How do antihypertensive medications work?

Mechanisms of Antihypertensive Medications

Antihypertensive medications work through various mechanisms that target different physiological pathways to reduce blood pressure by decreasing cardiac output, reducing peripheral vascular resistance, or both.

Major Classes of Antihypertensive Medications and Their Mechanisms

Diuretics

• Mechanism: Inhibit sodium reabsorption in distal tubules, reducing blood volume and vascular resistance 1
• Examples: Hydrochlorothiazide, chlorthalidone
• Primary effect: Reduce blood volume initially, with long-term effect of decreasing peripheral vascular resistance
• Clinical significance: Particularly effective for low-renin hypertension and in Black patients 1

ACE Inhibitors

• Mechanism: Block conversion of angiotensin I to angiotensin II, reducing vasoconstriction and aldosterone secretion 2
• Examples: Lisinopril, enalapril
• Primary effect: Decrease peripheral resistance by preventing formation of angiotensin II (a potent vasoconstrictor)
• Clinical significance: Particularly beneficial in patients with diabetes, heart failure, or kidney disease 1, 3

Angiotensin Receptor Blockers (ARBs)

• Mechanism: Block angiotensin II receptors, preventing vasoconstriction and aldosterone release
• Examples: Candesartan, losartan
• Primary effect: Decrease peripheral resistance
• Clinical significance: Similar benefits to ACE inhibitors but with fewer side effects like cough 1

Calcium Channel Blockers (CCBs)

• Mechanism: Inhibit calcium influx into vascular smooth muscle and cardiac cells 4
• Examples: Amlodipine, nicardipine
• Primary effect: Cause vasodilation, reducing peripheral vascular resistance
• Clinical significance: Particularly effective in elderly patients and those with isolated systolic hypertension 1

Beta-Blockers

• Mechanism: Block beta-adrenergic receptors, reducing heart rate and cardiac output 2
• Examples: Metoprolol, atenolol
• Primary effect: Decrease cardiac output and inhibit renin release
• Clinical significance: Particularly useful in patients with coronary artery disease or heart failure 1

Specialized Antihypertensive Agents

Aldosterone Antagonists

• Mechanism: Block aldosterone receptors, reducing sodium retention and potassium excretion
• Examples: Spironolactone, eplerenone
• Clinical significance: Preferred in primary aldosteronism and resistant hypertension 2

Alpha-Blockers

• Mechanism: Block alpha-adrenergic receptors, causing vasodilation
• Examples: Doxazosin, prazosin
• Clinical significance: Often used as add-on therapy, particularly in men with benign prostatic hyperplasia

Physiological Impact on Blood Pressure Regulation

1. Cardiac Output Reduction:

   • Beta-blockers, central adrenergic inhibitors, and diuretics primarily reduce cardiac output 5
   • This decreases the volume and force of blood ejected from the heart

2. Peripheral Resistance Reduction:

   • ACE inhibitors, ARBs, CCBs, and alpha-blockers primarily decrease peripheral resistance 5
   • This allows blood vessels to dilate, creating less resistance to blood flow

3. Combined Effects:

   • Many agents work through multiple mechanisms
   • For example, diuretics initially reduce blood volume but long-term also decrease peripheral resistance

Clinical Application Based on Patient Characteristics

• Low-renin hypertension: Diuretics and calcium channel blockers are most effective 5
• High-renin hypertension: ACE inhibitors, ARBs, and beta-blockers are most effective 5
• Comorbid conditions determine optimal agent selection:
  • Diabetes: ACE inhibitors or ARBs preferred 1
  • Chronic kidney disease: ACE inhibitors or ARBs preferred 1, 6
  • Heart failure: Diuretics, beta-blockers, ACE inhibitors, ARBs 1
  • Coronary artery disease: Beta-blockers and CCBs preferred 1

Combination Therapy Considerations

Most patients require multiple medications to achieve target blood pressure. Effective combinations include:

• Thiazide diuretic + ACE inhibitor/ARB: Complementary mechanisms where the diuretic activates the renin-angiotensin system, which is then blocked by the ACE inhibitor/ARB 2
• CCB + ACE inhibitor/ARB: Complementary vasodilatory effects through different pathways
• CCB + thiazide diuretic: Effective combination for resistant hypertension

Important Clinical Considerations

• Avoid certain combinations: ACE inhibitors with ARBs or direct renin inhibitors increase cardiovascular and renal risk 2
• Target blood pressure: Generally <130/80 mmHg for most patients according to current guidelines 2
• Medication timing: Some evidence suggests giving at least one antihypertensive at bedtime may reduce cardiovascular events 2

By understanding these mechanisms, clinicians can select appropriate antihypertensive therapy based on individual patient characteristics and comorbidities to effectively control blood pressure and reduce cardiovascular risk.