Antihypertensive Drugs

Hypertension is the single most exam-rich topic in cardiovascular pharmacology, and NEET PG loves it because it sits at the crossroads of physiology, pharmacology and clinical medicine. A solid candidate is expected to know not only the mechanism of each class but, far more importantly, the drug of choice (DOC) in a specific clinical scenario — pregnancy, diabetic nephropathy, isolated systolic hypertension, a hypertensive emergency in a young asthmatic, and so on. The examiners also reliably mine the class-specific adverse effects (ACE inhibitor cough, dihydropyridine ankle oedema, methyldopa-induced positive Coombs test) because these are clean, single-best-answer facts.

This note walks through the classification, mechanisms, indications, scenario-based drug of choice, adverse effects, contraindications and interactions, then ends with a stepwise clinical approach and a rapid-revision block. Targets to remember at the outset: the general BP goal is < 140/90 mmHg, tightened to < 130/80 mmHg in diabetics, chronic kidney disease (CKD) and established cardiovascular disease per current Indian/ACC-AHA practice.

Classification of antihypertensive drugs

The drugs fall into a handful of functional groups. The first-line agents for uncomplicated essential hypertension are the A/C/D trio (ACE inhibitor or ARB, Calcium channel blocker, Diuretic), with beta-blockers no longer routinely first-line unless there is a compelling indication.

Class	Prototype drugs	Primary site of action
ACE inhibitors	Enalapril, Ramipril, Lisinopril, Captopril	Angiotensin-converting enzyme
Angiotensin receptor blockers (ARBs)	Losartan, Telmisartan, Valsartan, Olmesartan	AT1 receptor
Calcium channel blockers (dihydropyridine)	Amlodipine, Nifedipine, Felodipine, Cilnidipine	Vascular L-type Ca²⁺ channels
Calcium channel blockers (non-dihydropyridine)	Verapamil, Diltiazem	Cardiac + vascular L-type channels
Thiazide / thiazide-like diuretics	Hydrochlorothiazide, Chlorthalidone, Indapamide	Distal convoluted tubule (Na-Cl symporter)
Loop diuretics	Furosemide, Torsemide	Thick ascending limb (NKCC2)
Potassium-sparing diuretics / MRAs	Spironolactone, Eplerenone, Amiloride	Collecting duct
Beta-blockers	Metoprolol, Atenolol, Bisoprolol, Carvedilol, Labetalol	β-adrenoceptors (± α)
Alpha-1 blockers	Prazosin, Terazosin, Doxazosin	Vascular α1 receptors
Centrally acting α2 agonists	Clonidine, Methyldopa, Guanfacine	Brainstem α2 / imidazoline receptors
Direct vasodilators	Hydralazine, Minoxidil	Arteriolar smooth muscle
Renin inhibitor	Aliskiren	Renin (juxtaglomerular)
Parenteral emergency agents	Sodium nitroprusside, Nitroglycerin, Esmolol, Fenoldopam, Nicardipine	Various

High-yield: Mnemonic for first-line classes — "ABCD": A = ACE inhibitor/ARB, B = Beta-blocker (now reserved for compelling indications), C = Calcium channel blocker, D = Diuretic.

Mechanism of action

The renin-angiotensin-aldosterone system (RAAS) is the central axis. Renin converts angiotensinogen to angiotensin I; ACE converts angiotensin I to angiotensin II, the potent vasoconstrictor that also drives aldosterone release.

