Brimolol Mechanism of Action

Pharmacotherapeutic group: Ophthalmological, antiglaucoma preparations and miotics - beta-blocking agents - timolol, combinations. ATC code: S01ED51.
Pharmacology: Pharmacodynamics: YSP BRIMOLOL EYE DROP consists of two active substances: brimonidine tartrate and timolol maleate. These two components decrease elevated intraocular pressure (IOP) by complementary mechanisms of action and the combined effect results in additional IOP reduction compared to either compound administered alone. YSP BRIMOLOL EYE DROP has a rapid onset of action.
Brimonidine tartrate is an alpha-2 adrenergic receptor aqonist that is 1000-fold more selective for the alpha-2 adrenoreceptor than the alpha-1 adrenoreceptor. This selectivity results in no mydriasis and the absence of vasoconstriction in microvessels associated with human retinal xenografts.
It is thought that brimonidine tartrate lowers IOP by suppressing aqueous humour inflow and enhancing uveoscleral outflow. Timolol is a beta-1 and beta-2 non-selective adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic (membrane-stabilising) activity. Timolol lowers IOP by reducing aqueous humour formation. The precise mechanism of action is not clearly established, but inhibition of the increased cyclic AMP synthesis caused by endogenous beta-adrenergic stimulation is probable.
Pharmacokinetics: YSP BRIMOLOL EYE DROP: There were no statistically siqnificant differences in brimonidine or timolol AUC between YSP BRIMOLOL EYE DROP and the respective monotherapy treatments. Mean plasma Cmax values for brimonidine and timolol following dosing with YSP BRIMOLOL EYE DROP were 0.0327 and 0.406 ng/mL respectively.
Brimonidine: After ocular administration of 0.2% eve drops solution in humans. plasma brimonidine concentrations are low. Brimonidine is not extensively metabolised in the human eye and human plasma protein binding is approximately 29%. The mean apparent half-life in the systemic circulation was approximately 3 hours after topical dosing in man.
Brimonidine is well absorbed and rapidly eliminated. The major part of the dose (around 74% of the dose) was excreted as metabolites in urine within five days; no unchanged drug was detected in urine. The metabolism is mediated largely by aldehyde oxidase and cytochrome P450. Hence, the systemic elimination seems to be primarily hepatic metabolism.
Brimonidine binds extensively and reversibly to melanin in ocular tissues without any untoward effects. Accumulation does not occur in the absence of melanin. Brimonidine is not metabolised to a great extent in human eyes.
Timolol: After ocular administration of a 0.5% eye drops solution in human undergoing cataract surgery, peak timolol concentration was 898 ng/mL in the aqueous humour at one hour post-dose. Part of the dose is absorbed systemically where it is extensively metabolised by the liver. The half-life of timolol in plasma is about 7 hours. Timolol is partially metabolised by the liver with timolol and its metabolites excreted by the kidney. Timolol is not extensively bound to plasma protein.