In a patient with chronic hypertension whose blood pressure remains 140/100 mm Hg despite max‑dose amlodipine 10 mg daily, what is the appropriate next pharmacologic step?

Upgrading Antihypertensive Therapy from Maximum-Dose Amlodipine

Direct Recommendation

Add either an ACE inhibitor/ARB (e.g., lisinopril 10–20 mg or losartan 50–100 mg daily) or a thiazide-like diuretic (chlorthalidone 12.5–25 mg daily preferred over hydrochlorothiazide) to achieve guideline-recommended dual therapy. 1, 2

Rationale for Adding a Second Agent

• Your patient has stage 1 hypertension (140/100 mmHg) despite maximum-dose amlodipine 10 mg, which requires treatment intensification within 2–4 weeks to reduce cardiovascular risk. 1, 2
• Combination therapy targeting complementary mechanisms (vasodilation plus renin-angiotensin blockade or volume reduction) achieves blood pressure control more effectively than uptitrating a single agent. 1, 2
• The 2017 ACC/AHA and 2024 ESC guidelines explicitly recommend adding a second drug class rather than continuing monotherapy when blood pressure remains ≥140/90 mmHg. 1, 2

Preferred Add-On Options

Option 1: ACE Inhibitor or ARB (First-Line for Most Patients)

• Adding an ACE inhibitor (lisinopril 10–20 mg) or ARB (losartan 50–100 mg) provides complementary renin-angiotensin system blockade alongside amlodipine's vasodilation. 1, 2
• This combination is particularly beneficial for patients with diabetes, chronic kidney disease, heart failure, or coronary artery disease. 1, 2
• The ACE-I/ARB + calcium channel blocker regimen may reduce amlodipine-related peripheral edema. 2, 3
• For Black patients specifically, the combination of amlodipine plus a thiazide diuretic may be more effective than amlodipine plus an ACE inhibitor/ARB. 1, 2

Option 2: Thiazide-Like Diuretic (Alternative First-Line)

• Adding chlorthalidone 12.5–25 mg daily (preferred) or hydrochlorothiazide 25 mg daily creates an effective calcium channel blocker + diuretic regimen. 1, 2
• Chlorthalidone is superior to hydrochlorothiazide due to its longer duration of action (24–72 hours vs 6–12 hours) and stronger cardiovascular outcome data from the ALLHAT trial. 2
• This combination is especially effective in elderly patients, Black patients, and those with volume-dependent hypertension. 1, 2

Blood Pressure Targets and Monitoring

• Target blood pressure is <130/80 mmHg for most adults, with a minimum acceptable goal of <140/90 mmHg. 1, 2, 4
• Re-measure blood pressure 2–4 weeks after adding the second agent, aiming to achieve target within 3 months of therapy modification. 1, 2, 4
• If adding a thiazide diuretic, check serum potassium and creatinine 2–4 weeks after initiation to detect hypokalemia or renal function changes. 1, 2
• If adding an ACE-I/ARB, monitor serum potassium and creatinine at least annually (or 2–4 weeks after initiation if higher risk). 1, 2

Progression to Triple Therapy (If Needed)

• If blood pressure remains ≥140/90 mmHg after optimizing dual therapy, add the third agent from the remaining class to form triple therapy (ACE-I/ARB + calcium channel blocker + thiazide diuretic). 1, 2
• This evidence-based triple combination targets three complementary mechanisms: renin-angiotensin blockade, vasodilation, and volume reduction. 1, 2
• Single-pill combinations are strongly preferred when available, as they significantly improve medication adherence. 1, 2

Fourth-Line Therapy for Resistant Hypertension

• If blood pressure remains ≥140/90 mmHg despite optimized triple therapy at maximum tolerated doses, add spironolactone 25–50 mg daily as the preferred fourth-line agent. 1, 2
• Spironolactone provides additional reductions of approximately 20–25 mmHg systolic and 10–12 mmHg diastolic when added to triple therapy. 1, 2
• Monitor serum potassium and creatinine 2–4 weeks after initiating spironolactone, especially when combined with an ACE-I/ARB, due to hyperkalemia risk. 1, 2

Critical Steps Before Adding Medication

• Verify medication adherence first—non-adherence is the most common cause of apparent treatment resistance. 2, 5
• Confirm elevated readings with home blood pressure monitoring (≥135/85 mmHg) or 24-hour ambulatory monitoring (≥130/80 mmHg) to exclude white-coat hypertension. 2, 4
• Review for interfering substances: NSAIDs, decongestants, oral contraceptives, systemic corticosteroids, and herbal supplements (ephedra, licorice) can all elevate blood pressure. 2, 5
• Screen for secondary hypertension if blood pressure is severely elevated (≥180/110 mmHg) or resistant to therapy—evaluate for primary aldosteronism, renal artery stenosis, obstructive sleep apnea, and pheochromocytoma. 2, 4, 5

Lifestyle Modifications (Adjunct to Pharmacotherapy)

• Sodium restriction to <2 g/day provides a 5–10 mmHg systolic reduction and enhances the efficacy of all antihypertensive classes. 1, 2
• Weight loss of approximately 10 kg reduces blood pressure by about 6.0/4.6 mmHg (systolic/diastolic). 2
• The DASH dietary pattern (high in fruits, vegetables, whole grains, low-fat dairy; low in saturated fat) lowers blood pressure by roughly 11.4/5.5 mmHg. 2
• Regular aerobic exercise (≥30 minutes most days, ≈150 minutes/week moderate intensity) reduces blood pressure by approximately 4/3 mmHg. 2
• Limit alcohol intake to ≤2 drinks/day for men and ≤1 drink/day for women. 2

Common Pitfalls to Avoid

• Do not add a beta-blocker as the second agent unless there are compelling indications (angina, post-myocardial infarction, heart failure with reduced ejection fraction, or atrial fibrillation requiring rate control)—beta-blockers are less effective than ACE-I/ARBs or diuretics for stroke prevention and cardiovascular events in uncomplicated hypertension. 1, 2
• Do not combine an ACE inhibitor with an ARB (dual renin-angiotensin blockade)—this increases adverse events (hyperkalemia, acute kidney injury) without additional cardiovascular benefit. 1, 2
• Do not delay treatment intensification—stage 1 hypertension at 140/100 mmHg requires prompt action within 2–4 weeks to reduce cardiovascular risk. 1, 2, 4
• Do not assume treatment failure without first confirming adherence and ruling out secondary causes or interfering substances. 2, 5