• ACE inhibitors block conversion of angiotensin I to angiotensin II, reducing vasoconstriction and aldosterone-mediated salt/water retention. Because ACE is identical to kininase II, ACE inhibitors also raise bradykinin — this is the basis of the dry cough and angioedema.
• ARBs selectively block the AT1 receptor. They do not raise bradykinin, so cough and angioedema are far less frequent — the classic reason to switch an ACE-inhibitor-intolerant patient to an ARB.
• Dihydropyridine CCBs preferentially relax vascular smooth muscle (vasoselective), producing arteriolar dilation; reflex tachycardia can occur with short-acting agents.
• Non-dihydropyridine CCBs (verapamil > diltiazem) act on the AV node and myocardium, slowing heart rate and reducing contractility — hence useful in rate control but dangerous combined with beta-blockers.
• Thiazides inhibit the Na-Cl cotransporter in the DCT; the chronic antihypertensive effect is partly vasodilatory, not merely natriuretic.
• MRAs (spironolactone) antagonise aldosterone at the collecting duct — the key drug in resistant hypertension and primary hyperaldosteronism.
• Beta-blockers reduce cardiac output, inhibit renin release, and reduce central sympathetic outflow.
• Central α2 agonists (clonidine, methyldopa) stimulate presynaptic α2 receptors in the brainstem vasomotor centre, reducing sympathetic outflow. Methyldopa is a prodrug converted to α-methylnorepinephrine, a false transmitter.
• Sodium nitroprusside releases nitric oxide, dilating both arterioles and veins (balanced vasodilator); its metabolism liberates cyanide and then thiocyanate.

High-yield: ACE inhibitors and ARBs dilate the efferent glomerular arteriole, lowering intraglomerular pressure — this is the renoprotective mechanism in diabetic nephropathy, but also why an acute rise in serum creatinine (up to ~30%) is expected and acceptable on starting them.

Indications and drug of choice in specific scenarios

This is the most heavily examined section. Memorise the table as discrete one-to-one facts.

Clinical scenario	Drug of choice	Reason / key point
Hypertension in pregnancy (chronic)	Labetalol, Methyldopa, Nifedipine	Methyldopa has the longest safety record; labetalol is now often first
Pre-eclampsia / eclampsia (acute severe)	Labetalol or hydralazine IV (+ MgSO₄ for seizures)	MgSO₄ is for seizure prophylaxis, not BP
Diabetic nephropathy / proteinuria	ACE inhibitor or ARB	Reduce intraglomerular pressure, slow albuminuria
Isolated systolic hypertension (elderly)	Dihydropyridine CCB or thiazide	Target wide pulse pressure of stiff arteries
Resistant hypertension (on 3 drugs incl. diuretic)	Spironolactone	Add-on of choice per PATHWAY-2 trial
HTN with stable angina / post-MI	Beta-blocker (± ACE inhibitor)	Reduces myocardial O₂ demand, mortality benefit
HTN with heart failure (HFrEF)	ACE inhibitor/ARNI + beta-blocker + MRA	Mortality benefit triad
HTN with benign prostatic hyperplasia	Alpha-1 blocker (prazosin/tamsulosin)	Dual benefit on bladder outlet
Hypertensive emergency (general)	Sodium nitroprusside / labetalol / nicardipine	Lower MAP by ≤ 25% in first hour
Pheochromocytoma (pre-op)	Phenoxybenzamine first, then beta-blocker	Never beta-block first — unopposed α crisis
Aortic dissection	IV beta-blocker (esmolol/labetalol) first, then nitroprusside	Control dP/dt before vasodilating
Hypertensive emergency in pregnancy	Labetalol, hydralazine, nifedipine	Avoid nitroprusside (fetal cyanide)
Hypertension with migraine	Beta-blocker (propranolol) or CCB	Shared prophylactic benefit

High-yield: In pheochromocytoma, the sequence is α-blockade before β-blockade. Giving a beta-blocker first leaves α-mediated vasoconstriction unopposed, precipitating a hypertensive crisis. Eponym-style fact: phenoxybenzamine is a non-competitive (irreversible) α-blocker.

High-yield: ACE inhibitors / ARBs are absolutely contraindicated in pregnancy — they cause fetal renal dysgenesis, oligohydramnios and skull hypoplasia (second/third trimester teratogenicity). This is a recurrent single-best-answer trap when the stem mentions a pregnant diabetic with proteinuria — the answer is labetalol/methyldopa, NOT an ACE inhibitor.

Stepwise approach to the hypertensive patient

A clean algorithm to reproduce under exam pressure:

Confirm sustained elevation (≥ 140/90 on repeated readings or ABPM) → Stage and risk-stratify (look for target-organ damage and diabetes) → Start lifestyle measures (DASH diet, salt < 5 g/day, weight loss, exercise) → Choose first drug by comorbidity (ACE-I/ARB if diabetes/CKD; CCB or thiazide if elderly/ISH) → If not at target in 4 weeks, add a second class (A + C or A + D combination preferred) → Still uncontrolled, go to three drugs (A + C + D) → Resistant hypertension confirmed → add spironolactone → Refer / screen for secondary causes (renal artery stenosis, primary aldosteronism, pheochromocytoma).

