Introduction to Anti-anginals, Diuretics & Antihypertensive Agents
This massive cardiovascular unit covers three interconnected drug classes. Anti-anginals relieve the crushing chest pain of angina by dilating coronary arteries or reducing cardiac workload. Diuretics increase urine output to reduce blood volume and edema. Antihypertensives lower dangerously high blood pressure through multiple mechanisms — from ACE inhibition to central sympatholytic action. Understanding the chemical basis of each mechanism is essential.
Syllabus & Topics
- 1Anti-anginal Agents – Introduction: Angina pectoris = chest pain due to myocardial ischemia (oxygen demand > supply). Three drug strategies: (1) Reduce oxygen demand. (2) Increase coronary blood supply. (3) Both.
- 2Vasodilators – Organic Nitrates: Amyl nitrite (rapid-acting inhalant), Nitroglycerin/GTN (sublingual, prototype – releases NO → activates guanylyl cyclase → ↑cGMP → smooth muscle relaxation), Pentaerythritol tetranitrate (long-acting), Isosorbide dinitrate (prophylactic oral use).
- 3Vasodilators – Non-Nitrate: Dipyridamole – inhibits phosphodiesterase → ↑cAMP → vasodilation. Also inhibits adenosine uptake. Used as antiplatelet + anti-anginal.
- 4Calcium Channel Blockers – Phenylalkylamine: Verapamil – selective for cardiac calcium channels (Class IV antiarrhythmic), reduces heart rate and contractility. Used in supraventricular tachycardia.
- 5Calcium Channel Blockers – Benzothiazepine: Diltiazem HCl – intermediate selectivity between cardiac and vascular smooth muscle. Bepridil HCl – also blocks sodium channels.
- 6Calcium Channel Blockers – Dihydropyridines: Nifedipine (prototype – potent vasodilator, reflex tachycardia), Amlodipine (ultra-long acting, once daily), Felodipine, Nicardipine, Nimodipine (selective for cerebral vessels – subarachnoid hemorrhage).
- 7Diuretics – Carbonic Anhydrase Inhibitors (CAIs): Acetazolamide (prototype), Methazolamide, Dichlorphenamide. Inhibit carbonic anhydrase in proximal tubule → ↓HCO₃⁻ reabsorption → mild diuresis. Also used in glaucoma (↓aqueous humor production).
- 8Diuretics – Thiazides: Chlorothiazide (prototype), Hydrochlorothiazide (most commonly prescribed), Hydroflumethiazide, Cyclothiazide. Act on distal convoluted tubule → inhibit Na⁺/Cl⁻ co-transporter. Moderate efficacy. First-line antihypertensive.
- 9Diuretics – Loop Diuretics: Furosemide (Lasix – most powerful), Bumetanide (40x more potent than furosemide), Ethacrynic acid (only non-sulfonamide loop diuretic – safe in sulfa allergy). Act on thick ascending limb of loop of Henle → inhibit Na⁺/K⁺/2Cl⁻ co-transporter. High ceiling diuretics.
- 10Diuretics – Potassium-Sparing: Spironolactone (aldosterone antagonist – competitive), Triamterene, Amiloride (block epithelial sodium channels ENaC in collecting duct). Weak diuretics but prevent dangerous hypokalemia when combined with thiazides.
- 11Diuretics – Osmotic: Mannitol – freely filtered, not reabsorbed → osmotically retains water in tubular lumen. IV only. Used for cerebral edema, acute renal failure, and glaucoma.
- 12Antihypertensive – ACE Inhibitors: Captopril (first oral ACE inhibitor, contains sulfhydryl group), Enalapril (prodrug → enalaprilat), Lisinopril (active drug, no hepatic activation needed), Benazepril HCl, Quinapril HCl. Inhibit Angiotensin Converting Enzyme → ↓Angiotensin II → ↓aldosterone → vasodilation + natriuresis.
- 13Antihypertensive – Centrally Acting: Methyldopate HCl (prodrug → α-methylnorepinephrine → stimulates central α2 receptors → ↓sympathetic outflow), Clonidine HCl (direct central α2 agonist), Guanabenz acetate.
- 14Antihypertensive – Adrenergic Neuron Blockers: Guanethidine monosulphate – depletes norepinephrine from peripheral sympathetic nerve terminals. Reserpine – irreversibly blocks VMAT → depletes catecholamine stores → depression (major side effect).
Learning Objectives
Frequently Asked Questions (FAQs)
Q1. How Does Nitroglycerin Relieve Angina?
Nitroglycerin is metabolized to release nitric oxide (NO), which activates soluble guanylyl cyclase and increases intracellular cGMP levels. Elevated cGMP causes smooth muscle relaxation, leading to venodilation (reducing preload), coronary artery dilation (increasing oxygen supply), and decreased myocardial oxygen demand, thereby relieving anginal pain.
Q2. Why Is Nifedipine Different from Verapamil?
Both Nifedipine and Verapamil are calcium channel blockers. Nifedipine primarily acts on vascular smooth muscle, producing potent vasodilation and reflex tachycardia. Verapamil predominantly affects cardiac tissue, decreasing heart rate and contractility, and is therefore preferred in arrhythmias, while nifedipine is commonly used in hypertension.
Q3. Why Is Furosemide Called a “High-Ceiling” Diuretic?
Furosemide acts on the thick ascending limb of the Loop of Henle by inhibiting the Na⁺/K⁺/2Cl⁻ co-transporter. Since this segment reabsorbs about 25–30% of filtered sodium, its inhibition results in profound diuresis, with up to 15–25% of filtered sodium excreted. This large effect gives it a “high-ceiling” compared to thiazides, which act on the distal convoluted tubule and affect only about 5% of sodium reabsorption.
Q4. What Is the Mechanism of ACE Inhibitors Like Captopril?
Captopril competitively inhibits angiotensin-converting enzyme (ACE), blocking the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. This reduces aldosterone secretion (decreasing sodium and water retention) and increases bradykinin levels by preventing its degradation. The overall effect is vasodilation and blood pressure reduction. The sulfhydryl group in captopril binds to the zinc ion at the active site of ACE.
Q5. Why Does Reserpine Cause Depression?
Reserpine irreversibly inhibits the vesicular monoamine transporter (VMAT2), preventing storage of norepinephrine, dopamine, and serotonin in synaptic vesicles. These neurotransmitters are subsequently degraded in the cytoplasm, leading to depletion of brain monoamines, particularly serotonin, which can result in severe depression.