First Edition

BLOCK 4 ENDOCRINE SYSTEM, GENITOURINARY SYSTEM & AUTACOIDS

COPYRIGHT MBBS NOTES © DATO FARID FADZILAH

HORMONES & HORMONE ANTAGONISTS

A. Anterior Pituitary Hormones 1. Enumerate growth hormone preparations and IGF-1 preparation. ** 2. Enumerate growth hormone release inhibitors and growth hormone antagonist. ** 3. Describe the pharmacological actions of growth hormone. ** 4. Describe the therapeutic uses of the following: growth hormone preparations, growth hormone antagonist, growth hormone release inhibitors and IGF-1 preparation. ** 5. List the adverse effects of the following: growth hormone preparations, growth hormone antagonist and growth hormone release inhibitors. ** 6. Enumerate prolactin inhibitors. ** 7. Describe the therapeutic uses and adverse effects of bromocriptine. ** 8. Describe the therapeutic uses of various gonadotropin preparations. ** 9. Describe the adverse effects of gonadotropins. ** 10. Enumerate GnRH agonists. *** 11. Explain the mechanism of action of GnRH agonists. *** 12. Explain the rationale for combining GnRH agonists with receptor antagonists in prostatic carcinoma. *** 13. Describe other therapeutic uses of GnRH agonists with their route of administration ** 14. Describe the adverse effects of GnRH agonists. * 15. Enumerate GnRH antagonists. * 16. Describe the advantages of GnRH antagonists over GnRH agonists. * 17. Describe the therapeutic uses of GnRH antagonists. *

B. Thyroid & Anti-Thyroid Drugs 1. Describe the thyroid hormone biosynthesis and indicate the sites of action of various anti-thyroid drugs. *** 2. Classify antithyroid drugs based on chemistry and mechanism of action. *** 3. Describe the mechanism of action of thioamides. *** 4. Describe the important pharmacokinetic features of thioamides. *** 5. Describe the therapeutic uses of thioamides. *** 6. List the adverse effects of thioamides. *** 7. List the thyroid and non-thyroid uses of iodine/iodides. *** (Tripathi) 8. Explain the role of iodides in the preoperative preparation for thyroidectomy. *** 9. Describe the adverse effects of iodides. *** 10. Discuss the role of radioactive iodine in the treatment of hyperthyroidism. *** 11. Explain the role of beta blockers in the management of hyperthyroidism. *** 12. List the drugs used in management of thyroid storm. *** 13. Describe the role of each drug used in the management of thyroid storm. *** 14. List the drugs used in the management of thyrotoxicosis during pregnancy. *** (Katzung) 15. List thyroid hormone preparations. *** 16. Describe the uses of thyroid hormone preparations. *** 17. List the adverse effects of thyroid hormone preparations. *** 18. Describe the pharmacological differences between levothyroxine sodium and liothyronine. *** (Katzung) 19. Describe the important pharmacokinetic features of thyroid hormone preparations. ** (Katzung) 20. Describe the precautions to be taken during the administration of thyroid hormone preparations. ** (Katzung) C. Insulin & Other Anti-Diabetic Drugs 1. Describe the chemistry, bio-synthesis, secretion and mechanism of action of insulin. *** 2. List the sources of insulin preparations. *** 3. Classify insulin preparations based on their duration of action. *** 4. Explain the characteristic features of regular insulin. *** (Katzung) 5. Explain the characteristic features of following insulin preparations: insulin lispro, NPH insulin, insulin glargine and insulin detemir. ** (Katzung) 6. Describe various insulin treatment regimens. ** (Katzung) 7. List insulin delivery systems. ** (Katzung) 8. Describe the management of complications of insulin therapy. *** 9. Explain the drug interaction between insulin and beta blockers. *** 10. Classify oral anti-diabetic drugs based on their chemistry. *** 11. Explain the mechanism of action of sulfonylureas. *** 12. Describe the adverse effects of sulfonylureas. *** 13. Describe the important drug interactions of sulfonylureas. *** 14. Describe the important features of various sulfonylureas. ** 15. Describe the mechanism of action of repaglinide/nateglinide. *** 16. Describe the role of repaglinide and nateglinide in the management of diabetes. *** 17. Explain the mechanism of action of biguanides. *** 18. List non-diabetic uses of metformin. *** 19. Describe the adverse effects of biguanides. *** 20. List the contraindications for biguanides. *** 21. Describe the mechanism of action of thiazolidinediones. *** 22. Describe the role of thiazolidinediones in diabetes. *** 23. List the adverse effects of thiazolidinediones. *** 24. Describe the mechanism of action of - glucosidase inhibitors. *** 25. List the adverse effects and contraindications of - glucosidase inhibitors. *** 26. Describe the mechanism of action of incretin-mimetics, dipeptidyl peptidase-4 inhibitors, amylin-mimetic drugs and sodium-glucose cotransporter-2 inhibitors. ** 27. Explain the role of incretin-mimetics, dipeptidyl peptidase-4 inhibitors, amylin-mimetic drugs and sodium-glucose cotransporter-2 inhibitors in diabetes. ** 28. Choose a suitable anti-diabetic drug for the following: mild diabetes, mild diabetes with obesity, mild diabetes with COPD, mild diabetes with high risk for hypoglycaemia and postprandial hyperglycemia. ***

D. Adrenocortical Steroids & Their Analogues 1. Classify glucocorticoids based on their duration of action. *** 2. Enumerate mineralocorticoids. *** 3. Compare the relative glucocorticoid and mineralocorticoid activity of various glucocorticoids. *** 4. Describe the mechanism of action of corticosteroids at cellular level. *** 5. Describe the important pharmacokinetic features of corticosteroids. *** 6. Explain the pharmacological actions of corticosteroids. *** 7. Explain the therapeutic uses of corticosteroids. *** 8. Describe the adverse effects of corticosteroids. *** 9. Describe the effects of long-term steroid therapy on HPA axis. *** 10. Describe the measures to minimize HPA axis suppression. *** 11. Describe the important contraindications of glucocorticoids. *** 12. State two examples each of steroids which are administered as *** a) Inhaled steroids b) Eye/ear drops c) Dermatological preparations d) IV/IM injections e) Intra-articular injections

E. Gonadal Hormones a) Oestrogens, Progestins & Contraceptives 1. Enumerate natural and synthetic . *** 2. Describe the principal actions of estrogens on: sex organs, secondary sex characters and metabolism. *** 3. Describe the mechanism of action of . *** 4. Describe the advantages of transdermal over oral estrogens. *** (Tripathi) 5. Explain the benefits and risks of Hormone Replacement Therapy (HRT). *** (Tripathi) 6. Describe the current status of HRT. *** (Tripathi) 7. Describe the dosage of estrogen in HRT. ** (Tripathi) 8. Describe the role of progestin in HRT. *** (Tripathi) 9. Describe the other therapeutic uses of estrogens. ** 10. Describe the adverse effects of estrogens. *** 11. Enumerate Selective Estrogen Receptor Modulators (SERMs). *** 12. Discuss the role of clomiphene citrate in infertility. *** 13. Explain the rationale for each therapeutic use of tamoxifen and raloxifene. *** 14. Describe the adverse effects of tamoxifen and raloxifene. *** 15. Describe the therapeutic use of fulvestrant. * 16. Enumerate aromatase inhibitors. ** 17. Describe the therapeutic uses of aromatase inhibitors. **

b) Progestins 1. Enumerate progestins. *** 2. Describe the principal actions of progesterone on: target organs, body temperature and metabolism. *** 3. Describe the mechanism of action of progesterone. *** 4. Explain the therapeutic uses of progesterone. *** 5. Describe the adverse effects of progesterone. *** 6. Enumerate antiprogestins. *** 7. Explain the therapeutic uses of . ***List the adverse effects of mifepristone. *** 8. Enumerate Selective Progesterone Receptor Modulators (SPRM). ** 9. List the therapeutic uses of Selective Progesterone Receptor Modulators (SPRM). ** c) Contraceptives 1. List the various groups of oral contraceptive (OC) preparations with examples for each. *** 2. Describe the regimen of combined pills used for contraception. *** 3. List the advantages and disadvantages of phased regimens and mini pills. ** (Tripathi) 4. Describe the regimens used in postcoital contraception. *** 5. List different types of injectable contraceptive preparations with examples. *** 6. List the advantages and disadvantages of injectable contraceptive preparations. *** 7. List hormonal drug delivery systems used for contraception. ** 8. Explain the mechanism of action of hormonal contraceptives. *** 9. Describe the health benefits of hormonal contraceptives. *** 10. Describe the adverse effects of hormonal contraceptives. *** 11. List the contraindications of hormonal contraceptives. *** 12. Describe the drug interactions of OCPs that may lead to contraceptive failure. *** 13. Describe the mechanism of action of centchroman. * 14. List the drugs used as male contraceptives. *

d) & Drug Treatment Of Erectile Dysfunction 1. Enumerate androgen preparations. *** 2. Describe principal actions of and on different target organs. *** 3. Describe the mechanism of action of androgens. *** 4. Describe the therapeutic uses of androgens. *** 5. Describe the adverse effects of androgens. *** 6. Enumerate anabolic steroids. *** 7. Describe the therapeutic uses of anabolic steroids. *** 8. Describe adverse effects of anabolic steroids. *** 9. Describe the mechanism of action of . ** 10. Describe the therapeutic uses of danazol. ** 11. List the adverse effects of danazol. ** 12. Explain the role of / in the treatment of prostatic cancer. *** 13. Enumerate 5- reductase inhibitors. *** 14. Describe the therapeutic uses of 5- reductase inhibitors. *** 15. List the adverse effects of 5- reductase inhibitors. *** 16. Enumerate drugs used for erectile dysfunction. *** 17. Explain the role of phosphodiesterase-5 inhibitors in the treatment of erectile dysfunction. ***

PARATHYROID HORMONE (PTH), VITAMIN D, CALCITONIN & DRUGS AFFECTING BALANCE

A. Calcium 1. Describe the therapeutic uses of various calcium preparations. *** (Tripathi) 2. List the adverse effects of calcium. *** (Tripathi)

B. Parathyroid Hormone 1. Describe the actions of PTH on: bone, kidney and intestine. ** 2. Explain the role of teriparatide in the treatment of osteoporosis. ** 3. Describe the therapeutic uses of cinacalcet. **

C. Calcitonin 1. Describe the actions of calcitonin on: bone and kidney. ** 2. Describe the therapeutic uses of calcitonin. ** 3. List the adverse effects of calcitonin. **

D. Vitamin D 1. Describe the actions of vitamin D on: intestine, bone and kidney. *** 2. Describe therapeutic uses of various vitamin D preparations. ***

E. Bisphosphonates 1. Classify bisphosphonates (bPNs) based on their potency. ** 2. Describe the mechanism of action of bPNs. ** 3. Describe the therapeutic uses of bPNs. ** 4. Explain the adverse effects of bPNs. ** 5. List the drugs used in the treatment of osteoporosis. ***

OXYTOCIN & OTHER DRUGS AFFECTING UTERUS

1. List oxytocics. *** 2. Describe the mechanism of action of oxytocin. *** 3. Describe the pharmacological actions of oxytocin. *** 4. Describe the important pharmacokinetic features of oxytocin. *** 5. Describe the therapeutic uses of oxytocin. *** 6. List the adverse effects of oxytocin. *** 7. Explain why oxytocin is preferred over ergometrine/PGs for uterine inertia. *** 8. Describe the obstetric uses, adverse effects and contraindications of ergot alkaloids. *** 9. List tocolytics acting through different mechanisms. *** 10. Describe the role of beta-2 agonists as tocolytics. **

AUTACOIDS

A. Drug Therapy Of Migraine 1. Enumerate drugs used in the treatment of mild, moderate and severe migraine. *** 2. Enumerate drugs used for the prophylaxis of migraine. *** 3. Describe the role of following drugs in migraine: triptans, ergot alkaloids. ** 4. Describe the other therapeutic uses of ergot alkaloids. * 5. Describe the adverse effects and contraindications of the following: sumatriptan and ergot alkaloids. ***

B. Anti-Histaminics 1. Enumerate first generation and second generation antihistaminics. *** 2. Describe the therapeutic uses of antihistaminics. *** 3. Describe the adverse effects of antihistaminics. *** 4. Describe the advantages of second generation antihistaminics over the first generation antihistaminics. ***

C. Prostaglandins 1. Explain the therapeutic uses of different prostaglandin preparations. *** 2. List the adverse effects of prostaglandins. ***

HORMONES &

HORMONE

ANTAGONISTS

ANTERIOR PITUITARY HORMONES

CLASSIFICATION OF ANTERIOR PITUITARY HORMONES

 Somatotropin Growth hormone  Somatrem preparation  Sermorelin

 Mesacermin IGF-1 preparation  Mesacermin rinfabate

 Somatostatin Growth hormone releasing  Optreotide inhibitor  Sandostatin  Lancreotide

