Drugs for Hypertension

Definition: HTN = SBP >130 mmHg or DBP >80 mmHg on at least two occasions. BP goal for most patients is <130/80 mmHg.

First-line choices (most guidelines): Thiazide diuretics, ACE inhibitors, ARBs, Calcium Channel Blockers (CCBs). Beta-blockers are used when there is a compelling indication (e.g. heart failure, post-MI, angina).

1. Diuretics

All diuretics initially lower BP by reducing blood volume (Na+ and water excretion), which decreases cardiac output. With long-term use, a reduction in peripheral vascular resistance also contributes.

A. Thiazide diuretics (First-line)

Drug	Brand
Hydrochlorothiazide	Microzide
Chlorthalidone	(generic)
Indapamide	(generic)
Metolazone	Zaroxolyn

Mechanism: Inhibit Na+/Cl- cotransporter in distal convoluted tubule
Advantage: Useful in combination with beta-blockers, ACEi, ARBs, K+-sparing diuretics
Caution: NOT effective if GFR <30 mL/min/m² (except metolazone)
Side effects: Hypokalemia, hyperuricemia (gout), hyperglycemia

B. Loop diuretics

Drug	Brand
Furosemide	Lasix
Bumetanide	Bumex
Torsemide	Demadex
Ethacrynic acid	Edecrin

Use: When thiazides are ineffective (CKD, GFR <30), or in heart failure with fluid overload
Side effects: Hypokalemia, ototoxicity (especially ethacrynic acid)

C. Potassium-sparing diuretics

Drug	Brand
Spironolactone	Aldactone
Eplerenone	Inspra
Amiloride	Midamor
Triamterene	Dyrenium

Spironolactone/Eplerenone = aldosterone receptor antagonists; used in resistant HTN, heart failure, post-MI
Side effects: Hyperkalemia; spironolactone causes gynecomastia (eplerenone is more selective, less so)

2. ACE Inhibitors (ACEi)

Drug	Brand
Lisinopril	Prinivil, Zestril
Enalapril	Vasotec
Ramipril	Altace
Benazepril	Lotensin
Captopril	Capoten
Fosinopril	Monopril
Quinapril	Accupril

Mechanism: Block conversion of Ang I → Ang II; reduce aldosterone → reduced Na+ retention and vasoconstriction. Also increase bradykinin levels.
Compelling indications: Diabetes (nephroprotective), CKD with proteinuria, heart failure, post-MI, recurrent stroke prevention
Side effects: Dry cough (bradykinin), angioedema (contraindication), hyperkalemia, teratogenic (avoid in pregnancy)

3. Angiotensin II Receptor Blockers (ARBs)

Drug	Brand
Losartan	Cozaar
Valsartan	Diovan
Candesartan	Atacand
Irbesartan	Avapro
Telmisartan	Micardis
Olmesartan	Benicar
Azilsartan	Edarbi

Mechanism: Block AT1 receptor directly - same benefits as ACEi but do NOT raise bradykinin
Advantage over ACEi: No dry cough; still avoid in pregnancy (teratogenic)
Key use: Substitute when ACEi causes cough or angioedema; diabetic nephropathy

4. Calcium Channel Blockers (CCBs)

A. Dihydropyridines (DHP) - Vascular selective

Drug	Brand
Amlodipine	Norvasc
Nifedipine	Procardia, Adalat
Felodipine	Plendil
Nicardipine	Cardene

Block L-type Ca²+ channels in vascular smooth muscle → vasodilation → ↓ peripheral resistance
Advantage: Antihypertensive effect is independent of dietary sodium intake and NSAIDs
Side effects: Peripheral edema, reflex tachycardia, flushing

B. Non-dihydropyridines (Non-DHP) - Cardiac selective

Drug	Brand
Verapamil	Calan, Isoptin
Diltiazem	Cardizem, Dilacor

Block Ca²+ channels in myocardium AND vessels → reduce HR and contractility in addition to vasodilation
Contraindicated in heart failure with reduced EF (HFrEF)
Use: HTN + angina or atrial arrhythmias

