Negative inotropic activity 1,4-dihydropyridines

Dihydropyridine-CA have been developed with a certain degree of vascular selectivity, which implies that at therapeutic doses such compounds would have less negative influence on cardiac contractile force or none at all. Indeed, a few of such compounds are devoid of cardiodepressant (negative inotropic) activity. Examples of such compounds are amlodipine, felodipine, isradip-ine, lacidipine, lercanidipine and manidipine. 

A quantitative structure-activity relationship for the negative inotropic activity of a small series of 1,4-dihydro-pyridines has been developed (47.). For 2,6-dimethyl-3,5-dicarbo-methoxy-4-(substituted phenyl)-1,4-dihydropyridines the effect of the phenyl substituent is determined primarily by steric effects. Thus, for ortho-substituted derivatives,... 

Calcium-channel blockers in current clinical usage affect the slow L-type channel. They are usually classified by their chemical structure, which determines their selectivity for vascular smooth muscle over myocardium, and hence their potential to slow the heart rate (negative inotropic activity) see Table 23. T, (below). Interactions due to additive inotropic effects will therefore apply only to the benzothiazepine (diltiazem) and phenyla-Ikylamine-type (verapamil) calcium-channel blockers, and usually not to the dihydropyridine-type (e.g. nifedipine) calcium-channel blockers. All three types of calcium-channel blocker will have additive hypotensive effects with other drugs with blood-pressure lowering activity. 

Current data suggest little benefit on clinical outcomes beyond symptom relief for calcium channel blockers in the setting of ACS.43 Moreover, the use of first-generation shortacting dihydropyridines, such as nifedipine, should be avoided because they appear to worsen outcomes through their negative inotropic effects, induction of reflex sympathetic activation, tachycardia, and increased myocardial ischemia.43 Therefore, calcium channel blockers should be avoided in the acute management of MI unless there is a clear symptomatic need or a contraindication to p-blockers. 

In the dihydropyridine class it is also evident that the ester functions at C3 and of the 1,4-dihydropyridine ring are an important determinant of activity. Rodenkirchen et al (47), studying a limited series of compounds producing negative inotropic effects in cardiac muscle, suggested that activity decreases with increasing size of lipophilicity of the ester function. However, other studies (.48,4,9) have shown that bulky ester substitutions maintain or even increase activity in smooth muscle preparations (Table 2). 

However, the potency of a series of 1,4-dihydropyridines to inhibit [3H]ni-trendipine or [3H]nimodipine binding correlates well with the rank order of these compounds for inhibition of cardiac inotropic responses and for inhibition of smooth muscle contraction [26, 70, 85, 90, 104, 127]. This implies that the structure-activity dependence is similar for both binding and pharmacological activities, even if there is a difference in the concentrations at which effects are found [70]. Furthermore, diltiazem not only stimulates the binding of [3H]nimodipine to canine cardiac sarcolemma but also potentiates the negative inotropic response of perfused rat hearts to nimodipine [ 146]. Thus,... 

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