pulse rate has increased, renal function in long term therapy, lower dose or discontinue if BUN becomes hypotensive phenomena with patients abnormal. receiving antipsychotics all have been Liver Disease- Use with caution. The drug is noted. metabolized in the liver. -Abrupt withdrawal of the drug or • PRECAUTIONS AND WARNINGS: deliberate dose skipping, especially after -Neuroleptic malignant syndrome (NMS) prolonged therapy with large doses can reportedly occurs more frequently than cause onset of extrapyramidal symptoms, recognized (more in men). It is potentially and severe GI disturbances. Taper the dose fatal, but can be reversible if recognized when deciding to discontinue. and treated early. It resembles severe form -Diabetic or prediabetic patients should be of parkinsonian muscle rigidity, autonomic monitored for reduced glucose tolerance instability, hyperthermia, labile blood and loss of diabetes control. Warn these pressure, diaphoresis and altered mental patients. status that could progress to coma, acute • ADVERSE EFFECTS: respiratory or renal failure or Extra-pyramidal effects are the most cardiovascular collapse. Symptoms of NMS troublesome and unpredictable, i.e. can appear suddenly after initiation of dystonia, akathisia and tardative dyskinesia, therapy or after months of taking in phenothiazine therapy (refer to neuroleptic medication. To treat, one needs introduction of neuroleptics). to stop the drug immediately and give Other effects include dry mouth, intensive symptomatic and supportive care. constipation, nasal congestion, drowsiness -Tardative dyskinesia, a syndrome (caution patient against performing consisting of potentially irreversible, hazardous activities like driving or involuntary movements. Prevalence operating machines until full response to appears highest among the elderly, the drug is known), disturbances in especially women. Risk is increased as the temperature control and endocrine function duration of treatment and the total (monitor diabetic and thyroid patients and cumulative dose of the drug administered adjust dosing regimens), lower convulsion increase. Due to this fact, always prescribe threshold (might need to increase anticonvulsant dose and do not administer at

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the same time), postural hypotension- extrapyramidal symptoms may occur, as especially after parenteral therapy, well as agitation, convulsions, fever, cholestatic jaundice, photo-sensitization hypothermia, hyperthermia, and cardiac (avoid over exposure to sun or sunlamp), arrhythmias. blood dyscrasis, and skin reaction. Perform Treatment includes supportive measures. CBC, liver function tests, urinalysis, and Emetics are unlikely to be of value, take to EEG periodically during prolonged therapy. emergency room. • INTERACTIONS: • BRANDS: Overview of Chlorpromazine Largactil (Rhone-Poulenc Rorer), Taroctyl Drug-Drug Interaction (Taro), Thorazine (SKF). Drug Interaction ______Alcohol Co-administration may result in additive CNS 2) Haloperidol WHO,P depression, as well as increased occurrence of • DRUG SUMMARY: extra pyramidal reactions, alcoholic drinks or drugs A CNS agent, a potent, long acting containing alcohol should butyrophenone derivative, with anti- not be coadministered; while psychotic (tranquilizer) effects. Haloperidol taking this medication. is pharmacologically similar to those of Antacids and Decrease absorption, space piperazine phenothiazines but with anti- administration 2 hrs before somewhat higher incidence of extra- diarrheals or after administration of pyramidal effects, and less hypotensive and CPZ. relatively low sedative activity. Exerts Anti- Concomitant use with these strong antiemetic effects and impairs histamines; drugs may increase risk of central thermoregulation. Produces weak (astemizole & ventricular arrhythmia. central anticholinergic effects and transient terfenadine) and anti- orthostatic hypotension. Action thought to malarials be related to competitive blockade of post- Anti- TCAs and SSRIs increased synaptic dopamine receptors in the brain. depressants plasma concentrations of • INDICATIONS: them, or of the Psychotic disorder management. Tourette’s phenothiazine, increasing disorder, severe behavioral problems in side effects. Avoid children with combative, explosive hyper- concomitant use. excitability, also in hyperactive children Epinephrine Effects of these may be (short-term treatment) who show excessive and norepi- antagonized by CPZ. Do not motor activity with combative, impulsive nephrine coadminister these drugs. mood or aggression. For patients with Warn patients from OTC use. chronic schizophrenia requiring prolonged Propranolol Co-administration results in parenteral neuroleptic therapy. It can also increased plasma levels of be used as an antiemetic in small doses. both drugs, leading to hypo- • CONTRAINDICATIONS: tension. Use extreme Parkinson’s disease, seizure disorders, caution. coma, alcoholism, severe mental depression, thyrotoxicosis and hyper- • OVERDOSE: sensitivity. Symptoms primarily include CNS • depression to the point of somnolence, deep DOSAGE FORMS: sleep to coma. Hypotenison and Tablets, injection.

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Psychoactive Drugs • RECOMMENDED DOSAGE: in other activities requiring mental alertness Adult: Psychosis; and physical co-ordination until drug PO: 0.2-5 mg b.i.d. or t.i.d. response is known. IM: 2-5 mg q. 4-8 h. prn. *Because of long half-life of haloperidol, Severe Psychosis; therapeutic effects are slow to develop in PO: 3-5 mg b.i.d. or t.i.d., may need up to early therapy. 4-7 days are required to max. 100 mg/day. reach steady state levels, therefore do not IM: 2-5 mg, may repeat q.h. prn. (Also for make more than weekly dosage adjustments severe vomiting). in chronic therapy. Re-evaluate every 6 Child (3-12 y. or weight 15-40 kg): weeks. Psychosis: • USE IN SPECIAL CASES: PO: initially 0.5 mg/day (25-50 mcg/kg/d) Pregnancy- Same as chlorpromazine, divided to b.i.d. or t.i.d., may increase by (Category C). increments of 0.5 each 5-7 days, until up to Lactation- Haloperidol is excreted in breast 0.15 mcg/kg/d or therapeutic effect is milk, but safety in nursing mothers has not obtained, (max. of 10 mg/d). been established. Adverse effects in the (Do not give IM) infants have not been reported. Behavioral Disorders, Agitation/ Children- Not used for children < 3 yrs. old. Hyperkinesia; Renal Disease- Use caution, 40% of the drug PO only: 0.03-0.075 mg/kg/d, severe cases is excreted in urine within 5 days. may require more, use only for short-term Liver Disease- Use caution, the drug is administration. metabolized in the liver. • PRECAUTIONS AND WARNINGS: Directions: Individualize dosage. Same as chlorpromazine. *Debilitated or geriatric patients, and those • ADVERSE EFFECTS: with a history of adverse reactions to Same as chlorpromazine, but with less neurolepics, require less haloperidol. sedation and fewer antimuscarinic *Tablets may be taken with a full glass of symptoms. water or with food or milk. • INTERACTIONS and OVERDOSE: *Injection should be administered by deep Same as chlorpromazine. IM injection into the gluteus. Do not • BRANDS: exceed 3 ml per injection site. Haldol (McNeil-CPC), Halidol (Abic), Haloper *Dosing regimen should be tapered when (CTI), Peridol (Eastern Chem.), Peridor therapy is to be discontinued. Abrupt (Unipharm). termination of treatment can initiate extrapyramidal symptoms. *Advise patient not to drive a car or engage

______

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Anticonvulsant / Antiepileptic Drugs: SEIZURES

The terms seizures and convulsion maybe maintaining an effective plasma used interchangeable with epilepsy. A concentration of the medication. Careful seizure (convulsion) is defined as a adjustment of doses is necessary. Always paroxysmal involuntary disturbance of start with low doses and increase gradually brain function that maybe manifested as an until seizures are controlled, or there are impairment or loss of consciousness, over-dose effects. Dosage increase should abnormal motor activity, behavioral not occur until there has been enough time abnormalities, sensory disturbances, or for steady state concentration. Patients autonomic dysfunction. Epilepsy is the should be warned that activities requiring condition of having chronic recurrent alertness could be affected. Alcohol and seizures. A seizure originates in unstable other CNS depressants may aggravate cell membranes, or its surrounding these effects and should be avoided. supporting cells. This causes a small Therapy with several antiepileptic drugs number of cells to fire spontaneously. concurrently (polypharmacy) should be When this activity transmits to adjoining generally avoided. Patients are best areas, a seizure occurs. Seizures are nearly controlled with a single antiepileptic. The always correlated with abnormal and most appropriate choice of drug depends of excessive discharges in the brain. This can the type of epilepsy. Table-8.4 summarizes be detected and recorded on an electro- the recommended agents for certain cases. encephalogram (EEG). Combination drug regimen should be When evaluating a patient, one should added only if seizures continue despite attempt to define factors that have resulted high plasma concentration or toxic effects. in the convulsion and to provide a detailed Abrupt withdrawal of antiepileptics should description of the seizure, so as to classify be avoided since this may precipitate its type. The first step in the management severe rebound seizures. Reduce dose in of epilepsy is to confirm that the patient stages, even if it may take months. has a seizure disorder, and not a condition Changing from one drug regimen to that mimics it. Then we need to identify another should be made cautiously. what are the causes to remedy them. In recent years, several new anti- Antiepileptic drugs either prevent the epileptic agents have reached the market to spontaneous firing or inhibit the treat very specific conditions as propagation of abnormal firing. monotherapy or combination. Such drugs Recent studies have shown that up to 70% include lamotrigine, gabapentin, vigabatrin, of newly diagnosed children and adults can oxcarbazepine and zonisamide. Due to the be successfully treated (complete control of high cost and insufficient post-marketing seizure for several years) with anti-epileptic data about these agents, they will not be drugs. After 2-5 years of successful discussed at this time. treatment drugs can be withdrawn in about [Advise patient to carry medical 70% of children and 60% of adults without identification card or jewellery bearing relapse (WHO. 1997). Up to 30% of information about the diagnosis or patients may not respond to drug therapy. medications in use, in case of emergency.] The object of treatment in epilepsy is to prevent the occurrence of seizures by

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Table – 8.4: Summary for Use of Antiseizure Medication (monotherapy) Seizure Type Primary Agent Secondary Agent Partial seizures Carbamazepine (#1) Phenytoin, Valproic acid Clobazam Phenobarbital Tonic-clonic Carbamazepine (#1) Primidone/Phenobarbital (Grand mal) Phenytoin, or Valproic Acid Clobazam Absence seizures Ethosuximide (#1) Clonazepam, (Petit mal) Valproic acid Lamotrigine Myoclonic, Atonic Valproic acid Phenytoin Clobazam Clonazepam Lamotrigine Status Epilepticus Diazepam IV Lorazepam IV (Initial therapy) #1: First choice for treatment. Reference: Seear M, editor. The pocket pediatrician (low price edition). Cambridge: Cambridge University Press, 1997; p. 356.

Pregnancy and lactation: There is an To counteract the risk of neural tube increased risk of birth defects with the use defects, adequate folate supplements are of anticonvulsants. In view of the risk of advised for women before and during neural tube and other defects, patients who pregnancy. In view of the risk of neonatal may become pregnant should be informed bleeding with carbamazepine, phenol- of the risk and referred for advice. barbital and phenytoins, prophylactic Pregnant patients should be offered vitamin k1 (phytomenadione) is counseling and antenatal screening. recommended for the neonate and the Nevertheless, the advantage of using proper mother before delivery. Antiepileptic drugs antiepileptic drugs during pregnancy can be used safely during lactation, with the outweighs the disadvantage. exception of phenobarbital and Antiepileptic therapy may become less ethosuximide. effective in pregnancy because the drugs Table-8.5 gives a summary of the are cleared from the body. Hence, doses available agents and compares their may have to be increased in some drugs. pharmacokinetic characteristics.

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Table-8.5: Summary of Antiepileptic Drugs and Their Characteristics Drug CBZ CLZ ESX PHNOB PHNY VALP nahlanot benzo- Character inostilbene succinimide barbiturate hydantoin related to diazepine any Half-life 15 - 20 20 - 60 ∼ 50 - 120 8 - 60 8 - 12 (hrs.) 60 Therapeutic 20-70 blood level 4 - 12 40 - 100 15 - 40 10 - 20 50 - 100 (mcg/ml) mg/ml Time (hr) to 2 - 4 5 - 10 10 - 15 14 - 28 5 - 10 2 - 4 steady-state Pregnancy Cat. C Cat. D Cat. C Cat. D Cat. D Cat. D excreted, excreted, excreted, excreted, excreted, excreted, Lactation caution avoid avoid avoid caution caution NE, Children* NE < 6 y NE, < 3 y caution all safe no < 2 y caution Renal warning, contra- caution, caution caution caution Disease avoid indicated avoid caution, Hepatic warn in caution, caution caution caution avoid Disease severe avoid cases

* Safety and efficacy; NE: not established. - CBZ: carbamazepine, CLZ: clonazepam, ESX: ethosuximide, PHNOB: phenobarbital, PHNY: phenytoin, VALP: valproic acid. - Refer to the individual monographs for more detail.

1) Carbamazepine WHO,P Other cases that CBZ is used for (even though there is no specific indication) • DRUG SUMMARY: include: psychiatric disorders, including Carbamazepine (CBZ) is an inostilbene prophylaxis for manic-depressive illness, derivative related to the Tricyclic trigeminal neuralgia pain, resistant Antidepressants (TCAs). Its mechanism of schizophrenia, dyscontrol symptoms, and action is not clearly known. CBZ has a management of alcohol withdrawal. wider therapeutic index than phenytoin. • CONTRAINDICATIONS: The relationship between dose and plasma Hypersensitivity to CBZ or to TCAs. concentration is linear, but monitoring Patient with atrioventricular conduction plasma concentration is important in abnormalities (unless paced). Patient on determining optimum dosage. MAOI regimens or within 2 weeks of • INDICATIONS: MAOI therapy. CBZ is used as first line treatment in • DOSAGE FORMS: simple and complex partial (temporal lobe) Tablets, suspension. seizures, generalized tonic-clonic (Grand • RECOMMENDED DOSAGE: mal). It can be used for most types of Adult: 100-200 mg PO b.i.d. increased by epilepsy except absence seizures. 200 or 400 every 2 to 3 days. In frail or elderly patients: 50 mg PO b.i.d.

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Maintenance usual dose; 800 - 1200 mg/d Liver Disease- Use with caution, since CBZ in divided doses; max. 1600 mg/d. is metabolized in liver to active metabolites, Child: < 6 yrs.: initially 10-20 mg/kg/d, and can induce liver microsomal enzymes. given b.i.d or t.i.d (suspension q.i.d), then • PRECAUTIONS AND WARNINGS: increased at 5-7 day intervals; maintenance -Use caution in patients with bone marrow dose not to exceed 35 mg/kg/d. depression, hypertension, history of hepatic 6-12 yrs.: 100 mg PO b.i.d. (50 mg 4 times or cardiac disease. daily of suspension). gradually increased at -Patients on oral contraceptives should be increments of 20%, not to exceed 1000 informed that CBZ may cause break mg/d (maybe calculated on basis of 20-30 through bleeding and may affect the mg/kg/d in 3 or 4 divided doses/day). reliability of oral contraceptive. Use alternative contraceptive methods. Directions: Start dosing low then increase • over 1-2 wks, until clinical benefit. ADVERSE EFFECTS: *Time to reach steady state for the drug: 2- GI disturbances, dizziness, drowsiness, 4 days. visual disturbances (especially double vision *Therapeutic blood level: 4-12 mcg/ml. associated with peak plasma concentration), *CBZ suspension will produce higher peak constipation, anorexia, cholestatic jaundice levels than the same dose given as the are common side effects, most should tablet, therefore start with low doses (i.e. decrease within few days of therapy. Other Child 6-12 years ½ tsp q.i.d.), then increase effects that may occur include acute renal slowly. failure, agranulocytosis, aplastic anemia, *Shake suspension well before use, and do thrombocytopenia, hypothyroidism, and not administer it with other liquid other blood disorders. medicinal agents or diluents. Patients should be monitored every 6 *Administer with food. months. • *Regular patient visits should be scheduled INTERACTIONS: to check progress, and perform lab tests. Overview of Carbamazepine Drug-Drug Interaction *When adding CBZ to existing anti- Drug Interaction convulsant therapy, gradually do so, Anti- CBZ may increase level of monitoring the other drug that may be Epiletpics lithium, and markedly gradually decreased (phenytoin increased). decrease the levels of other • USE IN SPECIAL CASES: antiepiletpics. Pregnancy- Use only when potential benefit CBZ and phenytoin may outweighs the risk of teratogenesis/ mutually enhance one congenital malformation potential including another’s metabolism. Spina Bifida, Category C. Erythromycin May increase the effects of Lactation- Use with caution. CBZ is excreted or CBZ. Avoid combination if in breast milk. Because of potential serious Isoniazid possible; otherwise monitor side effects, decide whether to discontinue serum CBZ concentration to nursing or to discontinue drug taking into avoid toxicity. account the importance of drug to mother. Children- Safety and efficacy are not established for children < 6 years old. Renal Disease- Use with caution, the drug is eliminated in urine and feces. Prescribe CBZ if benefit outweighs risk of use.

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Barbiturates (i.e. phenobarbital, primidone) 2) Clonazepam WHO,P are liver enzyme inducers thus when CBZ is given • DRUG SUMMARY: concurrently, CBZ levels are Clonazepam is a CNS drug, decreased due to increased benzodiazepine derivative with strong metabolism thus increased anticonvulsant activity and several other rate of clearance. No loss of seizure control has been pharmacological properties characteristic of reported, but avoid the drug class. It suppresses spike and concomitant use of wave discharge in absence seizures, and barbiturates unless clearly decreases amplitude, frequency, duration, indicated, and the patient’s and spread of discharge in minor motor CZB blood levels and thera- seizures. Its sedative side-effects may be peutic efficacy should be prominent. observed very closely then. • INDICATIONS: Oral anti- CBZ may decrease the Indicated for use alone or with other drugs coagulants effects of oral anticoagulants in absence seizures, myoclonic and akinetic and and theophylline, use with theophylline caution. seizures, and Lennox-Gastaut syndrome. Also in absence seizures not responding to • OVERDOSE: succinimides or valproic acid, infantile Symptoms and signs first appear after 1-3 spasms and restless legs. hours. Neuromuscular disturbances are the • CONTRAINDICATIONS: most prominent symptoms. Cardiovascular Hypersensitivity to benzodiazepines, disorders are generally mild, unless very respiratory depression, porphyria, acute high doses (> 60 g) have been ingested. narrow-angle glaucoma, and breast-feeding. Other symptoms include: irregular • DOSAGE FORMS: breathing, respiratory depression, hypo- Tablets, drops. tension, nausea, vomiting, and urinary • RECOMMENDED DOSAGE: retention. Adult: 1.5 mg/d PO in 3 divided doses, Treatment: There is no specific antidote. increased by 0.5-1 mg every 3 days, until Need to irrigate the stomach repeatedly seizures are controlled or until intolerable even if more than 4 hours have passed side effects, max. 20 mg/d. following ingestion. Charcoal adminis- Child: (up to 10 y or 30 kg) tration is effective in enhancing the 0.01-0.03 mg/kg/d (not to exceed 0.05 elimination; 50-100 g can be given initially mg/kg/d) in 3 divided doses, may be followed by 25 g q. 4 h. increased to 0.25-0.5 mg/kg every 3 days; • BRANDS: max. 0.2 mg/kg/d or 3 mg daily. Carbi (Alphapharm/Genmedix), Tegrepine Directions: This drug needs 5-10 days to (JePharm), Tegretol (Ciba-Geigy), Teril (Taro). ______reach steady state concentrations. *Therapeutic blood level ranges from 20- 70 ng/ml. *If doses cannot be equally divided, the largest dose should be given at bedtime. *May take with food or water if stomach upset occurs. *Up to 30% of patients have shown a loss of anticonvulsant activity within 3 months

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Antiepileptic Drugs of administration. Dosage adjustment might • ADVERSE EFFECTS: be needed. Most common: drowsiness, sedation and *Patient should be advised not to stop dizziness; (advise patient not to drive or taking medication abruptly, and if missed a engage in activities requiring mental dose can take it as soon as remembered, or alertness and physical co-ordination until if too close to next dose, just take then. The the drug reaction is fully known), ataxia, dose should not be doubled (2 tablets taken behavioral changes, hyperactivity, at the same time). irritability, aggressiveness, violent • USE IN SPECIAL CASES: behavior, disobedience, bronchial Pregnancy- Use only if benefit of treatment hypersecretion, rash and thrombocytopenia. outweighs risk to fetus (Category D). Benzo- • INTERACTIONS: diazepines and their metabolites cross the Overview of Clonazepam placenta freely and can accumulate in the Drug-Drug Interaction fetal circulation, causing malformation, Drug Interaction neonatal drowsiness and withdrawal Alcohol and Concomitant use of these with symptoms. Other CNS clonazepam will increase Lactation- Contraindicated use; lethargy and depressants sedation and CNS depression. weight loss may occur in infant. Benzo- Antacids Use of antacids may alter the diazepines are excreted in breast milk and can rate of absorption, do not use accumulate in circulation, since neonate concomitantly, space ad- cannot metabolize the drug. ministration time if needed. Children- Use with caution, since long term Anti- Use with other antiepileptics use on growth and development is unknown. epileptics accelerates metabolism of Use smaller doses if have to use. clonazepam, reduce its effect, Renal Disease- Warning, in case of presence phenytoin levels may of severe impaired renal function. The drug is increase. Monitor blood levels. excreted primarily in urine, with half-life of Antihyper- Concomitant use enhance 18-40 hrs. tensives hypotensive effect, use with Liver Disease- Use with caution, drug is caution. metabolized in the liver. Use smaller doses. Opioid These enhance sedative Warning in severe cases; can precipitate analgesics, effects. Use with caution. coma. & muscle • relaxants PRECAUTIONS AND WARNINGS: (baclofen) -Use caution in renal disease, COPD, drug controlled open-angle glaucoma, children • OVERDOSE: (because of unknown consequences of Symptoms: drowsiness, confusion, long-term use on growth and development), somnolence, impaired co-ordination, and mixed seizure disorders. diminished reflexes and lethargy. Severe -Prolonged use of therapeutic doses can cases cause serious symptoms like lead to dependence. hypotonia, hypotension, hypnosis, coma -Withdrawal syndrome has occurred after but rarely death. as little as 4-6 weeks of treatment. Do not Treatment: induce vomiting if it has not discontinue drug abruptly, decrease occurred spontaneously, employ general gradually over 4-8 weeks if patient has supportive measures, along with immediate been on medication for prolonged time. gastric lavage or ipecac, follow with Withdrawal symptoms include: activated charcoal administration and a convulsions, tremor, abdominal and muscle saline cathartic. cramps, vomiting and sweating.

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• BRANDS: • USE IN SPECIAL CASES: Clonex (Teva), Klonopin/ Rivotril (Roche). Pregnancy- Ethosuximide may be terato- ______genic, elevated incidence of birth defects, risk vs. benefit evaluation has to be made 3) Ethosuximide WHO,P (Category C). Lactation- Avoid. Significant amount has • DRUG SUMMARY: been detected in breast milk. Hyper- Ethosuximide is a succinimide anti- excitability and poor suckling have been convulsant that reduces frequency of reported in infant. epileptic attacks. There is little information Children- Safety in children < 3 y. has not about its mechanism of action. Unlike been established. phenytoin and carbamazepine, it does not Renal Disease- Use with caution. 20% of drug is excreted unchanged via the kidney. inhibit voltage-gated Na+ channels; unlike Abnormal renal function has been reported in phenobarbital and clonazepam, it does not humans while using this medication. Perform enhance the postsynaptic actions of GABA. urinalysis periodically. • INDICATIONS: Liver Disease- Use with caution. The drug is Treatment of choice for absence seizure metabolized in the liver. Abnormal liver (petit mal); which is its only indication. function has been reported. Administer with • CONTRAINDICATIONS: extreme caution to patients with known liver Hypersensitivity to succinimides, severe disease, and perform liver tests periodically. liver or renal disease. • PRECAUTIONS AND WARNINGS: • DOSAGE FORMS: -Hematologic effects; blood dyscrasias Capsules, syrup. (some fatal) have occurred, therefore, • RECOMMENDED DOSAGE: perform periodic blood counts. If signs or Adult: 20 mg/kg/d or 250 mg b.i.d. PO, symptoms of infection (i.e. sore throat, may increase every 4-7 days by 250 mg fever) develop, consider blood counts at prn.; max. dose of 1.5 g/d should be that point. administered under direct specialized -Dosage adjustment or changes should be medical supervision. done slowly. Abrupt withdrawal of Child: 6-12 y; Same as adult, optimal anticonvulsant medication may precipitate dose is 20 mg/kg/d. absence status. 3-6 y; 250 mg/d, may increase every 4-7 -Need to order blood, liver or renal tests if days prn.; max. 20 mg/kg/d or 1 g/d. any of the following occur: Skin rash, joint

Directions: Therapeutic levels are from 40 pain, unusual bleeding or bruising, - 100 ug/ml. Inadequate dosage is the major unexplained fever, and/or blurred vision. cause of therapeutic failure. Advise patient to report any of these. *Start at 20 mg/kg/d to get lowest effective Recommend strict caution against therapeutic level and titrate up as needed. pregnancy as your patient starts on this *May be taken with food if GI distress medication, with hormonal and non- occurs. hormonal methods. • *Warn patient not to discontinue ADVERSE EFFECTS: medication abruptly or change dosage, Most common; GI upset (take with food to except on doctor’s advice. This may lower incidence), anorexia and weight loss precipitate a seizure. (advise patient to monitor weight on a weekly basis, if excessive loss, might need to lower the dose), epigastric distress, hiccups, drowsiness, dizziness (warn

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Antiepileptic Drugs against hazardous tasks such as driving or the threshold for motor cortex stimuli, its operating machinery) and headache. activity is not related to the sedative effect. Rarely, psychotic states, rashes including It exerts maximal anticonvulsant action at erythema multiforme, Stevens Johnson doses below those required for hypnosis, Syndrome, lupus erythematosus, and blood this has made its clinical utility as an dyscrasias have been reported. antiepileptic accepted. It is the drug of • INTERACTIONS: choice for febrile and neonatal seizures. Overview of Ethosuximide Tolerance or psychological and physical Drug-Drug Interaction dependence may occur with continued use. Drug Interaction Restrict use, limit prescribing and Anti- Isoniazid increases plasma dispensing to the amount required for the bacterials level of ethosuximide, high interval until the next appointment. risk of toxicity. Avoid • INDICATIONS: concomitant use. As an anticonvulsant; use for treatment of Anti- These have antagonistic depressants effects; the convulsive partial and generalized tonic-clonic (grand and anti- threshold may be lowered. mal), cortical focal seizures, and in psychotics Use with caution. prolonged (≥ 15 min.) febrile convulsions Other anti- Use with other antiepileptics or recurrent convulsions in neonates and epileptics enhance toxicity and effect, young children. Not used for absence increase sedation, i.e. CBZ seizures. Also used as injection in decreases ethosuximide level, emergency control associated with status phenytoin level is increased. epilepticus unresponsive to diazepam, Monitor patient carefully tetanus and toxic reactions. Used as until you stabilize condition. hypnotic sedative for short-term (2 wks.) • OVERDOSE: treatment of insomnia. Symptoms of acute ethosuximide overdose • CONTRAINDICATIONS: include: confusion, sleepiness, Sensitivity to barbiturates, manifest hepatic unsteadiness, coma with slow, shallow or familial history of porphyria, severe respiration, hypotension, hypo- or hyper- respiratory or renal disease, history of thermia, absent reflexes, nausea, vomiting, previous addiction to sedative hypnotics, coma with respiratory depression can and pregnancy. occur. • DOSAGE FORMS: Treatment includes usual supportive Tablets, suppository. measures, charcoal, hemoperfusion, hemo- • RECOMMENDED DOSAGE: dialysis may be indicated. Adult: 60-180 mg/day PO; max. 6 mg/kg/d • BRANDS: in divided doses. Zarontin (Park-Davis). (For acute convulsions 200-320 mg IM or ______IV, repeated q. 6 h. as necessary).

Child: 3-8 mg/kg/day PO. 4) Phenobarbital WHO,P (In Status Epilepticus 15-20 mg/kg IV over 10-15 min.).

• DRUG SUMMARY: Directions: Therapeutic serum concent- Phenobarbital/Phenobarbitone is a long- rations of 15-40 ug/ml produce anti- acting barbiturate, that is classified as a convulsant activity in most patients; these CNS agent, anticonvulsant, sedative are usually reached after 2-3 weeks of hypnotic. Phenobarbital limits the spread therapy. of seizure activity by causing an increase in

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• USE IN SPECIAL CASES: mouth sores, easy bruising or bleeding, tiny Pregnancy- Avoid use. Barbiturates are broken blood vessels under the skin. reported teratogenic drugs, (Category D). -Phenobarbital increases incidence of Barbiturates readily cross the placental osteomlacia, rickets, and anemia. Advise barrier and distribute throughout fetal tissues. patient to increase intake of vitamin D- Withdrawal symptoms occur in infants born fortified foods (i.e. milk) and folate intake to mothers who have received the drug during (fresh green leafy vegetables, fruits, etc.) or the last trimester. Neonatal coagulation take supplements if deficiency symptoms defects that may cause bleeding within 24 h occur. of birth have been associated with barbiturate -Caution patients to adhere to barbiturates use as well, Vitamin K should be given then. regimen, intervals between doses should Lactation- Avoid use. Small amounts are not be changed. Patient should not stop excreted in breast milk. Drowsiness in taking drug abruptly because of danger of nursing infant has been reported. withdrawal symptoms (8-12 h. after last Children- Barbiturates repeatedly produce dose), which can precipitate status excitement rather than depression in some epilepticus, or death. people. They may produce irritability, • aggression, and cognitive deficits in children. ADVERSE EFFECTS: Significantly lower IQs were noted after long Drowsiness, headache, dizziness, nystag- term use, for up to 6 months from mus, ataxia, anemia, osteomalacia (vitamin discontinuation of therapy. For infants who D and folic acid deficiencies), liver develop physical dependence, phenobarbital damage, paradox excitement and can be given, and after withdrawal symptoms hyperactivity in children, dulled intellect, are relieved, gradually decrease the dosage, restlessness and confusion in the elderly. until you completely withdraw the • INTERACTIONS: medication over 2-3 weeks. Overview of Phenobarbital Renal Disease- Contraindicated in patients Drug-Drug Interaction with impaired renal function. Barbiturates are Drug Interaction excreted either partially or completely Alcohol Alcohol should not be unchanged in the urine. consumed while taking Liver Disease- Do not use in patients showing phenobarbital due to additive premonitory signs of hepatic coma. CNS effects, may severely Barbiturates are metabolized primarily by impair judgment and abilities, hepatic microsomal enzymes. Administer and possible death. with caution and initially in reduced doses in Anti- These potentiate adverse susceptible hepatic disease patients. depressants effects of phenobarbital. Use • PRECAUTIONS AND WARNINGS: caution. Oral contra- Phenobarbital increases -Use caution in impaired hepatic, ceptives metabolism of OC, need to use respiratory functions, and in patients with alternative methods of diabetes mellitus. Elderly and children contraception in addition or sometimes have paradoxical response instead of hormonal OC to (behavioural disturbances and hyperkinesia), prevent pregnancy. inform family members. Oral anti- Phenobarbital may decrease -Warn patient to avoid potentially coagulants, absorption or increase hazardous activities until full response to anticonvul- metabolism of these drugs; sants, the drug is known. corticosteroids, patients might need dosage -Patient should inform the doctor if any of digoxin adjustments and monitoring. the following occur: fever, sore throat,

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Antiepileptic Drugs

• OVERDOSE: • RECOMMENDED DOSAGE: Symptoms: Onset of symptoms may not Adult: 100 mg (125 mg suspension) PO occur until several hours after pheno- t.i.d., increased gradually by 100 mg/wk. barbital ingestion. CNS and respiratory until seizures are controlled. depression, constriction of the pupils, Can start with a loading dose of up to 15-18 ataxia, tachycardia, hypotension, lower mg/kg or 1 g. body temperature and coma. Usual maintenance dose: 300-400 mg/d; Treatment is mainly supportive. Maintain max. dose 600 mg/d. adequate airway with assisted respiration Child: initially 5 mg/kg in 2-3 divided and oxygen administration as necessary. If doses may be increase gradually to max. the patient is conscious and has not lost the 300 mg/d after the therapeutic level is gag reflex, emesis may be induced with reached. ipecac. After completion of vomiting, Usual maintenance dose: 4-8 mg/kg/d. administer 30 gm of activated charcoal in a Directions: Start with small dose and glass of water. If emesis is not possible gradually increase. Time to reach steady perform gastric lavage and continue with state for the drug is 5-10 days. Therapeutic the supportive and symptomatic treatment blood level; 10-20 mcg/ml. measures as required. *Treatment must continue as long as • BRANDS: condition continues. Phenobarb (Eastern Chem.), Phenobarbital *If the patient has been free of seizures for (Rekah). several years, then the drug should be ______slowly withdrawn. Do not stop medication abruptly which may precipitate status WHO,P epilepticus, reduce gradually. 5) Phenytoin *Take medication with food to reduce GI upset possibility. • DRUG SUMMARY: • USE IN SPECIAL CASES: Phenytoin is a CNS agent, anticonvulsant, Pregnancy- Avoid use. Teratogenic effects cardiovascular and antiarrhythmic agent, have been reported (Category D). CBZ might hydantoin derivative chemically related to be safer to use. phenobarbital. The mechanism of action is Lactation- Use with caution, phenytoin is not exactly known. It has a narrow excreted in small amounts. Drowsiness and therapeutic index and the relation between decreased suckling activity have been dose and plasma concentration is non- reported in one infant. But therapeutic levels linear; therefore, a small dose increase may have little risk to the nursing infant. produce large rise in plasma concentration Children- Safe. The absorption of oral with acute toxic side effects. phenytoin is slower in pediatrics and is poor • INDICATIONS: in neonates. Monitor carefully to avoid Epilepsy; status epileptics, grand mal toxicity. (tonic-clonic) and partial seizures. Renal Disease- Use caution, metabolites are Also it is used as an antiarrhythmic agent. excreted by the kidney. • CONTRAINDICATIONS: Liver Disease- Reduce dose to avoid toxicity. Phenytoins are metabolized in the liver and Pregnancy, hypersensitivity to hydantoin can induce liver microsomal enzymes. products, sinus bradycardia, complete or incomplete heart block. • DOSAGE FORMS: Capsule, pediatric suspension.

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• PRECAUTIONS AND WARNINGS: • OVERDOSE: -Caution use in impaired hepatic and renal Lethal dose in adults is estimated to be 2-5 g. function, alcoholism, and severe Symptoms include nystagmus, ataxia, myocardial insufficiency. tremor hyperflexia, lethargy, slurred -Adjustment of phenytoin dosage for speech, nausea and vomiting. Patient may patients on insulin or of sulfonylurea become comatose and hypotensive. dosage may be necessary. Patients on Treatment: Supportive measures are prolonged therapy should have adequate required to prevent respiratory or intake of vitamin D containing foods. circulatory depression. Hemodialysis can -Observe for symptoms of folic acid be considered since phenytoin is not deficiency; neuropathy or mental dys- completely bound to plasma proteins. function. Advise patient not to change drug Repeat dose of activated charcoal by mouth brand when refilling prescription. to enhance elimination. Differences in brands can alter phenytoin • BRANDS: serum levels (change bioavailability). Dilantin / Epanutin (Park Davis). • ADVERSE EFFECTS: ______Usually dose related; drowsiness, dizziness, ataxia, confusion, GI disturbances. Also 6) Valproic Acid WHO,P hirsutism, gingival hyperplasia (very (and derivatives) common, need to advice patient on proper oral hygiene), blood dyscrasias, folate • DRUG SUMMARY: deficiency, megaloblastic anemia, osteo- (Divalproex sodium, sodium valproate) malacia due to interference with vitamin D Valproic acid (VA) is an antiepileptic metabolism. agent, chemically unrelated to other drugs. • INTERACTIONS: Its mode of action is not fully understood Overview of Phenytoin but may involve a modification in levels of Drug-Drug Interaction GABA in the brain. Plasma concentrations Drug Interaction are not a useful index of efficacy. Need to Antacids Antacids decrease effect of monitor patient’s therapeutic response. hydantoins. If there is a need • to administer an antacid, give INDICATIONS: 1 hr before or 2 hrs after Epilepsy; effective in both absence and phenytoin administration. mixed types of generalized seizures. Chloram- Marked inhibition of the • CONTRAINDICATIONS: phenicol, metabolism of these drugs Hepatic disease or significant hepatic isoniazid, may occur. Use with dysfunction, and hypersensitivity to and benzo- caution. diazipines valproic acid. TCAs, Phenytoin may displace these • DOSAGE FORMS: phenyl- drugs. Use with caution. Tablets as sodium valproate; capsule: butazone, valproic acid; syrup (200mg/5ml), solution valproic acid and (200mg/ml): sodium valproate. salicylates • RECOMMENDED DOSAGE: Influenza Using this vaccine during (Doses should be adjusted to the needs of vaccine phenytoin treatment may individual patients to achieve adequate increase seizure activity. Use control of seizures). caution, and monitor patient Adult: 15 mg/kg/d in divided total daily if need to give the vaccine. doses, increase at 1 week intervals by 5-10

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Antiepileptic Drugs mg/kg/d, until seizures are controlled. • PRECAUTIONS AND WARNINGS: Max. dose 60 mg/kg/d. - Liver function tests should be done at Child: For children up to 20 kg or about least every 2 months especially during 4 yrs.; initially start with 10-15 mg/kg/d in first 6 months of therapy. divided doses. Increase gradually (in 5-10 − Tell patient not to stop taking mg/kg/wk) to therapeutic effects. (range medication without consultation, and to 20-30 mg/kg/d). take medication the same time every day. For children > 20 kg; initially 400 mg/d in − In elderly, due to a decrease in unbound divided doses, increased gradually to 20-30 clearance of valproate, reduce starting dose, mg/kg/d; max. 35 mg/kg/d. and base therapeutic dose on clinical

Directions: If GI disturbances occur, may response. administer this drug with food. − Inform diabetic patient that VA may *Dose should be gradually increased over a cause a false positive test for urine ketones. couple of weeks. • ADVERSE EFFECTS: *Time of administration (intervals) should GI disturbances, increased or decreased be standardized for patients to avoid appetite and weight, transient hair loss, inappropriate fluctuations in plasma headache, CNS depression (advise patient concentrations. not to engage in hazardous activities like *The drug is readily absorbed from the GI driving or operating heavy machinery until tract, and needs 2-4 days to reach steady they know that they don’t become drowsy state. Therapeutic blood level ranges from from taking the drug), drowsiness, 50 - 100 mcg/ml. emotional upset, and prolonged bleeding • USE IN SPECIAL CASES: time. Rarely in children: mental stimulation, Pregnancy- Need to evaluate benefit/risk aggressiveness and hyperactivity has been situation (Category D). Increased risk of reported. neural tube defects, neonatal bleeding and • OVERDOSE: hepatotoxicity in the fetus. Symptoms: May result in somnolence, heart Lactation- Use with caution. Concentration block, visual hallucinations, and deep of VA in breast milk are 1-10 % of serum coma. Treatment: Valproic acid is absorbed concentrations. It is not known what effect very rapidly, efficacy of gastric lavage this would have on a nursing infant. varies with time since ingestion. Use Children- Children < 2 yrs. are at increased general supportive measures and carefully risk of developing fatal hepatotoxicity, maintain adequate urinary output. especially those with history of liver disease, metabolic disorder, or are on multiple anticonvulsants. Renal Disease- Use with caution. Excretion is primarily in urine. Need to avoid accumulation. Liver Disease- Avoid use. Contraindicated in active or severe liver disease states. Can precipitate hepatotoxicity or liver failure in susceptible patients. The drug is metabolized in the liver, and is a liver enzyme inducer.

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• INTERACTIONS: Warfarin Valproic acid can displace Overview of Valproic warfarin from protein Drug-Drug Interaction binding sites, need to monitor Drug Interaction coagulation tests. Unlike Phenytoin, Concomitant administration phenytoin and CBZ, valproic carba- of hepatic enzyme inducers acid does not induce hepatic mazepine, such as phenytoin, CBZ, or enzymes. or pheno- phenobarb., may enhance the barbital metabolism of valproic acid. • BRANDS: In turn, valproic acid has been Depakote (Abbott), Depalept (CTI), Valporal reported to cause rises in (Teva). phenobarb. (and primidone) ______concentrations in plasma. The interaction between VA and 7) Diazepam WHO,P phenytoin is complex and

involves inhibition of • phenytoin metabolism as well DRUG SUMMARY: as competition for protein Diazepam is a CNS agent, very fast acting binding sites. benzodiazepine, anticonvulsant, anxiolytic- hypnotic. Refer to page 181 for monograph.

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Antiparkinsonism Agents Antiparkinsons drugs: PARKINSON’S DISEASE

Parkinsonism is a neurological disease that Up-to-this-date, there are no neuro- is characterized by tremor, rigidity, akinesia protective agents that have demonstrated to and disorders of posture and equilibrium. It be effective in preventing or slowing the is a progressive degeneration of pigment- development of symptoms in this disease, containing cells of the substantia nigra thus improving the quality and expectancy leading to deficiency of dopamine. The of life of most patients, and research is onset is slow and progressive with undergoing in this field. About 10-20% of symptoms advancing over months to years. patients are unresponsive to current Diagnosis is based on clinical presentation, treatments (BNF 2001, p. 237). where at least 2 of tremor, bradykinesia or Drugs that are used to treat Parkinson rigidity must be present. Patient disability disease symptoms are divided into two can be classified by the Hoehn and Yahr groups: scale as; early (stage 1 and 2), middle First, the anticholinergic drugs (stage 3), or advance (stages 4 or 5) (include antimuscarinic) which are most Parkinson (Drug & Therapeutic Prespective, useful in improving symptoms of tremor 2001). and rigidity. Patients with minimal Current therapy for Parkinson’s is symptoms (mostly young onset) benefit palliative (will ease the symptoms only but from them. These agents seem to be equally does not cure). Drug therapy is aimed at effective. correcting or modifying the neuro- The second group consists of the transmitter defects by inhibiting the effect dopaminergic agents, which combat the of acetylcholine or enhancing the effect of dopamine deficiency. Effectiveness of dopamine. The goal is to provide maximum medication varies from one individual to relief from symptoms and mobility of the the other. Levodopa has been the gold patient. Drug therapy is initiated when the standard for treatment, even with many new patients find that their symptoms interfere drug classes being discovered. It remains with their functional status. All patients the most effective agent and maintains a with gait impairment postural instability key role in the management of should be treated, as these symptoms can Parkinsonism (Drug & Therapeutic lead to falls and serious injury. Therefore, Perspective, 2001). However the on-off functional status is what determines phenomenon and dyskinesia associated therapy. Treatment philosophy: do not start with the long-term dose lead to the greater or increase the doses of drugs until there is use of alternative drugs. loss of function.

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A) ANTICHOLINERGIC DRUGS

1) Benztropine Mesylate Lactation- Use with caution. An inhibitory effect on lactation will occur. Safety on • DRUG SUMMARY: lactating infant has not been established. A synthetic centrally acting anticholinergic Children- Contraindicated in children < 3 yrs. Safety and efficacy in older children (antimuscurinic) agent, that is chemically have not been established. similar to atropine and diphenhydramine. Renal Disease- Use with caution. Safety has Acts by diminishing excess cholinergic not been established effect associated with dopamine deficiency. Liver Disease- Use with caution. Safety has Suppresses tremor and rigidity, but does not not been established. alleviate tardive dyskinesia. (It is similar to • PRECAUTIONS AND WARNINGS: benzhexol/ trihexyphenidyl, but excreted -Rapid or pounding heart beat, confusion, more slowly). eye pain or rash may be an indication of • INDICATIONS: hypersensitivity. For use in the therapy of all forms of -In geriatric patients (> 60 yrs) of age, the parkinsonism. May also be used to control possibility of increased sensitivity of extrapyramidal disorders (except increases. Strict dosage regulations are dyskinesia) due to neuroleptic drugs like required. phenothiazines, haloperidol. Commonly -Mental confusion, disorientation, and used with levodopa therapy. psychotic-like symptoms may develop. • CONTRAINDICATIONS: -Antihistamines (e.g. diphenhydramine) Hypersensitivity to the drug, angle-closure have mild antiparkinsons effect and can be type glaucoma, obstructive disease of GU useful in patients with minimal symptoms. or GI tracts, susceptibility to tachycardia, -Caution in cardiovascular disease, hepatic and children < 3 years of age. or/and renal impairment. • DOSAGE FORMS: -Avoid abrupt discontinuation of treatment. Tablets. -Advise the patient to use caution in hot • RECOMMENDED DOSAGE: weather to avoid heat stroke or heat Adult: 0.5-1 mg/d PO gradually increase in exhaustion. increments of 0.5 at 5-6 day intervals, to • ADVERSE EFFECTS: the smallest amount necessary for optimal Dry mouth; which can be relieved by relief of parkinsonism; max. 6 mg/d. sucking hard candy, chewing gum or 1-2 mg PO b.i.d. for extrapyramidal adequate fluid intake. Difficult urination or reactions. constipation may occur; stool softeners can

Directions: Onset needs 1 h., and duration be used. Also sedation, drowsiness, 6-10 h. restlessness, mental confusion, tachycardia, *Administer immediately after meals to decreased sweating (increased prevent GI irritation. susceptibility to heat stroke), and blurred *Patients taking drug at bedtime have vision. shown greater relief and better compliance. • USE IN SPECIAL CASES: Pregnancy- Use when clearly needed and potential benefits outweigh potential hazards to fetus (Category C). Safety for use during pregnancy has not been established.

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Antiparkinsonism Agents

• INTERACTIONS: P Overview of Benztropine 2) Trihexyphenidyl Drug-Drug Interactions Drug Interaction • DRUG SUMMARY: Alcohol, These have additive sedative Trihexyphenidyl HCl, or Benzhexol, is a CNS and depressant effects. Warn synthetic tertiary amine, anticholinergic, depressants patients about the side effects, antimuscarinic agent similar to atropine. if they have to be given concomitantly. Synthetic anticholinergics have more Amantadine, These have additive selective CNS activity than naturally TCAs, MAO anticholinergic effects. occurring belladonna alkaloids, so they inhibitors, Monitor patients response if cause fewer side effects. It acts by blocking and concomitant use cannot be excess acetylcholine at certain cerebral quinidine avoided, and adjust the synaptic sites. anticholinergic drug dose • INDICATIONS: accordingly. Adjunct in treatment of all forms of Digoxin Serum level of digoxin may parkinsonism. It is also used in controlling be increased, use caution, extrapyramidal disorders (except tardive monitor levels to avoid dyskinesia) due to neuroleptic medication. toxicity. • Haloperidol Effects are variable. A CONTRAINDICATIONS: delayed reaction may occur, Hypersensitivity, narrow-angle glaucoma, where worsening of schizo- pyloric or duodenal obstruction, prostatic phrenic symptoms occur. hypertrophy or bladder-neck obstructions, Avoid concomitant use. If and megacolon. cannot avoid, monitor • DOSAGE FORMS: patients routinely and closely, Tablets, elixir. and tailor haloperidol dose as • RECOMMENDED DOSAGE: necessary. Adult: 1-2 mg the first day, increase by 2 Pheno- Therapeutic action of thiazines phenothiazines may be mg increment at intervals of 3-5 days, until decreased. Tailor the dose of total usual dose of 6-10 mg is given daily; the phenothiazine as needed. max. 15 mg/d.

