Conflicts of Interest

Top 10 Prescribed Medications . Pharmaceutical Company Speakers Bureau: in Pediatrics None . Pharmaceutical Consulting: None . Medical Device or Lab Consulting: None Anthony J. Busti, MD, PharmD, BSN, FNLA, FAHA . Stock or Financial Interests in Pharmaceutical Faculty, High‐Yield MED Reviews and Medical Device Companies: None Editor‐in‐Chief, Pharmacology Weekly San Antonio, TX . Drug Company Funded Research: None Emergency Medicine Residency Program Johns Hopkins Hospital Baltimore, MD

2

Pediatrics: Absorption

. Oral: The Pediatric Patient – Gastric fluids are essentially neutral in the first hrs of life; by the 2nd yr of life gastric output is equal to adult Pharmacokinetics & Pharmacodynamics on per kg basis. – pH‐dependent passive diffusion • full‐term infant: declines from 6‐8 at birth, 1‐3 after 24 hours – Gastric‐emptying time • Not significantly slower, though may not reach adult times until 6‐8 months.

3 4

Pharmacokinetics Pharmacokinetics: Clearance Pathways

. First Pass Metabolism: NAT – Clinical Application: Esterase FMO • Lidocaine vs. mexiletine (Mexitil) MAO • Propranolol (Inderal) • Meperidine (Demerol) UGT ≈ 35% CYP450

– Influenced by: • Influx & efflux transporters • Phase I (CYP450) mediated metabolism • Phase II mediated metabolism FMO = flavin monooxygenase MAO = monoamine oxidase NAT = n-acetyltransferase UGT = Uridine glucuronosyltransferase 6 5 Williams J et al. Drug Metab Disp 2004;32:1201-08. NOTE: NOT ALL drugs require transporters to get across cell membranes! Some will make it across by diffusion depending on the charge and degree NOTE: NOT ALL drugs require transporters to get across cell membranes! Some will make it across by diffusion depending on of lipophilicity. 7 the charge and degree of lipophilicity. 8

Pediatrics: Distribution Pharmacokinetics . Distribution: . Volume of distribution: – To understand where drug can be and is measured, one – Influence on hydrophilic & lipophilic needs to have a basic understanding of the various “fluid – Ex. Aminoglycosides: are hydrophilic and distribute more into extracellular space so more needed to achieve plasma compartments” in the body where drug can reside. levels. Total Body Water (60% of body weight; 70kg = 42 L)

. Plasma protein binding: Intracellular Extracellular (40% or 2/3 of body weight; 28 L) (20% or 1/3 of body weight; 14 L) – In neonates, albumin 80% of an adult and ‐1 acid (mainly K+, Mg+) (mainly Na+, Cl‐, HCO‐_ glycoprotein also less than adult

– Bilirubin can compete with binding sites on albumin with Plasma Interstitial other meds. (5% or 1/4 of body weight; 3L) (15% or 3/4 of body weight; 10 L) (mainly protein) (No protein)

9 10

Pharmacokinetics Pharmacokinetics

. Phase I Metabolism: . Phase I Metabolism: – Oxidation / Reduction via primarily the CYP450 – Oxidation / Reduction via primarily the CYP450 enzyme system. enzyme system. • Found in the liver (mainly), intestine, lungs and kidneys. • The major groups in drug metabolism & drug interactions • Purpose is for microsomal (CYP450) enzymes to give/add a include 1,2,3, and 4; they are then further divided into functional group to the drug molecule in preparation for groups by chemical structure A,B,& C. These are then sub‐ phase II metabolism and/or elimination. Those functional divided into sub‐groups 1,2,3, etc… groups are: • Most common: CYP 1A2, 2C9, 2C19, 2D6, 3A4 – COOH – CYP2B6 (3% of meds) – OH – CYP2E1 (4% of meds) – NH2 – CYP2C19 (8% of meds) – SH – CYP1A2 (11% of meds) • Metabolite can be active or inactive – CYP2C9 (16% of meds) • Require presence of NADPH, O2 to function – CYP2D6 (19% of meds) – CYP3A4 (36% of meds)

11 12 Pharmacokinetics Pharmacokinetics . Phase II Metabolism: . Phase I Metabolism: – Conjugation reactions carried out by mainly – Oxidation / Reduction via primarily the CYP450 nonmicrosomal enzymes that add a compound to the enzyme system. drug to increase hydrophilicity (these compounds to be highly polar or ionized). Almost always inactive • Subject to induction and inhibition metabolites. • Are subject to genetic polymorphisms. • Glucuronidation (e.g., via UDP‐glucuronosyltransferases; – Examples: 2C9 (warfarin), 2C19 (clobazam; clopidogrel), 2D6 UGT1A1) (tamoxifen; psych meds; beta‐blockers) – Most common one – Only one in Phase II metabolism that is microsomal enzyme as CYP450 • Sulfation: sulfotransferases (SULT) • Acetylation: N‐acetyltransferase (NAT) • Glutathione conjugation (e.g. for acetaminophen) • Methylation – methyltransferase (MT)

13 14

Pharmacokinetics: UGT Enzymes Pediatrics: Elimination

UGT1A6 UGT1A3 UGT1A6 . Glomerular filtration, tubular secretion, tubular UGT1A10 UGT2B7 reabsorption may take several weeks to 1 year UGT1A8 to develop fully

