, Volume 66, Issue 4, pp 477-496
Date: 17 Sep 2012

Moxonidine

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Summary

Abstract

Moxonidine (Physiotens®, Moxon®, Cynt®) is an orally administered imidazoline compound with selective agonist activity at imidazoline I1 receptors and only minor activity at α2-adrenoceptors. Moxonidine acts centrally to reduce peripheral sympathetic activity, thus decreasing peripheral vascular resistance. In patients with mild to moderate hypertension, moxonidine reduces blood pressure (BP) as effectively as most first-line antihypertensives when used as monotherapy and is also an effective adjunctive therapy in combination with other antihypertensive agents. It improves the metabolic profile in patients with hypertension and diabetes mellitus or impaired glucose tolerance, is well tolerated, has a low potential for drug interactions and may be administered once daily in most patients. Thus, moxonidine is a good option in the treatment of patients with mild to moderate hypertension, particularly as adjunctive therapy in patients with the metabolic syndrome.

Pharmacological Properties

Moxonidine is a centrally acting selective agonist at imidazoline I1 receptors, tor which it has an affinity >30-fold that for α2-adrenoceptors. Moxonidine inhibits peripheral sympathetic activity, which decreases peripheral vascular resistance and results in significant decreases in systolic and diastolic BP (SBP and DBP). Moxonidine has minimal effect on cardiac haemodynamics and reduces left ventricular mass. Markers of endothelial dysfunction and end-organ damage, including microalbuminuria, improved in hypertensive patients who achieved BP control with moxonidine. Moxonidine also improved the metabolic profile of patients with hypertension and type 2 diabetes or impaired glucose tolerance. Oral moxonidine is rapidly absorbed, although the maximum antihypertensive effect occurs 3–4 hours after administration.

Oral bioavailability is 88% and is unaffected by food. No first-pass metabolism occurs and moxonidine is mostly excreted unchanged in the urine.

Therapeutic Efficacy

In well designed, 8-week trials, monotherapy with moxonidine 0.2–0.6 mg/day reduced sitting DBP to a significantly greater extent than placebo (mean change from baseline −10.7 to −13.2 vs −2.3 to −9mm Hg) in patients with mild to moderate essential hypertension. Sitting SBP also improved from baseline to a significantly greater extent with moxonidine than with placebo (mean −19.5 to −24.9 vs −1.2 to −13mm Hg). Reductions in sitting SBP and DBP with moxonidine 0.2–0.8 mg/day at 8 weeks were similar to those with enalapril 5–20mg once daily, atenolol 50–100 mg/day (except in postmenopausal women where atenolol reduced BP to a greater extent than moxonidine), hydrochlorothiazide 25mg once daily and rilmenidine 1–2 mg/day. At 26 weeks, reductions in sitting SBP and DBP with moxonidine 0.2–0.4 mg/day were similar to those with nifedipine sustained release 20–40 mg/day.

Once-daily adjunctive moxonidine 0.4mg was also effective in patients with mild to moderate hypertension in well designed trials. In patients who did not respond to moxonidine monotherapy, mean improvements in sitting DBP at 4 weeks were −7.3mm Hg with moxonidine 0.4mg once daily plus amlodipine 5mg once daily, −4.8mm Hg with moxonidine 0.4mg once daily plus enalapril 10mg once daily and −3.2mm Hg with moxonidine 0.4mg once daily plus hydrochlorothiazide 12.5mg once daily. In another trial, changes in sitting SBP and DBP after 8 weeks’ treatment were significantly greater with once-daily moxonidine 0.4mg plus hydrochlorothiazide 25mg than with the respective monotherapies (−27 vs −20 and −22mm Hg and −16 vs −12 and −13mm Hg).

Tolerability

Moxonidine was generally well tolerated in clinical trials in patients with mild to moderate hypertension. In placebo-controlled monotherapy trials, 36–43% of moxonidine recipients experienced treatment-emergent adverse events versus 22–29% of placebo recipients and ≈32% and 35% of enalapril and hydrochlorothiazide recipients, respectively. Dry mouth was the most common adverse event with moxonidine monotherapy, affecting 11–20% of patients; other all-cause adverse events included diarrhoea, headache, bronchitis, nausea, dizziness and back pain. Other than dry mouth, asthenia and fatigue, adverse events in moxonidine monotherapy recipients were not generally related to α2-adrenoceptor inhibition. No new adverse events were reported in combination therapy trials.

Moxonidine was also well tolerated in a pooled analysis of postmarketing surveillance studies in 91 170 patients, about two-thirds of whom received moxonidine as monotherapy. Adverse events affected 9.4% of patients, causing 1.8% to discontinue treatment, and were generally not related to dosage, treatment duration, sex or age; dry mouth affected 4.2% of patients aged >65 years versus 2.7% of those aged <40 years.

Various sections of the manuscript reviewed by: Y. Ahmedani, Baqai Institute of Diabetes and Endocrinology, Baqai Medical University, Karachi, Pakistan; V.G. Athyros, Atherosclerosis and Metabolic Syndrome Units, Department of Internal Medicine, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece; A. Basit, Baqai Institute of Diabetes and Endocrinology, Baqai Medical University, Karachi, Pakistan; A. Fawwad, Baqai Institute of Diabetes and Endocrinology, Baqai Medical University, Karachi, Pakistan; M.M. Hoven, Department of General Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands; R. Padwal, Division of Internal Medicine, University of Alberta Hospital, Edmonton, Canada; B. Roca, Department of Medicine, General Hospital of Castellon, Castellon, Spain; A. Whaley-Connell, Department of Internal Medicine, Division of Nephrology, University of Missouri School of Medicine, Columbia, Missouri, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘moxonidine’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE search terms were ‘moxonidine’ and ‘hypertension’ or ‘antihypertensive’. EMBASE search terms were ‘moxonidine’ and ‘hypertension’. AdisBase search terms were ‘moxonidine’ and ‘hypertension’ or ‘antihypertensive’. Searches were last updated 22 February 2006.
Selection: Studies in patients with essential hypertension who received moxonidine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Moxonidine, hypertension, imidazoline I1 receptor, metabolic syndrome, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.