Complex changes in blood flow occur with liver disease. Resistance to hepatic portal blood flow rises in cirrhosis, and portasystemic and intrahepatic shunts reduce drug delivery to hepatocytes. The pattern of change caused by disease relates to the manner in which the healthy liver treats a drug and there are two general classes:
• Drugs that are rapidly metabolised and highly extracted in a single pass through the liver. Clearance of such compounds is normally limited by hepatic blood flow but in severe liver disease less drug is extracted from the blood as it passes through the liver due to poor liver cell function, and portasystemic shunts allow a proportion of blood to bypass the liver altogether. Therefore the predominant change in the kinetics of drugs that are given orally is increased systemic availability. Accordingly the initial and maintenance doses of such drugs should be smaller than usual. When liver function is severely impaired the t'/? of drugs in this class may also be lengthened.
• Drugs that are slowly metabolised and are poorly extracted in a single pass through the liver. The rate-limiting factor for elimination of this type of drug is metabolic capacity, and the major change caused by liver disease is prolongation oft Consequently the interval between doses of such drugs may need to be lengthened, and the time to reach steady-state concentration in the plasma (5 x tY2) is increased.
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