The introduction of the selective imidazoline receptor agonist moxonidine represents a new approach to the pharmacological management of essential hypertension. Moxonidine is approved for the treatment of essential hypertension in various European countries (Austria, Croatia, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Lithuania, Luxembourg, the Netherlands, Norway, the Russian Federation, Poland, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, Ukraine, U.K.), as well as Egypt, Indonesia, the Philippines, and South Africa.
THE SYMPATHETIC NERVOUS SYSTEM AND CARDIOVASCULAR DISEASE
The sympathetic nervous system (SNS) has re-emerged in recent years as an important factor in the pathogenesis of hypertension and cardiovascular diseases such as arrhythmias, congestive heart failure and coronary heart disease. Some current theories on the pathogenesis of hypertension depict increased activity of the SNS as a response to environmental factors encountered in modern living, including high calorie intake and alcohol consumption, obesity, physical inactivity and psychological stress (1). Increased sympathetic activity is thought to lead to increased blood pressure and to metabolic abnormalities that increase the risk of atherosclerotic disease (2,3).
Several groups of investigators have reported the SNS to be increased in a majority of patients with high blood pressure (4-6). Furthermore, patients with evidence of increased SNS activity seem to have greater blood pressure variability (7). Increased blood pressure variability is associated with greater damage to vulnerable organs such as the brain, heart and kidneys. These data suggest that reducing the activity of the sympathetic nervous activity is a desirable target in the management of high blood pressure.
In addition, there is evidence to suggest that increased sympathetic activity may be the common denominator of the clustering of cardiovascular risk factors, which often occurs in patients with high blood pressure. This phenomenon has been described as 'metabolic syndrome' by Reaven et al. (8-10) and in similar terms by other workers (11,12). These abnormalities include hyperinsulinaemia and glucose intolerance, dyslipoproteinaemia, increased haematocrit, and visceral or male-pattern obesity, all of which have been associated with increased risk for atherosclerotic vascular disease. Pathophysiologic mechanisms have been identified to explain how increased activity of the SNS can cause all these abnormalities (3,13).
Overactivity of the SNS may therefore participate in pathogenesis of hypertension and be central to all aspects of metabolic syndrome. Hypertension is only one factor influencing risk of coronary heart disease, and drugs that merely control hypertension may not eliminate the risk associated with factors such as hyperinsulinaemia and dyslipidaemia. Not surprisingly, therefore, the reduction in the risk for coronary artery diseases by diuretic-based therapy was much less than expected from the reduction in blood pressure (14). By contrast, a drug that diminishes sympathetic nervous activity may favourably affect all coronary risk factors. Moxonidine is such a drug.
OUTLINE DESCRIPTION OF MOXONIDINE
The pharmacology of moxonidine has been studied extensively (15-17). The drug is a selective imidazoline receptor agonist. Moxonidine stimulates imidazoline type 1 (I1) receptors in the cardiovascular regulatory centres of the medulla oblongata. Selective stimulation of I1 receptors inhibits central sympathetic activity, leading to a reduction in blood pressure, but avoids the unwanted side-effects (e.g. sedation and dry mouth) associated with the stimulation of α2-adrenoceptors (18). The selectivity of moxonidine for I1 receptors therefore combines blood pressure lowering efficacy with a good clinical tolerability profile.
Moxonidine has predictable, well defined clinical pharmacokinetics characterized by rapid and almost complete absorption after oral administration (19). Bioavailability in man is approximately 88%, indicating little or no first-pass hepatic metabolism; absorption is not affected by food. Moxonidine has a plasma half-life of 2.5 h and undergoes predominantly renal excretion, with 60-80% of an oral dose eliminated unchanged in the urine. Only 5-10% of an orally administered dose is converted to metabolites that have little pharmacological activity. No clinically meaningful variations in pharmacokinetics have been identified in patients of different age or sex. Moxonidine may be used in patients with impaired renal function, with attention to dose titration (20), and appears to have little potential for drug-drug interactions (21).
The usual therapeutic dose of moxonidine in essential hypertension is 0.2-0.4 mg, taken either once or twice daily. Systolic and diastolic trough:peak ratios for moxonidine (n = 34) are 0.70 and 0.72, respectively, indicating that the drug can provide satisfactory 24 h control of blood pressure from a single daily dose (22). The blood pressure lowering efficacy of moxonidine is consistent and dependable in men and women of all ages. The principal haemodynamic effect of moxonidine is mediated via a sustained reduction in systemic vascular resistance (23). Cardiac output is maintained and cardiovascular reflexes are not compromised. Preliminary data indicate that the drug has potentially advantageous effects on left ventricular hypertrophy (24) and improves coronary blood flow (25).
MOXONIDINE IN ESSENTIAL HYPERTENSION
Moxonidine has been evaluated in 30 controlled trials involving some 3400 patients since 1983. Moxonidine has been shown to have antihypertensive efficacy at least comparable to established agents, and to be suitable for use either as initial monotherapy or as one element in combination regimens. The blood pressure lowering effect of moxonidine has been shown to be sustained in long-term use (26).
