Combigan Mechanism of Action

Pharmacotherapeutic group: Ophthalmological beta-blocking agents: Timolol, combinations. ATC code: S01ED51.
Pharmacology: Pharmacodynamics: Mechanism of action: COMBIGAN 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.
Combigan has a rapid onset of action.
Brimonidine tartrate is an alpha-2 adrenergic receptor agonist 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 enhancing uveoscleral outflow and reducing aqueous humour formation.
Timolol is a beta₁ and beta₂ 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.
Clinical effects: In these well-controlled, double-masked clinical studies, COMBIGAN (twice daily) produced significantly greater decreases in mean diurnal IOP compared with timolol (twice daily) and brimonidine (twice daily or three times a day) when administered as monotherapy.
In a study in patients whose IOP was insufficiently controlled following a minimal 3-week run-in on any monotherapy, additional decreases in mean diurnal of 4.5, 3.3 and 3.5 mmHg were observed during 3 months of treatment for COMBIGAN (twice daily), timolol (twice daily) and brimonidine (twice daily), respectively.
In addition, the IOP-lowering effect of COMBIGAN was consistently non-inferior to that achieved by adjunctive therapy of brimonidine and timolol (all twice daily).
The IOP-lowering effect of COMBIGAN has been shown to be maintained in double-masked studies of up to 12 months.
Pharmacokinetics: Plasma brimonidine and timolol concentrations were determined in a crossover study comparing the monotherapy treatments to COMBIGAN treatment in healthy subjects. There were no statistically significant differences in brimonidine or timolol AUC between COMBIGAN and the respective monotherapy treatments. Mean plasma C_max values for brimonidine and timolol following dosing with COMBIGAN were 0.0327 and 0.406 ng/mL, respectively.
Brimonidine: After ocular administration of 0.2% eye 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.
Following oral administration to 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 5 days; no unchanged drug was detected in urine. In vitro studies, using animal and human liver, indicate that 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. After instillation of brimonidine tartrate 0.2% eye drops to the rabbit, peak drug concentration was 0.647 μg/mL in the aqueous humour within 1 hour post-dose. Brimonidine concentrations declined subsequently in a biphasic manner with an initial half-life of 1 hour, followed by a slower terminal elimination phase from 6 to 24 hours post-dose.
Timolol: After ocular administration of a 0.5% eye drops solution in humans 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 in 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.