Cardiovascular, Renal, Gastrointestinal, Respiratory and Haemopoietic Pharmacology
Study Mode • 11 Questions
Peptic Ulcer Disease — Classification and Triple Therapy for H. pylori
Standard Answer:
(2023 Main, 2023 Resit, 2018/19, 2017, 2016, 2014, 2011, 2010 — recurs heavily) Classification of drugs used in PUD: 1. Antisecretory agents - Proton pump inhibitors (PPIs): Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole - H2-receptor antagonists: Ranitidine, Cimetidine, Famotidine - Anticholinergics (obsolete): Pirenzepine 2. Neutralizing agents (antacids): Aluminium hydroxide, Magnesium hydroxide, Calcium carbonate, Sodium bicarbonate 3. Mucosal protective agents: Sucralfate, Bismuth compounds, Misoprostol (PGE1 analogue) 4. Anti-H. pylori antimicrobials: Amoxicillin, Clarithromycin, Metronidazole, Tetracycline Four characteristics of an ideal antacid: 1. Rapid onset and adequate duration of acid-neutralizing action 2. Should not produce systemic alkalosis (non-absorbable/non-systemic) 3. Should not cause significant constipation or diarrhoea 4. Should not interfere with absorption of other drugs/nutrients, and be palatable and inexpensive Rationale for triple therapy in H. pylori eradication: Standard triple therapy = PPI + Amoxicillin + Clarithromycin (or Metronidazole if penicillin-allergic), for 10–14 days. • The PPI raises intragastric pH, which (a) directly reduces acid-related mucosal damage, (b) increases the stability and activity of antibiotics that are acid-labile or pH-dependent (clarithromycin is degraded in acid), and (c) promotes H. pylori into an actively dividing state, making it more susceptible to cell-wall-active antibiotics like amoxicillin. • Two antibiotics with different mechanisms are combined to overcome the increasing rates of H. pylori antibiotic resistance and achieve eradication rates unattainable with monotherapy, since H. pylori resides both intracellularly and within gastric mucus, requiring multiple agents with different penetration and mechanisms (amoxicillin: cell wall synthesis inhibition; clarithromycin: protein synthesis inhibition; metronidazole: DNA damage in anaerobic-like microaerophilic organism). • Eradicating H. pylori removes the major aetiological driver of peptic ulcer recurrence, in contrast to acid suppression alone which heals but does not cure the ulcer diathesis. Pharmacology of Omeprazole (2018/19): Irreversibly inhibits the H⁺/K⁺-ATPase (“proton pump”) on the luminal surface of gastric parietal cells, the final common pathway of acid secretion regardless of stimulus (histamine, gastrin, or ACh). Given as an inactive prodrug that is acid-activated within the parietal cell canaliculus, forming a sulfenamide that covalently binds the pump — hence its effect outlasts its plasma half-life (irreversible inhibition; new pump synthesis required for recovery). Uses: peptic ulcer disease, GERD, Zollinger-Ellison syndrome, NSAID-associated ulcer prophylaxis, part of H. pylori eradication regimens. Adverse effects: headache, diarrhoea, increased risk of enteric infections (C. difficile), long-term risk of hypomagnesemia, vitamin B12 deficiency, osteoporosis/fracture risk, and rebound acid hypersecretion on withdrawal. Mechanism of anti-emetic/prokinetic effect of Metoclopramide (2017, 2016): Dopamine D2-receptor antagonist both centrally (chemoreceptor trigger zone, accounting for antiemetic effect) and peripherally in the GI tract, where D2 blockade removes dopamine’s inhibitory tone on GI motility; also acts as a 5-HT4 agonist enhancing ACh release from myenteric neurons, and a 5-HT3 antagonist at higher doses (further antiemetic action). Net effect: increased lower oesophageal sphincter tone, increased gastric and duodenal motility/emptying (prokinetic), and antiemetic action. Adverse effects: extrapyramidal symptoms (dystonia, akathisia, tardive dyskinesia — due to central D2 blockade), hyperprolactinemia/galactorrhea. Cimetidine (short notes) (2015): H2-receptor antagonist reducing histamine-stimulated gastric acid secretion; notable for inhibiting CYP450 (many drug interactions — warfarin, phenytoin, theophylline), and antiandrogenic effects (gynaecomastia, reduced libido) — largely superseded by ranitidine/famotidine and PPIs. Aggressive vs Defensive factors in acid-peptic disease (2010): • Aggressive factors: gastric acid, pepsin, H. pylori infection, NSAIDs/aspirin (COX-1 inhibition reducing protective prostaglandins), bile reflux, smoking, alcohol • Defensive factors: mucus-bicarbonate layer, mucosal blood flow, prostaglandins (E2, I2), epithelial cell renewal, tight junctions • Drug classes eliminating aggressive factors: antisecretory agents (PPIs, H2 blockers), antacids, anti-H. pylori antibiotics — mode of action as above. • Drug classes enhancing defense: Misoprostol (PGE1 analogue — stimulates mucus/ bicarbonate secretion, maintains mucosal blood flow; used for NSAID-ulcer prophylaxis), Sucralfate (forms protective ulcer-adherent barrier in acidic environment), Bismuth compounds (coats ulcer base, has mild antibacterial activity against H. pylori).