Moxonidine versus angiotensin converting enzyme-inhibitor
The blood pressure lowering effect of moxonidine (0.2-0.4 mg once daily) was comparable to that of enalapril (5-10 mg once daily) in an 8-week placebo-controlled study in 140 adult patients with mild or moderate hypertension (22). The reduction in sitting diastolic blood pressure (DBP) with moxonidine was comparable to that obtained with enalapril, and was consistently greater than that seen with placebo.
The efficacy of moxonidine (0.2 or 0.4 mg/day for 8 weeks) was also reported to be comparable to enalapril (10 or 20 mg/day for 8 weeks) in a study conducted in 41 hypertensive patients with a baseline DBP of 95-115 mmHg (27). Moxonidine has also been shown to compare favourably with captopril (28,29).
Moxonidine versus beta-blocker
Moxonidine (0.2-0.4 mg once daily) displayed antihypertensive efficacy comparable to that of atenolol (50-100 mg once daily) in an 8-week randomized, double-blind trial in 63 hypertensive patients with a baseline sitting DBP of 95-114 mmHg (30). Moxonidine reduced mean sitting blood pressure from 166 ± 10/100 ± 5 to 149 ± 21/90 ± 9 mmHg, compared with a reduction from 169 ± 11/101 ± 6 to 149 ± 21/87 ± 8 mmHg with atenolol (difference not statistically significant).
Moxonidine versus calcium antagonist
Wolf reported that the blood pressure lowering efficacy of moxonidine was comparable to sustained-release nifedipine in a 26-week, multicentre, parallel-group study in 229 patients with mild or moderate hypertension (31). Treatment was initiated with 0.2 mg moxonidine once daily or 20 mg nifedipine once daily. These doses were doubled by switching to twice-daily dosing if DBP remained greater than 90 mmHg after 4 weeks. A satisfactory response to therapy (defined as DBP ≤90 mmHg or a reduction in DBP of >10 mmHg) was achieved in 81.5% of patients treated with moxonidine and in 90.7% of patients assigned to nifedipine at the conclusion of the study (difference not statistically significant).
Moxonidine versus diuretic
Once-daily moxonidine exhibited antihypertensive efficacy comparable to that of hydrochlorothiazide (HCTZ) in an 8-week, randomized, double-blind, placebo-controlled, multicentre study (32). The mean blood pressure reduction achieved after 8 weeks of treatment with moxonidine was 20 ± 20/19 ± 9 mmHg, compared with 22 ± 21/13 ± 8 mmHg with HCTZ. In both groups, 70% of patients achieved a DBP of less than 90 mmHg or a reduction in DBP of at least 10 mmHg.
Moxonidine in combination regimens
An additive antihypertensive effect of moxonidine plus HCTZ has been reported by Frei et al. (32). More recent data acquired in a U.K. study indicate that a combination of moxonidine plus a calcium antagonist or ACE-inhibitor is also effective in hypertension therapy (33). These observations are important in light of the recent report from the Hypertension Optimal Treatment study, indicating that up to 72% patients may require combination therapy to achieve satisfactory control of blood pressure (34).
TOLERABILITY OF MOXONIDINE
Moxonidine has been generally well tolerated in clinical trials (22,26-33,35). The incidence of clinical adverse events has been relatively low; severe events have been uncommon, and their association with moxonidine use has been judged to be weak or nonexistent. No evidence has emerged of any potentially deleterious effects on blood-lipid fractions, glucose metabolism or uric acid. No consistent or clinically pertinent adverse impacts of moxonidine on the severity or course of concomitant diseases have been reported in clinical studies of moxonidine. The adverse event profile of moxonidine has recently been reviewed in detail (36).
Clinical experience indicates that moxonidine is an efficacious and well tolerated drug comparable, and sometimes superior, to established antihypertensive medications such as ACE-inhibitors, diuretics, β-blockers and calcium antagonists. Moxonidine has a good clinical tolerability profile, which may be attributed to its selectivity for I1-imidazoline receptors. This good tolerability, combined with its lack of untoward effects on concomitant diseases, and suitability for use either as first-line therapy or in combination, suggests that this new agent will be acceptable and appropriate for a wide range of patients with hypertension.
Recent reports encourage the belief that the specific mode of action of moxonidine in reducing sympathetic activity may prove especially beneficial in hypertensive patients who have increased sympathetic tone. Microneurography studies have demonstrated that moxonidine reduces muscle sympathetic nerve activity in patients with hypertension (37). Moreover, there are indications that moxonidine has potentially favourable effects on glucose and insulin metabolism (38,39). All these observations suggest that moxonidine may offer advantages over antihypertensive drugs that only lower blood pressure, notably in the area of coronary risk reduction. This attractive possibility should be properly evaluated in a prospective morbidity and mortality study. In view of the fact that the doxazosin arm of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) recently was discontinued because doxazosin, despite its favourable effect on the metabolic syndrome, failed to reduce cardiovascular events when compared to diuretic therapy, morbidity and mortality data become increasingly important (40).
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