Calcium channel antagonist interactions

The P-blockers propranolol and timolol are FDA-approved for migraine prophylaxis, but other drugs in the class are also as effective.46 Cautious dosage titration is advised for those patients who do not have other indications for P-blocker use. Rizatriptan interacts with propranolol and thus dosages must be titrated downward, or another triptan chosen for abortive therapy.36 Comorbid reactive airway disease is a relative contraindication to P-blocker prophylaxis, and patients with cardiac conduction disturbances should be closely monitored. Calcium channel antagonists are often used when patients cannot tolerate P-blockers. They are purported to beneficially... 

Bauerle, H.-D. Seelig, J., Interaction of charged and uncharged calcium channel antagonists with phospholipid membranes. Binding equilibrium, binding enthalpy, and membrane location, Biochemistry 30, 7203-7211 (1991). 

Available evidence suggests that a single unifying mechanism does not exist but rather that various vasodilators may act at different places in the series of processes that couple excitation of vascular smooth muscle cells with contraction. For example, the vasodilators known as calcium channel antagonists block or limit the entry of calcium through voltage-dependent channels in the membrane of vascular smooth muscle cells. In this way, the calcium channel blockers limit the amount of free intracellular calcium available to interact with smooth muscle contractile proteins (see Chapter 14). 

Pinacidil is three- and tenfold more potent than hydralazine and minoxidil, respectively. It does not interact with alpha, beta, cholinergic, or histaminergic receptors, and also does not produce vasodilation via an indirect effect that is mediated by adenosine, prostaglandin, or endothelial-derived relaxant factor. Its vasodilating activity does not resemble that brought about by the conventional calcium-channel antagonists. Thus, pinacidil-induced vascular relaxation is a direct effect mediated by a novel mechanism. 

This is a calcium-channel antagonist, which can produce potentiation of suxamethonium and non-depolarizing neuromuscular blockers at doses within the therapeutic range. Verapamil also exacerbates the increase in serum potassium levels after the administration of suxamethonium. To date, there are no established data about such interactions between other calcium-channel blockers and... 

In a retrospective case-control study, a primary diagnosis of hypoglycemia was identified in 413 patients registered as diabetic in 1993 (164). Five controls of the same age and sex, without hypoglycemia, were selected for each case from the same cohort. The relative risks of hypoglycemia with ACE inhibitors, beta-blockers, calcium antagonists, and salicylates were determined. There was an association between enalapril and sulfonylureas. However, other ACE inhibitors could not be identified as a risk factor. There was no interaction with beta-blockers, calcium channel blockers, or salicylates. 

However, the studies on the calcium channel blockers remained centered even today around the l,4-dihydropyridine class. Since this class of compounds can also act as calcium channel activators, attention has always been drawn towards their structure-activity relationship studies. Attempts were made to differentiate in the mechanisms of their agonist and antagonist activities. On the basis of the force field and quantum mechanical calculations, Holtze and Marrer [51] discovered a imique area of the molecular potentials where Ca agonists and antagonists possess potential of opposite sign. These authors demonstrated that the molecular potential of a simple receptor site was reduced by interaction with calciiun channel activators and, on the contrary, increased by interaction with calcium channel blockers. These opposite effects probably could be the basis for the opposite actions of DHP enantiomers at the potential-dependent calcium channel. 

FIGURE 24.3 The 1,4-dihydropyridine nucleus as a privileged structure. In addition to classically established antagonist and activator interactions at the L-type of voltage-gated calcium channel appropriately substituted 1,4-dihydropyridines can interact, often with high selectivity, at a variety of other ion channels and receptors as depicted. 

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