. Results in decreased dose requirement

UGT1A4 UGT1A1

15 Williams J et al. Drug Metab Disp 2004;32:1201-08. 16

17 18 Factors Affecting Therapy Pharmacokinetics

. Creatinine Clearance: Zero‐order Kinetics (Elimination) 1st‐order Kinetics (Elimination) Rate of drug elimination per hour is Rate of drug elimination per hour is – Schwartz Method: CLcr = K x L/Scr “independent” of drug concentration (i.e. “dependent” on drug concentration (i.e., • L = length (cm), Scr = serum creatinine in mg/dL the same “amount” is eliminated per the more drug in body the more hour regardless of how much drug is in eliminated per hour) • K = age specific proportionality constant: the body – LBW < 1 yr = 0.33, Full term < 1 yr = 0.45, 2‐12 yr 0.55, 13‐21 yr Cp decreases “linearly with time” Cp decreases “exponentially with time” female = 0.55, 13‐21 yr male = 0.70 1half‐life = 50% of original dose gone 2 half‐lives = 75% of original dose gone – Traub Method: CLcr = 0.48 x height (cm)/Scr 3 half‐lives = 87.5% of original dose gone 4 half‐lives = 93.75% of original dose gone • CLcr = creatinine clearance in mL/min/1.73m2, Scr = serum Examples: aspirin, ethanol, phenytoin Examples: gentamicin, vancomycin creatinine in mg/dL Note: Will see a straight line with a graph NOT using logarithmic scale.

19 20

Top Medical Conditions

. The Top Medical Conditions in Pediatrics: The Pediatric Patient – Asthma The Top Medical Conditions & – GI complications Medications Prescribed – Allergies – Infectious Problems – Now = Hyperlipidemia

21 22

Top 10 Drugs in Pediatrics Top 10 Drugs in Pediatrics

. The 10 Most Commonly Prescribed Medications: . The 10 Most Commonly Prescribed Medications: 1. Amoxicillin 1. Amoxicillin 2. Cefdinir 2. Cefdinir 3. Azithromycin 3. Azithromycin 4. Cipro/Dex Otic 4. Cipro/Dex Otic 5. Albuterol 5. Albuterol 6. Mometasone 6. Mometasone 7. Budesonide 7. Budesonide 8. Cetrizine 8. Cetrizine 9. Montelukast 9. Montelukast 10. Ibuprofen 10. Ibuprofen

23 24 Beta‐Lactams Beta‐Lactams

. Mechanism of action take home points: . Bactericidal – Beta‐lactam antibiotics inhibit cell wall synthesis in bacteria . Time dependent killing by inhibiting the enzyme transpeptidase (or also called Beta‐lactam ring penicillin binding protein). This eventual causes lysis of the bacteria and release of intracellular contents – Bacteriocidal – Time dependent killing • We only need to achieve a certain drug concentration and keep it there; more drug is not necessarily better. • This is different that “concentration dependent killing” where more drug or higher concentrations work better.

Beta‐lactam ring is subject to attack by beta‐lactamases made from bacteria 25 26

Beta‐Lactams Beta‐Lactams . Aminopenicillins: . Aminopenicillins: – General Uses: • Otitis media, bacterial sinusitis, Lower UTI, Salmonella (amox), Shigella (amp), H. – Are more hydrophilic facilitating passage through porins. pylori, and infective endocarditis prophylaxis in dental procedures (2 g x 1) for – Expanded gr‐ coverage to include H. influenza; E. coli, and high risk patients. – Women’s Health/Pregnancy: PCN and ampicillin are also used for culture Proteus species due to better penetration of outer cell wall of + for group B streptococcus from a vaginal/rectal swab at 35‐37 weeks gr‐ bacteria (via the porins) and greater binding to gestation. transpeptidase, but ring is still open to penicillinase attack • This is done to reduce risk for GBS pneumonia, sepsis, & meningitis. (compare side groups on nafcillin). – DOC in Listeria (meningitis) – ampicillin • Also recommended in empiric treatment of meningococcal meningitis caused by – Good activity against PCN‐resistant pneumococci one of few Neisseria meningitidis which can be life threatening if left untreated (Waterhouse – Friderichsen syndrome). Add to 3rd generation cephalosporin (ceftriaxone). of antibiotics effective against enterococcus. – Memory tool: – Coverage against anaerobes • H: Haemophilus influenza • E: Escherichia coli • L: Listeria monocytogenes • P: Proteus mirabilis • S: Salmonella; Shigella 27 28

Beta‐Lactams Top 10 Drugs in Pediatrics

Dosage Drug Usual Dose Misc. Form . The 10 Most Commonly Prescribed Medications:

Adjust for renal fx. F=0.4 results 1. Amoxicillin in diarrhea (may cause more 2. Cefdinir C.diff); > absorption if on empty Adults: 250-500 mg q stomach; good for Shigella; not Ampicillin 6hrs 3. Azithromycin PO/IV as good for Salmonella; SE: rash (Principen) Peds: 50-100mg/kg/d (especially if given for 4. Cipro/Dex Otic in 4 divided doses viral/mononucleosis (EBV) viral infection). 5. Albuterol Preg Cat: B; Lact Cat: L1 6. Mometasone Adjust for renal; F = 0.95; good Adults: 250-500 mg for Salmonella; poor for Shigella; 7. Budesonide Amoxicillin q8h SE: rash (especially if given for (Amoxil; PO 8. Cetrizine Peds: 20-50 mg/kg/d in viral/mononucleosis (EBV) viral Trimox) 2-3 divided doses. infection). 9. Montelukast Preg Cat: B; Lact Cat: L1 10. Ibuprofen

29 30 Beta‐Lactams: Cephalosporins Generation of Beta‐Lactams: Cephalosporins Gr+ Coverage Gr‐ Coverage Cephalosporin & CNS penetration for most 1st generation . Cephalosporins: – Bactericidal – Broken down into 5 generations; each generation essentially see greater gr‐ coverage and CNS 2nd generation penetration • 1st generation has greatest affinity for PBPs in S aureus. • Cefuroxime, cefotaxime, ceftriaxone, ceftazidime, & cefepime have good CNS penetration when meninges are inflamed. • With the exception of ceftaroline, they DO NOT work against MRSA. 3rd generation None of them cover for enterococcus. • Their additional structure to protects against beta‐lactamases (i.e., penicillinases) but now more susceptible to cephalosporinases) 4th generation – Allergy cross‐sensitivity of about 1% with penicillin allergic patients 5th generation