• OVERDOSE: Directions: Dosage should be Symptoms: Characterized by the adverse individualized, initial dose should be low reactions. Can include: circulatory collapse, and increased gradually. May be taken cardiac arrest, respiratory depression or before or after meals depending on how arrest, toxic psychosis, shock, coma, stupor, patient reacts. foul smelling breath, dilated and sluggish *Elderly > 60 years; better to give them pupils. after meals since they are more sensitive to Treatment: Immediately following the drug. If cause excess mouth dryness, ingestion, remove remaining drug from the better to administer before meals unless stomach by inducing emesis, or by gastric causes nausea. lavage (unless patient with convulsive or *Trihexyphenidyl is best tolerated at 3 psychotic state). Activated charcoal is an divided doses, given at meal times. High effective adsorbent. Treatment is symp- doses may be divided into 4 parts: tomatic, need advanced life support setting. mealtimes and bedtime. • BRANDS: *Need to reduce dose if use concomitantly Cogentin (MSD). with levodopa. Trihexyphenidyl 3-6 mg/d ______in divided doses is adequate in this case.

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*When substituting for another anti- B) DOPAMINERGIC DRUGS cholinergic drug, usual procedure is partial substitution initially, with progressive 1) Amantadine reduction in other medications as the dose of trihexyphenidyl is increased. • DRUG SUMMARY: • USE IN SPECIAL CASES:: A synthetic primary amine, antiviral agent Pregnancy- To be used only if potential that has modest antiparkinson effect. It benefits justify the potential risks (Category improves bradykinetic disabilities, as well C). Risk cannot be ruled out. as tremor and rigidity. Its exact mechanism Lactation- Safety has not been established. is not clear, but thought to be due to An inhibitory effect on lactation may occur. increase release of dopamine. It is less Infants are usually sensitive to anticholinergic agents, hence better to stop use of effective than levodopa, but slightly more medication. effective than anticholinergic agents are. It Children- Safety and efficacy have not been has the advantage of having a low established. incidence of side effects. Renal Disease- Use with caution. The drug is • INDICATIONS: excreted in urine. Safety has not been Parkinson’s Disease/Syndrome, drug established. induced extra-pyramidal reactions, Liver Disease- Use with caution, safety has idiopathic or post encephalitic cases, as not been established. initial therapy or as adjunct with • PRECAUTIONS & WARNINGS: anticholinergic drugs or levodopa. Same as benztropine. Also used for prophylaxis and symptomatic • ADVERSE EFFECTS & OVERDOSE: treatment of influenza A infections. Same as benztropine. • CONTRAINDICATIONS: • INTERACTIONS: Hypersensitivity to amantadine. Overview of Trihexyphenidyl • DOSAGE FORMS: Drug-Drug Interactions Tablets, capsules. Drug Interaction • RECOMMENDED DOSAGE: Chlorprom- Trihexyphenidyl reduces Adult: 100 mg 1-2 times/day; azine, effect of these. max. 400 mg/day. haloperidol, Do not administer together

and pheno- unless clearly indicated (see Dosing Guidelines in Renal Impairment thiazines interactions of benztropine). Cl Cr Suggested Maintenance Digoxin Increases bioavailability of (ml/min./ 2 regimen digoxin, monitor levels of 1.73m ) digoxin to prevent toxicity > 80 100 mg b.i.d. and tailor dose as needed. 60 200 mg/100 mg, on alternate days MAO These potentiate action of 50-40 100 mg/day Inhibitors trihexyphenidyl, avoid use 30 200 mg twice weekly concomitantly. 20 100 mg three times weekly

• Brands: Directions: Start with 100 mg/day, then Artane (Lederle), Parkizol (JePharm.), Partane after one to several wks., increase if patient (Taro). has other serious illness or is on other ______antiparkinsonism medication. *Use with levodopa has been shown to exhibit rapid effect. *After few months a patient might show decreased efficacy, may increase dose or

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Antiparkinsonism Agents temporarily discontinue drug for several • INTERACTIONS: weeks. Overview of Amantadine *If patient is not responding, other Drug-Drug Interactions antiparkinson drugs might be necessary. Drug Interaction • USE IN SPECIAL CASES: Anti- Anticholinergic side effects Pregnancy- Avoid. There are no adequate or cholinergic may be increased. If cannot well-controlled studies of amantadine in drugs avoid concomitant use, pregnant women (Category C). monitor patient’s response Lactation- Use caution. It is excreted in and adjust doses accordingly. breast milk, but safety has not been Hydrochloro This combination decreases established. thiazide plus urinary excretion of triamterene amantadine. Use with caution. Children- Safety and efficacy are not These may inhibit renal established. Quinidine derivatives clearance of amantadine in Renal Disease- 90% of drug is excreted in males (but not females), urine unchanged. Elimination is prolonged in increasing risk of amantadine renal insufficiency. Dose reduction is toxicity. Use with caution in necessary in renal impairment to prevent males. accumulation. Refer to recommended dosage. Thiazide These may increase the risk Liver Disease- Use Caution. The drug is not diuretics for developing adverse effects metabolized, most of it is eliminated from the of amantadine. Use with body unchanged. caution. • PRECAUTIONS AND WARNINGS: • -Use caution in patients with history of BRANDS: epilepsy or other type seizures. A-parkin (Dexxon), Partivel (Trima), Symmetrel (Ciba-Geigy). -Dose reduction of amantadine is ______recommended, in patients with hepatic disease, psychosis, congestive heart failure P (CHF), peripheral edema, and renal 2) Bromocriptine impairment. • • ADVERSE EFFECTS: DRUG SUMMARY: Usually dose related; dizziness, light- Bromocriptine mesylate is a semi-synthetic headedness, difficulty in concentrating, potent dopamine receptor agonist. The insomnia, irritability, dry mouth, dopaminergic neurons are involved in the constipation, and orthostatic hypotension. control of motor function. Bromocriptine acts by direct stimulation of surviving • OVERDOSE: dopamine receptors. It should be reserved Symptoms include nausea or vomiting, for patients for whom levodopa alone is no anorexia, CNS effects, tremor, blurred longer adequate or can’t be tolerated. If vision, possible convulsions. patients did not respond to levodopa, they Treatment: There is no specific antidote. are poor candidates for bromocriptine. Refer to emergency room immediately. For Bromocriptine relieves akinesia, rigidity CNS toxicity: IV physostigmine may be and tremor. Some studies have shown that administered. Apply supportive measures using bromocriptine as first-choice sole along with immediate gastric lavage or therapy in earlier stages of disease has induction of emesis. Force fluids, IV if improved disability. But there is a decline necessary. Acidification of urine to increase in efficacy with long term use. Addition of elimination of drug from the body maybe levodopa then may be necessary. used.

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• INDICATIONS: even collapse within an hour of the first Parkinsonism, but not drug induced dose. Advise patient to take first dose with extrapyramidal symptoms. food and in bed. Patients often tolerate Also used for endocrine disorders (i.e. subsequent doses well. acromegaly, amenorrhea, galactorrhea). -Warn patients against driving or operating • CONTRAINDICATIONS: machinery due to the side effects especially Hypersensitivity to ergot alkaloids, severe early in therapy (the dizziness, drowsiness, ischemic heart disease, pituitary tumor, and and hypotension). glaucoma. Bromocriptine may cause first- -Use caution in renal and hepatic dose phenomenon that can trigger sudden dysfunction. cardiovascular collapse. Do not use in -Need to perform periodic evaluation of patients with a history of myocardial hepatic, renal, hematopoietic and infarction (MI) or severe arrhythmia. cardiovascular systems with long term • DOSAGE FORMS: therapy. Tablets. • ADVERSE EFFECTS: • RECOMMENDED DOSAGE: Mostly are dose related. Headaches, Adult: Initially 1.25 mg twice daily, titrate dizziness, light-headedness, sedation, every 2 wks. by 2.5 mg/d to ensure that the dyskinesia, depression, or mania, delusions, lowest dosage producing an optimal orthostatic hypotension, palpitation, therapeutic response is not exceeded. arrhythmia, constipation or diarrhea, nasal Usual range is 10 - 40 mg/day. congestion, and abdominal pain. Painless (Safety of dosages exceeding 100 mg/d has digital vasospasm is a common not been demonstrated.) complication of long term treatment (usually in treatment of acromegaly), that Directions: Take with meals to avoid GI can be reversed with lowering dose; advise disturbances. patient to avoid exposure to cold. *Always start with lowest dose possible • and titrate up. INTERACTIONS: *Do not discontinue drug abruptly. Overview of Bromocriptine • Drug-Drug Interactions USE IN SPECIAL CASES: Drug Interaction Pregnancy- Avoid. Discontinue medication Alcohol Bromocriptine decreases without delay if patient should get pregnant tolerance to alcohol, advise during therapy (Category B). patient not to drink while on Lactation- Avoid. Bromocriptine prevents this medication. lactation, therefore, do not administer to Antihyper- These agents add to hypo- mothers who want to breast-feed. tensive tensive effect, use caution, Children- Safety and efficacy in children < inform patient not to change 15 years have not been established. body position very quickly Renal Disease- Use with caution. Safety has when rising or sitting down. not been established. 85% of drug is excreted in feces in 5 days, while only 3- 6% is eliminated in urine. Liver Disease- The drug is metabolized in the liver. Use with caution in patients with liver disorders. • PRECAUTIONS AND WARNINGS: -Some patients are very sensitive to the hypotensive effect of the drug, and may

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Antiparkinsonism Agents

Oral May interfere with action of metabolism of levodopa in the brain. The Contra- the drug. Avoid use addition of carbidopa reduces the amount ceptives concomitantly. Advise patient of levodopa required by about 75% because to use alternative measures of levodopa plasma levels and t½ are contraception. increased. This decreases the incidence of Pheno- These decrease the efficacy side effects like nausea and vomiting thiazines of bromocriptine. Use associated with levodopa. A disadvantage caution. is an increased incidence of abnormal Sympatho- These increase/exacerbate the mimetics side effects of bromocriptine involuntary movement. like tachycardia and cardiac • INDICATIONS: dysfunction. Symptomatic treatment of idiopathic, postencephalitic Parkinson’s disease, and • OVERDOSE: parkinsonism following carbon monoxide Treatment: Acute overdose, employ general and manganese intoxication. supportive measures, along with immediate • CONTRAINDICATIONS: gastric lavage. Administer IV fluids and Hypersensitivity to carbidopa or levodopa, maintain an adequate airway. Monitor ECG narrow angle glaucoma, and history of to observe any developments of arrhythmia. suspected melanoma. • BRANDS: • DOSAGE FORMS: Lactopar (Birzeit), Parilac (Teva), Parlodel The mixture is expressed in x/y proportions, (Sandoz). ______where x and y are the strengths in milligrams of carbidopa and levodopa 3) Carbidopa/Levodopa WHO,P respectively. Tablets: 10/100, 25/100, 25/250 • • DRUG SUMMARY: RECOMMENDED DOSAGE: Co-careldopa, is a mixture of carbidopa and Adult: For patients not currently levodopa. Levodopa is a metabolic receiving levodopa: precursor of dopamine, a catecholamine 1 tablet carbidopa 10 mg/ levodopa 100 mg neurotransmitter, which unlike dopamine or 25/100 t.i.d. increased by 1 tablet q.d. or readily crosses the blood brain barrier. q.o.d up to 6 tablets/day. Levodopa, being a dopaminergic agent, For patients receiving levodopa already: combats the dopamine deficiency in 1 tablet of 25/250 t.i.d. or q.i.d., adjusted by Parkinson’s. 0.5 or 1 tablet, up to 8 tablets/day, or max. 200 mg carbidopa. Carbidopa, a derivative of methyldopa, is a peripheral dopa-decarboxylase inhibitor. Directions: The optimum daily dose must Decarboxylase inhibitors, (i.e. carbidopa, be determined by careful titration in each benserazide) are given with levodopa. individual patient. When transferring When levodopa is given alone, large doses patients from levodopa, 3 tablets of must be administered to compensate for carbidopa/levodopa 25/250 should be peripheral decarboxylation to provide substituted for 4 g levodopa. The levodopa adequate amounts of dopamine at the should be discontinued 8-12 hrs before- appropriate sites. Decarboxylase inhibitors hand. prevent the metabolism of levodopa and *Therapeutic effects may take few weeks. thereby make more levodopa available to *Administer with food if GI upset occurs. transport to the brain. The decarboxylase *Avoid vitamin products containing inhibitors do not cross the blood brain vitamin B6 (pyridoxine), due to drug-drug barrier and therefore do not affect interactions.

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• USE IN SPECIAL CASES: • INTERACTIONS: Pregnancy- Use only when clearly needed Overview of Co-careldopa (Category C). Effects in pregnancy are Drug-Drug Interactions unknown, both levodopa and carbidopa have Drug Interaction caused malformations in rabbits. Anti- These may enhance levodopa Lactation- Avoid. Do not administer to cholinergic effects, but can exacerbate nursing mothers, the drug is widely agents involuntary movements. If distributed in most tissues and excreted in necessary increase levodopa breast milk. or decrease anticholinergic. Children- Safety for use in children < 18 Iron salts, The pharmacologic effect of years is not established for carbidopa. Safety Oral levodopa may be decreased. for use in children < 12 years is not If necessary to coadminister, established for levodopa. observe patient’s response Renal Disease- The drug is excreted in urine. and increase the co-carledopa Use caution in renal disorders. accordingly. Liver Disease- Use with caution. MAOI It may precipitate hyper- • tensive crisis. Avoid PRECAUTIONS AND WARNINGS: concomitant use. -Use caution in cardiovascular, hepatic, Methyldopa Increases hypotensive CNS pulmonary or renal disorders, history of effects. Use with caution. peptic ulcer, psychiatric states, endocrine Pheno- These may antagonize effects diseases, seizure disorders. thiazines, of levodopa. -Monitor vital signs particularly during haloperidol period of dosage adjustment, and report Phenytoin, These may interfere with alterations in BP, pulse and respiratory rate, papaverine levodopa effects. Avoid use behavior changes. unless clearly indicated; -Uncontrollable movements of the face, monitor patient’s response. eyelids, mouth, tongue, arms, hands or legs, Pyridoxine Reduces effectiveness of mood or mental changes, irregular (B6) levodopa; avoid concomitant use. heartbeat or palpitations, severe or Tricyclic TCAs potentiate postural persistent nausea and vomiting can be signs antidepress hypotension. Use with of intolerance to the medication. ants caution. -For diabetic patients: warn patient that the medication may interfere with urine tests • OVERDOSE: for sugar or ketones, causing false results. Same as bromocriptine. • ADVERSE EFFECTS: • BRANDS: Are those of enhanced levodopa effects; Dopicar (Assia/Riesel), Sinemet (Dupont involuntary movements (dyskinetic, Pharm). dystonic, choreiform), muscle twitching, headache, dizziness, confusion, insomnia, ______mental disturbances, suicidal tendencies in psychiatric patients, blurred vision, diplopia, nausea, dry mouth, dysphagia, dark urine, urinary frequency, hoarseness, hemolytic and nonhemolytic anemia. Elevations of liver function; BUN, AST, ALT, LDH, alkaline phosphates have been reported.

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Chapter 9: OPHTHALMIC PREPARATIONS

A) ANTI-INFECTIVE PREPARATIONS 1) Antibiotics 2) Antivirals

B) ANTI-INFLAMMATORY PREPARATIONS 1) Corticosteroids 2) Other anti-inflammatory preparations

C) β-BLOCKERS 1) Timolol

D) MYDRIATICS AND CYCLOPLEGICS 1) Atropine sulphate

E) MISCELLANEOUS OPTHALMIC PREPARATIONS

OPTHALMIC PREPARATIONS

The eye is vulnerable to any external insult. for individual use. Eye-drops contain a Common problems that are seen include suitable preservative, never-the-less, they infections (conjunctivitis-red eye, and should not be used for more than 4 weeks trachoma), injury or burns, allergy and after opening the container (unless stated glaucoma (raised intraocular pressure in the specifically by the manufacturer). After that, a eye). new container should be opened (if Eye drops and eye ointments are the treatment has to be continued) and the old most commonly used dosage forms for the one should be discarded. management of eye problems. Eye drops Note: Generally it is unadvisable for penetrate the globe, probably through the patients to continue to wear contact lenses- cornea, in order to produce their therapeutic unless medically indicated when receiving eye- effect. drops. Some drugs can spoil hydrophilic soft lenses. Therefore, unless eye-drops are Some eye drops have systemic effects specifically indicated as safe to use with that result from the absorption of the drug hydrophilic contact lenses, the lenses should be into the general circulation. This occurs removed before instillation and not worn during either through the conjunctival vessels, or the period of treatment. from the nasal mucosa after the excess of the preparation has drained down through A) ANTI-INFECTIVE the tear duct. These systemic effects are PREPARATIONS usually undesirable. For example, timolol (a β-blocker) administered as eye drops Infections of the eye can be due to bacteria may induce bronchospasm or bradycardia or viruses. Most acute eye infections can be in susceptible individuals. Eye ointments treated topically. Ideally, eye-drops should are often applied to lid margins, or may be instilled very frequently (at least every 2 also be used in the conjunctival sac for hours). In order to avoid sleeping other conditions especially when a disturbances, one can use eye-ointment for prolonged action is required. nighttime because of its longer duration of When two different preparations in the action. An eye-ointment will also soften form of eye-drops are required at the same crusts that cause the lids and eyelashes to time of the day, for example pilocarpine adhere together when the patient is asleep. and timolol in glaucoma, dilution and A small quantity of eye ointment is applied overflow may occur when one immediately to the eye or inside the lower lid. follows the other. The patient should It is very important to educate the therefore leave an interval of a few minutes patient of prevention of the spread of eye between the two drugs. At night, an eye infections; minimize physical contact with ointment for the second drug will reduce other people, do not use same handkerchief the problem. or towel, a child should not attend school In addition to these two dosage forms, until the infection is cured. we have eye lotions that are used for the irrigation of the conjunctival sac. They act This chapter will discuss some mechanically to flush out irritants or antibiotics used in ophthalmic preparations foreign bodies as a first aid treatment. and some antiviral agents that are used Preparations for the eye should be sterile mainly in ophthalmic herpes infections. when issued. For routine use, they are supplied in multiple-application containers

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Ophthalmic Preparations

• 1) Antibiotics . DOSAGE FORM: Drops, ointments and tablets. • DRUG SUMMARY: Table-9.1: Antibiotics Used It is preferred to use antibiotics that are For Eye Infections rarely used to treat systemic infections (see Medication Indication precautions below). Always take in Erythro- Prophylaxis of ophthalmia consideration the possibility of systemic mycin neonatorum due to Neisseria absorption and systemic effects of these gonorrhoeae or Chlamydia antibiotics. Some of the most commonly trachomatis. used antibiotics have a wide spectrum of Chloram- Use only in those serious activity, these include: phenicol infections for which less Tetracycline WHO,P Chloramphenicol potentially dangerous drugs WHO,P WHO,P are ineffective or contra- , Framycetin, Gentamicin , indicated. and Neomycin. Chlortetra Local treatment for infections, Norfloxacin has a spectrum of activity -cycline including trachoma. similar to that of gentamicin. Gentamicin Tetracycline Massive (endemic areas) and tobramycin are effective for treating HCl trachoma (recommended by infections due to Pseudomonas aeruginosa. WHO). Fusidic acid is useful in the treatment of *For detailed information about these infections caused by Staphylococcus spp. antibiotics, refer to anti-infective chapter.

Note: • CONTRAINDICATIONS: 1) Propamidine isethionate is of little value Hypersensitivity to any component of these in bacterial infections, but is specific for the products; epithelial herpes simplex keratitis treatment of acanthamoeba keratitis that is (dendritic keratitis); vaccinia; varicella; a rare but devastating condition. Mercuric mycobacterial infections of the eye; fungal oxide eye ointment, even for short periods, diseases of the ocular structure; use of is NOT recommended. steroid combinations after uncomplicated 2) Many antibiotic preparations contain a removal of a corneal foreign body. corticosteroid. Such mixtures should not be • RECOMMENDED DOSAGES: used unless a patient is under close Eye-drops: Apply at least every 2 hours; specialist supervision. They should not be reduce frequency as infection is controlled; prescribed for undiagnosed ‘red eye’ which continue for 48 hrs. after healing. is sometimes caused by herpes simplex. Eye-ointment: Apply either at night (if eye- • INDICATIONS: drops used during the day) or 3-4 times Trachoma, ocular infections: Treatment of daily (if eye-ointment used alone). superficial ocular infections involving the Short-term courses with tetracyclines can conjunctiva or cornea due to strains of be used for control of bacterial infections microorganisms susceptible to the during seasonal epidemics of con- antibiotics. junctivitis, and may be repeated annually. Table-9.1 indicates the main used Directions: Tilt the head back, place antibiotics for the treatment of eye medication in conjunctival sac and close infections. eyes. To reduce systemic absorption, apply light finger pressure on lacrimal sac for 1 min. following instillation; this retards passage of drops via nasolacrimal duct into areas of potential absorption, such as: nasal and pharyngeal mucosa. Eye-ointments are

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often applied to lid margins for blepharitis, • PRECAUTIONS AND WARNINGS: they may also be used in the conjunctival 1. Sensitization might occur from the sac for other conditions especially where a topical use of an antibiotic, this may prolonged action is required. To avoid contraindicate the later use of the drug in contamination, do not let the tip of serious infections. For this reason it is container touch any surface. Close cap preferred that the antibiotics used topically well after using. are ones that are not ordinarily used In case of Trachoma: systemically. Also there is a possibility of -Tetracycline hydrochloride eye ointment cross-sensitivity to occur. applied to both eyes twice daily for 5 2. Hematopoietic toxicity has occurred consecutive days or once daily for 10 days, occasionally with the systemic use of each month for 6 months. chloramphenicol and rarely with topical -Chlorotetracycline eye ointment may also administration. be used. Chloramphenicol is not as 3. Do not use topical antibiotics in deep- effective. seated ocular infections or in those that are -For active trachoma in the individual, one likely to become systemic. Use of or both of the following is/are effective: antibiotics (especially prolonged or repeated (i) For adults, orally administered sulphon- therapy) may result in bacterial or fungal amides for 2 weeks; for children, overgrowth of non-susceptible organisms. erythromycin should be used. Such growth may lead to a secondary (ii) Tetracycline eye ointment three times infection. daily for 6 weeks. Also see drug summery • ADVERSE EFFECTS: above. *Sensitivity reactions such as transient • USE IN SPECIAL CASES: irritation, burning, stinging, itching, Pregnancy- Use only when clearly indicated. inflammation, etc. Avoid fluoroquinolones and chloramphenicol. *Chloramphenicol: Grey-syndrome in Category B; erythromycin, tobramycin. infants, hematological events including Category C; gentamicin, tetracyclines, aplastic anemia have been reported, but it is ciprofloxacin, norfloxacin, ofloxacin, and rare; and transient stinging. polymyxin B. *Aminoglycosides: Localized ocular toxicity Safety of eye preparations for use during and hypersensitivity, lid itching, lid swelling, pregnancy has not been established. conjunctival erythema, etc. Lactation- It is not known whether *Fluoroquinolones: White crystalline ciprofloxacin, norfloxacin, or ofloxacin precipitates (it resolves in most patients appear in breast milk following ophthalmic within 2 weeks), lid margin crusting, use. Exercise caution when administering conjunctival hyperemia, bad/bitter taste in ciprofloxacin to a nursing mother. Because the mouth, allergic reactions, lid edema, of the potential for adverse reactions in tearing, corneal staining, photophobia, nursing infants from norfloxacin, ofloxacin, corneal infiltrates, nausea, decreased vision, chloramphenicol, and tobramycin; decide chemosis. whether to discontinue nursing or • OVERDOSE: discontinue the drug, taking into account Symptoms: Most include exaggerated side the importance of the drug to the mother. effects of each category. Symptoms of Children- Tobramycin is safe and effective tobramycin overdose include punctate in children. Safety and efficacy of keratitis, erythema, increased lacrimation, ophthalmic fluoroquinolones in infants < 1 edema, and lid itching. These may be y., and polymyxin-B/trimethoprim in similar to adverse reactions. infants < 2 mon. have not been established.

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Treatment: A topical overdose of any Table-9.2: Schedules for Recommended Doses antibiotic may be flushed from the eyes of Idoxuridine with warm tap water. Initially, place 1 drop into • BRANDS: infected eye(s) every hour during Refer to price list. the day and q. 2 h. at night. Continue until corneal ulcers have ______healed, usually within 7 days. Primary Then reduce dosage to 1 q. 2 h. 2) Antivirals Schedule during the day and q4h at night. To minimize recurrences, Herpes simplex infections are the most continue therapy at this reduced dosage for 3-7 days after common ophthalmic viral infections. They complete healing. produce, for example, dendritic corneal Max. treatment period is ≤ 21 d. ulcer and can be treated with acyclovir; Instill 1 drop every minute for 5 alternatively idoxuridine may be used. minutes. Repeat q. 4 h., day and Treatment has to be started early in the Alternative night. Maximum treatment is for infection for the antiviral agent to be Schedule 21 days, or for 3-5 days after effective and inhibit the replicating virus. healing is complete.

WHO Directions: For optimal results, keep Idoxuridine infected tissues saturated with the antiviral. • • USE IN SPECIAL CASES: DRUG SUMMARY: Pregnancy- Idoxuridine crosses the placenta Idoxuridine is a pyrimidine nucleoside used barrier and produces fetal malformations in the topical and ophthalmic treatment of when administered topically to the eyes of viral infections. It inhibits replication of the pregnant rabbits in clinical doses and when virus. administered by various routes in high doses • INDICATIONS: to other rodents. Safety for use during Herpes simplex keratitis: Epithelial pregnancy has not been established. infections (especially initial attacks), Use only if clearly needed and when the characterized by the presence of dendritic potential benefits outweigh the potential ulcers, respond better than stromal hazards to the fetus (Category C). infections. Lactation- It is not known whether • CONTRAINDICATIONS: idoxuridine is excreted in breast milk. Hypersensitivity to idoxuridine or any Because of the potential for tumorigenicity component of the formulation. shown for idoxuridine in animal studies, decide whether to discontinue nursing or to • DOSAGE FORMS: discontinue the drug, taking into account the Drops, ointments. • importance of the drug to the mother. RECOMMENDED DOSAGE: Children- Safety and efficacy have not been There are two different schedules as established. indicated in table-9.2. • PRECAUTIONS AND WARNINGS: Note: Topical corticosteroids may be used 1. May cause sensitivity to bright light; his with idoxuridine in some conditions as may be minimized by wearing sun glasses. indicated by the specialist. It is important to 2. Recurrences of infection may be seen if continue idoxuridine therapy a few days after medication is not continued for 5-7 days the steroids have been withdrawn (see after the epithelial lesion has apparently precautions and warnings). healed.

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3. Corticosteroids can accelerate the 1) Corticosteroids spread of a viral infection and are usually contraindicated in herpes simplex epithelial • DRUG SUMMARY: infections. Corticosteroids can be used topically, by 4. Some strains of herpes simplex appear subconjunctival injection, and systemically to be resistant. to treat uveitis and scleritis; they are also • ADVERSE EFFECTS: used to treat inflammation following eye Occasional irritation, pain pruritus, operations. inflammation or edema of the eyes or lids, Topical corticosteroids should normally be allergic reactions, photophobia, corneal used only under expert supervision and they clouding, stippling, and punctate defects in should not be prescribed for undiagnosed the corneal epithelium. ‘red eye’. • INTERACTIONS: There are two main dangers from topical Boric acid containing solutions: Co- corticosteroids. First the ‘red eye’ may be administration may result in a precipitate caused by herpes simplex virus that formation which may cause irritation. produces a dendritic ulcer; corticosteroids • OVERDOSE: aggravate the condition which may lead to Local: Overdose will not ordinarily cause loss of vision or even loss of the eye. acute problems. Should accidental over Second, arising from the use of eye-drop dosage in the eye(s) occur, flush with water formulation, a ‘steroid glaucoma’ may be or normal saline. produced, after a few weeks of treatment, Accidental ingestion: Animal data indicate especially in patients predisposed to chronic simple glaucoma. that the minimum systemic dose that will produce toxic effects is many times greater Use of a combination product containing a than the quantity in a commercial bottle. corticosteroid with an anti-infective is Also metabolic breakdown and excretion rarely justified. take place very rapidly. Thus, no untoward consequences should be expected from There are large numbers of corticosteroidal accidental ingestion of even an entire bottle preparations that are used in ophthalmic of the solution. Drink fluid to dilute. preparations. Examples of these corticosteroids are: betamethasone, dexa- • BRANDS: methasone, fluorometholone, hydrocortisone Virusan (Teva). acetate, and prednisolone.

______All have similar indications, cautions, and side effects. B) ANTI-INFLAMMATORY PREPARATIONS Betamethasone WHO,P Will be discussed as the prototype of this Inflammatory problems of the eye are best group. treated by corticosteroids. In addition other • INDICATIONS: anti-inflammatory preparations are used. In Local treatment of inflammation. this chapter, these drugs will be discussed. • CONTRAINDICATIONS: Acute superficial herpes simplex keratitis; fungal disease of ocular structures; vaccinia, varicella and most other viral diseases of the cornea and conjunctiva; ocular tuberculosis; hypersensitivity; after

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Ophthalmic Preparations uncomplicated removal of a superficial • PRECAUTIONS AND WARNINGS: corneal foreign body. -If there is moderate to severe inflam- • DOSAGE FORMS: mation, use higher strengths. Under certain Tablets, drops, ointments. conditions systemic therapy may be • RECOMMENDED DOSAGE: required. Treatment duration varies with type of -Prolonged use may result in glaucoma, lesion and may extend from a few days to elevated IOP, optic nerve damage, defects several weeks, depending on therapeutic in visual acuity and field of vision, response. posterior subcapsular cataract formation, or Relapse may occur if therapy is reduced too secondary ocular infections from pathogens rapidly; taper dose over several days. liberated from ocular tissues. (Relapses are more common in chronic -Acute untreated eye infection may be active lesions than in self-limited masked or activity enhanced by steroids. conditions that usually respond to re- Fungal infections of the cornea have been treatment). reported with long-term local steroid Suspensions and solutions: Instill 1 to 2 applications. Therefore suspect fungal drops into the conjunctival sac every hour invasion in any persistent corneal ulceration during the day and every 2 hours during the where a steroid has been used, or is being night. When a favorable response is used. observed, reduce dosage to 1 drop every 4 • ADVERSE EFFECTS: hours. Later, 1 drop 3 to 4 times daily may Glaucoma (elevated IOP) with optic nerve suffice to control symptoms. For post- damage, loss of visual acuity and field operative inflammation, instill 1 to 2 drops defects; posterior subcapsular cataract 4 times daily beginning 24 hours after formation; secondary ocular infection from surgery; continue throughout the first 2 pathogens, including herpes simplex weeks of the postoperative period. liberated from ocular tissues; exacerbation Ointments: Apply a thin coating in the of viral and fungal corneal infections; lower conjunctival sac 3 or 4 times a day. transient stinging or burning; blurred When a favorable response is observed, vision, discharge, discomfort, ocular pain, reduce the number of daily applications to foreign body sensation, hyperemia, and twice, and later to once a day as a pruritis. maintenance dose if sufficient to control • BRANDS: symptoms. Ointments are particularly Refer to price list. convenient when an eye pad is used and ______may be the preparation of choice when prolonged contact of drug with ocular tissue is needed. 2) Other Anti-Inflammatory • USE IN SPECIAL CASES: Pregnancy- Use only when clearly indicated Preparations and when potential benefits outweigh potential hazards (Category C). Other preparations used for the topical Lactation- It is not known whether topical treatment of inflammation and allergic steroids are excreted in breast milk. Exercise conjunctivitis include antihistamines, caution when administering to a nursing oxyphenbutazone, and sodium cromo- mother. glycate. From these agents sodium Children- Safety and efficacy have not been cromoglycate will be discussed. established in children.

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Sodium Cromoglycate P days, but longer treatment for up to 6 weeks (Cromolyn Sodium) is sometimes required. Once a symptomatic improvement has been established, • DRUG SUMMARY: continue therapy for as long as needed to It has been shown that cromolyn sodium sustain improvement. inhibits the degranulation of sensitized mast 3. Corticosteroids may be used cells that occurs after the exposure to concomitantly with cromolyn ophthalmic specific antigens. Cromolyn has no intrinsic solution. vasoconstrictor, antihistaminic or anti- • ADVERSE EFFECTS: inflammatory activity. Transient ocular stinging or burning upon • INDICATIONS: instillation is the most common side effect. Conjunctivitis: Treatment of vernal kerato- • BRANDS: conjunctivitis, vernal conjunctivitis, and Opticrom (Fisons). vernal keratitis. ______• CONTRAINDICATIONS: Hypersensitivity to cromolyn or to any of C) β-BLOCKERS the other ingredients. • DOSAGE FORMS: Glaucoma is a condition characterized by Drops, ointment. an increase in the intraocular pressure • RECOMMENDED DOSAGE: (IOP). It is primarily a disease of middle 1 or 2 drops in each eye for 4 to 6 times a age. In most cases the rise in the ocular day at regular intervals. One drop of 2% pressure is due to the reduction in the contains approximately 1.6 mg cromolyn aqueous humor outflow while the inflow sodium. remains constant. Glaucoma is treated by the application of Directions: The effect of cromolyn sodium eye-drops containing β-blockers, miotics, therapy is dependent on its administration or adrenaline (and guanethidine). Also at regular intervals, as directed. acetazolamide and dichlorphenamide are • USE IN SPECIAL CASES: given by mouth in emergency or before Pregnancy- There are no adequate and well- surgery, mannitol may be given by controlled studies in pregnant women. Use intravenous infusion. during pregnancy only if clearly needed Probably the most common condition is (Category B). chronic simple glaucoma where the Lactation- It is not known whether the drug is excreted in breast milk. Exercise caution obstruction is in the trabecular meshwork. when cromolyn is administered to a nursing It is commonly first treated with a topical woman. β-blocker and other drugs added as Children- Safety and efficacy in children < 4 necessary to control the intraocular years of age have not been established. pressure, e.g. adrenaline or pilocarpine. • PRECAUTIONS AND WARNINGS: The most commonly used β-blocker for the 1. Patients may experience a transient treatment of glaucoma is Timolol. stinging or burning sensation following instillation of cromolyn. 2. The recommended frequency of administration should not be exceeded. Symptomatic response to therapy (decreased itching, tearing, redness, and discharge) is usually evident within a few

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Ophthalmic Preparations

1) Timolol WHO,P completely and continue with timolol. If a higher dosage is required, substitute 1 drop • DRUG SUMMARY: 0.5% twice daily. The exact mechanism of its ocular Replacement therapy (multiple agents): antihypertensive action is not established, When transferring a patient from several but it appears to be a reduction of aqueous concomitantly administered agents, indivi- production. However, some studies show a dualize dosage. If any of the agents is an slight increase in outflow facility with ophthalmic β-blocker, discontinue it before timolol. starting timolol. Adjust 1 agent at a time, at • INDICATIONS: intervals of not less than 1 week. Continue Glaucoma: Lowering IOP in patients with the agents being used and add 1 drop of chronic open-angle glaucoma. They are 0.25% twice a day. The next day, mainly used in chronic simple glaucoma. discontinue one of the other agents. • CONTRAINDICATIONS: Decrease or discontinue remaining agents Bronchial asthma, a history of bronchial according to patient response. If a higher asthma or severe chronic obstructive dosage is required, use 1 drop of 0.5% pulmonary disease; sinus bradycardia; timolol twice daily. second-degree and third-degree AV block; Directions: Tilt head back, place overt cardiac failure; cardiogenic shock; medication in conjunctival sac, and close hypersensitivity to any component of the eyes. To reduce systemic absorption, apply products. light finger pressure on lacrimal sac for 1 • DOSAGE FORMS: min. following instillation; this retards Drops of 0.25% and 0.5%. passage of drops via nasolacrimal duct into • RECOMMENDED DOSAGE: areas of potential absorption such as nasal Initial therapy: 1 drop of 0.25% twice and pharyngeal mucosa. daily. If clinical response is not adequate, • USE IN SPECIAL CASES: change the dosage to 1 drop of 0.5% Pregnancy- There have been no adequate and solution twice a day. If the IOP is well-controlled studies in pregnant women. maintained at satisfactory levels, change Use during pregnancy only if the potential the dose to 1 drop once a day. Since the benefits outweigh potential hazards to the pressure-lowering response may require a fetus (Category C). few weeks to stabilize, evaluation should Lactation- Topical timolol is excreted in include a determination of IOP after milk. Because of the potential for serious adverse reactions from timolol in nursing approximately 4 weeks of treatment. infants, decide whether to discontinue Replacement therapy (single agent): nursing or discontinue the drug taking into When the patient is transferred from one account the importance of the drug to the β topical ophthalmic -blocker to timolol, mother. discontinue that agent after proper dosing Children- Safety and efficacy for use in on one day, and start treatment the next day children have not been established. with 1 drop of 0.25% timolol twice daily. • PRECAUTIONS AND WARNINGS: Increase to 1 drop of 0.5% solution twice a -Systemic absorption may follow topical day if response is inadequate. When application. Therefore the same adverse changing from an agent other than an reactions found with systemic β-blockers β ophthalmic -blocker, on the first day may occur with topical use (refer to β- continue with the agent being used and add blockers in the cardiovascular chapter). 1 drop 0.25% timolol twice daily. The next -It can reduce resting and maximal exercise day, discontinue the previously used agent heart rate even in healthy subjects. Also it

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might precipitate cardiac failure. GI disturbances, fatigue, and sleep Discontinue at the first sign or symptom of disturbances. cardiac failure. • INTERACTIONS: -Non-allergic bronchospasm patients or Overview of Timolol patients with a history of chronic bronchitis Drug-Drug Interactions or emphysema should receive β-blockers Drug Interaction with caution since they may block Other β- Use caution due to the bronchodilation produced by catechol- blockers potential for additive systemic effects. amine stimulation of β2-receptors. (oral) -Withdraw β-blockers before major Epinephrine Use of epinephrine with β surgery, since their use then is (ophthalmic) topical -blockers is controversial. controversial. Some reports indicate that the initial -Administer with caution to patients subject effectiveness of the combi- to spontaneous hypoglycemia or to diabetic nation decreases over time. patients. It may mask the signs and Quinidine One case of sinus bradycardia symptoms of acute hypoglycemia. has been reported with the -β-blockers may mask the signs of coadministration of ophth. hyperthyroidism (e.g., tachycardia). timolol. Manage patients suspected of developing Verapamil Coadministration of ophth. thyrotoxicosis carefully to avoid abrupt timolol has caused brady- β cardia and asystole withdrawal of -blockers that might precipitate a thyroid storm. • OVERDOSE: -Use with caution in patients with Symptoms: With excess use, or an cerebrovascular insufficiency. overdose, systemic β-blockers side effect -The immediate objective in the treatment such as bradycardia, hypotension, of angle-closure glaucoma is to reopen the bronchospasm and acute cardiac failure angle by constricting the pupil with may occur. If these occur, discontinue miotics. β-blockers have little or no effect therapy and initiate appropriate supportive on the pupil. When they are used to reduce therapy. elevated IOP in angle-closure glaucoma, Treatment: If ocular overdosage occurs, use with a miotic. flush eye(s) with water or normal saline. If -β-blockers may potentiate muscle accidentally ingested, efforts to decrease weakness. further absorption may be appropriate -Diminished responsiveness to timolol after (gastric lavage). prolonged therapy has been reported. • BRANDS: • ADVERSE EFFECTS: Sinoptic (Eastern Chem.), Tiloptic Ophthalmic adverse effects as: (Assia/Riesel), Timolin (JePharm). Ocular irritation including conjunctivitis; ______blepharitis; keratitis; blepharoptosis; decreased corneal sensitivity; visual disturbances including refractive changes (due in some cases to withdrawal of miotics); diplopia; ptosis. In addition, systemic side effects may occur from the systemic absorption of timolol, these include: bradycardia, heart failure, bronchospasm, peripheral vasoconstriction,

218

Ophthalmic Preparations

D) MYDRIATICS & CYCLOPLEGICS • CONTRAINDICATIONS: Primary glaucoma or a tendency toward Anticholinergic agents block the response glaucoma (e.g., narrow anterior chamber of the sphincter muscle of the iris and the angle); hypersensitivity to belladonna muscle of the ciliary body to cholinergic alkaloids or any component of the products; stimulation, producing papillary dilation adhesions (synechiae) between the iris and the lens; children who have previously had a (mydriasis) and paralysis of ciliary muscles severe systemic reaction to atropine. (cycloplegia). They vary in potency and • DOSAGE FORMS: duration of action. Short acting, relatively Drops, ointment. weak mydriatics, such as tropicamide 0.5% • (duration of action 3 hr.), facilitate the RECOMMENDED DOSAGE: examination of the fundus of the eye. See table -9.3. Cyclopentolate 1% (duration of action up Directions: To avoid contamination, do not to 24 hrs.) or atropine (duration of action 7 touch the dropper’s tip to any surface and days or longer) are preferable for producing replace cap after using. Keep out of the cycloplegia for refraction in young reach of children; wash your own hands children. and the child’s following administration; keep away from heat. • 1) Atropine Sulphate WHO,P USE IN SPECIAL CASES: Pregnancy- Safety for use during pregnancy has not been established. Give to a pregnant • INDICATIONS: woman only if clearly needed (Category C). -For cycloplegic refraction and for dilating Lactation- It may be detectable, in very small the pupil in inflammatory conditions of the amounts, in breast milk. But even though it is iris and uveal tract. compatible with breast-feeding. -Treatment of iridocyclitis mainly to Children- Use with extreme caution in prevent posterior synechiae, often with infants and small children. Excessive use in phenylephrine 10% eye-drops (2.5% in children and in certain susceptible individuals children, elderly, and those with cardiac may produce systemic toxic symptoms. disease).

Table-9.3: Recommended Doses of Atroptine Sulphate Instill 1 or 2 drops of 1% solution into the Uveitis eye(s) up to 4 times daily. Adults Instill 1 or 2 drops of 1% solution into eye(s) 1 Refraction hr before refracting. Solution Instill 1 or 2 drops of 0.5% solution into the Uveitis eye(s) up to 3 times daily. Children Instill 1 or 2 drops of 0.5% solution into the Refraction eye(s) twice daily for 1 to 3 days before examination. Apply a small amount in the conjunctival sac up to 3 times daily. Ointment Compress the lacrimal sac by digital pressure for several minutes after instillation. Note: Individuals with heavily pigmented irises may require larger doses.

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• PRECAUTIONS AND WARNINGS: Systemic: Dryness of the mouth and skin; -Use it with caution in the elderly and blurred vision; photophobia with or without others where increased IOP may be corneal staining; tachycardia; headache; encountered. parasympathetic stimulation; somnolence; -Determine the IO tension and the depth of visual hallucinations. In addition to other the angle of the anterior chamber before toxic manifestations of antichlolinergic and during use to avoid glaucoma attacks. drugs. • -Avoid excessive systemic absorption by OVERDOSE: compressing the lacrimal sac by digital Ocular: If ocular overdosage occurs, flush pressure for 1 to 3 min. after instillation. eye(s) with water or normal saline. Use of a -Use cycloplegics with caution in Down’s topical miotic may be required. syndrome patients and in children with If accidentally ingested, treat with brain damage. symptomatic and supportive care.. -May produce drowsiness, blurred vision or Systemic: If symptoms develop (see sensitivity to light (due to dilated pupils); adverse reactions), patients usually recover observe caution while driving or spontaneously when the drug is performing other tasks requiring alertness, discontinued. In cases of severe toxicity, coordination or physical dexterity. give physostigmine salicylate. Have -May cause sensitivity to light. Protect eyes atropine (1 mg) available for immediate in bright illumination during dilation. injection if physostigmine causes • ADVERSE EFFECTS: bradycardia, convulsions or broncho- Local: Increased IOP; transient constriction. • stinging/burning; irritation with pro-longed BRANDS: use (e.g., allergic lid reactions, hyperemia, Atrospan (Fisher), Atroped (Eastern Chem.). conjunctivitis, etc.).

E) MISCELLANEOUS OPHTHALMIC PREPARATIONS USED

These agents should be prescribed by specialists and can be summarized in the following table:

Name of the Drug Indication Acetylcysteine Tear deficiency, impaired mucus production. Inhibition of intraoperative miosis during cataract surgery (but Diclofenac sodium does not possess intrinsic mydriatic properties); postoperative inflammation in cataract surgery. Hydroxyethylcellulose Tear deficiency. Lignocaine HCl Local anesthetic. Liquid paraffin Tear deficiency. Oxybuprocaine HCl Local anesthetic. Proxymetacaine HCl Local anesthetic. Zinc sulphate Treatment of excessive lacrimation.