High-yield: A single-pill A + C or A + D combination is preferred over uptitrating one drug — combination at low dose gives better BP control with fewer adverse effects (additive efficacy, opposing side-effect profiles).

Adverse effects

Drug class	Signature adverse effects (exam favourites)
ACE inhibitors	Dry cough (bradykinin), angioedema, hyperkalaemia, first-dose hypotension, acute kidney injury in bilateral renal artery stenosis, teratogenicity, dysgeusia (captopril)
ARBs	Hyperkalaemia, AKI in renal artery stenosis; no cough
Dihydropyridine CCBs	Pedal/ankle oedema (not fluid overload — precapillary dilation), flushing, headache, gingival hyperplasia (nifedipine), reflex tachycardia
Non-DHP CCBs	Bradycardia, AV block, constipation (verapamil), worsening heart failure
Thiazides	Hypokalaemia, hyponatraemia, hyperuricaemia (gout), hyperglycaemia, hypercalcaemia, hyperlipidaemia
Loop diuretics	Hypokalaemia, hypocalcaemia, ototoxicity, metabolic alkalosis
Spironolactone	Hyperkalaemia, gynaecomastia (eplerenone spares this)
Beta-blockers	Bradycardia, bronchospasm, fatigue, masking of hypoglycaemia, ↑ triglycerides, sexual dysfunction
Methyldopa	Positive direct Coombs test, autoimmune haemolytic anaemia, hepatotoxicity, sedation, ↑ prolactin
Clonidine	Sedation, dry mouth, rebound hypertension on abrupt withdrawal
Hydralazine	Drug-induced lupus (SLE), reflex tachycardia, fluid retention
Minoxidil	Hypertrichosis, pericardial effusion, marked fluid retention
Sodium nitroprusside	Cyanide/thiocyanate toxicity, methaemoglobinaemia
Alpha-1 blockers	First-dose orthostatic hypotension (give at bedtime)

High-yield mnemonics:

• Thiazide metabolic effects — the "hyper-G-L-U-C" / 4 hypers and 3 hypos": hyperGlycaemia, hyperLipidaemia, hyperUricaemia, hyperCalcaemia; hypoKalaemia, hypoNatraemia, hypoMagnesaemia.
• Methyldopa = positive Coombs. Classic two-liner pairing in NEET PG.
• Hydralazine + procainamide + isoniazid are the prototypical drug-induced lupus triad ("HIP").

High-yield: The ACE-inhibitor cough is dry, non-productive, occurs in roughly 5–20% (higher in women and Asians), is dose-independent, may take weeks to appear and weeks to resolve. Management = switch to an ARB.

High-yield: CCB-induced ankle oedema results from preferential precapillary (arteriolar) dilation raising capillary hydrostatic pressure; it is not responsive to diuretics. Adding an ACE inhibitor/ARB (which dilates the postcapillary venule too) reduces it.

Contraindications

Drug / class	Key contraindications
ACE inhibitors / ARBs	Pregnancy, bilateral renal artery stenosis, hyperkalaemia, history of angioedema
Non-DHP CCBs (verapamil/diltiazem)	HFrEF, 2nd/3rd-degree AV block, combination with beta-blockers
Beta-blockers	Severe asthma/COPD, sick sinus syndrome, high-grade AV block, acute decompensated HF, cocaine-induced HTN (unopposed α), pheochromocytoma before α-blockade
Thiazides	Gout, severe hyponatraemia, sulfa allergy (relative)
Spironolactone	Hyperkalaemia, severe renal impairment, Addison's disease
Methyldopa	Active hepatic disease, pheochromocytoma
Sodium nitroprusside	Pregnancy (fetal cyanide), hepatic/renal failure (toxic metabolite accumulation)
Aliskiren	Combination with ACE-I/ARB (esp. in diabetes — ALTITUDE trial harm)

High-yield: In cocaine-associated chest pain/hypertension, beta-blockers are avoided (unopposed alpha vasoconstriction → coronary spasm); use benzodiazepines and CCBs/nitrates.