Congestive Cardiac Failure / Heart Failure Drug Classification and Digoxin
Standard Answer:
(Recurs across nearly every year: 2023 Main, 2022, 2021 Main, 2021 Resit, 2018/19, 2017, 2016, 2014, 2013, 2011, 2010) Classification of drugs used in heart failure management, with benefit of each class: 1. Diuretics (loop — furosemide; thiazide) – relieve congestion/oedema by reducing preload; symptomatic relief only, no clear mortality benefit alone. 2. ACE inhibitors (e.g., Lisinopril, Enalapril) / ARBs (e.g., Candesartan, Losartan) – reduce afterload and preload, block deleterious RAAS-mediated remodeling; proven mortality benefit. 3. Beta-blockers (Bisoprolol, Carvedilol, Metoprolol succinate) – block chronic sympathetic overactivation that drives remodeling and arrhythmia; proven mortality benefit (started at low dose, titrated slowly). 4. Mineralocorticoid receptor antagonists (Spironolactone, Eplerenone) – block aldosterone-mediated fibrosis/remodeling and sodium retention; mortality benefit in moderate-severe HF (RALES trial). 5. Cardiac glycosides (Digoxin) – positive inotrope; improves symptoms and reduces hospitalization but no mortality benefit; useful especially in HF with atrial fibrillation. 6. Vasodilators (Hydralazine + Isosorbide dinitrate) – reduce afterload/preload; particularly beneficial in African-American patients per A-HeFT trial, or when ACEi/ARB contraindicated. 7. ARNI (Sacubitril/Valsartan) – combines neprilysin inhibition (↑ natriuretic peptides) with ARB; superior mortality benefit to ACEi in modern guidelines. 8. SGLT2 inhibitors (Dapagliflozin, Empagliflozin) – newer addition with proven mortality/hospitalization benefit regardless of diabetes status. Mechanism of action and pharmacological effects of cardiac glycosides (Digoxin): • Inhibits the Na⁺/K⁺-ATPase on the cardiac myocyte membrane → intracellular Na⁺ accumulates → reduced Na⁺ gradient decreases activity of the Na⁺/Ca²⁺ exchanger (which normally extrudes Ca²⁺ in exchange for Na⁺ influx) → intracellular Ca²⁺ accumulates → increased Ca²⁺ available for release from sarcoplasmic reticulum during excitation-contraction coupling → positive inotropy (increased force of contraction). • Vagomimetic (parasympathomimetic) action – increases vagal tone, slowing AV nodal conduction and sinus rate → useful for rate control in atrial fibrillation/flutter. • Increases automaticity at higher/toxic concentrations, predisposing to ectopic arrhythmias. Indications: Heart failure with reduced ejection fraction (particularly with concomitant atrial fibrillation), rate control in AF/flutter. Digitalis intoxication: • Predisposing factors: hypokalemia (increases digoxin binding to Na/K-ATPase), hypomagnesemia, hypercalcemia, renal impairment (reduced excretion), hypothyroidism, drug interactions (quinidine, verapamil, amiodarone displace digoxin/ reduce clearance). • Manifestations: GI (nausea, vomiting, anorexia), visual disturbances (yellow-green vision, halos — xanthopsia), cardiac arrhythmias (the most dangerous — premature ventricular contractions, bigeminy, AV block, ventricular tachycardia/fibrillation — due to increased automaticity and delayed conduction), CNS (confusion, delirium). • Treatment: stop digoxin, correct electrolytes (especially potassium), digoxin-specific antibody fragments (Digibind/DigiFab) for severe toxicity, antiarrhythmics (lidocaine, phenytoin) for ventricular arrhythmias, avoid quinidine/procainamide (can worsen), temporary pacing for severe bradyarrhythmia/AV block.
