Assessment of systemic adverse reactions induced by ophthalmic beta-adrenergic receptor antagonists

To assess quantitatively the risks of ophthalmic beta-blocking agents for c ardiovascular and respiratory adverse reactions, we analyzed the binding ki netics of beta-blocking agents to the beta-1 and beta-2 adrenoceptors. The relationship between the occupancies for beta-1 and beta-2 adrenoceptors an d the effects on the exercise pulse rate or the forced expiratory volume in one second (FEV1) after topical administration of carteolol, befunolol, ti molol and betaxolol was analyzed using a ternary complex model. The beta-1 and beta-2 receptor occupancies after ophthalmic administration were calcul ated to be quite high as well as those after oral administration. The maxim um occupancies for beta-1 and beta-2 receptors after ordinary ophthalmic ad ministration were 52% and 88% for carteolol, 52% and 61% for befunolol, 62% and 82% for timolol, and 43% and 3% for betaxolol, respectively. Concave r elationships were obtained between a decrease in exercise pulse rate and th e beta-1 receptor occupancy and between a decrease in FEV1 and beta-2 recep tor occupancy, respectively. Nasolacrimal occlusion was estimated to decrea se the exercise pulse rate and FEV1 by 65% and 50%, respectively. The beta- 1 and beta-2 adrenoceptor occupancies were proved to be the most appropriat e indicators for cardiac and pulmonary adverse reactions evoked by ophthalm ic beta-blocking agents.