What are alternative antihypertensive medications besides Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs)?

Alternative Antihypertensive Medications Besides ACE Inhibitors and ARBs

Thiazide diuretics, calcium channel blockers (CCBs), and beta-blockers are the primary alternative antihypertensive medication classes besides ACE inhibitors and ARBs, with mineralocorticoid receptor antagonists as an additional option for resistant hypertension. 1

First-Line Alternative Options

Thiazide/Thiazide-like Diuretics

• Mechanism: Inhibit sodium and chloride reabsorption in the distal convoluted tubule
• Examples: Chlorthalidone, indapamide, hydrochlorothiazide
• Key considerations:
  • Preferred for most patients as first-line therapy according to AHA/ACC/CDC guidelines 1
  • Long-acting agents (chlorthalidone, indapamide) are preferred due to better cardiovascular outcomes 1
  • Monitor for electrolyte abnormalities, especially hypokalemia
  • Particularly effective in Black patients and older adults (>55 years) 1

Calcium Channel Blockers (CCBs)

• Mechanism: Block calcium influx into vascular smooth muscle cells, causing vasodilation
• Examples: Amlodipine, nifedipine, diltiazem, verapamil
• Key considerations:
  • Dihydropyridine CCBs (amlodipine, nifedipine) are preferred for hypertension 1
  • Particularly effective in Black patients and older adults (>55 years) 1
  • Can cause peripheral edema (25% with amlodipine 10mg daily) 2
  • Amlodipine has demonstrated significant reductions in both office and ambulatory blood pressure 3
  • Non-dihydropyridine CCBs (diltiazem, verapamil) should be avoided in heart failure with reduced ejection fraction 1

Beta-Blockers

• Mechanism: Block beta-adrenergic receptors, reducing heart rate and cardiac output
• Examples: Metoprolol, bisoprolol, carvedilol
• Key considerations:
  • Recommended by CHEP guidelines as a first-line option 1
  • Particularly beneficial in patients with coronary artery disease, post-MI, or heart failure 1
  • Beta-1 selective agents (metoprolol, bisoprolol) are preferred in patients with COPD 1
  • Metoprolol has been shown to be effective when used alone or with thiazide diuretics 4
  • May be less effective as monotherapy in Black patients 5

Second-Line Options

Mineralocorticoid Receptor Antagonists

• Mechanism: Block aldosterone receptors, reducing sodium reabsorption and potassium excretion
• Examples: Spironolactone, eplerenone
• Key considerations:
  • Recommended for resistant hypertension (uncontrolled on 3 medications including a diuretic) 1
  • Particularly effective when added to ACE/ARB, thiazide, and CCB combination 1
  • Monitor for hyperkalemia, especially when combined with ACE/ARB 1
  • Eplerenone showed 15% mortality reduction in post-MI patients with LV dysfunction 1
  • Avoid in patients with elevated serum creatinine (>2.5 mg/dL in men, >2.0 mg/dL in women) or potassium >5.0 mEq/L 1

Alpha-Blockers

• Mechanism: Block alpha-adrenergic receptors, causing vasodilation
• Examples: Doxazosin, prazosin
• Key considerations:
  • Typically used as fourth-line agents 1
  • Can be considered in resistant hypertension 6
  • May cause orthostatic hypotension, especially with first dose

Combination Therapy Considerations

• Multiple-drug therapy is often required to achieve blood pressure targets 1
• Effective two-drug combinations include:
  • CCB + thiazide diuretic
  • CCB + beta-blocker
  • Thiazide diuretic + beta-blocker 1
• For three-drug combinations, CCB + thiazide + beta-blocker is recommended 1

Special Populations

Coronary Artery Disease

• Beta-blockers are first-line therapy regardless of BP levels 1
• CCBs can be added if BP control is inadequate 1

Heart Failure

• Beta-blockers (carvedilol, metoprolol, bisoprolol) are recommended 1
• Mineralocorticoid receptor antagonists are effective 1
• Dihydropyridine CCBs should only be used if BP remains uncontrolled 1

Chronic Kidney Disease

• Thiazide diuretics are effective if eGFR >30 mL/min/1.73m²
• Loop diuretics should be used if eGFR <30 mL/min/1.73m² 1
• Monitor renal function and electrolytes regularly 1

COPD

• Beta-1 selective blockers may be used 1
• CCBs and diuretics are preferred options 1

Common Pitfalls and Caveats

1. Edema with CCBs: Dihydropyridine CCBs frequently cause peripheral edema, which may reduce compliance 2

2. Electrolyte monitoring: Regular monitoring of electrolytes is essential with diuretics and mineralocorticoid receptor antagonists 1

3. Beta-blocker initiation: Start with low doses and titrate gradually to avoid bradycardia and hypotension 1

4. Resistant hypertension: Consider adding a mineralocorticoid receptor antagonist before trying less evidence-based alternatives 1

5. Medication adherence: Poor adherence is a common cause of apparent treatment failure 6

By selecting appropriate alternatives to ACE inhibitors and ARBs based on patient characteristics and comorbidities, effective blood pressure control can be achieved while minimizing adverse effects.