List all antihypertensive drug classes with their mechanisms of action, clinical uses, side effects, and contraindications.

Comprehensive Antihypertensive Drug Classes: Mechanisms, Uses, Side Effects, and Contraindications

Primary First-Line Agents

1. Thiazide and Thiazide-Like Diuretics

Mechanism of Action:

• Inhibit sodium-chloride cotransporter in the distal convoluted tubule, promoting natriuresis and reducing plasma volume 1
• Long-term effect includes direct vasodilation through reduced vascular smooth muscle calcium 2

Specific Agents and Dosing:

• Chlorthalidone 12.5–25 mg once daily (preferred due to prolonged half-life and proven CVD reduction) 1
• Hydrochlorothiazide 25–50 mg once daily 1
• Indapamide 1.25–2.5 mg once daily 1
• Metolazone 2.5–5 mg once daily 1

Clinical Uses:

• First-line for most patients, especially elderly with isolated systolic hypertension 1, 3, 4
• Heart failure (reduces preload) 3
• Secondary stroke prevention 3
• Most cost-effective option for uncomplicated hypertension 1, 3, 4
• Black patients (superior efficacy due to lower renin activity) 3

Side Effects:

• Hypokalemia and hyponatremia (monitor electrolytes regularly) 1, 3
• Hyperuricemia (may precipitate gout) 1, 3
• Hyperglycemia and new-onset diabetes 1
• Dyslipidemia 3
• Sexual dysfunction 2

Contraindications:

• Active gout (unless on uric acid-lowering therapy) 1, 3
• Severe hyponatremia 5
• Pregnancy (relative) 2

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2. ACE Inhibitors (ACEIs)

Mechanism of Action:

• Block conversion of angiotensin I to angiotensin II, reducing vasoconstriction and aldosterone secretion 2
• Increase bradykinin levels (contributes to vasodilation and cough side effect) 2

Specific Agents and Dosing:

• Lisinopril 10–40 mg once daily 1, 3
• Enalapril 5–40 mg once or twice daily 1, 3
• Ramipril 2.5–20 mg once or twice daily 1, 3
• Captopril 12.5–150 mg 2–3 times daily 1
• Benazepril 10–40 mg once or twice daily 1
• Fosinopril, Moexipril, Perindopril, Quinapril, Trandolapril (various dosing) 1

Clinical Uses:

• Heart failure (reduces mortality and hospitalizations) 1, 3, 5
• Post-myocardial infarction or left ventricular dysfunction 1, 3
• Diabetic nephropathy (type 1 and 2) 3, 5
• Chronic kidney disease with proteinuria (slows progression) 3, 5
• Coronary artery disease 3, 5
• Non-Black patients as first-line 5

Side Effects:

• Dry cough (10–20% of patients, due to bradykinin accumulation) 2
• Hyperkalemia (especially with CKD, potassium supplements, or K-sparing drugs) 1, 3
• Angioedema (rare but serious, 0.1–0.5%) 1, 2
• Acute kidney injury in bilateral renal artery stenosis 1, 3
• Hypotension (first-dose effect) 2

Contraindications:

• Pregnancy (teratogenic, causes fetal renal injury) 1, 3, 5
• History of angioedema with ACEIs 1
• Bilateral renal artery stenosis 1, 3, 5
• Severe hyperkalemia (K⁺ >5.5 mmol/L) 5
• Do NOT combine with ARBs or renin inhibitors (increases harm without benefit) 1, 5

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3. Angiotensin II Receptor Blockers (ARBs)

Mechanism of Action:

• Block angiotensin II type 1 (AT1) receptors, preventing vasoconstriction and aldosterone release 2
• Do not affect bradykinin (lower cough incidence than ACEIs) 2

Specific Agents and Dosing:

• Losartan 50–100 mg once or twice daily 1, 3
• Valsartan 80–320 mg once daily 1, 3
• Irbesartan 150–300 mg once daily 1, 3
• Candesartan 8–32 mg once daily 1, 3
• Azilsartan 40–80 mg once daily 1
• Olmesartan, Telmisartan, Eprosartan (various dosing) 1

Clinical Uses:

• ACEI-intolerant patients (especially cough) 1, 3
• Type 2 diabetic nephropathy 3
• Heart failure (when ACEIs not tolerated) 3
• Chronic kidney disease with albuminuria 5
• Same compelling indications as ACEIs 1, 3

Side Effects:

• Hyperkalemia (similar frequency to ACEIs) 1, 3
• Angioedema (rare, <0.1%, lower than ACEIs) 1
• Acute kidney injury in bilateral renal artery stenosis 1
• Hypotension 2
• Note: Patients with ACEI-induced angioedema can receive ARB after 6-week washout 1

Contraindications:

• Pregnancy (teratogenic) 1, 3, 5
• Bilateral renal artery stenosis 5
• Severe hyperkalemia 5
• Do NOT combine with ACEIs or renin inhibitors 1, 5

