Pharmacotherapeutic group: Imidazoline receptor agonists, moxonidine. ATC Code: C02AC05.
Pharmacology: Pharmacodynamics: In different animal models, moxonidine has been shown to be a potent antihypertensive agent. Available experimental data suggests that the site of the antihypertensive action of moxonidine is the central nervous system (CNS). Within the brainstem, moxonidine has been shown to selectively stimulate 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. Stimulation of the imidazoline receptors appears to reduce sympathetic activity and lower blood pressure.
Moxonidine distinguishes itself from other sympatholytic antihypertensives by exhibiting only low affinity for known α2-adrenoceptors, as compared to imidazoline receptors. This low affinity to α2-adrenoceptors may account for a low incidence of sedation and dry mouth with moxonidine.
In humans, moxonidine leads to a reduction of systemic vascular resistance and consequently arterial blood pressure. The antihypertensive effect of moxonidine has been demonstrated in double-blind, placebo controlled, randomized studies. Published data show that in hypertensive patients with left ventricular hypertrophy (LVH), for the same blood pressure reduction, the use of an Angiotensin II Antagonist (AIIA) together with moxonidine achieved an improved LVH regression compared to a free combination of a thiazide and a Calcium channel blocker.
In a therapeutic trial of two months' duration, moxonidine improved the insulin sensitivity index by 21% (decreased symptoms related to insulin resistant diabetes) in comparison to placebo in obese and insulin resistant patients with moderate hypertension.
Pharmacokinetics: Absorption: After oral administration of Physiotens, the moxonidine component is rapidly (tmax around 1 h) and almost completely absorbed from the upper gastrointestinal tract. The absolute bioavailability (amount of drug that reaches the blood stream unchanged) is about 88%, indicating no significant first-pass (liver) metabolism. Food intake has no influence on the pharmacokinetics of moxonidine.
Distribution: Plasma protein binding, as determined in vitro, was about 7.2%.
Biotransformation: In pooled human plasma samples, only dehydrogenated moxonidine was identified. The pharmacodynamic activity of dehydrogenated moxonidine is about 1/10 compared to moxonidine.
Elimination: Over a 24-hour period, 78% of the total dose was excreted in urine as parent moxonidine and 13% of the dose was excreted as dehydrogenated moxonidine. Other minor metabolites in urine accounted for approximately 8% of the dose. Less than 1% is eliminated via the faeces. The elimination half-lives of moxonidine and its metabolite are approximately 2.5 h and 5 h, respectively.
Pharmacokinetics in Hypertensive Patients: In hypertensive patients, no relevant pharmacokinetic changes were observed compared to healthy volunteers.
Pharmacokinetics in the Elderly: Age-related changes in pharmacokinetics have been observed and are most likely due to a reduced metabolic activity and/or slightly higher bioavailability (better absorption into the blood stream) in the elderly. However, these pharmacokinetic differences are not considered to be clinically relevant.
Pharmacokinetics in Children: As Physiotens is not recommended for use in children, no pharmacokinetic studies have been performed in this subpopulation.
Pharmacokinetics in Renal Impairment: Elimination of moxonidine is significantly correlated with creatinine clearance. In patients with moderate renal impairment (GFR 30-60 ml/min) steady-state plasma concentrations and terminal half-life are approximately 2 fold and 1.5 fold higher, respectively, compared to hypertensive patients with normal renal function (GFR > 90 ml/min). In patients with severe renal impairment (GFR < 30 ml/min) steady state plasma concentrations and terminal half-life are approximately 3-fold higher. No unexpected drug accumulation after multiple dosing was observed in these patients. In end-stage renal patients (GFR < 10 ml/min) undergoing hemodialysis the AUC (0.2 mg)/plasma concentrations (0.4 mg)and terminal half-lives are 6 fold and 4 fold higher, respectively, compared to hypertensive patients with normal renal function (0.2 mg). In patients with moderate renal impairment (0.2 mg)/in all groups (0.4 mg) maximum moxonidine plasma concentrations are only 1.5-2 fold higher.
In renally impaired patients, the dosage and frequency of dosage should be titrated (0.2 mg)/adjusted (0.4 mg) according to the individual's requirements.
Moxonidine is eliminated to a small extent by hemodialysis.
Toxicology: Preclinical safety data: 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.
Studies in animals have shown embryo-toxicity effects with maternal-toxicity doses.
Studies on reproduction toxicity showed no effect on fertility and no teratogen potential.
Embryotoxicological effects were seen in rat with doses at and above 9 mg/kg/day and in rabbit with doses above 0.7 mg/kg/day. In a peri- and post-natal study on rat influence on development and vitality was noted with doses at and above 3 mg/kg/day.