Growth hormone antagonist  Pegvisomant

 Bromocriptine Prolactin inhibitor  Dopamine  Cabergoline

 Nafarelin  Goserelin  Triptorelin GnRH agonist  Buserelin  Deslorelin  Histrelin  Leuprolide

 Cetrorelix  Ganirelix GnRH antagonist  Abarelix  Degarelix

GROWTH HORMONE

PHARMACOLOGICAL ACTION  Attainment of normal adult size  Increases size and mass of all body parts except brain and eyes  For development of sex organ, both growth hormone and gonadotropin are needed  Anabolic action on muscle (protein)  increase in muscle mass  Catabolic action on lipid  reduction in central adiposity  Anabolic and growth promoting effect of growth hormone are indirect & are mediated by activating insulin-like growth factor type 1 (IGF-1) at open epiphyses of long bones that causing bone growth

METABOLISM  Growth hormone reduces insulin sensitivity, hence decreases utilization of glucose by muscle and increases glycogenolysis which increases glycogen level  Growth hormone increases protein synthesis & promotes positive N2 balance  increases cellular uptake of amino acids  Growth hormone initially has insulin-like effect, followed by antagonist effect to insulin  Diabetogenic effect  decreased uptake of glucose into tissue and increased release of glucose from the liver  Increases mobilization of free fatty acids from adipose tissue (lipolysis), thus predisposing formation of ketone bodies especially among diabetic patients

GROWTH HORMONE PREPARATION

DRUGS Somatotropin, Somatrem, Sermorelin

INTRODUCTION  Human pituitary growth hormone such as Somatotropin is no longer used  Recombinant human growth hormone (rhGH) is most commonly used nowadays  The longer acting preparation are now available: Somatropin and Somatrem (both of them are equipotent to Somatotropin)  Sermorelin: synthetic form of growth hormone preparation

THERAPEUTIC USES  Somatotropin S.C.  permits many children with short stature to achieve normal adult height  Somatotropin S.C.  to treat adult onset growth hormone deficiency, which is usually due to damage to hypothalamus or pituitary caused by tumour, infection or radiation therapy  Used for increasing height of girls with Turner syndrome (failure of ovary to respond to pituitary hormone)  Used for AIDS-related muscle wasting  Potent anabolic agent approved for management of burn injuries  Sometimes it gets abused by athletes  Used for its anti-aging effects, but does not reverse manifestation of normal aging  Short bowel syndrome, usually associated with malabsorption  growth hormone promotes intestinal growth and improve patient condition

ADVERSE EFFECTS  Pain at site of injection  Precipitation of type 2 diabetes  Induction of insulin resistance  Arthralgia in hand and wrist  Carpal tunnel syndrome  Myalgia  Fluid retention and headache due to intracranial hypertension (visual change, nausea, vomiting)  Patients with Turner syndrome have high risk of otitis media  Lipodystrophy  Peripheral oedema (due to fluid and sodium retention)  Glucose intolerance  Scoliosis in children

CONTRAINDICATION  Cancer and other critically ill patients (increased morbidity)

IGF-1 PREPARATION

DRUGS Mesacermin, Mesacermin rinfabate

MESACARMIN  Combination of recombinant human IGF-1 with recombinant human IGF binding protein-3  Given by subcutaneous injection

THERAPEUTIC USES  Replacement of IGF-1 deficiency that is not responsive to exogenous growth hormone (Somatropin treatment)  IGF-1 deficiency occur due to :  Mutation of growth hormone receptor with aberrant growth hormone signaling  Development of antibody against growth hormone  Deficiency IGF binding protein-3

ADVERSE EFFECTS  Hypoglycaemia  Intracranial hypertension  Reversible rise in liver enzymes  Lymphoid tissue hypertrophy including enlarged tonsil  Lipohypertrophy (presumably secondary to activation of insulin receptor)

GROWTH HORMONE RELEASE INHIBITORS

DRUGS Somatostatin, Optreotide, Sandostatin, Lancreotide

SOMATOSTATIN  Primarily inhibits secretion of growth hormone  Also inhibits TSH from anterior pituitary, insulin from pancreas and gastrin from stomach  Use of Somatostatin is limited due to:  Very short half-life  Lack of specificity for inhibiting only growth hormone  Growth hormone rebound after discontinuation  Therapeutic uses:  Prevents bleeding from oesophageal varices  Prevents upper gastrointestinal bleeding from haemorrhagic gastritis, peptic ulcer, intestinal/pancreatic fistula or from hypersecretory tumour of intestinal tract  Diabetic ketoacidosis – acts as an adjuvant  Acromegaly (limited use)  Adverse effects:  Nausea  Diarrhoea  Dyspepsia  Steatorrhoea

OCTREOTIDE  Long acting analogue of Somatostatin  More potent than Somastostatin in inhibiting growth hormone release  Twice potent in reducing insulin secretion  Chance to get hyperglycemia as side effect is less compared to Somatostatin due to its weak inhibitor of insulin secretion  Therapeutic uses:  Reduce symptoms due to growth hormone-secreting pituitary tumour eg. acromegaly  AIDS-associated diarhoea  Breast cancer  Cushing’s syndrome  Insulinoma  Bleeding in oesophageal varices and peptic ulcer (as it decreases mucosal blood flow)  Control symptoms in patients having carcinoid syndrome, VIP-secreting tumour, gastrinoma, secretory diarrhoea associated with diabetes or irritable bowel syndrome  Adverse effects:  Nausea  Diarrhoea  Steatorrhea  Abdominal pain  Gall stones  Sinus bradycardia SANDOSTATIN  Slow release formulation of Octreotide  Adverse effects:  Abdominal pain  Nausea  Steatorrhoea  Gall stones (due to biliary stasis)  Long term use may lead to conduction defect and vitamin B12 deficiency

LANCREOTIDE  Similar to Octreotide  Therapeutic uses:  Used to treat thyroid tumor  Longer acting formulation used to treat acromegaly

GENERAL THERAPEUTIC USES

 Acromegaly

 Watery diarrhoea

 Hypokalaemia

 Achlorhydria

 Diabetic diarrhoea  Somastostatin receptor scintigraphy using radiolabel Octreotide  Useful in localizing neuroendocrine tumor having Somatostatin receptor and helps to predict response to Octreotide therapy  Acute control of bleeding from oesophageal varices

GROWTH HORMONE ANTAGONIST

PEGVISOMANT  Prevents peripheral growth hormone binding to its receptor and suppresses serum IGF-1 level  After its attachment with growth receptor, it allows its dimerization but blocks the ongoing conformational changes that activate signal transduction  However, formation of specific antibody limits its long term efficacy  Therapeutic uses:  Acromegaly  Highly effective alternative for use in patient who have not respond to Somatostatin analogue either as sole therapy  As temporary measure while waiting for radiation therapy  receives increased scrutiny as first line therapy  Adverse effects:  Elevation of hepatic transaminase  Lipohypertrophy at injection site

PROLACTIN INHIBITORS

DRUGS Bromocriptine, Dopamine, Cabergoline

BROMOCRIPTINE  Semi-synthetic ergot derivative  Acting as a potent Dopamine agonist mainly at D2 receptor  Weak α-adrenergic blockade

THERAPEUTIC USES  It relieves symptoms of parkinsonism that result from Dopamine deficiency in nigrostriatal pathway  Acromegaly  reduces growth hormone level, but less effective than Octreotide and Lancreotide  Restless leg syndrome  Hyperprolactinemia  Dopamine is the main factor controlling prolactin secretion  Hence, Bromocriptine (Dopamine agonist) effectively reduces the secretion of prolactin

ADVERSE EFFECTS  Nausea and vomiting (due to stimulation of Dopamine receptor in CTZ)  Postural hypotension (due to α-adrenergic blockade)  Constipation  Hallucination  Confusion  Psychosis  Behavioural alteration  Nasal congestion  Headache  Digital vasospasm

GnRH PREPARATION

DRUG Gonadrelin

THERAPEUTIC USES  Diagnostic use  Amennorhoea and infertility (due to deficient production of GnRH by pituitary)  Hypogonadotropic hypogonadism in males  delay puberty or defective spermatogenesis or oligozoospermia  Cryptochidism  To aid in vitro fertilization  to induce simultaneous maturation of several ova and to precisely time ovulation

ADVERSE EFFECTS  Ovarian hyperstimulation : polycystic ovary, pain in lower abdomen, ovary bleeding  Ovary enlargement: ascites and rupture  Spontaneous abortion  Precocius puberty in children  Gynaecomastia in male  Multiple pregnancy  Headache  Oedema  Allergic reaction

GnRH AGONISTS

DRUGS Nafarelin, Goserelin, Triptorelin, Buserelin, Deslorelin, Histrelin, Leuprolide

MECHANISM OF ACTION

Pulsatile administration Continuous therapy ↓ ↓ Increases FSH and LH Initially, increases gonadotropin secretion. ↓ Later, after 2 weeks of therapy: Ovulation down regulation of GnRH receptor due to their prolonged occupation by GnRH ↓ Decreases FSH and LH ↓ Suppression of ovulation and suppression of spermatogenesis

DRUGS ADMINISTRATION ROUTE THERAPEUTIC USES Nafarelin Nasal spray Endometriosis, uterine fibroid, precocious puberty Goserelin S.C. injection Endometriosis, uterine fibroid, prostate carcinoma Triptrorelin I.M. depot injection Prostate cancer Buserelin Nasal spray Endometriosis, prostate carcinoma Leuprolide I.M. depot injection Endometriosis, uterine fibroid, precocious puberty, prostate cancer Histrelin S.C. injection Prostate carcinoma, precocious puberty

GENERAL THERAPEUTIC USES  Prostatic carcinoma  Precocious puberty  Breast cancer in pre-menopausal women  Uterine fibroid  Endometriosis  Polycystic ovarian disease  Control ovarian hyperstimulation in assisted reproduction

ADVERSE EFFECTS  Hot flushes, headache and nausea  Osteoporosis  Breast atrophy  Vaginal dryness  Loss of libido GnRH ANTAGONISTS

DRUGS Cetrorelix, Abarelix, Ganirelix, Degrarelix

MECHANISM OF ACTION  Competitively block GnRH receptor in anterior pituitary  Inhibit FSH and LH release without initial stimulation  Males: decrease testosterone level, useful in advance prostate cancer  Female: to suppress endogenous LH surge during controlled ovarian hyperstimulation and to suppress oestrogen release from ovary

THERAPEUTIC USES  Advanced prostate cancer  GnRH antagonist is preferred over GnRH agonist because it does not cause initial increase (flare up) in gonadotropin secretion and does not cause histamine release  So it does not exacerbate cancer symptoms initially and does not cause anaphylactoid reaction  Uterine fibroid and endometriosis  As an adjuvant during in vitro fertilization (IVF)

RATIONALE OF COMBINING GnRH AGONIST WITH ANTAGONIST IN PROSTATIC CARCINOMA  GnRH antagonist does not cause initial increase (flare up) in gonadotropin secretion, but it will directly decrease GnRH secretion (hence decrease oestrogen secretion)  GnRH antagonist does not exacerbate cancer symptom initially  GnRH antagonist does not cause anaphylactoid reaction  GnRH agonist decreases testosterone level if it is administered as I.M. depot injection for 1-2 weeks

ADVANTAGES OF GnRH ANTAGONIST OVER GnRH AGONIST  Immediate gonadotropin suppression by competitive antagonism, so duration of administration become shorter  Carry lower risk of ovarian hyperstimulation syndrome and multiple pregnancy  Achieve more complete suppression of endogenous gonadotropin secretion than GnRH agonist

THYROID & ANTI-THYROID DRUGS

THYROID HORMONE BIOSYNTHESIS  Step 1: Uptake of iodine; iodide trapping by follicular cells  Step 2: Synthesis of thyroglobulin and oxidation of iodides  Step 3: Iodination of tyrosine  Step 4: Coupling of MIT and DIT  Step 5: Secretion and release of T3 and T4  Step 6: Transportation of T3 and T4 into plasma and their binding protein  Step 7: Peripheral activation of T3 and T4 & metabolism of thyroid hormone

CLASSSIFICATION OF ANTI-THYROID DRUGS a) Based on chemistry

Classification Drugs Mechanism of action

 Propylthiouracil  Inhibit thyroid peroxidase which is required Thioamide - derivatives  Carbimazole for oxidation of I (Step 2)  Methimazole  Inhibit iodination of tyrosine (Step 3)  Inhibit coupling of MIT/DIT to form thyroid hormone production (Step 4) 131 Radioactive iodine  Iodine  Emits γ-rays (for tracer studies) and β- particles  β-particles destroy thyroid parenchyma  destructive effect  causes pyknosis and necrosis  fibrosis of thyroid follicular cells (without damaging neighbouring tissue)

Iodides  Aqueous KI  High iodide concentration limits its own solution transport (Step 1)  Lugol’s iodine  Limits thyroid hormone release (Step 5)  Reduces thyroid blood flow

