List the commonly used antihypertensive drugs with their mechanisms of action, side effects, primary clinical indications, and major contraindications.

Antihypertensive Medications: Mechanisms, Side Effects, Uses, and Contraindications

First-Line Antihypertensive Drug Classes

For most patients with hypertension, initial therapy should be a thiazide-type diuretic, calcium channel blocker (CCB), ACE inhibitor (ACEI), or angiotensin receptor blocker (ARB), as these four classes are equally effective for reducing cardiovascular and renal events. 1, 2

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1. Thiazide and Thiazide-Like Diuretics

Mechanism of Action

• Act as indirect vasodilators by depleting salt and water from both the intravascular compartment and the intramural portion of arterioles, thereby diminishing responsiveness to catecholamine and angiotensin II stimulation 3
• Chlorthalidone (CTDN) is 4.2-6.2 mmHg systolic more potent than hydrochlorothiazide (HCTZ) by 24-hour measurements 4

Common Agents & Dosing

• Hydrochlorothiazide: 12.5-50 mg once daily 1
• Chlorthalidone: 12.5-25 mg once daily 1
• Indapamide: 1.25-2.5 mg once daily 1

Primary Clinical Uses (Compelling Indications)

• Elderly patients with isolated systolic hypertension 1
• Heart failure 1
• Secondary stroke prevention 1
• Most cost-effective first-line agent for uncomplicated hypertension 1, 2

Side Effects

• Hypokalemia, hyponatremia 1
• Hyperuricemia 1
• Dyslipidemia (possible caution) 1
• Hyperglycemia 1
• Ventricular ectopy (reduced when combined with potassium-sparing agents) 4

Contraindications

• Compelling: Gout (though may be used with allopurinol if necessary) 1
• Caution: Severe hyponatremia, recurrent hyperuricemia 2

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2. ACE Inhibitors (ACEIs)

Mechanism of Action

• Inhibit conversion of angiotensin I to angiotensin II, thereby decreasing vasoconstriction and aldosterone production 3
• Reduce both preload and afterload 5

Common Agents & Dosing

• Lisinopril: 10-40 mg once daily 1, 6
• Enalapril: 5-40 mg once or twice daily 1
• Ramipril: 2.5-20 mg once daily 1
• Captopril: 25-150 mg twice or three times daily (contains sulphydryl group with potential toxicity) 3

Primary Clinical Uses (Compelling Indications)

• Heart failure 1
• Left ventricular dysfunction post-myocardial infarction or established coronary heart disease 1
• Type 1 diabetic nephropathy 1
• Type 2 diabetic nephropathy (possible indication) 1
• Chronic kidney disease with proteinuria 1, 2

Side Effects

• Dry cough (most common, occurs in 10-20% of patients) 5, 7
• Hyperkalemia 1, 5
• Angioedema (rare but serious, 0.1-0.7%) 5
• Acute kidney injury (especially with bilateral renal artery stenosis) 5
• Hypotension (especially first dose) 5

Contraindications

• Compelling: Pregnancy (teratogenic, causes fetal harm) 1, 2
• Compelling: Renovascular disease (bilateral renal artery stenosis) 1
• Compelling: History of angioedema 8
• Caution: Renal impairment (use with close supervision when eGFR <30 mL/min/1.73m²) 1
• Caution: Peripheral vascular disease (association with renovascular disease) 1
• Never combine with ARBs (increases adverse effects without benefit) 2, 6

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3. Angiotensin II Receptor Blockers (ARBs)

Mechanism of Action

• Selectively block the angiotensin II type 1 (AT₁) receptor, blocking all physiological actions of angiotensin II relevant to hypertension 9, 7
• More complete blockade of the renin-angiotensin system than ACEIs 7

Common Agents & Dosing

• Losartan: 50-100 mg once or twice daily 1, 6
• Valsartan: 80-320 mg once daily 1
• Irbesartan: 150-300 mg once daily 1
• Candesartan: 8-32 mg once daily 1

Primary Clinical Uses (Compelling Indications)

• ACEI intolerance (especially cough-induced) 1
• Type 2 diabetic nephropathy 1
• Heart failure in ACEI-intolerant patients 1
• Left ventricular dysfunction after myocardial infarction (possible indication) 1
• Hypertension with left ventricular hypertrophy (possible indication) 1

Side Effects

• Placebo-like side effect profile (major advantage over ACEIs) 9, 7
• Hyperkalemia 1, 5
• Hypotension 5
• Acute kidney injury (rare) 5
• No cough (unlike ACEIs) 7

Contraindications

• Compelling: Pregnancy (teratogenic) 1, 2
• Caution: Renal impairment (use with close supervision when eGFR <30 mL/min/1.73m²) 1
• Caution: Peripheral vascular disease 1
• Never combine with ACEIs 2, 6

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4. Calcium Channel Blockers (CCBs)

