Mechanism Of Action

The OBBs lower IOP through a reduction in aqueous formation. There appears to be no change in aqueous outflow. Aqueous formation can decrease by as much as 50%.3-8

Despite the fact that OBBs have been in clinical use for more than 30 years, the exact mechanism of action has not been entirely elucidated. In normal physiology, when a beta-adrenergic agonist binds to its receptor, activation of a regulatory protein (G-protein) results. This stimulates membrane-bound adenyl cyclase, catalyzing conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). In the classic model for the mechanisms of action of OBBs, the intracellular cAMP acts as a second messenger that, through additional steps, ultimately stimulates production of aqueous from the ciliary processes.

It has been demonstrated that timolol and other beta blockers inhibit cAMP production in the ciliary body. However, the direct relationship between beta blocker effect on cAMP and IOP effect is not supported in all studies. In one study, there was no relationship between reduction of cAMP and IOP lowering.9 Further, IOP can decrease in response to drugs that increase cAMP.10 The dextro -isomer of timolol has a low affinity for beta receptors, yet this compound decreases aqueous flow as well as the higher affinity levo-isomer in the clinically available preparations.11 These observations suggest that the IOP-lowering effect of OBBs may not be mediated directly through competitive inhibition of beta receptors in the ciliary body. While it is accepted that OBBs lower IOP through a decrease in aqueous production, some evidence suggests we must not assume this is simply beta-adrenergic blockade mediated through the classic second-messenger system.

Alternative mechanisms have been suggested. One postulates that there is endogenous adrenergic tone controlling aqueous production mediated by epinephrine. In this model, ciliary processes are under continuous tonic stimulation to produce aqueous. Beta blockers are hypothesized to exert an effect by interfering with this tonic stimulation of normal aqueous production.12 The basis for such tonic stimulation remains speculative since there is no identified anatomic basis, but a model such as this could explain some of the inconsistencies discussed above.

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