What are the first-line anti-hypertensive (high blood pressure) medications?

First-Line Antihypertensive Medications

Thiazide or thiazide-like diuretics, particularly chlorthalidone, are the optimal first-line antihypertensive agents for most adults with hypertension, based on the strongest evidence for preventing cardiovascular disease, stroke, and heart failure. 1, 2, 3

Primary First-Line Options

Thiazide/Thiazide-Like Diuretics (Preferred)

• Chlorthalidone is the single best-supported agent based on head-to-head trials showing superiority over lisinopril for stroke prevention and over amlodipine for heart failure prevention in over 50,000 patients. 1, 3, 4
• Hydrochlorothiazide (often combined with amiloride or triamterene) is an acceptable alternative when chlorthalidone is unavailable. 4
• Long-acting thiazide-like agents (chlorthalidone, indapamide) demonstrate better cardiovascular outcomes than shorter-acting alternatives. 2
• Diuretics are significantly more effective than beta-blockers for stroke prevention and cardiovascular events. 1, 3

Calcium Channel Blockers (CCBs)

• Dihydropyridine CCBs (amlodipine, nifedipine) are equally appropriate first-line agents and particularly effective for stroke prevention. 1, 2, 5
• CCBs are preferred over ACE inhibitors in Black patients for preventing heart failure and stroke. 6
• Long-acting amlodipine provides effective 24-hour blood pressure control with once-daily dosing. 6

ACE Inhibitors and ARBs

• ACE inhibitors (lisinopril, enalapril) and ARBs (candesartan, losartan) are effective first-line options but showed slightly less efficacy than thiazides for stroke prevention in direct comparisons. 1, 3, 7
• These agents are the only class besides thiazides proven to reduce all-cause mortality compared to placebo. 4

Population-Specific Recommendations

Black Patients

• Start with thiazide diuretics or CCBs as first-line therapy. 1, 2
• ACE inhibitors and ARBs are less effective as monotherapy in this population. 1

Patients with Specific Comorbidities

• Albuminuria (≥30 mg/g): ACE inhibitors or ARBs are mandatory first-line agents. 2, 6
• Established coronary artery disease: ACE inhibitors or ARBs are preferred. 2, 6
• Heart failure with reduced ejection fraction: ACE inhibitors, ARBs, or beta-blockers (not first-line for uncomplicated hypertension). 1, 2
• Chronic kidney disease (GFR <30 mL/min): Loop diuretics preferred over thiazides. 1

Age Considerations

• Patients ≥55 years or Black patients of any age: CCBs or thiazide diuretics are generally more effective. 2
• Patients <55 years (white): ACE inhibitors or ARBs may be more effective initially. 2

Monotherapy vs. Combination Therapy Algorithm

Stage 1 Hypertension (130-139/80-89 mmHg)

• Start with single-agent therapy using one of the four first-line classes. 1, 2
• Titrate dose after 2-4 weeks if target BP (<130/80 mmHg) not achieved. 1

Stage 2 Hypertension (≥140/90 mmHg)

• Initiate two-drug combination therapy from different classes. 1, 2, 7
• Preferred combinations: ACE inhibitor/ARB + CCB, ACE inhibitor/ARB + thiazide, or CCB + thiazide. 3

Severe Hypertension (>20/10 mmHg above target or ≥160/100 mmHg)

• Mandatory two-drug combination at initiation, either as separate agents or fixed-dose combination. 1, 2
• Single-pill combinations may improve adherence. 2

Agents NOT Recommended as First-Line

Beta-Blockers

• Do not use as first-line therapy unless specific indications exist (prior MI, active angina, heart failure with reduced ejection fraction). 1, 2, 3
• Significantly less effective than diuretics for stroke prevention in older adults. 1, 3

Alpha-Blockers

• Not recommended as first-line due to inferior cardiovascular protection compared to thiazides. 3
• Associated with orthostatic hypotension, especially in older adults. 1

Critical Contraindications and Warnings

Never Combine

• ACE inhibitors + ARBs together: Increased adverse effects without additional benefit. 2
• Verapamil or diltiazem + beta-blockers: Increased risk of bradycardia and heart block. 1

Pregnancy

• Avoid ACE inhibitors, ARBs, and direct renin inhibitors (aliskiren) in pregnancy. 1

Bilateral Renal Artery Stenosis

• Risk of acute renal failure with ACE inhibitors, ARBs, and aliskiren. 1

Monitoring Requirements

• Thiazides: Monitor electrolytes (hypokalemia, hyponatremia) and glucose (can provoke hyperglycemia/diabetes, though this doesn't reduce cardiovascular efficacy). 1, 4
• ACE inhibitors/ARBs: Monitor potassium and creatinine, especially with CKD. 1
• CCBs: Dose-related pedal edema more common in women; avoid non-dihydropyridines in heart failure with reduced ejection fraction. 1