Diuretics — Classification and Principal Benefit of Each Class
Standard Answer:
(2023 Main, 2023 Resit, 2021 Main, 2021 Resit, 2018/19, 2017, 2016, 2013, 2012, 2010 — recurs in nearly every year) Class Example(s) Mechanism Principal benefit/use Loop Furosemide, Bumetanide Inhibit Na⁺/K⁺/2Cl⁻ Most potent diuretics — used diuretics cotransporter in in acute pulmonary oedema, thick ascending severe heart failure, limb of loop of refractory oedema Henle Thiazides Hydrochlorothiazide, Inhibit Na⁺/Cl⁻ First-line for hypertension; Chlorthalidone cotransporter in mild diuresis; ↓ urinary distal convoluted calcium (useful in tubule nephrolithiasis with hypercalciuria) Potassium- Spironolactone Block Na⁺ Used with loop/thiazide to sparing (aldosterone antagonist), reabsorption in prevent hypokalemia; diuretics Amiloride/Triamterene collecting duct/ spironolactone specifically (ENaC blockers) distal tubule, beneficial in heart failure reduce K⁺ (anti-remodeling) and secretion hyperaldosteronism Carbonic Acetazolamide Inhibit carbonic Glaucoma (↓ aqueous humor anhydrase anhydrase in formation), altitude sickness, inhibitors proximal tubule, metabolic alkalosis reducing HCO3⁻ correction reabsorption Osmotic Mannitol Osmotically retains Cerebral oedema, acute diuretics water in tubule glaucoma, prevention of lumen, especially acute renal failure (some proximal tubule settings) and descending limb Mechanism/pharmacology/side effects of Furosemide (2016): Inhibits the Na-K-2Cl symporter in the thick ascending limb, abolishing the countercurrent multiplication mechanism, producing profound natriuresis and loss of concentrating ability. Adverse effects: hypokalemia, hypomagnesemia, hyponatremia, metabolic alkalosis (due to increased H+ and K+ secretion distally from increased Na+ delivery and secondary hyperaldosteronism), ototoxicity (especially with rapid IV administration or with aminoglycosides), hyperuricemia (competes with urate for tubular secretion), hyperglycemia. Amiloride pharmacology (2018): Blocks epithelial sodium channels (ENaC) in the collecting duct principal cells, independent of aldosterone; causes mild natriuresis with potassium retention (potassium-sparing); used with kaliuretic diuretics to prevent hypokalemia; risk of hyperkalemia, especially combined with ACEi/ARB/spironolactone or in renal impairment. Named mineralocorticoid antagonist — mechanism, uses, side effects (2013): Spironolactone – competitively antagonizes aldosterone at the mineralocorticoid receptor in the collecting duct, reducing Na⁺ reabsorption and K⁺/H⁺ secretion. Uses: heart failure (mortality benefit via anti-fibrotic/anti-remodeling effect), primary hyperaldosteronism (Conn’s syndrome), resistant hypertension, ascites in cirrhosis, hirsutism/PCOS (antiandrogen effect). Side effects: hyperkalemia, gynecomastia and menstrual irregularities (due to antiandrogenic/progestogenic activity — less with eplerenone, a more selective analogue), GI upset. “Diuretic breaking” phenomenon (2023 Main): Refers to the reduced natriuretic response to continued diuretic administration, occurring via two mechanisms — (1) short-term braking, where acute diuresis activates compensatory neurohormonal mechanisms (RAAS activation, sympathetic activation) that promote sodium retention at other nephron segments, and (2) long-term braking, where chronic loop diuretic use causes hypertrophy of the distal convoluted tubule, increasing its Na⁺ reabsorptive capacity (“post-diuretic Na+ retention” and distal nephron adaptation). Justification for adding thiazides in hypertension management (sequential nephron blockade): combining a thiazide with a loop diuretic blocks the compensatory distal tubular sodium reabsorption that develops with loop diuretic monotherapy, restoring diuretic efficacy in resistant oedema — this is the basis of “sequential nephron blockade.”
