What are the main classes of antihypertensive drugs?
Blood pressure is cardiac output multiplied by peripheral resistance, and every antihypertensive acts on one of the systems that set them: the renin–angiotensin–aldosterone system, vascular smooth muscle, renal sodium handling or sympathetic outflow. Current guidelines name four first-line classes; the rest are add-on drugs or reserved for specific situations.
| Class | Examples | Where it acts | Place in therapy |
|---|---|---|---|
| ACE inhibitors | Ramipril, enalapril, lisinopril, perindopril | Block angiotensin-converting enzyme | First line |
| ARBs | Losartan, valsartan, telmisartan, olmesartan | Block the AT1 receptor | First line |
| Dihydropyridine CCBs | Amlodipine, nifedipine, felodipine | L-type calcium channels in arteriolar smooth muscle | First line |
| Thiazide / thiazide-like diuretics | Hydrochlorothiazide, chlorthalidone, indapamide | Na+–Cl− cotransporter, distal convoluted tubule | First line |
| Beta-blockers | Bisoprolol, metoprolol, carvedilol, labetalol, nebivolol | β-adrenergic receptors | Compelling indications only |
| Mineralocorticoid antagonists | Spironolactone, eplerenone | Aldosterone receptor | Fourth line for resistant hypertension |
| Alpha-1 blockers | Prazosin, doxazosin, terazosin | α1 receptors on vessels | Add-on only |
| Central α2 agonists | Clonidine, methyldopa | Brainstem sympathetic outflow | Add-on; methyldopa in pregnancy |
| Direct vasodilators | Hydralazine, minoxidil | Arteriolar smooth muscle | Resistant or special cases |
How do ACE inhibitors and ARBs work, and why do ACE inhibitors cause cough?
ACE inhibitors block angiotensin-converting enzyme — also called kininase II — which does two jobs: it converts angiotensin I to angiotensin II, and it breaks down bradykinin. Blocking it reduces angiotensin II (less vasoconstriction, less aldosterone, less sympathetic drive) and lowers intraglomerular pressure by relaxing the efferent arteriole, which reduces proteinuria. It also lets bradykinin accumulate.
ARBs block the AT1 receptor directly. Because they do not inhibit kininase II, bradykinin does not build up, so cough (1–4%) and angioedema are much less common than with ACE inhibitors.
| Effect | Detail |
|---|---|
| Dry cough | 5–20% (more in women, Asian patients, non-smokers); bradykinin, substance P and prostaglandins sensitise the cough reflex; starts 1–6 months in, settles 1–4 weeks after stopping; switch to an ARB |
| Angioedema | 0.1–0.7%, about 4-fold higher in Black patients; bradykinin-mediated swelling of face, lips, tongue and larynx |
| Hyperkalaemia | Less aldosterone; shared with ARBs |
| Rise in creatinine | Up to 30% is expected; more than 30% → look for bilateral renal artery stenosis or volume depletion |
| First-dose hypotension | Commoner in volume-depleted patients or those on high-dose diuretics |
| Teratogenicity | Fetal renal tubular dysplasia, oligohydramnios, pulmonary hypoplasia, skeletal defects — contraindicated in all trimesters; same for ARBs |
What are the differences between dihydropyridine and non-dihydropyridine CCBs?
| Feature | Dihydropyridines (amlodipine, nifedipine) | Non-dihydropyridines (verapamil, diltiazem) |
|---|---|---|
| Main site | Vascular smooth muscle — arteriolar dilators | Heart — SA and AV node, myocardium |
| Heart rate | Reflex tachycardia (more with short-acting forms) | Slow the heart and AV conduction |
| Use | Preferred CCBs for hypertension | Rate control in atrial fibrillation |
| Avoid in | — | HFrEF, second- or third-degree heart block, sick sinus syndrome |
| Typical adverse effects | Ankle oedema, headache, flushing, gingival hyperplasia | Bradycardia and AV block; verapamil raises digoxin levels by about 60–80% |
Why the ankles swell: dihydropyridines dilate the pre-capillary arterioles more than the venules, so capillary hydrostatic pressure rises and fluid filters out. It occurs in 5–30% (dose-dependent), is not fluid retention and does not respond to diuretics; adding an ACE inhibitor or ARB reduces it by dilating the post-capillary venules. Gingival hyperplasia occurs in 3–10%, more with nifedipine.