31 32

Beta‐Lactams: Cephalosporins Beta‐Lactams: Cephalosporins . 3rd Generation Cephalosporins: – See a reduction in gr+ coverage (especially with Staph. aureus), but may be slightly better against PCN‐resistant S. pneumoniae – Not reliable against Enterobacter species – gr‐ coverage increases especially against Enterobacteriaceae (E. coli, Klebsiella, and Proteus Penicillin Cephalexin spp.). • Also improved activity against H. influenzae, N. gonorrhea and meningitidis. • Ceftazidime has good coverage against P. aeruginosa • Ceftriaxone can be mixed with 1% lidocaine for IM injection

33 34

Beta‐Lactams: Cephalosporins Top 10 Drugs in Pediatrics

. The 10 Most Commonly Prescribed Medications: . 3rd Generation Cephalosporins: 1. Amoxicillin – Oral formulations: 2. Cefdinir • Cefdinir (Omnicef) 3. Azithromycin • Cefditoren (Spectracef) 4. Cipro/Dex Otic • Cefixime (Suprax) 5. Albuterol • Cefpodoxime (Vantin) • Ceftibuten (Cedax) 6. Mometasone – Parenteral formulations: 7. Budesonide • Cefotaxime (Claforan) 8. Cetrizine • Ceftazidime (Fortaz) 9. Montelukast • Ceftriaxone (Rocephin) 10. Ibuprofen

35 36 Protein Synthesis Inhibitors Macrolides . . Macrolides Bacteriostatic . MOA: Inhibit protein synthesis by binding to . Ketolides domain II & V on the 50S ribosomal subunit . Tetracyclines thereby interfering with the translocation . Glycylcyclines reaction where the developing peptide chain is moved from the receptor to the donor site. . Anaerobic agents – These sites of binding are also sites for inhibition by . Linezolid clindamycin, lincomycin, chloramphenicol, . Streptogramins streptogramins and so should not be used together for that reason. . Aminoglycosides

37 38

Macrolides Macrolides . General Uses: – Oral drug delivery: Otitis media, pharyngitis, URI & LRI, 3‐L‐cladinose CAP, PID (C. trachomatis; mainly azithromycin), bacterial group exacerbations of COPD; H. pylori (clarithromycin only one FDA approved), mycobacterium avium complex (MAC); Legionnaires disease (erythromycin & azithromycin). Erythromycin Azithromycin (azalide class) • With the increased number of people not immunizing, this class is useful at treating pertussis (“whooping cough” –inspiratory whoop after paroxysmal coughing)

– Ophthalmic drug delivery: Conjunctivitis and prophylaxis of ophthalmia neonatorum caused by Neisseria gonorrhoeae and Chlamydia trachomatis (erythromycin Telithromycin only) (ketolides class) Clarithromycin 39 40

Macrolides Dosage Drug Usual Dose Misc. Form Top 10 Drugs in Pediatrics No CYP3A4 interaction; t1/2 Azithromycin Adults: Z-pak: 500 mg day1; 250 mg day 2-5 =68hrs;  S. pneumo resistance . The 10 Most Commonly Prescribed Medications: (Zithromax; Z-pak; Tri-pak: 500 mg x 3 day being seen. ER form: absorbed in Tri-pak; Zmax PO/IV small intestine vs stomach with IR. Zmax (mild-Mod CAP & ABS): 2 g Mixed with 60 ml water & used in 1. Amoxicillin (extended release x 1 susp)) 12 hrs (1-2 hrs after meal). GI side Peds: 5-10 mg/kg/d effects = 17.2% 2. Cefdinir Adults: 250-500 mg q 12hrs; or Adjust for renal fx; CYP3A4 3. Azithromycin Clarithromycin 1000 mg qd for XL inhibitor (mech based inhibition). PO (Biaxin; Biaxin XL) Peds: 7.5-15mg/kg/d in 2 divided Only one for H. pylori SE: bad 4. Cipro/Dex Otic doses taste, GI upset, QT prolongation 5. Albuterol Erythromycin Adults: 250-500 mg q 6hrs SE: diarrhea, GI upset QT PO/IV Peds: 20-40mg/kg/d in 4 divided prolongation; CYP3A4 inhibitor, (Ery-Tab, E-Mycin) doses little H. influenzae coverage 6. Mometasone No renal or hepatic dosing; not 7. Budesonide Adults: C. difficile only: 200 mg absorbed – do NOT treat systemic Fidaxomicin infx; No DDI. Treats C. difficile PO bid x 10 days 8. Cetrizine (Dificid) (including NAP1/B1/027 strain). Peds: None No major SE. Does not cover gr- 9. Montelukast aerobes or gr- anaerobes. Spiramycin 10. Ibuprofen PO Not available in US Used mainly for gonorrhea. (Rovamycine)

41 42 Fluoroquinolones Fluoroquinolones Carboxyl‐group: DDI

fluorine . Bacteriocidal

. MOA: Current agents are “fluorinated” analogs of nalidixic acid which is not used because it doesn’t achieve systemic antibacterial levels. The name is partially derived from the fact that these drugs have a fluorine group on them. Inhibits protein synthesis by binding to DNA gyrase (topoisomerase II) and topoisomerase IV. This inhibits the relaxation of the supercoiled DNA thereby promoting breakage of DNA strands. Piperazinyl group at 7; Antipseudomonal activity . General Uses: – CAP, Nosocomial pneumonia, acute maxillary sinusitis, complicated and Ciprofloxacin uncomplicated UTI, prostatitis, some soft tissue infections, Crohn’s Disease.