Heparin vs Warfarin
Standard Answer:
(2023 Main, 2022 Main, 2021 Main, 2018/19, 2017, 2016, 2013 — recurs constantly) Feature Heparin Warfarin Mechanism Binds antithrombin III, Inhibits vitamin K epoxide reductase, accelerating its inhibition of preventing regeneration of reduced thrombin (factor IIa) and factor vitamin K, needed for γ-carboxylation Xa (unfractionated heparin (activation) of clotting factors II, VII, IX, X inhibits both; LMWH mainly and proteins C and S factor Xa) Route Parenteral (IV/SC) Oral Onset of action Immediate Delayed (2–3 days) — because it only prevents synthesis of new clotting factors; existing factors must first be cleared Monitoring aPTT (unfractionated heparin); INR (International Normalized Ratio) LMWH generally doesn’t require routine monitoring (anti-Xa if needed) Reversal Protamine sulfate (chemical Vitamin K (slow, takes hours); fresh frozen antagonism — binds and plasma or prothrombin complex neutralizes heparin) concentrate for rapid reversal Mechanism of Acts directly on already- Acts by blocking synthesis of new factors action circulating factors/antithrombin — hence delayed onset (existing factors explaining — hence rapid onset and rapid must degrade, which takes days, reflecting onset/reversal reversal with protamine their individual half-lives, especially factor difference II with a ~60hr half-life) and delayed reversal (new factors must be synthesized after vitamin K is given) Use in Safe (does not cross placenta) Contraindicated (teratogenic, crosses pregnancy placenta) Toxicity Heparin-induced Bleeding, skin necrosis (early, due to monitoring thrombocytopenia (HIT) — transient protein C/S deficiency before concern immune-mediated other factors fall) Direct oral anticoagulants (DOACs) vs traditional anticoagulants (2023 Main): DOACs (Dabigatran — direct thrombin/factor IIa inhibitor; Rivaroxaban, Apixaban, Edoxaban — direct factor Xa inhibitors) act directly on a single coagulation factor without requiring antithrombin as a cofactor (unlike heparin) or vitamin K-dependent synthesis (unlike warfarin). Advantages: predictable pharmacokinetics allowing fixed dosing without routine monitoring, fewer food/drug interactions, rapid onset and offset of action, lower risk of intracranial hemorrhage. Disadvantages: limited/specific reversal agents (idarucizumab for dabigatran; andexanet alfa for factor Xa inhibitors), higher cost, contraindicated in severe renal impairment (especially dabigatran, renally cleared), not established in mechanical heart valves or antiphospholipid syndrome.
Antihypertensive Drugs — Classification, ACEi/ARB Comparison, RAAS
Standard Answer:
(2023 Main [via RAAS], 2022 Main, 2018/19, 2016, 2013, 2012, 2010 — recurs heavily) Classification of antihypertensive drugs with one example per class: 1. Diuretics – Hydrochlorothiazide 2. Beta-blockers – Atenolol 3. Calcium channel blockers – dihydropyridines (Amlodipine); non-dihydropyridines (Verapamil, Diltiazem) 4. ACE inhibitors – Lisinopril 5. Angiotensin receptor blockers (ARBs) – Losartan/Candesartan 6. Direct renin inhibitors – Aliskiren 7. Alpha-1 blockers – Prazosin 8. Centrally-acting sympatholytics – Clonidine, Methyldopa (used in pregnancy) 9. Direct vasodilators – Hydralazine, Minoxidil
Aldosterone antagonists – Spironolactone
Standard Answer:
Role of RAAS in blood pressure regulation and pharmacological interventions: Renin (released from juxtaglomerular cells in response to ↓ renal perfusion, ↓ Na+ delivery to macula densa, or ↑ sympathetic activity) cleaves angiotensinogen to angiotensin I; ACE (mainly in pulmonary vasculature) converts angiotensin I to angiotensin II, a potent vasoconstrictor that also stimulates aldosterone release (Na+/water retention) and directly promotes cardiac/vascular remodeling. • Direct renin inhibitors (aliskiren) block the rate-limiting step. • ACE inhibitors block conversion of AT-I to