Verapamil considerations

Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 1998 64(2) 177-82. 

An additional example of a bioavailability-predicted absorption plot is shown for a series of calcium antagonists (Fig. 19.8). Again there is considerable scatter in the data, and the four compounds - felodipine, nisoldipine, diltiazem, and verapamil -are predicted to be much better absorbed than was actually observed. Some of these compounds are known to undergo rapid first-pass metabolic clearance, and are also P-gp inhibitors or substrates (diltiazem and felodipine are P-gp substrates nicardipine and nitrendipine are P-gp inhibitors [25] verapamil is a P-gp inhibitor), and this might contribute to the scatter obtained in the graph. 

Though the drug has now been used to treat a considerable number of patients suffering from angina pectoris, verapamil (XXI, iproveratril, Isoptin, Cordilox)... 

In a randomized placebo-controlled trial, the possible interactions of buspirone with verapamil and diltiazem were investigated. Both verapamil and diltiazem considerably increased plasma buspirone concentrations, probably by inhibiting CYP3A4. Thus, enhanced effects and adverse effects of buspirone are possible when it is used with verapamil, diltiazem, or other inhibitors of CYP3A4 (24). 

Stereoselectivity of verapamil and D600 actions has been reported for both cardiac and smooth muscle. The S (-) enantiomers are the more potent negative inotropic agents, Ca current antagonists and smooth muscle relaxants (9,13 5 1-58). Although the ratios reported vary considerably (Table 3), stereoselectivity is seen consistently in the inhibition of Ca2+-dependent events and quite generally is absent in non-Ca2+ events (.58,6.0) Stereoselectivity has also been reported for 1,4— dihydropyridines bearing non-identical ester substituents at the 3- and 5-positions (Table 4). 

Stereoselective metabolism is the most important process responsible for the stereoselectivity observed in pharmacokinetics. Verapamil has received considerable attention as an example of substrate stereoselective pharmacokinetics in humans. After oral administration, the drug undergoes an important stereoselective first pass metabolism, so that (— )-verapamil, the active enantiomer, has a two to three times lower bioavailability than its antipode. The (— )/(-f) plasma concentration ratio is therefore higher after intravenous than after oral administration. 

Information about the effects of calcium-channel blockers on phenytoin is limited, but what is known indicates that if diltiazem is given with phenytoin, the dosage of phenytoin may possibly need to be reduced to avoid toxicity. The case report of phenytoin toxicity with nifedipine is isolated, and of unknown importance. Phenytoin markedly reduces felodipine, verapamil and possibly nifedipine levels. Although not all calcium-channel blockers have been studied, most would be expected to interact with phenytoin similarly, as they are metabolised by the same isoenzymes (see Calcium-channel blockers , (p.860)). A considerable increase in the dosage of any calcium-channel blocker will probably be needed in the presence of phenytoin. Note that the manufacturers of nimodipine and nisoldipine contraindieate the eoneurrent use of phenytoin because of the possibility of a large reduction in their levels. 

Pbenobarbital markedly reduces felodipine, nifedipine and verapamil levels. A considerable increase in tbe dosage of these calcium-cbannel blockers will probably be needed in patients taking phenobarbital. Nimodipine effects are also markedly reduced by phenobarbital and the manufactarer contraindicates concurrent use. There is no direct information of interactions with other calcium-cbannel blockers, but as they are largely metabolised in the same way (see calcium-cbannel blockers , (p.860)) they would all be expected to interact similarly. 

Recent British clinical studies with Iproveratrll (verapamil) have been discussed.Despite considerable further work, the mode of action of this interesting agent remains an enigma.It appears to share some of the actions of the nitrates, e.g. increased CBF and lowered peripheral resistance.Unlike that produced by the nitrates, however, the Increased CBF results from dilation of the small resistance vessels. Like the 3-blocker drugs, Iproveratrll decreases heart rate In animals and has antlarrhythmlc activity but un- qU... 

---