Iodinated contrast  Oral ipodate  Inhibits 5’-deiodinase (DID-I and DID-II) media  Ipanoic acid enzymes, hence prevent conversion of T4 to  Diatrizoate (I.V.) T3 in the liver, kidney, pituitary gland and brain

b) Based on mechanism of action  Inhibits hormone synthesis (anti-thyroid drugs): Propylthiouracil, Methimazole, Carbimazole  Inhibits iodide trapping (ionic inhibitors): Thiocyanates, Perchlorates, Nitrates  Inhibits hormone release: Iodine, iodides of Na+ and K+, Organic iodide  Destroys thyroid tissue  Radioactive iodine (131Iodine, 125Iodine, 123Iodine)

THIOAMIDES

MECHANISM OF ACTION  Inhibit thyroid peroxidase which is required for oxidation of I- (Step 2)  Inhibit iodination of tyrosine (Step 3)  Inhibit coupling of MIT/DIT to form thyroid hormone production (Step 4)

IMPORTANT PHARMACOKINETIC FEATURES  Methimazole (an active metabolite of Carbimazole) is more potent than Propylthiouracil  Short plasma t1/2 which is 2-6 hours  Selectively accumulated in thyroid gland  Quickly absorbed orally  Widely distributed  Metabolized in the liver and excreted in urine  Carbimazole can enter into the milk and crosses placental barrier  hence can cause foetal hypothyroidism

THERAPEUTIC USES  Hyperthyroidism  Thyrotoxic crisis  Surgical subtotal thyroidectomy

ADVERSE EFFECTS  Pruritic or urticarial rash  Vasculitis  Arthralgia  Cholestatic jaundice  Lupus-like reaction  Agranulocytosis

IODINES & IODIDES

THERAPEUTIC USES OF IODINE & IODIDES  Pre-operative preparation for thyroidectomy in Grave’s disease  makes the thyroid gland becomes less vascular and more compact for easier operation  Thyroid storm  Lugol’s iodine or iodine containing radiocontrast media  Prophylaxis of endemic goitre  Iodized salt  Antiseptics  Tincture iodine, Povidone iodine

ROLE OF IODIDES IN THE PRE-OPERATIVE PREPARATION FOR THYROIDECTOMY  Make the gland less vascular and more compact  easier to operate on  β-blocker given adjunctively to prevent effects of thyrotoxicosis

ADVERSE EFFECTS OF IODIDES  Hypersensitivity  Chronic iodine toxicity (iodism) is characterized by:  Acneiform rash  Swollen salivary glands  Stomatitis  Metallic taste  Bleeding disorders  Conjunctivitis

RADIOACTIVE IODINES

ROLE OF RADIOACTIVE IODINE IN THE TREATMENT OF HYPERTHYROIDISM  131Iodine is most commonly used  123Iodine is for diagnostic use  131Iodine emits γ-rays and β-particles  It gets accumulated in thyroid gland  β-particles destroy thyroid parenchyma

THERAPEUTIC USES  Hyperthyroidism due to Grave’s disease  Toxic nodular goitre

ADVANTAGES  Simple, convenient and inexpensive  No surgical risk, scar or injury to parathyroid glands or recurrent laryngeal nerve  Once hyperthyroidism is controlled, cure is permanent

DISADVANTAGES  Hypothyroidism  Long latent period of response  Contraindicated in pregnancy  foetal thyroid destroyed, causing cretinism and other abnormalities if given during 1st trimester  Not suitable for young patients  more likely to develop hypothyroidism  Risk of thyroid carcinoma (rare)

ROLE OF β-BLOCKERS IN THE MANAGEMENT OF HYPERTHYROIDISM  In hyperthyroism, there is up-regulation of β1 receptors in myocardium  This increases sensitivity of heart to catecholamines  Non-selective β-blockers eg. Propranolol are used along with anti-thyroid drugs to:  Prevent thyrotoxicosis-induced tachycardia, tremors, sweating and anxiety  Inhibit peripheral conversion of T4 to T3  Pre-operative use before subtotal thyroidectomy  While awaiting response of Carbimazole and 131Iodine

ROLE OF DRUGS USED IN THE MANAGEMENT OF THYROID STORM

Drugs Role

Propylthiouracil  Blocks thyroid hormone synthesis  Blocks peripheral conversion of T4 to T3

Collosal iodine  Blocks thyroid hormone release

Sodium ipodate  Blocks thyroid hormone release  Blocks peripheral conversion of T4 to T3

Propranolol  Controls increased sympathetic activity and CVS manifestations  Blocks peripheral conversion of T4 to T3

Diltiazem  Used if patients have complications like asthma or heart failure

Hydrocortisone  Protects patients against shock  Blocks peripheral conversion of T4 to T3

DRUGS USED IN THE MANAGEMENT OF THYROTOXICOSIS DURING PREGNANCY  Propylthiouracil with lower dose because it does not cross placental barrier, greater plasma binding protein and less transferred to foetus  Thyroid supplement  Methimazole  risk of foetal scalp defect

THYROID HORMONE PREPARATIONS

DRUGS  Levothyroxine sodium (T4)  Liothyronine sodium (T3)

THERAPEUTIC USES  Hypothyroidism  Myxoedema coma  Hypothyroidism during pregnancy  Subclinical hypothyroidism  Endemic goitre  Endemic cretinism  Empirical use in refractory anaemia, menstrual disorder, chronic and non-healing ulcer  Papillary carcinoma  by suppressing TSH

ADVERSE EFFECTS  Tachycardia  Palpitation  Cardiac arrhythmias  Tremors  Weight loss  Headache  Diarrhoea  Insomnia  Heat intolerance

IMPORTANT PHARMACOKINETIC FEATURES  Oral bioavailability of Levothyroxine sodium is 75%  Severe hypothyroidism reduces oral absorption  Administered in empty stomach to avoid food interference  Reduced absorption: Sucralfate, Fe3+, Ca2+, proton pump inhibitors  Increased metabolism: CYP-3A4 inducers like Rifampicin, Phenytoin, Carbamazepine

PHARMACOLOGICAL DIFFERENCES

Levothyroxine sodium (T4) Liothyronine sodium (T3)

Half-life Long (7 days) Short (1 day) Potency Less potent More potent (3-4 times) Dosing Once daily dosing Multiple daily dosing Cost Low High Laboratory Easy Difficult measurement of serum level Cardiotoxicity Lower risk Higher risk Other advantages  Stability  Short-term suppression of TSH  Content uniformity  Special situation:  Lack allergenic foreign protein  Severe myxoedema  Produces both T3 and T4  Myxoedema coma (intracellular conversion)  Thyroid carcinoma surgery Preferred Yes No

PRECAUTIONS TO BE TAKEN DURING THE ADMINISTRATION

Myxoedema and  Low level of thyroid hormone protects heart against increasing coronary artery disease demands that could result in angina and MI in older patients  Correction of myxoedema must be done cautiously to avoid provoking arrhythmia, angina and acute myocardial infarction

Myxoedema coma  Give all drugs I.V. because patient absorbs poorly from other routes  Large pool of empty T3 and T4 binding sites must be filled before free thyroxine takes action

Pregnancy  Given early and adequate, important for foetal brain development

Administration  Avoid food such as bran, soy and coffee & drugs that will impair its absorption  Administered in empty stomach

Monitoring  Children should be monitored for normal growth and development  It takes 6-8 weeks to reach steady-state level in blood  In children: restlessness, insomnia, accelerated bone maturation and growth may be signs of thyroxine toxicity  In adults: increased nervousness, heat intolerance, episodes of palpitation and tachycardia, or unexplained weight loss may be the presenting symptoms

Reduced absorption  Sucralfate, Fe3+, Ca2+, proton pump inhibitors

Increased metabolism  CYP-3A4 inducers like Rifampicin, Phenytoin, Carbamazepine

INSULIN & OTHER ANTI-DIABETIC DRUGS

DIABETES MELLITUS  Chronic metabolic disease  Either no or inadequate insulin secretion with or without concurrent impairment of insulin action (important to determine because each need different treatment)  Types:  Type 1: insulin dependent diabetes mellitus  Type 2: non-insulin dependent diabetes mellitus  Type 3: others  Type 4: gestational diabetes mellitus

INSULIN

INTRODUCTION  Discovered in 1921 by Banting and Best  Synthesized by the β-cells of pancreas  Pre-pro-insulin (a single chain polypeptide precursor)  pro-insulin  insulin (formed by removal of the C-peptide from pro-insulin by proteolysis)  C-peptide (connecting peptide) in pro-insulin can produce immunogenic reaction, but also acts as a marker for insulin level as it is produced alongside insulin  Insulin consists of two peptide chains called A and B chains which are connected by a disulphide bridges

REGULATION OF INSULIN SECRETION  There is always a minimal level of insulin level throughout our body at all time  Regulated by chemical, hormonal and neural mechanisms

1) Chemical mechanism  Stimulates beta cells and release of insulin  Glucose:  First phase (within 2 minutes, brief)  Second phase (delayed, more sustained)  Mechanism of action: Glucose enter pancreatic beta cells by glucose transporter (GLUT2) ↓ ATP produced (glycolysis) ↓ Block ATP-sensitive potassium channels ↓ Lead to depolarization ↓ Promotes or activates voltage gated calcium channel (influx of Ca2+) ↓ Promotes exocytosis of insulin  Others: amino acids, fatty acids and ketone bodies

2) Hormonal mechanism  Glucagon-like peptide 1 (GLP-1)  Glucose-dependent insulinotropic polypeptide (GIP)  Vasoactive intestinal peptide (VIP)  Pancreozymin-cholecystokinin

Stimulate Beta Cells Insulin

Inhibit Inhibit `` Stimulate Alpha Cells Delta (D) Cells

Glucagon Somatostatin Inhibit

3) Neural mechanism  Adrenergic α2  decreases insulin release  Cholinergic-muscarinic  stimulates insulin release

Chemical mechanism of insulin secretion

MECHANISM OF ACTION OF INSULIN Insulin binds to insulin receptor on alpha subunits ↓ Depolymerization (come close together) ↓ Phosphorylate tyrosine residues of insulin receptor substrate protein (IRS-1 & IRS-2) ↓ IRS molecules bind to and activate other kinases ↓ Generation of various second messengers ↓ Activation or inhibition of enzymes involved in metabolic action of insulin – rapid actions; Activation of transcription factors, proliferation and differentiation of specific cells – long term effects

ACTIONS OF INSULIN  Insulin has profound effect on metabolism of carbohydrates, fat and protein  Facilitates entry of glucose into all cells in the body except RBCs, WBCs, liver and brain  DNA-mediated synthesis of glucose transporter and enzyme of amino acid metabolism  Growth regulation

 Inhibits glycogenolysis  Gluconeogenesis Liver  Promotes glycogen synthesis  Lipogenesis  Decreases protein breakdown

 Stimulates glucose uptake and oxidation Adipose tissue  Promotes formation and storage of triglycerides  Inhibits lipolysis

 Increases protein synthesis  Stimulates glucose uptake Muscles  Glycogen synthesis  Glycolysis  Inhibits protein breakdown

SOURCES OF INSULIN  Bovine and porcine insulin  Conventional insulin preparation  Disadvantages: allergy, resistance  Highly purified insulin preparations  Single peak insulin  Monocomponent insulin  Human insulin: recombinant DNA technology

INSULIN PREPARATION

Rapid and  Insulin lispro Taken 0-5 minutes ultra-short  Insulin aspart before meal acting  Insulin glulisine

Taken 30 minutes before  Regular insulin (human insulin) Short acting meal  Prompt insulin suspension or semi Lente

 Insulin zinc suspension or Lente Intermediate Does not need to be  Neutral protamine hagedorn (NPH) – human acting given with meal insulin

 Extended insulin zinc suspension or Ultra Lente Does not need to be  Insulin glargine Long acting given with meal  Insulin etermir  Protamine zinc insulin (PZI)

CHARACTERISTIC FEATURES

 Soluble, crystalline zinc insulin (zinc is given for stability), short acting  Forms hexamer (hexameric in nature):  This leads to delayed onset because of slow absorption due to the large size  hence prolonged time to peak injection  Given through subcutaneous injection where they are diluted by interstitial fluid to form dimers, then monomers and then being absorbed (monomerization)  Subcutaneous injection  onset of 30-45 minutes, peak around 2-3 hours, duration of 5-8 hours Regular insulin  If administered at meal time  leads to early post-prandial hyperglycaemia and late postprandial hypoglycaemia  Because of delayed onset, it needs to be given 30-45 minutes before meal time  Can be administered by I.V. route  Advantages of I.V.: useful for diabetic ketoacidosis, after surgery and acute infections  Dose-dependent onset and duration of action, variability of absorption  hence mismatching of insulin supply with need may occur