43 44

Fluoroquinolones Dosage Fluoroquinolones: Otic Drug Usual Dose Misc. Form Drug Usual Dose Misc. Not good for Strep. Pneumonia. Adults: PO: 500 mg bid; IV: Due to Pseudomonas aeruginosa or CYP1A2 inhibitor; F=0.7; SE: GI upset, Ciprofloxacin otic > 1 yr for Acute Otitis Media Ciprofloxacin 400 mg bid staphylococcus aureus. Comes in refilled, PO/IV QT prolongation, glucose changes, solution (0.2%), Externa: 1 single use container (Cipro) Peds: PO: 20-30mg/kg bid; IV: single use containers. Let dose penetrate tendon rupture, seizure risk; renal (Cetraxal) into affected ear bid x 7 days 6-10mg/kg bid (CF patients) dose CrCl < 50 ml/min; for 1 min before moving head. Norfloxacin Adults: PO: 400 mg bid Same SE’s as above: CrCl < 30 Ciprofloxacin 0.3% PO >6 months: Acute otitis media in (Noroxin) Peds: Not approved < 18y ml/min: adjust dose to once daily and Note: Dose is same for all indications; dexamethasone peds with tympanostomy tubes or avoid with viral infections Ofloxacin Adults: PO: 200-400 mg bid Same SE’s: CrCL 20-50 ml/min  daily; 0.1% suspension acute otitis externa in children & PO adults: 4 gtt in affected bid x 7d Comes in 7.5 mL (Floxin) Peds: Not approved < 18y if < 20 ml/min  50% of dose (Ciprodex Otic)

Adults: 250-750 mg qd; dose F=0.95; L-isomer of ofloxacin; Same Ciprofloxacin 0.2% Note: Only one NOT sterile and therefore Levofloxacin SE’s above; has P. aeruginosa PO/IV for CAP is now 750 mg qd and hydrocortisone >1 yr: Otitis externa: 3 gtt in should NOT be used if tympanic membrane (Levaquin) indication; resistance concern; adjust 1% suspension is ruptured. Avoid with viral infections Peds: Not approved < 18y affected ear bid x 7 d CrCl < 50 ml/min; (Cipro HC Otic) Comes in 10 mL bottle Moxifloxacin Adults: 400 mg qd F = >0.85; No renal adjustment; may Otitis externa = 6 months – 13 yrs: PO/IV cause most QT prolongation; NOT for (Avelox) Peds: Not approved < 18y 5 gtt qd x 7d. If > 13 yrs then 10 gtt UTI’s qd x 7d Ofloxacin 0.3% Adults: 320-640 mg qd F= 0.71; Renal adjust dose CrCl < 40 Acute Otitis Media = 1-12 yrs: 5 gtt Gemifloxacin solution Comes in 5, 10 mL PO Peds: 5-10 mg/kg/d generally ml/min; QT prolongation; NOT for bid x 10 d (Factive) (Floxin Otic) not recommend UTIs Chronic Supprative Otitis Media = > 12 yrs: 10 gtt in affected ear bid All of the fluoroquinolones are Pregnancy category: C and Lactation Risk Category: L3 for oral and IV. Avoid use of any di & tri valent cations (Al, Ca, Fe, Mg) within 2 hrs of taking FQ’s. This also includes sucralfate (which has Al) x 14 d

45 46

Top 10 Drugs in Pediatrics Comparative Pathophysiology

. The 10 Most Commonly Prescribed Medications: 1. Amoxicillin . Asthma: . COPD: 2. Cefdinir – Eosinophils – Neutrophils 3. Azithromycin – Airway hyperreactivity – No airway hyperreactivity 4. Cipro/Dex Otic – Bronchodilator response – Limited bronchodilator 5. Albuterol – Inhaled corticosteroid response 6. Mometasone response – Limited inhaled 7. Budesonide corticosteroid response 8. Cetrizine 9. Montelukast 10. Ibuprofen

47 48 Levels of Asthma Control Pharmacotherapy of Asthma

Controlled Partly Controlled . 2 agonists (Bronchodilators) Characteristic (All of the (Any present in Uncontrolled following) past week) . Corticosteroids Daytime symptoms <2 times per >2 times per week >3 features of partly week controlled asthma . Mast cell stabilizers Limitations of None Any in any week activities . Leukotriene modifiers Nocturnal symptoms/ None Any . Theophylline awakening Need for reliever/ <2 times per >2 times per week . Anti‐IgE Antibodies rescue treatment week Lung function Normal <80% predicted or (PEF or FEV1) personal best

