Dosing of drugs in hepatic impairment patient

Hepatic metabolism is an important rout of drug elimination. Dysfunction of the liver would leave to
changes in pharmacokinetics of drug. The clinical significance of the changes in drug metabolism and
elimination depends on the type and severity of the disease and on the pharmacokinetics of the drug. No
differences were reported for drugs such as chlorpromazine, warfarin, dicumarol, phenytoin or salicylate.
The elimination of many potent drugs is impaired in patients with chronic liver diseases.

Antipyrine has been used as a model drug to investigate the effects of liver disease on drug metabolism in
man because it is negligibly bound to plasma protein a tissues, and because it is eliminated almost
exclusively by hepatic metabolism with a low hepatic extraction ratio. Its t 1/2 and clearance are considered
sensitive indicator of liver function with respect to oxidative metabolism process.

The average antipyrine clearance in control subjects was about 51 ml/min. Patient with cirrhosis but no
signs of encephalopathy showed an average antipyrine clearance of 17 ml/min.

On the whole, it can be generalized that dosage should be reduced in patients with hepatic dysfunction.

Dose adjustment in renal failure

Drugs in patient with renal impairment have altered pharmacokinetic profile. Their renal clearance and
elimination rate are reduced, the elimination half-life is increased and the apparent volume of distribution
is altered. Thus, dose must be altered depending upon the renal function in such patients. For drugs
having low therapeutic index, the dosage adjustment is not essential. Dosage regimen need not to be
changed when the fraction of drug excreted unchanged, fu is ≤ 0.3 and the renal function RF is ≥ 0.7 of
normal.

The required dose in patients with renal impairment can be calculated by the simple formula.

Normal dose *RF

Dosage adjustment based on total body clearance

Dose adjustment based on elimination rate constant or half-life