Drugs and the Liver/Gastrointestinal System

Abstract

Liver dysfunction is common in acutely ill patients. Unlike renal dysfunction where glomerular filtration rate (GFR) can be used to guide dose adjustments, there is no corresponding parameter to gauge the degree of liver dysfunction. Drug dosages have to be adjusted based on knowledge of pharmacodynamics and pharmacokinetics in liver disease. Metabolism of drugs with high hepatic extraction ratio (HER) is mainly dependent on blood flow to the liver. With cirrhosis and portosystemic shunting, blood flow to the liver is reduced and so is metabolism of high HER drugs. Oral bioavailability is increased and dosages should be reduced to prevent accumulation. Metabolism of low HER drugs is mainly dependent on protein binding and the intrinsic metabolic capacity of the liver. Drugs which are highly protein bound have significantly higher unbound concentrations in liver dysfunction. This is due to several mechanisms – reduced synthesis of albumin and alpha-1 acid glycoprotein, accumulation of endogenous compounds such as bilirubin which interfere in plasma protein binding, and possible qualitative changes in albumin and alpha-1 acid glycoprotein. Unbound drugs are biologically active, leading to more rapid onset of action and also increased adverse effects. For water soluble drugs, ascites and edema increases the volume of distribution and larger doses may be needed. The gastrointestinal tract is subject to many changes in the acutely ill patient. Gastrointestinal motility may be reduced due to pain, hypotension, hypoxemia, sepsis or the use of drugs such as dopamine and opioids. Hypoalbuminemia in the ill patient leads to mucosal edema and impaired absorption of enteral feeds and drugs. Acutely ill patients are also at increased risk of developing stress ulcers, which may lead to clinically important bleeding. This may be prevented with the use of appropriate stress ulcer prophylactic drugs.