Exacerbations None Any within 1 year Any within 1 week

Note: applies also children 5 and younger. 49 50

NAEPP‐3 Treatment Steps Age Severity Birth to 4 yrs 5 to 11 yrs > 12 yrs Step 1Step 2Step 3Step 4Step 5 Step 6: HD inhaled steroid + Persistent HD inhaled steroid + HD inhaled steroid + Asthma education and environmental control LBA OR Singulair If step up therapy needed, assess inhaler technique and confirm symptoms are from asthma and not something else first. Asthma LBA + oral steroid LBA + oral steroid + oral steroid Rapid acting inhaled β2‐agonist PRN Step 5: (Alternatives treatment includes: inhaled anticholinergic, short‐acting oral β2‐agonist or short‐acting theophylline) HD inhaled steroid + HD inhaled steroid + HD inhaled steroid + Persistent Select one Select one To Step 3 To step 4 Asthma LBA OR Singulair LBA LBA treatment, select treatment add Step 4: MD inhaled steroid + MD inhaled steroid + MD inhaled steroid + one or more either Persistent Asthma LBA OR Singulair LBA LBA + oral steroid Low‐dose inhaled Low dose ICS (+) Medium‐or high‐ Oral corticosteroid Step 3: LD inhaled steroid + Persistent LD inhaled steroid + ICS long‐acting β2‐ dose ICS (+) long‐ (lowest dose) LBA OR Singulair OR Theo Asthma LBA agonist acting β2‐agonist MD inhaled steroid OR OR Controller options Leukotriene Medium or high‐ Leukotriene Anti‐IgE treatment MD Inhaled steroid alone modifier dose inhaled ICS modifier (omalizumab) MD Inhaled Steroid (alone) Step 2: Low dose ICS (+) Sustained release Persistent LD inhaled steroid LD Inhaled steroid LD Inhaled steroid leukotriene theophylline Asthma modifier Step 1: Intermittent none none none Low‐dose ICS (+) Asthma SR theophylline

51 52

Mechanism of Action: Beta‐2 Agonists Short Acting Inhaled 2 –Agonists R‐albuterol Age Onset Duration Drug Indication(s) Dose ATP (yrs) (min) (hrs)

(+) Albuterol HFA • Prevention, relief & ≥ 4; Adults: 2 puffs q4-6hr prn; Adenylate cyclase MDI treatment of reversible Exercise induced asthma: 2 Phosphodiesterase (Proventil & bronchospasm ProAIR puffs 15 min prior to exercise 5-8 3-6 (PDE‐4) Ventolin, • Prevention of exercise HFA ≥ AMP cAMP ProAir HFA) induced asthma 12 Peds: 1 puff q4-6hr prn • Relief of reversible Albuterol Adults: 2.5 mg q6-8hr prn bronchospasm inhalation soln ≥ 2 2-5 3-6 Protein Kinase Note: no prevention or treatment; (AccuNeb) Peds: 1 puff q4-6hr prn no EIA; but younger age Levalbuterol • Prevention & Adults: 2 puffs q4-6hr prn Cytosolic Ca2+ HFA MDI treatment of reversible ≥ 4 5-10 3-6 (Xopenex HFA) bronchospasm Peds: 2 puffs q4-6hr prn Levalbuterol • Prevention & Adults: 0.63-1.25 mg tid 5-6 (up to Inhalation soln treatment of reversible ≥ 6 10-17 Actin & Myosin Interaction 8 in some) (Xopenex) bronchospasm Peds: 0.31-0.63 mg tid Pirbuterol MDI • Prevention & Adults: 1-2 puffs q4-6hr prn Bronchodilation & (Maxair treatment of reversible ≥ 12 ≤ 55 Autohaler) bronchospasm Peds: None

Mast cell stabilization 54 53 ORAL: Short Acting 2 –Agonists Onset Duration Drug Indication(s) Age (yrs) Dose  Agonists (min) (hrs) 2 Adults: 2-4 mg q6-8hr • Relief of reversible Albuterol syrup ≥ 2 30 4-8 bronchospasm . Dosing: short vs. long‐acting Peds: 0.1-0.2 mg/kg q8hr – Positive response in asthma is a 200 ml or 12% in FEV1 Albuterol tabs Adults: 2-4 mg q6-8hr • Relief of reversible ≥ 2 (for IR) compared to baseline; (not the case for COPD) (VoSpire; 30 4-8 extended release bronchospasm ≥ 6 (for ER) Peds: 2 mg q6-8hr – Onset and duration of action in comparison short‐acting tabs) anticholinergics • Prevention & Adults: 20 mg tid - qid – Inhaler techniques vary with MDI vs. DPI’s Metaproterenol treatment of reversible ≥ 6 30 ≥ 4 syrup bronchospasm in – Inhaler vs. nebulizer delivery Peds: 10 mg tid - qid asthma or COPD – Use with exercise • Prevention & Adults: 20 mg tid to qid Metaproterenol treatment of reversible ≥ 6 30 ≥ 4 tabs bronchospasm in . Side Effects: Peds: 10 mg tid to qid asthma or COPD – Tremor • Relief of reversible – Heart palpitations bronchospasm Adults: 2.5-5 mg tid Terbutaline tabs • Tocolytic for premature ≥ 6 30 4-8 – Hypokalemia (Clinically insignificant – unless PO) labor (acute; short- Peds: 2.5 mg tid – Reduction in O2 Sat (those not on O2 supplementation) term use) 55 56 55

2 Agonists 2 Agonists . Levalbuterol (Xopenex): – Unlike racemic albuterol, levalbuterol is only the R‐albuterol isomer (active drug). – Dose is half of racemic albuterol – Overall, no differences in side effect profile and increases heart rate as racemic albuterol. – 3 x the cost of racemic albuterol

Levalbuterol Albuterol

57 58

Top 10 Drugs in Pediatrics Inhaled Corticosteroids: Mechanisms of Action . The 10 Most Commonly Prescribed Medications: . Direct action: 1. Amoxicillin – Inhibit cytokine‐induced production of pro‐ 2. Cefdinir inflammatory proteins 3. Azithromycin 4. Cipro/Dex Otic . Indirect actions: 5. Albuterol – Alter production of m‐RNA 6. Mometasone • Suppresses inflammatory system 7. Budesonide • Production of anti‐inflammatory mediators 8. Cetrizine • Increase production of 2‐receptors 9. Montelukast • Decrease broncho‐hyperreactivity 10. Ibuprofen • Decrease mucus production/hyper‐secretion

