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204 SECTION III Cardiovascular-Renal Drugs

H C CH
H C O 3 3 O CH 3
3
CH CH 3
H C O C CH 2 CH 2 CH 2 N CH 2 CH 2 O CH 3
3
C N
Verapamil

CH 3
NO 2
S N CH 2 CH 2 N
O O
O CH 3
H C O C C O CH 3
3
O C CH 3
H C N CH 3 O
3
H O
Nifedipine CH 3 Diltiazem

FIGURE 12–4 Chemical structures of several calcium channel-blocking drugs.

to depolarization. The result is a marked decrease in transmem- B. Organ System Effects
brane calcium current, which in smooth muscle results in long- 1. Smooth muscle—Most types of smooth muscle are depen-
lasting relaxation (Figure 12–3) and in cardiac muscle results in dent on transmembrane calcium influx for normal resting tone and
reduction in contractility throughout the heart and decreases in contractile responses. These cells are relaxed by the calcium channel
sinus node pacemaker rate and atrioventricular node conduction blockers (Figure 12–3). Vascular smooth muscle appears to be the
*
velocity. Although some neuronal cells harbor L-type calcium most sensitive, but similar relaxation can be shown for bronchiolar,
channels, their sensitivity to these drugs is lower because the chan- gastrointestinal, and uterine smooth muscle. In the vascular system,
nels in these cells spend less time in the open and inactivated states. arterioles appear to be more sensitive than veins; orthostatic hypo-
Smooth muscle responses to calcium influx through ligand- tension is not a common adverse effect. Blood pressure is reduced
gated calcium channels are also reduced by these drugs but not with all calcium channel blockers (see Chapter 11). Women may be
as markedly. The block can be partially reversed by elevating the more sensitive than men to the hypotensive action of diltiazem.
concentration of calcium, although the levels of calcium required The reduction in peripheral vascular resistance is one mechanism
are not easily attainable in patients. Block can also be partially by which these agents may benefit the patient with angina of effort.
reversed by the use of drugs that increase the transmembrane flux Reduction of coronary artery spasm has been demonstrated in
of calcium, such as sympathomimetics. patients with variant angina.
Other types of calcium channels are less sensitive to blockade Important differences in vascular selectivity exist among the
by these calcium channel blockers (Table 12–4). Therefore, tissues calcium channel blockers. In general, the dihydropyridines have a
in which these other channel types play a major role—neurons greater ratio of vascular smooth muscle effects relative to cardiac
and most secretory glands—are much less affected by these drugs effects than do diltiazem and verapamil. The relatively smaller
than are cardiac and smooth muscle. Mibefradil is a selective effect of verapamil on vasodilation may be the result of simulta-
T-type calcium channel blocker that was introduced for antiar- neous blockade of vascular smooth muscle potassium channels
rhythmic use but has been withdrawn. Ion channels other than described earlier. Furthermore, the dihydropyridines may differ in
calcium channels are much less sensitive to these drugs. Potassium their potency in different vascular beds. For example, nimodipine
channels in vascular smooth muscle are inhibited by verapamil, is claimed to be particularly selective for cerebral blood vessels.
thus limiting the vasodilation produced by this drug. Sodium Splice variants in the structure of the α1 channel subunit appear
channels as well as calcium channels are blocked by bepridil, an to account for these differences.
obsolete antiarrhythmic drug.
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