Verapamil, diltiazem, first-generation dihydropyridines are negative inotropics in that they inhibit calcium transport across the cell membrane and activate endogenous neurohumoral systems such as the renin-angiotensin system and sympathetic nervous system. Marked hemodynamic and clinical deterioration can occur in heart failure when the negative inotropic effects of calcium antagonists are not counterbalanced by their vasodilatory effects.
Short-term treatment with many calcium antagonists has been reported to cause pulmonary edema and cardiogenic shock, while long-term therapy has been shown to exacerbate the risk of CHF and death in patients with left ventricular dysfunction. Although these effects can be minimized by using sustained-release formulations or vasoselective agents, neither approach has succeeded in preventing the development of cardiovascular complications.
Diltiazem and verapamil-type calcium blockers in particular are not recommended in CHF due to systolic dysfunction; they are also contraindicated in combination with [3-blockade. Although calcium blockers intrinsically depress myocardial contractility, an increase in the left ventricular ejection fraction may occur in response to dihydropyridines such as nifedipine. This can be explained by reflex stimulation of the sympathetic nervous system, which counterbalances the intrinsic negative isotropic of the dihydropyridines.
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For these reasons, chronic nifedipine therapy may have deleterious effects in patients with CHF.
The addition of newer calcium blockers (felodipine, amlodipine) to basal ACE-inhibitor and diuretic therapy does not improve survival compared with placebo. These agents can be used for concomitant arterial hypertension and angina, where the long-term safety data show a neutral effect on survival.