Diltiazem clinical effects

Diltiazem is the only benzothiazepine in clinical use. Its molecular mechanism of action as well as its pharmacological effects closely resemble those of phenylalkylamines. 

In randomized, controlled, clinical trials, calcium channel blockers were as effective as p-blockers at preventing ischemic symptoms. Calcium channel blockers are recommended as initial treatment in IHD when /3-blockers are contraindicated or not tolerated. In addition, CCBs may be used in combination with /3-blockers when initial treatment is unsuccessful. However, the combination of a (1-blocker with either verapamil or diltiazem should be used with extreme caution since all of these drugs decrease AV nodal conduction, increasing the risk for severe bradycardia or AV block when used together. If combination therapy is warranted, a long-acting dihydropyridine CCB is preferred. (3-Blockers will prevent reflex increases in sympathetic tone and heart rate with the use of calcium channel blockers with potent vasodilatory effects. 

The effects of the prototypical calcium channel blockers are seen most prominently in the cardiovascular system (Table 19.1), although calcium channels are widely distributed among excitable cells. The following calcium channel-blocking drugs are clinically the most widely used compounds in this very extensive class of pharmacological agents amlodipine, diltiazem, isradipine, nifedipine, nicardipine, nimodipine, and verapamil. 

Results from two clinical studies of the interaction of diltiazem with simvastatin showed that diltiazem increased the Cmax of simvastatin (40) and enhanced its cholesterol-reducing effect (39). 

Calcium channel blockers can worsen myasthenic syndromes. Myasthenia gravis can deteriorate with oral verapamil (58). A patient with Lambert-Eaton syndrome and a small-cell carcinoma of the lung developed respiratory failure within hours of starting treatment with verapamil for atrial flutter, and required assisted ventilation (59). Only after verapamil had been withdrawn did breathing improve. Verapamil affects calcium channels in nerve membranes in animals, but the experimental concentrations used exceeded those found in clinical practice (59). Thus, the evidence for a drug-related effect is circumstantial. In another case, diltiazem triggered Lambert-Eaton syndrome, which improved with drug withdrawal (60). 

Co-administration of diltiazem with methylprednisolone increased plasma concentrations of methylprednisolone and its adrenal suppressant effects in nine healthy volunteers (29). Care should be taken when these two drugs are co-administered for a long period, even if the clinical relevance of this pharmacokinetic interaction still needs to be evaluated. 

Kocher HM, Steward M, Leather AJ, Cullen PT. Randomized clinical trial assessing the side-effects of glyceryl trinitrate and diltiazem hydrochloride in the treatment of chronic anal fissure. Br J Surg 2002 89(4) 413-17. 

The calcium channel blockers generally are considered seconder third-line options for preventive treatment when other drugs with established clinical benefit are ineffective or contraindicated. Verapamil is the most widely used calcium chaimel blocker for preventive treatment, but it provided only modest benefit in decreasing the frequency of attacks in two placebo-controlled studies." The therapeutic effect of verapamil may not be noted for up to 8 weeks after initiation of therapy. Side effects of verapamil may include constipation, hypotension, bradycardia, atrioventricular block, and exacerbation of congestive heart failure. Evaluations of nifedipine, nimodipine, diltiazem, and nicardipine have yielded equivocal results. ... 

Although suppression of the voltage-activated inward displacement of Ca + is undoubtedly the most widely discussed property of the substances listed in Table I, some of these drugs exhibit other properties that may be of clinical relevance. For example verapamil (61,62) and nifedipine bind to a receptors in brain, neurobiastomaglioma hybrid (63) and cardiac muscle cells (64). Verapamil and methoxyverapamil also bind fairly tightly to muscarinic receptors (65). Verapamil and D-600 have an inhibitory effect on Na+ and K" conductance, (23,63) an effect which apparently is not shared by nifedipine. Diltiazem slows the release of Ca + from smooth muscle sarcoplasmic reticulum (66). 

It is noteworthy that calcium inhibitory compounds with the ability to inhibit %a+ possess the most potent antiarrhythmic activity against both experimental and clinical arrhythmias (126). For example, nifedipine exerts minimal, if any, antiarrhythmic effect against ischemic induced arrhythmias in intact animals (6, 87, 131). Diltiazem and perhexiline, on the other hand, demonstrate variable antiarrhythmic effects dependent upon their dose and the mechanism responsible for arrhythmia production (ischemia, hypoxia, digitalis, aconitine) (102, 126, 151, 152). Only verapamil, which has been investigated in the largest number of experimental and clinical trials, has demonstrated consistent antiarrhythmic activity against cardiac arrhythmias regardless of cause (155) ... 

All Ca + channel blockers approved for clinical use decrease coronary vascular resistance and increase coronary blood flow. The dihydropyridines are more potent vasodilators than verapamil, which is more potent than diltiazem. The hemodynamic effects of these agents vary depending on the route of administration and the extent of left ventricular dysfunction. 

Ca + CHANNEL BLOCK The major electrophysiological effects resulting from block of cardiac Ca + channels are in slow-response tissues, the sinus and AV nodes. Dihydropyridines such as nifedipine, which are used commonly in angina and hypertension, preferentially block Ca + channels in vascular smooth muscle their cardiac effects, such as heart rate acceleration, result principally from reflex sympathetic activation secondary to peripheral vasodilation. Only verapamil, diltiazem, and bepridil block Ca + channels in cardiac cells at clinically used doses. These drugs generally slow heart rate, although hypotension can cause reflex sympathetic activation and tachycardia. The velocity of AV nodal conduction decreases, so the PR interval increases. AV nodal block occurs as a result of decremental conduction and increased AV nodal refractoriness, which form the basis for the use of channel blockers in reentrant arrhythmias whose circuit involves the AV node, such as AV reentrant tachycardia. 

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