Reduced hepatic blood flow

Liver blood flow constitutes a quarter of cardiac output. As well as changes in total blood flow, in liver disease there may be shunting of blood so that it is not delivered to functioning hepatocytes. Shunts may be intrahepatic or extrahepatic (mesenteric or splenic) and may divert more than 50 per cent of blood flow in chronic hepatic disease. Moreover, inhalational and intravenous anesthetic agents, the hypotension associated with epidural blockade, sympathetic nervous system activity, and mechanical ventilation all reduce hepatic blood flow.

The amount of drug extracted from blood passing through the liver is dependent upon the metabolic activity of the liver, the amount of unbound drug, and liver blood flow. The hepatic extraction ratio (ER) is defined as follows:

where CA is the concentration of drug entering liver, CV is the concentration of drug in the hepatic vein, and HBF is the hepatic blood flow. Thus, with high extraction drugs, clearance is dependent on the rate of hepatic blood flow.

Those drugs with a high extraction ratio, such as morphine (ER = 0.7) and lidocaine (lignocaine) (ER = 0.6), will have a reduced clearance with decreases in hepatic blood flow. When hepatic blood flow is reduced, the volume of distribution is usually unchanged and so the size of the first dose is unchanged. However, subsequent doses should be reduced in size or given less often.

The liver is particularly sensitive to hypoxia, with 70 per cent of its blood supply coming from the portal vein. Oxygen is needed by the cell for efficient drug metabolism to produce energy needed both for the reactions themselves and to make the enzymes. It is also needed as a substrate for drug oxidation, as a terminal electron acceptor, and for processes dependent upon the oxidation equilibrium (redox potential) of the cell.

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