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Chapter 10: Otic Preparations

A) DRUGS USED FOR OTITS EXTERNA

B) DRUGS USED FOR OTITIS MEDIA

C) DRUGS USED FOR EAR WAX

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OTIC PREPARATIONS

Most patients that attend a clinic with an A) DRUGS USED FOR OTITS ear problem tend to be children. The most EXTERNA common diseases that affect the ears are otitis externa, otitis media and Otitis Externa (OE): a disorder in which accumulation of waxy secretions in the there is an infection or inflammation of the external ear. Otitis media can further be external ear and ear canal (auditory meatal subdivided into acute otitis media without skin). More commonly seen in teenagers effusion, acute otitis media with effusion, and young adults. There is often a history chronic suppurative otitis media, which of recent exposure to water (i.e. swimming implies a non-intact tympanic membrane in polluted water) or mechanical ear trauma with 6 weeks (some references say 2 from scratching or foreign objects in the weeks) or more of middle ear drainage. ear. Although viruses cause some ear The two most common presentations are infections, bacteria cause most. There have otalgia (ear pain) that can range from been increasing reports of resistance to pruritis to severe pain that is exacerbated antimicrobial agents that are used for the by motion of the ear including chewing and common bacterial causes for ear infections by manipulation of the pinna and pressure (Strep. pneumoniae, H. influenzae and M. on the tragus, and otorrhea (discharge in or catarrhalis). The rates of these are different coming from the external auditory canal). between countries. Because of this, there If the inflammation is severe it can cause have been various debates on use of aural fullness and loss of hearing. The antibiotics for treatment of ear infections most common cause of otitis externa is (especially otitis media). Risks and bacterial infection mainly Pseudomonas benefits have to be outweighed for each aeuroginosa but also Staphylococcus case. [BMJ. 1997(12 July);315:98-102]. aureus, Entorobacter and other bacteria There is sufficient information to support can cause it, fungal growth such as encouragement of breast-feeding and Candida and Aspergillus can cause 10% of avoidance of tobacco smoke so as to the cases. It can also result from prevent occurrences of ear infections in noninfectious dermatological cause such as children. Preliminary results suggest that eczema or psoriasis. multivalent pneumococcal conjugate It is important to exclude an underlying vaccines that are immunogenic in infants chronic otitis media before treatment is and children older than 2 months are commenced. Many cases recover after efficacious in preventing otitis media thorough cleansing of the external ear canal caused by serotypes of Strep. pneumoniae by suction, or dry mopping. A frequent contained in this vaccine. problem in resistant cases is the difficulty In this chapter, general treatments for the in applying lotions and ointments previously mentioned diseases will be satisfactory to the relatively inaccessible discussed. Each category of agents; anti- affected skin. The most effective method is infective agents, analgesics and earwax to introduce a ribbon gauze dressing removers will be discussed within the soaked with corticosteroid eardrops or disease of concern. with an astringent such as aluminium acetate solution or 2% acetic acid. When this is not practical, the ear should be gently cleaned with a probe covered in cotton wool and the patient encouraged to

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Otic Preparations lie with the affected ear uppermost for ten perforation in such patients before minutes after the canal has been filled with prescribing these preparations. adequate quantity of one of the above In the presence of a perforation, refer mentioned solutions. patient to a specialist, where there may be A topical anti-infective is usually used closer supervision if drops are needed in for treatment that is not used systemically Otitis media. (such as neomycin), for only about a week (as excessive use may result in fungal B) DRUGS USED FOR OTITIS infections; and these may be difficult to MEDIA treat and require expert advice), unless the eardrum is perforated. Chloramphenicol Otitis Media (OM): is an infection and/or may also be used. Solutions containing an inflammation of the middle ear (area anti-infective and a corticosteroid are used behind the eardrum-typmanic membrane). for treating cases where infection is present OM is the second most prevalent disease of with inflammation and eczema. childhood after respiratory tract infections. When a resistant Staphylococcal It frequently occurs with respiratory infection (a boil) is present in the external infections. auditory meatus, flucloxacillin is the drug Infants and children are at highest risk of choice. The skin of the pinna adjacent to for OM with the peak between 6-13 months the ear canal is often affected by eczema, and incidence decreases with age with a and topical corticosteroid creams and marked decrease after 6 years. The ointments are then required and should be incidence is higher in boys, children in applied five or six times daily. Prolonged large daycare setting, those exposed to use should be avoided. second hand smoke, non-breast fed infants Ear drops and ointments should be and those with HIV or biological sibling or applied using 3-4 drops of a liquid parent with a significant history of OM, preparation or a similar quantity of and those with craniofacial anomalies, and ointment, warmed if necessary, inserted more in winter months. into the affected ear four times daily except The most commonly identified pathogens for fluoroquinolones which are applied are Streptococcus pneumoniae (30-50%), twice daily. The duration is for 3 days non-typable H. influenzae (20-30%) and beyond the cessation of symptoms Moraxella catarrhalis (1-2%), viruses (typically 5-7 days) but in severe cases 10- cause a minority of the disease. 14 days may be required. . If discharge is Diagnosis of OM is based on clinical profuse, eardrops applied directly may be symptoms which are: otalgia, fever, washed away; in these circumstances the hearing loss, generalized malaise and ear canal should be carefully cleaned and a otoscopic findings which include a 1 cm gauze wick impregnated with the hyperemic, opaque bulging tympanic eardrops should be introduced into it. membrane with poor mobility, purulent Note: When OE is treated topically with otorrhea with perforated tympanic preparations containing chlorhexidine, membrane may be present. aminoglycosides (e.g. neomycin), or polymyxins, in patients who have a Local treatment of acute otitis media is perforation of the tympanic membrane, ineffective and there is no place for drops there is an increased risk of drug-induced containing a local anesthetic or an autotoxicity (deafness). It is therefore antibiotic. Culture of any discharge is important to ensure that there is no helpful in selecting the appropriate

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treatment; simple analgesics such as prophylactic antibiotic (sulfisoxaole paracetamol are used to relieve pain. 50mg/kg/day or amoxicillin 20mg/kg/day Treatment: Some experts recommend once daily) at bed time during the winter watchful waiting for 24-48 hours after months can be tried but routine use of diagnosis of acute otitis media for patients prophylaxis has come into question due to older than 2 year and giving simple emergence of many resistant bacteria so it analgesia provided that close follow up is should be reserved for selected cases. feasible since OM has high rate of Chronic suppurative otitis media implies spontaneous resolution in 60-80%of the a non-intact tympanic membrane cases. The recommendation of the (perforation or tympanostomy tube present) American Academy of Pediatrics is to treat within 6 weeks or more of middle ear all cases of OM by giving a 5-7 days drainage (BMJ 2000; 321:126-127). In other course of antimicrobial agents in certain books it is defined if more than 2 weeks. children 2 years of age or older. Younger Any acute ear infection may become children and children with underlying chronic, and can be more dangerous than condition such as craniofacial anomalies, acute ear infection because if prolonged or chronic or recurrent OM or perforation of repeated, it may cause permanent damage tympanic membrane should receive to the ear. Chronic infection may show standard 10 day course (Red Book, 2000). less severe symptoms. The bacteria that Patients assessed at low risk for Strep. cause chronic infection are often different pneumonia resistance can be treated with from those that cause acute ear infection. usual dose amoxicillin 40-45 mg/kg/day in Usually the causative agents are 3 divided doses. Pseudomonas, Bacteroides, Staph. aureus Risk factor for resistance include: recent and proteus. Topical ear drops have been antibiotic exposure, age < 2 years, and day shown to be more effective than systemic care attendance. For patients at high risk antibiotics. Among the topical drops for resistance or with treatment failures quinolone antibiotics have been shown to when assessed after 3-5 days, suitable be more effective than aminoglycoside and alternative drugs include: high dose less ototoxic. Ofloxacin drops are amoxicillin 80-90 mg/kg/day in 2 or 3 approved for children older than 1 year. If divided doses is recommended (drug of topical antibiotics fail, parenteral choice) or high dose amoxicillin ceftazidime or imepenem should be used. clavulanate (80-90 mg/kg/day) of Surgery is usually needed as well after amoxicillin component or cefuroxime control for infection. (BMJ 2000; 321: 126- axetil (30 mg/kg/day in 2 divided doses). 127). Such cases should be under specialist For penicillin resistant cases erythromycin, supervision. It is important that antibiotic erythromycin-sulfisoxazole and in severe treatment does not replace drying the ear. cases or treatment failure clarythromycin It is also important to teach how to wick, so can be given. as to dry the ear. No cotton-tipped Even after the infection is cured, the applicator or sticks should be used. middle ear fluid may persist for weeks or Repeated courses of antibiotics should not months, and in the majority of cases, clears be given for draining ear. It is preferred to spontaneously. Treatment is indicated if take culture before starting treatment to effusions persist for 3 months or more. know the organism and the susceptibility to In recurrent acute otitis media, which is antibiotics. defined as 3 or more distinct and well documented episodes in 6 months or 4 episodes in 1 year, a daily dose of a

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Otic Preparations

C) DRUGS USED FOR EAR WAX not more effective than other indicated preparations that are less likely to cause Ear Wax: Wax-block or cerumen- irritation. impaction is the blockage of the ear canal Note: Syringing is best avoided in patients with cerumen (wax). The ear canal is lined with a history of recurring otitis externa, a with hair follicles and glands that produce a perforated eardrum, or previous ear waxy oil called cerumen. This protects the surgery. A person who has hearing only in ear by trapping dust, microorganisms, and one ear should not have that ear syringed foreign particles, and prevents them from because even a very slight risk of damage entering and damaging the ear. The wax is unacceptable in this situation. usually makes its way to the opening of the An available product in our market is ear where it falls out or is removed by Cerumol , which contains chlorbutol 5%, washing. paradichlorobenzene 2%, and arachis oil In some people, the glands produce more 57%. wax than can be easily excreted out the ear. This extra wax may harden within the ear Notes: canal and block the ear. More commonly, 1) For detailed information about all the the ear canal may be clogged by wax when mentioned medication in the following attempting to clean the ear causing table, refer to the related chapters, i.e. blockage as it goes deeper into the canal. anti-infective preparations, analgesics and Wax blockage may cause perforated steroids. eardrum, otitis media, otitis external as 2) Betamethasone and prednisolone sodium well as hearing loss if not treated. phosphate are both contra-indicated if an Wax may be removed by syringing with infection is present. body temperature water (cold or hot water 3) Sensitivity to the anti-infective or solvent may cause a response consisting of brief may occur and resistance to antibacterials but severe dizziness or vertigo). If is a possibility with prolonged use. necessary, wax can be softed before 4) Chloramphenicol eardrops contain syringing with simple remedies such as propylene glycol and cause sensitivity in olive oil or almond oil. The patient should about 10% of patients (the eye ointment lie with the affected ear facing upward for can be used instead). 5 to 10 minutes after a generous amount of the solution has been introduced into the Table-10.3 gives a summary of agents/ ear. Some proprietary preparations products that are used in ear problems in containing organic solvents can cause our market. irritation of the meatal skin, but they are

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Table-10.3: The following table contains some of the drugs on the market for The Treatment of Otitis Media, Otitis Externa, and Ear Wax Accumulation.

Drug Class Indications Administration Cautions Side effects Amoxicillin Anti-infective Treatment for Orally: 40-50 Be aware of Refer to anti- OM mg/kg/day, bacterial infectives divided into t.i.d. resistance. May chapter. not be active against Moraxella. Co-trimoxazole Anti-infective Treatment for Oral: 10 Do not Refer to anti- OM mg/kg/dose administer in infectives given b.i.d. infants less than chapter. 1 month old who are premature or jaundiced. Erythromycin Anti-infective Treatment for Orally: 50 Avoid Refer to anti- OM, for mg/kg/day, divided prolonged use. infectives penicillin q. 6 h., 4 times daily May not be chapter. sensitive active against patients H. Influenzae. Chloram- Anti-infective Bacterial Apply 2-3 times Avoid High phenicol preparation infection in daily prolonged use incidence of OE sensitivity reaction to vehicle. Clotrimazole Anti-infective Fungal Apply 2-3 times Occasional preparation infection in daily continuing skin irritation OE for at least 14 days or sensitivity. after disappearance of infection Gentamicin Anti-infective Bacterial Apply 3-4 times Avoid Local preparation infection in daily and at night prolonged use; sensitivity. OE risk of ototoxicity increased if perforated eardrum Neomycin Anti-infective Bacterial Apply eardrops Avoid Local Sulphate preparation infection in q. 2-3 h.; ear prolonged use; sensitivity. OE and OM ointment 2-4 times slight risk of daily. ototoxicity Reduce frequency increased if of application when perforated relief is obtained eardrum Tetracycline Anti-infective Bacterial Apply q. 2 h. Avoid Local Hydrochloride preparation infection in prolonged use sensitivity; OE stains skin and clothing. Beta- Anti- Eczematous Apply q. 2-4 h.; Avoid Steroid methasone inflammatory inflammation reduce frequency of prolonged use. glaucoma in Sodium preparations in OE application when predisposed Phosphate relief is obtained patients.

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Otic Preparations

Prednisolone Anti- Aczematous Apply q. 2-3 h.; Avoid Steroid Sodium inflammatory inflammation reduce frequency of prolonged use. glaucoma in Phosphate preparations in OE application when predisposed relief is obtained patients. Aluminum Astringent Inflammation Apply drops, or use Local - Acetate preparations in OE on a wick sensitivity. Cerumol Ear wax Occlusion or Instill 5 drops into Avoid Local (paradichloro- remover Partial ear with cotton prolonged use irritation, benzene, occlusion of wool plug and pain. benzocaine, external leave for 10-30 chlorobutanol , auditory Meatus min. ol-terebinth) due to Wax Warm Applied once Must be at Ear wax Soft, little waxy Vertigo may purified water body remover ear occur rarely temperature Oils Ear wax Hard wax- Applied once - Use 2-3 days (olive, almond) softners and lubricant, only. remover alleviate itching

______

Chapter 11: DERMATOLOGICALS

A) EMOLLIENTS, HUMECTANTS 1. Vaseline 2. Glycerin

B) ANTIPRURITICS, ANTIHISTAMINES, LOCAL ANESTHETICS 1. Zinc Oxide / Calamine 2. Lignocaine / Benzocaine

C) ANTIFUNGALS 1. Miconazole 2. Ketoconazole 3. Tolnaftate

D) ANTIBACTERIALS 1. Oxytetracycline 2. Neomycin/Gentamicin

E) ANTIVIRALS 1. Acyclovir

F) ANTISEPTICS / DISINFECTANTS 1. Ethyl Alcohol 2. Povidone-Iodine 3. Cetrimide 4. Chlorhexidine

G) ANTIPARASITICS 1. Scabicides: Benzyl Benzoate, Crotamiton 2. Pediculicides: Malathion, Lindane

H) KERATOLYTIC AGENTS 1. Salicylic Acid 2. Sulfur

I) MISCELLANEOUS 1. Topical corticosteroids: Betamethasone Valerate 2. Preparations for acne: Retinoic Acid/Tretinoin, Benzoyl Perxoide 3. Sunscreens

Dermatological Preparations

A large number of drugs are available for When there is skin irritation, the topical skin therapeutics. Many of the underlying cause of irritation should be preparations available should be always sought and appropriate antipruritic prescribed by dermatologists, to ensure therapy instituted. Although topical expert advice and supervision. The antibiotic agents may be valuable in the “vehicle” of a preparation refers to the management of some infected skin carrier-base that brings the drug into close conditions such as impetigo and infected contact with the skin. Both the vehicle and eczema, they should not be used the active ingredients are important in indiscriminately, thus resulting in the treating skin disease. Skin preparations may emergence of resistant bacterial strains. As contain preservatives, anti-oxidants, for topical steroids, they are used perfumes and coloring agents that may give frequently for the symptomatic relief and rise to adverse reactions. Before choosing a control of inflammatory and allergic skin specific preparation, factors such as conditions, and they are often prescribed cosmetic acceptability to the patient, without regard for the appropriateness of suitability for the condition, safety and the indication, the potential for adverse stability should be considered. effects or proper concern for the potency of

• Creams are chosen for wet and the preparation. Topical corticosteroids weeping skin conditions. They are should generally not be used in the cosmetically acceptable and have proved presence of bacterial (including good delivery systems for various drugs. tuberculosis), fungal or viral infections of Generally, creams are cosmetically more the skin. acceptable than ointments as they are less Excessive drying and defatting of the greasy and easier to apply. skin should be avoided, e.g., hot baths, • Ointments are greasy preparations, alcoholic skin preparations, detergents and suitable for chronic dry skin lesions. They alkaline soaps. are more occlusive than creams, promoting ______hydration and the penetration of specific drugs, but are disadvantageous in oozing A) EMOLLIENTS & conditions. HUMECTANTS • Lotions may be preferred to creams or ointments when it is intended to apply a Emollients/Barriers are occlusive agents or thin layer of the preparation over a large or moisturizers used to prevent or relieve the hairy area. signs and symptoms of dry skin. Emollients • Powders may contain one or more are used to rehydrate and soothe the skin, active ingredients with or without auxiliary and are valuable in all conditions substances. They are useful as adjunctive characterized by dryness, scaling and agents, intended to be applied to skin for cracking of the skin. Frequent application therapeutic, prophylactic or lubricant is usually needed and continued purposes. They are used in folds where prophylactic use is recommended. friction may occur between opposing skin The oily nature of these emollients surfaces. They should not be applied in promote water retention because the areas that are very moist as they tend to moisture of the skin cannot pass through cake and abrade the skin. the oily film. The frequency of application depends on the degree of dryness of the

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Dermatological Preparations skin. The most common emollients are the affected area in water for 5-10 min., petrolatum jelly (vaseline), lanolin, and then patting it dry and applying vaseline to liquid petrolatum (mineral oil). Lanolin it. and mineral oil are not very effectively • PRECAUTIONS AND WARNINGS: used for the treatment of dry skin. Petrolatum should not be applied over However, combinations with other puncture wounds, infections, or lacerations formulations are very common. because its high occlusive ability may lead Humectants are hydrating agents that to inflammations and infections. Excessive draw water into the stratum corneum to hydration should also be avoided. Use hydrate the skin. They are used in caution when applied around the nasal conjunction with emollients to treat and mucosa because it can obstruct breathing. prevent dry skin. The difference between an • ADVERSE EFFECTS: emollient and a humectant is that an Adverse effects are rarely seen with the emollient retains the water that is already topical use of vaseline, however acne is in the skin while a humectant adds water to possible. the skin. The most common humectants • BRANDS: available are: glycerin, propylene glycol, Petroleum Jelly, Vaseline. and phospholipids. ______

1) Vaseline 2) Glycerin

• DRUG SUMMARY: • DRUG SUMMARY: Vaseline or petrolatum jelly is one of the Glycerin is one of the most common most effective emollients available. It is not hydrating agents. In addition to its very well tolerated by patients due to its hydrating effect, glycerin provides greasiness and staining properties. It can lubrication to the skin surface. also be used in conjunction with other It is indicated for use in the treatment and products as an ointment base. prevention of dry skin. It can also be used • INDICATIONS: as a skin protectant and as a solvent for For treatment and prevention of dry skin. different pharmaceutical agents. The only • CONTRAINDICATIONS: contraindication for use is hypersensitivity Hypersensitivity to petrolatum. to glycerin. • DOSAGE FORMS: ______Ointment. • RECOMMENDED DOSAGE: Directions: to be applied to affected area(s) as needed. Frequency of application depends on how dry the skin is. It can be used with hydrating agents like glycerin in order to hydrate the skin more effectively. *In some cases it is recommended to advise the patient to hydrate the skin by soaking

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B) ANTIPRURITICS, Directions: it is safe for use in infants, ANTIHISTAMINES & LOCAL children and adults. ANESTHETICS *Avoid contact with the eye(s). Flush with running water if contact with the eyes Pruritis or itching may occur with any type occurs. of systemic or skin disease. Pruritis can • PRECAUTIONS AND WARNINGS: cause redness, local irritation and For external use only. It should not be sometimes lesions if untreated. It can also applied to ulcers or infected skin lesions be a form of dermatitis. Several associated with pus. pharmaceutical products are available for • ADVERSE EFFECTS: the treatment of pruritis depending on the Rare adverse effects are noted which include: cause of it. Most formulations are available local irritation, burning, and stinging. as combined products. The key in the • BRANDS: treatment is to identify and then Adinol Ointment (Teva), Caladerm (JePharm), Calatrim Lotion (Trima), Dyprotex (Mediline), discontinue the aggravating factor of the itching before initiating therapy. The Calamine Lotion (Sam-On). mentioned drugs are some of the most ______common ingredients found in antipruritic products. 2) Lignocaine / Benzocaine

• WHO,P DRUG SUMMARY: 1) Zinc Oxide / Calamine Lignocaine is a topical local anesthetic that temporarily relieve pain by preventing the • DRUG SUMMARY: transmission of nerve impulses. Zinc oxide is an astringent with antipruritic • INDICATIONS: properties. It is combined with ferric oxide For the temporary relief of pain, burning, to make calamine. Calamine is a pink itching, discomfort, and irritations in local colored powder that is not soluble in water. skin disorders. It can also be used for local It has astringent, antiseptic, antibacterial, anesthesia of mucous membranes including and antipruritic action. When applied to oral, nasal and laryngeal membranes as the skin, the evaporation of water produces well as anal pruritis and hemorrhoids. a cooling effect and the oozing of watery • CONTRAINDICATIONS: discharge is reduced. Hypersensitivity to any of these products. • INDICATIONS: • DOSAGE FORMS: It can be used in mild cases of dermatitis Ointment, cream, spray, lozenges, gel. and poison ivy. In some cases calamine can • RECOMMENDED DOSAGE: be used to treat diaper rash and to relieve To be applied to the affected area as the itching caused by chicken pox. It is needed. generally used as an antipruritic agent. Directions: Use the minimal amount • CONTRAINDICATIONS: possible to avoid systemic side effects. Hypersensitivity to any of the ingredients. • *Do not apply oint./creams/gel to the eyes. DOSAGE FORMS: *Lozenges should be sucked and not Lotion, ointment, cream. chewed for soothing laryngeal discomfort. • RECOMMENDED DOSAGE: *When using the oral anesthetic applied to To be applied to the affected area(s) as the mouth and throat (like the lozenges or needed (3-4 times/day). spray), use caution while swallowing food. Ingestion of food should be delayed for 1

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Dermatological Preparations hour after using these products to prevent the diaper area in infants/ children/ and choking. even adults . . . etc. • USE IN SPECIAL CASES: In most cases, topical antifungals are Pregnancy- Use when the benefits outweigh used. Ideally, skin infections should be the potential hazards to the fetus, (Category examined by a dermatologist to confirm C). Safety for use during pregnancy has not diagnosis before the treatment is begun. been established yet. One or two applications The primary effect of most antifungal drugs will not cause harm. is to prevent colonization of new tissue by Lactation- Use caution. Sufficient data is not the organisms. The crucial factor for the available. successful treatment of skin fungal Children- Not to be used in infant < 1 y. of infections is to understand the kinetics of age. Safe in children > 1 y., but decrease the turnover of epidermal cells. In some dose depending on the age, body-weight and complicated cases oral antifungals are physical condition. needed to treat the fungal infections. • PRECAUTIONS AND WARNINGS: There are a lot of products containing - Use the minimal effective dosage to avoid antifungal agents on the market. Studies systemic absorption and side effects. have not proven superiority of one product • ADVERSE EFFECTS: over the other in treating most localized Adverse effects are dose related. Local infections of the skin. Topical antifungal adverse effects might include: burning, agents include the broad spectrum stinging, and tenderness. Cutaneous lesions, imidazoles and triazoles (i.e. butoconazole, urticaria, edema, contact dermatitis are also clotrimazole WHO,P, econazole, ketoconazole, noticeable. Anaphylactic reactions and miconazole WHO,P, terconazole, nyastatinP shock can also result from hypersensitivity. (for candidal infections only), and • INTERACTIONS: tolnaftate. *Class I antiarrhythmic agents: caution Miconazole will be used as the prototype should be exercised when using these for the imidazole antifungal agents. agents together since the toxic effects are increased (synergistic action). [For more information about the oral antifungal agents available, refer to the anti- • OVERDOSE: infectives chapter.] Systemic absorption may occur due to overdosage with topical treatment. CNS (convulsions) and cardiovascular (hypo- 1) Miconazole WHO,P tension) complications can occur. Refer to an emergency setting for symptomatic and • DRUG SUMMARY: supportive care. Miconazole is an imidazole derivative • BTRANDS: broad spectrum antifungal agent. It inhibits Esracain (Rafa), Xylene. growth of different vulvovaginal ______candidiasis (Moniliasis and vaginal yeast infections) and dermatophytes such as C) ANTIFUNGALS Candida ablicans, Trichophyton rubrum and active forms of Tinea versicolor . . . One of the most common skin diseases are etc. It exerts fungicidal effect by altering fungal infections. They can occur anywhere the permeability of the fungal cell in the body especially the areas that are membrane. mostly wet or sweaty. Such areas include the soles of the feet, between the toes, and

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• INDICATIONS: • BRANDS: Tinea pedis (athlete’s foot), Tinea cruris Daktarin/Gyno-Daktarin (Abic/Janssen), Daktazole (jock itch), Tinea corporis (ringworm) and (JePharm), Fungazole (Pharmacare), Fungitirin vaginal and cutaneous candidas. (BPC). • CONTRAINDICATIONS: ______Hypersensitivity to miconazole. • DOSAGE FORMS: 2) Ketoconazole Cream, powder, lotion, oral gel; suppositories/ ovules and cream for vaginal • DRUG SUMMARY: use. Ketoconazole is another imidazole broad- • RECOMMENDED DOSAGE: spectrum antifungal agent. It works by Directions: Apply to affected skin areas altering the permeability of the cell twice a day (morning and night) for 2 membrane of different types of fungus and weeks. If treating tinea pedis use for 1 yeast. It is significantly better absorbed month. after oral administration than other *For vaginal use: use supp./ovules daily at imidazoles, but has been associated with bedtime for 3 days; cream twice a day, for hepatotoxicity. 7 days. • INDICATIONS: *For external use only. Avoid contact with Cream: for the treatment of tinea corporis the eyes. (ringworm), tinea cruris (jock itch) and • USE IN SPECIAL CASES: timea pedis (athlete’s foot). Pregnancy- Avoid unless clearly needed Shampoo: reduction of scaling due to (Category B), specially in first trimester. dandruff, seborrhoic dermatitis and There have been reports of birth defects (i.e. Pityriasis versicolor (Tinea versicolor). cardiovascular, oral clefts, spina bifida and • CONTRAINDICATIONS: hypospadias), observed when product was Hypersensitivity to this group of antifungal used vaginally during the first trimester, but agents. no solid data is available to associate • DOSAGE FORMS: miconazole with congenital defects. Cream, shampoo (both 2%). Lactation- Not enough clinical information is • RECOMMENDED DOSAGE: available, use caution when applying on a *Cream: Apply to affected area and nursing mother. surroundings once daily. Results can be • PRECAUTIONS AND WARNINGS: seen as soon as treatment is initiated. Discontinue if severe irritation occurs. Use for at least 2 weeks to reduce the Vaginal products may interact with latex possibility of recurrence. products including diaphragm and Tenia pedis may require 6 weeks of condoms. Warn patients. treatment. • ADVERSE EFFECTS: When used to treat seborrheic dermatitis it Irritation, burning, and allergic contact should be applied twice a day for up to 4 dermatitis. weeks or when improvement is seen. • INTERACTIONS: *Shampoo: Moisten hair and scalp No drug interactions have been noted with thoroughly with water, then apply a topical use of miconazole. sufficient amount to produce enough lather. • OVERDOSE: Massage throughout the scalp and hair for Refer to the anti-infectives chapter. around one minute. Rinse hair thoroughly with warm water.

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Dermatological Preparations Repeat as before but leave it on for an • OVERDOSE: additional 3 minutes and rinse thoroughly. Shampoo: if ingested, employ supportive Dry hair with towel or warm airflow. measures; gastric lavage with sodium Shampoo hair twice a week for 4 weeks bicarbonate. with at least 3 days between each • BRANDS: shampooing. Nizoral (Abic/Jennsen) For Pityriasis versicolor it should be used ______once daily for five days. *For external use only. Avoid contact with 3) Tolnaftate the eyes. • USE IN SPECIAL CASES: • DRUG SUMMARY: Pregnancy- Use only if the potential benefits Tolnaftate is effective in the treatment of outweigh the potential hazards on the fetus superficial fungus infections of the skin. (Category C); sufficient studies are Because of its superficial action it might be unavailable. administered with oral anti-fungal agents Lactation- Safety has not been established like Griseofulvin [for more information yet. Use caution when used in nursing refer to the anti-infectives chapter], or mothers. Ketoconazole. Children- Safety and efficacy in children has • not been established yet. INDICATIONS: • PRECAUTIONS AND WARNINGS: It is effective for the treatment of Tenia Discontinue if sensitivity reactions occur. pedis (athlete’s foot), Tenia cruris (jock The cream contains sulfites that might itch), and Corporis (ringworm). It can also cause hypersensitivity reactions in be used for preventing superficial fungal susceptible individuals. infections. This agent is not suitable for Shampoo might cause removal of the curls deep infections of the nails or hair follicles. • in permanently waved hair. CONTRAINDICATIONS: • ADVERSE EFFECTS: Hypersensitivity to the drug or product. • Cream: Severe irritation, pruritis, stinging, DOSAGE FORMS: and allergic reactions. Cream, solution, gel, powder (all as 1%). • Shampoo: increase in normal hair loss, RECOMMENDED DOSAGE: abnormal hair texture, irritation, mild Directions: Apply to affected areas twice a dryness of skin, itching, and dryness/ day for 2 to 4 weeks. Only small quantities oiliness of hair and scalp. are required. • INTERACTIONS: *Affected areas should be clean and dry Overview of Ketoconazole before application of the product. Drug-Drug Interaction *For external use only. Drug Interaction *Avoid contact with the eyes. Astemizole These antihistamines should be • PRECAUTIONS AND WARNINGS: and avoided even with the topically If no improvement is seen within 4 weeks, terfenidine administered ketoconazole. patient should be re-evaluated. Severe cardiovascular adverse • ADVERSE EFFECTS: reactions may occur. Mild irritation and allergic reactions might occur (rarely).

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• OVERDOSE: • INDICATIONS: Incidents of toxicity with topical use are Used for infection prophylaxis in minor very rare. If it occurs use symptomatic and cuts, wounds, burns, and skin abrasions. It supportive care. also aids in healing and treating superficial • BRANDS: infections of the skin. Athletes Foot (Scholl), Pitrex (Teva), Tinaderm • CONTRAINDICATIONS: (Shering), Tinasol (Fischer). Hypersensitivity to the drug. ______• DOSAGE FORMS: Ointment. • RECOMMENDED DOSAGE: D) ANTIBACTERIALS Directions: Apply to infected area(s) 1 to 4 times a day. Cover with sterile bandage if Antibacterials are used to treat and prevent needed. topical infections. Different kinds of *For external use only. Not to be used on antibiotics are used depending on the type the eyes; there are special preparations for of organism. Since there are a lot of ophthalmic use. products on the market, remember these • PRECAUTIONS AND WARNINGS: points: Long term use may lead to overgrowth of

• Although topical antibiotics are non-susceptible bacteria or fungi. indicated for infective skin conditions, they Discontinue if redness, irritation, swelling should not be used indiscriminately, thus or pain persists or increases, or if secondary resulting in the emergence of resistant infections occur. The ointment might stain bacterial strains, which precludes future clothes. • systemic use of the antibiotic. Mupirocin ADVERSE EFFECTS: (Bactroban®) is an example of a commonly Yellow to brown stains may occur on the used broad spectrum topical antibiotic skin as mentioned above. Skin irritation which is abused. Resistant Staph. aureus to and rash might occur in some cases. Hyper- mupirocin are emerging. Mupirocin should sensitivity reactions are very common. • not be used as a first-line agent or in BRANDS: hospitals, and should be used when other Jordacycline (Jordan), Oxycin (BPC), Tetracare topicals (i.e. tetracyclines) fail. When used, (Pharmacare), Tetrapharm (JePharm), Teva- cycline Derm (Teva). avoid use for longer than 10 days. • ______Use of combination products of an antibiotic and corticosteroids should be WHO,P avoided in bacterial infections. 2) Neomycin or Gentamicin

• DRUG SUMMARY: Neomycin and Gentamicin are aminogly- 1) Oxytetracycline coside antibiotics that are active against gram negative bacteria as well as • DRUG SUMMARY: Staphylococcus infections. They work by Oxytetracycline is a broad-spectrum inhibiting protein synthesis, they are tetracycline antibiotic that inhibits protein bactericidal. Resistance for neomycin is synthesis. It is usually used in combination very common and limits its use. Because of with polymixin B. Its use may be limited the resistance factor it is mostly used in because it oxidizes and turns the skin combinations with other antibiotics such as yellowish-brown. polymixin B and/or bacitracin. Use of these

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Dermatological Preparations agents on large areas of the skin should be E) ANTIVIRALS avoided especially in children, in the elderly and in those with impaired renal Antiviral drugs should be only function, due to risk of nephrotoxicity and prescribed by a specialist. Cases of ototoxicity. Patients sensitive to neomycin recurrent labial and genital herpes simplex may be treated with gentamicin. should be treated as early as possible. • INDICATIONS: [For more information about systemic Used for the prevention and the treatment antivirals, refer to the anti-infectives chapter.] of infections secondary to minor cuts, wounds, burns, and skin abrasions. 1) Acyclovir • CONTRAINDICATIONS: Hypersensitivity to drug. • DRUG SUMMARY: • DOSAGE FORMS: Acyclovir (also written as aciclovir) is an Cream, ointment. antiviral that inhibits the viral DNA • RECOMMENDED DOSAGE: replication. It is only effective if started at Directions: Apply to infected area(s) 1 to 4 onset of infection. Some decrease in the times a day. Covering the infected area(s) duration of viral shedding has been noted. with sterile bandage is possible. • INDICATIONS: • PRECAUTIONS AND WARNINGS: It is used for the management of initial and -Hypersensitivity reactions are very recurrent episodes of herpes genitalis and in common. genital and labial cases of herpes simplex -Chronic use of topical aminoglycoside viral infections as injection. antibiotics increases the possibility of Acyclovir is not a cure for herpes simplex sensitization. Discontinue use if symptoms infections, it might benefit in treating of hypersensitivity appear. recurrent attacks. • -Use with care in treating burns and trophic CONTRAINDICATIONS: ulceration because it can lead to systemic Hypersensitivity to the drug. • absorption and systemic adverse effects, DOSAGE FORMS: especially in children and in renal impaired Cream, ointment. patients. • RECOMMENDED DOSAGE: • ADVERSE EFFECTS: Directions: Apply to infected area(s) every Ototoxicity and nephrotoxicity are common 3 hours (or 6 times a day) for 7 days. especially if applied to large areas for long Application should start as early as periods of time for this group of drugs. possible (as soon as the signs and Possible photosensitization with gentamicin symptoms occur). has been reported. *Use rubber gloves when applying to • BRANDS: lesions to prevent the spreading of the Garamycin (Schering), Gentatrim (Trima), lesions to other area(s) in the body or Garamine (Jordan Chemical Lab). transmitting the virus to other individuals. ______*The ointment should thoroughly cover all lesions. *For external use only. Avoid use on the eyes; special preparation available for eyes.

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• USE IN SPECIAL CASES: 1) Ethyl Alcohol (Ethanol) P Pregnancy- Use only if the potential benefits outweigh the potential hazards on the fetus • DRUG SUMMARY: (Category C). Well-controlled clinical studies It is a widely used antiseptic and a on pregnant women have not been done. disinfectant that exerts bactericidal and Lactation- It is not known whether it is fungicidal action in concentrations at 70%. excreted in the breast milk. Use caution when In concentrations above 80% its used on nursing mothers. bactericidal effect is low. It has virucidal • PRECAUTIONS AND WARNINGS: action at 90%. It is less effective against Dose should not be exceeded. No data is HBV viruses. available that proves that acyclovir prevents Used as an antiseptic agent before the transmission of the infections to other injections to prevent topical infections. It is people, or prevent recurrence infections not a desirable wound antiseptic because it when applied in the absence of signs and causes irritation in already damaged tissues, symptoms. Not to be used to prevent and may delay healing. recurrent HSV infection. • • CAUTION: The solution is flammable. ADVERSE EFFECTS: Avoid use on broken skin and the eyes. Mild pain, burning/stinging, pruritis, rash, Intended for external use only. and vulvitis. • • ADVERSE EFFECTS: may include BRANDS: local irritation, burning and stinging Virax (BPC), Zovirax (GlaxoWellcome). especially in cases when it is used on open ______wounds or on broken skin. ______

F) ANTISEPTICS/ WHO,P DISINFECTANTS 2) Povidone-Iodine

• DRUG SUMMARY: Antiseptics and disinfectants are generally A disinfectant and antiseptic that is active used to destroy and inhibit the growth of against bacteria, fungi, viruses, protozoa, pathogenic micro-organisms. There is no and cysts. Concentrations of 4-10 % are clear difference between them. available in the market. The term antiseptic is used to a • INDICATIONS: chemical agent that destroys or inhibits As an antiseptic and disinfectant for the micro-organisms on living tissues having treatment and prevention of contaminated the effect of limiting or preventing the wounds and for pre-operative preparation harmful results of infection. of the skin and mucous membranes. It also However a disinfectant is a chemical acts as a disinfectant for the equipment agent that destroys microorganisms, but it used in the operation. does not necessarily kill all the micro- • CONTRAINDICATIONS: organisms, but reduces them to a level that Hypersensitivity to the drug, should not be is not harmful. It can be applied to the used on patients with non-toxic nodular living tissues as well as inanimate objects. colloid goiter.

• DOSAGE FORMS: Solution, powder, ointment (10% povidone iodine=1% iodine).

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Dermatological Preparations • RECOMMENDED DOSAGE: It is susceptible to contamination with Directions: To be applied on the skin or micro-organisms therefore precautionary mucous membrane. Ointment maybe measures should be taken. Avoid use in applied to affected area 2-4 times daily. body cavities. *Disinfecting the equipment should be Hypersensitivity reactions are common done according to regular protocols taken after repeated use. by the institution. • ADVERSE EFFECTS: *For external use only, not to be applied on Irritation is possible but rare. It usually open skin. Avoid contact with the eye(s). occurs after several applications. There • PRECAUTIONS AND WARNINGS: have been rare reports of burns due to Avoid use in pregnancy and lactation. concentrated solutions of cetrimide. Neonatal hypothyroidism has been • OVERDOSE: reported. If ingested, cetrimide causes nausea, • ADVERSE EFFECTS: vomiting, esophageal damage and necrosis. Local irritation, itching, and pruritis are It can also cause cyanosis, depression of the possible but rare. When applied to severe CNS, hypotension, coma, and it might lead burns or to large areas systemic adverse to death. Treat ingestion by treating the reactions might occur. symptoms, avoid emesis and lavage. • BRANDS: • BRANDS: Betadine (Rafa), Iodocare (Pharmacare), Iodo- Capillon (Gramse), Cetrimide (Vitamed). Vit (Vitamed), Polydine (Fischer). (refer to the price list for other products) ______

3) Cetrimide 4) Chlorhexidine WHO,P

• DRUG SUMMARY: • DRUG SUMMARY: Cetrimide is an antiseptic with great It is an antiseptic and a disinfectant bacterial activity against gram-positive effective against a wide range of bacteria bacteria. In higher concentrations it is (excluding bacteria that cause tuberculosis), active against gram-negative bacteria. It has fungi, and viruses. It is available as a variable activity against fungus and viruses. gluconate and an acetate salt. • INDICATIONS: • INDICATIONS: It is used as an antiseptic for cleansing skin, Used to disinfect the skin, wounds, burns, wounds, and burns. It is mainly used in and to clean instruments and hard surfaces. combination with other agents like It is used as a surgical scrub, hand rinse and chlorhexidine (explained below). It is also a wipes. The chlorhexidine wipes are used as component of some shampoos to remove a cleanser for acne vulgaris. It is also used scales in seborrhea. as a mouthwash to prevent gingivitis and to • CONTRAINDICATIONS: prevent plaque. Hypersensitivity to the drug. It is found in combinations with other • DOSAGE FORMS: antiseptics especially cetrimide (refer to Solution: 0.1-1% (further dilution is required cetrimide). before use), cream: 0.5% • CONTRAINDICATIONS: • PRECAUTIONS AND WARNINGS: Hypersensitivity to the drug. For external use only. Avoid contact with • DOSAGE FORMS: the eyes. Solution, mouthwash, dental gel, cream.

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• RECOMMENDED DOSAGE: G) ANTIPARASITICS *As a disinfectant: for emergency disinfection of clean instruments, emerse Scabies: It is a parasitic skin infestation the instruments in a 0.5% solution of the caused by Sarcoptes scabiei. It burrows gluconate or the acetate mixed with 70% itself beneath the stratum corneum. It does alcohol. For storage and disinfection not bite or sting, but it is characterized by emerse for 30 minutes in 0.05% solution. secondary inflammation and intense *As an antiseptic: chlorhexidine gluconate itching. It is usually associated with poor (0.05% aqueous solution) is used to hygiene, crowded conditions, and venereal disinfect wounds, burns, and other damaged disease. It is usually transmitted through skin disorders. bodily contact with an infested host, *As a mouthwash: 0.2% chlorhexidine clothing, bedding or toilet use. gluconate is used twice a day after brushing Pediculosis: is an infestation with lice. and flossing. There are three types: Pediculosis capitis *As a dental gel: 1% chlorhexidine caused by head louse, Pediculosis corporis gluconate is used after brushing with the caused by body louse and Pediculosis pubis normal tooth paste twice a day. caused by crab louse.

*For external use only. In treating infected patients it is important *Keep out of the eyes and ears (when using to examine contacts for evidence of the topical solution). infection and treat accordingly. Emphasis *Avoid exposing it to excessive heat. on proper hygiene (i.e. changing sheets and • USE IN SPECIAL CASES: towels) for preventing reinfestation is Pregnancy- Use with caution. No data is essential. It may be recommended to treat available about the use of chlorhexidine in family members in close contact for pregnant women. preventive measures. Lactation- Use with caution. There has been some reports about the excretion of Scabicides and Pediculicides are used for chlorhexidine in breast milk. Use only therapy of these infections. when the benefit of its use outweighs the risk on the infant. 1) SCABICIDES • PRECAUTIONS AND WARNINGS: -Do not use on a regular basis on wounds a) Benzyl Benzoate WHO,P involving more than the superficial layer of the skin. It might cause deafness if applied • INDICATIONS: in the middle ear. It is used in the eradication of scabies. It is -When using the mouthwash do not also used as a pediculicide. swallow solution, only use it as a gargle. • CONTRAINDICATIONS: • ADVERSE EFFECTS: Hypersensitivity to the drug. Irritation, dermatitis, photosensitivity, and • deafness. DOSAGE FORMS: • Lotions and emulsions. BRANDS: • Bactosept concentrate/ Bactroscrub (Vitamide), RECOMMENDED DOSAGE: Uniscrub (Seton). Apply to the whole body from the neck ______down after a bath. Directions: *The concentrated lotion is applied to adults, while the diluted lotion is required for infants and children (other products are preferred for their use).

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Dermatological Preparations Individual product instructions should be cleansing bath is required after 48 hours followed. Another coat may be applied after the last application. when the first application dries up. *Change clothing and linen the next *The residue should be washed off after 24 morning to prevent reinfestation. hours. *For external use only. *A second application may be required • USE IN SPECIAL CASES: after 5 days. Pregnancy- Avoid use. It is not known *Clothing and bedding should be cleaned in whether it can cause fetal harm, use on boiling water to prevent re-infestation. pregnant women only if clearly needed • PRECAUTIONS AND WARNINGS: (Category C). For external use only. Avoid contact with Lactation- Use caution. No clinical studies the eye(s) and face. are available concerning the use of it in Safety for use in pregnancy (Category C) breast-feeding mothers. and lactation is not established. Use only if Children- Safety and efficacy for use in clearly needed. children have not been established. • ADVERSE EFFECTS: • PRECAUTIONS AND WARNINGS: It might irritate the skin, mucous membrane Do not apply to acutely inflamed skin, the and the eye(s). eyes or mouth. If severe irritation occurs • OVERDOSE: discontinue use. Do not apply near the If ingested, it stimulates the CNS and eyes, mouth, and mucous membrane. causes convulsions. • ADVERSE EFFECTS: Treatment involves gastric lavage and Local irritation and allergic sensitivity symptomatic measures. reactions might occur. • BRANDS: • OVERDOSE: Benzocide (Trima), Scabicide (BPC), Scabiex If ingested it can cause convulsions, (Rekah). nausea, vomiting, abdominal pain, burning ______and irritation of oral esophageal and gastric mucousa. Do not induce vomiting. Take to b) Crotamiton the hospital for supportive and symptomatic care. When applying large amounts • DRUG SUMMARY: of it topically to children it might cause It is used as an antipruritic for itch due to cyanosis. • scabicides, however, it is not really known BRANDS: how it exerts its effect. Crutex (BPC), Eurax (Novartis C.H.), Scabicin (Fischer). • INDICATIONS: ______Used for the eradication of scabies and symptomatic treatment of pruritis due to scabies. • CONTRAINDICATIONS: Hypersensitivity to the drug. • DOSAGE FORMS: Cream, lotion. • RECOMMENDED DOSAGE: Directions: After bathing, apply to the whole body from the neck down. A second application is advisable in 24 hours. A

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2) PEDICULICIDES • ADVERSE EFFECTS: Irritation of the scalp has occurred. Other a) Malathion adverse effects are rare. • INTERACTIONS:

• Exposure to carbamate or organo- DRUG SUMMARY: phosphate-type insecticides or pesticides Malathion is a lousicidal and ovicidal that when using malathion may increase the is dispensed by prescription only. The possibility of systemic absorption. Advise advantage of its use is that it is less toxic patients using malathion to protect them- than other products because it rapidly selves from these insecticides or pesticides. hydrolyzes and detoxifies. Other interactions are possible if per- • INDICATIONS: cutaneous absorption of malathion occurs. Treatment of head lice and their ova. • OVERDOSE: • CONTRAINDICATIONS: Oral ingestion of malathion may cause Sensitivity to it or any of its products. systemic adverse reactions. These reactions • DOSAGE FORMS: are delayed reactions that can occur 12 Lotion 0.5%. hours after ingestion. • RECOMMENDED DOSAGE: Symptoms of overdose include- Abdominal Directions: Apply to dry hair and rub cramps, anxiety, unsteadiness, confusion, gently until the scalp moistens. Allow it to diarrhea, labored breathing, dizziness, dry naturally. Do not cover or use any watery eyes, pinpoint pupil, seizures and heat to dry it up. After 8 to 12 hours rinse bradycardia. hair and apply a non-medicated shampoo. Treatment- Induce vomiting promptly or Rinse, then comb hair with a fine toothed lavage the stomach with 5 % sodium comb to remove dead lice and eggs. Repeat bicarbonate solution. within 7 to 9 days if required. Severe respiratory distress is one of the • USE IN SPECIAL CASES: most serious overdose symptoms, requiring Pregnancy- Use during pregnancy only if artificial respiration and doses of IV or IM clearly needed (Category B). atropine. Lactation- Exercise caution when using in Patient should be observed continuously for nursing mothers. It is not known whether it is signs of deterioration due to delayed excreted in breast milk. absorption. Children- Safety and efficacy in children < 2 • BRANDS: years of age have not been established. Nouryl (Chefaro), Prioderm (NAPP/Rafa). However the use of it in children between the ______ages of 2 and 11 years of age had shown no documented problems. • PRECAUTIONS AND WARNINGS: b) Lindane -It contains flammable alcohol. The lotion • should not be exposed to open flames or DRUG SUMMARY: electric heat. Do not smoke while applying Lindane (Gamma Benzene Hexachloride) is lotion or while hair is wet. an ectoparasiticide and an ovicide; kills scabies and their eggs. It is not used for -For external use only. Avoid contact with nd the eyes. If it gets in the eye accidentally, prevention. It is a 2 line treatement for flush immediately with running water. those who cannot tolerate other safer agents, or treatment with other products has failed.

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Dermatological Preparations • INDICATIONS: • USE IN SPECIAL CASES: Treatment of Pediculus capitis (head lice) Pregnancy- It should not be used more than and Pediculus pubis (crab lice) and their once during pregnancy. There are no ova. The cream and lotion are also adequate studies in pregnant women, but use indicated for scabies. is not contraindicated (Category B). • CONTRAINDICATIONS: Lactation- Lindane is secreted in breast milk Hypersensitivity to the active ingredient or in low concentrations when applied. The low the product. It is also contraindicated in concentrations make it unlikely that it will neonates since it is easily absorbed from cause serious adverse reactions. If necessary, advise the patient to use an alternative their skin, and in patients with known method of feeding for 2 days. seizures disorders. • Children- Contraindicated in neonates. In DOSAGE FORMS: young children, lindane tends to get absorbed Lotion, cream, shampoo (all as 1%). from the skin more than in adults. There is a • RECOMMENDED DOSAGE: potential of CNS toxicity when it is applied Rubber gloves should be worn during the topically. Seizures have occurred after application of lindane products. excessive use or ingestion of lindane. It *Cream and lotion: Scabies- Apply a thin should not be used prophylactically. layer to dry skin, to the whole body from • PRECAUTIONS AND WARNINGS: the neck down, rub thoroughly. Leave on For external use only as directed. for 8 to 12 hours then wash thoroughly with Use extreme caution in elderly or patients warm water (not hot). One application weighing less than 50 kg (110 lbs). should be curative. Avoid contact with the eyes or face, if it *Lotion: Pediculosis Pubis- Apply a occurs flush eyes or face with water sufficient quantity to cover the hair and the immediately. Avoid use on open cuts or skin in the pubic area and other infested broken skin. areas like the thighs, trunk and axillary Oils and creams used simultaneously with region. Leave in place for 12 hours then lindane can enhance its absorption. If an wash thoroughly. Reapplication is not oil based product is used on the hair, it necessary unless living lice is found. It can should be washed out and hair should be be reapplied after 7 days. Sexual partner dried before using lindane. should be treated concurrently. • ADVERSE EFFECTS: *Lotion: Pediculosis Capitis- Apply a Adverse reactions include: CNS adverse sufficient quantity to cover the affected effects ranging from dizziness to areas. Rub into the scalp and hair and leave seizures/convulsions and death (especially in place for 12 hours then wash thoroughly. after misuse of the product). Reapplication is not necessary unless living Irritation from lindane can cause lice is found. It can be reapplied after 7 eczematous eruptions. days. Itching, redness, swelling, burning or skin *Shampoo: Pediculosis Capitis and Pubis- rash may occur, and must not be confused Apply a sufficient quantity to dry hair. with ineffective treatment. Work thoroughly into the hair and keep in • OVERDOSE: place for 4 minutes. Add small amounts of As mentioned above, CNS adverse water until a lather forms. Rinse hair and reactions occur after extensive use or oral then towel dry. Comb hair with a fine ingestion of lindane causing seizure attacks toothed comb, to remove the nits and nit and even death. shells. Treatment of the overdose includes gastric lavage, or speed gastric emptying by using

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saline cathartics. Treat seizure attacks with • RECOMMENDED DOSAGE: phenobarbital or diazepam. For specific instructions for use of these • BRANDS: products, refer to individual product Bicide (Fischer), Parazine (Al-Razi). labeling by the manufacturer. ______Directions: For external use only. *Soak the affected area with warm water for 5 minutes before application to enhance H) KERATOLYTIC AGENTS the effect. Then apply to affected area. Remove any loose tissue with brush or A keratolytic agent is an agent used to cloth then dry thoroughly. dissolve or break down keratin. These *If treating warts, improvement should agents are used for several skin conditions occur in 1 or 2 weeks and maximum results including warts, corns, seborrhea, and even should be expected in 4 to 6 weeks. Some used in some anti-dandruff products. warts might take up to 12 weeks to go away. Apply only on the wart or affected area. Avoid application to the skin 1) Salicylic Acid WHO surrounding it. • USE IN SPECIAL CASES: • DRUG SUMMARY: Pregnancy- Use during pregnancy if the A keratolytic agent that is considered safe potential benefits outweigh the potential risks on the fetus (Category C). There are no and effective. It produces desquamation of adequate studies in pregnant women. the horny layer of skin, while not affecting Lactation- Use with caution. No well- the structure of the epidermis. It causes the controlled studies have been performed to epithelium to swell, soften, macerate and prove if topical salicylic acid is excreted in then desquamate. breast milk. • INDICATIONS: • PRECAUTIONS AND WARNINGS: Salicylic Acid is used as an aid in the Avoid contact with the eyes, mucous removal of extra keratin in hyperkeratotic membranes, and normal skin surrounding skin disorders, such as plantar warts, the warts. If contact with eyes or mucous psoriasis, calluses and corns. It is also used membranes occurs, immediately flush with alone or in combinations to treat dandruff, water for 15 minutes. seborrheic dermatitis, acne, and tinea Avoid inhaling salicylic acid vapor. infections. Prolonged use over large areas especially in • CONTRAINDICATIONS: young children and patients with hepatic or Hypersensitivity to salicylic acid or any of renal impairment may cause salicylate its components. toxicity (for more details refer to overdose). It is also contraindicated in infants, • ADVERSE EFFECTS: diabetics, and patients with impaired Local irritation may occur from contact circulation. It should not be used for with normal skin surrounding the affected birthmarks or warts with hair growing from area. If irritation occurs, temporarily them, genital or facial warts, or warts on discontinue then resume use with caution. mucous membranes. It should not be used • INTERACTIONS: on broken, irritated or infected skin. Interactions have been reported with the • DOSAGE FORMS: use of topical salicylates. Solution 17%, ointment 3%, cream 2%, gel [Refer to the NSAIDs chapter for more details.] 17%.