60 59 Inhaled Corticosteroids Inhaled Corticosteroids Age Max Drug Indication(s) Dose Onset Age Max (yrs) Benefit Drug Indication(s) Dose Onset (yrs) Benefit • Maintenance of Beclomethasone Adults: 40-320 mcg bid treatment of asthma as 1-2 MDI • Maintenance of ≥ 5 3-4 wks Flunisolide MDI wks prophylaxis Adults: 500-1000 mcg bid treatment of asthma as (AeroBid; AeroBid- 1-4 (QVAR) Peds: 40-80 mcg bid • Asthmatics requiring ≥ 6 - prophylaxis M; Aerospan HFA – wks Budesonide inhln Adults: Flexhaler=360-720 mcg systemic steroids that Peds: 500 mcg bid • Asthmatics requiring built in spacer) powder (Pulmicort bid; Turbuhaler=200-800 mcg need to be reduced or Flexhaler; systemic steroids that bid. ** Once-daily dosing for ≥ 6 24 hrs 1-2 wks stopped Pulmicort need to be reduced or mild asthma Fluticasone HFA • Maintenance of Adults: 88-880 mcg bid Turbuhaler) **Preg stopped Peds: Flexhaler=180-360 bid; Category B** Turbuhaler=200-400 mcg bid (Flovent Diskus; treatment of asthma as ≥ 4 24 hrs 1-2 wks Flovent HFA) prophylaxis Peds: 88 mcg bid Budesonide inhln Adults: none • Maintenance of • Asthmatics requiring suspension 2-8 treatment of asthma as ≥ 6 4-6 wks Triamcinolone Adults: 400-800 mcg bid days systemic steroids that (Pulmicort Peds: 250-500 mcg bid or 250- (Azmacort) ≥ 6 1 wk 2+ wks Respules) prophylaxis need to be reduced or 1000 mcg daily *(built in spacer) Peds: 200-600 mcg bid stopped • Maintenance of Adults: 80-320 mcg bid; Ciclesonide Adults: 220-440 mcg bid (*440 **Once-daily dosing for mild 1-4 Mometasone (Alvesco)* treatment of asthma in ≥ 12 1-2 wks • Maintenance of mcg bid if on oral steroids); asthma wks furoate inhalation ≥ 4; (pro-drug) patients >12 yrs of age **Once-daily dosing for mild 1-2.5 Peds >12 yrs: same as adult powder treatment of asthma as 1-2 wks ≥ 12 asthma hrs (Asmanex) prophylaxis Peds: none

Note: No COPD indications. 61 Note: No COPD indications. 62

Corticosteroids Corticosteroids

. Dosing Consideration During Exacerbation: . Oral or IV therapy: – Burst therapy (10‐14 day course) – Step Down approach – Tapering generally not necessary if less than 14 days of use – Once controlled, decrease dose by 25% every 2 for at least 8 weeks . Side Effects: – If by inhalation: risk of thrush (rinse mouth) – Remember, late phase can take several weeks to – Effects on bone growth resolve – Adrenal suppression – In patients with mild asthma, once‐a‐day dosing – Osteoporosis – Cataracts options exist for: – Worsen glucose control (mainly in diabetics) • Budesonide – Avascular necrosis of the femoral head/neck • Ciclesonide – Elevation in WBC • Mometasone furoate – Decreased thyroid function (decreases TSH secretion from the pituitary)

63 64

Corticosteroids Top 10 Drugs in Pediatrics

. Counseling: . The 10 Most Commonly Prescribed Medications: – Inhaler technique based on the device 1. Amoxicillin 2. Cefdinir – Use in the right order if on short acting 3. Azithromycin bronchodilator 4. Cipro/Dex Otic – Importance of daily use and not for acute 5. Albuterol exacerbations 6. Mometasone – Rinse mouth with water after inhaler use to prevent 7. Budesonide oral thrush 8. Cetrizine • Candidiasis 9. Montelukast 10. Ibuprofen

65 66 Top 10 Drugs in Pediatrics Background

. The 10 Most Commonly Prescribed Medications: . Seasonal (“hay‐fever”) vs. Perenneal (yr round) 1. Amoxicillin . Nose normal function: 2. Cefdinir – Heat, warm, & clean air coming in 3. Azithromycin . Immune Response: 4. Cipro/Dex Otic – Early: IgE Ab bind to allergen ‐> mast cells; release of pro‐ inflammatory mediators within min and causes 5. Albuterol vasodilation (swelling & congestion) 6. Mometasone – Late: Influx of WBCs, activation of lymphocytes 7. Budesonide . Risk Factors: 8. Cetrizine – Family history, atopic dermatitis, asthma 9. Montelukast – Social & Environmental: active/passive smoking, pollen, 10. Ibuprofen mold, dust mites, animals, strong odors

67 68

Treatment General Approach to Treatment

. Nonpharmacological: . First‐line is typically to control symptoms in acute – Allergen Avoidance setting: – Antihistamines (oral, intranasal, or ocular) . Pharmacotherapy – Decongestants (both PO & topical) – Antihistamines (oral, nasal sprays, ocular) –  Intranasal Steroids (Mod‐Severe Disease) – Intranasal Steroids . Maintenance Treatment: – Leukotriene Modifiers – Antihistamines (oral, intranasal, ocular) – Nasal Steroids (excellent for & is usually first line in perennial . Immunotherapy rhinitis) – Allergy shots – Addition of a leukotriene modifier (mainly montelukast) – Immunotherapy for resistant or specific cases

69 Ann Allergy Asthma Immunol 1998;81:478-518. 70

Medication Therapy Antihistamines

. Competitively inhibit H1 receptors preventing binding by Medication Congestion Itching Runny Nose Sneezing histamine. They are more effective at preventing the actions of histamine than reversing it. Anticholinergics - - +++ - – H1 activation in the central nervous system (CNS) is needed for wakefulness; if antagonized can cause sedation and appetite and Antihistamines + +++ ++ +++  cognitive & psychomotor performance and neurotransmission in the CNS

Cromolyn Sodium ++++ – Very little H2 receptor antagonism – (1st generation antihistamines mainly): Have cross antagonist Decongestants +++ - - - reactivity/inhibition of muscarinic receptors in the CNS which can result in anticholinergic side effects (causing dry mouth, urinary Leukotriene retention, constipation, increase pulse). +++- Receptor Blockers • The older, first generation can also interact with alpha receptors, 5‐HT receptors, and human ether‐a‐go‐go (hERG) K+ ion channels (why older Intranasal Steroids ++ +++ +++ +++ agents contributed to cardiac toxicity).