5. Beta-Blockers (β-Blockers)

Drug	Brand	Selectivity
Metoprolol	Lopressor, Toprol-XL	β1-selective
Atenolol	Tenormin	β1-selective
Bisoprolol	(generic)	β1-selective
Carvedilol	Coreg	Non-selective + α1 blockade
Labetalol	Normodyne	Non-selective + α1 blockade
Propranolol	Inderal	Non-selective
Acebutolol	(generic)	β1-selective
Esmolol	Brevibloc	β1-selective (IV, short-acting)

Mechanism: Reduce cardiac output by blocking β1 receptors; also reduce renin release
Compelling indications: Heart failure (carvedilol, metoprolol), post-MI, angina, tachyarrhythmias
Side effects: Bradycardia, fatigue, masking of hypoglycemia symptoms, bronchospasm (non-selective agents in asthmatics), erectile dysfunction
Labetalol/carvedilol (combined α+β blockade) are preferred in HTN emergencies and pheochromocytoma

6. Centrally Acting Agents (α2 Agonists)

Drug	Notes
Clonidine	Oral or transdermal patch; used in resistant HTN; does not reduce renal blood flow
Methyldopa	Drug of choice for HTN in pregnancy; multiple daily doses required

Mechanism: Stimulate α2 receptors in the CNS → reduce sympathetic outflow → lower BP and HR
Side effects (clonidine): Sedation, dry mouth (xerostomia), constipation, hypotension
Important: Abrupt withdrawal of clonidine causes rebound hypertension; taper dose when stopping

7. Direct Vasodilators

Drug	Notes
Hydralazine	Arterial vasodilator; used in resistant HTN and HTN in pregnancy (IV form)
Minoxidil	Reserved for severe resistant HTN; causes significant reflex tachycardia and fluid retention
Sodium nitroprusside	IV only; used in hypertensive emergencies
Nitroglycerine	IV; primarily venous dilation; used in HTN with acute coronary syndromes

Side effects of hydralazine: Reflex tachycardia, fluid retention, drug-induced lupus with long-term use
Both hydralazine and minoxidil typically need co-administration of a beta-blocker (to blunt reflex tachycardia) and a diuretic (to prevent fluid retention)

8. Renin Inhibitor

Drug	Brand
Aliskiren	Tekturna

Direct renin inhibitor; rarely used alone; contraindicated with ACEi or ARBs in diabetics or those with CKD (risk of hyperkalemia, acute kidney injury)

Drug Selection by Comorbidity

Drug classes indicated in treating hypertension with concomitant diseases

Comorbidity	Preferred Drug(s)
Diabetes	Thiazide, ACEi, ARB, CCB
CKD / Proteinuria	ACEi or ARB (first choice)
Heart failure (HFrEF)	Diuretic, β-blocker, ACEi/ARB, aldosterone antagonist
Post-MI	β-blocker, ACEi/ARB, aldosterone antagonist
Stable ischemic heart disease	β-blocker, ACEi/ARB, CCB
Recurrent stroke prevention	Diuretic, ACEi/ARB
Pregnancy	Methyldopa, labetalol, nifedipine (avoid ACEi/ARBs)
Pheochromocytoma	Labetalol or phentolamine (never β-blocker alone)
Resistant HTN	Add spironolactone, clonidine, or direct vasodilator

Recent Evidence: A 2025 Lancet meta-analysis (PMID 40885583) confirmed that drug combinations are significantly more effective than monotherapy. The 2024 ESC Guidelines (PMID 39210715) recommend initiating therapy with a RAAS blocker (ACEi/ARB) + CCB combination in most patients, reserving thiazide diuretics as a third agent.

- Lippincott Illustrated Reviews: Pharmacology, Ch. 8 | Goodman & Gilman's Pharmacological Basis of Therapeutics, Ch. 49

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