 β-chain: proline (B28B29), lysine (B29B28)  Very low propensity to self-associate to form dimers  Stabilize into hexamers  After subcutaneous injection  it quickly dissociates into monomers Insulin lispro (hence rapidly absorbed)  Onset of 5-15 minutes, peak around 1 hour  Provides post-prandial insulin replacement  Less risk of post-prandial hypoglycaemia

 Onset of action is delayed by combining insulin and protamine  Onset of 2-5 hours, duration of 4-5 hours  Proteolytic tissue enzymes  degrade protamine  permit insulin NPH insulin absorption  Action is highly unpredictable  Variability of absorption

 Attachment of two arginine molecules to β-chain carboxyl terminal  Substitution of glycine for asparagine (A21)  Soluble in acidic medium  Subcutaneous injection  precipitates in body pH  insulin molecules Insulin glargine slowly dissolve away from the crystalline depot  low and continuous level  Should not be mixed with other insulin  Long acting, ‘peakless’ insulin  Action is maintained for 11-24 hours  provides basal insulin replacement  Administered once daily

 B30 threonine X: Myristic acid attached to B29 lysine  Increases self-aggregation and albumin binding Insulin determir  Dose-dependent onset of action of 1-2 hours and duration of action >24 hours  Administered twice daily to obtain a smooth background insulin level

 NPH + Lispro/Aspart/Glulisine insulin (acutely mixed) Mixture of  Premixed formulations: Neutral protamine lispro (NPL) + Lispro (50%/50%; insulin 75%/25%)  Neutral protamine aspart (NPA) + Aspart insulin

INSULIN TREATMENT REGIMEN  Post-prandial insulin requirement level control  Basal insulin requirement level control

Conventional insulin therapy  One injection/day to many injection/day  Intermediate or long acting insulin alone or with short or rapid acting insulin or pre-mixed insulin  Sliding-scale regiment  adjustable administration and usage of treatment depending on meal consumption  For basal requirement, we have long acting and short acting Long acting: once daily before breakfast Short acting: twice daily before morning and maybe before lunch  For post prandial controls, we have regular and rapid acting Regular acting: 30-45 minutes before meal Rapid acting: immediately after meal  30:70 mixture of regular and NPH insulin  Injected subcutaneously before breakfast and dinner  Insulin glargine once daily before breakfast or bedtime + 2-3 mealtime injections of rapid acting insulin (Lispro/Aspart insulin) Intensive insulin therapy  Total daily requirement of insulin is assessed by testing urine or blood glucose levels  Requirement varies in different patients  calculation has to be individualized  Half the total daily insulin dose covers basal insulin requirements  Remainder includes post-prandial and other high blood sugar corrections  Meal or snacks requirement is calculated by considering carbohydrates content of meal, current plasma glucose levels and target glucose level  High blood sugar correction formula  predicted fall in plasma glucose after 1U of rapid acting insulin (diurnal variation in insulin sensitivity can be considered)  Devices:  Continuous subcutaneous insulin infusion devices (CSII)  Insulin pumps  Portable pen injectors  Advantages:  Greater flexibility in diet  Provides round the clock euglycaemia  Reduces the occurrences and slows the progression of diabetic complications  Delays end organ damages

INSULIN DELIVERY SYSTEMS  Inhaled insulin  Implantable pumps  External artificial pancreas  Intra-peritoneal or oral insulin

COMPLICATIONS OF INSULIN THERAPY  Hypoglycaemia  Signs and symptoms: Autonomic symptoms Dizziness, headache and fatigue “Hypoglycaemic unawareness”  can lead to coma and death  Prevention: Diabetic cards and sugar supply  Treatments: Mild  oral glucose, Dextrose Severe  50 ml of 50% Dextrose I.V. Glucagon 0.5-1.0 mg subcutaneous/intramuscular injection  Local reactions: lipodystrophy, swelling and erythema  Allergy  Insulin resistance  Insulin requirement is increased to >100 U/day  Development of IgG anti-insulin antibodies

DRUG INTERACTION BETWEEN INSULIN & β-BLOCKERS  Delayed recovery from hypoglycaemia because the glycogenolysis is block (through β2 receptors)  Masking of warning signs of hypoglycaemia (through β1 receptors) ANTI-DIABETIC DRUGS

CLASSIFICATION  Sulfonylureas  First generation: Tolbutamide, Chlorpropramide  Second generation: Glibenclamid, Glipizide, Gliclazide, Glimepiride  Meglitinide analogues: Repaglinide, Nateglinide  D-phenylalanine derivatives: Nateglinide  Biguanides: Metformin, Phenformin  Thiazolidinedines: Rosiglitazone, Pioglitazone  Alpha glucosidase inhibitors: Acarbose, Miglitol, Vaglibose

SULFONYLUREAS

DRUGS  First generation: Tolbutamide, Chlorpropramide  Second generation: Glibenclamid, Glipizide, Gliclazide, Glimepiride

IMPORTANT FEATURES  Stimulates insulin release from pancreatic β-cells  Chronic administration  sensitize target tissue to the action of insulin, inhibit hepatic gluconeogenesis and decrease glucagon levels  Not effective in type 1 diabetes mellitus because there is no functioning β-cells  Glimepiride and Gliclazide have extra anti-oxidant action

MECHANISM OF ACTION Sulfonylurea binds to SUR1 ↓ Inhibits ATP sensitive K+ channels ↓ Depolarization of β-cells ↓ Stimulates voltage gated calcium channels ↓ Increase influx of Ca2+ ↓ Degranulation occurs and increase release of stored insulin from β-cells

ADVERSE EFFECTS  Hypoglycaemia  lower incidence with Glipizide, Gliclazide, Glimepiride  Hypersensitivity reaction  Weight gain  Nausea  Vomiting  Contraindicated in pregnancy  Chlorpropramide  cholecystatic jaundice, photosensitivity, haematologic toxicity, alcohol intolerance (hence not used anymore)

DRUG INTERACTIONS  Salicylates/Sulphonamides X Sulfonylureas  Displacement from plasma binding site  Warfarin/ X Sulfonylureas  Decrease metabolism of Sulfonylureas (increased toxicity)  Phenytoin/Rifampicin X Sulfonylureas  Enzyme induced (hence increased efficacy)  Propanolol X Sulfonylureas  Mask the effect of diabetes (autonomic response)  severe hypoglycaemia

MEGLITINIDE ANALOGUES

DRUGS Repaglinide, Nateglinide

MECHANISM OF ACTION Meglitinide analogue binds to SUR1 ↓ Inhibits ATP sensitive K+ channels ↓ Depolarization of β-cells ↓ Stimulates voltage gated calcium channels ↓ Increase influx of Ca2+ ↓ Degranulation occurs and increase release of stored insulin from β-cells

ROLE IN THE MANAGEMENT OF DIABETES MELLITUS  Rapid onset and shorter duration of action  Controls post-prandial hyperglycaemia  Lower risk of serious hypoglycaemia  Used in type 2 diabetes mellitus alone or in combination with other anti-diabetics

BIGUANIDES

DRUGS Metformin, Phenformin

MECHANISM OF ACTION  Suppress hepatic gluconeogenesis  Promote peripheral uptake and utilization of glucose  reduce insulin resistance  Retard intestinal absorption of glucose  Promote insulin binding to its receptor

THERAPEUTIC USES OF METFORMIN  Anorectic action  Treat hirsutism  Enhances infertility in patients with polycystic ovarian syndrome (PCOS)

ADVERSE EFFECTS  Gastrointestinal adverse effects: metallic taste, anorexia, nausea  Lactic acidosis  Vitamin B12 deficiency  Rarely causes hypoglycaemia

CONTRAINDICATIONS  Peripheral neuritis  Renal and hepatic diseases  Asthma  Chronic obstructive pulmonary disease (COPD)  Congestive heart failure  Alcoholics

THIAZOLIDINEDIONES

DRUGS Rosiglitazone, Pioglitazone

MECHANISM OF ACTION  Activate peroxisome proliferators activated receptor gamma (PPAR-γ)  Hence promote transcription of insulin responsive genes

ROLE IN DIABETES MELLITUS  Increase insulin sensitivity and reverse insulin resistance  Increase the number of GLUT-4 receptor  hence promote peripheral glucose uptake and utilization  Suppress hepatic gluconeogenesis  Reduce HbA1C level  Increase HDL cholesterol level  Decrease triacylglycerol level

* Use in combination with Sulmetformin

ADVERSE EFFECTS  Plasma volume expanders  Can lead to oedema and weight gain  Hepatic dysfunction  Glitazones + Insulin  precipitation of congestive heart failure

α-GLUCOSIDASE INHIBITORS

MECHANISM OF ACTION  Competitive inhibitors of α-glucosidase and α-amylase  Decrease digestion and absorption of polysaccharide  Used as an adjuvant

ADVERSE EFFECTS  Hypokalaemia  Gastrointestinal adverse effects

CONTRAINDICATIONS  Intestinal bowel disease  Intestinal obstruction

OTHERS

MECHANISM OF ACTION

 Drug: Exenatide (synthetic GLP-1)  Stimulate insulin secretion Incretin mimetics  Decrease glucagon release  Slow gastric emptying  decrease nutrient absorption  Decrease appetite (acting on hypothalamus)

 Drugs: Sitaglipin, Vildaglipin Dipeptidyl peptidase-4  Inhibit dipeptidyl peptidase-4 inhibitors  Hence, prevent degradation of GLP-1 and other Incretins  prolonging their action

 Drug: Pramlintide (synthetic amylin analogue)  Anorectic action Amylin mimetics  Inhibit glucagon secretion  Delay gastric emptying  Reduce post-prandial hyperglycaemia

Sodium-glucose co-  Drugs: Dapaglifozin, Serglifozin transporter-2  Decrease the amount of glucose reabsorption from the proximal inhibitors convoluted tubule and increase its urinary excretion

ROLE IN DIABETES MELLITUS  Incretin mimetics  reduce post-prandial hyperglycaemia  Dipeptidyl peptidase-4 inhibitors  adjuvant in type 2 diabetes mellitus  Amylin mimetics  adjuvant in type 1 and type 2 diabetes mellitus

ADRENOCORTICAL STEROIDS & THEIR ANALOGUES

CLASSIFICATION OF GLUCOCORTICOIDS  Short acting (8-12 hours): , Cortisone  Intermediate acting (12-36 hours): Prednisone, Prednisolone, Methylprednisolone, Triamcinolone  Long acting (36-72 hours): Betamethasone, Dexamethasone

MINERALOCORTICOIDS  Fludrocortisone  DOCA (Deoxycorticosterone acetate)

COMPARING RELATIVE GLUCOCORTCOIDS & MINERALOCORTICOIDS ACTIVITY a) Hydrocortisone  Glucocorticoids : Mineralocorticoids = 1 : 1 (equal action)  Rapid acting and short duration of action  Used in acute adrenal insufficiency b) Prednisolone  More potent and more selective Glucocorticoids actions  Glucocorticoids : Mineralocorticoids = 5 : 0.8  Intermediate duration of action c) Dexamethasone  Very potent and highly Glucocorticoids  Glucocorticoids : Mineralocorticoids = 30 : 0)  Long acting  No fluid retention due to no Mineralocorticoids activity

MECHANISM OF ACTION OF CORTICOSTEROIDS AT CELLULAR LEVEL

Glucocorticoids ↓ Bind to cytotoxic glucocorticoids receptor ↓ Steroid-receptor complex translocate to nucleus ↓ Bind to the GRE on regulatory region of genes ↓ Transcription of specific mRNA ↓ Regulation of protein synthesis ↓ Hormonal response

IMPORTANT PHARMACOKINETIC FEATURES OF CORTICOSTEROIDES  All steroids except DOCA are absorbed orally  Glucocorticoids can also be given I.V., I.M. or topically  Cortisol has high first pass metabolism  90% are bound to the plasma proteins  Corticosteroids are metabolized by hepatic microsomal enzymes and excreted in urine

ADMINISTRATION OF STEROIDS  Inhaled steroids: Beclomethasone, Budesonide  Eye drops: Prednisolone, Dexamethasone  Dermatological preparations: Prednisolone, Triamcinolone  I.V/. I.M. injections: Hydrocortisone, Prednisolone, Methylprednisolone  Intra-articular injection: Hydrocortisone acetate, Prednisolone acetate, Triamcinolone, Dexamethasone acetate

PHARMACOLOGICAL ACTIONS OF CORTICOSTEROIDS

Carbohydrates and  Decrease peripheral utilization of glucose protein metabolism  Promote gluconeogenesis  Promote glycogen deposition on the liver  Enhance protein breakdown and mobilization of amino acids from peripheral tissue (muscle, connective tissue and skin)  Increase blood glucose level and diabetes-like state, worsen the already pre-existing diabetic state  Protein wasting

Fat metabolism  Permissive action on lypolytic effects of Growth hormone, Adrenaline and Thyroxine  Redistribution of body fat from the peripheral stores to the central locations of the body (back of neck, shoulders, abdomen and face)

