What are the best initial antihypertensive medications and their starting doses for a patient with hypertension?

Best Initial Antihypertensive Medications and Starting Doses

For most patients with hypertension, initiate treatment with a thiazide-like diuretic (chlorthalidone 12.5-25 mg daily preferred over hydrochlorothiazide), an ACE inhibitor (lisinopril 10 mg daily), an ARB (losartan 50 mg daily), or a calcium channel blocker (amlodipine 5 mg daily), with the specific choice guided by race and comorbidities. 1, 2

First-Line Medication Classes and Starting Doses

Thiazide/Thiazide-Like Diuretics

• Chlorthalidone 12.5-25 mg once daily is the preferred thiazide diuretic due to its longer half-life and superior cardiovascular outcomes data from landmark trials 1, 3, 2
• Hydrochlorothiazide 25 mg once daily is acceptable if chlorthalidone is unavailable, though it provides less 24-hour blood pressure control 1, 3
• Chlorthalidone demonstrates significantly greater systolic BP reduction on 24-hour ambulatory monitoring compared to hydrochlorothiazide at equivalent doses (12.4 mm Hg vs 7.4 mm Hg reduction) 3

ACE Inhibitors

• Lisinopril 10 mg once daily is the recommended starting dose for most adults 4
• Reduce to 5 mg once daily in patients taking diuretics or with possible intravascular depletion 4
• Titrate up to 20-40 mg daily based on blood pressure response 4, 2

Angiotensin Receptor Blockers (ARBs)

• Losartan 50 mg once daily is the usual starting dose 5
• Reduce to 25 mg once daily in patients with possible intravascular depletion (e.g., on diuretic therapy) 5
• Titrate to maximum of 100 mg once daily as needed 5, 2

Calcium Channel Blockers

• Amlodipine 5 mg once daily is the recommended starting dose 6, 2
• Titrate up to 10 mg once daily based on blood pressure response 6

Race-Based Treatment Recommendations

Black Patients

In Black adults with hypertension, initial treatment should include a thiazide-type diuretic or calcium channel blocker rather than an ACE inhibitor or ARB alone. 1, 7

• Thiazide diuretics and calcium channel blockers are more effective as monotherapy in Black patients compared to ACE inhibitors or beta-blockers 7
• Black patients have greater risk of angioedema with ACE inhibitors 7
• The preferred initial approach is a single-pill combination of ARB + calcium channel blocker OR ARB + thiazide diuretic 7
• Two or more antihypertensive medications are typically required to achieve BP target <130/80 mm Hg in Black adults 1

Non-Black Patients

• Any of the four first-line classes (thiazide diuretic, ACE inhibitor, ARB, or calcium channel blocker) is appropriate 1, 2
• ACE inhibitors or ARBs are particularly beneficial in patients with chronic kidney disease, heart failure, or coronary artery disease 6

Blood Pressure Targets

• Target BP <130/80 mm Hg for most adults 1, 2
• Minimum acceptable target is <140/90 mm Hg 1
• For adults ≥65 years, target SBP <130 mm Hg 2
• Achieve target within 3 months of initiating therapy 6, 7

Combination Therapy Approach

Most patients require two or more medications to achieve blood pressure control. 1

When to Start Combination Therapy

• Stage 2 hypertension (≥160/100 mm Hg) warrants initial two-drug combination therapy 6
• Single-pill combinations improve adherence and should be prioritized 7

Preferred Two-Drug Combinations

• ACE inhibitor or ARB + calcium channel blocker 6
• ACE inhibitor or ARB + thiazide diuretic 6
• Calcium channel blocker + thiazide diuretic (particularly effective in Black patients) 1, 7

Three-Drug Combination

• ACE inhibitor or ARB + calcium channel blocker + thiazide diuretic represents guideline-recommended triple therapy 6

Special Populations

Patients with Diabetes

• Any first-line agent is appropriate 1
• Target BP <130/80 mm Hg 6
• ACE inhibitors or ARBs provide additional renal protection 6

Patients with Chronic Kidney Disease

• ACE inhibitors or ARBs are preferred due to renoprotective effects 6
• Monitor serum potassium and creatinine 2-4 weeks after initiation 6

Elderly Patients (≥65 years)

• Start at low doses and titrate gradually 1
• Target SBP <130 mm Hg if well tolerated 1
• Thiazide diuretics and calcium channel blockers are particularly well-tolerated 8

Dose Adjustments for Specific Conditions

Hepatic Impairment

• Losartan: start at 25 mg once daily in mild-to-moderate hepatic impairment 5

Renal Impairment

• Lisinopril: reduce initial dose to 5 mg once daily if creatinine clearance 10-30 mL/min; 2.5 mg once daily if on hemodialysis or creatinine clearance <10 mL/min 4

Critical Monitoring Parameters

• Reassess blood pressure within 2-4 weeks after initiating or adjusting therapy 6, 7
• Check serum potassium and creatinine 2-4 weeks after starting ACE inhibitor, ARB, or diuretic 6
• Confirm diagnosis with home blood pressure monitoring (target <135/85 mm Hg) or 24-hour ambulatory monitoring (target <130/80 mm Hg) 7

Common Pitfalls to Avoid

• Do not use ACE inhibitor or ARB monotherapy as initial treatment in Black patients—combination with calcium channel blocker or thiazide diuretic is more effective 7
• Do not combine ACE inhibitor with ARB—this increases adverse events (hyperkalemia, acute kidney injury) without additional cardiovascular benefit 1, 6
• Do not use beta-blockers as first-line therapy unless compelling indications exist (post-MI, heart failure, angina)—they are less effective for stroke prevention and cardiovascular outcomes 1, 6
• Do not delay treatment intensification in patients with stage 2 hypertension—prompt action reduces cardiovascular risk 6
• Verify medication adherence before escalating therapy, as non-adherence is the most common cause of apparent treatment resistance 6