Other types of calcium channels are less sensitive to blockade by these calcium channel blockers (Table 12–4). Therefore, tissues in which these other channel types play a major role—neurons and most secretory glands—are much less affected by these drugs than are cardiac and smooth muscle. Mibefradil is a selective T-type calcium channel blocker that was introduced for antiarrhythmic use but has been withdrawn. Ion channels other than calcium channels are much less sensitive to these drugs. Potassium channels in vascular smooth muscle are inhibited by verapamil, thus limiting the vasodilation produced by this drug. Sodium channels as well as calcium channels are blocked by bepridil, an obsolete antiarrhythmic drug.
B. Organ System Effects 1.
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 (Figure 12–3). 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 hypo-tension is not a common adverse effect. Blood pressure is reduced with all calcium channel blockers (see Chapter 11). Women may be more sensitive than men to the hypotensive action of diltiazem. The reduction in peripheral vascular resistance is one mechanism by which these agents may benefit the patient with angina of effort. Reduction of coronary artery spasm 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. The relatively smaller effect of verapamil on vasodilation may be the result of simultaneous blockade of vascular smooth muscle potassium channels described earlier. Furthermore, the dihydropyridines may differ in their potency in different vascular beds. For example, nimodipine is claimed to be particularly selective for cerebral blood vessels. Splice variants in the structure of the α1 channel subunit appear to account for these differences.
2.
Cardiac muscle—Cardiac muscle is highly dependent on calcium influx during each action potential for normal function.
* At very low doses and under certain circumstances, some dihydro-Impulse generation in the sinoatrial node and conduction in pyridines increase calcium influx. Some special dihydropyridines, eg, the atrioventricular node—so-called slow-response, or calcium-
Bay K 8644, actually increase calcium influx over most of their dose range. 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. In 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.
Important differences between the available calcium channel blockers arise from the details of their interactions with cardiac ion channels and, as noted above, differences in their relative smooth muscle versus cardiac effects. Sodium channel block is modest with verapamil, and still less marked with diltiazem. It is negligible with nifedipine and other dihydropyridines. Verapamil and diltiazem interact kinetically with the calcium channel receptor in a different manner than the dihydropyridines; they block tachycardias in calcium-dependent cells, eg, the atrioventricular node, more selectively than do the dihydropyridines. (See Chapter 14 for additional details.) On the other hand, the dihydropyridines appear to block smooth muscle calcium channels at concentrations below those required for significant cardiac effects; they are therefore less depressant on the heart than verapamil or diltiazem.
3.