71 72 1st Generation (“Sedating”): Antihistamines 2nd Generation (“Non‐Sedating”): Antihistamines Drug Dosage Form Adult Dose Ped Dose Misc

Age <6: 1mg q4-6 Often 1-2nd choice, Drug Dosage Form Adult Dose Ped Dose Misc Brompheniramine 4mg, 8 mg LA, 12 mg 4 mg q4-6h Age 6-12: 2-4 mg less sedation (30%) SR, 2mg/5cc (max 24 mg/d) Oral Drugs (Dimetane) q4-6h; max 12mg/d compared to others 10-15% of pts sedation Age 2-5: 0.2-0.4 Take on empty Age 6-11 month: 2.5 Carbinoxamine 4 mg scored tab; oral compared to others (due to 4-8 mg q6-8 hrs mg/kg/d in 3-4 stomach. Avoid in Cetirizine mg qd solution = 4 mg/5 cc 5, 10 mg, 5mg/5cc 10 mg qd being an acid metabolite of (Arbinoxa; Palgic) divided doses ages < 2 & elderly (Zyrtec) Age 12-23 month: hydroxyzine (Atarax), long- 2.5-5 mg QD Age <6: 1mg q4-6 Often 1-2nd choice, acting; give qhs; now OTC Chlorpheniramine 4mg, 8 mg LA, 12 mg 4 mg q4-6h Age 6-12: 2-4 mg less sedation (30%) Is active (S) enantiomer of SR, 2 mg/5cc (max 24 mg/d) Levocetirizine Ages 6-11: 2.5 mg (Chlor-Trimeton) q4-6h; max 12mg/d compared to others 5 mg tabs 5 mg qd cetirizine;  potency (30-fold) qd (Xyzal) & H receptor dissociation Children may  1 Clemastine 1.34-2.68 mg BID 1.34, 2.68 mg, Age 6-12: 1-2 tsp experience sedation 0.5mg/5cc BID Loratadine 10 mg, 10 mg Age 2-5: 5 mg qd Metabolized by 2D6, 3A4 to (Tavist) (max 8.04 mg/d) or paradoxical effect 10 mg qd (Claritin) Reditab,5mg/5cc Age >6: 10 mg qd desloratadine. Available OTC 2-6 yrs: 2 mg q8-12 Other uses: Spasticity 4 mg tablet; syrup = 2 Metabolite of loratadine; more Cyproheptadine 4-20 mg/d in 3 hrs in SCI, Migraine Desloratadine 5 mg tab, 5 mg mg/5 cc (473 mL, 480 5 mg qd 12: 5 mg qd potent H blocker and longer divided doses 7-14 yrs: 4 mg q8- prophylaxis in peds, Reditab 1 (Periactin) mL bottles) (Clarinex) half-life. 12 hrs appetite stimulant. Metabolite of terfenadine (off Age 2-6: 6.25 mg > 30% incidence of 6-11: 30 mg bid market due to QT q4-6h (max 37.5 sedation, confusion, Fexofenadine 60 mg cap, 30, 60, 60 mg BID or Diphenhydramine 25-50 mg q4-6 h 12: 60 mg bid or prolongation). Caution with 25, 50, 12.5 mg/5cc mg) dizziness, etc.. 180 mg tab 180 mg qd (max 300 mg QD) (Allegra) 180 qd hepatic dysfunction; about (Benadryl) Age 6-12: 12.5-25 10% of pts get sedation mg q4-6 (max150) Age 2-6: 50 mg in Hydroxyzine 10, 25, 50, 100 mg, 3-4 divided doses 25-50 mg TID-QID (Atarax; Vistaril) 10mg/5cc, 25 mg/5cc Age 6-12: 50-100 in 3-4 divided doses 73 74

Side Effect Profiles Side Effect Profiles . First Generation Antihistamines: . Cardiac Safety Issues: – Cross the BBB and has cross antagonist reactivity with – Due to terfenadine and astemizole (affected the hERG K+ muscarinic receptors in addition to histamine ion channels thereby contributing to QT prolongation and receptors, thus resulting in anticholinergic effects torsades de pointes); now taken off market. The metabolite of terfenadine (i.e., fexofenadine) not a – Anticholinergic side effects – confusion, dizziness, concern. Both were also CYP3A4 substrates and urinary retention, xerostomia (dryness), diplopia, interactions worsened risk. glaucoma (intraocular pressure) – Current 2nd generation antihistamines don’t have this toxicity . Second Generation Antihistamines: st – Do not readily cross the BBB and thus do not inhibit H1 . Overdoses (mainly concerned with 1 generation): receptors that cause the sedation – Hyperthermia – With the exception of cetirizine (Zyrtec), most are – Excessive dryness considered “non‐sedating” and less anticholinergic – Flushed skin side effects. Since cetirizine is the metabolite of – Dilation of pupils +/‐ blurred vision hydroxyzine and thus shares structural similarities it is –  Altered mental status can act centrally to a small degree = sedation – Need to rule out other causes: e.g., encephalitis, metabolic and electrolyte abnormalities. 75 76