AT-II, also preventing breakdown of bradykinin (a vasodilator) — contributing to their antihypertensive effect but also causing the characteristic dry cough and risk of angioedema. • ARBs block the AT1 receptor directly, without affecting bradykinin metabolism — hence lower incidence of cough. • Aldosterone antagonists (spironolactone) block the downstream mineralocorticoid effect. Comparison of Lisinopril (ACEi) and Candesartan (ARB): • Both reduce blood pressure and afford renal/cardiac protection by interrupting the RAAS; both are used in hypertension, heart failure, and diabetic nephropathy. • Lisinopril additionally increases bradykinin (via ACE inhibition), which contributes to efficacy but also causes a dry cough (up to 20%) and a small risk of angioedema. • Candesartan does not affect bradykinin metabolism, giving a similar antihypertensive/ renoprotective effect with a much lower incidence of cough and angioedema, making it a preferred alternative in patients intolerant of ACE inhibitors. • Both are contraindicated in pregnancy (fetotoxic) and require caution in bilateral renal artery stenosis (risk of acute renal failure) and in hyperkalemia. Verapamil mechanism in Hypertension, Arrhythmia, Angina (2018): Non-dihydropyridine calcium channel blocker, blocking L-type Ca²⁺ channels in vascular smooth muscle and cardiac tissue (SA/AV node, myocardium). * Hypertension: vasodilation of arterioles → ↓ peripheral vascular resistance. * Arrhythmia: slows conduction through the AV node (negative dromotropic effect) — used for supraventricular tachyarrhythmias (e.g., AVNRT, rate control in AF). * Angina: reduces myocardial oxygen demand via negative inotropy/chronotropy and reduces afterload via vasodilation; also relieves coronary vasospasm (useful in Prinzmetal/vasospastic angina). * Adverse effects: constipation, bradycardia, AV block, negative inotropy (caution in heart failure), avoid combining with β-blockers (risk of severe bradycardia/heart block). Propranolol as antihypertensive, antianginal, antiarrhythmic (2014, 2013): * Non-selective β-blocker (β1 and β2). * Antihypertensive: ↓ cardiac output (negative inotropy/ chronotropy), ↓ renin release from JG cells (β1-mediated), possible central sympatholytic effect. * Antianginal: ↓ heart rate and contractility → ↓ myocardial O2 demand; prolongs diastole → improved coronary perfusion. * Antiarrhythmic (Class II — Vaughan Williams): ↓ sympathetic drive to SA/AV node, ↓ automaticity, slows AV conduction — useful for supraventricular arrhythmias, rate control in AF, and post-MI arrhythmia prophylaxis. * Adverse effects: bronchospasm (β2 blockade — contraindicated in asthma), bradycardia, heart block, fatigue, masking of hypoglycemia symptoms in diabetics, rebound hypertension/tachycardia on abrupt withdrawal. Hydralazine and Isosorbide Dinitrate (2011): * Hydralazine – direct arteriolar vasodilator (mechanism not fully clear, possibly via NO release/K+ channel opening in smooth muscle); reduces afterload; reflex tachycardia and fluid retention are common (often combined with a β-blocker and diuretic); used in heart failure (with nitrates, especially in African-American patients per A-HeFT), hypertensive emergencies, and safe in pregnancy-related hypertension. * Isosorbide dinitrate – organic nitrate, metabolized to nitric oxide, which activates guanylate cyclase → ↑ cGMP → smooth muscle relaxation; predominantly venodilation at lower doses (↓ preload), arteriolar dilation at higher doses; used in angina and, combined with hydralazine, in heart failure. Nitroglycerin pharmacology and interaction with Sildenafil (2015): Nitroglycerin releases NO, activating guanylate cyclase, raising cGMP, causing venodilation (↓ preload, ↓ myocardial O2 demand) and, at higher doses, coronary and arteriolar dilation — used in angina, acute coronary syndrome, hypertensive emergencies, and (as sodium nitroprusside) hypertensive