Calcium metabolism  Decrease Ca2+ uptake from the gut and electrolyte balance  Increase Ca2+ ion excretion through kidney  Cause fluid retention (Na+ ion and water reabsorption)  Promote K+ ion excretion

Cardiovascular system  Directly stimulate cardiac output  Permissive role  pressor effects of Adrenaline and Angiotensin-II  Cautiously used in hypertensive

Blood cells  Decrease circulating lymphocytes, eosinophils and basophils  Increase RBC, platelets and neutrophils in circulation

Anti-inflammatory  Suppress early components of inflammation (oedema, pain, hat, fibrin effect deposition) and late components of inflammation (collagen synthesis, wound healing)  Induce production of lipocortin

Arachidonic acid Glucocorticoids

Stimulates production

Phospholipase A2 Lipocortin Inhibit

Prostaglandins, Leukotrienes, Plasma activating factor

 Lipocotin blocks production and release of inflammatory cytokines (IL- 1, IL-6, TNF-α)  Suppress fibroblast proliferation  Impair recruitment of leucocytes at the site of inflammation  Reduce the number of lymphocytes (T cells and B cells)  Decrease IgE-dependent release of histamine leukotrienes from basophils  reduced capillary permeability

Immune response  Suppress cell-mediated immunity (delayed hypersensitivity, graft rejection)  Inhibit genes that codes for the cytokines  IL-1 to IL-6 (most important being IL-2), and IFN-gamma  reduces T-cell proliferation  Interfere with the function of complement and NK-cells  Suppress humoral immunity

THERAPEUTIC USES OF CORTICOSTEROIDS A) Endocrine Diseases 1. As replacement therapy a) Acute adrenal insufficiency (Addisonian crisis):  Symptoms: dehydration, weakness, lethargy, hyponatremia, hyperkalaemia, severe hypertension  Using Hydrocortisone I.V. along with adequate maintenance of fluid and electrolyte balance b) Chronic adrenal insufficiency  Hydrocortisone orally  May be supplemented with Fludrocortisone c) Congenital adrenal hyperplasia  Genetic deficiency of 21-β-hydroxylase enzyme which is involved in glucocorticoids precursor conversion to cortisol (cortisol production)  Leads to a shift to androgenic pathway which leads to excess of androgen  lead to masculinization  Treatment involve Hydrocortisone orally

2. As diagnosis for Cushing’s syndrome

Dexamethasone suppression test

Normal suppression of cortisol Failure of suppression of cortisol production after administration of production after administration of Dexamethasone due to negative Dexamethasone due to feedback mechanism hypersecretion of ACTH or Cortisol

HPA axis is intact Pituitary or adrenal tumours

B) Non-Endocrine Diseases 1. Anti-inflammatory therapy:  Rheumatoid arthritis  Osteoarthritis  Acute gouty arthritis  Ulcerative colitis  Crown’s disease  Allergic conjunctivitis  Iridocyclitis  Eczematous skin lesions

2. Bronchial asthma  Inhaled or systemic glucocorticoids  Fluticasone, Beclomethasone  Moderate to severe asthma

3. Severe allergic reactions  Anaphylactic shock + adrenaline + asthma  Angioneurotic oedema  Chronic urticarial  Hay fever

4. Immunosuppressive therapy  Collagen vascular disease: systemic lupus erythematosus, polyarthritis nodosa, sarcoidosis  Skin grafts and organ transplant  Nephrotic syndrome  Prednisolone  Haemolytic anaemia  Idiopathic thrombocytopenic purpura  Myasthenia gravis  Autoimmune disease  Chronic demyeliting polyneuropathies

5. Stimulation of lung maturation of foetus  Glucocorticoids  given to mother to speed up preterm foetus lung development  Preferred drug is Betamethasone because of less placental metabolism and less maternal binding protein

6. Infective diseases  Pneumocystis jirovecii pneumonia  MAC (mycobacterium avium complex) infection  used only as an adjuvant drug to decrease the inflammatory reaction

7. Malignancies  Leukaemia  Hodgkin’s and other lymphomas

8. Cerebral oedema  Dexamethasone or Betamethasone

ADVERSE EFFECTS OF CORTICOSTEROIDS  Cushing’s syndrome  Fragile skin  Hirsutism  Acne  Myopathy and muscle wasting  Hyperglycaemia and a diabetic-like state (glycosuria)  Susceptibility to infections:  Latent TB reactivation due to immunosuppressant activity  Delay wound healing due to decreased collagen synthesis  Peptic ulcers:  Due to decreased prostaglandin production  Due to increased gastrin and pepsin perforation and bleeding  Ocular effects: cataract, glaucoma  Osteoporosis and osteonecrosis due to Ca2+ resorption, decreased absorption and decreased formation  Growth retardation is seen in children  Foetal abnormalities: intrauterine growth retardation, gestational diabetes, pre-eclampsia  CNS side effects: euphoria, manic depressive, psychosis, insomnia, nervousness

EFFECT OF LONG TERM STEROID THERAPY ON HPA AXIS  Suppression of HPA axis  Abduction withdrawal causes flare up of the underlying disease  Precipitate withdrawal syndrome: fever, arthralgia, malaise, anorexia, myalgia  Subjected to stress  acute adrenal insufficiency (severe hypotension, shock, coma, death)

MEASURES TO MINIMIZE HPA AXIS SUPPRESSION  Gradual withdrawal of steroids  Use shorter acting steroids for shorter period of time  Alternate day of therapy  2/3rd of the dose in the morning and another 1/3rd in the evening to mimic the normal secretion of cortisol  Local preparation is used whenever possible

CONTRAINDICATIONS OF GLUCOCORTICOIDS  Peptic ulcers  Osteoporosis  Hypertension  Epilepsy  Diabetes mellitus  Herpes simplex keratitis  mask the evidence of disease progression  Irreversible loss of vision and cloudiness of cornea (corneal opacity)

OESTROGENS

CLASSIFICATION  Natural steroidal oestrogens: Estradiol benzoate, Estradiol crypionate, Estradiol enanthate, Estradiol valarate  Synthetic steroidal oestrogens: Ethinyl estradiol, Mestranol, Quinesterol,  Synthetic non-steroidal oestrogens: Diethylstilbesterol (Stilboesterol), Dienesterol, Chlorotrianisene, Methallenestril  Conjugated oestrogens: Sodium estrone sulfate, Sodium equiline sulfate

PRINCIPAL ACTIONS

 Fallopian tubes, uterus and vagina  pubertal growth and development & thickening and cornification of vaginal epithelium Sex organs  Mammary glands  pubertal growth & proliferation of ducts and stroma  Uterine endometrium  proliferation  Cervix  watery secretion to facilitate sperm penetration  Growth of hair as per female pattern (axillary, pubic) Secondary sex  Distribution of fat as per female contours characteristics  Pigmentation of nipples and genital organs  Anabolic effect  Weak diabetogenic action, glucose intolerance Metabolism  Maintain bone mass and decrease bone resorption by antagonizing osteoclastogenic effects of PTH and IL-6

MECHANISM OF ACTION  Oestrogens bind strongly to sex hormone binding globulin (SHBG) – 90%  Free oestrogens enter cells and bind to 2 types of oestrogen receptors  ER-α: uterus, vagina, breast, hypothalamus, pituitary, blood vessels  ER-β: prostate gland  Sequence of events: Oestrogen binds to oestrogen receptor (ER) ↓ Release ER from stabilizing proteins (heat shock proteins or Hsp90) ↓ Receptor-hormone complex binds oestrogen response elements in the nucleus ↓ Transcription and translation of mRNA ↓ Protein synthesis  Non-genomic effects: rapid stimulation of endothelial nitric oxide synthase (eNOS) to provide vasodilatation and cardioprotective effects  Oestrogens stimulate progesterone receptor (PR) synthesis & potentiate target tissue responses due to progesterone ADVANTAGES OF TRANSDERMAL ESTRADIOL OVER ORAL OESTROGENS  Beneficial effects of transdermal Estradiol on menopausal symptoms, bone density, vaginal epithelium and plasma gonadotropin level  However, serum lipid profile is less marked  Milder systemic side effects  Avoid high hepatic delivery  plasma levels of TBG, CBG, angiotensinogen and clotting factors are not elevated  hence risk of thromboembolic phenomena may not increase

BENEFITS OF HORMONE REPLACEMENT THERAPY (HRT)  Menopausal symptoms and atrophic changes (primary indication)  Prompt and complete response of vasomotor symptoms  Improves general physical, mental and sexual well being  Genital and dermal atrophic changes arrested  Solves vulvar and urinary problems  Relieves local symptoms  Osteoporosis and fracture  Restores Ca2+ balance  Prevents further bone loss and excess fracture risk  CVS events  Ostrogen improves HDL:LDL ratio  Retards atherogenesis  Reduces arterial impedance  Increases NO and PGI2  Prevents hyperinsulinaemia  reduces hypertension, cardiovascular diseases, coronary artery disease, myocardial infarction, stroke  Cancer  protective effect on colorectal carcinoma

RISKS OF HORMONE REPLACEMENT THERAPY (HRT)  CVS events  Progestin  in older women with pre-existing cardiovascular diseases, increased risk of venous thromboembolism and myocardial infarction  No secondary prophylaxis of coronary artery disease in long term  Cognitive function and dementia  Cause slight deterioration  Incidence of dementia doubled  Cancer  Oestrogens enhance growth of breast cancer  Induce endometrial hyperplasia  Progestin  irregular uterine bleeding  Long term: endometrial carcinoma  Oestrogen  slight increased risk of gallstones  Migraine  progestin triggers migraine

CURRENT STATUS OF HRT  Main indication of HRT: vasomotor and other symptoms in peri-menopausal period  Young women + premature menopause deserve HRT  Hysterectomized women have oestrogen alone; while with intact uterus, oestrogen and progestin are given  Peri-menopausal women are given cyclical HRT rather than continuous HRT  HRT is not the best option to prevent osteoporosis and fractures  HRT affords no protection against CVD, conventional dose combined HRT may even increase risk of venous thromboembolism, myocardial infarction and stroke  HRT does not protect against cognitive decline; may increase the risk of dementia  Combined HRT increases risk of breast cancer, gall stones and migraine  Used at smallest effective dose and shortest duration  Transdermal HRT may have certain advantages over oral HRT  The need for HRT should be assessed in individual women and not prescribed routinely

DOSAGE OF OESTROGEN IN HRT  Lower than in contraception  Conjugated oestrogen: 0.625 mg/day/cyclically (3 weeks treatment with 1 week gap) or continuously  Lower dose: 0.3-0.45 mg/day  Progestin 2.5 mg/day is added for 10-12 days for each month

ROLE OF PROGESTIN IN HRT  Attenuates metabolic and CVS benefits of oestrogen  Blocks increased risk of dysfunctional uterine bleeding and endometrial carcinoma by oestrogen stimulation on endometrium

OTHER THERAPEUTIC USES OF OESTROGENS  Post-menopausal hormone replacement therapy (ERT)  ERT in primary ovarian failure  Primary ovarian failure due to ovarian dysgenesis or hypopituitarism  Oestrogen in cyclical pattern given  Progesterone is added during last week of every month to induce menstrual bleeding when puberty develops  Dysfunctional uterine bleeding  Due to chronic anovulatory cycles (disruption of follicular and luteal phase)  Progestin is given cyclically to stop bleeding  Oestrogen as an adjuvant  Dysmenorrhoea  Menstrual bleeding with discomfort and pain  First line drugs: NSAIDs  Cyclical oestrogen therapy (with progestin) provides benefits  Acne and hirsutism  Cyclical oestrogen (with progestin) suppress ovarian production of androgens by inhibiting gonadotropin release from pituitary  Not a suitable treatment for boys  Rarely used nowadays  Carcinoma of prostate  Use of oestrogen is outdated  GnRH agonists with/without androgen antagonist is preferred

ADVERSE EFFECTS OF OESTROGENS  Males:  Gynaecomastia  Feminization  Decrease libido  Females:  Breast tenderness, migraine, headache, nausea  Withdrawal bleeding, amenorrhoea, endometrial hyperplasia  Risk of breast cancer, increased incidence of vaginal and cervical adenocarcinoma in female offspring  Both sexes:  Gall stones and gall bladder disease  Hepatic dysfunction  Predisposition to thromboembolic disorders  Precipitation of diabetes and fluid retention

SELECTIVE OESTROGEN RECEPTOR MODULATORS (SERMs)

INTRODUCTION  SERMs are non-steroidal synthetic agents whose agonist or antagonist activities on oestrogen receptor (ER) are tissue selective  Examples: Clomiphene, Tamoxifen, Doloxifen, Toremifen, Fulvestrant, Raloxifene, Ormeloxifen