Mechanism of Action

• Block voltage-gated L-type calcium channels in vascular smooth muscle and cardiac tissue, causing vasodilation and (for non-dihydropyridines) reduced cardiac contractility and conduction 5

A. Dihydropyridine CCBs

Common Agents & Dosing

• Amlodipine: 2.5-10 mg once daily 1
• Nifedipine (long-acting): 30-90 mg once daily 1
• Felodipine: 2.5-10 mg once daily 1

Primary Clinical Uses (Compelling Indications)

• Elderly patients with isolated systolic hypertension 1
• Angina (possible indication) 1
• Black patients (preferred over ACEIs/ARBs due to lower renin activity) 2, 6

Side Effects

• Peripheral edema (dose-dependent, 10-30%) 5
• Headache 5
• Flushing 5
• Reflex tachycardia (less with long-acting formulations) 5

Contraindications

• No compelling contraindications for dihydropyridines 1
• Never use short-acting nifedipine capsules (associated with adverse cardiovascular events) 1

B. Non-Dihydropyridine CCBs (Rate-Limiting)

Common Agents & Dosing

• Diltiazem: 180-360 mg once daily (extended-release) 1
• Verapamil: 120-480 mg once daily (extended-release) 1

Primary Clinical Uses (Compelling Indications)

• Angina 1
• Atrial fibrillation (rate control) 8

Side Effects

• Constipation (especially verapamil) 5
• Bradycardia 5
• AV block 5
• Peripheral edema (less than dihydropyridines) 5

Contraindications

• Compelling: Heart block (second- or third-degree without pacemaker) 1, 2
• Compelling: Heart failure with reduced ejection fraction (negative inotropic effects) 1, 2
• Caution: Combination with beta-blockade (risk of severe bradycardia) 1

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5. Beta-Blockers

Mechanism of Action

• Act centrally and peripherally by decreasing cardiac output, decreasing renin release, inhibiting prejunctional release of norepinephrine, and through central mechanisms 3
• Cardioselective agents preferentially block β₁-receptors in the heart 5

Common Agents & Dosing

Cardioselective

• Metoprolol succinate: 50-200 mg once daily 1, 8
• Metoprolol tartrate: 100-200 mg twice daily 1
• Atenolol: 25-100 mg twice daily 1
• Bisoprolol: 2.5-10 mg once daily 1

Combined α- and β-Receptor Blockers

• Carvedilol: 12.5-50 mg twice daily 1
• Labetalol: 200-800 mg twice daily 1

Primary Clinical Uses (Compelling Indications)

• Myocardial infarction 1
• Angina 1
• Heart failure (bisoprolol, metoprolol succinate, carvedilol preferred) 1
• Atrial fibrillation (rate control) 8
• NOT recommended as first-line for uncomplicated hypertension 2, 6, 8

Side Effects

• Fatigue 5
• Bradycardia 5
• Bronchospasm (less with cardioselective agents) 5
• Worsening heart failure (may improve with specialist management) 1
• Peripheral vasoconstriction 5
• Dyslipidemia (possible caution) 1
• Erectile dysfunction 5
• Masking of hypoglycemia symptoms 5

Contraindications

• Compelling: Asthma or severe chronic obstructive pulmonary disease 1
• Compelling: High-grade AV block (second- or third-degree) 8
• Caution: Peripheral vascular disease 1
• Caution: Diabetes (except with coronary heart disease) 1
• Caution: Heart failure (may worsen, but can be beneficial under specialist care) 1
• Avoid abrupt cessation (risk of rebound hypertension and cardiac events) 1

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6. Alpha-1 Blockers

Mechanism of Action

• Block α₁-adrenergic receptors in vascular smooth muscle, causing vasodilation 3

Common Agents & Dosing

• Doxazosin: 1-16 mg once daily 1
• Prazosin: 2-20 mg two or three times daily 1
• Terazosin: 1-20 mg once or twice daily 1

Primary Clinical Uses (Compelling Indications)

• Benign prostatic hypertrophy (BPH) 1
• Second-line agent in patients with concomitant BPH 1

Side Effects

• Orthostatic hypotension (especially first dose and in elderly) 1
• Dizziness 5
• Headache 5

Contraindications

• Compelling: Urinary incontinence 1
• Caution: Postural hypotension 1
• Caution: Heart failure when used as monotherapy 1

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7. Potassium-Sparing Diuretics & Aldosterone Antagonists

Mechanism of Action

• Aldosterone antagonists (spironolactone, eplerenone): Block mineralocorticoid receptors 5
• ENaC inhibitors (amiloride, triamterene): Block epithelial sodium channels in the distal tubule 5

Common Agents & Dosing

• Spironolactone: 25-100 mg once daily 1
• Eplerenone: 50-100 mg once or twice daily 1
• Amiloride: 5-10 mg once daily 4