crises. Sildenafil, a PDE-5 inhibitor, prevents breakdown of cGMP, potentiating and prolonging the vasodilatory effect of nitrates — co-administration causes severe, potentially fatal hypotension; concurrent nitrate use with PDE-5 inhibitors is absolutely contraindicated. Sodium nitroprusside (2015): Direct arterial and venous vasodilator, releases NO spontaneously (non-enzymatically); used IV for hypertensive emergencies; metabolized to cyanide, which is further converted to thiocyanate — risk of cyanide toxicity with prolonged use/high doses, especially in renal/hepatic impairment; requires light protection (photosensitive). Minoxidil (2015): Prodrug activated to minoxidil sulfate, opens ATP-sensitive K+ channels in vascular smooth muscle → hyperpolarization → relaxation, causing potent arteriolar vasodilation; used in severe/resistant hypertension; adverse effects: reflex tachycardia, fluid retention, hypertrichosis (also used topically for androgenetic alopecia). Captopril mechanism (2014, 2013): ACE inhibitor (see Q above); mechanism of action in heart failure — reduces afterload (via ↓AT-II) and preload (via ↓aldosterone-mediated Na+/ water retention), and blunts pathological cardiac remodeling. Atropine as pre-anaesthetic agent, Dopamine in cardiogenic shock, Prazosin in BPH, Ethanol in ethylene glycol poisoning (2016): * Atropine (pre-anaesthetic): antimuscarinic — reduces airway/salivary secretions and prevents vagally-mediated bradycardia during intubation/surgical manipulation. * Dopamine in cardiogenic shock: dose-dependent receptor activation — low dose (renal/dopaminergic D1 receptors, renal vasodilation), moderate dose (β1, positive inotropy/chronotropy — the basis for use in cardiogenic shock to improve contractility and cardiac output), high dose (α1, vasoconstriction). * Prazosin in BPH: α1-blockade relaxes smooth muscle in the prostate capsule and bladder neck, relieving bladder outlet obstruction. * Ethanol in ethylene glycol poisoning: ethanol competitively inhibits alcohol dehydrogenase (higher affinity than ethylene glycol/methanol), preventing formation of toxic metabolites (glycolic/oxalic acid from ethylene glycol; formic acid from methanol) — fomepizole is now the preferred, more specific antidote by the same mechanism.
Antiarrhythmic Drugs — Vaughan Williams Classification
Standard Answer:
(2016, 2014, 2013, 2010) Class Mechanism Examples Class I (Na+ channel Block fast Na+ IA: Quinidine, Procainamide (moderate Na blockers) channels, slow phase block, prolong AP); IB: Lidocaine, Mexiletine 0 depolarization (mild Na block, shorten AP, selective for ischemic/depolarized tissue); IC: Flecainide, Propafenone (marked Na block, minimal effect on AP duration) Class II (β-blockers) ↓ sympathetic drive, ↓ Propranolol, Esmolol, Metoprolol automaticity, slow AV conduction Class III (K+ channel Prolong Amiodarone, Sotalol, Dofetilide blockers) repolarization/action potential duration, prolong refractory period Class IV (Ca²⁺ Slow conduction Verapamil, Diltiazem channel blockers, through AV node non-dihydropyridine) Unclassified agents Adenosine – activates A1 receptors, opens K+ channels, hyperpolarizes and transiently blocks AV node (drug of choice for terminating AVNRT); Digoxin – vagomimetic AV nodal slowing; Magnesium sulfate – used in torsades de pointes Advantages of Vaughan Williams classification: provides a logical framework linking electrophysiological mechanism to clinical choice of drug for a specific arrhythmia; aids in predicting drug interactions and additive toxicity (e.g., avoiding combining multiple QT-prolonging Class III agents); facilitates teaching and recall. Limitations: some drugs have multiple mechanisms across classes (e.g., amiodarone has Class I, II, III, and IV properties), and the system does not fully capture the complexity of arrhythmia mechanisms (e.g., re-entry vs automaticity).
