What is the first‑line pharmacologic treatment for primary hypertension in adults?

First-Line Medication for Hypertension

For adults with primary hypertension, initiate treatment with any of four first-line drug classes: thiazide or thiazide-like diuretics, ACE inhibitors, angiotensin receptor blockers (ARBs), or long-acting dihydropyridine calcium channel blockers (CCBs), with thiazide diuretics—particularly chlorthalidone—providing the strongest evidence for cardiovascular outcomes. 1, 2

Drug Class Selection Algorithm

General Adult Population (Non-Black, No Compelling Indications)

• Any of the four first-line classes may be used with comparable efficacy for blood pressure reduction and cardiovascular protection 1, 2
• Thiazide diuretics (especially chlorthalidone) are optimal based on the highest-quality evidence from large randomized trials showing superior prevention of heart failure compared to calcium channel blockers and superior stroke prevention compared to ACE inhibitors 1, 3, 4
• Chlorthalidone demonstrates greater 24-hour blood pressure reduction than hydrochlorothiazide at equivalent doses (12.4 mmHg vs 7.4 mmHg systolic reduction) 5
• When thiazides cannot be used, ACE inhibitors (captopril, lisinopril, or ramipril) are the preferred alternative 3

Black Patients Without Heart Failure or CKD

• Initiate with thiazide diuretics or calcium channel blockers as first-line therapy 1, 2, 6
• ACE inhibitors and ARBs are less effective in this population for stroke and heart failure prevention 1, 7
• ARBs may be better tolerated than ACE inhibitors (less cough and angioedema) but offer no proven cardiovascular advantage 1

Patients With Diabetes Mellitus

• ACE inhibitor or ARB is the preferred first-line agent 2, 6

Patients With Chronic Kidney Disease (Stage 3+ or Albuminuria ≥300 mg/day)

• ACE inhibitor or ARB is first-line therapy 2, 6

Post-Myocardial Infarction or Stable Ischemic Heart Disease

• Combine a β-blocker with an ACE inhibitor or ARB 2

Heart Failure With Reduced Ejection Fraction

• Combine an ACE inhibitor or ARB, a β-blocker, and a diuretic 2

Monotherapy vs. Combination Therapy Strategy

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

• Initiate single-agent monotherapy and titrate dosage sequentially, adding agents from different classes as needed 1, 2, 6

Stage 2 Hypertension (≥140/90 mmHg or >20/10 mmHg Above Goal)

• Begin with two-drug combination therapy from different first-line classes, preferably as a single-pill combination 1, 2, 6
• Combination therapy using submaximal doses from two classes produces larger blood pressure reductions (typically 9/5 mmHg per agent) with fewer adverse effects than maximal dosing of a single agent 2, 8
• Single-pill combinations improve medication adherence and persistence 1, 2

Recommended Two-Drug Combinations

• Thiazide diuretic + (ACE inhibitor or ARB) 1, 2
• Calcium channel blocker + (ACE inhibitor or ARB) 1, 2

Blood Pressure Targets

• <140/90 mmHg for all patients without comorbidities 1, 2, 6
• <130/80 mmHg for adults <65 years and those with known cardiovascular disease or 10-year ASCVD risk ≥10% 2, 6
• <130 mmHg systolic for non-institutionalized adults ≥65 years 2
• <130/80 mmHg for patients with diabetes mellitus or chronic kidney disease 2, 6
• Diastolic pressure should not fall below 60-70 mmHg in high-risk patients; optimal diastolic range is 70-79 mmHg 2

Comparative Efficacy of First-Line Classes

Thiazide Diuretics vs. Other Classes

• Thiazides reduce total cardiovascular events by 12% compared to beta-blockers (RR 0.88,95% CI 0.78-1.00) and by 7% compared to calcium channel blockers (RR 0.93,95% CI 0.89-0.98) 4
• Thiazides reduce heart failure by 26% compared to calcium channel blockers (RR 0.74,95% CI 0.66-0.82) and by 49% compared to alpha-blockers (RR 0.51,95% CI 0.45-0.58) 4
• Thiazides reduce stroke by 11% compared to ACE inhibitors (RR 0.89,95% CI 0.80-0.99) 4
• No antihypertensive drug class demonstrates clinically important advantages over first-line thiazides for total mortality 4

Dose-Response Relationships

• Hydrochlorothiazide shows clear dose-dependent blood pressure lowering: 6.25 mg reduces BP by 4/2 mmHg, 12.5 mg by 6/3 mmHg, 25 mg by 8/3 mmHg, and 50 mg by 11/5 mmHg 8
• Chlorthalidone at 12.5-75 mg/day reduces BP by 12/4 mmHg 8
• Indapamide at 1.0-5.0 mg/day reduces BP by 9/4 mmHg 8
• Thiazides reduce pulse pressure by 4-6 mmHg, exceeding the 3 mmHg reduction with ACE inhibitors/ARBs and 2 mmHg with beta-blockers 8

Monitoring Schedule

• Monthly follow-up after initiating or changing medications until blood pressure target is achieved 1, 2, 6
• Every 3-5 months for patients at goal 1, 2, 6
• Allow at least 4 weeks between dose adjustments to observe full blood pressure response 2, 7
• Monitor serum creatinine, eGFR, and potassium within 1-2 weeks of initiating ACE inhibitors, ARBs, or diuretics, after each dose increase, and annually thereafter 2, 7
• An increase in creatinine up to 50% above baseline or to 3 mg/dL (whichever is greater) is acceptable 2, 7

Critical Contraindications and Cautions

Absolute Contraindications

• ACE inhibitors and ARBs are contraindicated in pregnancy due to fetal toxicity 2, 7
• Never combine an ACE inhibitor with an ARB (or add a direct renin inhibitor) due to increased adverse effects without additional benefit 2, 6, 7

Important Cautions

• Beta-blockers should not be first-line in uncomplicated hypertension, especially in patients >60 years, because they are 36% less effective than calcium channel blockers and 30% less effective than thiazides for stroke prevention 1, 6
• Alpha-blockers are not first-line therapy because they are less effective for cardiovascular disease prevention than thiazides 1
• Black patients have greater risk of angioedema with ACE inhibitors 7
• Thiazides reduce serum potassium, increase uric acid, and increase total cholesterol and triglycerides in a dose-related manner 8

Special Populations

Older Adults (≥65 Years)

• Target systolic <130 mmHg for non-institutionalized, ambulatory adults 2
• Exercise caution when initiating combination therapy in those at risk for orthostatic hypotension 2

Pregnancy

• Switch to methyldopa, nifedipine, or labetalol if pregnancy occurs during treatment 2