What are the dihydropyridines (calcium channel blockers)?

Dihydropyridines: A Class of Calcium Channel Blockers

Dihydropyridines are a major subclass of calcium channel blockers that selectively target L-type calcium channels in vascular smooth muscle, causing arterial vasodilation with minimal effects on cardiac conduction or contractility. 1

Mechanism of Action

Dihydropyridines work by:

• Inhibiting the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle 2
• Binding to specific sites on the α1-subunit of the L-type calcium channel 1
• Demonstrating high selectivity for arterial/arteriolar tissues, including coronary arteries 1
• Causing vasodilation, which reduces peripheral vascular resistance and blood pressure 2

Unlike non-dihydropyridine CCBs (verapamil and diltiazem), dihydropyridines have:

• Minimal negative chronotropic and dromotropic effects on sinoatrial and atrioventricular nodal conducting tissue
• Less pronounced negative inotropic effects on cardiomyocytes 1

Common Dihydropyridine Agents

The dihydropyridine class includes:

• Amlodipine
• Felodipine
• Nifedipine
• Nisoldipine
• Isradipine
• Nicardipine
• Nitrendipine
• Lacidipine (not available in the US) 1

Clinical Applications

Dihydropyridines are indicated for:

1. Hypertension: Effective as monotherapy or in combination with other antihypertensive agents 1
2. Angina pectoris: Particularly effective for:
   • Exertional angina: Reduces total peripheral resistance and myocardial oxygen demand 2
   • Vasospastic (Prinzmetal's) angina: Blocks coronary artery spasm 2
3. Raynaud's syndrome: May provide benefit due to peripheral vasodilatory effects 3
4. Isolated systolic hypertension: Particularly effective in this condition 3

Pharmacological Properties

• Duration of action: Varies from short-acting (e.g., immediate-release nifedipine) to long-acting (e.g., amlodipine) 1
• Metabolism: Metabolized in the liver by cytochrome P450 3A4 1
• Half-life: Newer agents (amlodipine) have longer half-lives compared to older agents 4

Side Effects

Common adverse effects include:

• Peripheral edema (particularly of lower limbs) - nifedipine has the highest risk, lacidipine the lowest 5
• Headache, dizziness, flushing
• Hypotension
• Palpitations
• Reflex tachycardia (more common with short-acting agents) 1

Important Clinical Considerations

1. Avoid rapid-release, short-acting dihydropyridines (e.g., immediate-release nifedipine) in the absence of concomitant beta-blockade due to increased risk of adverse cardiovascular events 1

2. Long-acting dihydropyridines (e.g., amlodipine) are preferred over short-acting ones, particularly when used in combination with beta-blockers 1

3. Combination therapy:

   • Dihydropyridines work well with ACE inhibitors, ARBs, or diuretics
   • Combining with RAS blockers reduces the risk of peripheral edema 5

4. Outcome data:

   • Long-acting dihydropyridines like amlodipine show better protection against stroke compared to intermediate-acting agents 4
   • However, they may be associated with a higher risk of heart failure compared to other antihypertensive classes 4

5. Contraindications and cautions:

   • Generally safe in mild left ventricular dysfunction
   • Unlike non-dihydropyridines, they can be used in patients with heart failure or conduction abnormalities 1

Differences from Non-dihydropyridine CCBs

Dihydropyridines differ from non-dihydropyridines (verapamil, diltiazem) in several ways:

• More selective for vascular smooth muscle
• Minimal effects on cardiac conduction system
• Less negative inotropic effect
• More likely to cause peripheral edema and reflex tachycardia
• Less likely to cause bradycardia or heart block 1

Dihydropyridines represent an important class of calcium channel blockers with distinct pharmacological properties that make them particularly useful for hypertension and angina management, with newer long-acting agents offering improved safety profiles compared to older short-acting formulations.