CLOMIPHENE CITRATE

ROLE IN INFERTILITY  Clomiphene is an orally active SERM with both agonist and antagonist properties  Mechanism of action: Acts as a competitive antagonist of ER in hypothalamus ↓ Fails oestrogen’s negative feedback effects on GnRH release ↓ ↑ GnRH release ↓ ↑ FSH and LH secretion ↓ Facilitates ovulation (treat infertility due to anovulation)  Not used in primary ovarian or pituitary failure  Also used to treat male infertility due to oligozoospermia  increased gonadotropin secretion promotes testosterone secretion and spermatogenesis

TAMOXIFEN

THERAPEUTIC USES  ER antagonist in breast cells, blood vessels and some peripheral sites  ER agonist in uterus, bone, liver and pituitary  Used to treat breast carcinoma (pre- and post-menopausal women)  It up-regulates TGF-β (down-regulation of TGF-β associated with progression of malignancy)  Prevents post-menopausal osteoporosis and improves bone density  Up-regulation of TGF-β (this cytokine keeps a balance between osteoblast and osteoclast)  Improvement of lipid profile, thus lowering coronary artery disease risk (ER agonist actions on liver)

ADVERSE EFFECTS  Increased risk of endometrial cancer and deep vein thrombosis  due to ER agonist effects on uterus and blood coagulation factors  Hot flushes, vomiting, menstrual irregularities  Anorexia, mild leucopenia, mild ocular effects

RALOXIFENE

THERAPEUTIC USES  Anti-oestrogenic effects on breast and endometrial tissue  Oestrogenic effects on bone, lipid metabolism and blood coagulation  Treatment and prevention of osteoporosis in post-menopausal women  Maintains favorable lipid profile  Reduces risk of breast cancer (in ER positive)

ADVERSE EFFECTS  Hot flushes  Leg cramps  Increased risk of deep vein thrombosis and pulmonary embolism  due to oestrogenic effect on blood coagulation  No risks of endometrial carcinoma (does not stimulate endometrial proliferation)  Does not relieve menopausal hot flushes

FULVESTRANT

THERAPEUTIC USES  Pure anti-oestrogen  Treats Tamoxifen-resistant breast cancer  Down regulates ER by promoting degradation of ER by proteasomal enzymes

AROMATASE INHIBITORS

CLASSIFICATION  Aminoglutethimide  Non-steroidal agent: Anastrozole, Letrozole, Fadrozole, Vorozole  Selective steroidal: ,

MECHANISM OF ACTION  Aromatase inhibitors stop the production of oestrogen in post-menopausal women  They work by blocking the enzyme aromatase, which turns the hormone androgen into small amounts of oestrogen in the body  This means that less oestrogen is available to stimulate the growth of hormone-receptor- positive breast cancer cells  Aromatase inhibitors can't stop the ovaries from making oestrogen, so aromatase inhibitors only work in post-menopausal women

THERAPEUTIC USES  “ER expressing breast carcinoma” which is resistant to Tamoxifen  Adjunct to androgen antagonist in precocious (premature) puberty  Excessive aromatase syndrome

PROGESTINS

CLASSIFICATION

 Hydroxyprogesterone acetate (I.M.)  Medroxyprogesterone acetate (I.M./oral)  (oral) Progesterone analogues  Dihydrogesterone (oral)  Nomegestrol (oral)  Micronized natural progesterone

 Norethindrone ()  Norethynodrel 19-nortestosterone  (Ethinyl estrenol) Oral derivatives 

Newer 19-  nortestosterone  Norgestimate Oral derivatives 

PRINCIPAL ACTIONS

 Fallopian tubes, uterus and vagina  inhibition of uterine contraction; growth and development  Uterine endometrium  induce secretory phase in oestrogen- primed endometrium Sex organs  Mammary glands  development of alveo-lobular secretory system of breast for lactation  Cervix  viscous, scanty mucous secretion as a barrier to sperm penetration  Body temperature  thermogenic  ↑ basal insulin level and insulin response to glucose  ↑ fat deposition and appetite Metabolism  ↓ HDL & ↑ LDL  Stimulates respiration  Catabolic actions

MECHANISM OF ACTION  89% progesterone bound to corticosteroid binding globulin and serum albumin  Free progesterone enters cell and binds to progesterone receptors (PR-α and PR-β)  Sequence of events: Progesterone binds to PR ↓ Release PR from stabilizing proteins (heat shock proteins or Hsp90) proteins ↓ Receptor-hormone complex binds progesterone response elements (in the nucleus) ↓ Transcription and translation of mRNA ↓ Protein synthesis  Progesterone inhibits synthesis of ER to limit tissue response to oestrogen

THERAPEUTIC USES  Hormone replacement therapy (HRT)  Dysfunctional uterine bleeding  Endometriosis  Inoperable endometrial carcinoma  Treat pre-menstrual tension  Diagnosis for oestrogen secretion and endometrial responsiveness  Treat premature labour and infertility

ADVERSE EFFECTS  Breast engorgement  Rise in body temperature  Headache  Fluid retention  Depression and irritability  Acne  Weight gain  Decreased libido  Irregular menstrual cycle and breakthrough bleeding  Increased risk of thromboembolism  19-nortestosterone derivatives ↓ HDL  exhibit atherogenicity

ANTI-PROGESTINS

DRUGS Mifepristone, Onapristone, Gestinone

THERAPEUTIC USES  Termination of pregnancy  Block progesterone support to endometrium  endometrial shedding  Release prostaglandin  induce uterine contraction  Progesterone secretion decrease  cervix softened  favorable condition for abortion  As contraceptive  Emergency contraception  Also taken 2 days after mid-cycle to prevent conception  For softening of cervix  softening and dilation of cervix prior to surgical abortion  For induction of labour  induction of labour following intrauterine foetal death  Endometriosis  Uterine fibroids (leiomyomas)  For progesterone-dependent brain neoplasm (meningioma)  For progesterone-dependent breast cancer  Cushing’s syndrome  anti-androgenic and anti-glucocorticoid activities

ADVERSE EFFECTS  Failed abortion  Prolonged bleeding (which stops spontaneously)  Abdominal cramps  Vomiting  Diarrhoea  Anorexia

SELECTIVE PROGESTERONE RECEPTOR MODULATORS (SPRMs)

DRUGS Ulipristal acetate, Asoprisnil, Proellex (CDB-4124)

THERAPEUTIC USES  Emergency contraception (Ulipristal)  Uterine leiomyoma  Endometriosis Asoprisnil and Proellex  Fibroid tumours  Breast cancer

CONTRACEPTIVES

ORAL CONTRACEPTIVES

CLASSIFICATION  Combination pills (oestrogen + progestin)  Ethinyl estradiol (30 μg) + Norgestrel (30 μg)  Ethinyl estradiol (30 μg) + Levonorgestrel (150 μg)  Ethinyl estradiol (50 μg) + Norgestrel (0.5 mg)  Mestranol (50 μg) + Norethindrone (1 mg)  Ethinyl estradiol (30 μg) + Desogestrel (150 μg)  Mini pills (progestin-only pills):  Norethindrone (350 μg)  Norgestrel (75 μg)  Post-coital (after morning) pills:  Levonorgestrel  Ethyl estradiol  Levonorgestrel  Mifepristone  Ulipristal (SPRM)  Centchroman: Non-hormonal oestrogen receptor antagonist

REGIMEN OF COMBINED PILLS USED FOR CONTRACEPTION  Tablet Levonorgestrel 0.25 mg + Ethinyl estradiol 50 μg  Dispense 63 tablets  Take one tablet daily for 21 days, starting on 5th day of menstruation  Next course to be started after a gap of 7 days  Review after 3 months

PHASE REGIMEN  Advantages:  Triphasic regimen permits reduction of total steroids without compromising efficacy by mimicking normal hormonal pattern in menstrual cycle  Recommended for women: >35 years No withdrawal or breakthrough bleeding while on monophasic pill When other risk factors are present  Higher efficacy (98-99.9%)  Disadvantages:  No withdrawal or breakthrough bleeding while on monophasic pill

MINI PILLS  Advantages:  Eliminate oestrogen and its associated long term risks  Alternative for women contraindicated to oestrogen  Disadvantages:  Irregular menstrual cycle  Ovulation in 20-30%  Lower efficacy (96-98%)

REGIMENS USED IN POST-COITAL CONTRACEPTION 1) 2 tablets of progestin Levonorgestrel (0.75 mg each) First tablet taken as soon as possible (within 48 hours of coitus) Second tablet taken after 12 hours 2) Single tablet progestin Levonorgestrel (1.5 mg) taken once within 48 hours of coitus 3) Ethinyl estradiol (50 μg each) + Levonorgestrel (250 μg each) Take two tablets each within 72 hours of coitus Next two tablets after 12 hours 4) Mifepristone (600 mg) single dose  taken within 72 hours of coitus 5) Ulipristal (SPRM)  single dose 30 mg taken within 5 days

INJECTABLE CONTRACEPTIVES

PREPARATIONS  Depot medroxyprogesterone acetate  DMPA  Depot Provera  Combined oestrogen-progestin injectable contraceptives  Estradiol valerate + 17-hydroxy progesterone caproate  Estradiol crypionate + DMPA

ADVANTAGES  No need for daily ingestion of pills (as it is long acting)  Highly effective (I.M. as only solution)  Useful in patient where complications is a problem, heavy menstrual bleeding and ostrogen contraindicated (eg. migraine, thromboembolism, edema, hypertension, diabetes mellitus)  Provide single defined and predictable bleeding every month (combined oestrogen + progesterone)

DISADVANTAGES  Complete disruption of menstrual bleeding pattern or total amenorrhoea (more common with DMPA)  Not suitable for adolescent girls and lactating mothers  DMPA is restricted to women who unlikely to use others effectively

HORMONAL DRUG DELIVERY SYSTEMS USED FOR CONTRACEPTION 1. Oral 2. Injectable depot 3. Norplants (subcutaneous implants) 4. Intrauterine inserts

HORMONAL CONTRACEPTIVES

MECHANISM OF ACTION  Inhibition of gonadotropin release from pituitary by reinforcement of normal feedback inhibition  Progestin ↓ frequency of LH secretory pulse  Oestrogen ↓ FSH secretion Inhibit LH surge  no ovulation  Minipill and progestin-only injectable attenuate LH surge but less consistently  irregular ovulation  Thicken cervical mucus secretion  hostile sperm penetration due to progestin action (all methods except post-coital pill)  Hyperproliferation, hypersecretory or atrophic endometrium  unsuitable for implantation (especially mini pills and post-coital pill)  Uterine and tubal contractions  disfavour fertilization  Dislodge a just implanted blastocyst or interfere with fertilization or implantation

HEALTH BENEFITS  Oestrogen-progesterone pill reduces risk of functional ovarian cysts, ovarian cancer, endometrial cancer, fibrocystic breast disease and bleeding uterine fibroids  More regular menses, with reduced blood loss, less premenstrual tension and dysmenorrhoea  Lower incidence of ectopic pregnancy, endometriosis and pelvic inflammatory disease  Iron deficiency anaemia and rheumatoid arthritis (less common)  Combined pills with newer progestins (Desogestrel)  lack androgenic side effects, hence safer for women suffering from weight gain, acne, hirsutism or ↑ LDL  Combined pill (oestrogen + anti-androgen acetate) is useful to treating acne and hirsutism

ADVERSE EFFECTS

Mild adverse effects (withdrawal is not needed)  Oestrogenic effects:  Nausea and migraine  Breast tenderness  Mild oedema  Withdrawal bleeding  Progestogenic effects:  Increased appetite and weight gain  Acne and mild hirsutism  Decreased libido  Increased body temperature

Moderate (warrant discontinuation)  Oestrogenic effect:  Vertigo  Leg and uterine cramps  Precipitation of diabetes  Progestogenic effect:  Breakthrough (spotting) bleeding  Monilial vaginitis (urethral dilatation and bacteriuria)  Amenorrhea (even after stoppage)

Serious (needs stoppage of the drug)  Oestrogenic effects (mainly):  Thromboembolism  Cholecystic jaundice and cholelithiasis  Hepatic adenoma  Higher progestin content:  Risk for MI and cerebrothrombosis  Risk for cancer (controversial)

CONTRAINDICATIONS  Pregnancy (risk of congenital limb deformities)  Genital carcinoma  Masculinization of female and cryptorchism in male offspring  Thromboembolic disorder  Hepatic, renal and gall bladder diseases  Breast carcinoma  Undiagnosed vaginal bleeding  Diabetes mellitus  Obesity  Hypertension  Porphyria  Epilepsy (oral contraceptives decrease seizure threshold) DRUG INTERACTIONS OF OCPS THAT MAY LEAD TO CONTRACEPTIVE FAILURE a) Enzyme inducers  Increase metabolism of oestrogenic and progestational components  Drugs: Phenytoin, Phenobarbitone, Primidone, Carbamazepine, Rifampicin, Itonavir b) Suppression of intestinal microflora  Deconjugation of oestrogen excreted in bile fails  Enterohepatic circulation interrupted  Blood level falls  Drugs: Tetracyclines, Ampicillin

