What are calcium channel blockers?

Calcium Channel Blockers: Mechanism and Clinical Applications

Calcium channel blockers (CCBs) are medications that inhibit calcium influx through high-voltage-activated L-type calcium channels in vascular smooth muscle and cardiac tissue, leading to smooth muscle relaxation and reduced myocardial contractility. 1

Mechanism of Action

• CCBs inhibit the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle cells by blocking L-type calcium channels, reducing intracellular calcium availability for muscle contraction 1, 2
• This calcium channel inhibition leads to arterial vasodilation, decreased peripheral vascular resistance, and reduced blood pressure 1
• The blockade of calcium influx affects both myocardial and vascular smooth muscle contraction to varying degrees depending on the specific agent 1

Classification

CCBs are classified into two main structural and functional categories:

Dihydropyridines (DHP)

• Examples: amlodipine, felodipine, nifedipine, nisoldipine 1
• Characteristics:
  • High selectivity for vascular L-type calcium channels 1
  • Produce pronounced coronary and systemic vasodilation 1
  • Minimal effects on cardiac conduction and contractility 1
  • Exert antianginal effects by reducing oxygen demand and improving coronary dilation 1
  • May cause reflex tachycardia, especially with short-acting formulations 1, 3

Non-dihydropyridines

• Examples: verapamil (phenylalkylamine) and diltiazem (benzothiazepine) 1, 4
• Characteristics:
  • Less selective for vasculature than dihydropyridines 1
  • More pronounced effects on myocardial contractility 1
  • Significant effects on cardiac pacemaker and atrioventricular conduction cells 1, 5
  • Negative inotropic (contractility) and chronotropic (heart rate) effects 1
  • Reduce oxygen demand through reductions in afterload, heart rate, and myocardial contractility 1

Clinical Applications

Hypertension

• All CCBs effectively reduce blood pressure across diverse patient populations regardless of age, sex, race/ethnicity, or sodium intake 3
• Particularly effective in elderly patients and African Americans 6
• Can be used as monotherapy or in combination with other antihypertensive agents 7

Angina

• All CCBs have similar antianginal efficacy compared to other antianginal drugs 1
• Particularly effective in vasospastic (Prinzmetal's) angina, either alone or in combination with nitrates 1, 2
• Dihydropyridines reduce oxygen demand through decreased afterload 1
• Non-dihydropyridines provide additional benefit through heart rate reduction 1, 5

Cardiac Arrhythmias

• Non-dihydropyridines (verapamil, diltiazem) are effective for:
  • Atrial fibrillation or flutter rate control 5
  • Paroxysmal supraventricular tachycardia 7
  • AV nodal reentrant tachycardias 5

Side Effects and Precautions

Common Side Effects

• Dihydropyridines: hypotension, headache, dizziness, flushing, palpitations, peripheral edema 1, 3
• Verapamil: constipation (especially in elderly), hypotension, bradycardia 1, 3
• Diltiazem: bradycardia, AV block, hypotension 1
• Leg edema is common to all CCBs 1

Important Precautions

• CCBs do not improve survival in patients with chronic stable angina with or without myocardial infarction 1
• May have deleterious effects when used in patients with heart failure 1, 8
• All CCBs are metabolized by cytochrome P450 3A4, creating potential for drug interactions 1
• Diltiazem and verapamil should not be combined with ivabradine due to risk of severe bradycardia 1
• Rapid-release, short-acting dihydropyridines (e.g., nifedipine) should be avoided without concomitant beta-blockade due to increased adverse potential 1
• Verapamil and diltiazem should be avoided in patients with pulmonary edema or severe LV dysfunction 1

Clinical Pearls

• CCBs reduce blood pressure more significantly in hypertensive than normotensive patients 7
• Responsiveness to CCBs appears to be directly related to age and inversely related to plasma renin activity 6
• Long-acting formulations are preferred over short-acting ones to minimize fluctuations in blood pressure and reduce side effects 8
• CCBs are often combined with renin-angiotensin system inhibitors for enhanced antihypertensive effects 7
• When selecting a CCB, consider the specific pharmacological properties: dihydropyridines for predominant vasodilation, non-dihydropyridines when rate control is also desired 3, 9