What are the metabolic adverse effects of thiazide diuretics?
Thiazides block the Na+–Cl− cotransporter (NCC) on the apical membrane of the distal convoluted tubule, which normally reabsorbs about 5–10% of filtered sodium chloride. They have the strongest outcome evidence of any class (ALLHAT). NICE prefers a thiazide-like diuretic such as indapamide over bendroflumethiazide or hydrochlorothiazide when starting or changing a diuretic. Below an eGFR of 30, loop diuretics are preferred because thiazides lose efficacy.
| Change | Mechanism |
|---|---|
| Hypokalaemia (commonest; 10–40% at higher doses) | More sodium reaches the collecting duct → ENaC-driven K+ secretion, plus secondary hyperaldosteronism |
| Hyponatraemia | Impaired free-water excretion in the diluting segment — older women and low body mass at most risk |
| Hyperuricaemia (may precipitate gout) | Competition with urate for OAT1/OAT3 in the proximal tubule |
| Hypercalcaemia (mild) | Enhanced proximal reabsorption after volume depletion; can unmask primary hyperparathyroidism |
| Hyperglycaemia | Hypokalaemia impairs β-cell insulin release; lower insulin sensitivity |
| Hyperlipidaemia | Transient rise in LDL and triglycerides, usually resolving within a year |
When are beta-blockers, alpha-blockers and central agents used?
Beta-blockers are no longer first-line for uncomplicated hypertension in any major guideline: they prevent stroke less well than other classes (atenolol in particular, in the LIFE and ASCOT trials). Their place is heart failure with reduced ejection fraction (carvedilol, metoprolol succinate, bisoprolol), after myocardial infarction and rate control in atrial fibrillation. Labetalol blocks β and α1 receptors (β:α ratio about 3:1 IV and 7:1 oral) and is a preferred drug in pregnancy.
- Beta-blocker cautions: bronchospasm with non-selective drugs (asthma); can mask hypoglycaemia; avoid in phaeochromocytoma without prior α-blockade and in Prinzmetal angina (unopposed α effect); taper over 1–2 weeks — abrupt stopping causes rebound hypertension, tachycardia and angina.
- Alpha-1 blockers (prazosin, doxazosin): not for monotherapy — the ALLHAT doxazosin arm had 25% more cardiovascular events, mainly heart failure, than chlorthalidone. Useful as add-on in men with BPH. First-dose syncope, greatest with prazosin, so start low at bedtime.
- Clonidine: stimulates α2 and imidazoline I1 receptors in the rostral ventrolateral medulla, cutting sympathetic outflow. Dry mouth and sedation; abrupt withdrawal → rebound hypertensive crisis.
- Methyldopa: central α2 agonist used in pregnancy; rare hepatotoxicity. NICE: stop within 2 days after birth and switch to another drug.
- Hydralazine: arteriolar dilator causing reflex tachycardia and salt retention; drug-induced lupus (antihistone antibodies) in 5–10% on more than 200 mg/day, mostly slow acetylators. Still first-line IV/IM in severe pre-eclampsia.
- Minoxidil: potent arteriolar dilator for resistant hypertension; needs a loop diuretic and a beta-blocker; causes hirsutism.
- Spironolactone: preferred fourth-line drug for resistant hypertension (PATHWAY-2); gynaecomastia and hyperkalaemia; eplerenone is more selective.
Which drug should be started first according to current guidelines?
Guidelines differ, and exam keys often follow NICE NG136 (UK). The 2025 ACC/AHA guideline (as summarised in StatPearls) takes a different line: all four first-line classes are suitable for every patient, race-based choices are dropped, the usual target is below 130/80 mm Hg, and stage 2 hypertension (≥ 140/90 mm Hg) is started on a single-pill combination of two first-line drugs.