MECHANISM OF ACTION OF CENTCHROMAN  It is a non-steroidal oestrogen antagonist or selective oestrogen receptor modulators (SERMs)  Potent competitive antagonist at peripheral oestrogen receptors & suppress proliferative stage of endometrium  Accelerates ovum transport without affecting ovulation

DRUGS USED AS MALE CONTRACEPTIVES  Testosterone undecanoate  Testosterone undecanoate + depot Medroxyprogesterone acetate (DMPA)  Gossypol

ANDROGENS & DRUG TREATMENT OF ERECTILE DYSFUNCTION

ANDROGENS

CLASSIFICATION  Natural androgens: Testosterone, Dihydrotestosterone, Dehydroepiandosterone,  Synthetic androgens: , , Testosterone undeconoate,

PRINCIPAL ACTION

 Sexual differentiation in foetus  Penile and scrotal growth in male child Male reproductive system  Growth of prostate and seminal vesicle  Spermatogenesis  Maintenance of sexual function in men  Govern changes in puberty  Appearance of pubic, axillary and beard hair Secondary sexual  Male pattern baldness characteristics  Growth of larynx and thickening of vocal cords  Masculinity  Feedback control of LH and FSH Central nervous system  Increase libido  Aggressiveness  Increase protein synthesis and decrease excretion of nitrogen  Decrease protein breakdown Anabolic action  Na+ ion and water retention  Increase bone density, muscle mass and haeme synthesis  Increase liver synthesis of clotting factor, triglyceride lipase, α1-antitrypsin and haptoglobin Metabolic effect  Decrease HDL  Accelerate erythropoiesis  Increase linear skeletal growth Bones  Closure of epiphysis  Increase bone density Skin  Increase activity of sebaceous gland (thicker and oilier skin)  Hirsutism  Deepening of voice  Frontal baldness Female  Enlargement of clitoris  Prominent musculature  Suppression of ovulation and irregular menstruation

MECHANISM OF ACTION  Androgen bound to two major proteins: albumin (40%) and sex hormone binding gamma globulin (58%)  2% are unbound or free, which is active and available for interaction with peripheral target cells  It binds to intracellular androgen receptor, initiating a series of events of DNA transcription and modification of protein synthesis leading to spermatogenesis, sexual differentiation, sexual maturation at puberty, external virilisation and gonadotropin regulation  Androgen-receptor complex binds to DNA response element which cause multiple coactivator proteins recruited resulting in transcription of mRNA for tissue specific protein synthesis

THERAPEUTIC USES

Therapeutic uses Explanation

1. Testicular failure Either primary (in children) or secondary (later in life) 2. Hypopituitarism Hypogonadism is a feature of hypopituitarism 3. AIDS-related muscle Improve weakness and muscle wasting wasting 4. Hereditary angioneuretic Increase synthesis of complement (C1) esterase inhibitor oedema 5. Ageing Improve bone mineralization and muscle mass

ADVERSE EFFECTS  Virilisation, masculinization, hirsutism and frontal baldness of female  Shrunken breast and deepening of voice seen in female  Clitoral hypertrophy and menstrual irregularity  Acne  Sustained and painful erection  Oligozoospermia and infertility (decreased testosterone production)  Precocious puberty  Shortening of stature  Oedema  Cholestatic jaundice  Hepatic carcinoma and cirrhosis  Gynaecomastia (conversion of testosterone to oestrogen)  Lowering of HDL and increase in LDL  Pseudohermaphroditism in genetically female foetus  Prostatic neoplasm in elderly

ANABOLIC STEROIDS

DRUGS   Methandienone

THERAPEUTIC USES

Therapeutic uses Explanation

1. Catabolic states (acute Reduce nitrogen loss over short periods illness, severe trauma, major Transient effect in elderly, under-nourished, debilitated surgery) person 2. Renal insufficiency Reduce production thus reduce frequency of dialysis treatment 3. Osteoporosis In elderly male who is immobilized 4. Suboptimal growth in boys Brief spurts in linear growth 5. Hypoplastic, haemolytic and Increased RBC count and hemoglobin % malignancy associated anaemia 6. Enhance physical ability in Transient increase strength of exercised muscle athletes

ADVERSE EFFECTS  Same as Androgens  Sport abuse:

Men Women Both

 Testicular atrophy  Inhibition of ovulation  Cholestatic jaundice  Sterility  Hirsutism  Worsen lipid profile  Gynaecomastia  Frontal alopecia  Acne  Deepening of voice  Increase aggressiveness  Psychotic symptoms  Increased risk of coronary artery disease

DANAZOL

MECHANISM OF ACTION  Suppress gonadotropin release from pituitary gland in both sexes  Inhibition of testicular and ovarian function  Mild androgenic, anabolic and progestational activity

THERAPEUTIC USES  Treatment of endometriosis, fibrocystic disease of breast and premenstrual tension syndrome  Prevents attack of hereditary angioneurotic oedema  Treat infertility in women  Prevent bleeding episodes in haemophilics

ADVERSE EFFECTS  Hot flushes  Loss of libido  Muscle cramps  Amenorrhoea

FLUTAMIDE

ROLE OF FLUTAMIDE IN TREATMENT OF PROSTATIC CANCER  Non-steroidal androgen receptor antagonist  Active metabolite 20- inhibits testosterone and DHT binding to androgen receptor  Blocks androgen action on accessory sex organ as well as pituitary gland  Use for treatment of prostatic carcinoma, hirsutism and frontal baldness  Cause hepatotoxicity and mild gynaecomastia

BICALUTAMIDE

ROLE OF BICALUTAMIDE IN TREATMENT OF PROSTATIC CANCER  Newer potent orally active androgen receptor antagonist  Administered as single dose  Used along with GnRH agonist or castration  Marked relief in bone pain and other symptoms due to metastasis  Cause side effects of hot flashes, chills, oedema and loose stools

5-α-REDUCTASE INHIBITORS

DRUGS   Turoseride  Bexlosteride  Izonstreride

THERAPEUTIC USES  Suppress DHT-mediated prostatic tumor growth and benign prostatic hyperplasia  Treat male pattern baldness  Obstructive urine flow  used with α -adrenoceptor antagonist eg.

ADVERSE EFFECTS  Decreased libido  Decreased volume of ejaculation on prolonged used  Impotence  Skin rashes  Swelling of lips

DRUG TREATMENT OF ERECTILE DYSFUNCTION

DRUGS  Phosphodiesterase-5 inhibitors: Sildenafil, Congeners, Tadalafil, Vardenafil  Intracavernosal injection therapy: Alprostadil  Transcutaneous application therapy: Glyceryl trinitrate, Papaverine, , Alprostadil  Herbal agents: Ginseng, Kava, Ginkgo biloba  Adjuvant drugs: Dapoxetine

ROLE OF PHOSPHODIESTERASE-5 INHIBITORS

Sexual arousal ↓ Nitric oxide PDE-5 inhibitors ↓ GTP Guanylyl cyclase ↓ cGMP 5’-GMP Protein kinase G ↓ PDE-5 Decreased Ca2+ ↓ Smooth muscle relaxation ↓ Penile erection

 Sildenafil inhibits PDE-5 selectively and thus increases cGMP levels by inhibiting its breakdown  Potentiation of NO action  It is indicated for treatment of erectile dysfunction due to organic or psychogenic causes  No effect in the absence of sexual stimulation and should be taken approximately one hour prior to the anticipated sexual activity

ADVERSE EFFECTS  Headache  Nasal congestion  Flushing  Mild decrease in blood pressure  Loose motion  Dizziness  Disturbance of colour vision

CONTRAINDICATION  Contraindicated in patient with concurrent use of organic nitrates as it is able to potentiate the activity of NO

PARATHYROID HORMONE, VITAMIN D, CALCITONIN & DRUGS AFFECTING CALCIUM BALANCE

CALCIUM

PREPARATION a) Oral preparation   Calcium lactate  Calcium carbonate  Calcium dibasic phosphate b) Parenteral preparation  Calcium gluconate  Calcium chloride

THERAPEUTIC USES

Therapeutic uses Drug preparation Explanation

Tetany  Mild: oral calcium  Reversing muscle spasm  Severe: Calcium gluconate  Additional of I.V. fluid and (injected I.V. follows with oxygen inhalation slow I.V. infusion)

Dietary supplement  Especially for growing children, pregnant, lactating and menopausal women  Reduce bone loss  Given to patients who has bone fracture

Osteoporosis  HRT, Raloxifene or  Ensure calcium deficiency not Alendronate occur  Calcium + Vitamin D (adjuvant)

Dermatoses, paresthesias,  Calcium gluconate (I.V.)  Psychological, due to warmth weakness and vague and subjective effects complaint

ADVERSE EFFECTS  Constipation  Bloating  Excess gas (especially with Calcium carbonate)

PARATHYROID HORMONE

ACTIONS OF PARATHYROID HORMONE a) Bone  Acts on PTH receptor on osteoblasts and induces receptor activator of nuclear factor for KB ligand (RANK-L)  Interacts with receptor activator of nuclear factor for KB receptor (RANK receptor) on osteoclasts and osteoclast precursors  Increases the activity and the number of osteoclasts (cells responsible for bone resorption) especially when PTH is in excess  as in low to physiological dose it increases bone formation  Active osteoclasts secrete acid and proteolytic enzymes which resorb bone matrix  PTH increases resorption of calcium from bone b) Kidney  Acts directly to increase renal tubular reabsorption of Ca2+ ion 3+  Increases renal tubular excretion of PO4 ion 3+ 2+  Results in decreased serum PO4 ion and increased serum Ca  Stimulates conversion of calcifediol to calcitriol that amplifies effect of PTH c) Intestine 2+ 3+  Increases Ca ion and PO4 ion absorption through induction of calcitriol synthesis  Calcitriol enhances absorption of Ca2+ ion from enterocytes

TERIPARATIDE

 Human recombinant PTH (rPTH)  Stimulates bone formation  Increases bone mineral density in individuals with history of fractures, osteopenia and osteoporosis  Its effects are faster and markedly than oestrogens and bisphosphonates  S.C. injection 20 IU/day for 12-18 months  Laso being used as diagnosis to differentiate pseudohypoparathyroidism from true hypoparathyroidism

CINACALCET

 Calcimimetic drug  Calcium sensing receptor (CaSR) on parathyropid gland regulates PTH secretion  Cinacalcet activates CaSR and blocks PTH secretion by this mechanism  Therapeutic uses:  Treatment of secondary hyperparathyroidism in chronic renal failure  Treatment of PTH releasing parathyroid carcinoma  Adverse effect: hypocalcaemia CALCITONIN

ACTIONS OF CALCITONIN d) Bone  Opposite effect of PTH  Inhibits process of bone resorption by direct inhibitory action on osteoclasts  Decreases their ruffled surface which form contact with the resorptive surface  Promotes deposition of post-prandial Ca2+ ion into the bone e) Kidney 2+ 3+  Inhibits proximal tubular Ca ion and PO4 ion reabsorption  Acts directly on the kidney

THERAPEUTIC USES  Paget’s disease  Osteoporosis  Hypercalcaemic states:  Hyperparathyroidism  Hypervitaminosis D  Osteolytic bone metastasis  Hypercalcaemia of malignancy

ADVERSE EFFECTS  Nausea  Flushing  Tingling sensation in fingers  Altered taste  Allergic reaction  Interferes with action of Digoxin

VITAMIN D

ACTIONS OF VITAMIN D f) Bone  Induces RANK-L which presents on osteoblasts  increases osteoblast-mediated activation of osteoclasts  Promotes differentiation of osteoclast precursors  Helps in bone mineralization 2+ 3+  Enhances reabsorption of Ca ion and PO4 ion g) Kidney  Both calcitriol and calcifediol enhance proximal tubular reabsorption of both Ca2+ 3+ ion and PO4 ion h) Intestine 2+ 3+  Vitamin D stimulates Ca ion and PO4 ion absorption  Calcitriol binds to its receptor which presents on gut and leads to selective increase in synthesis of calcium channels  Acts directly on the basolateral membrane to modulate Ca2+ ion uptake across GIT mucosa  Activation of vitamin D receptor promotes endocytic capture of Ca2+ ion and transports it across duodenal mucosa cell in vesicular form

VITAMIN D PREPARATION  Alfacalcidiol and Dihydrotachysterol  active in the absence of renal 1-α-hydroxylase  Calcipotriol  causes lesser hypercalcaemia  Doxercalciferol and Paricalcitol  lower PTH without significant rise in plasma Ca2+ ion level  Cholecalciferol  Ergocalciferol and Calcitriol

THERAPEUTIC USES  Renal rickets  Vitamin D dependent rickets Alfacalcidiol and Dihydrotachysterol  Vitamin D resistant rickets  Hypoparathyroidism  Psoriasis  Calcipotriol  Secondary hyperparathyroidism with chronic renal disease  Doxercalciferol and Paricalcitol  Prevent deficiency symptoms  Cholecalciferol  Senile or post-menopausal osteoporosis  Faconi syndrome