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Dermatological Preparations • OVERDOSE: eczema the patient has. In the initial stages, Salicylate toxicity may occur with before starting the treatment, one should prolonged use especially in young children find out the cause of these conditions. Then or with patients with renal or hepatic the first step is to avoid the causative impairment. agent. Be aware of the symptoms of salicylate Agents that can be used in treating the toxicity that includes: nausea, vomiting, dermatitis include: dizziness, loss of hearing, tinnitis, lethargy, 1. Bath products/oatmeal baths and oil baths hyperpnea, diarrhea, and psychic (mineral or vegetable oil) disturbances. Discontinue use of the drug. 2. Emollients and moisturizers (vaseline, • BRANDS: petrolatum or lanolin) Oxy-clean (SK-Beecham), Salatac (Dermal 3. Astringents (witch hazel) Labs), Zino Pads (Scholl), Salisol-2 (Rekah). 4. Antipruritics and protectants (zinc oxide ______and calamine) 5. Keratin-softening agents (urea and alpha hydroxy-acid/ lactic acid). 2) Sulfur Patients with moderate to severe • DRUG SUMMARY: conditions should be referred to a Sulfur is a keratolytic agent that provides dermatologist for initiation of appropriate peeling and drying actions. It is also a mild therapy. Avoid use of topical cortico- antiseptic, a mild antifungal and a steroids at the primary care level, especially in infants and children. parasiticide. Because of these properties ______this agent is found in many preparations combined with other drugs for the b) PREPARATIONS FOR treatment of acne, dandruff, seborrhoeic conditions, scabies, and superficial fungal PSORIASIS: infections. It is also used in some creams Psoriasis is a chronic recurrent disease for oily skin. characterized by dry silvery scaling plaques It can cause hypersensitivity reactions as of various sizes. Under these plaques there well as discoloration of certain metals, so are flat topped pink/red lesions. Lesions use caution when applied. appear in small areas of the body for short ______periods of time with unpredictable remissions and exacerbations. Since there I) MISCELLANEOUS are several types of psoriasis, this skin disorder is better managed by a a) PREPARATIONS FOR dermatologist, to avoid misdiagnosis and further complications. ECZEMA: The duration of psoriasis is variable.

Eczema is a superficial skin disorder Lesions may last a lifetime or may characterized by redness, edema, oozing, disappear quickly causing either hypo- crusting, scaling and itching. Eczema and pigmentation or hyper-pigmentation. dermatitis are usually used interchange- The most important factor in the ably. Causes of eczema/dermatitis include: treatment of psoriasis is to relieve its allergens, irritants, infections and in some symptoms. The agents available do not cases the cause is unknown. cure psoriasis, they only reduce its severity The treatment of such conditions and its symptoms. The most common depends on the cause and the type of symptom of psoriasis is dry skin

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accompanied with pruritis. Gentle rubbing Topical steroids are used for the of emollients with or without hydrating management of seborrhea in cases when all agents, or oatmeal baths might help ease the other shampoos did not work. the itching and remove the scales. Hydrocortisone lotion for example should Each stage of the disease is treated be applied once daily until the symptoms differently. Acute psoriatic onset, decrease then used intermittently to avoid characterized by severe erythematous exacerbation. Long term use of lesions, calls for soothing local therapy hydrocortisone is not recommended. A with emollients. Tars, salicylic acid, and more potent topical steroid is sometimes aggressive UV radiation therapy must be indicated when hydrocortisone fails to avoided at this stage because of potential work. irritant effect. As the acute process subsides and the usual thick-scaled plaques appear, 1) TOPICAL CORTICOSTEROIDS more potent therapy with agents such as keratolytics may be used. • DRUG SUMMARY: Topical corticosteroids are a group of c) PREPARATIONS FOR agents used for their anti-inflammatory SEBORRHEA: activities. They act against most causes of inflammation including mechanical, Seborrhea is a form of dermatitis chemical microbiological and immuno- characterized by a group of eruptions logical. When applied to an inflamed site it occurring in the areas of the greatest causes a decrease in edema, erythema and sebaceous gland (i.e. the scalp, face, and pruritis. Most available products used trunk). contain Betamethasone. Seborrhea usually occurs in hairy areas especially in the scalp; it appears like a dull Betamethasone Valerate WHO,P yellowish-red lesion with oily appearing scales. Pruritis is very common. There are • INDICATIONS: many different kinds of seborrhea including Betamethasone is used in relieving seborrhea capitis; which is the most inflammations and pruritis for different common type of seborrhea. Seborrhea forms of dermatitis, eczema, psoriasis, and might occur in newborns and infants during first- and second-degree burns. It can be the first 12 weeks of life and it is called used alone or as adjunctive treatment cradle cap. It often clears up by 8-12 depending on the case. months of age. Seborrhea is sometimes Corticosteroids in combination with considered as an extension of dandruff. antifungals to relieve yeast infections, and However, dandruff is considered as a stable with antibiotics to relieve secondary condition while seborrhea fluctuates in dermatoses are marketed. But combination severity. products of these should be avoided unless The treatment of seborrhea is generally clearly indicated. the same as dandruff but with some Different bases (like ointment, cream, lotion, exceptions. Frequent cleansing with a non- gel ...etc.) might change the potency and the medicated shampoo should be tried first. indication of the agent (refer to table-11.1). If there is no response, seborrhea should be • CONTRAINDICATIONS: treated with shampoos containing Hypersensitivity to any corticosteroid. pyrithione zinc, selenium sulfide, salicylic Monotherapy in primary bacterial acid and coal tar. infections such as impetigo, paryonchia,

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Dermatological Preparations erysipelas, cellulitis, angular cheilitis, administration to the least amount compatible erythrasma, treatment of rosacea, perioral with effective therapy. Chronic corticosteroid dermatitis or acne; use on the face, groin or therapy may interfere with the growth and axilla; and prolonged ophthalmic use. development of children. • DOSAGE FORMS: • PRECAUTIONS AND WARNINGS: Refer to table-11.1. -Systemic absorption of topical cortico- • RECOMMENDED DOSAGE: steroids has produced reversible HPA axis Directions: To be applied sparingly to suppression, Cushing’s syndrome, hyper- affected areas 2 to 4 times a day. glycemia and glycosuria. Conditions that *For external use only. Avoid contact with increase systemic absorption include: the eyes unless indicated. application of potent corticosteroids, use *Some studies show that applying cortico- over large areas, prolonged use, and steroids once or twice a day is as effective occlusive dressings. as three or more. Some researches advise -Local irritation may occur and requires applying it twice a day until clinical discontinuation of the agent. Allergic response is achieved and then only as contact dermatitis might develop especially frequently as needed to control the when applied to dry skin or open wounds. condition. Avoid using potent corticosteroids on the *Short term or intermittent therapy (every face, groin and axillae. It might result in other day, or once a week, or 3 to 4 atrophic changes. consecutive days per week) may be more -Do not use topical corticosteroids as sole effective and cause fewer adverse effects therapy on widespread plaque psoriasis. It than continuous regimens using lower has been reported that withdrawal of the potency products. treatment of psoriasis with corticosteroids *Use low potency agents in children, on may provoke pustular psoriasis. large areas, and on body sites especially -The use of corticosteroids on infection prone to steroid damage such as face, sites might worsen the infection. scrotum, axilla, flexures and skin folds. Discontinue the use of corticosteroids and Reserve higher potency agents for areas apply an antifungal or an antibacterial and conditions resistant to treatment with agent. milder agents. -Occlusive dressings might increase the • USE IN SPECIAL CASES: chance of bacterial infections. Use Pregnancy- Use in pregnancy only if the appropriate measures. potential benefits outweigh the potential • ADVERSE EFFECTS: hazards on the fetus (Category C). Local burning, itching, irritation, erythema, Corticosteroids are teratogenic in animals dryness, pruritis, hypopigmentation, when administered systemically at relatively allergic contact dermatitis, numbness of low dosages. The more potent corticosteroids fingers, stinging, cracking, skin atrophy, are teratogenic after dermal application in secondary infections, maceration of the animals. No well-controlled studies have been skin. done on pregnant women. Prolonged application around the eyes can Lactation- Exercise caution. It is not known cause cataracts, and glaucoma. whether topical corticosteroids could result in sufficient systemic absorption to produce (Systemic adverse reactions are common. detectable quantities in breast milk. Refer to Chapter 1: anti-inflammatories Children- Children may be more susceptible drugs for more details.) to topical corticosteroid-induced HPA axis suppression and Cushing-syndrome. Limit

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Table–11.1: Relative Potency of Selected Topical Corticosteroidal Products CONCENT- DRUG DOSAGE FORM RATION I. Very High potency Augmented betamethasone dipropionate Ointment 0.05% Clobetasol propionate Cream, Ointment 0.05% Diflorasone diacetate Ointment 0.05% II. High potency Augmented betamethasone dipropionate Cream 0.05% Betamethasone dipropionate Cream, Ointment 0.05% Bethamethasone valerate Ointment 0.1% Diflorasone diacetate Cream, Ointment (emollient base) 0.05% Fluocinonide Cream, Ointment, Gel 0.05% Fluocinolone acetonide Cream 0.2% Triamcinolone acetonide Ointment 0.1% Desoximetasone Cream, Ointment 0.25% Gel 0.05% III. Medium potency Betamethasone dipropionate Lotion 0.05% Betamethasone valerate Cream 0.1% Fluocinolone acetonide Cream, Ointment 0.025% Triamcinolone acetonide Cream , Ointment 0.025% Lotion 0.1% Cream, Ointment 0.5% Fluticasone propionate Lotion 0.05% Cream, Ointment 0.005% Desoximethasone Cream, 0.05% Ointment Cream IV. Low potency Desonide Cream 0.05% Dexamethasone sodium phosphate Cream 0.1% Fluocinolone acetonide Cream, Solution 0.01% Hydrocortisone Lotion 0.25% Solution 1% Cream, Ointment 0.5%, 1%, Hydrocortisone acetate Lotion 2.5% Cream, Ointment 0.5%, 1% * Drug Facts and Comparisons, 2000:1633-34.

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Dermatological Preparations 2) PREPARATIONS FOR ACNE Retinoic Acid (Tretinoin)

Acne vulgaris is the most common • DRUG SUMMARY: adolescent skin disorder. It is an Retinoic acid is a vitamin A acid with an inflammatory pilosebaceous disease that unknown mode of action. It is reported that involves oil glands and hair follicles of the it increases the turnover of follicular skin, primarily on the face and trunk. Acne epithelial cells and stimulates mitotic occurs due to an interaction between activity. hormones, keratinization, sebum, and • INDICATIONS: bacteria which determines the severity of Used for topical treatment of acne vulgaris. the acne. Acne is rarely cured, but its It can also be used to improve spots and symptoms can be controlled. Agents will wrinkles. reduce symptoms and minimize permanent • CONTRAINDICATIONS: scarring. Hypersensitivity to it or any of its The management of acne depends on its metabolites. severity. Some researches indicate that • DOSAGE FORMS: acne can be aggravated by different kinds Cream, gel, solution. of food such as peanuts, chocolate, fats and • RECOMMENDED DOSAGE: carbohydrates in an indirect way. So dietary Directions: Apply once a day, before restrictions can be the first step in the bedtime, to the entire affected area. Hands management of acne. The skin should be should be washed thoroughly after cleansed from excess sebum, the ducts applying. should be unblocked, and the pilo- *If irritation occurs after application, apply sebaceous orifice should not be closed. The every other day to minimize the irritation. patient should avoid any cosmetics that are Local erythema and peeling might occur at oil based. The agents that can be used can the application site. be either topical or oral agents depending *During the early weeks of therapy, on the severity of the lesions. exacerbation of inflammatory lesions may There is another kind of acne called occur due to the action of the medication on ‘deep’ acne, which causes deep lesions and deep, previously undetected lesions; which requires vigorous treatment. In these cases is not a reason to discontinue therapy. a referral to a dermatologist is required to *Therapeutic results should be seen after 2 decrease scarring and help prevent further to 3 weeks, but in some cases it might take lesions. Oral antibiotics and isotretinoin up to 6 weeks. might be required. *Patients may use cosmetics, but the face The treatment of acne depends on the should be washed out and cleansed before severity of the condition. Superficial acne applying Tretinoin. may be treated with washing the affected *Keep away from the eyes, mouth, angles areas at least twice a day with medicated or of the nose, and mucous membranes. non-medicated soap. For more complicated • USE IN SPECIAL CASES: cases or in cases of superfacial pustular Pregnancy- Elevated serum concentrations of acne refer the patient to a dermatologist. retinoic acid in early gestation are considered teratogenic in humans. Because topical In this section the most used products preparation administration (if occlusive for the treatment of acne are discussed. dressings are not used) has relatively poor systemic absorption, it is thought not to be of significant risk to the fetus. Congenital

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malformations have rarely been reported • BRANDS: following topical use, but without conclusive Locacid (Fabre/Mediline), Retavit (CTI/CTS), evidence. Use should be avoided (Category Retin-A (Cilag/JC Health Care). C). ______Lactation- Exercise caution. It is not known whether topical corticosteroids could result in Benzoyl Perxoide sufficient systemic absorption to produce detectable quantities in breast milk. The • DRUG SUMMARY: minimal absorption that could result precludes any clinically significant amounts Benzoyl peroxide is an antibacterial agent. in breast milk. It is preferably to avoid use. It removes excess sebum, reduces fatty • PRECAUTIONS AND WARNINGS: acids and lipids produced by the causative -Avoid excessive application since it might bacteria, and causes peeling and drying. • worsen the condition. Application of a thin INDICATIONS: layer on the affected area should be enough Treatment of mild to moderate acne to give good results. vulgaris and oily skin. It might be used in -Sun exposure should be minimized or severe acne as an adjunct with other agents avoided when applying tretinoin. such as antibiotics, sulfur/salicylic acid Sunscreen products are recommended to preparations. • avoid sunburns and irritation. CONTRAINDICATIONS: • ADVERSE EFFECTS: Hypersensitivity to the drug. Patients Sensitive skin may become red, inflamed, allergic to benzoic acid or its derivatives and blistered. Discontinuation of tretinoin might be allergic to benzoyl peroxide. • is advised until the skin improves. DOSAGE FORMS: Decreasing the frequency of application Liquid: 2.5%, 5%, 10% (used as wash). might be helpful. • RECOMMENDED DOSAGE: Temporary hyper- or hypo-pigmentation is Directions: Prior washing of the affected possible. All adverse effects have been area with medicated or non-medicated soap reversible upon discontinuation. is required. • INTERACTIONS: *For external use only. Avoid contact with Significant skin irritation might occur when the eyelids, lips, mucous membranes and using other anti-acne topical products such damaged skin. as sulfur, benzoyl peroxide, or salicylic *When used as a cleanser, wash once or acid. twice a day, rinse thoroughly and pat dry. Medicated soaps, cleansers, and astringents *Control the amount of drying and peeling containing high percentage of alcohol, by modifying dose frequency or might have an extensive drying effect concentration. which might increase irritation and interact *When used as the primary treatment of with tretinoin. acne: apply once daily; gradually increase • OVERDOSE: to 2-3 times a day if needed. If excessive Oral ingestion of tretinoin may lead to the dryness occurs, dosage should be reduced. same side effects as those of vitamin A oral *In some cases severe irritation might intake. (for more details refer to the develop causing discontinuation of therapy vitamins & minerals chapter.) until the irritation clears. Resume therapy with less frequent application. • USE IN SPECIAL CASES: Pregnancy- Use in pregnant women only if clearly needed. It is not known whether

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Dermatological Preparations benzoyl peroxide can cause fetal harm when safer than UVB. UVB was known as used by pregnant women (Category C). tanning vs. UVB which was burning. Now, Regular use should be avoided. it is realized that UVA is just as damaging. Lactation- It is not known whether benzoyl UVB radiation is absorbed primarily by the peroxide is excreted in breast milk. epidermis, while the longer wavelengths of Administer with caution to nursing mothers. UVA penetrate the skin more deeply-into Children- Safety and efficacy in children the dermis-where they may damage under 12 yrs. have not been established. underlying structures including blood • PRECAUTIONS AND WARNINGS: vessels. -Benzoyl peroxide is an oxidizing agent Protection from UV rays can be that might bleach the hair or colored fabric. achieved by three means: avoiding -Some of these products contain sulfites, exposure to sunlight; by remaining out of which might cause allergic reactions in the sun, covering the skin with protective susceptible patients. Use caution or avoid clothing, and using chemical agents on the its use in patients allergic to sulfites. skin to absorb or block solar rays. -Some studies indicate that it is a tumor Chemical agents that block or absorb promoter, however, there is no evidence UV rays have been categorized traditionally that the drug is a carcinogen in humans. as physical (inorganic) sunblocks or • ADVERSE EFFECTS: chemical organic sunscreens (see table Excessive drying, peeling, erythema, and 11.2). This is based on their mechanism of possible edema. Allergic contact dermatitis action in protecting the skin against UV has occurred in some cases. radiation. • INTERACTIONS: Physical sunscreens are opaque Tretinoin use with benzoyl peroxide might formulations that reflect, scatter, absorb, cause excessive skin irritation. and/or physically block radiation. They are • OVERDOSE: important because they block the entire UV Symptoms include: excessive scaling, spectrum. They are best used in protecting erythema or edema. localized, sun sensitive areas such as the Treatment of overdose starts by nose, lips, nasal mucosa, and shoulder. discontinuing of application. Reinstate Their effectiveness depends on the application at reduced dosage after signs thickness of application. They can be messy and symptoms disappear. To increase the and cosmetically unappealing for healing of the irritation, use emollients and application over large areas of the body. cool compresses or topical corticosteroids Chemical sunscreens work by absorbing in severe cases. and thus blocking the transmission of UV • BRANDS: radiation to the epidermis. These are more Acne Mask (Neutrogena/Lapidot), Akneroxid varied in characteristics than physical (Hermal Chemie), OXY (SK-Beecham). sunscreens. They can be useful for daily ______application over a prolonged period and most are cosmetically acceptable 3) SUNSCREENS preparations. Products available contain combinations Ultraviolet (UV) light is the most energetic of these agents to cover most UV radiation. and thus potentially the most damaging to Sunscreens are divided into different human skin. UV light is differentiated into kinds or strengths depending on the Sun UVC (200-290 nm), UVB (290-320), and Protection Factor (SPF). The SPF is the UVA rays (320-400 nm). Traditional sunscreen’s effectiveness in protecting thinking has long held that UVA was much against sunburn; the SPF value is the length

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of time an individual may be exposed to (very water-resistant), depending on the UV radiation when a sunscreen is applied, ability to bind to the skin, and their compared to when it is not, and not get resistance to removal by sweating, exercise burned (minimal erythema). The range or swimming (substantivity). Water- extends from a value of 2 (minimal) to (45 resistant products remain effective in water ultra-high protection). An SPF-15 for at least 40 minutes, while water-proof sunscreen absorbs 93% of UV radiation, last 80 minutes. while increasing the SPF to 30 raises it to Advise people to use sunscreens 96.7%. correctly, since many use an insufficient Skin types differ from person to person. quantity resulting in less than expected That is why there are different types of protection. Application should be 15-30 sunscreens to suit these different types of min before going into the sun, and skin. Also, certain medication use (table reapplied 3-4 times if exercising outdoors 11.3) can cause photosensitivity (photo- or swimming. Cotton clothes provide best allergy or phototoxicity) that one should protection as long as they don’t become caution patients about, and advise use of wet. Protection is needed even on cloudy protective sun measures. days because 60-80 % of UV rays can pass Sunscreen products maybe used safely through clouds. on infants younger than 6 months of age when adequate clothing and shading are not Topical sunscreen products are available. considered complementary drugs in the It is also important to note that products WHO essential drug list, without any are labeled as water-resistant or water-proof specific agents listed.

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Table 11.2: Available Physical (Inorganic) and Organic Sunscreens * Range of Physical Agents Special notes protection Titanium dioxide 290-700 nm Provide best protection against UV light from reaching the skin. They can cause folliculitis, Zinc Oxide 290-700 nm acne, and may stain clothing. Organic Sunscreen Agents Provide acceptable efficacy against UVB, but Aminobenzoic acid (PABA) 260-313 nm transmits most UVA. PABA esters: Esters are more acceptable products because Padimate O 290-315 nm they are less irritating and can be more substantive. Cinnamates: Their effectiveness depends mainly on the Octylmethoxycinnamate 280-310 nm properties of the vehicle used. May cause or Cinoxate 270-328 nm aggravate eczema or acne. Salicylates: They are week sunscreens, therefore must be Homosalicylate 290-315 nm used in higher concentrations. They do not Octyl salicylate 260-310 nm bind well to the skin and maybe removed Triethanolamine salicylate 296-320 nm easily by sweat. Avobenzone (Parasol 1784) 310-400 nm Block long wave UVA. Benzophennones: They are often combined with other sunscreens Oxybenzone 270-350 nm to provide broader UVA protection. They are Dioxybenzone 206-380 nm reported to aggravate eczema or acne. Sulisobenzone Anthranilites: Weak UV blocker, so it is combined with menthyl anthranilate 322-350 nm other sunscreen agents.

* Kim HI, Ghalai FE, Tennessen WW. Here comes the sun. Contmp Pediatr. 1997;14:41-69.

Table-11.3: A Partial List of Drugs that May Cause Photosensitivity Medications Examples Antihistamines cyproheptadine, diphenhydramine Anti-infectives tetracycline, nalidixic acid, sulfonamides Antipsychotic agents phenothiazines, haloperidol Diuretics thiazides, acetazolamide, amiloride NSAIDs phenylbutazone, ketoprofen, naproxen Miscellaneous captopril, carbamazepine, quinidine, oral contraceptives, amiodarone, coal tar

(For more information about these agents, refer to each individual agent in previous chapters) ______

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Chapter 12: VITAMINS AND MINERALS

A) VITAMINS 1. Fat-Soluble Vitamins Vitamins A, D, E, K 2. Water-Soluble Vitamins Vitamins B1, B6, B12, Folic acid, Niacin, Ascorbic acid

B) MINERALS 1. Ca 2. Fe 3. F 4. I 5. K

A) VITAMINS

Vitamins are potent non-caloric, organic Vitamins are classified in 2 categories: compounds that are essential in small fat soluble vitamins and water-soluble quantities for the specific body functions of vitamins. growth, maintenance, and reproduction. Fat soluble vitamins (i.e. A, D, E, K) Because most vitamins (with the exception generally occur in fats and oils of foods. of vitamin D) cannot be synthesized by the Once absorbed they are stored in the liver body in sufficient quantities to meet and fatty tissue until the body needs them. metabolic needs, they must be supplied by Since they are stored and excess can be food or supplementation. The only disease taken in, especially in the form of a vitamin can cure is the one caused by a supplements, toxicity can occur. For deficiency of that vitamin. The best example, high dose of vitamin A, can vitamin sources are the natural ones (i.e. produce loss of appetite, itching, loss of vegetables and fruits). However, the way weight and enlarged liver and spleen (refer the food is prepared, served and stored have to toxicity symptoms of other vitamins). major influence on its nutritional value. All other vitamins are water soluble Guidelines for the clinical assessment of vitamins (i.e. B, C,...). Cooking and over- nutritional status include: evaluation of washing can take them out of the foods. growth, development, fitness, medical and The body absorbs them easily, and just as dietary history observations of signs easily excretes them in the urine, so adverse consistent with deficiencies. effects are diminished. Nonetheless some The Recommended Dietary Allowances water-soluble vitamins can still cause (RDAs) are levels of daily intake of diarrhea by irritating the intestines (i.e. essential nutrients that, based on scientific doses of vitamin C > 1 gm/d), or interfere knowledge, the Food and Nutrition Board with common laboratory results (also Judges approved to be adequate to meet the vitamin C). known nutrient needs of most healthy Access to good nutrition should be the persons. They are not requirements, they priority for public health in all countries. are recommended daily intakes of certain Encouraging individual and government essential nutrients. Based on available spending on unnecessary vitamin scientific knowledge, they are considered to preparations does not contribute to the be adequate. They vary for age and sex, public health need. It is wrong to suggest with extra allowances for women during that a capsule or tablet can replace the pregnancy and lactation, as well as from nutrients in foods, and it diverts efforts to one country to another. They also don’t solve problems of hunger, malnutrition and apply to cover therapeutic nutritional vitamin imbalances. requirements in cases of disease or other abnormal states (i.e., metabolic disorders, weight reduction, drug therapy . . .). Although it is generally believed that vitamins are harmless, there are real dangers related to the use of some of them. Excessive use of one or more vitamins may causes toxicity (i.e. Vitamin D), or may cause relative deficiencies of other essential micro-nutrients (i.e. salts and minerals).

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Table 12.1: Fat Soluble Vitamins Vitamin Natural Deficiency Toxicity Comments (other names) Sources Symptoms Symptoms

Fortified dairy products, Impaired growth, painful Red blood cell breakage, nose bleeds, In cases of deficiency; WHO eggs, liver, spinach and joints, cracked teeth, bone pain, headaches, abdominal Adult dose:

A other dark leafy greens, depression, night blindness, cramps and pain, vomiting, diarrhea, 10000-20000 IU/d for 2 months. deep orange fruits and spots, and possibly anemia over-reactivity of immune system, Child (1-8 y): vegetables. (microcytic). blurred vision, loss of appetite, dry 5000-10000 IU/d for 2 months. carotene)

Vitamin skin, liver and spleen enlargement as RDA=child: 400-700 mcg RE, adult males: (Retinol, retinal, well as bone and joint pain. 1000 mcg, female: 800 mcg. Self-synthesis with Rickets; (Ca abnormalities), Raised blood calcium, excessive thirst, Supplements containing > 100 IU are not sunlight, fortified milk, abnormal growth, misshaped headaches, irritability, loss of appetite, advisable. eggs, liver, and sardines. bones (bowing of the legs), kidney stones, mental and physical * Doses of 400 IU (10 mcg of

D joint pain, malformed teeth, retardation. cholecalciferol) are not advisable unless muscle spasm, osteomalacia. there is a specific disease state. * Dose for Rickets is 1000-4000 IU. calciferol)

Vitamin * Effectiveness of supplements Avoid use of supplements in infants and depends on adequate Ca intake. children who have adequate exposure to (Calciferol, chole- sunlight or a normal diet. RDA=10 mcg cholcalciferol (100 IU). Polysaturated plant oils Red blood cell breakage, Nausea, headache, blurred vision, 300-400 IU/24 hours prescribed for (margarine, salad anemia, degeneration of flatulence and diarrhea. deficiencies.

dressings), green and nervous and muscular With doses of ≥ 1000 IU/ 24h chronic There is no evidence that it is protective E leafy vegetables, wheat systems, weakness, leg use it augments the effects of anti- against arterio-sclerosis, cancer, pulmonary germ, nuts and seeds. cramps, fibrocystic breast clotting medication. damage, heart disease, peptic ulcer, burns, disease. or inflammation of skin disorders. Vitamin RDA= child: 10 IU, males and pregnant

(Alpha-tocopherol) (Alpha-tocopherol) females: 15, females:12, lactating females: 16-18. Bacterial synthesis in Deficiency is always Interference with anti-clotting Vitamin K supplementation will not

the digestive tract, associated with pathologic medication, vitamin K analogues may counteract the anticoagulant effect of K liver, green leafy conditions; may be due to cause jaundice. Hemolytic anemia, heparin, but it counteracts the effects of vegetables, cabbage malabsorption syndrome or hyperbilirubinemia have been reported warfarin. type vegetables, milk. liver disease. Hemorrhaging with large doses in newborns. RDA=child: 15-45 mcg (according to age) Vitamin phytona-dione) phytona-dione) (Phylloquinone, (Phylloquinone, is the most common Adult males: 65-80 mcg symptom. Adult females: 45-65 mcg.

Table 12.2: Use in Special Cases

Vitamin Pregnancy Lactation Renal Disease Liver Disease A Safety of amounts > 5000 IU/d RDA for nursing mothers is Vit. A toxicity and elevated plasma It is stored and metabolized in during pregnancy has not been 6000 IU. Ca and alkaline phosphatase the liver. In liver cirrhosis established. Avoid use in excessive Human milk supplies sufficient concentrations have been reported in Vit. A deficiency can occur, doses, animal reproduction studies Vit. A for infants unless chronic renal failure patients. and supplementation is have shown fetal abnormalities. maternal diet is grossly recommended. inadequate. D Safety in amount > 400 IU/d is not Vit. D is excreted in breast milk The kidney of uremic patients might Elevated liver enzyme tests established. Avoid larger doses, in limited amounts. Monitor not be able to adequately synthesize can occur with high doses. animal studies have shown fetal infants’ serum Ca concentration calcetriol (the active hormone Use caution. abnormalities. if mother is taking large doses to formed form precursor of Vit. D). avoid hypercalcemia in the child. Hypocalcemia and secondary hyperparathyroidism that can lead to metabolic bone disease of renal failure. E Safety is not established. No No harmful effects have been No harmful effects have been noted. Use caution with high doses. reported teratogenicities in human or noted. animal studies. K It crosses the placenta, but not It is excreted in breast milk. Use Use caution with high doses. Repeated large doses of Vit. K reported to cause harm to the fetus, only when clearly needed. may further depress liver or affect the reproduction capacity. function.

Vitamins and Minerals

Table 12.3: Selected Water Soluble Vitamins Vitamin Natural Deficiency Toxicity Comments (other names) Sources Symptoms Symptoms Pork, ham, liver, Beriberi, edema, enlarged heart, No symptoms reported Alcoholism and high carbohydrate diet may be

1 whole grains, abnormal heart rhythms, wasting, with doses of up to 500 causes of thiamin deficiency. B legumes, nuts. weakness, difficulty walking, loss of mg. Dose for Beriberi is 25 mg b.i.d. or t.i.d. for 5 reflexes, mental confusion, and days, followed by daily dose of 5 mg for 1 paralysis. month. thiamine) (Thiamin, Vitamin RDA= child: 0.7-1.3 mg, adult males: 1.5 mg, adult females: 1.1 mg.

Milk, yogurt, meat, Cracks at corners of mouth, No toxicity has been For deficiency, a dose of 50-200 mg/24 hours 6

B banana, leafy green hypersensitivity to light, reddening of reported. High doses of may be required

vegetables, lentils, cornea, and skin rashes. Severe cases 200-600 mg have been RDA= child: 1-1.7 mg,

WHO whole-grain, or include convulsions, sideroblastic shown to inhibit prolactin. adult males: 2 mg,

pyridoxal) pyridoxal) enriched breads and anemia, and peripheral neuropathy. adult females: 1.5 mg. Vitamin (Pyridoxine, (Pyridoxine, cereals. Animal products: Anemia (large-cell type-macrocytic No toxicity symptoms Anemia can be due to lack of intrinsic factor meat, fish, milk, anemia), smooth tongue, fatigue, known. necessary for absorption. Supplementation is of

cheese, eggs, . . . hypersensitivity reactions of the no use. 12

B etc. skin, neurological abnormalities: May mimic folate deficiency. ataxia, parasthesia, hyporeflexia, ***Need to exclude folate deficiency anemia Babinski, clonus and coma. before starting to supplement with B12 therapy***. Vitamin

(Cyano-cobalamin) (Cyano-cobalamin) RDA= child: 0.7-2 ug, adult males and females 2 ug. Milk, eggs, meat, Pellagra, diarrhea, black-smooth Diarrhea, heartburn, ulcer Dose for Pellagra: 300-500 mg/d, in divided

poultry, fish, whole tongue, irritability, loss of appetite, irritation, vomiting, doses. three

WHO

grain and enriched dizziness, mental confusion dizziness, painful flush For hyperlipidemias, in doses of 1-2 g t.i.d. breads and cereals, progressing to psychosis or and rash (niacin rush), RDA= child: 9-17 mg, and all protein- delirium, flaky skin rash on areas sweating, abnormal liver adult male: 20 mg, Niacin nicotin-amide, nicotin-amide,

(nicotinic acid, containing foods. exposed to sun. function, low blood adult female: 15 mg. vitamin B) pressure.

Vitamin Natural Deficiency Toxicity Comments (other names) Sources Symptoms Symptoms Leafy green Anemia (macrocytic or No toxicity reported. (Food canning, long exposure to heat, and vegetables, legumes, megaloblasitic), GI disorders, extensive refining may destroy 50-100% of seeds, liver, yeast, suppression of immune system, * Folic acid in doses > 0.1 mg naturally occurring folic acid.) lean beef. smooth red tongue, depression, daily may obscure pernicious Correction of deficiency is usually 1 mg/24 hrs. mental confusion, irritability anemia in that hematological ***Rule out pernicious anemia before and forgetfulness, fainting remission can occur while administration of Folic acid.*** (masks vitamin B12 deficiency). neurologic manifestations remain progressive. In populations with moderate to high prevalence anemia dose is 0.5 mg/24 hours (WHO recommendations).

WHO Doses > 1 mg are not necessary except in some life-threatening hematological disease. RDA= child: 50-150 ug, adult male: 200 ug, adult female: 150-180 ug

Folic acid In pregnant women: The RDA for folate is 0.4 mg/24 hrs, and 0.8 mg/24 hrs if clinical symptoms are present. Studies have proved that

(folate, folacin, pteroyl-gutamic acid) acid) pteroyl-gutamic folacin, (folate, folic acid supplementation can decrease the incidence of neural tube defect; it should be started before conception and continued until 12 weeks of pregnancy. The dose 0.4 mg, and 4 mg in those with previous history of neural tube defect. Citrus fruit, cabbage Scurvy, anemia (microcytic), Nausea, abdominal cramps, Claims for use as prevention of common cold

type vegetables, dark pinpoint hemorrhages, diarrhea, excessive urination, have been unsupported by well designed- green vegetables, suppression of immune system, fatigue, insomnia, rashes, controlled studies.

WHO,P strawberries, bleeding gums, loosened teeth, interference with medical Doses of > 200 mg are rarely indicated, even peppers, lettuce, muscle degeneration and pain, tests, aggravation of gout though most products on the market contain > tomatoes, potatoes, hysteria, bone fragility, rough symptoms. 500 mg! and mangos. skin, failure of wounds to heal. High doses of 1 g/24 hours, increase side (Ascorbic acid) Vitamin C effects. RDA= child: 40-50mg, adult: 60mg.

Vitamins and Minerals

Table 12.4: Use in Special Cases

Vitamin Pregnancy Lactation Renal Disease Liver Disease

B1 Safe. Studies have not shown an It is not known if the drug is Excess thiamin is excreted in In patients with liver disease increased risk of fetal excreted in breast milk. No the urine. (cirrhosis, encephalopathy) there abnormalities. harmful effects have been No harmful effects have been is an increased need for thiamin reported. reported. use. B6 Requirements are increased during pregnancy and lactation to 2.0-2.5 It is metabolized in the liver and excreted in the urine. Use caution mg/d. Do not use excessive amounts during lactating if using doses larger than RDAs. ( > 10 mg/tablet) since pyridoxine may inhibit lactation by prolactin suppression. B12 Requirements are increased during pregnancy and lactation to 2.6 No reports of harmful effects in these cases. Use caution in severe mcg/24 hours. No harmful effects were reported. (Max. amount cases. absorbed from a single oral dose is 1-5 mcg.) C It is not known whether it can Ascorbic acid is excreted in No reports of toxicity. cause fetal harm or can affect breast milk, but no harmful reproduction capacity. Do not take effects have been reported. very large doses. Folic Safe. Pregnant women are more Folic acid is excreted in breast No reports harmful effects. Acid prone to develop folate deficiency, milk, without any harmful leading to complications of effects to the nursing child. pregnancy and fetal abnormalities. RDAs during lactation are Studies in pregnant women have 0.26-0.28 mg/day. not shown any harmful effects with the increased dose recommendations. (See table 12.3) > 1 mg doses are not necessary. Niacin Use of doses larger than RDAs in pregnancy and lactation have not Use caution. 1/3 of the dose is Prolonged use of very high doses been studied for safety. Use only when clearly needed. excreted unchanged in the urine. (> 6 g/24 hrs.) can cause liver damage.

Minerals constitute about 4% of body WHO definition of anemia for pregnant weight. Minerals are present in the body in a women is when hemoglobin blood level is diverse array of organic compounds such as below 11 g/100 ml (hemoglobin > 80%). The phosphoproteins, phospholipids, hemoglobin, WHO has suggested that all pregnant women and thyroxin, in inorganic compounds such in high-risk areas receive iron supplements as sodium chloride, potassium chloride, (due to the large numbers who suffer iron- calcium and phosphate as free ions. They are deficiency anemia), especially during the last involved in regulating cell membrane four to five months of pregnancy. Iron permeability, osmotic pressure, and acid-base supplementation, however, is a curative and water balance in the body. approach, and emphasis should be on Unlike vitamins, minerals exist in plants prevention. in varying amounts, according to the Administration of combination composition of the soil in which the plant is preparations of iron with folate, B12 or cobalt grown. has little justification in a pregnant woman Vitamins and minerals, particularly iron, unless clearly indicated. It is better to are regularly prescribed or taken during identify type of anemia of the patient pregnancy. The belief that because they are before prescribing or recommending ‘natural’ substances and are harmless, causes supplementation when possible. a lot of overuse. The need for iron Furthermore, when supplementation is supplementation in pregnant women, is a implemented, it should not keep out further controversial subject. It is important to note regular Hb-level tests and follow-ups of that international agencies such as WHO and antenatal visits to assure efficacy, better UNICEF strongly promote and support the compliance in taking the treatment and routine iron supplementation during giving proper dietary counseling. pregnancy. That is especially done in those The major mineral content of the skeleton countries where pregnant women are more consists of calcium and phosphorous. Ca is likely to be or become anemic due to another element that requires special poverty, malaria epidemics and/or high attention in women’s health. Since women prevalence rates of intestinal parasites. are 6-8 times more likely to get osteoporosis However, many industrialized countries have (often known as brittle bone disease) than abandoned this policy preferring a selective men, it is important to start prevention iron supplementation according to the measures including education to all women patient’s need. at high risk (refer to the RDAs table for Most pregnant women have a lower iron needs at the different stages). level in the blood since the mother’s blood There are no sufficient studies or data on volume is increased in order to supply the our region that records prevalence of growing baby. The human body, if not nutritional deficiencies. The primary health malnourished, has large reserves of iron in care provider’s role is to screen and prevent the liver and bone marrow, and during such cases when possible. The improvement pregnancy these stores are used. But the of general nutrition is the most important in demands made on women’s bodies from all, whether children or women before and blood loss due to early, frequent and closely during pregnancy, as well as giving spaced pregnancies make them vulnerable to supplementation when needed. nutritional deficiencies, especially anemia.

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Table 12.5: Summary of Selected Minerals Mineral Natural Sources Deficiency Symptoms Toxicity Symptoms Comments Milk and milk products, Stunted growth in Excess Ca is excreted except in Absorption of supplements varies between Ca small fish (canned children, adult bone loss hormonal imbalance states. salts. Ca carbonate has the highest content of Ca WHO,P sardines with bones), elemental Ca. Side effects include GI (osteoporosis). * It has not been shown that Ca causes (calcium) bean curd, broccoli, disturbances such as nausea and constipation. fetal harm when taken as supplements. beets, greens and RDA= child: 800 mg, adult: 800 mg-1200 mg. legumes. Red meat, fish, poultry, Fatigue, weakness, iron Acute overdose of 200 mg/kg may be Supplements may cause GI discomfort, shellfish, eggs, legumes, deficiency (pernicious) fatal. nausea, diarrhea or constipation, and dark dried fruits, green anemia, split or spoon- stool. Advise patient to eat foods rich in fiber leaves. shaped nails, sore tongue, Iron overload: infections, liver to prevent diarrhea or constipation. dyspnea on exertion, injury, possible increased risk of heart * Sustained release or enteric-coated Fe WHO,P * People with normal palpation. attack, acidosis, bloody stools, and preparation reduce the amount of available (iron) Fe levels should not shock. iron, since they transport iron beyond the take Fe supplements place of absorption, the duodenum. chronically. RDA= child: 10 mg, adult male: 10-12 mg, adult female: 15 mg. Pregnant: 30 mg. Municipal water (not to Dental decay, increased Salivation, abdominal pain, vomiting, F supplements can be given to children as a exceed 2-8 parts per risk of osteoporosis as the diarrhea, dehydration, thirst, tremor, preventive measure for dental decay in areas F WHO million), mouthwash. person gets older. mental irritability, dental fluorosis with low F level in the water. (fluorine) (Each city should test (molting of tooth enamel) with chronic RDA= child: 0.7-2 mg, adult male: 4 mg, their water supply for F over dosage of Ca & F. adult female: 3 mg. levels). Salt water, fish, Hypothyroidism (goiter), Depressed thyroid activity. Chronic Iodine supplements should be only vegetables produced in cretinism. intoxication (iodism), include administered under direct medical supervision. I WHO soil with high content of unpleasant taste burning in mouth or Iodide (the reduced form of iodine) crosses the (iodine) iodide. throat, soreness of the teeth and gums, placenta readily. swelling of eyes lids. RDA= 70-150 ug, adult: 150ug All whole/fresh foods: Deficiency accompanies Muscular weakness, triggers vomiting, GI discomfort (i.e. nausea, diarrhea, etc.) are meats, milk, fruits dehydration, causes irregular heart beats in susceptible common side effects of supplements. Can K (especially bananas), muscular weakness, patients. decrease by taking the potassium supplements (potassium) vegetables, grains, paralysis and confusion. In patients with renal failure do not use with meal. legumes. Can cause death. to avoid hyperkalemia or cardiac arrest!

Table 12.6: Significant Drug Interactions Vitamin/ Drug involved Description Mineral Cholestyramine Absorption of Vit. A is reduced. A Mineral Oil Use of mineral oil interferes with the intestinal absorption of Vit. A. Oral contraceptives These significantly increase plasma Vit. A levels.

Levodopa Pyridoxine (B6) reduces effectiveness of levodopa. Avoid supplementation that contain > 5 mg pyridoxine/24 hours in such patients. B 6 Serum levels of these drugs maybe decreased, leading to sub- Phenobarbital, therapeutic levels. Advise patients taking these drugs not to take high phenytoin dose supplements.

Aminosalicylic The biologic and therapeutic action of Vit. B12 may be reduced. There acid is no need to administer aminosalicylic acid to patients with B12 deficiency (megaloblastic anemia), who are taking supplementation. B12 An abnormal Schilling test and false symptoms of Vit. B12 deficiency may also occur. Alcohol Excessive alcohol intake (longer than 2 weeks) may cause malabsorption of vitamin B12. Oral estrogen Ascorbic acid increases serum levels of estrogen contained in oral contraceptives or estrogen replacement therapy, leading to increased adverse effects. Warn patient against intake of high doses of Vit. C supplements. C Warfarin The anticoagulant action of warfarin may be reduced. Do not co- administer Vit. C in large doses. Glucose lab. tests Doses of ≥ 500 mg Vit. C, will cause false negative urine glucose tests. Advise patient against intake of this vitamin supplementation 48-72 hours before conducting blood/urine tests. Antacids/Mg Hypermagnesemia may develop in patients with chronic renal disease. containing Hypercalcemia in patients on digitalis may precipitate cardiac D Digitalis arrhythmias. Patients on Digoxin should avoid use of high doses of Glycosides Vit. D supplements. Mineral oil, Reduce absorption of Vit. D, especially with prolonged use. Monitor Cholestyramine patients who are taking these drugs chronically, for signs of deficiency. Oral High doses of Vit. E increases the effect of anticoagulants, so it E anticoagulants increases the risk of bleeding. Anticoagulants Anticoagulant effects are antagonized by Vit. K. Physicians should K warn patients against taking supplements while on this medication. Aminosalicylic Decreased serum folate levels may occur during concurrent use. Avoid acid concomitant use unless clearly needed. Folic Acid Hydantoins If folic acid is required (refer to drug interactions), need to monitor serum hydantoin (i.e. phenytoin) levels to avoid lower therapeutic levels of the anticonvulsant, and adjust dosage as needed. Lovastatin It has been reported that co-administration of niacin have resulted in rhabdomyolysis (a fatal disease marked by destruction or degeneration Niacin of skeletal muscles). Avoid co-administration. Sulfinpyrazone Uricosuric effect may be inhibited by nicotinic acid. Advise patient against taking large dose supplementation if using this medication.

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Vitamins and Minerals

Atenolol Bioavailability of atenolol may be decreased, resulting in decreased beta blockade. Warn patients against large dose supplementation. Caffeine High intake of beverages containing caffeine (> 10 cups/day of coffee) increases loss of Ca though the urine. Iron Salts GI absorption of iron may be reduced. If both minerals are indicated Ca salts for use, space out their administration time, or use Ca carbonate and not another Ca salt. Tetracyclines The absorption and serum levels of tetracyclines may be decreased, decreasing its anti-infective response. Do not co-administer. Warn patients. Verapamil High doses of Ca supplements increase the toxicity of verapamil. This can be reversed by discontinuing the Ca salts (supplement). Antacids GI absorption of iron is reduced. Do not administer at the same time Cimitidine interval. Ascorbic acid Ascorbic acid may enhance the absorption of Iron from the GI, but this increase may not be significant. Levodopa, Marked reduction of the absorption of this medication , may be due Penicillamine, to chelation or complex formation with iron. Do not co-administer. Fe Salts Quinolones Tetracyclines Co-administration decreases absorption of both drugs, due to complex formation. Do not co-administer, and warn the patient. Coffee, tea Consumption of these with a meal or 1 hour after the meal, may significantly inhibit the absorption of dietary iron. Warn your patients. Dairy products Do not administer fluoride supplements with dairy products. F Calcium fluoride is formed, which is poorly absorbed. Lithium carbonate Concomitant use may result in hypothyroidism. Do not co- I administer. Concurrent use may result in hyperkalemia. Do not use ACE Inhibitors concomitantly. Potassium-sparing These diuretics will increase potassium retention and can produce diuretics severe hyperkalemia. Do not use concomitantly. K Digitalis Use caution in these patients. Potassium antagonizes digitalis preparations. A decrease in K level favor digoxin binding, increasing the likelihood of digitalis toxicity. Increased K levels decreases digitalis binding and decreases digitoxin effect. Be very careful.

