Antithyroid Agents — Classification and Propylthiouracil
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(2023 Main, 2023 Resit, 2022 Main, 2021 Resit — recurs every year) Classification of antithyroid agents: 1. Thioamides: Propylthiouracil (PTU), Methimazole, Carbimazole (prodrug of methimazole) 2. Iodides (high-dose): Lugol’s iodine, potassium iodide — used short-term pre-operatively 3. Radioactive iodine (¹³¹I) – ablative therapy 4. Beta-blockers – symptomatic control (not antithyroid per se, but adjunctive) 5. Anion inhibitors (historical) – Potassium perchlorate Mechanism of action of Propylthiouracil: 1. Inhibits thyroid peroxidase, blocking oxidation and organification of iodide and coupling of iodotyrosines (MIT/DIT) to form T3/T4. 2. Uniquely (compared to methimazole) also inhibits peripheral conversion of T4 to T3 via inhibition of type 1 deiodinase — giving it an additional, faster-acting effect useful in thyroid storm. Onset of action: Delayed — because thioamides only block new hormone synthesis; they do not affect release of hormone already stored in colloid, so clinical effect is seen only after existing thyroid hormone stores are depleted (days to weeks). Adverse effect profile: agranulocytosis (most serious — requires monitoring for fever/sore throat and immediate blood count if suspected), hepatotoxicity (more with PTU, including rare fulminant hepatic failure — reason PTU is now reserved mainly for first trimester of pregnancy and thyroid storm), rash, arthralgia, vasculitis (rare). Agents used for adjuvant therapy in hyperthyroidism: • Beta-blockers (Propranolol) – rapid symptomatic control of tachycardia, tremor, anxiety (also blocks peripheral T4→T3 conversion at high doses) • Iodides (Lugol’s solution) – acutely inhibit hormone release (Wolff-Chaikoff effect) and reduce gland vascularity pre-operatively • Glucocorticoids – inhibit peripheral T4→T3 conversion, used in thyroid storm • Radioactive iodine or surgery – for definitive/long-term treatment
Sulphonylureas and Diabetes Drug Classes
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(2023 Resit, 2021 Resit, 2014 — recurs) Classification of sulphonylureas: • First-generation: Tolbutamide, Chlorpropamide • Second-generation: Glibenclamide (glyburide), Glipizide, Glimepiride Mechanism of action: Bind the SUR1 subunit of the ATP-sensitive K⁺ (K-ATP) channel on pancreatic β-cells, closing the channel → membrane depolarization → opening of voltage-gated Ca²⁺ channels → Ca²⁺ influx → insulin release (independent of glucose, i.e., insulin secretagogues requiring functioning β-cells). Side effect profile: Hypoglycemia (most important, can be prolonged, especially with long-acting agents like chlorpropamide/glibenclamide, and in renal/hepatic impairment or elderly), weight gain, rarely hyponatremia (chlorpropamide, via potentiation of ADH), disulfiram-like reaction with alcohol (chlorpropamide), GI upset. Broader classification of antidiabetic drugs (2014): 1. Insulin – all types (rapid, short, intermediate, long-acting) 2. Sulphonylureas – as above (insulin secretagogues) 3. Meglitinides – Repaglinide, Nateglinide (similar mechanism, shorter action, taken with meals) 4. Biguanides – Metformin (↓ hepatic gluconeogenesis, ↑ peripheral insulin sensitivity, via AMP-kinase activation; does not cause hypoglycemia alone; risk of lactic acidosis in renal impairment) 5. Thiazolidinediones – Pioglitazone (PPAR-γ agonist, ↑ insulin sensitivity in adipose/ muscle; risk of fluid retention, heart failure, weight gain) 6. Alpha-glucosidase inhibitors – Acarbose (delays intestinal carbohydrate absorption; GI side effects — flatulence, diarrhoea) 7. DPP-4 inhibitors – Sitagliptin (prevents breakdown of incretins GLP-1/GIP, enhancing glucose-dependent insulin release) 8. GLP-1 receptor agonists – Exenatide, Liraglutide, Semaglutide (incretin mimetics, ↑ glucose-dependent insulin secretion, ↓ glucagon, delay gastric emptying, promote weight loss) 9. SGLT2 inhibitors – Empagliflozin, Dapagliflozin (block renal glucose reabsorption, causing glucosuria) Mechanism/adverse effects of Insulin, Metformin, Acarbose (2014): • Insulin – binds insulin receptor (tyrosine kinase), promotes glucose uptake (via GLUT4 translocation in muscle/fat), glycogen synthesis, lipogenesis, protein synthesis; adverse effects: hypoglycemia, weight gain, lipodystrophy at injection sites, allergic reactions (rare with human/analogue insulin). • Metformin – as above; adverse effects: GI upset (most common — nausea, diarrhoea), lactic acidosis (rare but serious, especially in renal impairment/hypoxic states), vitamin B12 deficiency with long-term use. • Acarbose – as above; adverse effects: flatulence, bloating, diarrhoea (undigested carbohydrate fermented by colonic bacteria). Pioglitazone, Radioactive iodine, Crystalline zinc insulin (short notes) (2010): • Pioglitazone – see above. • Radioactive iodine (¹³¹I) – taken up by thyroid follicular cells (via Na/I symporter) and concentrated in colloid, emitting beta particles that destroy thyroid tissue over weeks; used for definitive treatment of Graves’ disease and toxic nodular goitre; contraindicated in pregnancy/breastfeeding; risk of eventual hypothyroidism requiring lifelong levothyroxine replacement. • Crystalline zinc insulin (regular/soluble insulin) – short-acting insulin, onset ~30 min, peak 2–4 hr, duration 6–8 hr; can be given IV (unlike depot insulins) — useful in diabetic ketoacidosis management.
