What is the mechanism of action of calcium channel blockers (CCBs)?

Mechanism of Action of Calcium Channel Blockers

Calcium channel blockers inhibit the transmembrane influx of calcium ions through voltage-dependent L-type calcium channels in vascular smooth muscle and cardiac tissue, leading to vasodilation, reduced peripheral vascular resistance, and decreased blood pressure. 1, 2

Fundamental Mechanism

• CCBs block L-type (long-acting, slowly activating) calcium channels in the plasma membrane, preventing extracellular calcium from entering cells where it normally triggers muscle contraction 1
• The voltage-gated L-type channel normally allows sufficient calcium entry to initiate contraction through calcium-induced intracellular calcium release from the sarcoplasmic reticulum 1
• By reducing intracellular calcium availability, CCBs inhibit the contractile processes that depend on calcium as an activator messenger 2, 3
• This mechanism produces arterial vasodilation and decreased peripheral vascular resistance, resulting in reduced blood pressure 2, 4

Drug Class Distinctions and Binding Sites

Dihydropyridines (Amlodipine, Nifedipine, Felodipine, Nisoldipine)

• Dihydropyridines bind to a common site on the α1-subunit of the L-type channel and are highly selective for arterial/arteriolar tissues, including coronary arteries 1
• They have high selectivity for L-type channels in the vasculature, producing pronounced coronary and systemic vasodilation with minimal cardiac effects 1
• Their antianginal action results from reducing oxygen demand through decreased afterload and improving coronary dilation 1
• Reflex tachycardia is not uncommon, especially with short-acting formulations, due to their potent vasodilatory effects 1

Non-Dihydropyridines (Verapamil, Diltiazem)

• Non-dihydropyridines bind to different sites on the α1-subunit and are less selective for vascular smooth muscle, affecting both vasculature and cardiac tissue 1
• They have pronounced effects on myocardial contractility and cardiac pacemaker/atrioventricular conduction cells, producing negative inotropic, chronotropic, and dromotropic effects 1
• Verapamil (phenylalkylamine) and diltiazem (benzothiazepine) have greater effects on the atrioventricular node than the sinoatrial node, potentially causing high-degree AV block in susceptible patients 1
• Their antianginal action results from reducing oxygen demand through combined reductions in afterload, heart rate, and myocardial contractility 1

Cardiovascular Effects

Vascular Effects

• Direct action on vascular smooth muscle causes relaxation and vasodilation of both coronary and peripheral arteries 2, 5
• CCBs dilate main coronary arteries and coronary arterioles in both normal and ischemic regions 5
• They are potent inhibitors of coronary artery spasm, whether spontaneous or induced, making them particularly effective for vasospastic (Prinzmetal's variant) angina 1, 5

Cardiac Effects

• Electrical activity through the AV node depends significantly on calcium influx through slow channels; by decreasing calcium influx, CCBs prolong the effective refractory period within the AV node and slow AV conduction in a rate-related manner 5
• Non-dihydropyridines reduce myocardial contractility and slow heart rate, contributing to decreased myocardial oxygen consumption 1, 5
• Dihydropyridines have minimal direct cardiac effects but may cause reflex tachycardia due to peripheral vasodilation 1

Blood Pressure Effects

• CCBs reduce systemic vascular resistance (afterload) against which the heart works, both at rest and during exercise, by dilating peripheral arterioles 1, 5
• The magnitude of blood pressure reduction correlates with the height of pretreatment elevation 2
• Plasma concentrations correlate with antihypertensive effect in both young and elderly patients 2

Clinical Implications of Mechanism

• Both dihydropyridine and non-dihydropyridine CCBs are indicated for hypertension and angina pectoris, though their mechanisms of benefit differ 1
• The antianginal effects result from afterload reduction (decreased systolic blood pressure), coronary vasodilation, and in non-dihydropyridines, heart rate slowing 1
• CCBs are particularly effective for angina due to coronary spasm (Prinzmetal's variant or cold-induced angina) due to their potent anti-spasm properties 1, 5

Important Mechanistic Caveats

• Non-dihydropyridine CCBs may predispose to high-degree atrioventricular block when administered to patients with preexisting AV nodal disease or when combined with other AV node-depressing agents like β-blockers 1
• Rapid-release, short-acting dihydropyridines (e.g., nifedipine) cause sudden vasodilation and reflex tachycardia, increasing adverse potential, and must be avoided without concomitant β-blockade 1, 6
• All CCBs are metabolized by hepatic cytochrome P450 3A4; diltiazem and verapamil should not be combined with ivabradine due to risk of severe bradycardia 1
• Serum calcium concentration is not affected by CCBs despite their mechanism of blocking calcium channels 2, 5