Calcium channel blockers pharmacokinetics

All of the following statements regarding the pharmacokinetics of calcium channel blockers are correct EXCEPT... 

The pharmacokinetic properties of these drugs are set forth in Table 12-5. The choice of a particular calcium channel-blocking agent should be made with knowledge of its specific potential adverse effects as well as its pharmacologic properties. Nifedipine does not decrease atrioventricular conduction and therefore can be used more safely than verapamil or diltiazem in the presence of atrioventricular conduction abnormalities. A combination of verapamil or diltiazem with 3 blockers may produce atrioventricular block and depression of ventricular function. In the presence of overt heart failure, all calcium channel blockers can cause further worsening of heart failure as a result of their negative inotropic effect. Amlodipine, however, does not increase the mortality of patients with heart failure due to nonischemic left ventricular systolic dysfunction and can be used safely in these patients. 

Sica DA. Calcium channel blocker class heterogeneity select aspects of pharmacokinetics and pharmacodynamics, j Clin Hypertens. 2005 7(suppl l) 21-26. 

The calcium channel blockers are divided into three chemical classes, each with different pharmacokinetic properties and clinical indications (Figures 19.11 and 19.12). 

Pharmacokinetics. Calcium channel blockers in general are well absorbed from the gastrointestinal tract and their systemic bioavailability depends on the extent of first-pass metabolism in the gut wall and liver, which varies between the drugs. All... 

A pharmacokinetic interaction has been described between carbamazepine and the calcium channel blockers... 

However, some calcium channel blockers have pharmacokinetic interactions diltiazem, verapamil, nicardipine, and amlodipine increase ciclosporin concentrations, whereas nifedipine, felodipine, and isradipine do not (SED-14, 604) (SEDA-21, 210) (SEDA-21, 212)... 

Effects of grapefruit juice on the pharmacokinetics of the calcium channel blockers nifedipine and nisoldipine. Curr Ther Res Clin Exp 1998 59 619-34. 

Azuma J, Yamamoto I, Wafase T, Orii Y, Tinigawa T, Terashima S, Yoshikawa K, Tanaka T, Kawano K. Effects of grapefruit juice on the pharmacokinetics of the calcium channel blockers nifedipine and nisoldipine. Curr Ther Res Clin Exp 1998 59 619-34. 

The interaction with grapefrnit jnice observed with several calcium channel blockers, inclnding felodipine, nifedipine, and nisoldipine, has not been confirmed with verapamil. A single dose of grapefrnit jnice had no effect on the pharmacokinetics of verapamil in 10 hypertensive patients taking chronic verapamil (31). 

Since acute DIN appears to be dose related, pharmacokinetic and pharmacodynamic monitoring is an important means of preventing toxicity. However, the persistent presence of therapeutic or low cyclosporine concentrations cannot preclude nephrotoxicity. Calcium channel blockers may antagonize the vasoconstrictor effect of cyclosporine by dilating glomerular afferent arterioles and preventing acute decreases in renal blood flow and glomerular filtration. Lastly, decreased doses of cyclosporine or tacrolimus, primarily when used in combination with other non-nephrotoxic immunosuppressants, may minimize the risk of toxicity, but this may increase the risk of chronic rejection. 

The calcium channel blockers are rapidly and completely absorbed after oral administration (see Table 28.11 for summary of pharmacokinetic parameters). Prehepatic first-pass metabolism by CYP3A4 enzymes occurs with some orally administered calcium channel blockers, especially verapamil, with its low bioavailability of 20 to 35%. The bioavailability of diltiazem is 40 to 67%, of nicardipine 35%, of nifedipine 45 to 70%, and of amlodipine 64 to 90%. Verapamil is metabolized by CYP3A4 N-demethylation to its principal metabolite, norverapamil, which retains approximately 20% of the activity of verapamil, and by 0-demethylation (CYP2D6) into inactive metabolites. Diltiazem is metabolized by enzyme hydrolysis to its primary metabolite, desacetyl derivative, which retains approximately 25 to 50% of the activity of diltiazem. The oral bioavailability of diltiazem and verapamil may be increased with chronic use and increasing dose (i.e., bioavailability is nonlinear). Diltiazem undergoes ... 

---