Mechanism of Action: Intranasal Steroids Top 10 Drugs in Pediatrics Cell Membrane (‐) NSAIDs Steroids Phospholipase A2 COX‐2’s . Arachidonic Acid Steroids The 10 Most Commonly Prescribed Medications: Zileuton Aspirin 1. Amoxicillin (‐) (‐) (‐) 2. Cefdinir 5‐Lipoxygenase Cyclooxygenase (COX) 3. Azithromycin Leukotrienes (LT) 4. Cipro/Dex Otic ‐LTB4 (chemotaxis & activation neutrophil 5. Albuterol adhesion) Prostaglandin (PG)H2  ‐LTC4, D4, E4 (vasoconstriction, vascular 6. Mometasone permeability, bronchoconstriction) Prostaglandin Synthetase Thromboxane Synthetase (‐) 7. Budesonide

Montelukast Misoprostol (+) 8. Cetrizine PGE TXA2 Zafirlukast (PGE1 analogue) ‐ PGE2 (vasodilation, pain, fever) ‐Vasoconstriction 9. Montelukast ‐ PGI2 (vasodilation, inhibit platelet ‐Plt aggregation aggregation) 10. Ibuprofen

77 78 Mechanism of Action: Leukotriene Modifiers Leukotriene Modifiers Cell Membrane (‐) NSAIDs Steroids Phospholipase A2 COX‐2’s Arachidonic Acid Steroids Zileuton Aspirin (‐) . Leukotriene Receptor Antagonists: (‐) (‐) – Montelukast (Singulair) 5‐Lipoxygenase Cyclooxygenase (COX) – Zafirlukast (Accolate) Leukotrienes (LT)

‐LTB4 (chemotaxis & activation neutrophil adhesion) Prostaglandin (PG)H2  . 5‐Lipoxygenase Inhibitor: ‐LTC4, D4, E4 (vasoconstriction, vascular permeability, bronchoconstriction) Prostaglandin Synthetase Thromboxane Synthetase – Zileuton (Zyflo; Zyflo CR) –taken off the market and now (‐) back on by another company Montelukast Misoprostol (+) PGE TXA2 Zafirlukast (PGE1 analogue) ‐ PGE2 (vasodilation, pain, fever) ‐Vasoconstriction ‐ PGI2 (vasodilation, inhibit platelet ‐Plt aggregation aggregation)

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Leukotriene Modifiers Age Drug Dosing Notes (yrs) Top 10 Drugs in Pediatrics Leukotriene Receptor Antagonist FDA approved for asthma, allergic rhinitis, & EIA. . The 10 Most Commonly Prescribed Medications: 5-10 mg daily in Preg B; CYP2C9, 3A4 substrate; CYP2C8 Montelukast the evening (if  2 inhibitor; no interactions with theophylline, digoxin, 1. Amoxicillin (Singulair) used for asthma) fexofenadine. If taking for allergies time of day for 2. Cefdinir administration does not matter. FDA approved for asthma. Preg B; CYP2C9 3. Azithromycin major substrate; Inhibitor of 1A2, 2C9, 2D6, 3A4. 20 mg bid on Interacts with warfarin. Taking with food 4. Cipro/Dex Otic Zafirlukast empty stomach  5 decreases bioavailability 40%.Cases of (Accolate) (1-hr before or 2- 5. Albuterol hepatotoxicity, eosinophilia, vasculitis. Monitor hrs after a meal) AST/ALT. Avoid with breastfeeding due to 6. Mometasone tumorigenicity seen with animal studies. 5-Lipoxygenase Inhibitors 7. Budesonide Preg C; CYP1A2, 2C9, 3A4 minor substrate; 8. Cetrizine Zyflo: 600 mg qid Inhibitor of 1A2; interactions with theophylline, Zileuton with food warfarin, propranolol. Common SE: HA (> 10%) 9. Montelukast (Zyflo; Zyflo CR: 600  12 Cases of hepatotoxicity (mainly in older females). 10. Ibuprofen Zyflo CR) mg bid within 1 Monitor AST/ALT baseline, then monthly x 3, then hour of food q2-3months thereafter. Avoid with ETOH due to 81 risk of liver toxicity. 82

World Health Organization (WHO) Drug Therapy Considerations Treatment Ladder . Ceiling effect . Route of administration Predominantly Nociceptive Pain Predominantly Neuropathic Pain . Pill burden . Tolerance Strong Opioid Severe Adjuvant(s) . Physical Dependence  Adjuvant(s) Pain  Strong Opioid . Patient specific factors: Weak Opioid Moderate Adjuvant(s) – Side effects from other medications  Adjuvant(s) Pain  Weak Opioid – Liver function (specifically synthetic function)

Nonopioid Adjuvant(s) – Whether opioid requires activation  Adjuvant(s) Mild  Nonopioid – Dosage form Pain – Don’t forget about treating depression!

83 84 Mechanism of Action: NSAID Drug Categories Cell Membrane Phospholipid . Non‐Opioid Agents Phospholipase A2 (PLA2) Aspirin Ibuprofen Arachidonic Acid – Acetaminophen, NSAIDs (‐)(‐) – Formulations: Transdermal/Topical, Oral, Parenteral 5‐Lipoxygenase Cyclooxygenase (COX) Leukotrienes (LT) Prostaglandin (PG)H . Opioids 2 Prostaglandin Synthetase Thromboxane Synthetase – Agonists/antagonists, Weak Opioids, Strong Opioids

PGD PGE – Formulations: Transdermal/Topical, Oral, Parenteral 2 (‐)(+)TXA2 PGE2 . PGF2 Adjuvants Platelet – Antidepressants Aggregation TXB2 Figure. Mechanism of action of aspirin and NSAIDs Copyright. Pharmacology Weekly, Inc. – Anticonvulsants Thrombus

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