Page 219 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 205

the calcium channel blockers. Excitation-contraction coupling in all possible future roles of calcium blockers in the treatment of osteo-
cardiac cells requires calcium influx, so these drugs reduce cardiac porosis, fertility disorders and male contraception, immune modu-
contractility in a dose-dependent fashion. In some cases, cardiac lation, and even schistosomiasis. Verapamil does not appear to block
output may also decrease. This reduction in cardiac mechanical transmembrane divalent metal ion transporters such as DMT1.
function is another mechanism by which the calcium channel
blockers can reduce the oxygen requirement in patients with angina. Toxicity
Important differences between the available calcium channel
blockers arise from the details of their interactions with cardiac ion The most important toxic effects reported for calcium channel
channels and, as noted above, differences in their relative smooth blockers are direct extensions of their therapeutic action. Excessive
muscle versus cardiac effects. Sodium channel block is modest inhibition of calcium influx can cause serious cardiac depression,
with verapamil, and still less marked with diltiazem. It is negli- including bradycardia, atrioventricular block, cardiac arrest, and
gible with nifedipine and other dihydropyridines. Verapamil and heart failure. These effects have been rare in clinical use.
diltiazem interact kinetically with the calcium channel receptor in Retrospective case-control studies reported that immediate-acting
a different manner than the dihydropyridines; they block tachy- nifedipine increased the risk of myocardial infarction in patients
cardias in calcium-dependent cells, eg, the atrioventricular node, with hypertension. Slow-release and long-acting dihydropyridine
more selectively than do the dihydropyridines. (See Chapter 14 calcium channel blockers are usually well tolerated. However,
for additional details.) On the other hand, the dihydropyridines dihydropyridines, compared with angiotensin-converting enzyme
appear to block smooth muscle calcium channels at concentra- (ACE) inhibitors, have been reported to increase the risk of adverse
tions below those required for significant cardiac effects; they are cardiac events in patients with hypertension with or without diabe-
therefore less depressant on the heart than verapamil or diltiazem. tes. These results suggest that relatively short-acting calcium channel
blockers such as prompt-release nifedipine have the potential to
3. Skeletal muscle—Skeletal muscle is not depressed by the enhance the risk of adverse cardiac events and should be avoided.
calcium channel blockers because it uses intracellular pools of Patients receiving β-blocking drugs are more sensitive to the car-
calcium to support excitation-contraction coupling and does not diodepressant effects of calcium channel blockers. Minor toxicities
require as much transmembrane calcium influx. (troublesome but not usually requiring discontinuance of therapy)
include flushing, dizziness, nausea, constipation, and peripheral
4. Cerebral vasospasm and infarct following subarachnoid edema. Constipation is particularly common with verapamil.
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 subarach- Mechanisms of Clinical Effects
noid hemorrhage. Nimodipine was approved for use in patients Calcium channel blockers decrease myocardial contractile force,
who have had a hemorrhagic stroke, but it has been withdrawn. which reduces myocardial oxygen requirements. Calcium channel
Nicardipine has similar effects and is used by intravenous and block in arterial smooth muscle decreases arterial and intraventricular
intracerebral arterial infusion to prevent cerebral vasospasm asso- pressure. Some of these drugs (eg, verapamil, diltiazem) also possess
ciated with stroke. Verapamil, despite its lack of vasoselectivity, is a nonspecific antiadrenergic effect, which may contribute to periph-
also used—by the intra-arterial route—in stroke. Some evidence eral vasodilation. As a result of all of these effects, left ventricular
suggests that calcium channel blockers may also reduce cerebral wall stress declines, which reduces myocardial oxygen requirements.
damage after thromboembolic stroke. Decreased heart rate with the use of verapamil or diltiazem causes a
further decrease in myocardial oxygen demand. Calcium channel-
5. Other effects—Calcium channel blockers minimally interfere blocking agents also relieve and prevent focal coronary artery spasm
with stimulus-secretion coupling in glands and nerve endings in variant angina. Use of these agents has thus emerged as the most
because of differences between calcium channel type and sensitivity effective prophylactic treatment for this form of angina pectoris.
in different tissues. Verapamil has been shown to inhibit insulin Sinoatrial and atrioventricular nodal tissues, which are mainly
release in humans, but the dosages required are greater than those composed of calcium-dependent, slow-response cells, are affected
used in management of angina and other cardiovascular conditions. markedly by verapamil, moderately by diltiazem, and much less by
A significant body of evidence suggests that the calcium chan- dihydropyridines. Thus, verapamil and diltiazem decrease atrio-
nel blockers may interfere with platelet aggregation in vitro and ventricular nodal conduction and are often effective in the man-
prevent or attenuate the development of atheromatous lesions in agement of supraventricular reentry tachycardia and in decreasing
animals. However, clinical studies have not established their role ventricular rate in atrial fibrillation or flutter. Nifedipine does
in human blood clotting and atherosclerosis. not affect atrioventricular conduction. Nonspecific sympathetic
Verapamil has been shown to block the P-glycoprotein respon- antagonism is most marked with diltiazem and much less with
sible for the transport of many foreign drugs out of cancer (and verapamil. Nifedipine does not appear to have this effect, prob-
other) cells (see Chapter 1); other calcium channel blockers appear ably because reflex tachycardia in response to hypotension occurs
to have a similar effect. This action is not stereoselective. Verapamil most frequently with nifedipine and much less so with diltiazem
has been shown to partially reverse the resistance of cancer cells to and verapamil. These differences in pharmacologic effects should
many chemotherapeutic drugs in vitro. Some clinical results suggest be considered in selecting calcium channel-blocking agents for the
similar effects in patients (see Chapter 54). Animal research suggests management of angina.