Verapamil clearance

Velosulin 13 Velosulin BR 471 Venn diagram 111 Venous thrombosis 23 Verapamil clearance 1594 Verluma 21... 

PO/IV. Well absorbed, 80% metabolized in first pass. 90% protein bound. Metabolites are active. Half-life is 5 hrs but may be up to 20 hrs in patients with cirrhosis. Patient on IV blockers or digitalis. A-V node block, sick sinus syndrome, cardiogenic shock, heart failure, hypotension. Beta blockers or digitalis Increases likelihood of bradycardia or A-V blockade. Quinicfine or prazosin Increases hypotension. Digoxin levels are increased. Cimetidine reduces verapamil clearance. Calcium supplements may inhibit actions of verapamil. Depolarization (leading to contraction) of vascular smooth muscle is dependent on calcium entry. Vasodilation is induced by calcium entry blockers because they inhibit calcium influx. 

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. 

It was determined that 9.5% of an oral 80-mg dose of verapamil was absorbed in a 70-kg test subject. However, because of extensive bio transformation during its first pass through the portal circulation, the bio availability of verapamil was only 25%. Assuming a liver blood flow of 1500 mLAmin, the hepatic clearance of verapamil in this situation was... 

This theory was further explored in an anaesthetised pig model, which facilitated portal vein and bile sampling [86], However, the hepatic extraction ratio and the biliary clearance of fexofenadine were unaffected by verapamil in the pig model. The question as to why verapamil/ketoconazole increase the fraction absorbed (i.e. based on appearance kinetics) and yet the fraction absorbed estimated on the basis of disappearance kinetics (i.e. /err) for the intestinal segment appears unchanged remains to be explored and most likely reflect multiple interplay between absorptive and efflux drug transporters in the intestinal tissue. 

Contraindications include baseline prolongation of the QT interval, use of other QT-prolonging drugs history of torsades de pointes a creatinine clearance of less than 20 mL/minute simultaneous use of verapamil, cimetidine, or ketoconazole uncorrected hypokalemia or hypomagnesemia and pregnancy or breast-feeding. 

Dofetilide is 100% bioavailable. Verapamil increases peak plasma dofetilide concentration by increasing intestinal blood flow. Eighty percent of an oral dose is eliminated by the kidneys unchanged the remainder is eliminated by the kidneys as inactive metabolites. Inhibitors of the renal cation secretion mechanism, eg, cimetidine, prolong the half-life of dofetilide. Since the QT-prolonging effects and risks of ventricular proarrhythmia are directly related to plasma concentration, dofetilide dose must be based on the estimated creatinine clearance. Treatment with dofetilide should be initiated in hospital after baseline measurement of the QTc and serum electrolytes. A baseline QTC of > 450 ms (500 ms in the presence of an intraventricular conduction delay), bradycardia of < 50 beats/min, and hypokalemia are relative contraindications to its use. 

Drug-drug interactions involving fexofenadine have been reported which includes not only interactions with concomitant chugs, but also those with fruit juices. Concomitant use of itraconazole (303), verapamil (304), and ritonavir (305) increased the area under the curve of the plasma concentration (AUC) and peak plasma concentration (Cmax) of fexofenadine following oral administration, but did not affect the elimination half-life. Itraconazole and verapamil did not affect the renal clearance of fexofenadine, while the effect of ritonavir on the renal clearance was not examined. Considering the absence of the effect on the renal clearance, these interactions will include the inhibition of intestinal... 

Hedman A, Angelin B, Arvidsson A, et al. Digoxin-verapamil interaction reduction of biliary but not renal digoxin clearance in humans. Clin Pharmacol Ther 1991 49 256-262. 

Oral verapamil has been shown to increase peak plasma levels, prolong the terminal half-life, and increase the volume of distribution at steady state of doxorubicin (282). Gigante et al. (283) performed similar studies in which the pharmacokinetics of doxorubicin in combination with verapamil given at high doses intravenously were followed for 17 patients with advanced neoplasms. The steady-state concentration and systemic and renal clearances were found to be statistically similar for various doses of verapamil and doxorubicin, and for doxorubicin administered alone. 

The ratio of renal clearance of digoxin to creatinine clearance decreased with the coadministration of clarithromycin (0.64 and 0.73), and was restored (1.30) after administration of clarithromycin had stopped (326). The role of P-gp efflux in this interaction was confirmed using an in vitro kidney epithelial cell line (326). The administration of itraconazole, a P-gp inhibitor, with digoxin resulted in an increased trough concentration and a decrease in the amount of renal clearance, possibly by an inhibition of the renal tubular secretion of digoxin via P-gp (329). The P-gp modulator verapamil has also been shown to decrease the renal clearance of digoxin (330). 

Drugs metabolized by CYP that interact with cimetidine include, but are not limited to, the following lidocaine, quinidine, midazolam, triazolam, nifedipine, verapamil, and fentanyl (4). In each instance, inhibition of CYP by cimetidine results in reduced metabolic clearance and increases in serum concentrations of the other drug, which can lead to the expected toxicity and adverse experiences characteristic of the other drug. 

Relationship between rat intestinal absorption clearance and lipid solubility. The results shown with the squares represent the relationship between intestinal absorption clearance (ka) observed from the in situ jejunum loop in the presence ( ) and absence ( ) of cyclosporin A in rats and octanol-buffer (pH 7.0) partition coefficients (log D) determined in this study. The numbers refer to 1, atenolol 2, nadolol 3, acetamide 4, celiprolol 5, acebutolol 6, doxorubicin 7, timolol 8, sulfathiazole 9, quinidine 10, sulfamethoxazole 11, digoxin 12, cyclosporin A 13, vinblastine 14, b-estradiol 15, verapamil. Modified from A.Tsuji and I. Tamai. Pham. Res., 13 963—977 (1996). 

CALCIUM CHANNEL BLOCKERS BUSULFAN t plasma concentrations of busulfan and t risk of toxicity of busulfan such as veno-ocdusive disease and pulmonary fibrosis, when co-administered with diltiazem, nifedipine or verapamil Due to inhibition of CYP3A4-mediated metabolism of busulfan by these calcium channel blockers. Busulfan clearance may be l by 25%, and the AUC of busulfan may t by 1500 p,mol/L Monitor clinically for veno-ocdusive disease and pulmonary toxicity in transplant patients. Monitor busulfan blood levels as AUC of below 1500 p,mol/L per minute tends to prevent toxicity... 

CALCIUM CHANNEL BLOCKERS TCAs t plasma concentrations of TCAs when co administered with diltiazem and verapamil. Reports of cardiotoxicity (first- and second-degree block) when imipramine is given with diltiazem or verapamil Uncertain, but may be due to a combination of i clearance of TCAs (both diltiazem and verapamil are known to inhibit CYP1A2, which has a role in the metabolism of amitriptyline, clomipramine and imipramine) and t intestinal absorption (diltiazem and verapamil inhibit intestinal P-gp, which may t amitriptyline bioavailability) Monitor ECG when commencing or altering treatment... 

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