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 migraine prophylaxis and treatment of esophageal spasm, pulmonary hypertension, or arterial vasospasm due to Raynaud’s disease.1
Understanding the physiology of calcium in the cardiovascular system is crucial to understanding the effects of CCBs. Influx of calcium is regulated by L-type calcium channels, which are found predominantly in the heart, vascular smooth muscle, and pancreatic β islet cells. Intracellular calcium facilitates sinoatrial node depolarization and propagation of the electrical signal through the atrioventricular node. Additionally, myocytes rely on L-type channels to allow intracellular calcium influx during the plateau phase (phase 2) of the action potential, which signals the release of stored calcium from the sarcoplasmic reticulum, allowing myocardial contraction. Calcium influx is also necessary for the release of insulin. Therefore, CCBs have multiple effects by blocking the entry of calcium required for normal pacemaker activity, atrioventricular nodal conduction, myocardial contraction, and insulin release.2
At therapeutic concentrations, CCBs bind to the α1 subunit of the L-type calcium channel, causing the channel to favor the closed state and thereby decreasing calcium entry. At very high concentrations, some CCBs (notably verapamil) may occupy the channel canal and completely block calcium entry. The results are 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.3 All CCBs undergo hepatic metabolism through CYP3A4.
The three main pharmacologic classes of CCBs are phenylalkylamines, benzothiazepines, and dihydropyridines (which is the class that includes most newer CCB agents) (Table 195-1). It is easiest to think of CCBs as dihydropyridines (all CCBs with generic names ending in “pine”) and nondihydropyridines.
TABLE 195-1Oral Calcium Channel Blockers ||Download (.pdf) TABLE 195-1 Oral Calcium Channel Blockers
|Class ||Standard Preparation (IR) Half-Life (h) ||Maximum Adult Daily Dose (milligrams) ||Comments |
|Nondihydropyridines || || ||More cardioselective |
|Phenylalkylamines || || || |
|Verapamil ||2–5 ||480 for IR and ER ||Most potent negative inotrope of all CCBs |
|Benzothiazepines || || || |
|Diltiazem ||3–5 ||480 for IR and 540 for ER || |
| Dihydropyridines (most newer calcium channel blockers fall into this class) || || ||More selective for vasculature |
|Nifedipine ||2 ||180 for IR and 90 for ER || |
|Amlodipine ||30–50 ||10 || |
|Nicardipine ||8–14 ||120 for IR and ER || |
|Felodipine ||8 ||10 || |
|Isradipine || ||10 || |
|Nimodipine ||Early: 1–2; terminal: 8–9 ||360 || |
|Nisoldipine ||7–12 ||34 || |
All CCBs relax vascular smooth muscle, reduce pacemaker activity, and decrease cardiac contractility. However, these effects occur at different dose ranges for each drug. All three CCB classes increase coronary blood flow in a dose-dependent fashion.4 Each group binds ...