NSAIDs — Mechanism, Tripartite Effects, New vs Traditional Generation
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(2023 Main, 2022 Main, 2017 — recurs heavily) Mechanism of action: NSAIDs inhibit cyclooxygenase (COX), the enzyme converting arachidonic acid to prostaglandin H2, the precursor of prostaglandins (PGE2, PGI2) and thromboxane A2. • COX-1 – constitutive, “housekeeping” isoform: gastric mucosal protection (PGE2/PGI2 maintain mucus/bicarbonate secretion and mucosal blood flow), renal blood flow autoregulation, platelet thromboxane A2 production. • COX-2 – mainly inducible at sites of inflammation (also some constitutive expression in kidney, brain, vasculature): mediates prostaglandin-driven inflammation, pain, and fever. Tripartite clinical effects (analgesic, antipyretic, anti-inflammatory): 1. Analgesic – ↓ prostaglandin-mediated sensitization of peripheral nociceptors to bradykinin/histamine; effective mainly for mild-moderate pain, especially of inflammatory origin. 2. Antipyretic – ↓ hypothalamic PGE2 synthesis, resetting the elevated hypothalamic thermoregulatory set-point back toward normal. 3. Anti-inflammatory – ↓ prostaglandin-mediated vasodilation, oedema, and leukocyte sensitization at the site of tissue injury. Advantages of new-generation (selective COX-2 inhibitors, e.g., Celecoxib, Etoricoxib) over traditional (non-selective) NSAIDs: Traditional NSAIDs (Ibuprofen, Diclofenac, Naproxen, Aspirin) inhibit both COX-1 and COX-2, so while providing anti-inflammatory/ analgesic benefit (COX-2), they also cause gastric mucosal damage/peptic ulceration and platelet dysfunction/bleeding tendency (COX-1 inhibition). Selective COX-2 inhibitors spare COX-1, therefore causing significantly less GI ulceration/bleeding and no antiplatelet effect, while retaining anti-inflammatory/analgesic efficacy. Disadvantage: selective COX-2 inhibition removes vasodilatory/antithrombotic PGI2 while sparing thromboxane A2 production (still COX-1 dependent, from platelets) — this imbalance is associated with an increased risk of cardiovascular thrombotic events (MI, stroke), which led to withdrawal of rofecoxib and restricted use of the class. Clopidogrel vs Low-dose Aspirin as antiplatelet agents: • Aspirin – irreversibly acetylates (inhibits) COX-1 in platelets, preventing thromboxane A2 synthesis (a potent platelet aggregant and vasoconstrictor); since platelets are anucleate and cannot synthesize new COX, this effect lasts the lifetime of the platelet (~7–10 days), despite aspirin’s own short plasma half-life. Low doses selectively spare endothelial COX-2-derived PGI2 (antiaggregant), preserving the antithrombotic benefit. • Clopidogrel – a prodrug (activated by CYP2C19) that irreversibly blocks the P2Y12 ADP receptor on platelets, preventing ADP-mediated activation of the glycoprotein IIb/IIIa complex, thereby inhibiting platelet aggregation via a completely different pathway from aspirin. Used alone in aspirin-intolerant patients or combined with aspirin (“dual antiplatelet therapy”) for synergistic effect after stenting/ACS.
