1. Calcium Channel Blockers

8. Smooth muscle: Most types of smooth muscle are dependent on transmembrane calcium influx for normal resting tone and contractile responses. These cells are relaxed by the calcium channel blockers. Vascular smooth muscle appears to be the most sensitive, but similar relaxation can be shown for bronchiolar, gastrointestinal, and uterine smooth muscle. In the vascular system, arterioles appear to be more sensitive than veins; orthostatic hypotension is not a common adverse effect. Blood pressure is reduced with all calcium channel blockers. The reduction in peripheral vascular resistance is one mechanism by which these agents may benefit the patient with angina of effort. Reduction of coronary arterial tone has been demonstrated in patients with variant angina. Important differences in vascular selectivity exist among the calcium channel blockers. In general, the dihydropyridines have a greater ratio of vascular smooth muscle effects relative to cardiac effects than do diltiazem and verapamil.

9. Calcium Channel Blockers Cardiac muscle: Cardiac muscle is highly dependent upon calcium influx for normal function. Impulse generation in the sinoatrial node and conduction in the atrioventricular node so-called slow response, or calcium-dependent, action potentials may be reduced or blocked by all of the calcium channel blockers. Excitation-contraction coupling in all cardiac cells requires calcium influx, so these drugs reduce cardiac contractility in a dose-dependent fashion. n some cases, cardiac output may also decrease. This reduction in cardiac mechanical function is another mechanism by which the calcium channel blockers can reduce the oxygen requirement in patients with angina.

10. Calcium Channel Blockers Skeletal muscle: Skeletal muscle is not depressed by the calcium channel blockers because it uses intracellular pools of calcium to support excitation-contraction coupling and does not require as much transmembrane calcium influx.

11. Calcium Channel Blockers Cerebral vasospasm and infarct following subarachnoid hemorrhage: Nimodipine, a member of the dihydropyridine group of calcium channel blockers, has a high affinity for cerebral blood vessels and appears to reduce morbidity following a subarachnoid hemorrhage. Nimodipine is therefore labeled for use in patients who have had a hemorrhagic stroke. Although evidence suggests that calcium channel blockers may also reduce cerebral damage following thromboembolic stroke in experimental animals, there is no evidence that this occurs in humans.

12. Calcium Channel Blockers Other effects: Verapamil has been shown to block the P- glycoprotein responsible for the transport of many foreign drugs out of cancer (and other) cells; other calcium channel blockers appear to have a similar effect. This action is not stereospecific. Verapamil has been shown to partially reverse the resistance of cancer cells to many chemotherapeutic drugs in vitro.