Drug- or hormone-induced adaptation: model of adrenergic hypersensitivity

A pharmacokinetic/pharmacodynamic model of hypersensitivity to adrenergic stimulation following abrupt withdrawal of chronic beta blockade was developed. The model employs the Hill equation, a term which describes the competition between isoproterenol and l-propranolol for beta receptors, and a kinetic term which characterizes the appearance and disappearance rates of up-regulated beta receptors. The model predicted peak chronotropic hyperresponsiveness to isoproterenol 48 hr following abrupt withdrawal of chronic treatment with daily propranolol doses of 160 mg, and a drug half-life of 3.5 hr. The model also predicted that increasing the dose rate and prolonging the half-life of propranolol delayed and decreased the extent of adrenergic hypersensitivity. The time-course of adrenergic hypersensitivity simulated by our model was in excellent agreement with that observed in studies which were published earlier by our laboratory. The model underestimated the extent of adrenergic hypersensitivity. The results of our simulation are consistent with a beta agonist-receptor-effector system, which involves spare receptors, amplification of response by second and third messengers, and beta agonist- antagonist-induced receptor regulation.