Protein Binding Most drugs are bound to some extent to plasma proteins,
primarily albumin, a1-acid glycoprotein, and lipoproteins.6 Most acidic drugs bind to albumin, whereas basic drugs bind to a1-acid glycoprotein. Protein binding effects both the distribution of drugs (because only the free or unbound fraction can readily cross cell membranes) and the apparent potency of drugs, again because it is the free fraction that determines the concentration of bound drug on the receptor. The extent of protein binding parallels the lipid solubility of the drug. This is because drugs that are hydrophobic are more likely to bind to proteins in the plasma and to lipids in the fat. For intravenous anesthetic drugs, which tend to be quite potent, the number of available protein binding sites in the plasma vastly exceeds the number of sites actually bound. As a result, the fraction bound is not dependent on the concentration of the anesthetic and only dependent on the protein concentration. Binding of drugs to plasma albumin is nonselective,
and drugs with similar physicochemical characteristics may compete with each other and with endogenous substances for the same protein binding sites. For example, sulfonamides can displace unconjugated bilirubin from binding sites on albumin, leading to the risk of bilirubin encephalopathy in the neonate. Age, hepatic disease, renal failure, and pregnancy
can all result in decreased plasma protein concentration. A lterations in protein binding are important only for drugs that are highly protein bound (e.g., .90%). For such drugs, the free fraction changes as an inverse proportion
with a change in protein concentration. If the free fraction is 2% in the normal state, then in a patient with 50% decrease in plasma proteins, the free fraction will increase to 4%, a 100% increase. Theoretically, an increase in free fraction of a d rug
may increase the pharmacologic effect of the drug, but in practice, it is far from certain that there will be any change in pharmacologic effect at all. The reason is that it is the unbound fraction that equilibrates throughout the body, including with the receptor. Plasma proteins only account for a small portion of the total binding sites for drug in the body. Because the free drug concentration in the plasma and tissues represents partitioning with all binding sites, not just the plasma binding sites, the actual free drug concentration that drives drug on and off receptors may change fairly little with changes in plasma protein concentration.