Contraceptive Agents — Classification and Non-Contraceptive Benefits
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(2023 Main, 2022 Main, 2021 Main, 2016, 2013, 2013 Resit — recurs heavily) Classification of pharmacological contraceptive agents: 1. Combined oral contraceptives (COC) – estrogen (ethinylestradiol) + progestin – inhibit ovulation via negative feedback suppression of FSH/LH (GnRH pulsatility), thicken cervical mucus, alter endometrium. 2. Progestin-only pills (“mini-pill”) – thicken cervical mucus, inhibit ovulation less consistently, alter endometrium. 3. Injectable progestins – Depot medroxyprogesterone acetate (DMPA), every 3 months. 4. Implants – Levonorgestrel/etonogestrel subdermal implants (long-acting, up to 3–5 years). 5. Intrauterine devices (IUD) – Copper IUD (spermicidal/inflammatory, non-hormonal); Levonorgestrel-releasing IUD (local progestin effect, thins endometrium, thickens mucus). 6. Emergency contraception – high-dose Levonorgestrel, or Ulipristal acetate (progesterone receptor modulator) — primarily delays/inhibits ovulation. 7. Barrier and other non-pharmacological methods – (not primarily pharmacological). How each class affects the menstrual cycle: COCs suppress the mid-cycle LH surge, preventing ovulation, and produce a thinner, atrophic endometrium (lighter, more regular, more predictable withdrawal bleeding). Progestin-only methods often cause irregular bleeding/amenorrhoea due to inconsistent ovulation suppression and endometrial thinning. Non-contraceptive benefits of oral contraceptives (also asked explicitly in 2021 Main and 2013 Resit as a stand-alone question): 1. Regulation of menstrual cycle and reduction of dysmenorrhoea 2. Reduced menstrual blood loss (protection against iron-deficiency anaemia) 3. Reduced risk of ovarian and endometrial cancer (with long-term use) 4. Improvement of acne and hirsutism (with anti-androgenic progestins, e.g., drospirenone) 5. Reduced risk of benign breast disease and functional ovarian cysts 6. Reduced risk of pelvic inflammatory disease Side effects, contraindications: thromboembolism (estrogen-related, increased risk in smokers >35 years, obesity), hypertension, mood changes, breast tenderness, nausea, breakthrough bleeding; contraindicated in history of VTE, estrogen-dependent cancers, severe liver disease, migraine with aura, uncontrolled hypertension, smokers over 35. Estrogen replacement therapy in postmenopausal women (2023 Main): Used to relieve vasomotor symptoms (hot flashes, night sweats), prevent osteoporosis (estrogen inhibits osteoclast activity), and improve urogenital atrophy symptoms. Must be combined with a progestin in women with an intact uterus (unopposed estrogen increases endometrial hyperplasia/cancer risk). Risks: increased risk of breast cancer with long-term combined use, venous thromboembolism, and (per the Women’s Health Initiative findings) increased cardiovascular risk when started many years after menopause — hence current guidance favours the lowest effective dose for the shortest necessary duration, ideally initiated close to menopause onset (“timing hypothesis”).
Osteoporosis / Bone Metabolism Agents
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(2018) Hormones in calcium/phosphate metabolism: • Parathyroid hormone (PTH) – ↑ bone resorption (osteoclast activation via RANKL upregulation on osteoblasts), ↑ renal calcium reabsorption, ↑ renal phosphate excretion, ↑ activation of vitamin D (1α-hydroxylase) → ↑ intestinal calcium absorption. Net effect: ↑ serum calcium, ↓ serum phosphate. (Note: intermittent PTH — teriparatide — paradoxically stimulates bone formation, used therapeutically for osteoporosis.) • Calcitonin – secreted by thyroid C-cells; ↓ bone resorption (inhibits osteoclast activity), ↓ serum calcium; used therapeutically (nasal spray/injection) for Paget’s disease, hypercalcemia, and adjunctively in osteoporosis (also has analgesic effect in osteoporotic fractures). • Vitamin D (calcitriol) – ↑ intestinal calcium/phosphate absorption, promotes bone mineralization at physiological levels, but promotes resorption at high levels/with PTH. Agents reducing osteoclast number, activity, and lifespan: • Alendronate (bisphosphonate) – binds hydroxyapatite in bone; taken up by osteoclasts during resorption, inhibits farnesyl pyrophosphate synthase in the mevalonate pathway, disrupting osteoclast cytoskeleton and inducing osteoclast apoptosis — reduces osteoclast number and activity. • Raloxifene (selective estrogen receptor modulator, SERM) – estrogen agonist effect on bone (reduces bone resorption, mimicking estrogen’s inhibitory effect on osteoclastogenesis via reduced RANKL/cytokine production) while acting as an estrogen antagonist on breast and endometrial tissue (reduced breast cancer risk, no endometrial stimulation). • Calcitonin – as above. • Denosumab (not in original list but relevant) – monoclonal antibody against RANKL, preventing osteoclast differentiation/activation.
