Calcium-Channel Blockers

Cardiac effects1. Decrease contractility (negative inotropy)

2. Decrease heart rate (negative chronotropy)

3. Decrease conduction velocity (negative dromotropy)

Vascular effects1. Smooth muscle relaxation

(vasodilation)

Therapeutic Use of Calcium-ChannelBlockers

Hypertension (systemic & pulmonary)

Angina

Arrhythmias

General Pharmacology

Currently approved CCBs bind to L-type calcium channels located on thevascular smooth muscle, cardiac myocytes, and cardiac nodal tissue(sinoatrial and atrioventricular nodes). These channels are responsible forregulating the influx of calcium into muscle cells, which in turn stimulatessmooth muscle contraction and cardiac myocyte contraction. In cardiac nodaltissue, L-type calcium channels play an important role in pacemaker currentsand in phase 0 of the action potentials. Therefore, by blocking calcium entryinto the cell, CCBs cause vascular smooth muscle relaxation (vasodilation),decreased myocardial force generation (negative inotropy), decreased heartrate (negative chronotropy), and decreased conduction velocity within theheart (negative dromotropy), particularly at the atrioventricular node.

Therapeutic Indications

CCBs are used to treat hypertension, angina and arrhythmias.

Arrhythmias

By causing vascular smooth muscle relaxation, CCBs decrease systemicvascular resistance, which lowers arterial blood pressure. These drugsprimarily affect arterial resistance vessels, with only minimal effects onvenous capacitance vessels.

Angina

The anti-anginal effects of CCBs are derived from their vasodilator andcardiodepressant actions. Systemic vasodilation reduces arterial pressure,which reduces ventricular afterload (wall stress) thereby decreasing oxygendemand. The more cardioselective CCBs (verapamil and diltiazem) decreaseheart rate and contractility, which leads to a reduction in myocardial oxygendemand, which makes them excellent antianginal drugs. CCBs can also dilatecoronary arteries and prevent or reverse coronary vasospasm (as occurs inPrintzmetal's variant angina), thereby increasing oxygen supply to themyocardium.

Arrhythmias

The antiarrhythmic properties (Class IV antiarrhythmics) of CCBs are relatedto their ability to decrease the firing rate of aberrant pacemaker sites withinthe heart, but more importantly are related to their ability to decreaseconduction velocity and prolong repolarization, especially at theatrioventricular node. This latter action at the atrioventricular node helps toblock reentry mechanisms, which can cause supraventricular tachycardia.

There are three classes of CCBs. They differ not only in their basic chemicalstructure, but also in their relative selectivity toward cardiac versus vascularL-type calcium channels. The most smooth muscle selective class of CCBs arethe dihydropyridines. Because of their high vascular selectivity, these drugsare primarily used to reduce systemic vascular resistance and arterialpressure, and therefore are primarily used to treat hypertension. They arenot, however, generally used to treat angina because their powerful systemicvasodilator and pressure lowering effects can lead to reflex cardiacstimulation (tachycardia and increased inotropy), which can dramatically

increase myocardial oxygen demand. Note that dihydropyridines are easy torecognize because the drug name ends in "pine."

Dihydropyridines include the following specific drugs:

amlodipine

felodipine

isradipine

nicardipine

nifedipine

nimodipine

nitrendipine

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 systemicvasodilator drug. This drug has a very important role in treating angina (byreducing myocardial oxygen demand and reversing coronary vasospasm) andarrhythmias. Diltiazem (benzothiazepine class) is intermediate betweenverapamil and dihydropyridines in its selectivity for vascular calciumchannels. By having both cardiac depressant and vasodilator actions,diltiazem is able to reduce arterial pressure without producing the samedegree 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 andlack of direct cardiac effects make dihydropyridines a less desirable choice forangina. Long-acting dihydropyridines have been shown to be safer anti-hypertensive drugs, in part, because of reduced reflex responses. The cardiacselective, non-dihydropyridine CCBs can cause excessive bradycardia,impaired electrical conduction (e.g., atrioventricular nodal block), anddepressed contractility. Therefore, patients having preexistent bradycardia,conduction defects, or heart failure caused by systolic dysfunction should notbe given CCBs, especially the cardiac selective, non-dihydropyridines. CCBs,

especially non-dihydropyridines, should not be administered to patients beingtreated with a beta-blocker because beta-blockers also depress cardiacelectrical and mechanical activity and therefore the addition of a CCBaugments the effects of beta-blockade.