Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Mylan Products Ltd, 20 Station Close, Potters Bar, Herts, EN6 1TL, UK
Pharmacotherapeutic group: Imidazoline receptor agonists, moxonidine
ATC code: C02AC05
In different animal models, Physiotens has been shown to be a potent antihypertensive agent. Available experimental data convincingly suggest that the site of the antihypertensive action of Physiotens is the central nervous system (CNS). Within the brainstem, Physiotens has been shown to selectively interact with I1-imidazoline receptors. These imidazoline-sensitive receptors are concentrated in the rostral ventrolateral medulla, an area critical to the central control of the peripheral sympathetic nervous system. The net effect of this interaction with the I1-imidazoline receptor appears to result in a reduced activity of sympathetic nerves (demonstrated for cardiac, splanchnic and renal sympathetic nerves).
Physiotens differs from other available centrally acting antihypertensives by exhibiting only low affinity to central α2-adrenoceptors as compared to I1-imidazoline receptors; α2-adrenoceptors are considered the molecular target via which sedation and dry mouth, the most common undesired side effects of centrally acting antihypertensives, are mediated.
In humans, Physiotens leads to a reduction of systemic vascular resistance and consequently in arterial blood pressure.
Oral moxonidine treatment of rats and dogs resulted in rapid and almost complete absorption and peak plasma levels within <0.5 hours. Average plasma concentrations were comparable in both species after p.o. and i.v. administration. The elimination half-lives of radioactivity and unchanged compound were estimated to be 1-3 hours. Moxonidine and its two main metabolites (4,5-dehydromoxonidine and a guanidine derivative) was predominantly excreted in the urine. No indication of moxonidine cumulation was observed in either species during chronic toxicity studies after 52 weeks.
In humans, about 90% of an oral dose of moxonidine is absorbed; it is not subject to first-pass metabolism and its bio-availability is 88%. Food intake does not interfere with moxonidine pharmacokinetics. Moxonidine is 10-20% metabolised, mainly to 4,5-dehydromoxonidine and to a guanidine derivative by opening of the imidazoline ring. The hypotensive effect of 4,5-dehydromoxonidine is only 1/10, and that of the guanidine derivative is less than 1/100 of that of moxonidine. The maximum plasma levels of moxonidine are reached 30-180 minutes after the intake of a film-coated tablet.
Only about 7% of moxonidine is bound to plasma protein (Vdss=1.8 ± 0.4 l/kg). Moxonidine and its metabolites are eliminated almost entirely via the kidneys. More than 90% of the dose is eliminated via the kidneys in the first 24 hours after administration, while only about 1% is eliminated via the faeces. The cumulative renal excretion of unchanged moxonidine is about 50-75%.
The mean plasma elimination half-life of moxonidine is 2.2-2.3 hours, and the renal elimination half-life is 2.6-2.8 hours.
Small differences between the pharmacokinetic properties of moxonidine in the healthy elderly and younger adults are unlikely to be clinically significant. As there is no accumulation of moxonidine, dosage adjustment is unnecessary provided renal function is normal.
No pharmacokinetic studies have been performed in children.
In moderately impaired renal function (GFR 30-60 ml/min), AUC increased by 85% and clearance decreased to 52%. In such patients the hypotensive effect of Physiotens should be closely monitored, especially at the start of treatment; additionally, single doses should not exceed 200 micrograms and the daily dose should not exceed 400 micrograms.
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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