Bronchial Asthma / COPD — Drug Classification
Standard Answer:
(2023 Main [via System 2 overlap], 2022 Main, 2021 Resit, 2018/19, 2017, 2016, 2012, 2010 — recurs heavily) Classification: 1. Relievers (bronchodilators) ◦ Short-acting β2-agonists (SABA): Salbutamol, Terbutaline — rapid relief of acute bronchospasm. ◦ Long-acting β2-agonists (LABA): Salmeterol, Formoterol — maintenance, always with inhaled corticosteroid. ◦ Anticholinergics: Ipratropium (short-acting), Tiotropium (long-acting) — block M3 receptor-mediated bronchoconstriction, particularly useful in COPD. ◦ Methylxanthines: Theophylline, Aminophylline — inhibit phosphodiesterase (↑ cAMP) and antagonize adenosine receptors; narrow therapeutic index. 2. Controllers (anti-inflammatory) ◦ Inhaled corticosteroids: Beclomethasone, Fluticosone, Budesonide — reduce airway inflammation, the cornerstone of persistent asthma control. ◦ Leukotriene modifiers: Montelukast (receptor antagonist), Zileuton (5-lipoxygenase inhibitor) — block leukotriene-mediated bronchoconstriction/inflammation. ◦ Mast cell stabilizers: Cromolyn sodium, Nedocromil — prevent mast cell degranulation (mainly prophylactic, exercise-induced asthma). ◦ Anti-IgE: Omalizumab — for severe allergic asthma. Choice of reliever vs controller (justification): Relievers (SABAs) act rapidly via β2-receptor-mediated bronchial smooth muscle relaxation (↑ cAMP via Gs-coupled receptor activation of adenylate cyclase), providing quick symptomatic relief during an acute attack, but do not address underlying airway inflammation and, if overused, are associated with tachyphylaxis/increased mortality risk in severe asthma. Controllers (inhaled corticosteroids) act on the underlying inflammatory process (reducing cytokine production, eosinophilic infiltration, mucosal oedema) and thus prevent exacerbations and preserve lung function over time, but have delayed onset and are not useful for acute symptom relief — hence the combined strategy of “reliever for symptoms, controller for underlying disease.” Advantages of nebulization/aerosolization: * Delivers drug directly to the airway, achieving high local concentrations with minimal systemic absorption/side effects. * More rapid onset of action for acute bronchospasm compared to oral/systemic routes. * Allows lower total doses to achieve therapeutic effect at the target organ. * Useful in patients (e.g., young children, the very dyspneic) who cannot effectively use metered-dose inhalers. * Reduces systemic adverse effects of corticosteroids and β-agonists compared to oral/ parenteral administration. Theophylline (mechanism, adverse effects) (2010): Non-selective phosphodiesterase inhibitor (↑ cAMP/cGMP, bronchodilation) and adenosine receptor antagonist (adenosine causes bronchoconstriction); also has mild anti-inflammatory and diaphragmatic-strengthening effects. Narrow therapeutic index — adverse effects include nausea, tremor, insomnia, tachyarrhythmias, and seizures at toxic levels; metabolism via CYP1A2 makes it prone to interactions (e.g., levels increased by cimetidine, ciprofloxacin; decreased by smoking, rifampin, phenytoin). Hydrocortisone in asthma (2010): Systemic glucocorticoid used in acute severe asthma exacerbations; suppresses airway inflammation via genomic mechanisms (inhibits NF-κB, reduces synthesis of pro-inflammatory cytokines, upregulates β2-receptor expression/ responsiveness — reverses β2-agonist tachyphylaxis); onset delayed (hours), hence given early in an exacerbation alongside bronchodilators. Zileuton pharmacology (2018): 5-Lipoxygenase inhibitor, blocking the synthesis of leukotrienes (LTB4, LTC4/D4/E4 — the cysteinyl leukotrienes responsible for bronchoconstriction, mucus secretion, and inflammatory cell recruitment) from arachidonic acid; used as add-on controller therapy in asthma; requires monitoring of liver function (hepatotoxicity risk); less commonly used than montelukast due to dosing frequency and hepatotoxicity.