BISPHOSPHONATES (BPNs)

CLASSIFICATION  First generation: Etidronate, Tiludronate  Second generation: Pamidronate, Alendronate, Ibandronate  Third generation: Risendronate, Zolendronate

MECHANISM OF ACTION  Inhibit osteoclastic resorption of bones by binding to the hydroxyapatite crystals of bone  Osteoclasts attach to the bone matrix during resorption, BPNs released which then internalized by endocytosis into the osteoclasts to accelerate their apoptosis  Also inhibit release of interleukins eg. IL-6 to suppress differentiation of osteoclast precursors  Overall, BPNs inhibit osteoclast-mediated resorption and promote bone remodeling by increasing bone density  Second and third generation bisphosphonates affect the metabolic pathway for isoprenoid lipid synthesis  BPNs inhibit prenylation of certain GTP-binding proteins involved in cytoskeletal organization, membrane ruffling and vesicle movement  Cause inactivation of osteoclast, impaired vesicle fusion and enhance apoptosis

THERAPEUTIC USES  Osteoporosis  as prophylaxis treatment  Reduce fracture rates  Treat hypercalcaemia due to malignancy  Paget’s disease  combined with Calcitonin  Osteolytic bone metastasis

ADVERSE EFFECTS  Gastric irritation  Oesophagitis  Flu-like symptoms (Ibandronate, Pamidronate)  Osteonecrosis of the jwas (high I.V. dose of Zolendronate)  Retrosternal pain  Leucopenia  Fever  Headache

DRUG TREATMENT OF OSTEOPOROSIS

1) Bisphosphonates  There are several different kinds of bisphosphonates  Some are taken by mouth, while others are given by intravenous injection (a slow injection into a vein)  Pamidronate, Ibandronate and Zoledronate are all types of bisphosphonates 2) Teriparatide and parathyroid hormone  These help regulate calcium levels in your blood  They come in a 'pen' syringe and are injected under your skin 3) Denosumab  This is used for post-menopausal women who can't take bisphosphonates  Also used in men who develop osteoporosis as a result of treatments for prostate cancer 4) Raloxifene  This is used to treat spinal osteoporosis in post-menopausal women following a fracture  It is given in tablet form and taken daily 5) Calcitonin  This isn’t often used in the UK, but it's available as an injection to reduce pain from pelvic and vertebral fractures in the time shortly after they occur  It should only be used for a maximum of 4 weeks 6) Strontium ranelate  This is taken daily at least 2 hours before or after food  It comes as a powder which you mix with water 7) HRT (hormone replacement therapy)  It is mainly used as a short-term therapy for early post-menopausal women with increased fracture risk who have troublesome menopausal symptoms 8) Calcium and vitamin D  Not getting enough calcium and vitamin D can increase your risk of fractures  You may be given supplements to help reduce your risk and to promote better responses to other treatments for osteoporosis

OXYTOCIN & OTHER

DRUGS AFFECTING

UTERUS

OXYTOCIN & OTHER DRUGS AFFECTING UTERUS

OXYTOCICS  Drugs or hormones used to enhance uterine contraction  List of oxytocics:  Hormone: Oxytocin  Ergot alkaloids: Ergometrine (Ergonovine), Methylergonovine, Dihydroergonovine  Prostaglandins: Dinoprostone (PGE2 analogue), Carboprost (PGF2α analogue), Misoprostol (PGE1 analogue)

OXYTOCIN

MECHANISM OF ACTION  Oxytocin stimulates oxytocin receptor on myometrium and causes:  Depolarization of muscle fibre  Ca2+ influx 2+  IP3 mediated intracellular Ca release  Increase in prostaglandin synthesis and release by the endometrium  All these cause myometrium contraction

PHARMACOLOGICAL ACTIONS a) Breast  Contraction of myoepithelial cells surrounding mammary alveoli, leading to milk ejection b) Uterus  Oestrogen sensitizes uterus to oxytocin action while progesterone decreases the sensitization  pregnant uterus is most sensitive  Oxytocin increases contraction of upper segment of uterus (fundus)  Facilitates relaxation of cervix and lower segment of uterus (body) c) Miscellaneous  Causes vasodilation  decreased blood pressure, reflex tachycardia  Helps in closure of umbilical vessels at time of birth  Weak ADH-like action  mild anti-diuretic effects  Released during sexual orgasm  role in mating and parenting behaviour as oxytocin receptors are also found in limbic system

IMPORTANT PHARMACOKINETIC FEATURES  t1/2 of 5 minutes  Not bound to plasma protein  Metabolized by liver and excreted through kidneys

THERAPEUTIC USES  Promotes milk ejection and results in breast engorgement  Initiation and augmentation of labour  early vaginal delivery, uterine inertia, caesarean section  Control of post-partum bleeding

ADVERSE EFFECTS  Foetal or maternal soft tissue injury  Rupture of uterus  Foetal asphyxia  Water intoxication if used with normal saline  due to weak anti-diuretic effects, which is serious in case of pre-eclampsia (hypertension in pregnancy with oedema or proteinuria)

WHY OXYTOCIN IS PREFERRED OVER ERGOMETRINE OR PROSTAGLANDINS FOR UTERINE INERTIA?  Oxytocin has short t1/2 and slow I.V. infusion, hence intensity of action can be controlled and action can be quickly terminated  Low concentration allows normal relaxation in between contractions  foetal oxygenation does not disturbed, hence prevents foetal hypoxia occurrence  Lower segment of uterus is not contracted, hence foetal descent is not compromised  Uterine contractions are consistently augmented

ERGOT ALKALOIDS

OBSTETRIC USES  Management of 3rd stage of labour  Treat post-partum haemorrhage  Ensure normal involution (physiological shrinkage of uterus after labour)

ADVERSE EFFECTS  Nausea  Vomiting  Headache  Decreased milk secretion  due to dopaminergic action, where there is inhibition of prolactin release

CONTRAINDICATIONS  Angina pectoris  Myocardial infarction  History of cerebrovascular disease, transient ischaemic heart attack and hypertension

TOCOLYTICS

TOCOLYTICS  Drugs used to enhance uterine relaxation  List of tocolytics:  Β2 agonists: Ritodrine, Salbutamol, Terbutaline, Orciprenaline, Isoxsuprine  Ca2+ channel blockers: Nifedipine  Others: sulphate

INDICATIONS  To prevent premature labour  Arrest threatened abortion  Used in dysmenorrhea

ROLE OF β2 AGONISTS AS TOCOLYTICS  Bind to β2 receptors on myometrium and activate adenylyl cyclase  This increases cAMP level which then activates cAMP-dependent protein kinase  Hence decreases Ca2+ ion concentration, leading to muscle relaxation

AUTACOIDS

DRUG THERAPY OF MIGRAINE

DRUGS USED IN THE TREATMENT OF MILD, MODERATE & SEVERE MIGRAINE

 Simple analgesics (Paracetamol, Aspirin)  NSAIDs (Ibuprofen, Naproxen, Diclofenac, Mephenamic acid, Indomethacin) Mild  Simple analgesics + NSAIDs + Anti-emetics (Metoclopramide, Domperidone, Prochlorperazine, Diphenhydramine, Promethazine)

Moderate  NSAIDs + Triptan/Ergot alkaloids + Anti-emetics

 Triptan/Ergot alkaloids + Anti-emetics + Prophylaxis: i. Propranolol or other β blockers Severe ii. Amitriptyline or other tricyclic anti-depressants (TCAs) iii. Flunarizine or other Ca2+ channel blockers iv. or Topiramate

DRUGS USED FOR THE PROPHYLAXIS OF MIGRAINE  β blockers: Propranolol, Timolol, Metoprolol, Atenolol  Tricyclic anti-depressants: Amitryptyline  Ca2+ channel blockers: Verapamil, Flunarizine  Anti-convulsants: Valproic acid, Gabapentin, Topiramate  5-HT antagonists: Methysergide,

TRIPTAN

ROLE IN MIGRAINE  Drugs: Sumatriptan, Rizatriptan  They are selective 5-HT1D/1B receptor agonists  They suppress nausea and vomiting caused by migraine  This is due to constriction of dilated cranial blood vessels, especially the arteriovenous shunts in carotid artery  They divert blood away from brain parenchyma  Sumatriptan also reduces 5-HT release at blood vessels  It may inhibit inflammatory neuropeptide release around the affected vessels and extravasation of plasma proteins across dural vessels  This suppress neurogenic inflammation of cranial vessels

ADVERSE EFFECTS OF SUMATRIPTAN  Tightness in head and chest  Feeling of heat and paresthesia in limbs  Dizziness  Weakness  Slight rise in blood pressure  Bradycardia  Coronary vasospasm  Myocardial infarction  Death  Rarely seizures and hypersensitivity reactions

CONTRAINDICATIONS OF SUMATRIPTAN  Ischaemic heart disease  Hypertension  Epilepsy  Hepatic or renal impairment  Pregnancy

ERGOT ALKALOIDS

ROLE IN MIGRAINE  Drugs: Ergotamine (oral/sublingual), Dihydroergotamine (parenteral)  They are partial agonist/antagonist at 5-HT1D/1B receptors in cranial vessels  They act by constricting the dilated cranial vessels by constriction of carotid arteriovenous shunt channels  They reduce neurogenic inflammation and leakage of plasma in dura mater

OTHER THERAPEUTIC USES  Ergotamine and Dihydroergotamine: migraine  Methysergide: migraine prophylaxis, carcinoid syndrome  Bromocriptine: parkinsonism, endocrine disorders  Ergometrine: uterine stimulant to prevent post-partum haemorrhage

ADVERSE EFFECTS  Nausea  Vomiting  Headache  Vasoconstriction

CONTRAINDICATIONS  Pregnancy  Peripheral vascular disease  Coronary artery disease  Hypertension

ANTI-HISTAMINICS

ANTI-HISTAMINICS  They are H1-receptor antagonists  First generation anti-histaminics  Highly sedative: Dimenhydrinate, Diphenhydramine, Doxylamine, Hydroxyzine, Promethazine  Moderate sedative: Pyrilamine, Cyproheptadine, Pheniramine, Clemastine  Mild sedative: Meclizine, Chlorpheniramine, Cinnarizine, Triprolidine  Second generation anti-histaminics: Astemizole, Fexofenadine, Cetirizine, Loratadine, Desloratadine, Levocetirizine, Ebastine

THERAPEUTIC USES

H1-receptor antagonists  Allergic rhinitis  Urticaria  Atopic dermatitis  Hay fever  Motion sickness  Anti-emetics  Nausea and vomiting due to pregnancy  Sleeping aids  as sedatives

H2-receptor antagonists  Gastroesophageal reflux disease (GERD) (, Ranitidine,  Duodenal and gastric ulcer disease Famotidine, Nizatidine)  NSAIDs-induced ulcers  Prevention of stress-related gastric bleeding  Prevention of ulcer recurrence  Zollinger-Ellison syndrome  Chronic urticarial

Histamine release inhibitors  Bronchial asthma (Cromolyn sodium,  Allergic rhinitis Nedocromil sodium)  Conjunctivitis

ADVERSE EFFECTS  Sedation  Dry mouth  Urinary retention  Constipation  Drug allergy  Teratogenic effects  hence avoided during pregnancy  Excitement  Hallucinations  Convulsions  Coma

ADVANTAGES OF 2ND GENERATION OVER THE 1ST GENERATION ANTI-HISTAMINICS  Absence of CNS depressant properties  no psychomotor impairment  Higher H1 selectivity  no anti-cholinergic side effects  Additional anti-allergic mechanism apart from histamine blockers (some also inhibits late phase allergic reaction by acting on leukotrienes or by anti-platelet activating factor effect)

PROSTAGLANDINS

THERAPEUTIC USES OF DIFFERENT PROSTAGLANDIN PREPARATIONS

Therapeutic uses Prostaglandin preparations

Abortion Dinoprostone, Carboprost, Misoprostol Labour, cervical priming Dinoprostone Post-partum haemorrhage Carboprost Peptic ulcer Misoprostol, Enprostil Prevent platelet aggregation Epoprostenol Pulmonary hypertension Epoprostenol, Treprostinil Patent ductus arteriosus Epoprostenol, Alprostadil Peripheral vascular disease Beraprost Glaucoma Latanoprost, Bimatoprost, Travoprost, Unoprostone Male impotence Alprostadil Reduce infarct size Iloprost Bronchial asthma Aerosolized PGE2

ADVERSE EFFECTS OF PROSTAGLANDINS  Vomiting  Diarrhoea  Fever  Brochoconstriction  Hypotension  Syncope  Dizziness  Flushing  Anaphylactic shock  Cardiovascular collapse  Ductus fragility and rupture  Gastrointestinal tract discomfort  Hyperostosis (excessive growth of bone)  Bone pain in liver disease patients  Hypercalciuria  Renal Ca2+ oxalate stones  Blurred vision  Brown pigmentation of iris  Dryness of eyes