Primary Clinical Uses

• Resistant hypertension (fourth-line agent) 2, 6
• Primary aldosteronism 1
• Heart failure with reduced ejection fraction 1
• Reduce ventricular ectopy and sudden cardiac death when combined with thiazides 4
• Reduce proteinuria beyond other RAAS inhibitors 4

Side Effects

• Hyperkalemia (most serious) 1, 5
• Gynecomastia and impotence (spironolactone > eplerenone) 1
• Menstrual irregularities 5

Contraindications

• Avoid with potassium supplements, other potassium-sparing diuretics, or significant renal dysfunction 1
• Avoid with ACEIs/ARBs in patients with eGFR <45 mL/min/1.73m² 2
• Severe hyperkalemia (K⁺ >5.5 mmol/L) 2

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8. Direct Renin Inhibitor

Mechanism of Action

• Directly inhibits renin, preventing conversion of angiotensinogen to angiotensin I 10

Common Agent & Dosing

• Aliskiren: 150-300 mg once daily 1, 10

Primary Clinical Uses

• Alternative to ACEIs/ARBs in selected patients 1

Side Effects

• Diarrhea 10
• Hyperkalemia 10
• Acute renal failure (in bilateral renal artery stenosis) 10

Contraindications

• Do not use in combination with ACEIs or ARBs (increased risk of hyperkalemia, hypotension, renal impairment) 1, 10
• Pregnancy 10
• Severe bilateral renal artery stenosis 10

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9. Centrally Acting Agents

Mechanism of Action

• Decrease blood pressure by diminishing sympathetic outflow from the vasomotor center 3

Common Agents & Dosing

• Clonidine: 0.1-0.8 mg twice daily (oral) or 0.1-0.3 mg weekly (patch) 1
• Methyldopa: 250-1000 mg twice daily 1

Primary Clinical Uses

• Reserved as last-line therapy due to significant CNS adverse effects 1
• Pregnancy (methyldopa, labetalol preferred) 2, 8

Side Effects

• Sedation, drowsiness 1
• Dry mouth 1
• Depression 5
• Rebound hypertension with abrupt discontinuation (clonidine) 1
• Drug-induced lupus (methyldopa at higher doses) 5

Contraindications

• Must taper clonidine to avoid hypertensive crisis 1
• Generally avoid in elderly due to CNS effects 1

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10. Direct Vasodilators

Mechanism of Action

• Directly relax vascular smooth muscle 3

Common Agents & Dosing

• Hydralazine: 100-200 mg two or three times daily 1
• Minoxidil: 5-100 mg once to three times daily 1

Primary Clinical Uses

• Reserved for resistant hypertension 1
• Must be used with a diuretic and beta-blocker to counteract sodium retention and reflex tachycardia 1

Side Effects

• Sodium and water retention 1
• Reflex tachycardia 1
• Drug-induced lupus-like syndrome (hydralazine at doses >200 mg/day) 1
• Hirsutism (minoxidil) 1
• Pericardial effusion (minoxidil) 1

Contraindications

• Coronary artery disease (reflex tachycardia may worsen angina) 5

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Critical Treatment Algorithms & Pitfalls

Initial Drug Selection Algorithm

1. If compelling indication exists (heart failure, post-MI, diabetic nephropathy, CKD with proteinuria): Choose the specific drug class indicated 1, 2
2. Black patients without compelling indication: Start with thiazide or CCB 2, 6
3. Non-Black patients without compelling indication: Start with thiazide, CCB, ACEI, or ARB 2, 6
4. Elderly or isolated systolic hypertension: Prefer thiazide or dihydropyridine CCB 1

Blood Pressure-Based Escalation

• Stage 1 (140-159/90-99 mmHg): Start with single agent 2, 6
• Stage 2 (≥160/100 mmHg or ≥20/10 mmHg above target): Start with two-drug combination, preferably single-pill formulation 1, 2, 6

Common Pitfalls to Avoid

• Never combine ACEI + ARB (increases adverse effects without benefit) 2, 6
• Never use beta-blockers as first-line unless compelling indication exists (post-MI, angina, heart failure) 2, 6, 8
• Never delay combination therapy in stage 2 hypertension 2, 6
• Never use short-acting nifedipine capsules 1
• Always verify medication adherence before labeling treatment failure 2
• Always screen for secondary hypertension when BP ≥180/110 mmHg or resistant to triple therapy 2
• Always taper clonidine to avoid rebound hypertensive crisis 1
• Always avoid ACEIs/ARBs in pregnancy (teratogenic) 1, 2

Resistant Hypertension (Fourth-Line)

• Add spironolactone 25-50 mg daily to triple therapy (ACEI/ARB + CCB + thiazide) 2, 6
• Relative potencies: spironolactone 25 mg ≈ amiloride 10 mg ≈ eplerenone 100 mg 4