Gout — Immunopathology and Drug Treatment
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(2018, 2016) Immunopathology of gout: Hyperuricemia leads to deposition of monosodium urate crystals in joints and periarticular tissue. These crystals are phagocytosed by synovial macrophages, activating the NLRP3 inflammasome, leading to caspase-1-mediated cleavage and release of IL-1β, which drives neutrophil recruitment and the intense inflammatory response characteristic of an acute gout flare. Drug treatment: Acute attack (anti-inflammatory, not urate-lowering): * NSAIDs (e.g., indomethacin) – first-line for most patients. * Colchicine – inhibits microtubule polymerization in neutrophils, impairing their migration, phagocytosis, and inflammasome activation; effective if given early in an attack; adverse effects: GI upset (diarrhoea, common and often dose-limiting), bone marrow suppression at high/prolonged doses. * Corticosteroids (oral or intra-articular) – for patients who cannot tolerate NSAIDs/colchicine (e.g., renal impairment). Chronic/urate-lowering therapy (never started during an acute attack): * Xanthine oxidase inhibitors: Allopurinol, Febuxostat – inhibit xanthine oxidase, blocking conversion of hypoxanthine/xanthine to uric acid, reducing uric acid production. * Uricosuric agents: Probenecid – inhibits renal tubular reabsorption of uric acid, increasing its excretion (contraindicated in patients with urolithiasis/renal impairment). * Uricase (Rasburicase, Pegloticase) – converts uric acid to the more soluble allantoin; used for refractory gout/ tumour lysis syndrome.
Clomiphene, Oxytocin, Hyperprolactinaemia
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(2015, 2013, 2010) Clomiphene (mechanism of action, adverse effects): A selective estrogen receptor modulator that competitively blocks estrogen receptors in the hypothalamus, preventing normal negative feedback of estrogen — the hypothalamus “perceives” low estrogen, leading to increased GnRH pulsatility, which increases pituitary FSH/LH secretion, stimulating ovarian follicular development and ovulation. Used for ovulation induction in anovulatory infertility (e.g., PCOS). Adverse effects: hot flashes, visual disturbances, ovarian hyperstimulation, multiple pregnancy (increased risk of twins), mood changes. Oxytocin: A nonapeptide hormone (synthesized in hypothalamus, released from posterior pituitary) acting on oxytocin receptors (Gq-coupled) on uterine myometrium to stimulate rhythmic contractions, and on myoepithelial cells of the breast to cause milk ejection (let-down reflex). • Uses: induction/augmentation of labour, control of postpartum haemorrhage (promotes uterine contraction and involution), management of incomplete/missed abortion. • Adverse effects: uterine hyperstimulation/tetanic contraction (risk of uterine rupture, fetal distress), water intoxication/hyponatremia at high doses/prolonged infusion (oxytocin has structural similarity to ADH and weak antidiuretic activity), hypotension with rapid IV bolus. Drug treatment of hyperprolactinaemia: • Dopamine agonists: Bromocriptine, Cabergoline – activate D2 receptors on lactotroph cells, mimicking dopamine’s normal tonic inhibitory control of prolactin secretion, thereby suppressing prolactin release and often shrinking prolactinomas. • Cabergoline is generally preferred (longer half-life, better tolerated, fewer GI/ orthostatic side effects than bromocriptine). • Used for: prolactinoma, drug-induced hyperprolactinaemia (where feasible to switch/ discontinue offending agent), and to restore fertility/menses in hyperprolactinaemic anovulation.
