What is the first‑line antihypertensive medication for a white adult male with uncomplicated primary hypertension and no contraindications?

First-Line Blood Pressure Medication for White Males

For a white adult male with uncomplicated primary hypertension, initiate treatment with chlorthalidone 12.5–25 mg daily as the optimal first-line agent; if chlorthalidone is unavailable or not tolerated, use a long-acting calcium-channel blocker such as amlodipine 5–10 mg daily. 1, 2, 3

Treatment Initiation Threshold

• Stage 1 hypertension (130–139/80–89 mmHg): Begin pharmacologic therapy when the patient has established cardiovascular disease or a 10-year ASCVD risk ≥10% calculated using the ACC/AHA Pooled Cohort Equations. 1, 2
• Stage 2 hypertension (≥140/90 mmHg): Start antihypertensive medication immediately alongside lifestyle modifications; do not delay beyond 3 months. 2
• Virtually all men aged ≥70 years and most aged ≥65 years have a 10-year ASCVD risk ≥10%, automatically meeting the treatment threshold at Stage 1 pressures. 2

Optimal First-Line Agent: Chlorthalidone

Chlorthalidone is the single best-supported first-line drug for white males based on the ALLHAT trial of >50,000 participants, which demonstrated superior prevention of heart failure compared with amlodipine (38% lower risk) and superior stroke prevention compared with lisinopril (15% lower risk). 1, 2, 3, 4

• Chlorthalidone 12.5–25 mg once daily provides 24-hour blood-pressure control because of its 40–60 hour half-life and large volume of distribution. 5, 6
• This agent reduces all-cause mortality, stroke, and heart failure more effectively than ACE inhibitors, calcium-channel blockers, or beta-blockers in head-to-head comparisons. 1, 7
• Chlorthalidone at 25 mg is more potent than hydrochlorothiazide 50 mg, particularly for overnight blood-pressure reduction. 5, 6

Alternative First-Line Agents

Calcium-Channel Blockers (CCBs)

• Long-acting dihydropyridine CCBs (amlodipine 5–10 mg daily or extended-release nifedipine) are equally effective as chlorthalidone for all cardiovascular events except heart failure, where thiazides remain superior. 1, 2
• Choose a CCB when thiazide diuretics are contraindicated (e.g., gout, severe hyponatremia) or poorly tolerated. 2

ACE Inhibitors

• ACE inhibitors (lisinopril 10–40 mg daily, ramipril, enalapril) are reasonable first-line options, particularly when albuminuria or established coronary artery disease is present. 1, 2
• However, in ALLHAT, lisinopril was 15% less effective than chlorthalidone for stroke prevention and 19% less effective for heart failure prevention in the general population. 1, 5

Angiotensin-Receptor Blockers (ARBs)

• ARBs (losartan 50–100 mg daily) are equally effective to ACE inhibitors for blood-pressure control and cardiovascular outcomes. 2, 3
• ARBs cause less cough and angioedema than ACE inhibitors but offer no additional cardiovascular benefit over thiazides in uncomplicated hypertension. 1

Monotherapy vs. Combination Strategy

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

• Start with single-agent monotherapy (chlorthalidone 12.5 mg or amlodipine 5 mg) and titrate the dose upward before adding a second agent from a different class. 1, 2, 3
• Reassess monthly after initiation or dose adjustment until the target blood pressure <130/80 mmHg is achieved. 1, 2

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

• Begin with a two-drug combination from different first-line classes, preferably as a single-pill formulation to improve adherence. 1, 2, 3
• Preferred two-drug regimens:
  • Chlorthalidone + ACE inhibitor or ARB 2, 3
  • Amlodipine + ACE inhibitor or ARB 2, 3
• Single-pill combinations markedly improve medication adherence and persistence compared with separate pills. 2, 3

Blood-Pressure Target

• Aim for a blood pressure <130/80 mmHg in all white males with hypertension, regardless of age or comorbidities. 1, 2
• For community-dwelling men aged ≥65 years, target systolic <130 mmHg if tolerated. 1, 2
• In high-risk patients, avoid lowering diastolic pressure below 70 mmHg because excessive reduction may increase adverse cardiovascular events. 2

Agents to Avoid as First-Line

Beta-Blockers

• Do not use beta-blockers as first-line therapy in uncomplicated hypertension, especially in men >60 years, because they are approximately 36% less effective than CCBs and 30% less effective than thiazides for stroke prevention. 1, 2, 3, 4
• Reserve beta-blockers for compelling indications: post-myocardial infarction, stable angina, heart failure with reduced ejection fraction, or atrial fibrillation requiring rate control. 2

Alpha-Blockers

• Alpha-blockers (doxazosin) are not first-line agents because they are less effective for cardiovascular disease prevention than thiazide diuretics; in ALLHAT, doxazosin was associated with an 80% higher rate of heart failure compared with chlorthalidone. 1, 5

Monitoring and Laboratory Follow-Up

• Check serum creatinine, eGFR, potassium, fasting glucose, and lipid panel at baseline. 2
• Repeat creatinine, eGFR, and potassium within 1–2 weeks after starting a thiazide diuretic, then annually. 2, 3, 4
• Maintain serum potassium >3.5 mmol/L when using thiazide diuretics to avoid increased ventricular ectopy and glucose intolerance. 4, 5
• An increase in serum creatinine up to 50% above baseline or to 3 mg/dL (whichever is greater) is acceptable. 2
• Schedule monthly follow-up visits after medication initiation or dose changes until the blood-pressure target is achieved, then every 3–5 months for maintenance. 1, 2, 3

Common Pitfalls to Avoid

• Delaying combination therapy in Stage 2 hypertension (≥140/90 mmHg) increases cardiovascular risk; always start two agents simultaneously in this setting. 2, 3
• Never combine an ACE inhibitor with an ARB (or add a direct renin inhibitor) because dual renin-angiotensin system blockade increases hyperkalemia and acute kidney injury without added cardiovascular benefit. 2, 3, 4
• Avoid using hydrochlorothiazide at doses <25 mg daily as monotherapy; doses below this threshold are either unproven or less effective in clinical outcome trials. 1
• Do not discontinue thiazide diuretics solely because of asymptomatic hyperuricemia; continue the diuretic and add allopurinol if needed. 5
• NSAIDs blunt the antihypertensive effect of thiazide diuretics; counsel patients to avoid chronic NSAID use. 5