Endocrine System & Metabolic Drugs

• Mechanism: ↑ peripheral insulin sensitivity; ↓ hepatic gluconeogenesis
• Does not cause hypoglycaemia or weight gain (weight-neutral / mild loss)
• Use: first-line monotherapy or in combination (synergistic with sulfonylureas)
• Adverse effects: GI distress (diarrhoea, nausea); lactic acidosis (rare but serious — caution in renal/hepatic impairment)

• Mechanism: inhibits intestinal α-glucosidase → delays carbohydrate digestion → blunts postprandial glucose spike
• No hypoglycaemia when used alone
• Adverse effects: flatulence, diarrhoea, abdominal bloating; rare hepatotoxicity

• Mechanism: block ATP-sensitive K⁺ channels in pancreatic β-cells → depolarisation → Ca²⁺ influx → insulin release
• Second-generation agents: glipizide (↓ dose in hepatic disease), glyburide (active metabolite; ↓ dose in renal disease)
• Adverse effects: hypoglycaemia (major risk), weight gain
• Drug interactions: cimetidine, salicylates, sulfonamides, insulin → ↑ hypoglycaemic effect

• Mechanism: stimulates insulin release from β-cells (short-acting)
• Dosed immediately before meals due to short half-life
• Use: adjunctive in Type 2; less risk of prolonged hypoglycaemia than sulfonylureas

• Mechanism: PPARγ agonists → modulate transcription of insulin-responsive genes → ↑ insulin sensitivity in adipose, muscle, liver
• Also ↓ hepatic gluconeogenesis and triglycerides; ↑ insulin receptor numbers
• Adverse effects: weight gain, fluid retention (oedema); less hypoglycaemia than sulfonylureas
• Rosiglitazone: cardiovascular safety concerns (restricted in some regions)

• GLP-1 = incretin hormone from small intestine → glucose-dependent insulin secretion
• Liraglutide: long-acting full agonist; used in combination
• Adverse effects: nausea, vomiting; hypoglycaemia when combined with sulfonylureas

• Mechanism: inhibit dipeptidyl peptidase-4 → prevent degradation of endogenous GLP-1 → ↑ incretin activity
• Weight-neutral; low hypoglycaemia risk

• Mechanism: block SGLT-2 in proximal renal tubule → ↑ urinary glucose excretion
• Adverse effects: UTIs, genital mycotic infections; osmotic diuresis
• Cardiorenal protective effects shown in trials

• Synthetic amylin; slows gastric emptying, ↓ glucagon, ↓ appetite
• Used in both Type 1 and Type 2 diabetes

• Estradiol = major natural estrogen
• Synthetics: ethinyl estradiol, mestranol, conjugated equine estrogens (Premarin)
• Rationale for synthetics: ↑ oral bioavailability, ↑ half-life, ↑ feedback inhibition of FSH/LH

• Female hypogonadism, menopause HRT (↓ bone resorption via ↓ PTH), contraception, dysmenorrhoea, uterine bleeding, acne

• Nausea, breast tenderness, endometrial hyperplasia, gallbladder disease, cholestasis, migraine, bloating
• Thrombotic risk: ↓ antithrombin III, ↑ factors II, VII, IX, X (dose-dependent)
• Endometrial cancer risk increased unless progestin is added
• Breast cancer risk: controversial, but caution in high-risk patients

• Anastrozole (aromatase inhibitor): ↓ oestrogen synthesis; used in postmenopausal ER+ breast cancer
• Clomiphene: blocks oestrogen feedback → ↑ FSH/LH → ovulation; used for infertility; ↑ multiple births

• Tissue-selective: agonist in bone, antagonist in breast, partial agonist in endometrium
• Use: ER+ breast cancer (adjuvant, metastatic); prophylaxis in high-risk women
• Risk: ↑ endometrial cancer (partial agonist effect on uterus)

• Agonist in bone; antagonist in breast and uterus
• Use: postmenopausal osteoporosis prophylaxis; breast cancer risk reduction
• No increased endometrial cancer risk (antagonist effect)

• Natural: progesterone; synthetics: medroxyprogesterone, norethindrone, desogestrel
• Uses: contraception (oral + oestrogen; depot IM every 3 months), HRT (with oestrogen to ↓ endometrial cancer risk)
• Adverse effects: ↓ HDL, ↑ LDL, glucose intolerance, breakthrough bleeding, androgenic effects (hirsutism, acne), weight gain, depression
• Mifepristone (progestin antagonist): abortifacient (with prostaglandins)

