Slow antagonist dissociation and long-lasting in vivo receptor protection

The ability of antagonists to form slowly dissociating complexes with their cognate receptors has repeatedly been proposed to contribute to their long-lasting clinical actions. Yet specific conditions seem to be necessary for this to take place. The elimination rate of the free antagonist and the variation of agonist concentration with time have important roles. Slowly dissociating antagonists are likely to exert longer efficient receptor protection in vivo than are fast-dissociating antagonists when the half-life of the antagonist-receptor complex exceeds that of the free antagonist. However, when the half-life of the free antagonist prevails, longer effective protection by slowly dissociating antagonists occurs only if the receptor is exposed to rapid fluctuations in free agonist concentration.