Drug interactions

• ACE-I/ARB + potassium-sparing diuretic or potassium supplements → dangerous hyperkalaemia.
• ACE-I/ARB + NSAIDs → reduced antihypertensive effect and AKI ("triple whammy" when a diuretic is also present).
• Verapamil/Diltiazem + beta-blocker → profound bradycardia, AV block, asystole risk.
• Sodium nitroprusside / nitrates + PDE-5 inhibitors (sildenafil) → catastrophic hypotension.
• Thiazides + lithium → reduced lithium clearance, lithium toxicity.
• Thiazides/loops + digoxin → hypokalaemia potentiates digoxin toxicity.
• Methyldopa / clonidine + tricyclic antidepressants → blunted antihypertensive effect.
• Clonidine + beta-blocker then abrupt clonidine withdrawal → severe rebound hypertension from unopposed α-stimulation.

High-yield: Never combine two RAAS blockers (ACE-I + ARB + aliskiren) routinely — the ONTARGET and ALTITUDE trials showed increased renal failure, hyperkalaemia and hypotension without outcome benefit.

Recently asked / exam angle

NEET PG and INI-CET stems have repeatedly tested the following angles, and they are worth rehearsing as direct recall:

• A pregnant woman with chronic hypertension — DOC is methyldopa / labetalol; ACE inhibitors are contraindicated. Examiners often disguise this by adding "with diabetes and proteinuria" to lure you toward an ACE inhibitor.
• A patient on an antihypertensive develops a dry persistent cough — identify the drug (ACE inhibitor) and the mediator (bradykinin); next step is switch to an ARB.
• Bilateral ankle oedema in a patient started on amlodipine — recognise it as a CCB class effect from precapillary dilation, not heart failure, and that diuretics do not help.
• Methyldopa and a positive direct Coombs test / autoimmune haemolytic anaemia — a recurring matched pair.
• Resistant hypertension on A+C+D — the add-on is spironolactone (PATHWAY-2).
• Pheochromocytoma management sequence — phenoxybenzamine (α) before beta-blocker.
• Sodium nitroprusside toxicity — cyanide accumulation; treatment with sodium thiosulfate / hydroxocobalamin; avoid in pregnancy and prolonged infusion.
• Aortic dissection — beta-blocker first to reduce shear stress (dP/dt) before adding a vasodilator.
• Drug causing lupus-like syndrome among antihypertensives — hydralazine.
• Cilnidipine — an L/N-type CCB that, unlike amlodipine, causes less pedal oedema and reduces sympathetic tone (a newer favourite distractor).

Rapid revision

• First-line classes for uncomplicated HTN = ACE-I/ARB, CCB, thiazide (A/C/D); beta-blockers only with compelling indication.
• DOC in pregnancy = methyldopa, labetalol, nifedipine; ACE-I/ARB absolutely contraindicated.
• DOC in diabetic nephropathy/proteinuria = ACE-I or ARB (efferent arteriolar dilation, renoprotective).
• DOC in isolated systolic hypertension of the elderly = dihydropyridine CCB or thiazide.
• Resistant hypertension add-on = spironolactone.
• ACE-inhibitor cough is due to bradykinin; switch to an ARB (no cough, no rise in bradykinin).
• Dihydropyridine CCBs cause ankle oedema (precapillary dilation), unresponsive to diuretics.
• Methyldopa → positive Coombs test and autoimmune haemolytic anaemia.
• Hydralazine → drug-induced lupus; minoxidil → hypertrichosis + pericardial effusion.
• Clonidine abrupt withdrawal → rebound hypertension; never stop suddenly.
• Pheochromocytoma: α-block (phenoxybenzamine) before β-block; never β-block first.
• Sodium nitroprusside → cyanide/thiocyanate toxicity; avoid in pregnancy and renal/hepatic failure.
• Avoid verapamil/diltiazem + beta-blocker (AV block); avoid dual RAAS blockade (ONTARGET/ALTITUDE harm).
• Thiazide metabolic profile = hyperglycaemia, hyperuricaemia, hyperlipidaemia, hypercalcaemia + hypokalaemia/hyponatraemia.