Verapamil pharmacodynamic effects

Table 1 Summary of the Pharmacodynamic Effects of Verapamil and Relative Potencies of the S and R Enantiomers...

Diltiazem, a benzothiazepine, has a pharmacodynamic and side-effect profile that is intermediary between those of nifedipine and verapamil. Diltiazem is mostly used in the treatment of stable angina. It also displays antihypertensive activity, although it is not widely used in antihypertensive treatment. In certain countries diltiazem is used as an antiarrhyth-mic agent with the same type of applications as verapamil. 

Ho PC, Ghose K, Saville D, Wanwimolruk S. Effect of grapefruit juice on pharmacokinetics and pharmacodynamics of verapamil enantiomers in healthy volunteers. Eur J Clin Pharmacol 2000 56(9-10) 693-698. 

Lamberg TS, Kivisto KT, Neuvonen PJ. Effects of verapamil and diltiazem on the pharmacokinetics and pharmacodynamics of buspirone. Clin Pharmacol Ther 1998 63(6) 640-5. 

The single stereogenic or chiral center in the chemical structure of verapamil results in two stereoisomers of verapamil S(-)-verapamil and R(+)-verapamil (Fig. 1). These enantiomers have different pharmacokinetic and pharmacodynamic properties (3,6-9). Although both enantiomers have similar types of pharmacologic activity, the S enantiomer has been shown to be the more potent with respect to several of the effects (3,6-8). 

The two stereoisomers of verapamil differ extensively in their pharmacodynamics. The S enantiomer is the more pharmacologically active of the two relative to the cardiovascular system (3,6-9). The cardiovascular pharmacod maniic effects and relative potency of S- and R-verapamil are summarized in Table 1. 

Figure 9 Pharmacodynamic relationship observed at steady state in 24 subjects for various doses of a sustained-release (once daily) verapamil formulation. The concentration measure used is the area under the S-verapamil concentration over the 24-hr dosing interval the effect measure used is the area under the PR interval curve (measured with Holter monitor) over the 24-hr dosing interval. The doses of sustained-release verapamil that resulted in each concentration-effect pair are also shown.

Although AGP is the most quantitatively important protein in the plasma binding of many basic drugs, it usually exhibits only low enantio-selectivity. This may have measurable pharmacokinetic and pharmacodynamic consequences, as is the case with, for instance, disopyramide, verapamil, and the p-blockers. More generally, however, clinically important effects due to enantioselective binding of drugs to AGP are much less frequently observed than for HSA. 

Pharmacokinetic and pharmacodynamic interactions between dofetihde 0.5 mg bd and verapamil 80 mg tds have been studied in 12 healthy men (62). At steady state verapamil increased the peak plasma concentration of dofetilide from 2.40 to 3.43 ng/ml, without other pharmacokinetic effects. This was accompanied by a small increase in the prolongation of the QTc interval produced by dofetilide alone, from 20 to 26 ms. Although this small effect is unlikely to be of chnical significance, it would be wise to avoid verapamil in patients taking dofetihde. 

Holtzman JL, Finley D, Mottonen L, Berry DA, Ekholm BP, Kvam DC, McQuinn RL, Miller AM. The pharmacodynamic and pharmacokinetic interaction between single doses of flecainide acetate and verapamil effects on cardiac function and drug clearance. Clin Pharmacol Ther 1989 46(l) 26-32. 

McCourty JC, Silas JH, Tucker GT, Lennard MS. The effect of combined therapy on the pharmacokinetics and pharmacodynamics of verapamil and propranolol in patients with angina pectoris. BrJ Clin Pharmacol (1988) 25, 349-57. 

Kuhlmann J. Effects of quinidine, verapamil and nifeciipine on the pharmacokinetics and pharmacodynamics of digitoxin during steady-state conditions, Arzneimittelforschmg( 9 T) 37, 545-8. 

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