Dyslipidemia — Drug Classification, Statins, Cholestyramine
Standard Answer:
(2018, 2016, 2014, 2013) Classification of drugs used in dyslipidemia: 1. HMG-CoA reductase inhibitors (statins): Atorvastatin, Simvastatin, Lovastatin, Rosuvastatin — inhibit the rate-limiting enzyme in hepatic cholesterol synthesis, upregulating LDL receptors → ↓ LDL-C (most effective for LDL lowering; also modest ↓ triglycerides, ↑ HDL). 2. Bile acid sequestrants (resins): Cholestyramine, Colestipol — bind bile acids in the gut, interrupting enterohepatic circulation, forcing hepatic conversion of cholesterol to new bile acids, upregulating LDL receptors. 3. Fibrates: Gemfibrozil, Fenofibrate — activate PPAR-α, ↑ lipoprotein lipase activity → primarily ↓ triglycerides, modest ↑ HDL. 4. Niacin (nicotinic acid): ↓ VLDL secretion (↓ triglycerides), ↑ HDL, ↓ LDL; limited by flushing (prostaglandin-mediated). 5. Cholesterol absorption inhibitors: Ezetimibe — blocks intestinal NPC1L1 transporter, ↓ dietary/biliary cholesterol absorption. 6. PCSK9 inhibitors: Evolocumab, Alirocumab — monoclonal antibodies preventing LDL receptor degradation, markedly ↓ LDL-C. Cholestyramine pharmacology: Non-absorbed anion-exchange resin; binds bile acids in the intestinal lumen, increasing their faecal excretion; this depletes the bile acid pool, upregulating hepatic 7α-hydroxylase and converting more cholesterol to bile acids, which in turn upregulates hepatic LDL receptors, increasing LDL clearance from plasma. Adverse effects: GI (bloating, constipation), impaired absorption of fat-soluble vitamins and other drugs (must separate dosing by hours), can raise triglycerides. Lovastatin pharmacology: Statin — competitively inhibits HMG-CoA reductase; adverse effects: myopathy/rhabdomyolysis (risk increased with fibrates, especially gemfibrozil — inhibits statin glucuronidation), hepatotoxicity (transaminase elevation), teratogenic (contraindicated in pregnancy).
Antihistamines (H1 receptor antagonists)
Standard Answer:
(2018, 2012) Classification: • First-generation (sedating): Diphenhydramine, Chlorpheniramine, Promethazine — lipophilic, cross blood-brain barrier, cause sedation and antimuscarinic effects. • Second-generation (non-sedating): Loratadine, Cetirizine, Fexofenadine — more selective for peripheral H1 receptors, minimal CNS penetration (P-glycoprotein substrate), less sedation. Clinical uses: allergic rhinitis, urticaria, allergic conjunctivitis, as adjuncts in anaphylaxis (after epinephrine), motion sickness and antiemetic (first-generation, e.g., promethazine, via central antimuscarinic/antihistaminic action), sedation/sleep aid (first-generation, off-label), pre-medication before blood transfusion/contrast administration. Adverse effects: First-generation — sedation, antimuscarinic effects (dry mouth, blurred vision, urinary retention), paradoxical excitation in children. Second-generation — generally well tolerated; rare cardiotoxicity (QT prolongation) with some early agents (terfenadine, astemizole — withdrawn) due to CYP3A4 interactions.
Rat Tail Flick Method / Pharmacology Laboratory Equipment
Standard Answer:
(Part II Resit — miscellaneous practical question) Five pharmacology laboratory equipment and uses: 1. Organ bath – for studying isolated tissue responses (e.g., guinea pig ileum, rat vas deferens) to drugs, measuring contraction/relaxation. 2. Kymograph/Physiograph (or digital data acquisition system) – records mechanical responses (contractions) of isolated tissue over time. 3. Rat tail flick apparatus (analgesiometer) – measures nociceptive/analgesic response by timing tail-withdrawal latency from a heat stimulus. 4. Sherrington’s rotating drum / smoked drum – historical recording device for muscle contraction tracings. 5. Animal restrainers/cages, dosing needles (gavage) – for controlled drug administration to laboratory animals. Rat tail flick experiment design: Rats are gently restrained; a radiant heat source (or hot water/hot plate) is applied to the tail, and the latency to tail withdrawal (“flick”) is recorded as the baseline. A test analgesic drug (e.g., morphine) is then administered, and the tail flick latency is re-measured at set time intervals; an increase in latency indicates an analgesic effect. A control group receiving vehicle/saline is included, and the effect can be reversed with an opioid antagonist (naloxone) to confirm the specificity of the analgesic mechanism.