What are the first-line treatment options for a general adult patient with hypertension and no significant comorbidities?

First-Line Hypertensive Agents

For adults with hypertension requiring pharmacologic treatment, initiate therapy 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). 1

Treatment Initiation Strategy

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

• Start with single-agent monotherapy from one of the four first-line classes 2
• Titrate dosage and sequentially add agents as needed to reach target 2

Stage 2 Hypertension (BP ≥140/90 mmHg or >20/10 mmHg above goal)

• Initiate with upfront low-dose combination therapy using two drugs from different first-line classes, preferably as a single-pill combination to improve adherence 1, 2, 3
• Preferred combinations include: RAS blocker (ACE inhibitor or ARB) + CCB, RAS blocker + thiazide diuretic, or CCB + thiazide diuretic 1, 3
• Never combine two RAS blockers (ACE inhibitor + ARB) together, as this increases adverse events without additional benefit 1, 3

Specific First-Line Agent Selection

Thiazide/Thiazide-Like Diuretics

• Chlorthalidone 12.5-25 mg once daily is the preferred thiazide diuretic based on the strongest evidence from over 50,000 patients in three major trials, demonstrating superior reduction in stroke and heart failure 3, 4
• Hydrochlorothiazide 12.5-50 mg once daily is an acceptable alternative when chlorthalidone is unavailable, though it has a shorter duration of action 3

ACE Inhibitors

• Lisinopril 10-40 mg once daily is effective across all grades of hypertension and reduces all-cause mortality 3, 5
• ACE inhibitors are particularly beneficial for patients with diabetes, chronic kidney disease, heart failure, or coronary artery disease 3, 6

Angiotensin Receptor Blockers (ARBs)

• Losartan 50-100 mg once daily is effective for hypertension and provides additional benefits in patients with left ventricular hypertrophy 3, 7
• ARBs are preferred over ACE inhibitors when patients cannot tolerate ACE inhibitor-related cough 3

Long-Acting Dihydropyridine Calcium Channel Blockers

• Amlodipine 5-10 mg once daily is the preferred long-acting dihydropyridine CCB 3, 4
• CCBs are particularly effective in Black patients and elderly patients 3

Race-Specific Considerations

For Black adults without heart failure or chronic kidney disease, initial treatment should include a thiazide diuretic or calcium channel blocker rather than an ACE inhibitor or ARB alone 1, 3

• The combination of CCB + thiazide diuretic may be more effective than CCB + ARB in Black patients 3
• Black patients typically have a low-renin hypertensive profile, making them less responsive to RAS blockade as monotherapy 5, 7

Blood Pressure Targets

• Target BP <140/90 mmHg for all patients with hypertension without comorbidities 1
• Target BP <130/80 mmHg for adults <65 years 2
• Target systolic BP <130 mmHg for patients with known cardiovascular disease 1
• Target systolic BP <130 mmHg may be reasonable for high-risk patients with diabetes, chronic kidney disease, or high CVD risk 1, 3

Escalation to Triple Therapy

When BP remains uncontrolled on dual therapy:

• Add a third agent from the remaining first-line classes to create triple therapy 1, 3
• The typical effective combination is: RAS blocker + CCB + thiazide diuretic 2, 3

Resistant Hypertension (Fourth-Line Agent)

When BP remains uncontrolled despite optimized triple therapy (RAS blocker + CCB + thiazide diuretic), add spironolactone 25-50 mg daily as the preferred fourth-line agent 1, 3

• If spironolactone is not tolerated, consider eplerenone (dosed higher at 50-200 mg, potentially twice daily) or a vasodilating beta-blocker 1

Critical Monitoring Parameters

• Reassess BP monthly after initiating or changing medications until target is achieved 1, 2
• Follow up every 3-5 months for patients at goal 1, 2
• Monitor serum potassium and creatinine within 2-4 weeks after starting ACE inhibitors, ARBs, or diuretics to detect hyperkalemia, hypokalemia, or acute kidney injury 2, 3
• Confirm medication adherence before escalating therapy, as non-adherence is the most common cause of apparent treatment resistance 3

Common Pitfalls to Avoid

• Do not delay treatment initiation for extensive laboratory testing or cardiovascular risk assessment—these can be performed after starting therapy 1
• Avoid using ACE inhibitors as monotherapy in Black patients without compelling indications 1, 3
• Do not lower diastolic BP to <60 mmHg, as this may increase cardiovascular risk in high-risk patients with treated systolic BP <130 mmHg 1
• Avoid rapid-acting agents like immediate-release nifedipine or hydralazine for routine hypertension management 8