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4. Calcium Channel Blockers (CCBs)

A. Dihydropyridines (DHP)

Mechanism of Action:

• Block L-type calcium channels in vascular smooth muscle, causing vasodilation 2
• Minimal cardiac effects (no negative inotropy or chronotropy) 2

Specific Agents and Dosing:

• Amlodipine 2.5–10 mg once daily 1, 3
• Long-acting nifedipine 30–90 mg once daily (extended-release only) 3, 6
• Felodipine 2.5–10 mg once daily 3

Clinical Uses:

• Elderly patients with isolated systolic hypertension 3, 5
• Black patients (superior efficacy) 3
• Angina pectoris 3
• Coronary artery disease 1

Side Effects:

• Peripheral edema (dose-dependent, 10–30%) 1, 2
• Headache 6
• Flushing 2
• Reflex tachycardia (less with amlodipine) 2
• Gingival hyperplasia 2

Contraindications:

• Heart failure with reduced ejection fraction (HFrEF) for non-amlodipine agents 1
• NEVER use short-acting nifedipine capsules (increases cardiovascular events, stroke, MI) 3, 6

B. Non-Dihydropyridines (Non-DHP)

Mechanism of Action:

• Block L-type calcium channels in cardiac tissue and vascular smooth muscle 2
• Negative inotropic and chronotropic effects 2

Specific Agents and Dosing:

• Diltiazem 180–360 mg once daily (extended-release) 3
• Verapamil 120–480 mg once daily (extended-release) 3

Clinical Uses:

• Angina pectoris 3
• Supraventricular arrhythmias (rate control) 2

Side Effects:

• Constipation (especially verapamil) 2
• Bradycardia 2
• AV block 2
• Worsening heart failure 5

Contraindications:

• Heart failure with reduced ejection fraction (HFrEF) 1, 5
• Second- or third-degree AV block without pacemaker 5
• Sick sinus syndrome 2
• Severe left ventricular dysfunction 1

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Secondary and Adjunctive Agents

5. Beta-Blockers

Mechanism of Action:

• Block β1-adrenergic receptors (cardioselective) or β1 and β2 receptors (non-selective), reducing heart rate, contractility, and renin release 2
• Some have additional α-blocking properties (carvedilol, labetalol) 2

Specific Agents and Dosing:

Cardioselective (β1):

• Metoprolol succinate 50–200 mg once daily 3
• Metoprolol tartrate 100–200 mg twice daily 3
• Atenolol 25–100 mg once or twice daily 3
• Bisoprolol 2.5–10 mg once daily 3

Combined α/β:

• Carvedilol 12.5–50 mg twice daily 3
• Labetalol 200–800 mg twice daily 3

Clinical Uses:

• Post-myocardial infarction (reduces mortality) 1, 3, 5
• Angina pectoris 1, 3
• Heart failure with reduced ejection fraction (carvedilol, metoprolol succinate, bisoprolol) 1, 3
• Atrial fibrillation (rate control) 2
• NOT recommended as first-line for uncomplicated hypertension (less effective for stroke prevention) 1, 5

Side Effects:

• Bronchospasm (especially non-selective) 5, 2
• Bradycardia and AV block 2
• Fatigue and depression 2
• Metabolic syndrome (weight gain, dyslipidemia, new-onset diabetes when combined with thiazides) 1
• Sexual dysfunction 2
• Peripheral vasoconstriction (cold extremities) 2
• Initial worsening of heart failure 5

Contraindications:

• Asthma or severe COPD 5, 2
• Second- or third-degree AV block without pacemaker 5
• Severe bradycardia 2
• Peripheral arterial disease with claudication 5
• Metabolic syndrome or high diabetes risk (especially with thiazide combination) 1

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6. Alpha-1 Blockers

Mechanism of Action:

• Block α1-adrenergic receptors on vascular smooth muscle, causing vasodilation 2
• Also relax prostatic smooth muscle 2

Specific Agents and Dosing:

• Doxazosin 1–16 mg once daily 3
• Prazosin 2–20 mg 2–3 times daily 3
• Terazosin 1–20 mg once or twice daily 3

Clinical Uses:

• Benign prostatic hyperplasia (BPH) with hypertension 3
• Second-line or add-on therapy 3

Side Effects:

• Orthostatic hypotension (especially first dose and in elderly) 3, 2
• Dizziness 2
• Reflex tachycardia 2
• Increased heart failure risk (ALLHAT trial stopped doxazosin arm early) 1

Contraindications:

• Severe orthostatic hypotension 2
• Not recommended as first-line due to inferior outcomes 1

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7. Aldosterone Antagonists (Potassium-Sparing Diuretics)

Mechanism of Action:

• Block mineralocorticoid receptors in distal tubule and collecting duct, reducing sodium reabsorption and potassium excretion 2

Specific Agents and Dosing:

