Calcium-Channel Blockers (CCBs)
- Decrease contractility
- Decrease heart rate
- Decrease conduction velocity
- Smooth muscle relaxation
Currently approved CCBs bind to L-type calcium channels located on the vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue (sinoatrial and atrioventricular nodes). These channels are responsible for regulating the influx of calcium into muscle cells, which in turn stimulates smooth muscle contraction and cardiac myocyte contraction. In cardiac nodal tissue, L-type calcium channels play an important role in pacemaker currents and in phase 0 of the action potentials. Therefore, by blocking calcium entry into the cell, CCBs cause vascular smooth muscle relaxation (vasodilation), decreased myocardial force generation (negative inotropy), decreased heart rate (negative chronotropy), and decreased conduction velocity within the heart (negative dromotropy), particularly at the atrioventricular node.
CCBs are used to treat hypertension, angina and arrhythmias.
Therapeutic Use of
(systemic & pulmonary)
By causing vascular smooth muscle relaxation, CCBs decrease systemic vascular resistance, which lowers arterial blood pressure. These drugs primarily affect arterial resistance vessels, with only minimal effects on venous capacitance vessels.
The anti-anginal effects of CCBs are derived from their vasodilator and cardiodepressant actions. Systemic vasodilation reduces arterial pressure, which reduces ventricular afterload (wall stress) thereby decreasing oxygen demand. The more cardioselective CCBs (verapamil and diltiazem) decrease heart rate and contractility, which leads to a reduction in myocardial oxygen demand, which makes them excellent antianginal drugs. CCBs can also dilate coronary arteries and prevent or reverse coronary vasospasm (as occurs in Printzmetal's variant angina), thereby increasing oxygen supply to the myocardium.
The antiarrhythmic properties (Class IV antiarrhythmics) of CCBs are related to their ability to decrease the firing rate of aberrant pacemaker sites within the heart, but more importantly are related to their ability to decrease conduction velocity and prolong repolarization, especially at the atrioventricular node. This latter action at the atrioventricular node helps to block reentry mechanisms, which can cause supraventricular tachycardia.
Different Classes of Calcium-Channel Blockers
There are three classes of CCBs. They differ not only in their basic chemical structure, but also in their relative selectivity toward cardiac versus vascular L-type calcium channels. The most smooth muscle selective class of CCBs are the dihydropyridines. Because of their high vascular selectivity, these drugs are primarily used to reduce systemic vascular resistance and arterial pressure, and therefore are primarily used to treat hypertension. They are not, however, generally used to treat angina because their powerful systemic vasodilator and pressure lowering effects can lead to reflex cardiac stimulation (tachycardia and increased inotropy), which can dramatically increase myocardial oxygen demand. Note that dihydropyridines are easy to recognize because the drug name ends in "pine."
Dihydropyridines include the following specific drugs: (Go to www.rxlist.com for specific drug information)
Non-dihydropyridines, of which there are only two currently used clinically, comprise the other two classes of CCBs. Verapamil (phenylalkylamine class), is relatively selective for the myocardium, and is less effective as a systemic vasodilator drug. This drug has a very important role in treating angina (by reducing myocardial oxygen demand and reversing coronary vasospasm) and arrhythmias. Diltiazem (benzothiazepine class) is intermediate between verapamil and dihydropyridines in its selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, diltiazem is able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines.
Side Effects and Contraindications
Dihydropyridine CCBs can cause flushing, headache, excessive hypotension, edema and reflex tachycardia. The activation of sympathetic reflexes and lack of direct cardiac effects make dihydropyridines a less desirable choice for angina. Long-acting dihydropyridines have been shown to be safer anti-hypertensive drugs, in part, because of reduced reflex responses. The cardiac selective, non-dihydropyridine CCBs can cause excessive bradycardia, impaired electrical conduction (e.g., atrioventricular nodal block), and depressed contractility. Therefore, patients having preexistent bradycardia, conduction defects, or heart failure caused by systolic dysfunction should not be given CCBs, especially the cardiac selective, non-dihydropyridines. CCBs, especially non-dihydropyridines, should not be administered to patients being treated with a beta-blocker because beta-blockers also depress cardiac electrical and mechanical activity and therefore the addition of a CCB augments the effects of beta-blockade.