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 androgen 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 estrogens. *** 2. Describe the principal actions of estrogens on: sex organs, secondary sex characters and metabolism. *** 3. Describe the mechanism of action of estrogen. *** 4. Describe the advantages of transdermal estradiol 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 mifepristone. ***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) Androgens & Drug Treatment Of Erectile Dysfunction 1. Enumerate androgen preparations. *** 2. Describe principal actions of testosterone and dihydrotestosterone 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 danazol. ** 10. Describe the therapeutic uses of danazol. ** 11. List the adverse effects of danazol. ** 12. Explain the role of flutamide / bicalutamide 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 CALCIUM 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 ANDROGEN RECEPTOR 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 zinc 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 (B28B29), lysine (B29B28) 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/Ketoconazole 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): Hydrocortisone, 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+ ion 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, Tibolone 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: Formestane, Exemestane
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) Megestrol acetate (oral) Progesterone analogues Dihydrogesterone (oral) Nomegestrol (oral) Micronized natural progesterone
Norethindrone (Norethisterone) Norethynodrel 19-nortestosterone Lynestrenol (Ethinyl estrenol) Oral derivatives Allylestrenol Norgestrel Levonorgestrel
Newer 19- Desogestrel nortestosterone Norgestimate Oral derivatives Gestodene
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 Cyproterone 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, Androstenedione Synthetic androgens: Methyltestosterone, Fluoxymesterone, Testosterone undeconoate, Mesterolone
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 Nandrolone Oxymetholone Stanozolol 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 urea 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-hydroxyflutamide 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 Finasteride Dutasteride 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. Terazosin
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, Minoxidil, 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 gluconate 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: Magnesium 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. Valproate 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, Cyproheptadine
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) (Cimetidine, 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