Reduced plasma proteins

Hepatic failure is associated with a number of alterations which can influence the binding of drugs within the blood, including the following:

1. decrease in serum albumin concentrations;

2. appearance of altered or defective plasma proteins;

3. accumulation of endogenous (e.g. bilirubin) and exogenous compounds which can displace drugs from albumin binding sites.

The influence of the consequent reduction in drug-protein binding is complex because it influences both the elimination and the distribution of the drug. With reduced binding there is an increase in the free fraction of the drug available for elimination; this helps to offset the reduction in drug metabolism caused by the liver disease. This effect is more significant with highly bound drugs; a 1 per cent reduction in the binding of a drug that is usually 99 per cent bound will double the free fraction of the drug. With an increase in proportion of active unbound drug, dosages may have to be reduced, despite normal total drug concentrations (bound and unbound), to avoid potential drug toxicity.

Reduced plasma drug binding will increase the volume of distribution by making more of the drug available for equilibration with extracellular tissues. This change will alter drug elimination half-life, irrespective of metabolism (t05 elim = ln2 * VJC where t05 elim is the half-life, Vd is the volume of distribution, and Cl is clearance), thus making half-life a measure of little use in liver failure. The increase in the elimination half-life of lorazepam is purely a result of reduced binding.

Clearance of tolbutamide (based on total drug concentration) is increased in acute hepatic failure secondary to reduced protein binding. Although total drug levels may decrease, free drug levels are constant as intrinsic clearance (based on free drug levels) is unchanged. Thus no alteration in dose is required.

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