In severe hepatic cirrhosis with both impaired liver cell function and well-developed channels shunting blood into the systemic circulation without passing through the liver, first-pass elimination is reduced and systemic availability is increased. The result of these changes is an increased likelihood of exaggerated response to normal doses of drugs having high hepatic clearance and, on occasion, frank toxicity.
Drugs that exhibit the hepatic first-pass phenomenon do so because of the rapidity with which they are metabolised. The rate at which drug is delivered to the liver, i.e. blood flow, is then the main determinant of its metabolism. Many other drugs are completely metabolised by the liver but at a slower rate and consequently loss in the first pass through the liver is unimportant. The parenteral dose of these drugs does not need to be reduced to account for presystemic elimination. Such drugs include diazepam, phenytoin, theophylline, warfarin.
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