Chemical formula: C₉H₁₂ClN₅O Molecular mass: 241.677 g/mol PubChem compound: 4810
In various animal models moxonidine has been shown to be a potent antihypertensive. Available experimental data indicate that the site of action of the antihypertensive effect of moxonidine is the central nervous system (CNS).
Moxonidine has been shown to bind selectively to the I1-imidazoline receptors in the brain stem. These imidazoline-sensitive receptors are concentrated in the rostral ventrolateral medulla, an area which is of crucial importance for central control of the peripheral sympathetic nervous system. The result of this effect on the I1-imidazoline receptors has been apparent in reduced activity in the sympathetic nerves. (demonstrated for cardiac, splanchnic and renal sympathetic nerves).
Moxonidine differs from other available centrally acting antihypertensives by having only a weak affinity for central alpha2-adrenoceptors compared to I1-imidazoline receptors alpha2-adrenoceptors are considered to be the molecular target though which most common side effects of centrally acting antihypertensives such as drowsiness and dry mouth – are mediated. In humans, moxonidine results in a reduction of systemic vascular resistance and consequently of arterial blood pressure.
The effects of moxonidine on mortality and cardiovascular morbidity are currently unknown.
In humans, about 90% of an oral dose of moxonidine is absorbed; there is no first-pass effect and the bioavailability is 88%. Food intake does not affect moxonidine.
The peak plasma concentration of moxonidine is reached in the course of 30-180 minutes after administration of a film-coated tablet.
Only about 7% of moxonidine is plasma protein bound (VDss =1.8 ± 0.4 l/kg).
10-20% of moxonidine is metabolised, principally to 4,5-dehydromoxonidine and a guanidine derivative on opening of the imidazoline ring. The hypertensive effect of 4,5-dehydromoxonidine is only 1/10 that of moxonidine and for the guanidine derivative it is less than 1/100.
Moxonidine and its metabolites are excreted almost exclusively via the kidneys. More than 90% of the dose is eliminated via the kidneys in the course of the first 24 hours after administration, but only about 1% is eliminated in the faeces. The cumulative elimination of unchanged moxonidine via the kidneys is about 50-75%. The mean plasma elimination half life is 2.2-2.3 hours and the renal elimination half-life is 2.6-2.8 hours.
Small variations in the pharmacokinetic properties of moxonidine in healthy elderly patients and young adults have not proved to be clinically significant. As there is no accumulation of moxonidine, a dosage adjustment is not necessary, provided that renal function is normal.
No pharmacokinetic studies in children have been performed.
In patients with moderately impaired renal function (GFR 30-60 ml/min), the AUC is increased by 85% and the clearance reduced by 52%. In these patients, the hypotensive effect of moxonidine should be monitored carefully, particularly at the beginning of treatment. In addition, the individual dose should not exceed 0.2 mg and the daily dose 0.4 mg.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Chronic oral treatment for 52 weeks of rats (with dosages of 0.12-4 mg/kg) and dogs (with dosages of 0.04-0.4 mg/kg) revealed significant effects of moxonidine only at the highest doses. Slight disturbances of electrolyte balance (decrease of blood sodium and increase of potassium, urea and creatinine) were found in the high dose rats and emesis and salivation only for the high dose dogs. In addition slight increases of liver weight were obvious for both high dose species.
Reproductive toxicity studies showed no effect on fertility and no teratogenic potential. Embryo-fetal toxicity was seen at doses associated with maternal toxicity.
Increased embryo-fetal loss and delayed fetal development were seen in rats with doses above 2 mg/kg/day and in rabbits with doses above 0.7 mg/kg/day. In a peri- and post natal study in rats reduced pup weight, viability and delayed development was noted with doses above 1 mg/kg/day.
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