Cimetidine elimination clearance

In patients with heart failure, lidocaine s volume of distribution and total body clearance may both be decreased. Thus, both loading and maintenance doses should be decreased. Since these effects counterbalance each other, the half-life may not be increased as much as predicted from clearance changes alone. In patients with liver disease, plasma clearance is markedly reduced and the volume of distribution is often increased the elimination half-life in such cases may be increased threefold or more. In liver disease, the maintenance dose should be decreased, but usual loading doses can be given. Elimination half-life determines the time to steady state. Thus, although steady-state concentrations may be achieved in 8-10 hours in normal patients and patients with heart failure, 24-36 hours may be required in those with liver disease. Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so increase the risk of toxicity unless infusion rates are decreased. With infusions lasting more than 24 hours, clearance falls and plasma concentrations rise. Renal disease has no major effect on lidocaine disposition. 

Metronidazole has been reported to potentiate the anticoagulant effect of coumarin-type anticoagulants. Phenytoin and phenobarbital may accelerate elimination of the drug, whereas cimetidine may decrease plasma clearance. Lithium toxicity may occur when the drug is used with metronidazole. 

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. 

The risk of development of tolerance and dependence with extended use of zolpidem appears to be less than with the use of hypnotic benzodiazepines. Zolpidem is rapidly metabolized to inactive metabolites by the liver via oxidation and hydroxylation. The elimination half-life of the drug is 1.5-3.5 hours, with clearance decreased in elderly patients. Dosage reductions are recommended in patients with hepatic dysfunction, in elderly patients, and in patients taking cimetidine. Rifampin, an inducer of hepatic cytochrome P450, decreases the half-life of zolpidem. 

Possible mechanisms responsible for this stereoselective renal clearance of pindolol appear to be stereoselective renal metabolism or stereoselective renal secretion (stereoselective binding to plasma proteins was not observed). Recently, Somogyi et al. investigated the effect of coadministration of dmetidine on the renal clearance of the two enantiomers of pindolol (58). Cimetidine significantly reduced the renal clearance of both enantiomers, but reduced the renal clearance of the R enantiomer by a greater extent than the S enantiomer. These data are consistent with the stereoselective renal elimination mechanism for pindolol, with the S enantiomer being preferentially cleared. 

Answer E. Cimetidine is an inhibitor of the hepatic cytochrome P450 isoform that metabolizes phenytoin, consequently decreases its clearance, and thus increases its elimination half-life. The hepatic metabolism of many other drugs can be inhibited by cimeti-dine, possibly necessitating dose reductions to avoid toxicity, including beta blockers, iso-niazid, procainamide, metronidazole, tricyclic antidepressants, and warfarin. 

Aluminum-containing antacids may decrease the absorption of quinine. Quinine may depress the hepatic enzyme system that synthesizes the vitamin-K-dependent clotting factors and thus may enhance the action of warfarin and other oral anticoagulants. Cimetidine may reduce quinine s oral clearance and increase its elimination half-life. Digoxin serum concentrations may be inaeased by concurrent quinine. 

A. Cimetidine, and to a lesser extent ranitidine, reduces hepatic clearance and prolongs the elimination half-life of several dmgs as a result of inhibition of cytochrome P-450 activity and reduction of hepatic blood flow. Examples of drugs affected include phenytoin, theophylline, phenobatbital, cyclosporine, morphine, lidocaine, calcium channel blockers, tricyclic antidepressants, and warfarin. 

Cimetidine not only reduces the metabolism of beta-blockers such as propranolol, it is also known to act as an inhibitor of tubular secretion of a number of organic cations. Therefore it is not surprising to see that the renal clearance of pindolol is substantially and stereoselectively reduced by coadministration of this drug [59]. The administration of 400 mg cimetidine twice a day for 2 days before and 2 days after pindolol administration resulted in 26% and 34% reductions in the renal clearances of S(—)- and R(-t-)-pindolol, respectively. Therefore the plasma concentrations of the R(-l-) enantiomer increased more drastically (47%) than those of the S(—) enantiomer (38%) in the presence of cimetidine [59]. Because renal clearance accounts for only 50% of pindolol elimination, the significant increases in the plasma concentrations of pindolol enantiomers as a result of cimetidine coadministration cannot be explained from the inhibition of its renal clearance only. Apparently, cimetidine also reduces the metabolism of pindolol. 

Cimetidine 400 mg daily for 4 days approximately halved the clearance of a single 600-mg dose of chloroquine base in 10 healthy subjects. The elimination half-life was prolonged from 3.11 to 4.62 days. It was suggested that these effects occurred because cimetidine inhibits the metabolism of chloroquine by the liver. The clinical importance of this interaction is uncertain, but it would seem prudent to be alert for any signs... 

A single 500-mg dose of mefloquine was given to 10 healthy subjects before and after they took cimetidine 400 mg twice daily for 28 days. The ci-metidine had no effect on the AUC or serum levels of mefloquine, but its half-life increased hy 50% (liom 9.6 to 14.4 days) and the oral clearance decreased hy almost 40%. In another study mefloquine was given to 6 healthy subjects and 6 patients with peptic ulcers, before and after cimetidine 400 mg twice daily for 3 days. In contrast to the first study, cimetidine increased the maximum plasma levels of mefloquine by about 42% and 20% and increased the AUC by about 37% and 32% in the healthy subjects and patients, respectively. The elimination half-life was increased, but not to a significant extent. ... 

The plasma levels of a 400-mg intravenous dose of enoxacin were higher when cimetidine 300 mg four times daily was given concurrently. Renal clearance and systemic clearance were reduced by 26% and 20%, respectively, and the elimination half-life was increased by 30%. ... 

Cimetidine decreased the total clearance of fleroxacin by about 25%, without much effect on renal clearance, and increased its elimination half-life by 32%. ... 

Another study found that cimetidine 300 mg four times daily for 5 days reduced the clearance of a single intravenous dose of verapamil by 21% and increased its elimination half-life by 50%. Cimetidine 400 mg twice daily for a week increased the bioavailability of verapamil from 35 to 42% and its clearance was reduced by almost 30% in another study. A further study found a small increase in the bioavailability of both enantiomers of verapamil. In contrast, other studies have found that the pharmacokinetics of verapamil were unaffected by cimetidine. ... 

Cimetidine 800 mg daily for 5 days was found to reduce the oral clearance of venlafaxine 50 mg every 8 hours by 40%, and to increase the AUC by 62% in 18 healthy subjects. It had no effect on the formation or elimination of the major active metabolite of venlafaxine, O-desmethylvenla-faxine (ODV). The total level of venlafaxine with ODV was found to be increased by only 13%. Thus the overall pharmacological activity of the two was only slightly increased by cimetidine and no special precautions would seem to be necessary on concurrent use. However, the manufacturers of venlafaxine suggest that the elderly and those with hepatic impairment may possibly show a more pronounced effect, and such patients should be monitored more closely, for venlafaxine adverse effects. 

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