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Calcium channel blockers (CCBs) are commonly used for the treatment of hypertension and angina pectoris and for ventricular rate control in supraventricular dysrhythmias. Less common uses include prophylactic treatment of migraine headaches, treatment of arterial vasospasm due to Raynaud's disease, esophageal spasm, and pulmonary hypertension.1 For the last 50 years, CCBs have accounted for more poisoning deaths than any other cardiovascular drug and are the second most common cause of prescription drug poisoning death.


Intracellular calcium is the primary stimulus for smooth and cardiac muscle contraction and for impulse formation in sinoatrial pacemaker cells. At therapeutic concentrations, CCBs bind to the subunit of the L-type calcium channel, causing the channel to favor the closed state and thereby decreasing calcium entry during the plateau phase (phase 2) of the transmembrane action potential. At very high concentrations, some CCBs (notably verapamil) may occupy the channel canal and completely block calcium entry. The result is profound smooth muscle relaxation, weakened cardiac contraction, blunted cardiac automaticity, and intracardiac conduction delay.1 Clinically, these effects produce hypotension and bradycardia. Animal data suggest that verapamil overdose also impairs myocardial carbohydrate intake, which contributes to the negative cardiac inotropy.2

The three main pharmacologic classes of CCBs are phenylalkylamines (verapamil and gallopamil), benzothiazepines (diltiazem), and dihydropyridines (nifedipine, amlodipine, and most newer agents—aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, lacidipine, lercanidipine, manidipine, nicardipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, and pranidipine).

All of these drugs relax vascular smooth muscle, reduce pacemaker activity, and decrease cardiac contractility; however, these effects occur at different dose ranges for each drug. In addition, all three classes increase coronary blood flow in a dose-dependent fashion.3 Each group binds a different region of the calcium channel and has different affinities for calcium channels in various tissues. Verapamil is the most potent negative inotrope of all CCBs, causing at least equal depression of heart contraction and vascular smooth muscle dilatation at any concentration.4 This combined cardiovascular effect may be one reason that verapamil overdose causes more deaths than all other CCBs combined.

Dihydropyridines bind more selectively to vascular smooth muscle calcium channels than to cardiac calcium channels and therefore relax smooth muscle at concentrations that produce almost no negative inotropy. The differences in the effects of these agents is the reason for preferential use of specific agents in particular clinical situations.5 For example, verapamil and diltiazem are used to manage hypertension, to achieve rate control in atrial flutter and atrial fibrillation, and to abolish supraventricular reentrant tachycardias. Dihydropyridines are typically used to treat diseases with increased peripheral vascular tone such as hypertension, Prinzmetal's angina, and vasospasm after subarachnoid hemorrhage.1

The original three CCBs—verapamil, nifedipine, and diltiazem—all have relatively short serum half-lives (Table 195-1). Consequently, extended-release formulations have been developed for all of these agents. Because extended-release formulations prolong drug ...

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