What is the initial approach to starting antihypertensive medication in patients with hypertension?

How to Start Antihypertensive Medication

For patients with blood pressure ≥160/100 mmHg, initiate treatment immediately with two antihypertensive medications, preferably as a single-pill combination, while patients with BP 140-159/90-99 mmHg can start with monotherapy unless they have high cardiovascular risk (diabetes, CVD, CKD, or organ damage), in which case dual therapy should be started immediately. 1, 2

Initial Treatment Strategy Based on Blood Pressure Level

Grade 2 Hypertension (BP ≥160/100 mmHg)

• Start with two-drug combination therapy immediately alongside lifestyle interventions 1, 2
• Single-pill combinations are strongly preferred over separate pills because they improve medication adherence and achieve faster BP control 2
• This approach is supported by evidence showing greater BP lowering with fixed-dose combinations than sequential monotherapy, though formal head-to-head trials comparing strategies are lacking 1

Grade 1 Hypertension (BP 140-159/90-99 mmHg)

• High-risk patients (those with established CVD, diabetes, CKD, organ damage, or age 50-80 years) should start dual therapy immediately 1, 2
• Low-to-moderate risk patients may start with monotherapy, but if BP remains elevated after 3-6 months of lifestyle intervention, escalate to combination therapy 1
• For diabetic patients with BP in this range, monotherapy is acceptable initially, though combination therapy is preferred 1

Special Populations Requiring Monotherapy

• Patients aged >80 years or frail elderly should be considered for monotherapy initiation with careful BP monitoring 1
• Patients with history of hypotension or drug-associated side effects warrant starting with single-agent therapy 1

First-Line Medication Classes

The four major first-line drug classes are 2, 3, 4:

• Thiazide or thiazide-like diuretics (chlorthalidone preferred over hydrochlorothiazide based on superior outcomes data) 5
• ACE inhibitors (lisinopril, enalapril, ramipril)
• Angiotensin receptor blockers (ARBs) (candesartan, losartan)
• Long-acting dihydropyridine calcium channel blockers (amlodipine, nifedipine)

Preferred Two-Drug Combinations

The most effective and well-tolerated combinations are 2, 3:

• Thiazide diuretic + ACE inhibitor
• Thiazide diuretic + ARB
• Calcium channel blocker + ACE inhibitor
• Calcium channel blocker + ARB

Avoid these combinations 1:

• ACE inhibitor + ARB (increased risk of hyperkalemia and AKI without added benefit)
• ACE inhibitor or ARB + direct renin inhibitor
• Thiazide + beta-blocker in patients with metabolic syndrome or high diabetes risk 2

Race-Specific Considerations

Black Patients

• Initial treatment should include a diuretic or calcium channel blocker, either alone or combined with a RAS blocker 1, 2
• For dual therapy: start with ARB + dihydropyridine CCB or dihydropyridine CCB + thiazide-like diuretic 1

Non-Black Patients

• Start with low-dose ACE inhibitor or ARB, then add dihydropyridine CCB 1
• Increase to full dose before adding third agent (thiazide/thiazide-like diuretic) 1

Compelling Indications for Specific Drug Classes

Diabetes with Albuminuria

• ACE inhibitor or ARB at maximum tolerated dose is mandatory first-line therapy for patients with urine albumin-to-creatinine ratio ≥30 mg/g 1, 2
• If one class is not tolerated, substitute the other 1

Heart Failure with Reduced Ejection Fraction

• Treatment must include ACE inhibitor (or ARB if ACE inhibitor not tolerated), beta-blocker, and diuretic/mineralocorticoid receptor antagonist if required 2

Chronic Kidney Disease with Albuminuria

• RAS blockers (ACE inhibitor or ARB) are recommended in the presence of albuminuria 2
• Target systolic BP of 120-139 mmHg 2

Specific Dosing Guidance

ACE Inhibitor (Lisinopril) Starting Doses 6:

• Standard starting dose: 10 mg once daily for most adults
• 5 mg once daily if patient is already on diuretics
• Usual maintenance range: 20-40 mg daily (maximum 80 mg, though doses above 40 mg show minimal additional benefit)

Calcium Channel Blocker (Amlodipine) Starting Doses 7:

• 5 mg once daily for most adults
• 2.5 mg once daily for small, fragile, elderly patients, or those with hepatic insufficiency
• Maximum dose: 10 mg once daily
• Wait 7-14 days between titration steps (can titrate faster if clinically warranted with frequent assessment) 7

Critical Pitfalls to Avoid

• Do not use sequential monotherapy as default approach in high-risk patients—this delays BP control and is frustrating for both patient and provider 2
• Monitor for orthostatic hypotension when initiating dual therapy in elderly patients, as hypotension may develop 1
• Check serum creatinine/eGFR and potassium at baseline, after dose changes, and at least annually when using ACE inhibitors, ARBs, or diuretics 1, 2
• Assess medication adherence proactively, as poor compliance is the most common cause of resistant hypertension 2

Follow-Up and Monitoring Schedule

• Monthly visits until BP target is achieved 2
• Target BP <130/80 mmHg for most patients; <140/90 mmHg is acceptable for lower-risk patients 1, 3
• Achieve target BP within 3 months of treatment initiation 1, 2
• Use home BP monitoring or ambulatory BP monitoring to confirm diagnosis and monitor treatment effectiveness 2

Lifestyle Modifications (Concurrent with Pharmacotherapy)

All patients should receive intensive lifestyle counseling 2, 3, 4:

• Sodium restriction to <1500 mg/day or reduction of at least 1000 mg/day
• Increased potassium intake (3500-5000 mg/day)
• Weight loss if overweight/obese
• Physical activity: aerobic or dynamic resistance exercise 90-150 minutes per week
• Alcohol moderation: ≤2 drinks per day in men, ≤1 per day in women
• DASH-like diet rich in fruits, vegetables, whole grains, and low-fat dairy products

Escalation for Inadequate Response

If BP remains uncontrolled on dual therapy 1, 2:

• Increase to full doses before adding third agent
• Add thiazide-like diuretic as third agent
• For resistant hypertension (uncontrolled on 3 drugs including diuretic), add low-dose spironolactone as fourth agent 2
• Reinforce lifestyle measures, especially sodium restriction 2
• Exclude secondary causes (obstructive sleep apnea, renal artery stenosis, primary aldosteronism) and assess medication adherence 2