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Table 12.7: Possible Drug Induced Nutritional Deficiencies With Chronic Use

Drug Group Drug Nutrient Depleted Diuretics Thiazides Potassium, zinc, magnesium Furosemide Calcium, potassium, magnesium Antihypertensives Hydralazine Vitamin B6 (Peripheral neuropathy) Anticonvulsants Phenytoin Vitamin D (Rickets, osteomalacia) Folate (megaloblastic anemia) Anticoagulants Warfarin Vitamin K

Anti-ulcer Cimetidine, Vitamin B12 (pernicious anemia) ranitidine (with long-term use) Antibiotics Tetracycline Calcium, Vitamin K

Anti-tubercular Isoniazid Vitamin B6, niacin, vitamin D Antihyperlipidemic Cholestyramine Fat Vitamin A, Vitamin K, B12 and folate. Analgesics Aspirin Ascorbic acid, potassium, iron.

Anti-inflammatory Colchicine Fat, Vitamin B12. Sulfasalazine Folate Antineoplastic, Methotrexate Folate, Vitamin B12, fat. antipsoriatic Laxatives Mineral oil Vitamins A, D, E, K, Calcium & Phenolphthalein phosphorus. (bisacodyl) Vitamin D, calcium, potassium.

______

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Chapter 13: VACCINES

1) BCG (Bacille Calmette-Guerin)

2) OPV / IPV (Oral and Inactivated Poliomyelitis Vaccines)

3) Tetanus Vaccine

4) DPT Vaccine (Diphtheria, Pertussis and Tetanus)

5) Measles Vaccine

6) MMR Vaccine

7) Hepatitis B Vaccine

8) Influenza Vaccine

9) Hib Vaccine (Haemophilus Influenza Type B)

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VACCINATION AND IMMUNIZATION

The vaccination and immunization terms Some of the terms that we should be are often used interchangeably. familiar with include: Vaccination is a term that denotes the Suspending fluids: These may be sterile administration of any vaccine. water or saline or complex fluids containing Immunization is a more inclusive term small amount of protein or other denoting the process of inducing or constituents derived from the medium or providing immunity artificially by biologic system in which the vaccine is administering a vaccine. Immunization can produced (e.g. serum proteins, egg antigens, be active or passive. Active immunization cell-culture-derived antigens). is protection produced by the person’s own Preservative, stabilizers, and antibiotics: immune system, as response to the These components of vaccines, antitoxins, administration of a vaccine or toxoid. This and globulins are used to inhibit or prevent type of immunity is usually permanent. bacterial growth in viral cultures of the final Passive immunization means protection by product or to stabilize the antigens or products produced by an animal or human, antibodies. Allergic reactions can occur if that are transferred to another human as a the recipient is sensitive to one of these vaccine. This protection usually disappears additives (e.g. phenols, albumin, glycine, over time. (CDC, 1995). and neomycin). There are three sources of antibody used Adjuvants: Many antigens evoke in passive immunization vaccines: insufficient immunologic responses when [1] homologous pooled human antibody- given in the natural state. Efforts to enhance immune globulin, [2] homologous human immuno-genicity include mixing antigens hyperimmune globulin, [3] heterologous with a variety of substances or adjutants hyperimmune serum- antitoxin. (e.g. aluminum phosphate or hydroxide). Vaccines containing adjuvant must be Vaccines are classified into two basic types: injected deep into the muscle mass; they Live attenuated vaccines that can be viral or should not be administered subcutaneously bacterial (i.e., measles, mumps, oral polio, or intradermally because this can cause BCG), and inactivated vaccines that are local irritation, inflammation, granuloma composed of either whole or fraction, formation, or necrosis. protein-based or polysaccharide-based, of either viruses or bacteria (i.e., influenza, Route of Administration: pertussis, hepatitis B, tetanus, haemophilus It is important to refer to each product label influenzae type b). for the proper site of administration. Subcutaneous (SC) injections are usually Vaccines may come from different administered into the thigh of infants and in sources of pharmaceutical companies, and the deltoid area of older children and adults. it is important to follow the directions of Intradermal (ID) injections are generally the manufacturer for administration, given on the volar aspect of the forearm, storage …etc, for each product. Vaccines except for human diploid-cell-rabies- have different inert (non-active) vaccine, with which reactions are less ingredients/ additives that can vary not only severe in the deltoid area. The preferred between different active material, but also sites for Intra-muscular (IM) injections are from one manufacturer to another. If the the anterolateral aspect of the upper thigh recipient is sensitive to one of these and the deltoid muscle of the upper arm. additives, allergic reactions can occur. The buttock should not be used routinely as

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Vaccines a vaccination site for infants, children, or Vaccinating Immunocompromized Persons: adults because of the risk of injury to the Severe complications have followed sciatic nerve. vaccination with live, attenuated virus vaccines and live bacterial vaccines among Administration in Special Cases: these patients. Killed or inactivated Vaccination During Pregnancy: There is vaccines do not cause danger to such no evidence that any live vaccine (including patients, and can be administered as Rubella) causes birth defects. The concern recommended for healthy persons. of infecting the fetus is theoretical. In general patients with asymptomatic-HIV, However, since there is a theoretical or limited immune system (i.e. asplenia or possibility, live vaccine should not be given renal failure) should not receive live to pregnant women (except O PV in some vaccines, expect for measles, mumps and cases). rubella. For persons with symptomatic-HIV

There is no convincing evidence of risk infection, MMR can be administered since from vaccinating pregnant women with there are accumulating evidence of its inactivated virus or bacteria vaccines, safety. toxoids, or IG preparations; therefore, in Vaccination during chemotherapy or high risk areas the vaccine should be given. radiation therapy should be avoided Tetanus and diphtheria toxoids are the only because antibody response is poor. Patients immunobiologic agents routinely indicated with leukemia in remission whose for susceptible pregnant women. Hepatitis chemotherapy has been terminated for 3 B, influenza and pneumococcal vaccines months may receive live-virus vaccines. are recommended for women at high risk Vaccines that are contraindicated for use in for infection and for complication of patients with severe immunocompromized influenza and pneumococcal disease. states that are symptomatic-HIV infected persons or not HIV-related (i.e. leukemia, Vaccination of Preterm Infants: Infants lymphoma) include: BCG, OPV, and born prematurely, regardless of birthweight, yellow fever. Such patients who are should be vaccinated at the same exposed to measles should receive immune chronological age and according to the globulin (IG) regardless of prior same schedule and precautions as full-term vaccination status. infants and children. Birthweight and size are not factors in deciding if a child is to be Vaccination of Persons with Hemophilia: vaccinated or not, except in hepatitis B People with bleeding disorders such as vaccine as first dose should be given when hemophilia are at risk of hematomas if the infant is 2 kg as seroconversion rate given intramuscular injections. In such were lower in those less than 2 kg (Red patients using the subcutaneous or Book, 2000). intradermal route for the vaccines should be done. Some products may only be given Vaccination and Breast-Feeding: neither intramuscularly; therefore, the live or killed vaccines affect the safety of manufacturer should be contacted for clear breast-feeding for mothers or infants. guidelines. Breast-feeding does not adversely affect immunization and is not contraindicated for Spacing and Timing of Vaccines: any vaccine. Breast-fed infants should be Some vaccines require administration of vaccinated according to routine more than one dose for development of an recommended schedules. adequate antibody response, and some vaccines require booster doses to maintain protection. Intervals between doses that are

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longer than those recommended do not lead that the live-virus vaccines are administered to a reduction in the final antibody levels. or 4-6 weeks afterwards. Therefore, it is not necessary to restart an -If administration of an IG preparation interrupted series or add extra doses of becomes necessary because of imminent vaccine (except oral typhoid). In contrast, exposure to disease, live-virus vaccines can giving doses of a vaccine at less than be given simultaneously with the IG recommended intervals may lessen the product, with the recognition that vaccine- antibody response and should be avoided. induced immunity might be compromised. Doses given at less than recommended The vaccine should be administered at a site intervals should not be counted as part of a remote from that chosen for the IG primary series. inoculation. Vaccination should be repeated about 3 months later unless serologic Many vaccines can safely and effectively testing indicates that specific antibodies be given simultaneously (on the same day, have been produced. not at the same site). [See tables-13.1 & -Live attenuated vaccine viruses might not 13.2]. replicate successfully, and antibody 1. Simultaneous administration: response could be diminished when the In general, an inactivated vaccine can be vaccine given after IG preparations. killed given either simultaneously or at any time vaccines can be given simultaneously or at before or after a different inactivated or a any time before or after an IG product is live vaccine. They can be administered at used. separate sites. Simultaneous administration of the most widely used live and inactivated Table–13.1: Guidelines for Spacing vaccines has not resulted in improved Live and Killed Antigen Administration antibody response or increased rates of Antigen Recommended minimum combination interval between doses adverse reactions. Simultaneous routine No spacing. May be given ≥ 2 killed administration of MMR, DPT, OPV and simultaneously or at any antigens IPV is recommended. There are no contra- interval between doses. indications to simultaneous administration Killed of any vaccine except with cholera and and live No spacing required. yellow fever vaccines. antigens 2. Non-simultaneous administration: 4 wk minimum interval if ≥ 2 live not administered When vaccines commonly associated with antigens local or systemic side effects are given simultaneously simultaneously, the side effects may be increased or exaggerated. Whenever If a child is not up-to-date on his or her possible, these vaccines should be given on vaccination, it may be necessary to separate occasions. “accelerate” the normal schedule in order to -Live-virus vaccines can interfere with the catch up. In this situation it is important to response of a tuberculin test. Tuberculin know how closely the doses can be spaced testing can be done either on the same day and still be effective for that specific case.

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Vaccines

Table - 13.2. Guidelines for Spacing the Administration of IG Preparations and Vaccines Simultaneous administration: Recommended minimum interval immunobiologic combination between doses None. Given at different sites or at any time IG and killed antigen between doses. Should generally not be given simultaneously. If unavoidable to do so, give at different sites and IG and live antigen revaccinate or test for seroconversion in 3 months. Non-simultaneous administration: immunobiologic administration Recommended minimum interval between doses First Second IG Killed antigen None Killed antigen IG None IG Live antigen 6 weeks and preferably 3 months. (3 mon. for measles) Live antigen IG 2 weeks.

The WHO Expanded Program of its needs. Recommendations for Immunization (EPI) has established immunizations practice scientific evidence recommendations for immunizing infants, of benefits, costs, and risks to achieve children, and adults that are based on optimal levels of protection against characteristics of vaccines, scientific infectious diseases. knowledge about the principles of active and passive immunization, and judgments by public health officials and specialists in [See EPI diseases, vaccine types and clinical and preventive medicine. Each recommendations in tables-13.3, 4 & 5, and country would modify the list according to Palestinian recommendations in table-13.6].

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Table – 13.3: Epidemiology of the EPI Target Disease Transmissible Subclinical Risk Factors for Disease Agent Reservoir Spread Duration of Natural Period Infection Immunity Infection Tuberculosis Mycobacerium Humans Airborne droplet As long as Common but not Not known. Low access to care, tuberculosis nuclei from sputum sputum acid fast important in Reactivation of old Immunodeficiency positive person Bacilli positive transmission infection commonly Malnutrition causes disease Alcoholism Diabetes Diphtheria Toxin producing Humans Close contact; Usually < 2 wks. Common Usually lifelong Crowding bacterium respiratory or Some chronic Low socioeconomic (C. diphtheria) cutaneous carriers status Tetanus Toxin producing Animal Spores enter body No person-person No No immunity Contamination of bacterium intestines through wounds/ transmission induced by umbilical cord (Cl. Tetani) soil umbilical cord infection Agricultural work Pertussis Bacterium Humans Close respiratory Usually < 3 wks. Mild illness Usually lifelong Young age (Whooping- (B. Pertussis) contact (starts before common may be Crowding cough) whoop is apparent) not be diagnosed Poliomyelitis Virus (serotypes Humans Fecal-oral, close Few days before 100-200 sub- Type-specific Poor environmental (Polio) 1,2 and 3) respiratory contact and after acute clinical infections immunity, hygiene symptoms for each paralytic lifelong case Measles Virus Humans Close respiratory 4 days before, until May occur Lifelong Crowding contact and 2 days after rash Low socioeconomic aerosolized droplets status Yellow Virus Humans Mosquito-borne Common in - Lifelong Mosquitoes fever Monkeys infections endemic areas Occupation Hepatitis B Virus Humans Perinatal; child- Chronic carriers > Common, If develops, lifelong HbeAg+ mother child; blood; sexual 30 yrs. especially in Multiple sex partners; spread infants IVDU, working with blood products.

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Table – 13.4: Characteristics of EPI Vaccines No. of Nature of Minimum potency Contains Disease Form doses* and Heat stability vaccine per dose Additives/Adjuvants route Tuberculosis Attenuated 50,000 to one million live Freeze dried None 1 ID Medium in dried bovis particles form, low in reconstituted form Diphtheria Toxoid At least 30 IU Fluid Al(OH)3/AlOP4 / Usually 3 IM High thimerosal (merthiolate) Tetanus Toxoid At least 40 IU in TT and 60 Fluid Al(OH)3/AlOP4 / Usually 3 IM High IU for T-component in DPT thimerosal when tested in mice Pertussis Killed whole At least 4 IU Fluid Al(OH)3/AlOP4 / Usually 3 IM Medium cell pertussis thimerosal bacterium Poliomyelitis Attenuated live Type 1 > 1 million Fluid None/ Stabilizer; 4 Oral Low viruses of 3 Type 2 > 100,000 Magnesium chloride or types Type 3 > 600,000 sucrose infectious units Measles Attenuated live At least 1000 infectious Powder for Small amount of 1 S/C Medium in dried virus units injection antibiotic & stabilizers form, low in reconstituted form Yellow fever Attenuated live At least 1000 mouse LD50 Powder for Stabilizing substances 1 S/C Medium in dried virus or the equivalent in PFU injection form, low in reconstituted form Hepatitis B HbsAg 2.5 to 20 mcg of HbsAg Fluid Al(OH)3/AlOP4 / Usually 3 IM High thimerosal

* Refer to individual drug monographs for scheduel and doses.

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Table – 13.5: Reported Vaccine Efficacy and Duration Vaccine Vaccine efficacy Duration of immunity after primary series BCG 20-80% vs. TB Unknown; some evidence that immunity wanes 75-86% vs. meningitis and miliary TB. with time. Diphtheria 97% clinical efficacy. Antitoxin levels decrease after 10 years from the Toxoid last dose. A booster administered every 10 years (as Td) may be administered. Tetanus Toxoid A complete tetanus toxoid series provides 100% efficacy. 3 doses are protective for 5 yrs; 5 doses may provide >20 years of protection. Boosters are recommended every 10 years. Pertussis 71- 84% protection. Estimate vary widely; efficacy higher Unknown; evidence that it wanes with time. against severe disease. IPV > 90% of recipients develop protective antibodies to all three Duration of immunity not known with certainty but poliovirus types after 2 doses, and at least 99% are immune provides protection for many years after a complete following 3 doses. Less local GI immunity is produced. series. OPV A single dose produces about 50% of immunity. Three doses As with other live virus vaccines, immunity is produce immunity to all 3 poliovirus types in > 95% of recipients. probably life-long. Produces local GI-intestinal and pharyngeal immunity. Measles > 95% at 12 months of age: 98% at 15 months of age Lifelong if boosted by wild virus circulating. (approx. 2-5% of children fail to respond to MMR 1st dose). Rubella 95% aged 12 months and older after a single dose. > 90% of vaccinated persons have protection for at least 15 years. Some studies indicted that one dose confers lifelong protection. Hepatitis B 80-100% effective in preventing infection or clinical hepatitis in > 13 years; further follow-up is ongoing. those who receive the complete course (3) of vaccine. (90-95% adequate antibody response in healthy adults, infants and adolescents. 75-95% effective in newborns from HepaAg+ mothers. 90% respond after age 40, 75% develop protection by the age of 60.) Influenza 90% protection from illness of healthy young adults. Immunity following inactivated influenza 30-40% effective in preventing illness among frail elderly vaccination rarely exceeds 1 year, depending on the persons, and 80% effective in preventing death. vaccine starin(s).

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Table – 13.6: Palestinian Immunization Schedule Vaccine Dose Route Site Course MOH Ages UNRWA Ages BCG 0.05 ml Intradermal Left upper arm -Primary -On first registration -At birth OPV 2 drops Oral Mouth -Primary series -At 2,4,6 mon. of age -At 2,4,6 of age -Booster -At 12 mon. of age -At 12 mon. of age -Booster -At school entry IPV 1 ml Subcutaneous Left upper arm -2 doses -At 1&2 mon. of age -At 1&2 mon. of age DPT 0.5 ml Intramuscular Lateral aspect of -Primary series -At 2,4,6 mon. of age -At 2,4,6 mon. of age the thigh -Booster -At 12-15 month of age -At 12 months. -At school entry Measles 0.5 ml Subcutaneous Left upper arm -3 doses -At 9 mon. -At 9 mon. Hepatitis 0.5 ml Intramuscular Lateral aspect of -Primary -At 0, 1,6 mon. of age -At birth, 1,6 mon. of B the thigh age MMR 0.5 ml Subcutaneous Left upper arm -Primary -At 15 mon. of age -At 15 mon. of age TT 0.5 ml Intramuscular Left upper arm -Booster -For 3rd prep. or 9th grade -At first pregnancy * -During -For primigravida & 5 yrs. -After 5 years of the pregnancy later first pregnancy Td 0.5 ml Intramuscular Left upper arm -Booster -Every 10 years, persons ≥ -At 15 yrs of age, 7 yrs of age. ninth grade -Wound management

*In case documentary evidence could be provided that full coverage has been attained, 3 primary series plus one booster and 2 doses of TT at school age (no need for additional boosters).

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1) BCG WHO,P immune response. Physicians should use (Bacille Calmette-Guerin) caution in such patients; administer the vaccine not less than 3 weeks after • VACCINE SUMMARY: discontinuation of the steroid therapy. BCG is a strain of tubercle bacillus that is • ADVERSE EFFECTS & OVERDOSE: used to prepare the vaccine against TB. Simple swelling and ulceration at the site BCG vaccine, a live attenuated vaccine, of injection may occur, as well as cold gives good protection in children, mainly abscess. Lymphatic glands swelling is most against miliary and meningeal tuberculosis. likely to occur if the needle used was not EPI recommends that all countries with sterile, the needle was injected too deep, or high incidence of TB infection should the dose was large or there is a problem in immunize with a single dose of BCG at or the manufactured vaccine. In such cases soon after birth. refer the child for symptomatic treatment. • INDICATIONS: ______Vaccine used for immunization against TB. • CONTRAINDICATIONS: 2) OPV / IPV WHO,P In patients with symptomatic HIV Oral Poliomyelitis Vaccine/ infection, or other severe immune (Inactivated Poliomyelitis Vaccine) deficiency disease including high doses of corticosteroids or chemotherapy drugs. • VACCINE SUMMARY: • RECOMMENDED DOSAGE: Polio is almost eradicated; therefore, Refer to tables-4, 5 & 6. measures are implemented to assure that all Always follow direction for reconstitution the population must continue to be covered by the manufacturer. with vaccination. Two kinds of vaccines Once reconstituted, the vaccine must be exist; OPV (the oral-live virus) and IPV protected from light, kept cold and (the inactivated-injectable virus). OPV is discarded at the end of the day. made of a weakened live polio virus. IPV • USE IN SPECIAL CASES: is made of polio virus that has been killed. Refer to introduction. It cannot cause polio. IPV is more Immunization of asymptomatic HIV expensive, but may be recommended for infants is advised when the risk of pregnant women, people with an impaired tuberculosis is high. immune system, and adults who have not • PRECAUTIONS AND WARNINGS, been immunized previously. Immunization INTERACTIONS: against polio forms a part of the WHO’s -When given properly, this vaccine is EPI. extremely safe. • INDICATIONS: A small red tender swelling about 10 mm An immunization against poliomyelitis (for may appear at the site of injection within prevention of permanent crippling, about 2 weeks (since BCG bacteria grow paralysis, and sometimes even death). slowly), which may also become an ulcer. • CONTRAINDICATIONS: The ulcer heals by itself, and leaves a small In patients with history of hyper-sensitivity scar, which is a good indicator that the reaction to the vaccine, and immuno- child has had the vaccine later on. If no compromized patients. OPV should not be scar develops, the dose must be repeated. given to anyone in a family with a known -Multiple repeat doses of BCG are not family history of immunodeficiency until recommended. the immune status of all family members is -Patients on long-term systemic high doses documented. of corticosteroids will have reduced

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Vaccines • DOSAGE FORMS: therapy, may result in insufficient response OPV-liquid bottle with dropper. IPV-vial. to OPV. IPV may be administered in such • RECOMMENDED DOSAGE: cases. Refer to tables 13.4, 5 & 6. • ADVERSE EFFECTS & OVERDOSE: -The OPV bottle dropper should not touch Usually there are no side effects with OPV. the child’s tongue/mouth. If the child spits Vaccine-associated paralytic polio (VAPP) the drop out, give another dose. is extremely small (~ one case/1.4 million -Doses may vary between different first dose receivers). VAPP is more likely manufacturers; instruction on the label of to occur in persons ≥ 18 years of age than the vaccine should always be checked. in children. -If child misses the usual time for a dose, ______the next dose can be given as soon as possible. Immunity will be good, even if 3) Tetanus Vaccine WHO,P there is a delay. There is no need to repeat earlier doses. • VACCINE SUMMARY: -A single dose of IPV does not result in Tetanus vaccines stimulate the production significant protection, therefore at least 2 of the protective antitoxin. Complete and doses of IPV must be given. appropriate times vaccination is nearly -The minimum interval between the first 3 100% effective in the prevention of doses of IPV, OPV, or any combination of tetanus. The vaccine is usually given to IPV and OPV is four weeks. children as a combination with diphtheria -If ≥ 2 doses of OPV have been given, and pertussis vaccines. Immunization there is little benefit in switching to IPV. against tetanus forms a part of the WHO’s • USE IN SPECIAL CASES: EPI. Refer to introduction. • INDICATIONS: • PRECAUTIONS AND WARNINGS, Vaccine used as active immunization INTERACTIONS: against tetanus (prevention of muscles to -The presence of a minor infection is not a spasm or lockjaw). contraindication. In patients with acute • CONTRAINDICATIONS: fever, persistent vomiting or diarrhea, the Acute febrile illness, history of severe vaccine should be postponed. If the child hypersensitivity or convulsions. has diarrhea when OPV is given, the • DOSAGE FORMS: vaccine may not work so well, because the Vial. organism that causes diarrhea may • RECOMMENDED DOSAGE: interfere. An extra dose of OPV may be Refer to tables-15.4, 5 & 6. given four weeks after the normal course is -Always follow directions for recon- administered. stitution by the manufacturer. -When children in the household receive Immunization of women can start at any OPV, immunocompromised household stage of pregnancy. Tetanus toxoid (TT) contacts or adults who are not adequately does not harm the fetus. See table 15.7 on vaccinated against polio are at small risk of schedule of TT for women of child-bearing contracting polio disease. age. -OPV can be given simultaneously with -The need for tetanus vaccine in wound any other childhood vaccines. management depends on both the condition -Under no circumstances should OPV and the patient’s immunization history. A administered by injection. dose of tetanus is only recommended if the -Administration of OPV to patients risk of infection is considered high. If more receiving corticosteroids or radiation

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than 10 yrs. have passed, a reinforcing dose given to an adult as prevention of tetanus should be given. from wound or injury that breaks the skin. • USE IN SPECIAL CASES: • CONTRAINDICATIONS: Refer to the introduction. In patients with severe hypersensitivity • PRECAUTIONS AND WARNINGS, history to the vaccine; history of INTERACTIONS: convulsion or shock in the following three -Vaccination should be postponed in days after the vaccination, encephalopathy patients with acute febrile illness. within 7 days for P component of DPT. -Booster doses should not generally be • DOSAGE FORMS: given at intervals of less than 10 years Vial. because of increased risk of severe local • RECOMMENDED DOSAGE: reactions. Refer to table 13.4,5&6. In general DPT is • ADVERSE EFFECTS & OVERDOSE: administered in four doses, and a booster. Pain, redness and swelling at the site of the Booster is given every 20 years as Td. injection may occur; this should go away -Table 13.7 shows the duration of the by itself and needs no treatment. immunity of different schedules for DPT Anaphylaxis and neurological reactions vaccination. have rarely occurred. -Always follow direction for adminis- ______tration by the manufacturer. -If child misses a dose of DPT, the next 4) DPT WHO,P dose can be given at any time after four (Diphtheria, Pertussis, and Tetanus weeks of the first dose. There is no need to Vaccines) repeat earlier doses.

Table – 13.7: Expected Duration of • VACCINE SUMMARY: Immunity after Different Immunization These vaccines are available as Schedules Duration of combinations so as to be given Schedule simultaneously. immunity (age) The DPT (or DTP) vaccine is a "3-in-1" A) 3 DPT in infancy 5 years vaccine that protects against diphtheria B) 4 DPT infancy and 2nd 8 years (which may lead to pneumonia, heart failure, year C) As in B plus one DT and paralysis), pertussis (whooping cough 18 years which could lead to pneumonia or bronchitis), at school entry D) As in C plus one DT and tetanus. It can be given to children less 40 years than 7 years old. at school leaving E) Two DT at School The DT vaccine is a "2-in-1" vaccine that 10 years does not contain pertussis, can be given to (if no A→D) F) 3 DT at school 15 years children less than 7 years old. (if no A→D) The Td vaccine is the "adult" vaccine. It is G) 5TT as recommended 40 years a "2-in-1" vaccine that protects against by EPI tetanus and diphtheria. It contains a slightly different dose of diphtheria vaccine than • USE IN SPECIAL CASES: the DT vaccine. It can be given to anyone Refer to introduction. older than 7 years old. • INDICATIONS: DPT vaccine is used for active immunization against the bacterial infections of diphtheria, pertussis, and tetanus. TT or Td may be

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Vaccines • PRECAUTIONS AND WARNINGS, • PRECAUTIONS AND WARNINGS, INTERACTIONS: INTERACTIONS: -For children above 10 years or adults a -Use extreme caution in patients with mild specially diluted adsorbed vaccine is used. hypersensitivity to eggs or neomycin. -DPT should not be used in persons with a -Always follow direction for reconstitution history of neurologic disorders. by the manufacturer. -Use caution in children who had -Administration to children less than 9 symptoms of: collapse or shock-like state months of age makes only 50% of the within 48 hours of previous dose, elevated vaccine effective. If a 6 month old baby is temp. of 40.5 or more within 48 hours of seriously exposed to measles, then the dose, and persistant inconsolable cry for vaccine may be given as long as another more than 3 hrs. dose is administered when the child is nine • ADVERSE EFFECTS & OVERDOSE: months old. Slight fever and crying may occur but of no -There are conflicting reports about effect significance. Fever that does not resolve of vitamin A supplementation on reducing within one day, or starts 24 hours after a the response to the measles vaccine. dose of DPT is not due to the vaccine. • ADVERSE EFFECTS: Local mild reaction such as swelling, Mainly fever and rash may occur. A fever redness or tenderness at the injection site may develop 5-10 days after the may occur. Rarely convulsions have been vaccination, and may last 1-2 days; a reported due to the pertussis part of DPT. simple analgesic may be administered if ______the fever is high. ______5) Measles Vaccine WHO,P WHO,P 6) MMR Vaccine • VACCINE SUMMARY: (Measles, Mumps and Rubella) This vaccine is available as a single vaccine or as a combination. In most • VACCINE SUMMARY: countries, including Palestine, measles The MMR vaccine is a "3-in-1" vaccine vaccine is used as a combination with that protects against measles, mumps, and mumps and rubella- (MMR) vaccine. rubella. MMR should be given irrespective • INDICATIONS: of previous measles vaccine, or history of Measles vaccine is used as active measles, mumps, or rubella infection. immunization against measles. • INDICATIONS: • CONTRAINDICATIONS: The vaccine is used for active In patients with history of anaphylactic immunization against measles, mumps and reactions or systemic hypersensitivity to rubella. neomycin, acute febrile illness including • CONTRAINDICATIONS: active untreated TB, and within 3 months Patients with anaphylactic reactions to of administration of IG, whole blood, or eggs, gelatin or neomycin. Children who other blood products containing antibodies. have received another live vaccine by • DOSAGE FORMS: injection within 3 weeks. Vial. • DOSAGE FORMS: • RECOMMENDED DOSAGE: Freeze-dried vial. Refer to table-4, 5 & 6. • RECOMMENDED DOSAGE: • USE IN SPECIAL CASES: Refer to table-4, 5 & 6. Refer to introduction.

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Dose should be reconstituted with the in high incidence areas of Hepatitis B diluent as indicated by the manufacturer, infections. and used within one hour. • INDICATIONS: • USE IN SPECIAL CASES: Hepatitis B vaccines are used for active Refer to introduction. immunization against HBV infections in Women known to be pregnant should not persons at high risk of contracting the receive the vaccine. Pregnancy should be disease. avoided for 2 months following receipt of • CONTRAINDICATIONS: the measles vaccine, and 3 months Serious allergic reaction to a prior dose of following MMR vaccine. of this vaccine, or a vaccine component. • PRECAUTIONS AND WARNINGS, Such allergic reactions are rare. INTERACTIONS: • DOSAGE FORMS: -Use caution in patients with history of Vial. hypersensitivity to eggs, gelatin, or • RECOMMENDED DOSAGE: neomycin streptomycin. Refer to table-15.4, 5 & 6. Hepatitis B -In children with untreated malignant vaccine is given as a series of three disease or altered immunity, and those injections (shots). receiving immunosuppressive drugs or -There are 2 different manufacturers that radiotherapy, or high dose corticosteroids. produce Hep. B vaccines. Vaccines made -MMR vaccine should not be given within by different manufacturers are inter- three months of an injection of IG. changeable as long as the manufacturer’s -If MMR is to be given to adult women, dosage recommendations are always pregnancy should be avoided for 3 month followed. {Note that Recombivax HB dose is (as for rubella vaccine). 5 ug (0.5 ml), while Engerix-B dose is 10 ug -MMR and other measles-containing (0.5 ml) for persons < 20 years of age.} vaccines are not recommended for HIV- -Most preparations are intended for infected persons with evidence of severe intramuscular use only. Do not administer immunosuppression. intravenously or intradermally unless there • ADVERSE EFFECTS: are clear directions from the manufacturer. As with measles; malaise, fever, and/or -The vial should be stored at 2 – 8 ºC, and rash may occur, most commonly after not freezed. vaccination and lasting about 2-3 days. • USE IN SPECIAL CASES: Parotid swelling may occur usually in the Refer to introduction. No information is third week; children with post vaccination available about the safety of the vaccine in symptoms are not infectious. pregnant women. However, because the ______vaccine contains only particles that do not cause HBV infection, there should be no 7) Hepatitis B Vaccine WHO,P risk. Since the vaccine does not contain a live virus, it may be used in cases of • VACCINE SUMMARY: immunodeficiency. However, response to Hepatitis B vaccine contains inactivated the vaccination in such persons may be hepatitis B virus (HBV) surface antigen suboptimal. • (HbsAg) adsorbed on aluminum hydroxide PRECAUTIONS AND WARNINGS, adjuvant. It is made biosynthetically from INTERACTIONS: yeast cells using recombinant DNA -It takes 6 months to confirm if there is techniques. EPI recommends this vaccine adequate protection from the vaccine.

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Vaccines -The vaccine should be used with caution breathing, hypotension or shock) after in patients with severely compromised eating eggs or egg products. cardiopulmonary status. • DOSAGE FORMS: • ADVERSE EFFECTS & OVERDOSE: Vials. When given properly the vaccine is • RECOMMENDED DOSAGE: extremely safe. The most common side For adults and children > 3 years; 0.5 ml effect observed is soreness at the injection given IM or deep SC (0.25 ml to children site. < 3 yrs). Vaccination produces immunity If the vaccine is administered too deep, after about 14 days, lasting for about 6 local reaction, ulcers and regional months to 1 year, therefore vaccine is lymphadentitis may occur. administered annually during October- There have been rare reports of myalgia or November. Children aged 6 mon. - 9 yrs. arthralgia, neurological, abnormal liver receiving the vaccine for the first time, function and dermatological side effects. should get 2 doses at 1 mon. interval. ______• USE IN SPECIAL CASES: Refer to introduction. 8) Influenza Vaccine WHO Babies as young as 6 months can get influenza vaccine. Children may have • VACCINE SUMMARY: more side effects with influenza vaccine Inactive influenza vaccines are used for compared to adults (See Vaccine Summary). active immunization against influenza. Only the split-virus vaccine should be used Because of the periodic changes in the in children. surface antigens of influenza virus, the Administration to pregnant women is WHO makes annual recommendations considered safe, but may be administered concerning the antigenic nature of this after the first trimester as a precaution to vaccine. Medical personals need to be minimize any concern of theoretical risk. updated every year with the changes. This • PRECAUTIONS AND WARNINGS, vaccine is listed in the WHO 10th EDL for INTERACTIONS: use in specific groups of individuals. -Persons with acute febrile illnesses Influenza vaccine comes as whole-virus, normally should not be vaccinated until split-virus, or purified surface antigen. their symptoms have cleared. Only split-virus or purified surface antigen -Use caution in patients with allergy to vaccine should be used in children because thimerosal or sulfite additives. these forms of the vaccine do not cause as -Certain drugs activity has been reported to much fever as whole-virus vaccine. be enhanced with administration of • INDICATIONS: influenza vaccine: the anticoagulant As a measure to prevent influenza warfarin, phenytoin and theophylline. Use infection, specially in high risk groups such vaccine with caution. as elderly, persons with chronic disorder of • ADVERSE EFFECTS & OVERDOSE: the cardiovascular, pulmonary, and/or renal Local reactions such as pain, erythema, system, severe anemia, compromised swelling or/and itching at the site of immune function, that are at risk of severe injections have been reported. Mild complications or dying after an influenza systemic reactions such as headache, infection. abdominal pain, muscle aches and • CONTRAINDICATIONS: dizziness have occurred. Rarely neurologic Persons with a history of any signs and symptoms have occurred. symptoms of anaphylactic reactions (hives, ______swelling of the mouth and throat, difficulty

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9) Hib Vaccine Hib vaccination schedule: (Haemophilus Influenzae Type B) -HibTITER: 3 doses, 2 months apart, starting at 2 months of age, with a • VACCINE SUMMARY: booster at 12-15 months of age. Hib vaccine is used for active -PedvaxHIB: 2 doses, 2 months starting immunization against Haemophilus at 2 months of age, with a booster at influenzae type b infections, a gram (-) 12-15 months of age. bacteria, one of the major causes of -ProHIBIT: 1 dose at 15 months to 5 meningitis and other severe systemic years of age, no booster needed. illness in young children (< 5 yrs). This -Children aged 13-48 months should be polysaccharide (or related oligasaccharide) given a single dose since they are at lower vaccine is linked to a protein carrier to risk and the vaccine is effective after a form a conjugate vaccine, so as to enhance single dose in this age group. Routine use immunogenicity effect compared with non- in older children > 5 years or adults is not conjugated vaccine. At this time, the EPI recommended. has not adopted routine use of this vaccine -Vaccine may be given simultaneously until full cost data analysis would be with DPT, measles, BCG or Hep B, as well available. as with IG. • INDICATIONS: • USE IN SPECIAL CASES: Vaccination against Haemophilus influenzae The safety of the vaccine for pregnant type b infections. women has not been established. On • CONTRAINDICATIONS: theoretical grounds, avoid vaccination In immunocompromized individuals. unless there is a substantial risk of • DOSAGE FORMS: infection of the women. Freeze dried preparation. • PRECAUTIONS AND WARNINGS, • RECOMMENDED DOSAGE: INTERACTIONS: -There are different schedules for Use caution in patients with vaccination according to the product. hypersensitivity to eggs, diphtheria toxoid, Always refer to the manufacturer’s and thimerosal additive. directions. In general, the conjugate • ADVERSE EFFECTS & OVERDOSE: vaccine is given by deep subcutaneous or These are very mild, and may include intramuscular injection in doses of 0.5 ml, headache, myalgia, low grade fever (1 out for 3 to 4 doses. The vaccine may be given of 100 doses) or other minor symptoms. at 2-4 months, 4-6 months and 12-15 Very rarely encephalitis has followed months of age. vaccination, generally in infants under 9 months of age.

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Vaccines Specific References: − CDC. Atkinson WL, et al (editors). − CVI (Children’s Vaccine Initiative). 1999(Jan). Epidemiology and prevention of 1998(July). New Vaccines: Hib-who is vaccine-preventable diseases, 5th ed. Dept. using it, who isn’t and why not? CVI. 16: of Health & Human Services, CDC, 13-15. Altanta. − Dagon R, et al. 1994. Epidemiology of − CDC. 1994. General recommendations pediatric meningitis caused by on immunizations of the advisory Haemophilus influenzae Type b, committee on immunization practices Streptococcus pneumoniae, and Neisseria (ACIP). MMWR. meningitidis in Israel: a 3-year nationwide − CDC. 1998. Haemophilus Influenzae prospective study. J Infec Dis. 169: 912-6. Type B (Hib) Vaccine: fact sheet. Medical − De Quadros CA. 1995(Jan.-Feb.). A Strategies Inc. template for the world. WHO; 1(48th): 5-6. − CDC. 1993(Apr). Recommendations of − UNRWA. 1990. Instructions and the Advisory Committee on Immunization information on immunization. United Practices (ACIP): use of vaccines and Nations Relief and Works Agency for immune globulins in persons with altered Palestinian Refugees in the Near East. immunocompetence. MMWR: 42 (No. RR-4).

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Table of Contents

Preface …………………………………………………………………………………...…ix How to use this manual ………………………………………………………………… . xi Abbreviations …………………………………………………………………………… xiii Pregnancy Categories …………………………………………………………………… xv

CHAPTER 1: ANALGESICS, ANTIPYRETICS, ANTI-INFLAMMATORY AND ANTIGOUT DRUGS ...... 1 A) ANALGESICS, ANTIPYRETICS, AND ANTI-INFLAMMATORY AGENTS ...... 2 1) Acetylsalicylic Acid WHO,P...... 3 2) Paracetamol WHO,P...... 5 3) Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) ...... 7 B) ANTIGOUT AGENTS...... 12 1) Allopurinol WHO,P...... 12 2) Sulfinpyrazone...... 14 3) Colchicine WHO,P...... 16

CHAPTER 2: CARDIOVASCULAR DRUGS...... 18 A) ANTIHYPERTENSIVES...... 19 1) DIURETICS...... 22 a) Thiazide Diuretics: Hydrochlorothiazide WHO,P ...... 22 b) Loop Diuretics: Furosemide WHO,P...... 23 c) Potassium Sparing Diuretics: Spironolactone WHO,P...... 25 2) BETA – BLOCKERS...... 27 a) Propranolol P ...... 27 b) Atenolol WHO, P ...... 29 3) ANGIOTENSIN CONVERTING ENZYME INHIBITORS (ACEI) ...... 30 a) Captopril WHO,P...... 31 4) CA CHANNEL BLOCKERS...... 33 a) Nifedipine WHO,P ...... 34 b) Verapamil WHO,P ...... 35 B) ANTI-ARRHYTHMICS ...... 37 1) Amiodarone ...... 38 2) Lidocaine WHO,P ...... 40 3) Quinidine WHO,P ...... 40 C) ANTIANGINA...... 40 1) Isosorbide Dinitrate WHO,P...... 41 D) ANTICOAGULANTS ...... 42 1) Aspirin WHO,P ...... 43 2) Warfarin WHO,P ...... 43 E) CONGESTIVE HEART FAILURE DRUGS ...... 45 1) Digoxin WHO,P ...... 46 F) LIPID LOWERING DRUGS...... 48 1) Fibric Acids: Bezafibrate ...... 49 2) Bile Acid Sequestrants: Cholestyramine ...... 50 3) HMG-COA Reductase Inhibitors: Simvastatin...... 52

CHAPTER 3: GASTRO-INTESTINAL DRUGS ...... 53 A) ANTACIDS & ULCER HEALING MEDICATION...... 54 1) Mg/Al Salt WHO,P ...... 56 2) Ranitidine WHO,P ...... 57 3) Omeprazole ...... 58 B) ANTISPASMODICS/ ANTICHOLINERGICS...... 59 1) Hyocine N-butyl Bromide P ...... 60 C) ANTIEMETICS...... 61 1) Metoclopramide WHO,P...... 61 2) Meclozine/Meclizine...... 63 D) DRUGS USED IN DIARRHEA ...... 63 1) Oral Rehydrating Salts WHO,P ...... 66 2) Antidiarrheal Agent: Loperamide P ...... 67 E) LAXATIVES...... 68 1) Bisacodyl P...... 70 2) Castor Oil...... 70 3) Glycerin P...... 71 4) Psyllium...... 71 F) ANTI-HEMORRHOIDAL ...... 72 1) Anusol (or other equivalent preparation WHO,P)...... 73

CHAPTER 4: RESPIRATORY DRUGS ...... 75 A) ANTIHISTAMINES ...... 77 1) Chlorpheniramine WHO,P ...... 77 2) Astemizole...... 79 B) NASAL DECONGESTANTS...... 81 1) Oxymetazoline ...... 82 2) Pseudoephedrine ...... 83 C) EXPECTORANTS ...... 84 1) Ammonium Chloride...... 84 2) Guaifenesin...... 84 D) ANTITUSSIVES/ COUGH SUPPRESSANTS ...... 85 1) Codeine ...... 85 2) Dextromethorphan HBr WHO ...... 87 E) MUCOLYTICS ...... 88 1) Acetylcysteine...... 88 2) Bromhexine...... 88 F) BRONCHODILATORS & ASTHMA MEDICATION ...... 88 1) Theophylline WHO,P (or soluble salt derivatives)...... 91 2) Salbutamol / Albuterol WHO,P ...... 94 3) Cromolyn WHO,P / Cromoglycate...... 95 4) Beclomethasone Dipropionate WHO,P ...... 97 5) Prednisolone WHO,P...... 98

CHAPTER 5: ANTI-INFECTIVE DRUGS...... 101 A) ANTI-BACTERIALS...... 104 1) Penicillins (β-Lactam)...... 104 a) Benzylpenicillin WHO,P & Phenoxymethyl penicillin WHO,P ...... 105 b) Cloxacillin WHO,P & flucloxacillin: (Penicillinase resistant penicillins) ...... 108

c) Ampicillin WHO,P & Amoxicillin WHO,P (aminopenicillins) ...... 109 d) Amoxicillin with Clavulanic Acid (Co-amoxiclav) WHO,P...... 111 2) Cephalosporins: CephalexinP, Cefadroxil and Cefaclor...... 113 3) Tetracyclines: Tetracycline ...... 116 4) Macrolides: Erythromycin WHO,P...... 118 5) Sulphonamides and Trimethoprim P ...... 120 6) Nitrofurantoin WHO,P...... 122 7) Nalidixic Acid WHO,P ...... 124 8) Fluoroquinolones: Ciprofloxacin WHO,P ...... 125 B) ANTI-TUBERCULOSIS...... 126 1) Isoniazid WHO,P ...... 128 2) Rifampicin WHO,P...... 129 3) Pyrazinamide WHO,P ...... 131 4) Ethambutol WHO,P ...... 131 C) ANTI-PARASITICS ...... 132 1) Metronidazole WHO,P ...... 132 2) Diloxanide Furoate WHO ...... 135 3) Mebendazole WHO ...... 135 4) Niclosamide...... 136 5) Albendazole WHO...... 137 D) ANTI-FUNGALS...... 137 1) Nystatin WHO,P...... 137 2) Miconazole WHO,P ...... 138 3) Griseofulvin WHO,P...... 139 C) ANTIVIRAL AGENTS...... 140 1) Acyclovir...... 140

CHAPTER 6: ENDOCRINE SYSTEM DRUGS ...... 143 A) ANTIDIABETIC DRUGS ...... 144 1) Insulin WHO,P ...... 146

2) Glibenclamide /Glyburide WHO,P ...... 149 3) Metformin WHO,P ...... 151 B) THYROID DRUGS...... 153 1) Thyroxine WHO,P ...... 153 2) Propylthiouracil WHO,P...... 155 C) CORTICOSTEROIDAL DRUGS ...... 156 1) Prednisone WHO,P ...... 158

CHAPTER 7: CONTRACEPTIVE PREPARATIONS...... 161 A) CONTRACEPTIVE DEVICES & BARRIERS...... 162 1) Intra-Uterine Devices (IUDs)...... 162 2) Spermicides and Condoms ...... 163 B) HORMONAL PREPARATIONS...... 164 1) Estrogenic and Combined Oral Contraceptives WHO,P ...... 164 2) Progestin-Only Products...... 168 a) Oral Progestogen-only Preparations ...... 168 b) Injectables: Medroxy-progesterone acetate WHO,P...... 169 c) Implants: Levonorgestrel...... 170 3) Emergency Pills...... 171

CHAPTER 8: PSYCHOTHERAPUTIC DRUGS...... 173 PSYCHOACTIVE DRUGS:...... 174 A) ANTIDEPRESSANTS...... 174 1) Amitriptyline WHO,P...... 175 2) Imipramine P...... 177 3) Fluoxetine...... 178 B) HYPNOTICS AND ANXIOLYTICS...... 180 1) Diazepam WHO,P ...... 181 2) Lorazepam...... 182 C) NEUROLEPTICS...... 183 1) Chlorpromazine WHO,P ...... 184 2) Haloperidol WHO,P...... 186 ANTICONVULSANT / ANTIEPILEPTIC DRUGS:...... 188 1) Carbamazepine WHO,P ...... 190 2) Clonazepam WHO,P ...... 192 3) Ethosuximide WHO,P ...... 194 4) Phenobarbital WHO,P ...... 195 5) Phenytoin WHO,P...... 197 6) Valproic Acid WHO,P ...... 198 7) Diazepam WHO,P ...... 181 ANTIPARKINSONS DRUGS: ...... 201 A) ANTICHOLINERGIC DRUGS...... 202 1) Benztropine Mesylate ...... 202 2) Trihexyphenidyl P ...... 203 B) DOPAMINERGIC DRUGS ...... 204 1) Amantadine...... 204 2) Bromocriptine P ...... 205 3) Carbidopa/Levodopa WHO,P...... 207

CHAPTER 9: OPHTHALMIC PREPARATIONS...... 209 A) ANTI-INFECTIVE PREPARATIONS...... 210 1) Antibiotics: Tetracycline WHO,P Chloramphenicol WHO,P, Framycetin, Gentamicin WHO,P, and Neomycin...... 211 2) Antivirals: Idoxuridine WHO ...... 213 B) ANTI-INFLAMMATORY PREPARATIONS ...... 214 1) Corticosteroids: Betamethasone WHO,P ...... 214 2) Other Anti-Inflammatory Preparations: Cromoglycate P /Cromolyn...... 216 C) β-BLOCKERS...... 216 1) Timolol WHO,P...... 217 D) MYDRIATICS & CYCLOPLEGICS ...... 219 1) Atropine Sulphate WHO,P ...... 219 E) MISCELLANEOUS OPHTHALMIC PREPARATIONS USED ...... 220

CHAPTER 10: OTIC PREPARATIONS...... 221 A) DRUGS USED FOR OTITS EXTERNA...... 222 B) DRUGS USED FOR OTITIS MEDIA...... 223 C) DRUGS USED FOR EAR WAX ...... 225

