Displacement of One Drug by Another from Carrier or Receptor Sites

Abstract

The medium of drug transfer is the water of plasma and extracellular fluid. Without complicating factors, the level of drug at a receptor site would be equal to that in the tissues and in plasma, and in dynamic equilibrium. Actually, almost all drugs are reversibly bound to proteins in plasma or tissue. The bound drug, often a high proportion of the total, acts as a reservoir, preventing wild fluctuations between ineffective and toxic levels of the biologically active unbound fraction. Displacement from a receptor site diminishes drug activity, but displacement from plasma or tissue proteins augments the effect by making more unbound drug available at the receptor site. Atropine has no intrinsic activity, but displaces acetylcholine or pilocarpine from receptors at para-sympathetic nerve endings. Similarly guanethidine competes with noradrenaline at sympathetic nerve endings, but in turn is displaced by amphetamine-like drugs. Many acidic drugs (phenylbutazone, sulfonamides, coumarin anticoagulants, salicylates, &c.) are highly bound to one or two sites on albumin molecules. When the limited carrying capacity of the plasma proteins is filled, any unbound surplus is usually soon metabolized or excreted, so the plasma level becomes restabilized. Meanwhile, however, there may be dramatic effects such as hypoglycemia, when sulfonamides are given to patients on tolbutamide, or bleeding when phenylbutazone is given to patients on warfarin. Although hormones, like thyroxine, insulin and cortisol, are carried by specific proteins, they too can be displaced. All the antirheumatic drugs so far examined have displaced cortisol and presumably driven it into tissues. This may be one mechanism of action. Possibly the sulfonylurea drugs act by displacing insulin from proteins in the pancreas, plasma or elsewhere.