DRUG INTERACTIONS ( CASE STUDIES RELATED TO ALTERED DRUG DISTRIBUTION )

(i) DISPLACEMENT FROM PROTEIN BINDING SITES :

An interaction of this type occurs when two drugs that are capable of binding to proteins are administered concurrently. Although they may bind at different sites on the protein molecule, the binding characteristics of one of the drugs is altered (NONCOMPETITIVE DISPLACEMENT). More significant situations are those in which both drugs re capable of binding to the same sites on the protein (COMPETITIVE DISPLACEMENT). Since there are only a limited number of protein binding sites, competition will exist and the drug that has the greater affinity for the binding sites will displace the other from plasma or tissue proteins. Protein bound fraction of a drug in the body is not pharmacologically active. An equilibrium exists between bound and unbound fractions and as the unbound or "free" form of the drug is metabolized and excreted, bound drug is gradually released to maintain the equilibrium and pharmacologic response. Binding of drugs to serum albumin is readily reversible and the albumin drug complex essentially serves as a reservoir. The maximum intensity of action of a highly bound drug may be decreased as a result of binding to albumin; the duration of action is also extended.

The risk of an interaction occuring is greatest with drugs that are highly bound (more than 90%) and that also have a small apparent volume of distribution. Since only a small fraction of the drug is available in the "free" form, the displacement of even a small fraction of amount bound to proteins could produce a considerable increase in activity.

a) WARFARIN - PHENYLBUTAZONE :

Both phenylbutazone and warfarin are extensively protein bound, especially to albumin. Phenylbutazone has a greater affinity for the binding sites, resulting in displacement of warfarin. The "free" drug quantities of warfarin are thus available in larger amount and activity of anticoagulant is increased and there is a risk of haemorrhage.

b) BILIRUBIN - SULPHONAMIDES :

Bilirubin is bound to albumin binding sites and drugs like sulphonamides are capable of displacement of bilirubin from albumin. SULPHISOXAZOLE can precipitate KERNICTERUS (presence of unconjugated bilirubin in brain) leading to pseudojaundice due to displacement from binding sites.

c) METHOTREXATE - SULPHONAMIDES :

Methotrexate is highly bound to plasma proteins. Salicylates and sulphonamides are capable of displacing it from the binding sites. So there is a potential for toxicity with methotrexate.

d) HYPOALBUMINEMIA :

Many drugs are extensively bound to plasma proteins. So decreased concentrations of proteins enhances the availability of free drugs and thus their activity. Adverse drug reactions are higher in patients with hypoalbuminemia (example, in renal and gastrointestinal diseases). When serum albumin concentration is less than 2.5g/100 ml, frequency of prednisone side effects is almost doubled.

e) PROTEIN - BINDING SITES AND DISEASED STATES :

Binding of phenytoin to plasma proteins was found to be decreased in patients with decreased or poor renal function. Greater amount of "free" phenytoin leads to toxicity. A number of acidic drugs such as WARFARIN, BARBITURATES, SALICYLATES are bound to a lesser extent in the case of impaired renal function.