CHAPTER 11: DERMATOLOGICALS ...... 229

A) EMOLLIENTS & HUMECTANTS...... 230 1) Vaseline...... 231 2) Glycerin...... 231 B) ANTIPRURITICS, ANTIHISTAMINES & LOCAL ANESTHETICS...... 232 1) Zinc Oxide / Calamine WHO,P ...... 232 2) Lignocaine / Benzocaine ...... 232 C) ANTIFUNGALS ...... 233 1) Miconazole WHO,P ...... 233 2) Ketoconazole ...... 234 3) Tolnaftate ...... 235 D) ANTIBACTERIALS...... 236 1) Oxytetracycline...... 236 2) Neomycin WHO,P or Gentamicin...... 236 E) ANTIVIRALS ...... 237 1) Acyclovir...... 237 F) ANTISEPTICS/ DISINFECTANTS...... 238 1) Ethyl Alcohol (Ethanol) P ...... 238 2) Povidone-Iodine WHO,P...... 238 3) Cetrimide...... 239 4) Chlorhexidine WHO,P ...... 239 G) ANTIPARASITICS...... 240 1) SCABICIDES: Benzyl Benzoate WHO,P,Crotamiton ...... 241 2) PEDICULICIDES: Malathion, Lindane...... 242 H) KERATOLYTIC AGENTS ...... 244 1) Salicylic Acid WHO ...... 244 2) Sulfur...... 245 I) MISCELLANEOUS ...... 245 1) TOPICAL CORTICOSTEROIDS: Betamethasone Valerate WHO,P...... 246 2) PREPARATIONS FOR ACNE: Retinoic Acid (Tretinoin) & Benzoyl Perxoide...... 25050 3) SUNSCREENS...... 251

CHAPTER 12: VITAMINS AND MINERALS...... 255 A) VITAMINS ...... 256 B) MINERALS...... 262

CHAPTER 13: VACCINES ...... 267 VACCINATION AND IMMUNIZATION...... 268 1) BCG WHO,P ...... 276 2) OPV / IPV WHO,P ...... 276 3) Tetanus Vaccine WHO,P...... 277 4) DPT WHO,P...... 278 5) Measles Vaccine WHO,P ...... 279 6) MMR Vaccine WHO,P ...... 279 7) Hepatitis B Vaccine WHO,P ...... 280 8) Influenza Vaccine WHO ...... 281 9) Hib Vaccine...... 282

APPENDIX A – PRICE LIST...... A-01 • ANALGESICS, ANTIPYRETICS, NON-STEROIDAL, ANTI-INFLAMMATORY, AND ANTIGOUT DRUGS ……………………………………………………..……………………... A-01 • CARDIOVASCULAR DRUGS ………………………………………………………..……... ……… A-04 • GASTROINTESTINAL DRUGS ………………………………………………………..…………..… A-07 • RESPIRATORY DRUGS ……………………………………………………………..…..…………… A-10 • ANTI-INFECTIVES …………………………………………………………………..……………..… A-15 • ENDOCRINE DISORDER DRUGS ………………………………………………..………………. A-21 • CONTRACEPTIVE PREPARATIONS ……………………………………………..…………….…. A-22 • ANTIEPILEPTICS …………………………………………………………………..….…………….. A-24 • ANTIPARKINSONISM ………………………………………………………………..….…….….…. A-25 • PSYCHOACTIVE DRUGS …………………………………………………………..….……….…… A-26 • OPHTHALMIC PREPARATIONS …………………………………………………….……..……… A-27 • OTIC PREPARATIONS …………………………………………………………………...….…….... A-29 • DERMATOLOGICALS …………………………………………………………………...…….……. A-30 • VITAMINS AND MINERALS ……………………………………………………………...……….… A-35 • VACCINES ……………………………………………………………………………………………... A-40

APPENDIX B – DEFINITIONS ...... A-42

APPENDIX C – SUMMARY OF DRUGS USED FOR ALLERGIC REACTION OR ANAPHYLACTIC SHOCK...... A-45

APPENDIX D – PHARMACEUTICAL COMPANIES AND DRUG STORES …. A-46

REFERENCES ...... A-48

GENERAL INDEX

Appendix

General Index

Amitriptyline, 175, A26 Artofen, 9 Ammonium chloride, 84 Ascorbic acid, 262, A35 A Amoxi, 111 Asmalin, 95 α-Methyldopa, 20 Amoxicare, 111 Aspirin, 2, 12, 43, A1 Abitren, 10, A2 Amoxicillin, 109, 224, A16 Assival, 182, A26 Abrolet, 6 Ampicillin, 109, A15 Astemizole, 78, 79 Acamol, 6, A1 Ampipharm, 111 Asthma Medication, 88, Acamoli, 6 Ampitricine, 111 A11 Acarbose, 144 Amyvil, 177 Astringents, 73 ACE Inhibitors, 30, 46, A5 Anabolic steroids, 149 Ateni, 30 Acebutolol, 38 Analgesics, 2 Atenolol, 29, A4 Acetaminophen, 5, A1 Anaphyl, 79 Athletes Foot, 236 Acetazolamide, 216 Ancozine, 63 Ativan, 183 Acetic acid, 222 Angilat, 35 Atroped, 220 Acetohexamide, 144 Antacids, 54, 55, A7 Atropine, 59, A28 Acetosal, 5 Anthranilites, 253 Atrospan, 220 Acetylcysteine, 88, 220, Antiarrhythmic, 197 Augmentin, 112 A14 Anticholinergic agents, 59, Avobenzone, 253 Acetylsalicylic Acid, 3, A1 201, A25 Antidepressants, 174 Acne Mask, 251 B Acrivistine, 78 Antidiabetic Drugs, 144, Actifid, A13 A21 β-blockers, 27, 149 Acyclovir, 140, 237 Antidiarrheal Agent, 63, 67 Baby Aspirin, 5, A1 Adalat, 35 Antiemetics, 61 Bacampicillin, 109 Adenosine, 38 Antigout Agents, 12 Bacitracin, 236 Adinol, 232 Anti-Hemorrhoidal, 72, 73, Bacloforte Inhaler, 98 Advil, 9 A9 Bactosept, 240 Aerolin, 95 Antihistamines, 77, A10 Bactrim, 122 Affectine, 179 Antihypertensives, 19 Bactroban, 236 Ahiston, 79 Anti-Infectives, 102, A15 Bactroscrub, 240 Albendazole, 137 Antiparasitics, 132 Barbiturates, 180 Albuterol, 94 Antiparkinsons Drugs, 201, BCG vaccine, 274, 276 Aldactone, 26 A25 Beclomethasone, 97, A12 Aldosprine, 26 Antipyretic, 2 Beconase Nasal, 98 Alka Seltzer, 5 Antituberculous Drugs, Becotide Inhaler, 98 Allergon, 79 126, 127 Benazepril, 31 Allopurinol, 12, 93, A3 Antitussives, 85 Benzene hexachloride, 242 Alloril, 14 Antivert, 63 Benzhexol, 202 Alprazolam, 180 Antiviral Agent, 140, A20 Benzocaine, 72 Alrin, 83 Anturane, 16 Benzocide, 241 Aluminium acetate Anusol, 73, A9 Benzodiazepines, 180, 182 solution, 222 Anxiolytics, 180 Benzophennones, 253 Amantadine, 204 A-parkin, 205 Benzoyl peroxide, 250 Amiloride, 25, A6 Apomoxyn, 111 Benzthiazide, 22 Aminobenzoic acid, 253 Aprical, 35 Benzyl benzoate, 240, A32 Amiodacore, 40 Artan, A25 Benzylkonium chloride, Amiodarone, 38, A5 Artix, 72 163

Benzylpenicillin, 105 Ceclor, 116, A17 Clarithromycin, 55, 119, Bepen, 108 Cefacare, 116 224 Betadine, 239 Cefaclor, 114, 115 Clemastine, 78 Betamethasone, 157, 214, Cefadrox, 116, A17 Clobazam, 180 225, 246, 248 Cefadroxil, 114, 115 Clobetasol, 248 Betaren, 10 Cefalex, 116 Clofibrate, 49 Bezafibrate, 49 Cefamandole, 114 Clomipramine, 174 Bezalip, 50 Cefazolin, 114 Clonazepam, 180, 192 Bicide, 243 Cefoperazone, 114 Clonex, 194 Biodroxil, 116 Ceforal, 116 Cloroyate, 79 Bisacodyl, 70, A9 Ceforanid, 114 Clotrimazole, 233 Bisoprolol, 27 Cefotaxime, 114 Cloxacillin, 105 Blocardril, 29 Cefotetan, 114 Clozapine, 184 Bonine, 63 Cefovit, 116 Co-amoxiclav, 111 Bretylium, 38 Cefoxitin, 114 Co-careldopa, 207 Brimocyclin, 118 Ceftazidime, 114 Cocoa Butter, 73 Bristamycin, 120 Ceftizoxime, 114 Codeine Phosphate, 85, 87, Broadacillin, 111 Ceftriaxone, 114 A10 Bromhexine, 88, A11 Cefuroxime Axetil, 114, Codical, 87 Bromocriptine, 205, A25 224 Cogentin, 203 Brompheniramine, 78 Celiprolol, 27 Colchicine, 12, 16, 17, A3 Brufen, 9 Cephalexin, 113, 115, A17 Colestipol, 51 Buffered Aspirin, 5 Cephalosporins, 113, A17 Coldex, A13 Bufsa, 5 Cephalothin, 114 Colifibrate, 149 Bumetanide, 23 Cephapirin, 114 Contraceptives, 149, 164, Bupropion, 174 Cephradine, 114 A22 Butoconazole, 233 Cetrimide, 239 Copper IUDs, 162 Chloramphenicol, 211, 223, Cordil, 42 A27 Cordorone, 40 C Chlorbutol, 225 Corotenol, 30 Caladerm, 232, A30 Chlordiazepoxide, 180 Corotrend, 35 Calamine, 73, 232, 245, Chlorhexidine, 223, 239, Corticosteroids, 149, 211, A30 A32 214, A27, A33 Calatrim, 232 Chlorotetracycline, 212 Cortisone, 157 Calcium, 263, 265, 266, Chlorothiazide, 22 Co-trimoxazole, 120 A35 Chlorpheniramine, 77, A10 Cough suppressants, 85 Calcium Channel Blockers, Chlorpromazine, 184 Coumadin, 45 33 Chlorpropamide, 144 COX-2, 7 Candistan, 138 Chlorthalidone, 22 Cromoglycate, 95 Capillon, 239 Cholestyramine, 49, 50 Cromolyn, 95, 216, A12 Caplenal, 14 Chol-Less, 51 Cromunal, 97 Capoten, 33 Cilazapril, 31 Crotamiton, 241, A32 Captopril, 14, 20, 31, A4 Cinnamates, 253 Curam, 112 Carbamazepine, 190, A24 Cinoxacin, 125 Cyproheptadine, 78 Carbi, 192 Cinoxate, 253 Ciprocare, 126 Carbidopa, 207, A28 D Cardiovascular Drugs, 18, Ciprofloxacin, 125, 212, A4 A19 Dakatrin, 139 Cardopril, 33 Ciprogis, 126 Daktarin, 234 Cartia, 5 Ciproxin, 126 Daktazol, 139, 234 Cascara, 69 Citalopram, 174 Daonil, 151, A21 Castor oil, 69, 70 Clamoxin, 109 Declamide, 151

Decongestants, 81 Emergency Pill, 171 Fludrocortisone, 156 Deltasone, 160 Emestop, 62 Fluorine/Fluoride, 265, A36 Depakote, 200 Emollients, 230 Fluorometholone, 214 Depalept, 200 E-Mycin, 120 Fluoroquinolones, 125, A18 Deraline, 29, A4 Enalapril, 31 Fluosinolone, 248 Dermatological Encainide, 38 Fluoxetine, 174, 178, A26 Preparations, 230, A30 Endep, 177 Fluoxicare, 179 Desipramine, 174, 176 Engerix, 284, A41 Flutine, 179 Desogestrel, 165 Enoxacin, 125 Fluvoxamine, 174 Dexamethasone, 157 Entogyl, 133 Folic acid, 260, 261, A35 Dexamol, 6, A1, A13 Epanutin, 198, A24 Fungazole, 234 Dextromethorphan, 87 Ephedrine sulphate, 74 Fungitirin, 234 Dextrothyroxine, 149 Erytab, 120 Furadantin, 124 Diabeta, 151 Erythrocare, 120 Furamide, 135 Diasix, 25 Erythrocin, 120 Furosemide/Frusemide, 20, Diazepam, 180, 181, A26 Erythrolet, 120 23, A4 Dichlorphenamide, 216 Erythromycin, 118, A17 Furovite, 25 Diclofen, 10 Erythroped, 120 Fusid, 25, A4 Diclofenac, 7, 220, A2 Erythropharm, 120 Diflorasone, 248 Erythroteva, 120 G Digitalis glycosides, 46 Esidrex, 23 Digitoxin, 46 Esmolol, 27, 38 Gabapentin, 188 Digoxin, 46, 61, A6 Esracain, 233 Garamine, 237 Dilantin, 198 Estrogens, 164 Garamycin, 237 Dilatam/dilapress, 37 Ethacrynic acid, 23 Gastro-Intestinal Drugs, 53, Diloxanide furoate, 135 Ethambutol, 127, 131 A7 Diltiazem, 20, 41, 149, A5 Ethanol, 238 Gemfibrozil, 49 Dioxybenzone, 253 Ethinyl estradiol, 164, 171 Gentamicin, 211, 236, A27, Diphenhydramine, 78 Ethosuximide, 194, A24 A31 Dipyrone, 3 Ethyl alcohol, 238 Gentatrim, 237 Diseptyl, 122 Ethynodiol, 165 Gestodene, 165 Disopam, 182 Expanded Program of GI-Care, 58 Disopyramide, 38 Immunization, 271 Glibenclamide/ Glyburide, Disoramin, 79 Expectorants, 84, A10 144, 149, A21 Disothiazide, 23 Glibetic, 151 Diuretics, 22, 46, A4 F Gliclazide, 144 Docusate, 69 Glimepiride, 144 Dopaminergic Agents, 201 Famotidine, 55 Glipizide, 144 Dopicar, 208 Fat Soluble Vitamins, 257, Gluben, 151 Doxepin, 174 A35 Glucocare, 151 Doxycycline, 64, 116 Febramol, 6, A1 Glucomet, 153 DPT, 273, 278, A40 Fedral, 95 Glucomin, 153 Duracef, 116 Felcol, 12 Gluconil, 151 Dyprotex, 232 Feldene, 12 Glucophage, 153 Felodipine, 33 Glycerin, 69, 71, 73, 231, E Femulen, 169, A23 A9 Fenoxypen, 108 Glyceryl guaiacolate, 84 Econazole, 233 Flagy, 133, A19 Glyphillin, 94 Elatrol/Elatrolet, 177 Flecainide, 38 Granexin, 125 Elavil, 177 Floxin, 126 Grifulin, 140 Electrosubs, 67 Flucloxacillin, 105, 108, Griseofulvin, 139 Eltroxin, A21 223, A15 Guaifenesin, 84

Guanethidine, 20, 216 Inhibace, 33 Lidocaine, 40 Gynera, 167, A22 Insulin, 146, A21 Lignocaine, 220, 232 Gyno-Daktarin, 139 Iodine, 266, A31 Lindane, 242 Gyno-Daktazol, 139 Iodocare, 239 Lipastop, 68 Iodo-Vit, 239 Lipid Lowering Drugs, 48, IPV, 276 A6 H Iron, 264, 265, A36, A37 Liquidone, 144 Isardipine, 33 Lisinopril, 31 H2-antagonists, 54, 55 Halazepam, 180 Isocarboxide, 174 Lispro, 146 Haldol, 187 Isocardide, 42 Lispro insulin, 144 Halidol, 187 Isofen, 9 Lithium, 175 Haloper, 187 Isoniazid, 127, 128, A19 Locacid, 250 Haloperidol, 61, 184, 186, Isophane insulin, 144 Local Anesthetics, 72 A26 Isophane-NPH, 146 Locid, 59 Harmonal, 182 Isoproterenol, 94 Lomefloxacin, 125 Hemoral, 74 Isordil, 42 Lomudal, 97 Hep. B vaccine, 280, A41 Isosorbide dinitrate, 41, A5 Loop diuretics, 23 Hib vaccine, 282 Isosorbide mononitrate, 41 Loperamide, 67, A8 HibTITER, 282 Isotard, 42 Loperid, 68 Hiconcil, 111 IUD, 162 Lorainide, 38 Hismal, 80 Loratadine, 78 Lorazepam, 180, 182, A26 Hismanal, 80 J Homosalicylate, 253 Lorivan, 183 Humulin, 149 Jeflex, 116 Lorocare, 183 Hydralazine, 20 Jordacycline, 236 Losec, 59 Hydran 60, 67 Lovastatin, 49, 52 Hydrochlorothiazide, 20, K 22, A4 M Hydrocortisone, 73, 97, K, 267 156, 248 Keflex, 116 Maalox, 57 Hydrocortisone acetate, 214 Ketoconazole, 234, A31 Macrodantin, 124 Hydroxyethylcellulose, 220 Klonopin, 194 Macrofuran, 124 Hyocine N-butyl Bromide, Macrolides, 93 60, A8 Magnagel, 57 Hypnotics, 180, A26 L Magnicillin, 109 Malathion, 241 Labetolol, 27 MAO Inhibitors, 149 I Lactase, 64 Maprotiline, 174 Lactopar, 207 Ibufen, 9 Measles Vaccine, 274, 276, Lactulose, 69 A40 Ibuprofen, 7, 8, A2 Lahistan, 80 Ikacor/Ikapress, 36 Meclizine/Meclozine, 61, Lamotrigine, 188 63, A8 Imipramine, 177, A26 Lanoxin, 48 Imodium, 68 Medroxy-progesterone Lansoprazole, 55 acetate, 169 Indapamide, 22 Largactil, 186 Indocaps, 11 Megacare, 109 Lasix, 25 Megalat, 35 Indocin, 11 Laxatives, 68, 69, A9 Indomed, 11 Mepral, 59 Levodopa, 207 Mestranol, 164 Indomethacin, 7, A3 Levofloxacin, 125 Indopharm, 11 Metamucil, 72 Levonorgestrel, 165, 170, Metaproterenol, 94 Indovis, 11 A22 Influenza vaccine, 93, 281, Metformin, 144, 145, 151, Levothyroxine, 153 A21 A41 Levozem, 37

Methicillin, 108 Nifedipine, 20, 34, 41, A5 P Methylcellulose, 69 Nimodipine, 33 Metoclopramide, 61, A8 Nisoldipine, 33 Padimate O, 253 Metolazone, 22 Nitrates, 40 Pamol, 6 Metoprolol, 27, A41 Nitrazepam, 180 Pantoprazole, 55 Metrocare, 133 Nitrofurantoin, 122, A18 Paracare, 6 Metrogyl, 133 Nitroprusside, 20 Paracetamol, 5, A1 Metronidazole, 55, 132, Nizatidine, 55 Parafin, 69 A19 Nizoral, 235 Paramol, 6 Metrozole, 133 Nonoxinol ‘9’, 163 Paramolan, 6 Metyrosine, 20 Nordette, 167, A22 Paravomine, 63 Mexiletine, 38 Norethisterone, 165 Parazine, 243 Mg/Al Salt, 56, A7 Norfloxacin, 125 Parilac, 207 Miconazole, 138, 233, A20, Norgestimate, 165 Parlodel, 207 A30 Norlip, 50 Paroxetine, 174 Microdiol, 167 Normalol, 30 Partivel, 205 Miglitol, 144 Normiten, 30 Pathoprim, 122 Mineral oil, 73 Norplant, 171 PedvaxHIB, 286 Minerals, 264, A35 Nortriptyline, 174, 176 Penbutolol, 27 Minocycline, 116 Nosacare, 83 Penibrin, 111 Minoxidil, 20 Nouryl, 242 Penicillins, 105, A15 Miphar, 25 Novolin, 149 Pentrexyl, 111 MMR vaccine, 274, 279, Novomit, 62 Peridol, 187 A40 NSAIDs, 2, 7, 8, 9, 10, 12, Peridor, 187 Moclobemide, 174 16, A2 Petrolatum, 231 Mono-Amine Oxidase Nurofen, 9 Pharmaprim, 122 Inhibitors, 174 Nystatin, 137, 233, A19 Phenelzine, 174 Moricizine, 38 Phenobarb, 197 Motrin, 9 O Phenobarbital, 195 Moxepharm, 111 Phenobarbitone, 195 Moxypen, 111 Octyl salicylate, 253 Phenolphthalein, 69 Moxyvit, 111 Ofloxacin, 125, 212, 224 Phenoxymethyl-penicillin, Mucolytics, 88, A11 Ogmin, 112 105 Mupirocin, 236, A31 Omeprazole, 55, 58, A7 Phenylephrine, 73, 81, A13 Mycobutin, 130 Opthalmic Preparations, Phenylpropanolamine, 81, 210, A27 A13 N Opticrom, 216 Phenytoin, 38, 177, 190, OPV, 274, 276 191, 197, A24 Nadolol, 27 Oral Rehydrating Salt Pilocarpine, 216 Nalcrom, 97 (ORS), 66, 67, A8 Pindolol, 27 Nalidixic acid, 124, A18 Otic Preparations, 222, A29 Pioglitazone, 144 Naphazoline, 81 Oxazepam, 180 Pirox, 12 Naproxen, 7, A2 Oxcarbazepine, 188 Piroxicam, 7, 11, A3 Nasivin, 83 Oxprenolol, 27 Pitrex, 236 Nazal Decongestants, A10 OXY, 251 Pivampicillin, 109 Nefazodone, 174 Oxybenzone, 253 Polycarbophil, 69 NegGram, 125 Oxybuprocaine, 220 Polydine, 239 Neomycin, 223, 236 Oxycin, 236 Polymixin B, 212, 236 Neuroleptics, 183 Oxy-clean, 244 Potassium, 266 Niacin, 261 Oxymetazoline, 81, 82, Potassium-Sparing Niclosamide, 136 A10 Diuretics, 25 Nicotinic Acid, 49 Oxytetracycline, 236, A31 Povidone-Iodine, 238, A31

Pramin, 62 R Simvastatin, 49, 52 Prazepam, 180 Sincomen, 26 Prazosin, 20 Rabeprazole, 55 Sinemet, 208 Prednisolone, 157, 214, 225 Rafapen, 108 Sinoptic, 218 Prednisone, 98, 157, 158, Ramipril, 31 Somophyllin, 94 160, A12 Randin, 58 Sotalol, 27, 38 Prednitab, 160 Ranitidine, 57 Sparfloxacin, 125 Prelosec, 59 Ratidine, 58 Spermicides, 163 Pressolat, 35 Razimol, 6 Spironolactone, 20, 25, A4 Primonil, 178 Recombivax HB, 284 Sporofulvin, 140 Prioderm, 242 Reglan, 62 Stomagel, 57 Prizma, 179 Rehidrat, 67 Stopit, 68 Probenecid, 11 Repaglinide, 144 Sulfatrim, 122 Probucol, 49 Reserpine, 20 Sulfinpyrazone, 14 Procainamide, 38 Resperidone, 184 Sulfisoxaole, 224 Procaine Penicillin, 107 Respiratory Drugs, 75 Sulfonylureas, 144 Procar, 40 Resprim, 122 Sulfur, 245 Prochlorperazine, 61, 184 Resyl, 85 Sulisobenzone, 253 Procyoxylene, 74 Retavit, 250 Sulphonamide, 120 Progesterones, 164, 168 Retin-A, 250 Sulpiride, 184 Progestin-Only Products, Retinoic Acid, 249 Sulprim, 122 168, A23 Rhinoclir, 83 Sunscreen Products, 252, ProHIBIT, 286 Rhumacare, 10 A34 Prolol, 29 Rifampin/rifampicin, 127, Supradyn, A39 Promazine, 184 129, A19 Symmetrel, 205 Promethazine, 61, 78 Rimactan, 130 Propranolol, 20, 27, 30, 41, Rivotril, 194 T A4 Robutussin, 85 Propylthiocil, 156 Rosiglitazone, 144 Taroctyl, 186 Propylthiouracil, 155, A21 Rufenal, 10 Td vaccine, 282, A40 Protectants, 73 Tegrepine, 192 Proton Pump Inhibitors, 54 S Tegretol, 192 Protriptyline, 174 Temocillin, 109 Proxymetacaine, 220 Terconazole, 233 Prozac, 179 Salbutamol, 94, A12 Salbuvent, 95 Teril, 192 Pseudoephedrine, 81, 83, Tetanus vaccines, 281, A40 A10 Salicylates, 149 Salicylic Acid, 246, 244, Tetracare, 236 Psychotheraputic Drugs, Tetracyclines, 116, 212, 173, A26 A32 Salisol-2, 244 A17, A31 Psyllium, 69, 71, A9 Tetrapharm, 118, 236 Pyrazinamide, 12, 127, 131 Saralasin, 20 Scabicide, 241 Tevacycline, 118, 236 Pyrithione Zinc, 246 Theo-dur, 94 Pyrocard, 16 Scabiex, 241 Scobutyl, 61 Theopharm, 94 Scopal, 61 Theophylline, 15, 91, A11 Q Selective Serotonin Theotard, 94 Reuptake Inhibitors, 174 Theotrim, 94 Questran, 51 Selenium Sulfide, 246 Thiazide, 149 Quinapril, 31 Senna, 69 Thiazolidinediones, 145 Quinidine, 40 Serepam, 182 Thioridazine, 184 Sertraline, 174 Thioxanthenes, 184 Simigel, 57 Thorazine, 186 Simovil, 52

Thyroid Hormones, 93, U Vitamin C, 260 149, 153 Vitamin D, 198, 257 Thyroxine, 153, A21 U-Gram, 125 Vitamin E, 257 Tiloptic, 218 Ulcer Healing Drugs, 54 Vitamin K, 257 Timolin, 218 Uniscrub, 240 Vitamins, 256, A35, A37 Timolol, 27, 217, A28 Urantoin, 124 Vitapen, 111 Tinaderm, 236 Uricnase, 14 Volmax, 95 Tinasol, 236 Urigram, 125 Voltaren, 10 Titanium dioxide, 253 Urix, 25 Voltin, 10 Tobramycin, 212 Tocainide, 38 W Tofranil, 178 V Tolazamide, 144 Warfarin, 43 Tolbutamide, 150 Vaccines, 268, A40 Valium, 182 Water Soluble Vitamins, Tolnaftate, 233, 235, A31 256, A35 Topical Antifungals, 233 Valporal, 200 Valproate, 198 White petrolatum, 73 Topical corticosteroids, 246 Wormex, 136 Torsemide, 23 Valproic Acid, 198 Tranquilizers, 186 Vaseline, 231, 245, A30 Tranylcypromine, 174 Vasoconstrictors, 72 X Trazodone, 174 Venlafaxine, 174 Tretinoin, 249 Ventocare, 95 Xylene, 233 Triamcinolone, 157, 248 Ventolin, 95 Xylometazoline, 81, 82 Triamterene, 25 Ventomin,95 Verac, 36 Triazolam, 180 Z Trichonazole, 133 Verapamil, 20, 35, 41, A5 Tricyclic Antidepressants, Vermacare, 136 Zadstat, 133 174 Vermazol, 136 Zantab, 58 Trihexyphenidyl, 202 Vermox, 136 Zantac, 58 Trimethoprim, 120 Viarex Inhaler, 98 Zarontin, 195 Trimpramine, 174 Vicrom, 97 Zinc oxide, 73, 232, 253 Triprolidine, 78 Vical, A39 Zinc sulphate, 220 Troglitazone, 144 Vigabatrin, 188 Zino Pads, 244 Trufen, 9 Virax, 238 Zocor, 52 Tryptal/Tryptalette, 177 Vitamin A, 257, A35 Zovirax, 141, 238 Tylenol, 6 Vitamin B1, 259 Zylol, 14 Vitamin B12, 259 Vitamin B6, 259

Appendix A – Price List

This list of drugs is based on the September 2002 cost price list from Palestinian drugstores and pharmacies. Drug prices constantly change in the Palestinian market so this information is to be used only as a guide for health professionals.

A- 1 A- 2 ANALGESICS, ANTIPYRETICS, NON-STEROIDAL ANTI-INFLAMMATORY, AND ANTIGOUT DRUGS

SELLING BRAND NAME STRENGTH DOSAGE MANUFAC- PRICE (NIS)/ # OF DOSAGE Name FORM TURER Generic FORM A) Analgesics, Antipyretics, and Non-Steroidal Anti-Inflammatory Agents ACETOSAL 300mg Tab. Rekah 9.00/40

500mg Tab. 10.00/20 ALKA SELTZER 324mg Efferv. Tab. Agis 8.00/10

(ASA) ASA 325mg

ASCRIPTIN Tab. RP Rorer 21.00/100 (ASA with antacid) AlOH 75mg MgOH 75mg ASPIRIN 81 81mg E.C. Tab. Bayer 16.00/30 ASPIRIN 100mg Tab. 10.00/30 BABY ASPIRIN 100mg Chew. Tab. JCL 6.00/20 CARTIA 100mg Tab. SK Beecham 16.00/28

Acetylsalicylic Acid MICROPIRIN 75mg Tab. Dexxon 30.00/10 TEVAPIRIN 100mg E.C. Tab. Teva 11.00/30 ABROL 500mg Tab. Rekah 5.00/30 ABROLET 150mg Supp. Rekah 10.00/12 250mg 14.00/5 ACAMOL 500mg Tab. Teva 11.00/20 ACAMOLI 80mg Chew. Tab. Teva 13.00/50 150mg Supp. 12.00/12 125mg/5ml Syr. (Stwbry) 13.00/100ml ALDOLOR 500mg Tab. CTI 14.00/50 100mg/ml Drops 13.00/20ml 120mg/5ml Syp. Sugar free 8.00/110ml DEXAMOL 500mg Cap. Dexxon 27.00/50

DEXAMOL KID 250mg Chew. Tab. Dexxon 12.50/20 125mg/5ml Syp (Stwbry 12.00/115ml or Cola) FEBRAMOL 500mg Tab. BPC 5.00/20

Paracetamol 120mg/5ml Syp (Stwbry) 7.00/100ml 150mg Supp. 5.00/6 300mg Supp. 7.00/6 OTAMOL 500 mg Tab. JePharm 5.00/20 120mg/5ml Syp (Stwbry) 9.00/120ml 300mg Suppository 5.00/5 PAMOL 150mg Supp. Eastern Chem. 5.00/5 300mg Supp. 5.00/5 500mg Supp. 8.00/5 125mg/5ml Syrup 7.00/100ml PARACARE 500mg Tab. Pharmacare 4.00/20 Syrup 7.50/100ml

A- 3 PARAMOL 500mg Tab. JCL 5.00/20 125mg/ml Syrup 7.00/100ml 150mg Supp. 3.00/5 300mg Supp. 3.50/5 500mg Supp. 6.50/5 30mg Chew. Tab. 10.00/20 ADEX 200 200mg Cap. Dexxon 13.60/30 ADEX 400 400mg 22.00/30 ARTOFEN 200mg Tab. Teva 12.00/20 400mg Tab. 22.00/50 600mg Tab. 22.00/30 BRUFEN 400 400mg Tab. Boots 16.00/30 IBUFEN 400mg Cap. Dexxon 13.00/30 600mg Cap. 18.30/30 ISOFEN 200mg Tab. JCL 7.00/20

Ibuprofen 400mg 15.00/20 NUROFEN 200mg Tab. Boots 16.00/12 24.00/24 TRUFEN 200mg Tab. JePharm 5.00/20 400mg Tab. 10.00/20 600mg Tab. 8.00/20 100mg/5ml Susp. (Orange) 15.00/100ml APO-NAPROXEN 250mg Tab. Apotex 33.00/30 500mg 65.00/30 NAPREX 250mg Tab. BPC 20.00/20 500mg Tab. 12.50/10 500mg Supp. 18.50/12 NAPROXI 250mg Tab. Gerard 29.00/5

Naproxen 500mg Tab. 29.00/5 NAXYN 250mg Tab. Teva 59.00/50 500mg Tab. 26.00/30 500mg Supp. 38.30/12 ABITRENE 25mg Tab. Abic 8.00/20 50mg Supp. 19.00/10 100mg S.R. Tab. 12.00/10 BETAREN 25mg Tab. Dexxon 13.00/30 50mg Tab. 27.00/30

BETAREN S.R. 100mg S.R. Tab. Dexxon 16.00/10 DICLOFEN 25mg Tab. JePharm 16.50/30 50mg Tab. 23.00/30 100mg S.R. Tab. 15.00/10 Diclofenac 12.5mg Supp. 11.00/6 75mg Supp. 28.00/10 100mg Supp. 42.00/15 1% Gel 14.00/30g RHUMACARE 50mg Tab. Pharmacare 22.00/30 1% Gel 18.00/50gm

A- 4 RUFENAL 25mg Tab. BPC 12.00/30 50mg Tab. 20.00/30 100mg S.R. Tab. 12.00/10 100mg Supp. 27.00/12 1% Gel 13.50/30g VOLTAREN 25mg Tab. Novartis 52.00/30 50mg Supp. 28.00/10 1% Gel 18.00/20g 34.00/50g VOLTAREN S.R. 100mg S.R. Tab. Novartis 54.50/10 VOLTIN 50mg Supp. Eastern Chem. 18.00/10 100mg 26.00/12 INDOCAPS 25mg Cap. JCL 10.00/24 100mg Supp. 13.00/10 INDOCIN 25mg Cap. Eastern Chem. 9.00/20 100mg Supp. 15.00/12 INDOLIN 25mg Cap. BPC 8.50/20 100mg Supp. 17.00/12 7.00/6 INDOMED 25mg Cap. Assia 18.00/30 100mg Supp. 20.00/12

Indomethacin INDOMED S.R. 75mg S.R. Caps Assia 37.00/10 INDOPHARM 25mg Cap. JePharm 7.50/20 75mg S.R. Cap. 17.50/16 100mg Supp. 18.00/12 INDOTARD 75mg S.R. Cap. CTI 35.50/10 INDOVIS 25mg Cap. CTI 15.00/30 FELCOL 10mg Cap. Eastern Chem. 21.00/20 20mg 29.00/20

FELDENE 20mg Cap. Pfizer 121.0040/30 20mg Suppository 51.00/12 0.5% Gel. 26.00/25gm

Piroxicam PIROX 20mg Cap. JePharm 33.00/20 20mg Supp. 24.00/6 0.5% Gel 17.00/30g Antigout Agents

ALLORIL 100mg Tab. Dexxon 35.50/50 300mg 35.50/20 ZYLOL 100mg Tab. Teva 43.00/50 300mg 43.00/20 Not in private Allopurinol URICNASE 100mg Tab. BPC market /20

ANTURAN 100mg Tab. Novartis 124.00/100 200mg 93.00/50 Sulfin -

pyrazone PYROCARD 100mg Tab. Trima 88.00/100

COLCHICINE 0.5mg Tab. Rafa 10.00/30 cine Colchi

A- 5 CARDIOVASCULAR DRUGS

SELLING BRAND NAME STRENGTH DOSAGE MANUFACT- PRICE (NIS)/

Name FORM URER # OF DOSAGE Generic FORM Diuretics

- DISOTHIAZIDE 25mg Tab. Dexxon 28.00/50 HC THZ ESIDREX 25mg Tab. Novartis 23.00/20 DIASIX 40mg Tab. JCL 8.50/20 FUROVITE 40mg Tab. Vitamed 12.50/25 FUSID 40mg Tab. Teva 34.00/50 100mg 131.00/100 LASIX 40mg Tab. HMR 24.00/20 Furosemide MIPHAR 40mg Tab. Pharbita 13.00/50 URIX 40mg Tab. BPC 13.00/20 - ALDACTONE 25m Tab. Searle 29.00/20 100mg 46.00/10 ALDOSPIRONE 25mg Tab. Teva 18.00/20

actone Sirpnol 100mg 61.00/20 Beta-Blockers BLOCADRIL 10mg Tab. BPC 6.50/20

40mg 9.50/20 DERALIN 10mg Tab. Abic 8.00/30 40mg 11.00/30 PROLOL 10mg Tab. Dexxon 5.50/50 40mg 14.00/50

Propranolol SLOW DERALIN 80mg S. R. Cap. Abic 61.00/30 160mg 114.00/30 ATENI 50mg Tab. Generics 43.00/30 100mg 60.00/30 COROTENOL 50mg Tab. JePharm 52.00/50 100mg 20.00/50 NORMALOL 25mg Tab. Dexxon 9.00/30 50mg 13.00/30 Atenolol 100mg 18.00/30 NORMITEN 25mg Tab. Abic 11.00/30 50mg 11.00/30 100mg 11.00/30 Angiotensin Converting Enzyme Inhibitors CAPOTEN 12.5mg Tab. BMS 255.00/100 25mg 261.00/90

50mg 455.00/90 CARDIOPRIL 25mg Tab. BCP 10.00/20 50mg 15.00/20

Captopril INHIBACE 12.5mg Tab. Pharma-Best 40.00/100 25mg 45.00/90 50mg 84.00/90

A- 6 Calcium Channel Blockers ANGILAT 10mg Tab. BPC 20.00/30 20mg Tab. 40.00/30

10mg Soft gel Cap. 35.00/75 MEGALAT 10mg Cap. Agis 66.00/90 OSMO-ADALAT 30mg S.R. Tab. Pharma-Clal 138.00/30

Nifedipine 60mg 209.00/30 PRESSOLAT 10mg Tab. Agis 40.50/20 20mg 51.00/20 IKACOR 40mg Tab. Teva 15.00/50 80mg 25.00/50

120mg 36.00/50 IKAPRESS 180mg S.R. Tab. Teva 90.40/30 240mg 35.50/30

Verapamil VERACOR 40mg Tab. Dexxon 17.00/60 80mg 29.00/60 120mg 44.00/60 DILAPRESS 120mg S.R. Tab. Abic 78.00/30 DILATAM 30mg Tab. Abic 11.00/30 60mg Tab. 20.00/30 120mg S.R. Tab. 82.00/30 240mg S.R. Tab. 112.50/30

Diltiazem LEVOZEM 30mg Tab. Dexxon 33.50/30 60mg 38.00/20 90mg 45.00/20 Other Cardiac Agents - 200mg Tab. CTI 24.00/30 AMIODACORE 150mg Amp. /6 arone Amiod PROCOR 200mg Tab. Unipharm 34.00/30 CORDIL 2.5mg Subling. Tab. Dexxon 5.50/40 5mg Subling. Tab. 6.00/40 10mg Tab. 9.00/50

20mg Tab. 12.00/50 40mg S.R. Tab. 46.00/25 ISOCARDIDE 2.5mg Subling. Tab. Sam-On 5.00/40 5mg Subling. Tab. 7.00/40 10mg Tab. 7.00/40 20mg Tab. 8.00/40 30mg Tab. 10.00/40

Isosorbide Dinitrate ISORDIL 10mg Tab. Wyeth Ayerst 46.00/100 ISOTARD 20mg S.R. Cap. CTI 14.00/20 40mg 22.50/20 60mg 32.00/20

COUMADIN NA 5mg Tab. Taro 19.00/20

Warfarin

A- 7

DIGOXINZORI4B 0.25mg Tab. Teva 12.00/40. LANOXIN 0.25mg Tab. 27.72/100 GSK

Digoxin 0.05mg/ml Elixir 55.00/50ml LIPID LOWERING DRUG Fibric Acids BEZALIP 200mg Tab. Boehringer 91.00/100 BEZALIP RETARD 400mg Long Acting Boehringer 52.00/30 Tab. NORLIP 100mg Tab. Unipharm 75.00/100 Bezafibrate 200mg 73.20/50 Bile Acid Sequestrants CHOL-LESS 4 gram Sachets Rafa 94.00/50 QUESTRAN 4 gram Sachets Mead- 144.00/5 ramine Cholesty Cholesty Johnson HMG-CoA Reductase Inhibitors

- SIMOVIL 5mg Tab. Assia/ Riesel 148.00/30 10mg 98.00/30

statin 20mg 142.00/30 Simva 40mg 768.00/30

- 6B LESCOL 20mg Tab. BMS 108.00/28 40mg 145.00/28 statin Fluvsa

A- 8 GASTROINTESTINAL DRUGS

SELLING BRAND NAME STRENGTH DOSAGE MANUFACT- PRICE (NIS)/ FORM URER # OF DOSAGE Name

Generic FORM Antacids & Ulcer-Healing MAALOX Al-hydroxide Suspension Rorer 24.00/355ml 225mg Mg-hydroxide 200mg/5ml MAALOX NO.1 Al-hydroxide Tab. Rorer 25.00/100 200mg, Mg-hydroxide 200mg/5ml MAALOX PLUS Al-hydroxide Suspension Rorer 27.00/355ml

225mg Tab. 25.00/50 Mg-hydroxide 200mg/5ml Simethicone MAGNAGEL Al-hydroxide Suspension JePharm 17.00/355ml Mg/Al Salts 6.0% Mg- trisilicate 7.5% MAGNAGEL Al-hydroxide Chewable JePharm 63.00/400 200mg Tab. Mg-trisilicate 300mg STOMAGEL Al-hydroxide Suspension JCL Not produced 500mg any more. Mg-trisilicate 750mg/ 15 ml GI-CARE 150 mg Tab. Pharmacare 14.00/20 RANDIN 150mg Tab. JePharm 14.50/20

RATIDINE 150mg Tab. BPC 16.00/20 300 mg 34.00/20 ZANTAB 150mg Tab. Teva 14.00/20 300 mg 14.00/10

Ranitidine ZANTAC 150mg Efferv. Tab. 90.00/20 GSK 300mg 85.00/10 ZANTAC 150mg Tab. GSK 81.00/20 300 mg 75.00/10 LOCID 20 mg Cap. JePharm 49.00/14

e LOSEC 10mg Cap. Abic 284.90/30 20mg 224.00/14 MARIAL 10mg Cap. JCL 30.00/14 20mg 55.00/14

Omeprazol MEPRAL 20 mg Cap. BPC 50.00/14 PEPTICUM 20 mg Cap. Pharmacare 60.00/15

A- 9

Antispasmodics/Anticholinergics

KOLIK Hyosciamine Drops JCL 9.00/10ml - Sulfate 0.125 gm, alcohol

Bromide 0.3ml/ml

Hyocine N SCOBUTYL Hyocine N-butyl Tab. JePharm 9.00/20 Butyl bromide 10 mg Anti-Emetics EMESTOP 10 mg Tab. BPC 12.00/20

de 5mg/5ml Syrup 6.00/30ml NOVOMIT 10 mg Tab. JePharm 9.00/20 5mg/5ml Syrup 8.00/60ml PRAMIN 10 mg Tab. Rafa 19.00/30 5mg/5ml Syrup 8.00/60ml

Metacloprami 5mg Supp. 11.00/6 20 mg Supp. 11.00/6

ANCOZINE Meclozine 15mg Supp. BPC 9.00/6

Pyridoxine 30mg ANCOZINE Meclozine 25mg Tab. BPC 12.00/20 lozine Pyridoxine 50mg Mec Meclizine/ PARAVOMINE Meclozine 25mg Tab. JCL 14.00/20 Pyridoxine 50mg Anti-Diarrhoeal ELECTRO-SUBS NaCl 3.50g Sachet BPC 4.00/sachet Na Bicarbonate 2.50g KCl 1.50g Glucose 20g HYDRAN NaCl 2.00g Sachet Teva 23.00/3 sachets

ion Salts Trisodium- Citrate 2.58g KCl 1.49g Dextrose 30g ORSET L.S. Glucose Efferv. Tab. Novartis 24.00/10 140mmol/L

Oral Rehydrat Na+ 56 mmol/L K+ 0 mmol/L Citrate 30 mmol/L Cl- 46 mmol/L DIACARE 2 mg Caps Pharmacare 10.00/8

IMODIUM 2 mg Caps JanssenCilag 26.00/10 IMODIUM CAPLET 2 mg Cap. JanssenCilag 20.00/10 IMODIUM 2 mg Solution JanssenCilag 22.00/100ml

Loperamide SOLUTION STOPIT 2 mg Caps Rafa 16.00/10

A- 10

Laxatives

BISALAX 5mg Supp. JCL 5.50/5 10 mg 8.00/5 dyl

Bisaco LAXADIN 5 mg E.C. Tab. Teva 15.00/50

GLYCERINE Glycerin 2.7g Supp. adult Rekah 11.00/20 lyce rin Glycerin Supp. child 7.00/5 G

- METAMUCIL Psyllium Powder Searle 13.00/100g ium Psyll Anti-Hemorrhoids ANUSOL Bismuth Supp. Park Davis 18.00/12 subgalate 59mg, Bismuth ox. 24mg, Balsam peru 49mg, ZnO 296 mg. ANUSOL Bismuth sub- Ointment Park Davis 17.00/25g galate 2.25g, Bismuth ox 0.875g, Balsam peru 1.875g, ZnO 10.75g/100g. HEMORAL H.C. Hydrocortisone Supp. JCL 13.00/6

acetate 0.5%, ns Lidocaine HCl 1.5%, ZnO 3% Bismuth subgalate 4% HEMORAL H.C. Hydrocortisone Ointment JCL 13.00/30g acetate 0.5%, Lidocaine HCl

Different Preparatio Different 1.5%, ZnO 5%, Bismuth subgalate 2% PROCTOCARE Fluocinolone Ointment Pharmacare 15.00/15g Acetonide 0.1%, Lidocaine HCL 20 mg PROCTOCEDYL Hydrocortisone Ointment HMR 11.00/15g 0.5% Supp. 11.00/12 Cinchocaine- HCl 0.5% PROCTO-GLYVENOL Tribenosid Cream Novartis 26.00/30g 400mg Supp. 29.00/10 Lindocain 40mg

A- 11 RESPIRATORY DRUGS

SELLING BRAND NAME STRENGTH DOSAGE MANUFACT- PRICE (NIS)/ FORM URER # OF DOSAGE Name Generic FORM COLD PREPARATIONS Antihistamines

AHISTON 2mg Tab. Teva 7.00/20 ALLERGON 3mg/5ml Syrup JCL 10.00/100ml 2mg Tab. 7.00/20 ANAPHYL 3mg/5ml Syrup Sam-On 8.00/120ml 2mg Tab. 5.00/20 CLOROYATE 3mg/5ml Syrup Pharmacare Not in market 2mg Tab. Chlorpheniramine DISORAMIN 2mg Tab. Dexxon 4.00/20

- HISMANAL 10mg Tab. Janssen 60.00/20

(No longer available in 1mg/ml Syrup 38.00/100ml

izol e market.) Astem LAHISTAN 10mg Tab. BCP 34.00/20 Nasal Decongestants ALRIN 0.05% Nasal Drops Teva 7.50/10cc Nasal Spray 10.00/15cc NASIVIN 0.025% Nasal Drops Merck 9.00/10cc 0.05% Nasal Drops 12.00/10cc Nasal Spray 14.00/10cc RHINOCLIR 0.05% Nasal Spray Agis 11.00/20ml Oxymetazoline NOSACARE 0.05% Nasal Spray Pharmacare 7.50/15cc

- OTRINOL 120mg SR Retard Cap. Novartis 22.00/10 SINUFED 30mg/5ml Syrup Trima 19.00/115ml 60mg Tab. 15.00/20 Pseudo ephedrine TAROPHED 30mg/5ml Syrup Taro 18.00/120ml Expectorants

- ROBITUSSIN 100mg/5ml Syrup A.H.Robins 20.00/20ml enesin Guaif RESYL (sugar free) 100mg/5ml Syrup Novartis 17.00/100ml Antitussives / Cough Suppressants

CODEINE 20mg Tab. Rekah 9.00/10 PHOSPHATE CODICAL 20mg Tab. Sam-On 9.00/10

Codeine 20mg codeine Tab. Pharmacare 12.00/20

Phosphate PARACOD 325mg APA Dextromethorphan HBr: Available only in combinations products in the market.

