Chemical formula: C₁₁H₁₀BrN₅ Molecular mass: 292.135 g/mol PubChem compound: 2435
Brimonidine is an alpha2-adrenergic receptor agonist that is 1000-fold more selective for the alpha2-adrenoceptor than the alpha1-adrenoreceptor.
This selectivity results in no mydriasis and the absence of vasoconstriction in microvessels associated with human retinal xenografts.
Topical administration of brimonidine tartrate decreases intraocular pressure (IOP) in humans with minimal effect on cardiovascular or pulmonary parameters. Limited data are available for patients with bronchial asthma showing no adverse effects.
Cutaneous facial application of a highly selective alpha2-adrenergic receptor agonist reduces erythema through direct cutaneous vasoconstriction.
Brimonidine has a rapid onset of action, with peak ocular hypotensive effect seen at two hours post-dosing. In two 1 year studies, brimonidine lowered IOP by mean values of approximately 4-6 mmHg.
Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of action. It is thought that brimonidine may lower IOP by reducing aqueous humour formation and enhancing uveoscleral outflow.
Clinical trials show that brimonidine is effective in combination with topical beta-blockers. Shorter term studies also suggest that brimonidine has a clinically relevant additive effect in combination with travoprost (6 weeks) and latanoprost (3 months).
After ocular administration of a 0.2% solution twice daily for 10 days, plasma concentrations were low (mean Cmax was 0.06 ng/ml). There was a slight accumulation in the blood after multiple (2 times daily for 10 days) instillations. The area under the plasma concentration-time curve over 12 hours at steady state (AUC0- 12h) was 0.31 ng·hr/ml, as compared to 0.23 ng·hr/ml after the first dose. The mean apparent half-life in the systemic circulation was approximately 3 hours in humans after topical dosing.
The plasma protein binding of brimonidine after topical dosing in humans is approximately 29%.
Brimonidine binds reversibly to melanin in ocular tissues, in vitro and in vivo. Following 2 weeks of ocular instillation, the concentrations of brimonidine in iris, ciliary body and choroid-retina were 3- to 17-fold higher than those after a single dose. Accumulation does not occur in the absence of melanin.
The significance of melanin binding in humans is unclear. However, no significant ocular adverse reaction was found during biomicroscopic examination of eyes in patients treated with brimonidine for up to one year, nor was significant ocular toxicity found during a one year ocular safety study in monkeys given approximately four times the recommended dose of brimonidine tartrate.
Following oral administration to man, brimonidine is well absorbed and rapidly eliminated. The major part of the dose (around 75% of the dose) was excreted as metabolites in urine within five 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.
No great deviation from dose proportionality for plasma Cmax and AUC was observed following a single topical dose of 0.08%, 0.2% and 0.5%.
The Cmax, AUC, and apparent half-life of brimonidine are similar in the elderly (subjects 65 years or older) after a single dose compared with young adults, indicating that its systemic absorption and elimination are not affected by age.
Based on data from a 3 month clinical study, which included elderly patients, systemic exposure to brimonidine was very low.
The absorption of brimonidine from brimonidine was evaluated in a clinical study in 24 adult subjects with facial erythema of rosacea. All enrolled subjects received a single-day ocular administration of a 0.2% eye drops solution of brimonidine followed by a once daily cutaneous application of brimonidine for 29 days (intra-individual comparison of systemic exposure). On Day 1 of the study, all subjects received 1 drop of the 0.2% eye drops solution in each eye, every 8 hours over a 24-hour period (3 doses in total).
After repeated cutaneous application of brimonidine on facial skin, no drug accumulation in plasma was observed throughout the treatment duration: the highest mean (± standard deviation) plasma maximum concentration (Cmax) and area under the concentration-time curve from 0 to 24 hours (AUC0-24hr) were 46 ± 62 pg/mL and 417 ± 264 pg.hr/mL respectively. These levels are significantly lower (2-fold) than those observed following single-day ocular administration of a 0.2% eye drops solution of brimonidine.
The protein binding of brimonidine has not been studied.
Brimonidine is extensively metabolised by the liver.
Urinary excretion is the major route of elimination of brimonidine and its metabolites.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
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