Prostaglandins, Leukotrienes, Autacoids
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(2016, 2013 Resit, 2010) Synthesis of prostaglandins and leukotrienes: Both derive from arachidonic acid, released from membrane phospholipids by phospholipase A2. • Cyclooxygenase (COX) pathway → PGG2/PGH2 → various prostaglandins (PGE2, PGF2α, PGI2/prostacyclin) and thromboxane A2 (via specific synthases in different tissues). • 5-Lipoxygenase (5-LOX) pathway → 5-HPETE → leukotriene A4 → leukotriene B4 (chemotactic for neutrophils) or, via conjugation with glutathione, the cysteinyl leukotrienes (LTC4, LTD4, LTE4 — potent bronchoconstrictors, increase vascular permeability, mediators of the “slow-reacting substance of anaphylaxis”). Therapeutic uses of prostaglandin analogues: 1. Misoprostol (PGE1 analogue) – prevention of NSAID-induced peptic ulcers; cervical ripening/labour induction; medical management of miscarriage/abortion (with mifepristone). 2. Dinoprostone (PGE2) – cervical ripening, labour induction. 3. Latanoprost (PGF2α analogue) – glaucoma (increases uveoscleral outflow of aqueous humor). 4. Alprostadil (PGE1) – maintaining patency of ductus arteriosus in duct-dependent congenital heart disease (neonates); erectile dysfunction (intracavernosal injection). 5. Carboprost (PGF2α analogue) – postpartum haemorrhage due to uterine atony (when oxytocin fails). Distinguishing mechanism of glucocorticoids vs leukotriene modifiers in asthma: Glucocorticoids act upstream, broadly suppressing transcription of multiple inflammatory mediators (cytokines, and indirectly reducing phospholipase A2 activity via induction of lipocortin/annexin-1, thereby reducing production of both prostaglandins and leukotrienes); leukotriene modifiers act narrowly, either blocking leukotriene receptors (montelukast) or inhibiting 5-lipoxygenase (zileuton) — a more targeted but generally less potent anti-inflammatory strategy restricted to the leukotriene pathway alone.
DMARDs and Rheumatoid Arthritis
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(2016, 2015) Examples of DMARDs (disease-modifying antirheumatic drugs): 1. Methotrexate – folate antagonist (inhibits dihydrofolate reductase); anchor drug for RA; also has anti-inflammatory effects at low doses independent of antifolate action (adenosine-mediated). 2. Sulfasalazine – combined sulfapyridine + 5-ASA; anti-inflammatory mechanism not fully clear. 3. Hydroxychloroquine – antimalarial with immunomodulatory effect (interferes with antigen processing/TLR signaling); risk of retinopathy with long-term use. 4. Leflunomide – inhibits dihydroorotate dehydrogenase, blocking pyrimidine synthesis in activated lymphocytes. 5. Biologic DMARDs – TNF-α inhibitors (Infliximab, Etanercept, Adalimumab), IL-6 receptor antagonists (Tocilizumab), Rituximab (anti-CD20, B-cell depletion), Abatacept (T-cell costimulation blocker).
Aspirin — Non-Analgesic/Non-Inflammatory Benefits
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(2021 Main, 2013 Resit, 2011) Three non-inflammatory (non-analgesic) benefits of aspirin, beyond its classical NSAID actions: 1. Antiplatelet/cardioprotective effect – low-dose irreversible COX-1 inhibition in platelets, preventing thromboxane A2-mediated aggregation; used in secondary (and selected primary) prevention of myocardial infarction and ischaemic stroke. 2. Colorectal cancer chemoprevention – long-term low-dose aspirin use is associated with reduced incidence of colorectal adenomas/carcinoma (proposed mechanisms include COX-2 inhibition in tumour tissue and antiplatelet effects reducing tumour-associated platelet aggregation/metastasis). 3. Antipyretic effect in febrile illness (distinct from its anti-inflammatory use) — though this overlaps with the classical tripartite action, it is often listed separately from anti-inflammatory joint/tissue effects. (A fourth sometimes cited: possible reduction in pre-eclampsia risk when used in high-risk pregnancy, via antiplatelet/anti-thromboxane effect on placental vasculature.) Mechanism, indications, adverse effects of Aspirin (with Sertraline, 2011): • Aspirin: irreversible COX-1/COX-2 inhibitor (acetylation); indications: analgesia, antipyresis, anti-inflammatory (higher dose), antiplatelet (low dose). Adverse effects: GI ulceration/bleeding, tinnitus/hyperventilation at toxic doses (salicylism), Reye’s syndrome in children with viral illness (hence avoided under age 16 for viral fever), bronchospasm in aspirin-sensitive asthmatics. • Sertraline: SSRI (selective serotonin reuptake inhibitor) — blocks serotonin reuptake transporter (SERT), increasing synaptic serotonin. Indications: major depressive disorder, anxiety disorders, OCD, PTSD. Adverse effects: GI upset, sexual dysfunction, insomnia/agitation, serotonin syndrome (especially combined with MAOIs or other serotonergic drugs), increased suicidal ideation risk in adolescents (black box warning), discontinuation syndrome.