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.
4.
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 after a subarachnoid hemorrhage. Nimodipine was approved for use in patients who have had a hemorrhagic stroke, but it has been withdrawn. Nicardipine has similar effects and is used by intravenous and intracerebral arterial infusion to prevent cerebral vasospasm associated with stroke. Verapamil, despite its lack of vasoselectivity, is also used—by the intra-arterial route—in stroke. Some evidence suggests that calcium channel blockers may also reduce cerebral damage after thromboembolic stroke.
5.
Other effects—Calcium channel blockers minimally interfere with stimulus-secretion coupling in glands and nerve endings because of differences between calcium channel type and sensitivity in different tissues. Verapamil has been shown to inhibit insulin release in humans, but the dosages required are greater than those used in management of angina and other cardiovascular conditions.
A significant body of evidence suggests that the calcium channel blockers may interfere with platelet aggregation in vitro and prevent or attenuate the development of atheromatous lesions in animals. However, clinical studies have not established their role in human blood clotting and atherosclerosis.
Verapamil has been shown to block the P-glycoprotein responsible for the transport of many foreign drugs out of cancer (and other) cells (see Chapter 1); other calcium channel blockers appear to have a similar effect. This action is not stereoselective. Verapamil has been shown to partially reverse the resistance of cancer cells to many chemotherapeutic drugs in vitro. Some clinical results suggest similar effects in patients (see Chapter 54). Animal research suggests possible future roles of calcium blockers in the treatment of osteoporosis, fertility disorders and male contraception, immune modulation, and even schistosomiasis. Verapamil does not appear to block transmembrane divalent metal ion transporters such as DMT1.
The most important toxic effects reported for calcium channel blockers are direct extensions of their therapeutic action. Excessive inhibition of calcium influx can cause serious cardiac depression, including bradycardia, atrioventricular block, cardiac arrest, and heart failure. These effects have been rare in clinical use.
Retrospective case-control studies reported that immediate-acting nifedipine increased the risk of myocardial infarction in patients with hypertension. Slow-release and long-acting dihydropyridine calcium channel blockers are usually well tolerated. However, dihydropyridines, compared with angiotensin-converting enzyme (ACE) inhibitors, have been reported to increase the risk of adverse cardiac events in patients with hypertension with or without diabetes. These results suggest that relatively short-acting calcium channel blockers such as prompt-release nifedipine have the potential to enhance the risk of adverse cardiac events and should be avoided. Patients receiving β-blocking drugs are more sensitive to the cardiodepressant effects of calcium channel blockers. Minor toxicities (troublesome but not usually requiring discontinuance of therapy) include flushing, dizziness, nausea, constipation, and peripheral edema. Constipation is particularly common with verapamil.
Mechanisms of Clinical Effects