• Spironolactone 25–100 mg once daily 3, 5
• Eplerenone 50–100 mg once or twice daily 3

Clinical Uses:

• Primary aldosteronism 3
• Heart failure with reduced ejection fraction (reduces mortality) 3
• Resistant hypertension (fourth-line agent) 5

Side Effects:

• Hyperkalemia (most serious, requires regular monitoring) 3, 5
• Gynecomastia and sexual dysfunction (spironolactone > eplerenone) 3
• Menstrual irregularities 2

Contraindications:

• Severe hyperkalemia (K⁺ >5.5 mmol/L) 5
• Severe renal impairment (eGFR <30 mL/min) 5
• Concurrent use with ACEIs/ARBs requires close monitoring 5

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8. Direct Renin Inhibitor

Mechanism of Action:

• Directly inhibits renin, blocking conversion of angiotensinogen to angiotensin I 2

Specific Agent and Dosing:

• Aliskiren 150–300 mg once daily 3

Clinical Uses:

• Alternative to ACEIs/ARBs in intolerant patients 3
• Limited evidence for cardiovascular outcomes 2

Side Effects:

• Diarrhea 2
• Hyperkalemia 3
• Angioedema (rare) 2

Contraindications:

• NEVER combine with ACEIs or ARBs (increased hyperkalemia, hypotension, renal impairment) 3, 5
• Pregnancy 2

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9. Centrally Acting Agents

Mechanism of Action:

• Stimulate α2-adrenergic receptors in brainstem, reducing sympathetic outflow 2

Specific Agents and Dosing:

• Clonidine 0.1–0.8 mg twice daily (oral) or 0.1–0.3 mg weekly (patch) 3
• Methyldopa 250–1000 mg twice daily 3

Clinical Uses:

• Last-line therapy when other agents unsuitable 3
• Methyldopa preferred in pregnancy 3, 5

Side Effects:

• Sedation and dry mouth 2
• Rebound hypertension with abrupt clonidine discontinuation 3, 5
• Depression 2
• Sexual dysfunction 2
• Positive Coombs test (methyldopa) 2

Contraindications:

• Depression (relative) 2
• Clonidine must be tapered before discontinuation 3, 5

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10. Direct Vasodilators

Mechanism of Action:

• Direct relaxation of arteriolar smooth muscle through various mechanisms 2

Specific Agents and Dosing:

• Hydralazine 100–200 mg 2–3 times daily 3
• Minoxidil 5–100 mg 1–3 times daily 3

Clinical Uses:

• Resistant hypertension (third- or fourth-line) 3
• Must be combined with diuretic and beta-blocker to prevent reflex tachycardia and sodium retention 3

Side Effects:

• Reflex tachycardia 2
• Sodium and water retention 3
• Lupus-like syndrome (hydralazine >200 mg/day) 3
• Hirsutism (minoxidil) 3
• Pericardial effusion (minoxidil) 3
• Headache 2

Contraindications:

• Coronary artery disease (reflex tachycardia may worsen angina) 2
• Systemic lupus erythematosus (hydralazine) 2

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Critical Treatment Principles

Combination Therapy Strategy

• Stage 2 hypertension (≥160/100 mmHg): Start with two-drug combination, preferably single-pill formulation 1, 3, 5
• Single-pill combinations markedly improve adherence 3, 5
• Preferred combinations: ACEI/ARB + CCB, ACEI/ARB + thiazide, CCB + thiazide 3

Absolute Contraindications to Combination

• NEVER combine ACEI + ARB + renin inhibitor (potentially harmful, no benefit) 1, 5

Race-Specific Recommendations

• Black patients: Thiazide or CCB preferred first-line (lower renin activity) 3, 5
• Non-Black patients: ACEI or ARB preferred first-line 5

Blood Pressure Targets

• Most adults: <130/80 mmHg 5
• Elderly ≥65 years: Individualize based on frailty, 130–139 mmHg systolic if tolerated 5
• Diabetes or CKD: <130/80 mmHg 5

Monitoring Requirements

• Reassess BP 2–4 weeks after initiating or adjusting therapy 5
• Achieve target within 3 months 5
• Monitor electrolytes (K⁺, Na⁺) with diuretics, ACEIs, ARBs, aldosterone antagonists 1, 5
• Monitor serum creatinine 7–14 days after starting ACEIs/ARBs in CKD 5

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Common Pitfalls to Avoid

1. Using immediate-release nifedipine (contraindicated, causes stroke/MI) 3, 6
2. Combining ACEI + ARB (increases harm) 1, 5
3. Beta-blockers as first-line without compelling indication (inferior stroke prevention) 1, 5
4. Abrupt clonidine discontinuation (causes rebound hypertension) 3, 5
5. Delaying combination therapy in stage 2 hypertension 5
6. Using ACEIs/ARBs in pregnancy (teratogenic) 1, 3, 5
7. Ignoring medication non-adherence before escalating therapy 5