• Combination of oestrogen (ethinyl estradiol, mestranol) + progestin (norgestrel, norethindrone)
• Suppress gonadotropins, especially midcycle LH surge
• Benefits: ↓ endometrial/ovarian cancer, ↓ dysmenorrhoea, ↓ endometriosis, ↓ PID, ↓ osteoporosis
• Interactions: antimicrobials and enzyme inducers ↓ contraceptive efficacy

• Methyltestosterone, oxandrolone, nandrolone (anabolic)
• Uses: male hypogonadism, anabolic effects (↑ muscle mass, ↑ RBCs, ↓ N₂ excretion); illicit athletic use
• Adverse effects: masculinisation, premature epiphyseal closure, cholestatic jaundice, aggression, dependence
• Flutamide: androgen receptor blocker; used in prostate cancer
• Leuprolide: GnRH agonist (repository form); ↓ testosterone via downregulation; used in prostate cancer
• Finasteride: 5α-reductase inhibitor; prevents conversion of testosterone → DHT; uses: BPH, male pattern baldness; teratogenic

• Iodide uptake into thyroid follicle (active transport)
• Oxidation of iodide → iodine (thyroid peroxidase)
• Iodination of tyrosyl residues on thyroglobulin → MIT and DIT
• Coupling of MIT + DIT → T₃; DIT + DIT → T₄
• Proteolytic release of T₃/T₄ from thyroglobulin into circulation
• Peripheral conversion of T₄ → T₃ (5′-deiodinase)

• Propylthiouracil (PTU) and Methimazole
• Inhibit thyroid peroxidase (block iodination and coupling)
• PTU also inhibits peripheral 5′-deiodinase (T₄ → T₃) at high doses
• Slow onset; used in uncomplicated hyperthyroidism
• Adverse effects: maculopapular rash, agranulocytosis (rare but serious), hepatotoxicity (PTU more than methimazole)
• Pregnancy: PTU preferred (higher protein binding → less placental transfer; methimazole associated with aplasia cutis)

• Used preoperatively in thyrotoxicosis: ↓ gland size, vascularity, and fragility
• Also inhibits proteolytic release of hormone (high doses)
• No long-term use — thyroid gland "escapes" after 10–14 days

• Most commonly used definitive therapy for hyperthyroidism (Graves disease, toxic nodules)
• Selectively destroys hyperfunctioning thyroid tissue
• Contraindicated in pregnancy; may cause hypothyroidism (common outcome)

• Propranolol: symptom control in hyperthyroidism (tachycardia, tremor); also inhibits T₄ → T₃ conversion
• Amiodarone: high iodine content; may cause hypo- or hyperthyroidism
• Lithium: inhibits hormone release; may cause goitre and hypothyroidism

• Uses: pituitary dwarfism, osteoporosis (anabolic effects)

• Uses: acromegaly, carcinoid syndrome, secretory GI tumours (e.g., VIPomas, glucagonomas)
• ↓ GH, insulin, glucagon, and GI secretions

• Uses: infantile spasms (West syndrome), adrenal function testing

• Repository (depot) forms; initially stimulate then downregulate gonadotropin release
• Uses: endometriosis, prostate carcinoma, uterine fibroids

• Uses: hypogonadal states, ovulation induction

• Prolactin-lowering; uses: hyperprolactinaemia (prolactinomas), Parkinson disease (adjunct)

• Uses: labour induction, postpartum haemorrhage (stimulates uterine contraction)

• Uses:
  • Central (neurogenic) diabetes insipidus
  • Haemophilia A (↑ factor VIII from liver)
  • von Willebrand disease (↑ vWF from endothelium)
  • Primary nocturnal enuresis

• Mechanism: pyrophosphate analogues; inhibit farnesyl pyrophosphate (FPP) synthase in the mevalonate pathway
• Disrupts protein prenylation in osteoclasts → cytoskeletal changes → osteoclast detachment → ↓ bone resorption
• First-line therapy for osteoporosis; also used in Paget disease
• Adverse effects: GI distress, oesophageal ulcers (alendronate — take with full glass of water, upright posture); etidronate/pamidronate may cause bone mineralisation defects

• Recombinant human PTH (1–34); daily subcutaneous injection
• Mechanism: intermittent exposure → stimulates osteoblasts → ↑ bone formation
• Continuous infusion would stimulate osteoclasts (bone resorption)
• Duration limited to < 2 years; potential risk of osteosarcoma (long-term)

• Monoclonal antibody that binds RANKL → prevents RANK activation on osteoclast precursors
• ↓ osteoclast formation, function, and survival → ↓ bone resorption
• Use: osteoporosis in patients with renal impairment (not cleared renally); also cancer-related bone disease

• Activates calcium-sensing receptor (CaSR) on parathyroid gland → ↓ PTH secretion
• Use: hyperparathyroidism in chronic kidney disease; hypercalcaemia in parathyroid carcinoma