Calcium Channel Blocking Agents Mechanisms of Action

Calcium channel blocking agents inhibit the entry of calcium into vascular smooth muscle cells and myocardial cells during the action potential, which triggers the contractile process. This calcium entry blockade leads to direct effects of vasodilation, negative inotropy, negative chronotropy (decreased heart rate), and negative dromotropy (decreased arteriovenous [AV]-nodal conduction) (36). The systemic vasodilation leads to reflex sympathetic activation, which, in turn, promotes an increase in AV-nodal conductions.

Table 2

Recommendations for the Use of P-Blocker Therapy Administered Early During Acute

Myocardial Infarction

Conditions for which there is evidence that treatment is beneficial, useful, and effective.

Patients without a contraindication to b-adrenoceptor blocker therapy who can be treated within 12 h of onset of infarction, irrespective of administration of concomitant throm-bolytic therapy.

Patients with continuing or recurrent ischemic pain.

Patients with tachyarrhythmias, such as atrial fibrillation with a rapid ventricular response.

Conditions for which evidence is less well established.

Non-Q wave MI.

Conditions for which evidence suggests treatment is not useful and may be harmful.

Patients with moderate or severe left ventricular failure or other contraindications to b-adrenoceptor blocker therapy.

Data from ref. 15.

Table 3

Recommendations for Long-Term Adminstration of P-Blockers (i.e., Secondary Prevention)

Conditions for which therapy is beneficial, useful, and effective. All but low-risk patients without a clear contraindication to b-adrenoceptor blocker therapy; treatment should begin within a few days of the event (if not initiated acutely) and continue indefinitely.

Conditions for which beneficial effects are less well established but weight of evidence favors their use.

Low risk patients without a clear contraindication to b-adrenoceptor blocker therapy. Conditions for which evidence suggests treatment is not useful and may be harmful. Patients with a contraindication to b-adrenoceptor blocker therapy.

Data from ref. 15.

The net clinical effects of the calcium channel blockers will be a composite of their direct effects and their reflex-mediated indirect effects. The two major categories of calcium channel blockers, the dihydropyridines (including nifedipine, amlodipine, and nicardipine) and the nondihydropyridines (including diltiazem and verapamil) differ fundamentally: the dihydropyridines have greater vascular selectivity, leading to more peripheral vasodilation, and the potential for increased reflex sympathetic activation, whereas the nondihydropyridines have greater myocardial selectivity with a greater negative inotropic, chronotropic, and dromotropic effect. Both types of calcium channel blockers prevent coronary vasoconstriction and lower blood pressure. Thus, the principal anti-ischemic effects of the calcium blockers are to reduce myocardial oxygen demand by lowering blood pressure (dihydropyridines and nondihydropyridines) and lowering contractility and heart rate (nondihydropyridines only), as well as preventing coronary vasoconstriction if it is present. It should be noted that if reflex sympathetic activation predominates, as may be observed with use of immediate-release dihydropy-ridines, then the increase in contractility and heart rate may lead to an exacerbation of oxygen supply/demand imbalance. The calcium channel blockers may also exert a fun-

Fig. 5. Typical odds of death, infarct development, and reinfarction by disease, type of trials, and drug. Areas of squares are proportional to numbers of patients. Bars, 95% confidence intervals. Portions to left of vertical line (corresponding to odds ratio < 1) indicate risk with treatment; portions to right of vertical line indicate increased risk with treatment. Upper 95% confidence limit for effect on mortality in unstable angina = 6.2. Note that treatment does not seem to reduce risk of any event. See original article for citation of specific trials. Reproduced with permission from ref. 37.

damental cardioprotective effect of limiting calcium influx during ischemia, thereby limiting the amount of necrosis that ensues from a given ischemic result (36).

Use of Calcium Channel Blockers in Patients with MI Dihydropyridine Calcium Blockers (Nifedipine and Nicardipine)

Early studies investigated the use of calcium channel blockers, particularly the dihy-dropyridines, for the early treatment of MI, but they were not found to be useful (Fig. 5) (37). Patients were generally included regardless of the direction of ST-segment deviation on presentation. The dihydropyridines were studied in particular because they could be safely combined with b-adrenergic blockers without the concern for excessive reduction in myocardial contractility or bradycardia. The available formulation of dihy-dropyridines in this early era consisted of short-acting nifedipine, and this agent was found to be actually detrimental when used without a b-blocker to blunt the reflex sympathetic activity (38-42). When combined with a b-blocker, nifedipine was significantly beneficial in reducing symptomatic manifestations of AMI (38). Many of the studies (17,26,37,43) may not be methodologically comparable because the doses tested varied,

Table 4

Secondary Prevention Trials of Calcium Channel Blocking Agents3

Event and agent Active Control Odds ratio (CI)

Mortality

Table 4

Secondary Prevention Trials of Calcium Channel Blocking Agents3

Event and agent Active Control Odds ratio (CI)

Mortality

Dihydropyridine

379/5137

335/5135

1.16 (0.99-1.35)

Verapamil

244/2644

266/2649

0.91 (0.76-1.10)

Diltiazem

180/1574

181/1577

0.99 (0.80-1.24)

Reinfarction

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Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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