A- 12

Mucolytics AGISOLVAN 200mg Granules Agis 12.00/12 (Sachets) MUCOMYST 200mg Granules Mead-Johnson 101.48/3 (Sachets) SIRAN 200 200mg Powder Sach. Temmler 40.00/30 Effervs. Tab. Pharma 40.00/30

Acetylcysteine BISOLVAN 8mg Tab. Boehringer 19.00/20 4mg/5ml Elixir 24.00/100ml

MUCOCARE 8mg Tab. Pharmacare 15.00/20 - 2mg/1ml Elixir 18.00/50ml SOLVEX 8mg Tab. Teva 19.00/20 Brom hexine

BRONCHODIALATORS AND ASTHMA MEDICATIONS GLYPHYLLIN Theoph. Na Tab. Teva 17.00/60 Glycinate 250mg THEO-DUR Theoph. Anhy. S.R. Tab. Key Pharm. 200mg 44.00/100 300mg 53.00/100 THEOTARD Theoph. Anhy. S. R. Cap. CTI 50mg 12.50/30

75mg 13.00/30 100mg 13.00/30 200mg 20.50/50 300mg 23.00/30

Theophylline THEOTRIM Theoph. Anhy. S.R. Tab. Trima 100mg 10.00/30 200mg 19.00/30 300mg 24.00/30 THEOPHARM Theoph. Anhy. S. R. Tab. JePharm 100mg 13.00/50 200mg 19.00/50 300mg 25.00/50

A- 13

VENTOCARE 2mg Tab. Pharmacare 4.00/20 2mg/5ml Syrup 10.00/180ml VENTOLIN 2mg Tab. GSK 32.00/100 2mg/5ml Syrup 14.00/150ml 100mcg/inhal. Aero. Spray 18.00/200doses VENTOLIN RESPI- 5mg/ml Solution for GSK 29.00/20cc RATOR SOLUTION Nebulizer VOLMAX 4mg Tab. GSK 30.00.50/14 8mg 36.00/14

Salbutamol / Albuterol FEDRAL 4mg Tab. Eastern Chem. 5.00/20 2mg/5ml Syrup 7.00/100ml

CROMUNAL 1mg/inhal. Inhaler Agis LOMUDAL 20mg Gelatin Caps Fisons 68.00/30 LOMUDAL 20mg Solution Fisons 144.00/48ml NEBULISER yn Sodium SOLUTION NALCROM 100mg Cap. Fisons 156.00/100 Cromol (Na Cromoglycate) (Na VICROM 1mg/inhal. Inhaler Fisons 43.70/200 BECLOFORTE 250mcg/inhal. Inhaler GSK metered doses

BECONASE 50mcg/inhal. Nasal GSK Aerosol BECOTIDE 50mcg/inhal. Inhaler GSK 58.00/200 metered doses

Dipropionate RHINOCORT 50mcg/spray Nasal Spray Agis 50.00/200 Beclomethasone Beclomethasone sprays VIAREX 50mcg/inhal. Inhaler Schering 49.00/200 PREDNITAB 5mg Tab. BPC 14.00/40

20mg 25.00/20 PREDNITONE 5mg Tab. Vitamed 20mg 33.00/30

Prednisone PREDNISONE 5mg Tab. Rekah 14.00/10 20mg 45.00/30

A- 14

Widely Used Combination Products Pseudoeph. 60mg Syrup 18.00/100ml ACTIFED SYRUP GSK Triprolidine 2.5mg ACTIFED Pseudoeph. 30mg Syrup GSK 19.00/100ml EXPECTORANT Triprolidine 1.25mg Gauifenasin 100mg ALCINAL Dextromethorph. Syrup Rekah 14.00/115ml

7.5mg Cap. 17.00/20 Guiaphen. 105mg Chlorphenar. 1mg Phenylprop. 12.5mg COLDEX Caffeine 30mg Tab. Teva 12.00/20 Chlorphenar. 2mg Phenylepher. 10mg Paracetamol 300mg COLDEX-NIGHT Dextromethor. 10mg Elixir Teva 18.00/60 ml Ephedrin. 8mg Chlorphen. 1mg Paracetamol 600mg DEXAMOL COLD Dextromethor. 10mg Cap. Dexxon 19.50/30 (Day care) Guiaphen. 200mg

INGREDIENTS Pseudoeph. 25mg - Paracetamol 325mg DEXAMOL COLD Dextromethor. 10mg Cap. Dexxon 6.50/10 (Night care) Chlorphenar. 2mg MULTI Pseudoeph. 25mg Paracetamol 500mg DEXAMOL SINUS Pseudoeph. 25mg Cap. Dexxon 40.00/ Paracetamol 500mg FEBRACOLD S.R. Pseudoeph. 120mg S.R. Cap. BPC 10.00/8 Chlorphenir. 8mg FLU Chlorphenir. 2.5mg Tab. JePharm 12.00/20 Phenyleph. 10mg Paracetamol 300mg Ascorbic Acid 100mg Caffeine 30mg FLU Each 5ml contain: Syrup JCL 12.00/60ml Chlorphenir. 1mg Phenylephrine 2mg

A- 15

FORMULA 444 Each 5ml contains: Syrup JePharm 12.50/120ml Dextromethor. 10mg Phenylpropan. 12.5mg Glycerly guaicolate 100mg HISTADEX Each 5ml contain: Syrup Vitamid 15.00/115ml Dexchlorphenir. 1mg Pseudoeph. 25mg HISTAFED Pseudoeph. 60mg Drags Trima 16.00/20 Triprolidine 2.5mg Syrup 18.00/115ml NUSSIDEX Pseudoephe. 25mg Tab. Teva 15.00/20 Dexchlorphen. 1mg Syrup 15.00/115ml PARAFLU Chlorphenir. 2.5mg Tab. JCL 9.50/20 Phenyleph. 10mg Paracetamol 300mg Ascorbic Acid 100mg Caffeine 30mg

INGREDIENTS PARAFLU Each 5ml contain: Syrup JCL 14.00/60ml - Chlorphenir. 1mg Phenylephrine 2mg PULMADRIN Each 5ml contain: Syrup BPC 10.00/100ml

MULTI Pseudoeph. 30mg Triprolidine 1.25mg TRICOLD Paracetamol 350mg Cap. Agis 14.00/20 Phenlephr. 10mg Dextrometh. 7.5mg TUSSIBAL Each 5ml Contain: Syrup JePharm 13.50/100ml EXPECTORANT Guaifenesin 100mg Pseudoeph. 30mg Triprolidine 1.25mg TUSSIBAL Each 5ml contain: Syrup JePharm 14.00/100ml HONEY Pseudoeph. 30mg Dextrometh. 10mg Triprolidine 1.25mg

A- 16 ANTI-INFECTIVES

SELLING BRAND NAME STRENGTH DOSAGE MANUFACT- PRICE (NIS)/

Name FORM URER # OF DOSAGE Generic FORM ANTI-BACTERIALS Penicillins RAFAPEN V-K 250mg Tab. Rafa 12.20/40 500mg Tab. 22.00/30 125mg/5ml Susp. 4.00/60ml 250mg/5ml Susp. 8.00/60ml RAFAPEN MEGA 990mg Cap. Rafa 32.00/20 ORACILLIN 250mg Tab. JePharm 7.00/20 500mg Tab. 14.00/20 125mg/5ml Susp. 7.00/100ml 250mg/5ml Susp. 11.00/100ml BEPEN V.K. 250mg Tab. BPC 6.00/20 Phenoxymethylpenicillin 500mg Tab. 13.50/20 250mg/5ml Susp. 10.00/100ml LOXAVIT 250mg Cap. Vitamed 6.50/10

500mg 20.00/10 ORBENIL 250mg Cap. Teva 8.70/12 500mg Cap. 12.00/10

Cloxacillin 125mg/5ml Syrup 14.00/60ml 250mg/5ml Syrup 21.30/60ml PENIBRIN 250mg Cap. Teva 5.30/12 500mg Cap. 8.20/10 125mg/5ml Susp. 4.10/60ml 250mg/5ml Susp. 8.50/60ml PENTREXYL 125mg/5ml Susp. BMS 4.00/60ml

250mg/5ml 5.00/60ml BROADA-CILLIN 250mg Cap. BPC 8.00/16 500mg Cap. 12.00/16

Ampicillin 125mg/5ml Susp. 5.50/60ml 250mg/5ml Susp. 8.00/60ml AMPIPHARM 250mg Cap. JePharm 7.00/16 500mg Cap. 12.00/16 125mg/5ml Susp. 5.00/60ml 250mg/5ml Susp. 8.00/60ml

MAGNICILLIN 250+250mg Caps BCP 20.00/16 250+500mg 30.00/16 icillin + icillin MEGACARE 500+250mg Cap. Pharmacare 30.00/16 250+125 Susp. 18.00/60ml Amp Flucoxacillin mg/5ml 23.00/100ml

A- 17

AMOXICARE 250mg Cap. Pharmacare 9.00/16 500mg Cap. 14.00/16 125mg/5ml Susp. 9.00/100ml 250mg/5ml Susp. 12.00/100ml 250mg/5ml Susp. 9.00/60ml AMOXITID 250mg Cap. BPC 8.50/16 500mg Cap. 13.50/16 750mg Cap. 14.50/12 125mg/5ml Susp. 8.50/60ml 250mg/5ml Susp. 8.50/60ml

HICONCIL 250mg Cap. Mead- 11.00/12 500mg Cap. Johnson 12.00/12 125mg/5ml Susp. 8.00/60ml 250mg/5ml Susp. 11.00/60ml

Amoxicillin MOXYPEN 250mg Cap. Teva 13.00/12 500mg Cap. 10.00/10 125mg/5ml Susp. 8.00/60ml 250mg/5ml Susp. 10.00/60ml MOXYVIT 250mg Cap. Vitamed 15.00/10 500mg Cap. 20.00/20 125mg/5ml Susp. 8.10/60ml 250mg/5ml Susp. 10.00/60ml MOXEPHARM 250mg Cap. JePharm 9.00/16 500mg Cap. 13.50/16 125mg/5ml Susp. 9.00/100ml 250mg/5ml Susp. 10.00/100ml AUGMENTIN 250-125mg Tab. GSK 85.00/20 500-125mg Tab. 128.00/20 875-125mg Tab. 128.00/14

457-75mg Susp. 70.00/70ml 250-62.5mg/5ml Susp. 70.00/100ml 125-31.25mg/5ml Susp. 46.00/100ml AUGMENTIN-Duo 400-57mg Susp. GSK 46.00/35ml Sugar Free Amoxicillin &

Clavulinic Acid CURAM 625 500-125 mg FC Tab. Sandoz 50.00/20 125-31.25mg /5ml Susp. 26.00/100ml OGMIN 250-62.5mg/5ml Susp. BPC 50.00/100ml 125-31.25mg/5ml Susp. 35.00/100ml

A- 18

Cephalosporins CEFORAL 250mg Cap. Teva 19.00/12 500mg Cap. 38.10/12 125mg/5ml Susp. 14.60/60ml 250mg/5ml Susp. 27.60/60ml CEFACARE 500mg Cap. Pharmacare 29.00/16 250mg/5ml Susp. 16.00/60ml CEFALEX 250mg Cap. BPC 18.00/16 500mg Cap. 29.00/16 125mg/5ml Susp. 10.00/100ml Cephalexin 250mg/5ml Susp. 21.00/100ml CEFOVIT 250mg Cap. Vitamed 11.00/10 500mg Cap. 22.00/10 125mg/5ml Susp. 12.00/60ml 250mg/5ml Susp. 19.00/60ml KEFLEX 500mg Cap. Lilly 71.00/20 125mg/5ml Susp. 27.00/100ml 250mg/5ml Susp. 37.00/100ml JEFLEX 250mg Cap. JePharm 18.00/16 500mg Cap. 30.00/16 Cephalexin 125mg/5ml Susp. 10.00/60ml 250mg/5ml Susp. 15.50/60ml CECLOR 250mg Cap. Lilly 48.00/12 500mg Caps 62.00/12 750mg MR* Cap. * (modified 73.00/12 125mg/5ml Susp. release) 36.00/60ml Cefaclor 250mg/5ml Susp. 54.00/60ml

CEFADROX 500mg Tab. BPC 31.00/12 125mg/5ml Susp. 12.00/60ml 250mg/5ml Susp. 20.00/60ml BIODROXIL 500mg Cap. Sandoz 43.00/12 Cefadroxil

Tetracyclines TEVA-CYCLINE 250mg Cap. Teva 6.00/20 BRIMO-CYCLIN 250mg Cap. BPC 5.50/16 500mg 10.00/16 TETRA-PHARM 250mg Cap. JePharm 5.00/16

Tetracycline 500mg 10.00/16 Macrolides

ERYC 250mg Cap. Taro 26.00/20 (Erythromycin base) ERYTHROCIN 250mg Tab. Abbott 59.50/100ml FILMTAB (Erythromycin Erythromycin stearate)

A- 19 ERYTHRO-TEVA 250mg Tab. Teva 11.00/12 (Erythromycin 500mg Tab. 21.40/10 Stearate) 125mg/5ml Susp. 11.00/60ml 200mg/5ml Susp. 13.40/60ml 400mg/5ml Susp. 25.00/60ml ERYTHROTAB Tab. BPC 18.00/24 (Erythromycin 250mg Stearate) ERYTHRO-PHARM 125mg/5ml Susp. JePharm 8.00/60ml (Erythromycin 200mg/5ml Susp. 12.00/60ml Ethylsuccinate) ERYTHROLET 25mg/5ml Susp. BPC 8.00/60ml (Erythromycin 200mg/5ml Susp. 11.50/60ml Ethylsuccinate) ERYTHROCARE 200mg/5ml Susp. Pharmacare 10.50/60ml (Erythromycin 400mg/5ml Susp. 20.00/60ml Ethylsuccinate) Trimethoprim & Sulphonamindes

DISEPTYL 80mg/400mg Tab. Rekah 10.00/20 40mg/200mg, 5ml Susp. 11.00/100ml RESPRIM 80mg/400mg Tab. Teva 13.10/20

160mg/800mg Tab. 10.90/10 40mg/200mg, 5ml Susp. 10.90/100ml SULFATRIM 80mg/400mg Tab. Vitamed 6.20/20 160mg/800mg Tab. 21.80/20 TMP/SMX 40mg/200mg, 5ml Susp. 10.00/100ml SULPRIM 80mg/400mg Tab. JePharm 10.50/20 160mg/800mg Tab. 10.50/10 (Strength written as TMP/SMX) (Strength as written 40mg/200mg, 5ml Susp. 10.00/100ml Antibacterials for UTI MACRODANTIN 50mg Macro- Procter & 213.00/100 100mg crystal Cap. Gamble 427.00/100 URANTOIN 100mg Tab. Rafa 41.84/500

Nitrofurantoin MACRO-FURAN 100mg Cap. BPC 35.00/24 NEGGRAM 250mg/5ml Susp. Sterling- 256.00/160ml

250mg Tab. Winthrop 95.00/56 500mg Tab. 140.00/56 1000mg Tab. 301.00/100 URIGRAM 500mg Tab. Trima 76.20/60 U-GRAM 250mg Tab. JePharm 45.00/50 Nalidixic Acid 500mg Tab. 90.00/50 250mg/5ml Susp. 43.00/100ml

A- 20

CIPROCARE 250mg Tab. Pharmacare 27.00/10

500mg 50.00/15 CIPROGIS 125mg Tab. Agis 24.00/6 250mg 69.00/10 500mg 175.00/10 750mg 252.65/10 Ciprofloxacin FLOXIN 250mg Tab. JePharm 68.00/20 500mg 68.00/10 ANTI-TUBERCULOSIS

- ISONIAZID 50mg Tab. Rekah 73.70/50

zide

Isonia

RIMACTAN 150mg Cap. Sandoz 250.70/80 - 300mg Cap. 250.70/40

picin 100mg/5ml Syrup 74.00/50ml Rifam - Not available in local - pharmacies.

amide Pyrazin - MYAMBUTOL 100mg Tab. Lederle 62.90/100 400mg 123.70/100 butol Etham

ANTI-PARASITICS FLAGYL 250mg Oral Tab. Specia 14.00/20 500mg Vag. Tab. 18.00/10 125mg/5ml Susp. 26.00/120ml METROGYL 250mg Oral Tab. Teva 6.30/20 500mg Vag. Tab. 6.00/10 METROZOLE 250mg Tab. BPC 6.00/20 500mg Tab. 15.00/ 125mg/5ml Susp. 14.00/100ml Metronidazole 1000mg Vag. Supp. 14.00/6 ENTOGYL 250mg Tab. JePharm 7.50/20 125mg/5ml Susp. 15.00/120ml VERMOX 100mg Tab. Abic 11.00/10

100mg/5ml Susp. 14.00/30ml

azole VERMAZOL 100mg Tab. JePharm 10.00/6

Mebend - 100mg/5ml Susp. 12.00/30ml

- YOMESAN 500mg Tab. Bayer 20.00/4 de ami Niclos

ESKAZOLE 400mg Tab. GSK 591.00/60

azole - Albend

A- 21

ANTI-FUNGALS NYSTATIN 100,000 U Vag. Tab. Taro 14.50/10

500,000 U Drags 42.00/28 100,000 U/ml Mixture 35.00/30ml CANDISTAN 100,000 U Vag. Tab. BPC 8.50/15 Nystatin 100,000 U/ml Oral Drops 9.00/12ml DAKTARIN ORAL 2% Gel Abic 41.00/40g GEL

GYNO-DAKTARIN 1200mg Ovule Abic 35.50/3 (vaginal inserts) Nitrate DAKTAZOL ORAL 2% Gel JePharm 12.00/40g GEL FUNGAZOLE 2% Cream Pharmacare 10.00/15g GYNO-DAKTAZOL 2% Vaginal JePharm 30.00/40g Miconazole Cream GYNO-DAKTAZOL 400mg Ovules JePharm 21.00/3 OVULES GRIFULIN FORTE 125mg Tab. Teva 24.00/60 -

fulvin SPORO-FULVIN 125mg Tab. JCL 17.50/20 Griseo 125mg/5ml Susp. 17.50/100ml ANTI-VIRALS SUPRAVIRAN 800mg Tab. Pharmacare 110.00/35 200mg/5ml Susp. 55.00/125ml

ZOVIRAX 200mg Tab. GSK 48.00/25 400mg Tab. 138.00/70 200mg/5ml Susp. 307.00/125ml Acyclovir VIRAX 200mg Tab. BPC Not in private pharmacies

A- 22 ENDOCRINE DISORDER DRUGS

SELLING DOSAGE MANUFACT- PRICE (NIS)/ BRAND NAME STRENGTH FORM URER

Name # OF DOSAGE Generic FORM ANTIDIABETICS Insulin

NOVOLIN R Regular IV or IM Novo Nordisk 120.00/10ml Insulin ular Regular IV or IM Lilly 102.00/10ml

Insulin HUMULIN R Reg Insulin NOVOLIN N NPH IM Novo Nordisk 120.00/10ml

NPH HUMULIN N NPH IM Lilly 120.00/10ml Oral agents

/ DAONIL 5mg Tab. HMR 62.00/100

DECLAMIDE 5mg Tab. JCL 7.00/20 GLUCOCARE 5mg Tab. Pharmacare 8.00/30

Glyburide GLUCONIL 5mg Tab. JePharm 7.00/30

Glibenclamide GLIBETIC 5mg Tab. Teva 10.00/30

- GLUCOPHAGE 850mg Tab. BMS 15.00/30

Met GLUCOMET 850mg Tab. BPC 10.00/30 formin - THYROID DISORDERS

- ELTROXIN 50mcg Tab. GSK 16.00/100

xine 100mcg 19.00/100 Thyro

PROPYL- 50mg Tab. Teva 12.00/30

PTU THIOCIL CORTICOSTEROIDS Refer to Prednisone in the Respiratory Chapter price list.

A- 23 CONTRACEPTIVE PREPARATIONS

SELLING BRAND NAME STRENGTH/ MANUFACT- PRICE (NIS)/ DOSAGE FORM URER # OF DOSAGE Name Generic FORM Combined Contraceptive Agents GYNERA Ethinyloestradiol 0.03mg Schering 27.00 Gestodene 0.075mg (21 Tab. sachet)

MINULET Ethinyloestradiol 0.03mg Wyeth 24.90 Gestodene 0.075mg (21 Tab. Gestodene sachet)

Ethinyloestradiol & Ethinyloestradiol

MINOVLAR Norethisterone 1mg Schering (mono-phasic): Ethinyloestradiol 0.05mg (21 Tab. sachet)

yloestradiol yloestradiol OVYSMEN Norethisterone 0.5mg Ortho 30.00 (mono-phasic): Ethinyloestradiol 0.035mg (21 Tab. thin Norethisterone & sachet) 7 Tab.: TRINOVUM Ortho 29.00 (Triphasic) Norethisterone 0.5mg (21 Tab. Ethinyloestradiol 35mcg sachet) 7 Tab.: erone & erone & Norethisterone 0.75mg Ethinyloestradiol 35mcg 7 Tab.: Ethinyloestradiol Norethist Norethisterone 1mg Ethinyloestradiol 35mcg MICROGYNON Levonorgestrel 0.15mg Schering 13.50 (mono-phasic) Ethinyloestradiol 0.03mg (21 Tab. sachet) NORDETTE Levonorgestrel 0.15mg Wyeth 13.00 (mono-phasic) Ethinyloestradiol 0.03ml (28 Tab. Ethinyloestradiol

Levonorgestrel & sachet) LOGYNON 6 Tab.: Schering 17.00 (tri-phasic) Levonorgestrel 0.05mg (21 Tab. Ethinyloestradiol 0.03mg sachet) 5 Tab.: Levonorgestrel 0.075mg Ethinyloestradiol 0.04mg 10 Tab.: Ethinyloestradiol Levonorgestrel & Levonorgestrel & Levonorgestrel 0.125mg Ethinyloestradiol 0.03mg

A- 24 TRINORDIOL 6 Tab.: Wyeth 19.00 (tri-phasic) Levonorgestrel 0.05mg (21 tab. sachet) Ethinyloestradiol 0.03mg 5 Tab.: Levonorgestrel 0.075mg Ethinyloestradiol 0.04mg 10 Tab.: Levonorgestrel 0.125mg Ethinyloestradiol 0.03mg Progestin Only Products

FEMULEN Ethynodiol diacetate 0.5mg Searle 19.00 (28 Tab.) (28 tab. sachet) DEPO-PROVERA Medroxy-progesterone Upjohn 49.00/ 1 ml Acetate 150 mg/ml (one dose vial) Progestin (Vial, IM)

A- 25 ANTIEPILEPTICS

SELLING DOSAGE MANUFACT- PRICE (NIS)/ BRAND NAME STRENGTH FORM URER # OF DOSAGE Name Generic FORM CARBI 200mg Tab. AlphaPharm 33.50/50

TEGRETOL 200mg Tab. Novartis 87.00/50 100mg/5ml Syrup 44.00/250ml 200mg CR Tab. 70.00/50 400mg CR Tab. 70.00/30 TEGREPINE 200mg Tab. JePharm 47.00/50 Carbamazepine TERIL 200mg Tab. Taro 65.00/50 400mg 54.00/30 KLONOPIN/ 2.5mg/ml Drops Roche 25.50/10ml RIVOTRIL pam

- CLONEX 0.5mg Tab. Teva 10.00/30 Clonaze 2mg 19.00/30

. ZARONTIN 250mg Cap. Parke-Davis 53.00/50

ESX Syrup 73.00/300ml

PHENOBARB 100mg Tab. Eastern Chem. 15.00/40 15mg Tab. 8.00/40

Phenobarb.

- 50mg Cap. Parke-Davis 130.00/500

EPANUTIN 100mg Cap. 34.00/100 toin

Pheny 30mg/5ml Susp. 19.85/100ml DEPALEPT 200mg Tab. CTI 55.90/40 500mg Tab. 129.00/40 200mg/ml Solution 41.00/50ml

acid 200mg/5ml Syrup 21.00/110ml

Valproic VALPORAL 200mg Cap. Teva 41.10/40 200mg/5ml Syrup 14.10/100ml

A- 26 ANTIPARKINSONISM

SELLING DOSAGE MANUFACT- PRICE (NIS)/ BRAND NAME STRENGTH FORM URER # OF DOSAGE Name

Generic FORM Anticholinergics

- COGENTIN 2mg Tab. MSD /20 Not available in the private Benzo Tropine market.

- ARTANE 2mg Tab. Lederle 34.00/100 5mg 38.00/100 PARTANE 2mg Tab. Taro 7.50/50 Trihexy Phenidyl 5mg 11.00/50 Dopaminergic Drugs - PARITREL 100mg Tab. Trima 47.00/20

adine SYMMETREL Amant 100mg Cap. Novartis 44.00/20

LACTOPAR Tab. BCP 65.00/30

- 2.5mg PARILAC 2.5mg Tab. Teva 102.00/30 10mg 214.00/20 Bromo criptine PARLODEL 2.5mg Tab. Novartis 107.00/30 SINEMET-110 10mg/ Tab. Dupont Not available 100mg in the market

/ SINEMET-275 25mg/ Tab. Pharm. Not available 250mg in the market SINEMET CR 50mg/ Tab. Pharm. 111.30/30 Levodopa

Carbidopa 200mg DOPICAR 25mg/ Tab. Assia/Riesel 76.00/30 250mg

A- 27 PSYCHOACTIVE DRUGS

SELLING BRAND NAME STRENGTH DOSAGE MANUFACT- PRICE (NIS)/ # OF DOSAGE Name FORM URER Generic FORM Antidepressants

AMYVIL 25mg Tab. JePharm Not in private market. ELATROL 25mg Tab. Assia/Riesel 12.50/50 ELATROLET 10mg Tab. Assia/Riesel 9.00/50 TRYPTAL 25mg Drags Unipharm 9.00/50 Amitriptyline TRYPTA-LETTE 10mg Drags Unipharm 4.00/50

- PRIMONIL 25mg Tab. Teva 9.00/50 amine Imipr TOFRANIL 25mg Tab. Novartis 37.00/50 AFFECTINE 20mg Cap. Taro 66.10/28

FLUOXICARE 20mg Cap. Pharmacare 26.00/14 FLUTINE 20mg Caps Teva 67.50/30 PRIZMA 20mg Tab. Unipharm 67.00/30 40mg 126.50/20 Fluoxetine PROZAC 20mg Cap. Lilly 101.00/14 216.10/28 Hypnotics And Anxiolytics ASSIVAL 2mg Tab. Teva 4.00/30 10mg 10.00/30 DIAZ 2mg Tab. Taro 3.80/30 5mg 6.70/30

10mg 10.30/30 DISOPAM 2mg Tab. Dexxon 2.80/30 5mg 4.80/30 10mg 6.00/30 Diazepam HARMONAL 2mg Tab. JCL 3.00/20 5mg 3.50/20 SEREPAM 2mg Tab. BPC 3.50/20 5mg 4.50/20 10mg 5.00/20

- LORIVAN 1mg Tab. Dexxon 14.00/50 LOROCARE 1mg Tab. Pharmacare 8.00/40 Lora zepam 2.5mg 8.50/20 Neuroleptics

TAROCTYL 25mg Tab. Taro 17.00/50

CPZ 100mg 20.00/50

HALIDOL/HALDOL 5mg Tab. Abic 35.25/60 - 2mg/ml Drops 12.87/15ml

Halo PERIDOL 5mg Tab. Eastern Chem. 9.00/20 peridol PERIDOR 1mg Tab. Unipharm 14.40/60

A- 28 OPTHALMIC PREPARATIONS

SELLING BRAND NAME STRENGTH DOSAGE MANUFACT- PRICE (NIS)/ eneric FORM URER # OF DOSAGE Name G FORM

ANTI1B -INFECTIVES Antibiotics

CHLOROCETIN 5% Eye Drops. Eastern Chem. 10.00/7ml 0.5% Eye Oint. 7.00/3.6g CHLOROPTIC 0.5% Eye Drops Allergan 17.50/10ml SYNTHO-MYCINE 5% Eye Oint. Abic 6.00/4g LOMIXIN 5mg/ml Eye Drops Jordan 9.00/10ml

Chloramphenicol RAMACETINE 5% Eye Oint. BCP 8.00/3.5g Eye Drops 5.50/10ml

JORDACYCLINE 0.5% Oxy. Eye Oint. JCL 7.5.00/4g OXYCIN 0.5% Oxy. Eye Oint. BCP 5.00/3.5g RECYCLINE 1% Tetrac. Eye Oint. Rekah 14.00/3.5g

Tetracyclines TEVACYCLINE 1% Tetrac. Eye Oint. Teva 9.00/3.5g

- GARAMYCIN 0.3% Solution Schering 9.00/5ml OPHTHALMIC Plough mycin Genta GENTICIN 0.3% Eye Drops JePharm 10.00/5ml Antivirals

- VIRUSAN 1mg Eye Drops Teva 7.00/7ml 5mg Eye Oint. 17.00/5g Idox uridine

Anti-Inflammatory Preparations OPTISOLONE 0.5% Pred- Eye Drops JePharm 9.00/5ml nisolone PREDNICORT 0.12% Drops Eastern Chem. 13.00/7ml 1% Forte 19.00/7ml Prednisolone Drops acetate STERODEX 0.1% Dexa- Eye Drops Fischer 11.00/5ml methasone Corticosteroid ULTRACORTENOL 0.5% Predni- Eye Oint. Novartis 23.00/5ml solone Eye Drops trimethyl- acetate

- OPTICROM 2% Eye Drops Fisons 71.00/13.5ml cate gly Cromo

A- 29

Beta-Blockers TILOPTIC 0.25% Eye Drops Assia/Riesel 14.00/5ml

0.5% 14.00/5ml SINOPTIC 0.25% Eye Drops Eastern Chem. 10.00/5ml 0.5% 12.00/5ml Timolol Maleate TIMOLIN 0.25% Eye Drops JePharm 14.00/5ml 0.5% 18.00/5ml Mydriatics and Cycloplegics

ATROSPAN 1% Eye Drops Fischer 10.00/10ml ATROPED 1% Eye Drops Eastern 10.00/10ml Sulfate Atropine Chemical

A- 30 OTIC PREPARATIONS

SELLING DOSAGE MANUFACT- PRICE (NIS)/ BRAND NAME STRENGTH

Name FORM URER # OF DOSAGE Generic FORM Ear Wax Removers CERUMOL Paradichloro- Drops Tamar 24.00/11ml benzene 2g Benzocaine 2.7g Chlorbutol 5g

Cerumol Ol-terebinth 10cc/100cc Most anti-infective and anti-inflammatory otic products are available in combination products: BETNESOL 0.1% Beta- Drops GSK 8.00/5ml methasone DEX-OTIC Each 1ml contains: Drops Teva 11.00/5ml Dexamethasone 1mg Neomycin 5mg Polymyxin 10,000 IU HYCOMYCIN Hydrocortisone Drops Teva 9.00/5ml 1.5% Ointment 9.00/3.5g Neomycin 0.5% NOVOCORT Dexamethasone Drops JCL 10.00/10ml 0.1% Neomycin 0.5% Polymyxin B 0.119% OTOCORT Dexamethasone Drops BCP 10.00/5ml 1mg Neomycin 5mg Combination Products Polymyxin B 10,000 IU/ml OTOSPORIN Polymyxin- Drops GSK 51.00/5ml B 10,000 IU Neomycin 5mg Hydrocortisone 10mg/ml POLYMICIN Polymyxin B Drops JePharm 10.00/5ml 2500 IU Chloramphenicol 0.2% w/v

A- 31 DERMATOLOGICALS

SELLING DOSAGE MANUFACT- PRICE (NIS)/ BRAND NAME STRENGTH FORM URER # OF DOSAGE Name Generic FORM General JOHNSON’S JELLY 100% pure Jelly Johnson & 12.00/250g Petroleum Johnson

VASELINE 100% pure Jelly Elida 15.00/212g Petroleum Faaberge VESALINE (scented) 100% pure Gel Medix 6.00/50g Vaseline Petroleum WHITE PETROLEUM White Jelly Lader 12.00/200g petroleum ADINOL 40% ZnO Ointment Teva 13.00/100 (includes mineral oil, +

vaseline.) CALADERM 12.5% Cream JePharm 10.00/30g Calamine Lotion 10.00/100ml Calamine 8% ZnO CALAMINE 15% Cal. Lotion Sam-On 9.00/100ml 5% ZnO CALATRIM 15% Cal. Lotion Trima 12.00/100ml

Zinc Oxide/ 5% ZnO DYPROTEX 40% ZnO Medicated Mediline 17.00/30g Pads

ESRACAIN 5% Lignoc. Ointment Rafa 11.00/20g ESRACAIN JELLY 2% Lignoc. Jelly Rafa 10.00/30g

Lignocaine XYLENE 2% Lignoc. Gel BPC 8.00/40g Antifungals DAKTARIN 2% Cream Abic 22.00/15g

Lotion 22.00/20ml DAKTAZOL 2% Cream JePharm 10.00/15gm Oral gel 17.00/40gm

Nitrate FUNGAZOLE 2% Cream Pharmacare 9.50/15gm Miconazole FUNGITRIN 2% Cream BPC 10.00/15gm Oral gel 14.00/30gm AGISTEN 1% Cream Agis 17.00/20g

Lotion 20.00/15ml MYCOHER-MAL 1% Cream Neopharm 20.00/20g Solution 22.80/20ml CANESTEN/ 1% Cream Agis/Bayer 17.00/20g AGISTIN Solution 20.00/20ml Clotrimazole CANAZOLE 1% Cream JePharm 13.00/20mg CANDIZONE 1% Cream BCP 15.00/15gm

A- 32

- NIZORAL 2% Cream Abic 40.00/15gm

Keto 2% Shampoo Abic 48.00/100ml

conazole NIZORAL

ATHLETES FOOT 1% Powder Scholl 25.70/80g PITREX 1% Ointment Teva 17.00/15g Solution 17.00/10ml Tolnaftate TINADERM 1% Solution Schering Not in the market. Antibacterials

RECYCLINE 3% Oxy. Ointment Rekah 14.00/14g TETRACARE 3% Oxy. Ointment Pharmacare 6.00/20g TETRAPHARM 3% Oxy. Ointment JePharm 7.50/20g OXYCIN 3% Ointment BCP 5.00/18g Tetracyc. Tetracycline JORDA-CYCLINE 3% Ointment JCL 7.50/16g Oxytetracycline / Tetracyc. GARAMYCIN 0.1% Genta. Cream Schering 13.00/15g Ointment 13.00/15g GENTATRIM 0.1% Genta. Cream Trima 15.00/15g Ointment 15.00/15g

Gentamycin GARAMINE 0.1% Genta. Cream JCL 12.00/16g - BACTROBAN 2% Ointment GSK 48.00/15g ocin Mupir Antivirals

SUPRAVIRAN 5% Cream Pharmacare Not in market yet. ZOVIRAX 5% Cream GSK 34.00/2g

Acyclovir 146.00/10g Antiseptics/Disinfectants

ETHYL ALCOHOL Different containers, depending on hospital or pharmacy. Ethyl Alcohol

BETADINE 10% Ointment Rafa (1% iodine) Solution 44.00/1L

Iodine POLYDINE 10% Solution Fischer 10.00/20ml - Tincture IODOCARE 10% Solution- Pharmacare Mouthwash 9.00/100ml Povidone IOSEPT 10% Solution BPC 11.00/100ml

A- 33 CARE 0.5% Cetrim. Solution Pharmacare 3.00/100ml first aid solution 0.05% Chlorh.

Not sold in CARE 15% 15% Cetrim. Solution Pharmacare private first aid solution 1.5% Chlorh. pharmacies. CETRIN 15% Cetrim. Concentrated Vitamid 52.00/1L 1.5% Chlorh. solution SAVIOR 0.5% Cetrim. Solution Travenol 7.00/100ml first aid solution 0.05% Chlorh. 0.15% Cetrim. Cetrimide & Chlorhexidine TISEPT Solution Seton 100ml 0.015% Chlorh. Not sold in pharmacies. UNISCRUB 4% Chlorh. Solution Seton 45.00/500ml Antiparasitics BENZOCIDE 12.5% Lotion Trima 30.00/100ml 25% SCABICIDE 25% Emulsion BCP 12.00/100ml Benzyl Benzyl Benzoate SCABIEX 25% Emulsion Rekah CRUTEX 10% Crotam. Cream BCP 14.50/20gm Lotion 12.50/50ml DUO-SCABIL 10% Crotam. Cream Agis 26.00/20g 8% Sulfur EURAX 10% Crotam. Cream Novartis 15.00/20g

Crotamiton Lotion 25.00/50ml SCABICIN 10% Crotam. Lotion Fischer 24.00/100ml - BICIDE 1% Lindane Cream Fischer 25.00/50ml ane

Lind PARAZINE 1% Lindane Cream al-Razi 24.00/200g NOURYL 0.5% Lotion Chefaro Not available in

- WB market.

Mal PRIODERM 1% Cream- Napp/Rafa 17.00/40g thion Shampoo Keratolytic Agents OXY CLEAN 3.5 % Sal. Soap GSK 17.00/Bar medicated soap acid SALATAC 12% Sal. acid Gel Dermal Labs 58.00/8g ZINO PADS 40% Sal. acid Pads Scholl 8.00/5 pads SALISOL-2 2% Sal. acid Solution Rekah 10.00/100ml

Salicylic Acid (contains ethanol 70%)

Not available as single agent products. Sulfur

A- 34 Miscellaneous BETACARE 0.1% Beta- Cream Pharmacare 10.00/15gm methasone Valerate BETACORT-V 0.1% Beta- Cream JCL 7.00/16gm methasone Valerate BETACORTEN 0.1% Beta- Cream Trima 10.00/15g methasone Ointment 10.00/15g 17-valerate BETAMESONE 0.1% Beta- Cream JePharm 7.00/15g methasone Ointment 7.00/15g Valerate BETNOVATE 0.1% Beta- Cream GSK 10.00/15g methasone Ointment 10.00/15g

Corticosteroids 17-valerate DERMOVATE 0.05% Cream GSK 24.00/25g Clobetazole Ointment 28.00/25g propionate PSORIDERM 0.05% Ointment BPC 17.00/25g Clobetazole propionate VALECORT 0.1% Beta- Cream BPC 12.00/15g methasone Ointment 8.50/15g Valerate LOCACID 0.5% Cream Fabre/Mediline 40.00/30g 0.1% Lotion 40.00/15ml RETAVIT 0.05% Cream CTI 36.00/20g 0.025% 20.00/20g 0.05% Gel 36.00/20g 0.025% 20.00/20g RETIN-A 0.05% Cream JanssenCilag 49.00/30g

Retinoic Acid Retinoic 0.025% 40.00/30g AIROL 0.05% Cream Roche 35.00/20g Lotion 52.00/50ml OXY 5% Vanishing - GSK 39.00/28g 10% cream 39.00/28g

Benzoyl Benzoyl Peroxide ACNEMASK 5% Lotion Neutrogena 22.00/

A- 35

Sunscreens

There7B are various products available in pharmacies that a person can choose from, which range in price (20-90NIS) and SPF (6-45) that cannot all be listed. But some examples include:

CAPITOL SOLEIL SPF 15 Face Cream Vichy 79.00/50ml 79.00/50ml SUN BLOCK SPF 25 SPF 45 84.00/50ml HYDROSOL SPF 6 Lotion Henkel/Raed 21.00/125ml SPF15 25.00/125ml SPF 25 29.00/125ml ULTRASOL SPF 15 Cream Dr. Fisher 25.00/50g SPF 25 30.00/50g

Various Ingredients SPF 34 35.00/50g SPF 45 40.00/50g

A- 36 VITAMINS AND MINERALS

SELLING DOSAGE MANUFACT- PRICE (NIS)/ BRAND NAME STRENGTH FORM URER # OF DOSAGE Name Generic FORM Fat Soluble Vitamins available as single products AVIPUR Vitamin A Drags Taro 17.00/30 50,000U Retinol EPHYNAL Vitamin E Chewable- Roche 27.00/30 100mg Drags EVITOL Vitamin E Tab. Teva 100mg 12.00/30 200mg 19.00/30 SANATOGEN Vitamin E Tab. Fisons 12.00/ tocopherol & - tocopherol 100mg thinyloestradiol

Alpha VITAMIN E/ 200IU/ 200mg Cap. Burton 42.00/45 caps (with wheat germ oil) 400IU/ 20mg Feingold 59.00/40 600IU/ 66mg 62.00/60 Water Soluble Vitamins available as single products

ANACRODYNE Vitamin B6 Tab. Rekah 13.00/ 30,100mg B. SIX 300 Vitamin B6 Tab. Sam-On 33.00/30

Pyridoxine 300mg C 500 Vitamin C Tab. Rekah 22.00/100 500mg REDOXON Vitamin C Efferves. Roche 16.00/10 1000mg Tab. VI-C 500 Vitamin C Chewable Sam-On 10.00/10 500mg Tab.

Ascorbic Acid Ascorbic VITASCARBOL Vitamin C Lozenges Specia 7.00/12 500mg FOLIC ACID Folic Acid Tab. Sam-On 15.00/30 5mg Acid Folic

3 NICOLAR Niacin/ Tab. Armour 263.00/100 Nicotinic

Vit. B Acid 500mg Minerals NOTE: The strengths below are expressed in their elemental equivalence. (i.e. 600mg of elemental calcium is equivalent to 1500mg of calcium carbonate)

CALTRATE 600 Ca Carbonate Enteric Lederle 57.00/60 600mg Coated Tab. TUMS Ca Carbonate Chewable 17.00/36 GSK Calcium 500mg Tab. 29.00/75

A- 37

FERRO 15 Ferrous Syrup Sam-On 16.00/120ml Gluconate 15mg/5ml FERRO 23 Ferrous Syrup Sam-On 18.00/120ml

Gluconate

Iron 23mg/5ml FERRO-GRAD Ferrous Tab. Abbott 17.00/30 Sulfate 105mg SLOW-FE Ferrous Slow Release Novartis 10.00/28 Sulfate 50mg Tab. FLUDEN Na Floride Tab. Rekah 8.00/100 0.5mg

FLUVIUM-20 Na Floride Tab. Rekah 26.00/60 20mg TEETH TOUGH Na Floride Oral drops Vitamed /50ml 0.25mg/2 drops Fluoride ZYMAFLUOR Na Floride Tab. Novartis 18.00/100 0.25 1 mg

SLOW-K Potassium Cl Slow Novartis 17.00/100 600mg (equiv. Release to 315 mg K+) Tab.

Potassium

A- 38

Vitamins and Minerals Available in COMBINATION PRODUCTS SELLING

BRAND2B NAME DOSAGE3B FORM/ MANUFACT- PRICE (NIS)/ STRENGTH URER # OF DOSAGE Name Generic FORM CALCIUM SANDOZ (Efferves. Tab.) Novartis 18.00/10 + VIT C Vit. C 1000mg Ca Gluconate 578mg, Ca Lactate 422mg, Cal Carbonate 327mg CAl-C-VITA (Effervesc. Tab.) Roche 20.00/10 Vit. C 1000mg

Ca 250mg Vit. D 300 IU Vit. B6 15mg Citric Acid 1350mg CALTRATE 600+ (Enteric Coated Tab.) Lederle 57.00/60

VIT. D. Ca Carbonate 1500 eq. to 600mg elemental Ca. + Vit. D 125 IU CENTRUM-V (Tab.) Lederle 55.00/30 Vit. A 5000 IU, Vit. E 30 IU Vit. C 90mg, Vit. B1 2.25mg Vit. B2 2.6mg, Vit. B6 3mg Vit. B12 9mcg, Vit. D 400 IU

Folic Acid 400mcg Niacin 20mg, Biotin 45mcg Vit. B5 10mg, Ca 16mg Phosphorus 125mg Iodine 27mg, Mg 100mg Copper 3mg, Mn 7.5mg K 7.5mg, Zn 22.5mg CENTRUM JUNIOR (Chewable Tab. ) Lederle 49.00/30 ADVANCED + IRON Vit. A 5000 IU, Vit. D 400 IU Vit. E 30 IU, Vit. C 60mg Vit. B6 2mg, Vit. B12 6mcg Vit. K 10mcg, Biotin 45mcg Folic Acid 400mcg Thiamine 1.5mg, Vit. B5 10mg Vit. B2 1.7mg, Niacin 20mg Iron 18mg, Mg 40mg Iodine 150mcg, Copper 2mg Phosphorus 50mg, Ca 108mg Zn 15mg, Chromium 20mcg Mn 1mg

A- 39 CENTRUM PLUS (Tab.) Lederle 55.00/30 Vit. A 4000 IU, Vit. E 30 IU Betacarotene 1000IU Vit. C 60mg, Vit. B1 1.5mg Vit. B2 1.7mg, Vit. B6 2mg Vit. B12 6mcg, Vit. D 400 IU Vit. K 25mcg, Niacin 20mg

Folic Acid 400mcg Biotin 30mcg, Vit. B5 10mg P 150mg, Ca 194mg, Iodine 150mcg, Iron 18mg Mg 100mg, Mn 2.5mg Cu 2mg, Zinc 15mg Cr 25mcg, Se 60mcg Molybedenum 60mcg Nickel 5mcg KIDDI (SYRUP) Pharmaton 40.00/100ml Vit. A 2000 IU Vit. D2 400 IU Vit. B1 10mg, Vit. B2 6mg, Vit. B12 10mcg, Vit. B6 3mg Ca 39 Phosphorous 61 mg Lycine pharmaton 200mg Nicotinamide sugar excip 10ml MATERNA (Tab.) Lederle 140.00/100 ENHANCE Vit. A 5000 IU, Vit. B1 3mg 48.00/30 FORMULA Vit. B2 3.4mg, Vit. B5 10mg Vit. B12 12mcg, Vit. B6 10mg Vit. D 400 IU, Vit. E 30 IU Niacin 20mg, Biotin 30mcg Iron 60mg, Ca 250mg Iodine 150mcg, Mg 25mg Copper 2mg, Zn 25mg Chromium 25mg, Mn 5mg Molybdenum25mcg ORACAL-D (Cap.) BPC 35.00 /50

Ca Carbonate 1500 eqv. to 600mg elemental Ca. + Vit. D 125 IU POLYVIT (Drags) Taro 66.00/30 Vit. A 5000 IU, Vit. B1 5mg Vit. B2 3mg, Vit. B6 1mg Vit. B12 20mcg, Vit. C 50mg Vit. D 400 IU, Vit. B5 3mg Folic Acid 2mg, Niacin 25mg Iron 3.3mg, Ca 60mg P 40mg, Mn 167mcg Mg 6.67mg SLOW-FOLIC (Tab.) Ferrous sulphate 160mg Novartis 15.00 /28 (eq. to 50 mg Fe), Folic acid 400 mcg

A- 40 STRESSTAB. (Tab.) Lederle 40.00/30 Vit. E 30 IU, Vit. C 600mg 1 2 Vit. B 15mg, Vit. B 15mg Vit. B6 25mg, Vit. B12 12mcg Niacin 100mg, Vit. B5 20mg Folic Acid 400mcg STRESSTAB. 600 (Tab.) Lederle 36.00/30 WITH IRON Vit. E 30 IU, Vit. C 600mg Vit. B1 15mg, Vit. B2 15mg Vit. B6 25mg, Vit. B12 12mcg Niacin 100mg, Vit. B5 20mg Folic Acid 400mcg Iron 27mg SUPRADYN N (Drags, Efferves. Tab.) Roche 35.00/30 Vit. A 3333 IU, Vit. B1 20mg Vit. B2 5mg, Vit. B6 10mg Vit. B12 5mcg, Vit. C 150mg

Vit. D 500 IU, Vit. E 10mg Vit. B5 11.6mg, Niacin 50mg Folic Acid 1mg, Biotin 0.25 Ca, Iron, Mg, Mn, Phosphorus, Copper Molybdenum, Zinc VI-DAYLIN PLUS (Syrup) Abbott 33.00/240 IRON Vit. A 2500 IU, Vit. D 400 IU

Vit. E 15 IU, Vit. C 600mg Vit. B1 1.05mg, Vit. B2 1.2mg Vit. B12 4.5mcg, Vit. B6 1.05mg Niacin 13.5 mg, Iron 10mg MINOVIT (Tab.) JePharm 14.00./30 Vit. A 800 IU, Vit. D 400 IU Vit. E 0.75MG, Vit. C 25mg Folic Acid 0.1mg, Vit. B1 5mg Vit. B2 1mg, Vit. B5 6mg Vit. B12 1mcg, Vit. B6 2mg Ferrous Ammon. Citrate 3mg Ca 40mg, Niacin 6mg Mg 20mg, Mn 4mg ABECIDEN (Tab.) BPC 18.00/30 Vit. A 5000 IU, Vit. B1 2.5mg Vit. B2 2.5mg, Vit. B6 2mg Vit. B12 10mcg, Vit. C 50mg Vit. D 400 IU, Vit. E 30 IU Niacin 30mg, Vit. B5 3mg Folic Acid 0.8mg Ca 125mg, Iron 18mg Mg 10mg, Iodine 0.15mg VICAL (Efferves. Tab.) BPC 14.00/10 Vit. C 1000mg, Ca 250mg Vit. D 300 IU, Vit. B6 15mg

There are several other products that contain various vitamins and minerals in other concentrations, or in combination with herbal or amino acids (i.e. ginseng, lysine, pantothenate) that will not be listed.