| Step | Recommendation |
|---|---|
| Step 1 | ACE inhibitor or ARB if type 2 diabetes (any age or origin) or under 55 and not of Black African or African–Caribbean origin. CCB if aged 55 or over, or of Black African or African–Caribbean origin — without type 2 diabetes. ARB preferred to ACE inhibitor in Black African or African–Caribbean adults |
| Step 2 | ACE inhibitor/ARB + CCB or thiazide-like diuretic (or CCB + ACE inhibitor/ARB or thiazide-like diuretic) |
| Step 3 | ACE inhibitor/ARB + CCB + thiazide-like diuretic |
| Step 4 (resistant) | Confirm with ABPM/HBPM and check adherence; add low-dose spironolactone if K+ ≤ 4.5 mmol/L, or an alpha- or beta-blocker if K+ > 4.5 mmol/L |
| Item | Value |
|---|---|
| Stage 1 | Clinic 140/90 to 159/99 mm Hg (ABPM/HBPM 135/85 to 149/94) |
| Stage 2 | Clinic ≥ 160/100 but < 180/120 mm Hg (ABPM/HBPM ≥ 150/95) |
| Stage 3 (severe) | Clinic systolic ≥ 180 or diastolic ≥ 120 mm Hg |
| Target, under 80 | Below 140/90 mm Hg |
| Target, 80 and over | Below 150/90 mm Hg |
| Condition | Preferred drug |
|---|---|
| Heart failure, post-MI, LV systolic dysfunction | ACE inhibitor or ARB (plus an evidence-based beta-blocker in HFrEF) |
| CKD with proteinuria; diabetes with albuminuria | ACE inhibitor or ARB |
| Atrial fibrillation needing rate control | Beta-blocker or non-dihydropyridine CCB |
| Benign prostatic hyperplasia (add-on) | Alpha-1 blocker |
| Gout | Losartan (uricosuric); be cautious with thiazides |
| Pregnancy | Labetalol, nifedipine, methyldopa |
Which antihypertensives are safe in pregnancy?
- Labetalol is the first choice for chronic hypertension in pregnancy (NICE NG133).
- Nifedipine if labetalol is unsuitable; methyldopa if both are unsuitable.
- Treatment target: 135/85 mm Hg.
- ACE inhibitors and ARBs: stop if the woman becomes pregnant — preferably within 2 working days of notification — and offer an alternative.
- Thiazides: possible increased risk of congenital abnormalities and neonatal complications; discuss alternatives.
- Severe hypertension in critical care (pregnancy or after birth): treat immediately with labetalol (oral or IV), oral nifedipine or IV hydralazine (NICE NG133).
Which drugs are used in a hypertensive emergency?
A hypertensive emergency is a marked rise in blood pressure with acute target-organ damage — pulmonary oedema, myocardial ischaemia, neurological deficit, acute kidney injury, aortic dissection or eclampsia. The aim is to lower the mean arterial pressure by 20–25% within the first 1–2 hours using rapid-onset, titratable IV drugs. Without organ damage, blood pressure is lowered gradually over days.
| Situation | Drug(s) | Note |
|---|---|---|
| Most emergencies | IV labetalol, esmolol, nicardipine, nitroglycerin | Oral clonidine and nifedipine have no role in the immediate management |
| Aortic dissection | IV esmolol first, ± nicardipine | Lower systolic BP below 140 mm Hg within the first hour; β-blockade first avoids reflex tachycardia and aortic shear stress |
| Pre-eclampsia / eclampsia | IV labetalol, IV/IM hydralazine, nifedipine | Hydralazine 5–10 mg IV/IM every 20–30 min |
| Nitroprusside | Rarely used now | Profound hypotension, tachyphylaxis and cyanide toxicity |
| Parenteral ACE inhibitor | Enalaprilat | 1.25 mg IV every 6 hours |
How are antihypertensives asked in NEET PG and INI-CET?
- Side-effect identification — dry cough (ACE inhibitor), pedal oedema (amlodipine), gum hypertrophy (nifedipine), lupus-like syndrome (hydralazine), hirsutism (minoxidil), gynaecomastia (spironolactone), first-dose syncope (prazosin).
- Contraindications — ACE inhibitor in bilateral renal artery stenosis or pregnancy; verapamil or diltiazem in heart block or HFrEF; non-selective beta-blocker in asthma.
- Drug of choice — pregnancy (labetalol in current guidelines; older keys and textbooks give methyldopa for chronic hypertension in pregnancy, so read the options), aortic dissection (esmolol), diabetic nephropathy (ACE inhibitor/ARB), resistant hypertension (spironolactone).
- Rebound — clonidine and beta-blocker withdrawal.
- Mechanism — bradykinin and kininase II; NCC in the distal convoluted tubule; α2/I1 in the medulla.
For past papers see the NEET PG pharmacology PYQs. Steroid-induced hypertension and fluid retention are covered under corticosteroids, and the obstetric side under postpartum haemorrhage and amniotic fluid.