A- 41 VACCINES

SELLING BRAND NAME STRENGTH DOSAGE MANUFACT PRICE (NIS)/ FORM -URER # OF DOSAGE Name Generic FORM

BCG As recommended by WHO BCG

POLIO SABIN As recommended Oral use GSK 19.59/1 dose by WHO only amp. OPV IMOVAX POLIO 0.5 ml contains SC or IM Pasteur inactivated poliovirus Merieux

IPV type 1,2 &3 for one immunization dose. TETANOL 0.5 ml contains Suspension Chiron

tetanus toxoid at given IM Gehring least 40 IU. or deep SC TETANUS 0.5 ml tetanus Suspension Rafa 4.00/1 dose Tetanus TOXOID PTAP toxoid as recom- for IM ampoule mended by WHO D.T.COQ Purified diphtheria Suspension Rhone toxoid at least 30 IU for injection Poulenc Purified tetanus given IM or group toxoid at least 60 IU deep SC

Bordetella pertussis at least 4 IU

DPT DiTePer Purified adsorbed Suspension Swiss Serum ANATOXAL diphtheria-tetanus- for injection and Vaccine BERNA Pertussis at least given IM or Institute deep SC 20,000 million- Berne Toxoids RIMEVAX Not less than 1.000 Lyophilized GSK 48.50/1 dose TCID50 of the powder to be vial Schwarz strain reconstituted Measles for SC only MMR VACCINE Live attenuated Freeze- Serum strains of Edmonston- Dried vial Institute of Zagreb measles, for dilution India LTD

mumps and Wistar given by RA 27/3 rubella virus. deep SC TRIMOVAX Live hyper-attenuated Powder for Pasteur MMR MERIEUX measles (Schwarz dilution Merieux strain), mumps (Urabe given SC or 9 strain), rubella IM. (RA27/3M strain)

A- 42

ENERGIX-B Pediatric: 10 ug in Solution GSK 77.00/1 dose 0.5ml rDNA for IM use vial for child.

hepatitis 102.00/1 dose Adult: 20ug/1ml vial for adult. EUVAX B Inj. Purified HBs Susp. for LG Antigen 10 ug in IM use Chemical

Hepatitis B 0.5 ml only Ltd. HEPAVAX-GENE 10 ug of HbsAG in IM injection Korea Green RECOMBINANT 0.5 ml only Cross Corp Every season there - Solution Price range is a different for IM use from 25 - 35 preparation NIS./1 dose

vaccine depending on vial. Influenza influenza strains. HibTitter Haemophilus-b Solution Lederle Lab 122.00/1 dose

saccharide 10ug in for IM vial 0.5ml (Diphtheria only Hib

Vaccine CRM 197 protein conjugate)

A- 43 Appendix B - Definitions

Word0B Definition Absorption The passage of the drug from its site of administration into the blood. Acquired Resistance Bacteria can become resistant by incorporating a “resistance factor” into their genes to render the antibiotic ineffective. Antibiotics Agents derived from natural substances. Antitoxin A solution of antibodies derived from the serum of animals immunized with specific antigens (e.g. diphtheria antitoxin and botulinum antitoxin) used to achieve passive immunity or for treatment. Autoinfection Infection by an organism existing within the body or transferred from one part of the body to another part. Bactericidal Agents that kill the microorganism. Bacteriostatic Agents that inhibit the growth of the microorganisms by producing reversible changes. This delay in the growth will give the immune system the chance to get rid of the microorganism. Bioavailability The fraction of the drug that reaches its action sites after administration by any route. It is the rate and extent of absorption of a drug from a dosage form as determined by its concentration/time curve in the systemic circulation or by its excretion in the urine. Bioequivalence When the same 2 dosage forms for the same active ingredient in the same dose give the same bioavailability criteria, i.e. the same maximum concentration (Cmax) at the same time (Tmax), that is their rates and extent of absorption do not show significant differences. Blood Dyscrasia A pathologic condition manifested by fever, sore mouth or throat, unexplained fatigue and easy bruising or bleeding. Broad Spectrum The range of activity extends to many micro-organisms. (e.g. Tetracyclines depress G+ve, G-ve, Rickettsiae and Chlamydiae.) Chemical When the same 2 dosage forms for the same active ingredient Equivalence contain the same amount of the active ingredient, obtained after chemical analysis. Coenzyme It is a dissociable, low-molecular weight, non-proteinaceous organic compound (often nucleotide) participating in enzymatic reactions as acceptor or donor of chemical groups or electrons. Compliance Faithful adherence by the patient to the prescriber’s instructions. Cross Resistance The passage of the acquired resistance to another bacterium. Cross-Sensitivity When a person is severely allergic to a certain drug, he/she might as well be sensitive to another drug which is similar in chemical structure or in pharmacological effect. e.g. Aspirin and other NSAIDs. Cumulative Effect Increase in drug effect that results when intake of repeated doses exceeds the rate of drug elimination form the body. Distribution The delivery of the drug to the tissues.

A- 44 Disulfiram Type An antabuse type reaction, that presents with symptoms such as facial Reaction flushing, pounding, headache, sweating, slurred speech, abdominal cramps, nausea, vomiting, tachycardia, fever, drop in blood pressure, dyspnea, and sense of chest constriction; symptoms may last up to 24 hours. Drug Any substance presented for treating, curing or preventing disease in human beings or in animals. A drug may also be used for making a medical diagnosis or for restoring, correcting, or modifying physiological functions. Elimination The process by which the drug’s concentration decreases in the body by metabolism and excretion. Enzyme Induction Stimulation of microsomal enzymes by a drug resulting in metabolism acceleration leading to decreased activity. Excipient Any component of a finished dosage form other than the indicated therapeutic active ingredient(s). Excretion The process whereby drugs are transferred from the internal to the external environment. The principal organs involved in this process are the kidneys, lungs, biliary system and intestines. Half-life (t1/2) Time required for concentration of a drug in the body to decrease by 50%. Half-life also represents time necessary to reach steady state or to decline from steady state after a change in dosing regimens. Immune Globulin A sterile solution containing antibodies from human blood. It is (IG) obtained by cold ethanol fractionation of large pools of blood plasma and contains 15-18% protein. Metabolism The process by which the drugs are modified in the body into a more or less water-soluble-substance, or more or less toxic substances. Milliequivalent Unit It is related to the total number of ionic charges in solution and (meq) also takes into account the valiance of the ions. Thus, it measures the amount of chemical activity of an electrolyte. Me-too drug It is a compound that is structurally very similar to already known drugs, with only minor pharmacological differences. Narrow Spectrum Agents that kill the microorganism. The range of activity for this antibiotic is small. It affects 1-2 micro-organisms only. (For example, Penicillin-G affects G+ve organisms and Neisseriae.) Pharmacodynamics The process of interaction of drugs with the cells. It includes: the binding of drugs to cells, their uptake, and intracellular metabolism, dose response relationships as well as therapeutic effects. (The effect of the drug on the body). Pharmacokinetics The process of handling of a drug within the body, which includes its absorption, distribution, metabolism, and excretion. (The effect of the body on the drug; or the drug fate in the body). Photosensitivity Drug induced skin changes resulting in unusual susceptibility to effects of sunlight or ultraviolet light.

A- 45 Procurement Selecting suppliers, placing and monitoring orders, checking delivery quantities and quality, and paying suppliers. Prodrug Any compound that undergoes biotransformation before exhibiting its pharmacological effects. Prodrugs can thus be viewed as drugs containing specialized non-toxic protective groups used in a transient manner to alter or to eliminate undesirable properties in the parent molecule. Pulmonary Edema Excessive fluid in the lung tissue manifesting one or more of the following: shortness of breath, cyanosis, persistent productive cough (frothy sputum may be blood tinged), expiratory rales (?), restlessness, increased heart rate, sense of chest pressure and/or anxiety. Superinfection / A new infection by an organism different from the initial Suprainfection infection being treated by antimicrobial therapy, presented by one or more of the following: black, hairy tongue, glossitis, stomatitis, anal itching, loose foul-smelling stools, vaginal itching or discharge, sudden fever, cough. Therapeutic When the same 2 dosage forms for the same active ingredient Equivalence provide the same therapeutic effect and safety. Therapeutic Window/ Range of drug concentration level, within which a particular drug Therapeutic Index has its safest and optimal therapeutic effects, that is, the limits (TI) between therapeutic and toxic response to a drug. Tolerance Decreased responsiveness to pharmacodynamic action of a drug that occurs during repeated administration of constant drug doses. Larger or more frequent doses or both are required to achieve the same effects observed with initial dosing. Toxoid A modified bacterial toxin that has been rendered nontoxic but retains the ability to stimulate the formation of antitoxin. Urinary Secretion The process by which drugs are secreted from the plasma into the kidney tubules (ex. Pen. G) in order to be excreted by the urine. Vaccine A suspension of live (usually attenuated) or inactivated microorganism (bacteria, viruses, or rickettsiae) or fraction of them, administered to induce immunity and thereby prevent infectious disease.

A- 46 A- 47

Appendix C Summary of drugs used for allergic reactions or anaphylactic shock

Allergic reactions, anaphylactic shock and conditions such as angioedema are medical emergencies that need immediate action to avoid cardiovascular collapse and/or death. Prompt treatments of possible laryngioedema, bronchspasm and/or hypotension are required.

1. Vital signs 3. Antihistamines Maintain an open airway; give oxygen by Administer promethazine or chlor- mask, restore blood pressure. phinarime by slow IV over 1 min. Promethazine: Adult 25-200 mg/d, Child: 2. A sympathomimetic as first line 1 mg/kg/d, deep IM or slow IV injection. treatment Epinephrine (adrenaline) 1:1000 given IM 4. Corticosteroids Adult 500 microgram (0.5 ml) Steroids do not have an immediate effect Child 6 mon.-6 yrs. 120 microgram (0.12 ml) on the symptoms but are useful in Child 6-12 yrs. 250 microgram (0.25 ml) reducing or eliminating further Infant < 6 mon. 50 microgram (0.05 ml) deterioration. Hydrocortisone by slow IV may be administered as follows: The dose may be repeated several times if Adult 100-300 mg necessary at 5 minute intervals, according Child up to 1 year 25 mg to the blood pressure, pulse and Child 1-5 yrs. 50 mg respiratory function. Child > 5 yrs. 100 mg

When patient is severely ill (i.e. shock) 5. Intravenous fluids and there is doubt about adequacy of the Start infusion with sodium chloride: 0.5-1 circulation and absorption from the IM liter during the first hour. Repeat if route, IV administration can be given necessary until circulation, tissue slowly in a dose of 500 microgram (5 ml perfusion and blood pressure improve. of the dilute 1:10,000 epinephrine) at a rate of 100 microgram per minute, until a 6. Asthma like symptoms response has been obtained. Half doses Bronchospasm unresponsive to of adrenaline (epinephrine) may be safer epinephrine: Salbutamol nebulized, 1 mL for patients on amitriptyline, imipramine, salbutamol respirator solution + 1 mL or beta-blocker. 0.9% sodium chloride solution. Repeated If cardiac arrest occurs, 1:10,000 2–4 hourly if necessary OR continue with epinephrine in a dose of 10 ml by IV is salbutamol, oral, 0.15 mg/kg 6 hourly for preferred through a central line. Atropine 24 hours. 3 mg IV as single dose maybe Can administer aminophylline 5 mg/kg IV administered or other cardiac drugs as over 20 mins. if salbutamol is not case requires. available.

* Refer to individual drug monographs for further details about individual drugs.

A- 48 A- 49

Appendix D Local Manufactures

Birzeit Palestine Pharmaceutical Company Jordan Chemical Laboratory (BPC) P.O. Box 58, Beit Jala, Palestine P.O Box 20, Birzeit, Palestine Tel: (970)-2-274-2855, 277-6880, 277-6881 Tel: (970)-2-295-6581, Fax: (970)-2-274-1072 Fax: (970)-2-295-3253 E-mail: [email protected], [email protected] E-mail: [email protected] MEGAPHARM Gama Chemical Company (GCC) Industrial Zone, Beit Hanoun, Gaza Strip P.O. Box 782, Beitunia, Palestine Tel: (970)-8-245-5011, 245-5012, Tel: (970)-2-290-0911, Fax: (970)-8-245-5051 Fax: (970)-2-290-0064 E-mail: [email protected], E-mail: [email protected] [email protected] Jerusalem Pharmaceutical Company Pharmacare Ltd Company (Pharmacare) (JEPHARM) P.O. Box 677, Ramallah, Palestine P.O. Box 3570, el-Bireh, Palestine Tel: (970)-2-290-0980/1, Tel: (970)-2-240-6550, Fax: (970)-2-290-5189 Fax: (970)-2-240-3246 E-mail: [email protected], E-mail: [email protected], [email protected] [email protected]

Registered Local Drug Stores

Act Medical Co., Jerusalem al-Rasheed D.S., Nablus Tel: 026799048, Fax: 026782818 Tel: 092388101, Fax: 2381894 al-Azouni Trading D.S., Nablus al-Razi D.S., Ramallah Tel: 092372296/2377231, Fax: 092371312 Tel: 022956395, Fax: 022956396 al-Barghouti Co. D.S., Ramallah al-Salameh D.S., Jerusalem Tel: 022985957 Tel: not available. al-Basheer D.S., Bethlehem al-Shak'a D.S., Nablus Tel: 022776666, Fax: 022742402 Tel: 092382660, Fax: 092381420 al-Du’wali D.S., Ramallah al-Thulathia D.S. Co., Nablus Tel: 022955797, 022955026 Tel: 092385304, Fax: 092385304 al-Hayya D.S., Jenin al-Walid Medical Trading Co., Ramallah Telfax: 062503074 Tel: 022956416, Fax: 022956413 al-Hayya D.S., Ramallah al-Watani D.S., Bethlehem Tel: 022989444, Fax: 022989444 Telfax: 022747033 al-Nour Medical Co. D.S., Jerusalem al-Wihda D.S., Nablus Tel: 022349788, Fax: 022349775 Tel: 0962382534, Fax: 2385820 al-Ram D.S., Jerusalem Beit Hanina D.S., Jerusalem Tel: 022349839, Fax: 022349735 Tel: 025857918, Fax: 025856257

A- 50 Bethlehem Medical D.S., Bethlehem Naseeb al-Jadeed D.S., Bethlehem Tel: 022742906, Fax: 022777414 Tel: 022774044, Fax: 022774045 Dana D.S., Jerusalem Nazal D.S., Ramallah Tel: 022348616 Telfax: 022955990 DespoMed Co., Jerusalem Nobil Co. for Medical Equipment, Ramallah Tel: 025834075/6, Fax: 025834077 Tel: 022900251, Fax: 022900890 F.A. Hanna D.S., Ramallah NutriPharm D.S., Hebron Tel: 026284985, Fax: 026284987 Telfax: 022226440 Hikmat for Medicines D.S., Hebron Omnipal Co. for Trade & Marketing, al-Bireh Tel: 022234177 Tel: 022958018, Fax: 022958019 Ibn al-Haytham D.S , Hebron Palestinian-British Co. for Trading & Tel: 022228550, Fax: 022226767 Contracting, Gaza Ibn Sina D.S., Nablus Tel: 082837708/ 082822726, Tel: 092378159, Fax: 092372264 Fax: 082823967 Intermed Co., Ramallah Pharmacare D.S., Jerusalem Tel: 026283822, Fax: 026272661 Tel: 025813515 InterPal Co. for Medical Imports, Gaza Razan D.S., Ramallah Tel: 082822728, Fax: 082822718 Telfax: 022985698 Khalil al-Rahman D.S., Hebron Riyam D.S., Jerusalem Tel: 022219366 Tel: 025810288, Fax: 025819047 Lyn Co. for Medical Equipment, Beitunia Sami Anabtawi D.S., Nablus Tel: 022902193, Fax: 022902204 Tel: 092374006, Fax: 092370237 Masrouji Trading Co., al-Bireh Siamco for Medicines and Trade, Ramallah Tel: 022404060, Fax: 022403958 Tel: 022963246, Fax: 0229559949 MediPharm Co. for Medical Needs, Sufian Med. Equipment Company, Jerusalem Bethlehem Tel: 022796863, Fax: 026263521 Tel: 022775245, Fax: 022775244 Sukhtyan Brothers Co., Nablus MediSerf D.S., Tulkarem Tel: 092377718 , Fax: 092387234 Telfax: 09 2676433 Sun Trading Co, Nablus Tel: 092397181, Fax: 092397184 MSS, Beitunia Tel: 022959372/3/4, Fax: 022959375 Tulkarem D.S., Tulkarem Nablus Co. for Med. Equipment, Nablus Tel: 092382821 Tel: 092389965, Fax: 092389966

A-51 References

American Pharmaceutical Association. 1993. Handbook of nonprescription drugs, 10th ed. Washington DC: APhA. Anonymous. 2001. Early Parkinson disease: dopamine agonists have increasingly important role in symptoms management. Drug & Therapeutic Perspectives; 17(17): 5-9. www.medscape.com/adis/DPT/2001/v17.n17/dtp1717.02/mig-pnt-dtp1717.02.html accessed on Jan 28 2002. Antibiotic Guidelines Sub-Committee. 1996. Victorian Drug Usage Advisory Committee: Antibiotic guidelines, 9th ed. VMPF-Therapeutics Committee. Atkinson WL, et al. (editors). 1999. Epidemiology and prevention of vaccine-preventable diseases, 5th ed. Atlanta: Department of Health & Human Services, CDC. Belongia EA and Schwartz B. 1998. Strategies for promoting judicious use of antibiotics by doctors and patients. British Medical Journal; 371: 668-671. Briggs GG, Freeman RK, Yaffe SJ. 1994. Drugs in pregnancy and lactation, 4th ed. Maryland: Williams & Wilkins. British National Formulary, (Number 41). 2001. British Medical Association and Royal Pharmaceutical Society of Great Britain. Center of Disease Control and Prevention (CDC). 1993. Recommendations of the Advisory Committee on Immunization Practices (ACIP): Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR. 42(No.RR-4). Center of Disease Control and Prevention (CDC). 1994. General recommendations on immunizations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Center of Disease Control and Prevention (CDC). 1998. Haemophilus Influenzae type B (Hib) vaccine: fact sheet. Medical Strategies Inc. Chetley, A. 1993. Problem drugs. Amsterdam: Health Action International-Atlas BV. Chobanian AV, et al. 2003. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure; the JNC 7th report. Journal of American Medical Association; 289(19): 2560-72. Couper MR & Mehta DK (editors). 2002. WHO model formulary. UK: WHO. Criag CR, Stitzel RE. 1994. Modern pharmacology, 4th ed. Philadelphia: Little, Brown and Company. CVI (Children’s Vaccine Initiative). 1998. New vaccines: Hib-who is using it, who isn’t and why not? CVI; 16: 13-15. Dagon R, et al. 1994. Epidemiology of pediatric meningitis caused by Haemophilus influenzae Type b, Streptococcus pneumoniae, and Neisseria meningitidis in Israel: a 3-year nationwide prospective study. Journal of Infectious Disease; 169: 912-6. De Quadros CA. 1995. A template for the world. WHO; 1(48th year): 5-6. Drug Facts and Comparisons. 2000. St. Louis, MO: Facts and Comparisons Inc.

Estimating drug requirements: a practical manual. 1991. Action programme on essential drugs and vaccines. WHO. Food and Drug Administration (FDA). 2003(March). FDA issues health advisory regarding labeling changes for lindane products: FDA talk paper. Gilman GA, et al. 1990. Goodman and Gilman’s: the pharmacological basis of therapeutics, 8th ed. New York: Pergamon Press Inc. Graedon J, Graedon T. 1996. The people’s pharmacy. New York: St. Martin’s Griffin. John Macleod. 1990. Davidson’s principles and practice of medicine. New York: Churchill Livingstone. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 1997. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Archives of Internal Medicine; 157:2413-2446. Laurance & Bennett. 1990. Clinical pharmacology. New York: Churchill Livingstone. Local companies’ vademecums. West Bank, Palestine. Martindale, the Extra Pharmacopoeia, 31th ed. 1996. London: Royal Pharmaceutical Society. Nelson WE (senior editor). 1992. Nelson textbook of pediatrics, 15th ed. Philadelphia: W.B. Saunders Co. Palestinian essential drugs list for primary health care. 1997. MOH, Palestine. Physicians’ Desk Reference (PDR), 50th ed. 1996. New Jersey: Medical Economics Co. Professional’s guide to patient drug facts. 1997. St. Louis, MO: Facts and Comparisons. Shannon MT, Wilson BA, Stang CL. 1995. Drugs and nursing implications, 8th ed. Connecticut: Appleton & Lange. Silverman HM (editor-in-chief). 1996. The pill book, 7th ed. New York: Batman Books. Tatro DS (editor). 1996. Drug interaction facts, 5th ed. St. Louis, MO: Facts and Comparisons Inc. The Standing Medical Advisory Committee, et al. 1990. Handbook of contraceptive practice, 1990 edition. London: Crown. UNICEF. 1996. The health of the Palestinian women in the West Bank and Gaza Strip. Jerusalem. UNRWA. 1990. Instructions and information on immunization. United Nations Relief and Works Agency for Palestinian Refugees in the Near East. USP DI: Drug information for the health care provider. 1994. Rockville, MD: The United States Pharmacopoeial Convention. WHO. 1992. The use of essential drugs: model list of essential drugs (7th list). Geneva: WHO. WHO. 1994. Out patient management of young children with ARI: participant manual. WHO. 1997. WHO model list of essential drugs, 10th list. Wilson JD (editor). 1991. Harrison's principles of internal medicine. New York: McGraw Hill Inc.

General Index

Ammonium Chloride, 93 A-parkin, 222 Amoxi, 122 Apomoxyn, 122 A Amoxicare, 122 Aprical, 39 α-Methyldopa, 24 Amoxicillin, 120, 245, A18 Artane, A27 Abeciden , A41 Ampicillin, 120, A17 Artofen, 10 Abitren, 11, A4 Ampipharm, 122 Ascorbic Acid, 285, A37 Abrolet, 7 Ampitricine, 122 Asmalin, 104 Acamol, 7, A3 Amyvil, 194 Aspirin, 3, 13, 47, A3 Acamoli, 7 Anabolic Steroids, 162 Assival, 199, A29 Acarbose, 157 Analgesics, 3 Astemizole, 87, 88, A12 ACE Inhibitors, 34, 50, A6 Anaphyl, 88 ASTHMA MEDICATION, Acebutolol, 42 Ancozine, 70 97, A13 Acetaminophen, 6 Angilat, 39 ASTRINGENTS, 80 Acetazolamide, 235 ANTACIDS, 61, 62 Ateni, 34 Acetic Acid, 243 ANTHRANILITES, 276 Atenolol, 33, A6 Acetohexamide, 157 ANTIARRHYTHMIC, 214 Athletes Foot, 259 Acetosal, 6 Anticholinergic Drugs, 66, Ativan, 200 Acetylcysteine, 97, 239, A13 218, A27 Atroped, 239 Acetylsalicylic Acid, 4, A3 ANTIDEPRESSANTS, 191 Atropine, 66, A30 Acne Mask, 274 ANTIDIABETIC DRUGS, Atrospan, 239 Acrivistine, 87 157, A23 Augmentin, 123, A18 Acyclovir, 151, 260, A33 ANTIDIARRHEAL AGENT, Avobenzone, 276 Adalat, 39 74, A10 ANTIEMETICS, 68, A10 Adenosine, 42 B Adinol, 255 ANTIEPILEPTIC, 205, A26 Advil, 10 ANTIFUNGALS, 148, 256, β-Blockers, 31, 162 Aerolin, 104 A22 Baby Aspirin, 6, A3 Affectine, 196 ANTIGOUT AGENTS, 13 Bacampicillin, 120 Ahiston, 88 ANTI-HEMORRHOIDAL, Bacitracin, 259 Albendazole, 148 79, 80, A11 Bacloforte Inhaler, 107 Albuterol, 103 Antihistamines, 86, A13 Bactosept, 263 Alcinal, A15 ANTIHYPERTENSIVES, Bactrim, 133 Aldactone, 30 23, A6 Bactroban, 259 Aldosprine, 30 ANTI-INFECTIVES, 113, Bactroscrub, 263 Alka Seltzer, 6 A17 Barbiturates, 197 Allergon, 88 ANTIPARASITICS, 143 BCG Vaccine, 303 Allopurinol, 13, 102 ANTIPARKINSONS Beclomethasone, 106, A14 Alloril, 15 DRUGS, 218, A27 Beconase Nasal, 107 Alprazolam, 197 ANTIPYRETIC, 3 Becotide Inhaler, 107 Alrin, 92 ANTI-TUBERCULOSIS, Benazepril, 35 Aluminium/Aluminum 137, 138, A21 Benzene Hexachloride, 265 Acetate Solution, 243 ANTITUSSIVES, 94, A12 Benzhexol, 219 Amantadine, 221, A27 Antivert, 70 Benzocaine, 79 Amiloride, 29 ANTIVIRAL AGENT, 151, Benzocide, 264 Aminobenzoic Acid, 276 A22 Benzodiazepines, 197, 199 Amiodacore, 44 Anturane, 17 Benzophennones, 276 Amiodarone, 42, A7 Anusol, 80 Benzoyl Peroxide, 273 Amitriptyline, 192, A48 ANXIOLYTICS, 197 Benzthiazide, 26

Benzyl Benzoate, 263, A34 Cascara, 76 Ciproxin, 137 Benzylkonium Chloride, 178 Castor oil, 76, 77 Citalopram, 191 Benzylpenicillin, 116 Ceclor, 127, A19 Clamoxin, 120 Bepen, 119 Cefacare, 127 Clarithromycin, 62, 130, 245 Betadine, 262 Cefaclor, 125, 126, A19 Clemastine, 87 Betamethasone, 170, 233, Cefadrox, 127 Clobazam, 197 246, 269, 271, A35 Cefadroxil, 125, 126 Clobetasol, 271 Betaren, 11 Cefalex, 127, A19 Clofibrate, 53 Bezafibrate, 53, A8 Cefamandole, 125 Clomipramine, 191 Bezalip, 54 Cefazolin, 125 Clonazepam, 197, 209, A26 Bicide, 267 Cefoperazone, 125 Clonex, 211 Bisacodyl, 77, A11 Ceforal, 127 Cloroyate, 88 Bisoprolol, 31 Ceforanid, 125 Clotrimazole, 256, A32 Blocardril, 33 Cefotaxime, 125 Cloxacillin, 116, A18 Bonine, 70 Cefotetan, 125 Clozapine, 201 Bretylium, 42 Cefovit, 127 Co-amoxiclav, 122, A18 Brimocyclin, 129 Cefoxitin, 125 Co-careldopa, 224, A27 Bristamycin, 131 Ceftazidime, 125 Cocoa Butter, 80 Broadacillin, 122 Ceftizoxime, 125 Codeine, 94, 96 Bromhexine, 97, A13 Ceftriaxone, 125 Codical, 96 Bromocriptine, 222, A27 Cefuroxime Axetil, 125, 245 Cogentin, 220 Brompheniramine, 87 Centrum, A39 Colchicine, 13, 17, 18, A5 Brufen, 10 Celiprolol, 31 Colestipol, 55 Buffered Aspirin, 6 Cephalexin, 124, 126, A19 Coldex, A16 Bumetanide, 27 Cephalosporins, 124, A19 Colifibrate, 162 Bupropion, 191 Cephalothin, 125 CONTRACEPTIVES, 162, Butoconazole, 256 Cephapirin, 125 A24 Cephradine, 125 Copper IUDs, 177 Cerumol, A31 Cordil, 46 C Cetrimide, 262 Cordorone, 44 Ca Salts, 290 Chloramphenicol, 203, 244, Corotenol, 34 Caladerm, 255, A32 A29 Corotrend, 39 Calamine, 80, 255, 268, A32 Chlorbutol, 246 Corticosteroids, 162, 230, Calatrim, 255 Chlordiazepoxide, 197 233, 269, A29 Cal-C-Vita, A39 Chlorhexidine, 244, 262, A34 Cortisone, 170 Calcium, 288, A39 Chlorotetracycline, 231 Co-trimoxazole, 131 Calcium Channel Blockers, Chlorothiazide, 26 Cough Suppressants, 94 37, A7 Chlorpheniramine, 86, A12, Coumadin, 49 Caltrate, A39 A48 COX-2, 8 Candistan, 149 Chlorpromazine, 201, A28 Cromoglycate, 104 Capillon, 262 Chlorpropamide, 157 Cromolyn, 104, 235, A14 Caplenal, 15 Chlorthalidone, 26 Cromunal, 106 Capoten, 37 Cholestyramine, 53, 54 Crotamiton, 264 Captopril, 15, 24, 35, A6 Chol-Less, 55 Curam, 123 Carbamazepine, 207, A26 Cilazapril, 35 Cyproheptadine, 87 Carbi, 209 Cinnamates, 276 Carbidopa, 224, A27 Cinoxacin, 136 D CARDIOVASCULAR Cinoxate, 276 DRUGS, 21, A6 Ciprocare, 137 Dakatrin, 150 Cardopril, 37 Ciprofloxacin, 136, 231, A21 Daktarin, 257 Cartia, 6, A3 Ciprogis, 137 Daktazol, 150

Daktazole, 257 Dyprotex, 255 Febracold, A15 Daonil, 164, A23 Febramol, 7 Declamide, 164 Fedral, 104 E DECONGESTANTS, 90, Felcol, 13 A12 Econazole, 256 Feldene, 13 Deltasone, 173 Elatrol/Elatrolet, 194 Felodipine, 37 Depakote, 217 Elavil, 194 Femulen, 184, A25 Depalept, 217 Electrosubs, 74 Fenoxypen, 119 Depo-provera, A25 Eltroxin, A24 Ferro-Grad, A38 Deraline, 33, A6 Emergency Pills, 186 Flagy, 144 DERMATOLOGICAL Emestop, 69 Flecainide, 42 PREPARATIONS, 253, Emollients, 253 Florine, A38 A32 E-Mycin, 131 Floxin, 137 Desipramine, 191, 193 Enalapril, 35 Flu, A16 Desogestrel, 180 Encainide, 42 Fluden, A38 Dexamethasone, 170 Endep, 194 Flucloxacillin, 116, 119, Dexamol, 7, A3, A15 Engerix, 307, A46 244, A17 Dextromethorphan, 96 Enoxacin, 136 Fludrocortisone, 169 Dextrothyroxine, 162 Entogyl, 144 Fluorine, 288 Diabeta, 164 Epanutin, 215, A27 Fluorometholone, 233 Diasix, 29 Ephedrine Sulphate, 81 Fluoroquinolones, 136 Diazepam, 197, 198, 217, Epinephrine, A48 Fluosinolone, 271 A28 Erytab, 131 Fluoxetine, 191, 195, A28 Dichlorphenamide, 235 Erythrocare, 131 Fluoxicare, 196 Diclofen, 11 Erythrocin, 131 Flutine, 196 Diclofenac, 8, 239, A4 Erythrolet, 131 Fluvoxamine, 191 Diflorasone, 271 Erythromycin, 129, A20 Fluvsa, A8 Digitalis Glycosides, 50 Erythroped, 131 Folic Acid, 285, A39 Digitoxin, 50 Erythropharm, 131 Fungazole, 257, A23 Digoxin, 50, 68, A8 Erythroteva, 131 Fungitirin, 257 Dilantin, 215 Esidrex, 27 Furadantin, 135 Dilatam/Dilapress, 41 Esmolol, 31, 42 Furamide, 146 Diloxanide Furoate, 146 Esracain, 256 Furosemide/Frusemide, 24, Diltiazem, 24, 45, 162 Estrogens, 179, A24 27, A6 Dioxybenzone, 276 Ethacrynic Acid, 27 Furovite, 29 Diphenhydramine, 87 Ethambutol, 138, 142 Fusid, 29, A6 Dipyrone, 4 Ethanol, 261 Diseptyl, 133 Ethinyl Estradiol, 176, 186, G Disopam, 199 A24 Disopyramide, 42 Ethosuximide, 211, A26 Gabapentin, 205 Disoramin, 88 Ethyl Alcohol, 261 Garamine, 260 Disothiazide, 27 Ethynodiol, 180 Garamycin, 260 DIURETICS, 26, 50 Expanded Program of GASTRO-INTESTINAL Docusate, 76 Immunization, 298 DRUGS, 59, A9 Dopaminergic Agents, 218 Expectorants, 93, A12 Gemfibrozil, 53 Dopicar, 225 Gentamicin, 230, 259 Doxepin, 191 F Gentatrim, 260 Doxycyline, 71, 127, 128 Gestodene, 180 DPT, 305, A45 Famotidine, 62 GI-Care, 65, A9 DTP, 297 Fat Soluble Vitamins, 281, Glibenclamide/Glyburide, Duracef, 127 A39 157, 162, A23

Glibetic, 164 Hyocine N-butyl Bromide, Kiddi, A43 Gliclazide, 157 67, A11 Klonopin, 211 Glimepiride, 157 HYPNOTICS, 197, A28 Glipizide, 157 L Gluben, 164 I Glucocare, 164 Labetolol, 31 Glucomet, 166 Ibufen, 10 Lactase, 71 Glucomin, 166 Ibuprofen, 8, 9, A4 Lactopar, 224, A27 Gluconil, 164, A23 Ikacor/Ikapress, 40 Lactulose, 76 Glucophage, 166 Imipramine, 194, A28 Lahistan, 89 Glycerin, 76, 78, 80, 254, Imodium, 75 Lamotrigine, 205 A11 Imovax, A42 Lanoxin, 52 Glyceryl Guaiacolate, 93 Indapamide, 26 Lansoprazole, 62 Glyphillin, 103 Indocaps, 12 Largactil, 203 Granexin, 136 Indocin, 12 Lasix, 29 Grifulin, 151 Indomed, 12 LAXATIVES, 75, A11 Griseofulvin, 150 Indomethacin, 8, A5 Levodopa, 224 Guaifenesin, 93 Indopharm, 12 Levofloxacin, 136 Guanethidine, 24, 235 Indovis, 12 Levonorgestrel, 180, 185, Gynera, 182, A24 Influenza Vaccines, 102, 308, A24 Gyno-Daktarin, 150 A43 Levothyroxine, 166 Gyno-Daktazol, 150 Inhibace, 37 Levozem, 41 Insulin, 159 Lidocaine, 44 H Iodine, 288 Lignocaine, 239, 255, A32 Iodocare, 262 Lindane, 265, A36 H2-antagonists, 61 Iodo-Vit, 262 Lipastop, 75 Halazepam, 197 IPV, 303 LIPID LOWERING DRUGS, Haldol, 204 Iron, 287, 288 52, A8 Halidol, 204 Isardipine, 37 Liquidone, 157 Haloper, 204 Isocarboxide, 191 Lisinopril, 35 Haloperidol, 68, 201, 203, Isocardide, 46 Lispro Insulin, 157, 159 A28 Isofen, 10 Lithium, 192 Harmonal, 199 Isoniazid, 138, 139 Locacid, 273, A37 Hemoral, 81, A11 Isophane Insulin, 157 LOCAL ANESTHETICS, 79 Hep. B Vaccine, 307, A43 Isophane- NPH, 159 Locid, 66 Hib Vaccine, 309 Isoproterenol, 103 Logynon, A25 HibTITER, 309 Isordil, 46 Lomefloxacin, 136 Hiconcil, 122, A18 Isosorbide Dinitrate, 45 Lomudal, 106 Hismal, 89 Isosorbide Mononitrate, 45 Loop Diuretics, 27 Hismanal, 89 Isotard, 46 Loperamide, 74, A11 Histafed, A17 IUD, 177 Loperid, 75 Homosalicylate, 276 Lorainide, 42 Humulin, 162 Loratadine, 87 J Hydralazine, 24 Lorazepam, 197, 199, A29 Hydran-60, 74 Jeflex, 127 Lorivan, 200 Hydrochlorothiazide, 24, 26 Jordacycline, 259 Lorocare, 200 Hydrocortisone, 80, 106, 169, Losec, 66 233, 271, A11, A48 Lovastatin, 53, 56 Hydrosol, A38 K Hydroxyethylcellulose, 239 Keflex, 127 Ketoconazole, 257, A33

Moclobemide, 191 Novomit, 69 M Mono-Amine Oxidase NSAIDs, 3, 8, 9, 10, 11, 13, Maalox, 64 Inhibitors, 162, 191 17, A4, A5 Macrodantin, 135 Moricizine, 42 Nurofen, 10 Macrofuran, 135 Motrin, 10 Nystatin, 148, 256, A22 Macrolides, 102, A19 Moxalactam, 125 Moxepharm, 122 Magnagel, 64 O Magnicillin, 120 Moxypen, 122 Malathion, 265 Moxyvit, 122 Octyl Salicylate, 276 Maprotiline, 191 MUCOLYTICS, 97, A13 Ofloxacin, 136, 231, 245 Marial, A9 Mupirocin, 259 Ogmin, 123 Measles Vaccine, 306, A42 Mycobutin, 141 Omeprazole, 62, 65, A9 Meclizine/Meclozine, 68, 70, OPTHALMIC A10 N PREPARATIONS, 229, Medroxy-Progesterone A31 Acetate, 184 Nadolol, 31 Opticrom, 235 Megacare, 120 Nalcrom, 106 OPV, 303 Megalat, 39 Nalidixic Acid, 135, A21 Oracal-D, A43 Mepral, 66, A10 Naphazoline, 90 Oral Rehydrating Salt (ORS), Mestranol, 179 Naproxen, 8,A4 73, 74, A10 Metamucil, 79 Nasivin, 92 Ovysem, A25 Metaproterenol, 103 Nefazodone, 191 Orset, 74 Metformin, 157, 158, 164, NegGram, 136 OTIC PREPARATIONS, 243 A23 Neomycin, 244, 259 Oxazepam, 197 Methicillin, 119 NEUROLEPTICS, 200 Oxcarbazepine, 205 Methylcellulose, 76 Niacin, 284 Oxprenolol, 31 Metoclopramide, 68, A10 Niclosamide, 147 OXY, 274 Metolazone, 26 Nicotinic Acid, 53 Oxybenzone, 276 Metoprolol, 31, 45 Nifedipine, 24, 38, 45, A7 Oxybuprocaine, 239 Metrocare, 144 Nimodipine, 37 Oxycin, 259 Metrogyl, 144 Nisoldipine, 37 Oxy-clean, 268 Metronidazole, 62, 143 Nitrates, 44 Oxymetazoline, 90, 91, A13 Metrozole, 144 Nitrazepam, 197 Oxytetracycline, 259, A33 Metyrosine, 24 Nitrofurantoin, 133, A21 Mexiletine, 42 Nitroprusside, 24 P Mg/Al Salt, 63, A9 Nizatidine, 62 Miconazole, 149, 256, A22, Nizoral, 258 Padimate O, 276 A32 Nonoxinol ‘9’, 178 Pamol, 7, A3 Microdiol, 182 Nordette, 182, A24 Pantoprazole, 62 Microgynon, A24 Norethisterone, 180 Paracare, 7 Miglitol, 157 Norfloxacin, 136 Paracetamol, 6, A3 Mineral Oil, 80 Norgestimate, 180 Parafin, 76 Minerals, 287 Norlip, 54 Paraflu, A17 Minocycline, 127 Normalol, 34 Paramol, 7 Minovit, A44 Normiten, 34, A6 Paramolan, 7 Minovlar, A24 Norplant, 186 Paravomine, 70, A10 Minoxidil, 24 Nortriptyline, 191, 193 Parazine, 267 Minulet, A24 Nosacare, 92 Parilac, 224 Miphar, 29 Nouryl, 265 Parlodel, 224 MMR Vaccine, 296, 306, Novocort, A31 Paroxetine, 191 A42 Novolin, 162 Partivel, 222

Pathoprim, 133 Procaine Penicillin, 118 RESPIRATORY DRUGS, PedvaxHIB, 309 Procar, 44 83, A12 Penbutolol, 31 Prochlorperazine, 68, 201 Resprim, 133 Penibrin, 122 Procyoxylene, 81 Resyl, 94 Penicillins, 115, A18 Progesterone, 179, 183 Retavit, 273 Pentrexyl, 122 Progestin-Only Products, Retin-A, 273 Peridol, 204, A29 183, A25 Retinoic Acid, 272, A35 Peridor, 204 ProHIBIT, 309 Rhinoclir, 92 Petrolatum, 254 Prolol, 33 Rhumacare, 11 Pharmaprim, 133 Promazine, 201 Rifampin/Rifampicin, 138, Phenelzine, 191 Promethazine, 68, 87, A48 140, A21 Phenobarb, 214 Propranolol, 24, 31, 34, 42, Rimactan, 141 Phenobarbital/ Pheno- 45, A6 Rimevax, A45 barbitone, 212, A26 Propylthiocil, 169 Rivotril, 211 Phenolphthalein, 76 Propylthiouracil, 168 Robutussin, 94 Phenoxymethyl-Penicillin, Proton Pump Inhibitors, 61, Rosiglitazone, 157 116 62, A9 Rufenal, 11 Phenylephrine, 80, 90 Protriptyline, 191 Phenylpropanolamine, 90 Proxymetacaine, 239 S Phenytoin, 42, 194, 207, 208, Prozac, 196 214, A26 Pseudoephedrine, 90, 92, Salbutamol, 103, A14, A48 Pilocarpine, 235 A12 Salbuvent, 104 Pindolol, 31 PSYCHOTHERAPEUTIC Salicylates, 162 Pioglitazone, 157 DRUGS, 189, A28 Salicylic Acid, 267, 269, A34 Pirox, 13 Psyllium, 76, 78, A11 Salisol-2, 268 Piroxicam, 8, 12, A5 Pulmadrine, A17 Saralasin, 24 Pitrex, 259 Pyrazinamide, 13, 138, 142 Scabicide, 264 Pivampicillin, 120 Pyrithione Zinc, 269 Scabiex, 264 Polio Vaccines, 303, A42 Pyrocard, 17 Scobutyl, 68 Polycarbophil, 76 Scopal, 68 Polydine, 262 Q Selective Serotonin Reuptake Polymixin B, 231, 259 Inhibitors, 191 Potassium, 288, 289 Questran, 55 Selenium Sulfide, 269 Potassium-Sparing Diuretics, Quinapril, 35 Senna, 76 29 Quinidine, 44 Serepam, 199 Povidone-Iodine, 261, A33 Sertraline, 191 Pramin, 69 Simigel, 64 R Prazepam, 197 Simovil, 56 Prazosin, 24 Rabeprazole, 62 Simvastatin, 53, 56, A8 Prednisolone, 170, 233, 246 Rafapen, 119, A17 Sincomen, 30 Prednisone, 107, 170, 171, Ramipril, 35 Sinemet, 225 173, A14 Randin, 65 Sinoptic, 237 Prednitab, 173 Ranitidine, 64, Slow-Fe, A38 Prelosec, 66 Ratidine, 65 Slow-Folic, A40 Pressolat, 39 Razimol, 7 Slow-K, A38 Primonil, 195 Recombivax HB, 307 Somophyllin, 103 Prioderm, 265 Reglan, 69 Sotalol, 31, 42 Prizma, 196 Rehidrat, 74 Sparfloxacin, 136 Probenecid, 12, 13 Repaglinide, 157 Spermicides, 178 Probucol, 53 Reserpine, 24 Spironolactone, 24, 29, A6 Procainamide, 42 Resperidone, 201 Sporofulvin, 151

Stomagel, 64 Tobramycin, 231 Ventolin, 104 Stopit, 75 Tocainide, 42 Verac, 40 StressTab, A41 Tofranil, 195, A28 Verapamil, 24, 39, 45 Sulfatrim, 133 Tolazamide, 157 Vermacare, 147 Sulfinpyrazone, 15 Tolbutamide, 163 Vermazol, 147 Sulfisoxaole, 245 Tolnaftate, 256, 258, A33 Vermox, 147 Sulfonylureas, 157 Torsemide, 27 Viarex Inhaler, 107 Sulfur, 268 Tranquilizer, 203 Vical , A41 Sulisobenzone, 276 Tranylcypromine, 191 Vicrom, 106 Sulphonamide, 131 Trazodone, 191 Vigabatrin, 205 Sulpiride, 201 Tretinoin, 272 Vitamin A, 282 Sulprim, 133 Triamcinolone, 170, 271 Vitamin B1, 284 SUNSCREEN PRODUCTS, Triamterene, 29 Vitamin B12, 284 275, A36 Triazolam, 197 Vitamin B6, 284 Supradyn, A41 Tricold, A17 Vitamin C, 285 Symmetrel, 222 Trichonazole, 144 Vitamin D, 215 Tricyclic Antidepressants, Vitamin D, 282 191, A28 Vitamin E, 282 T Trihexyphenidyl, 219 Vitamin K, 282 Taroctyl, 203 Trimethoprim, 131, A20 VITAMINS, 281, A37, A39 Td Vaccine, 305 Trimpramine, 191 Vitapen, 122 Tegrepine, 209 Trinordiol, A25 Volmax, 104 Tegretol, 209 Triprolidine, 87 Voltaren, 11 Temocillin, 120 Troglitazone, 157 Voltin, 11 Terconazole, 256 Trufen, 10 Teril, 209 Tums, A37 W Tetanus Vaccines, 304, A42 Tussibal, A16 Tetracare, 259 Tryptal/Tryptalette, 194 Warfarin, 47, A7 Tetracycline, 127, 231, A19, Tylenol, 7 Water Soluble Vitamins, 281 A29 White Petrolatum, 80 Tetrapharm, 129, 259 U Tevacycline, 129, 259 X Theo-dur, 103 U-Gram, 136, A20 Theopharm, 103 ULCER HEALING DRUGS, Xylene, 256 Theophylline, 16, 100, A13 61 Xylometazoline, 90, 91 Theotard, 103 Ultrasol, A36 Theotrim, 103 Uniscrub, 263 Thiazide, 162 Urantoin, 135 Z Thiazolidinediones, 158 Urigram, 136, A20 Zadstat, 144 Thioridazine, 201 Urix, 29, A6 Zantab, 65 Thioxanthenes, 201 Zantac, 65 Thorazine, 203 V Zarontin, 212, A26 THYROID DRUGS, 166 Zinc Oxide, 80, 255, 276, A32 Thyroid Hormone, 102, 162 VACCINES, 295, A45 Zinc Sulphate, 239 Thyroxine, 166, 186 Valium, 199 Zino Pads, 268 Tiloptic, 237 Valporal, 217 Zocor, 56 Timolin, 237 Valproate, 215 Zovirax, 152, 261, A22, A33 Timolol, 31, 236, A30 Valproic Acid, 215, A26 Zylol, 15 Tinaderm, 259 Vaseline, 254, 268 Zymafluor, A38 Tinasol, 259 Venlafaxine, 191 Titanium Dioxide, 276 Ventocare, 104