Moxonidine: A New and Versatile Antihypertensive : Journal of Cardiovascular Pharmacology

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Imidazolidine I1 Receptor Agonists and the Sympathetic Nervous System in Cardiovascular and Metabolic Diseases

Moxonidine: A New and Versatile Antihypertensive

Messerli, Franz

Editor(s): Mancia, Giuseppe; Esler, Murray

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Journal of Cardiovascular Pharmacology 35():p S53-S56,
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Abstract

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).

CONCLUSIONS

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).

REFERENCES

1. Pickering TG. The effects of environmental and lifestyle factors on blood pressure and the intermediary role of the sympathetic nervous system. J Hum Hypertens 1997;11(suppl 1):S9-18.
2. Rupp H, Jacob R. Excess catecholamines and the metabolic syndrome: should central imidazoline receptors be a therapeutic target? Med Hypotheses 1995;44:217-25.
3. Julius S, Gudbrandsson T. Early association of sympathetic overactivity, hypertension, insulin resistance, and coronary risk. J Cardiovasc Pharmacol 1992;20(suppl 8):S40-8.
4. Palatini P, Julius S. Association of tachycardia with morbidity and mortality: pathophysiological considerations. J Hum Hypertens 1997;11(suppl 1):S19-27.
5. Julius S, Pascual AV, London R. Role of parasympathetic inhibition in the hyperkinetic type of hypertension. Circulation 1981;64:760-4.
6. Anderson EA, Sinkey CA, Lawton WJ, Mark AJ. Elevated sympathetic nerve activity in borderline hypertensive humans. Hypertension 1989;14:177-83.
7. Mancia G, Di Rienzo M, Parati G, Grassi G. Sympathetic activity, blood pressure variability and end organ damage in hypertension. J Hum Hypertens 1997;11(suppl 1):S3-8.
8. Reaven GM. Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595-607.
9. Reaven GM. Syndrome X: 6 years later. J Intern Med 1994;236(suppl 736):13-32.
10. Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities-the role of insulin resistance and the sympathoadrenal system. N Engl J Med 1996;334:374-81.
11. Haffner SM, Fong A, Hazuda HP, Pugh JA, Patterson JK. Hyperinsulinaemia, upper body obesity, and cardiovascular risk factors. Metabolism 1988;37:338-45.
12. DeFronzo RA, Ferranini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia, and atherosclerotic vascular disease. Diabetes Care 1991;14:173-94.
13. Julius S, Gudbrandssen T, Jamerson K, et al. Hypothesis. The hemodynamic link between insulin resistance and hypertension. J Hypertens 1991;9:983-6.
14. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke and coronary heart disease. Part 2: short term reduction in blood pressure: overview of randomized drug trials in their epidemiological context. Lancet 1990;335:827-38.
15. Armah BI, Hofferber E, Stenzel W. General pharmacology of the novel centrally acting antihypertensive agent moxonidine. Arzneim Forsch 1988;38:1435-42.
16. Ernsberger P, Elliott HL, Weimann H-J, et al. Moxonidine: a second-generation antihypertensive agent. Cardiovasc Drug Res 1993;1:411-31.
17. Haxhiu MA, Dreshaj I, Schäfer SG, Ernsberger P. Selective antihypertensive action of moxonidine is mediated mainly by I1-imidazoline receptors in the rostral ventrolateral medulla. J Cardiovasc Pharmacol 1994;24(suppl 1):S1-8.
18. Van Zwieten PA. Centrally acting antihypertensives: a renaissance of interest. Mechanisms and haemodynamics. J Hypertens 1997;15(suppl 1):S3-8.
19. Weimann H-J, Rudolph M. Clinical pharmacokinetics of moxonidine. J Cardiovasc Pharmacol 1992;20(suppl 4):S37-41.
20. Kirch W, Hutt H-J, Plänitz V. Pharmacodynamic action and pharmacokinetics of moxonidine after single oral administration in hypertensive patients. J Clin Pharmacol 1990;30:1088-95.
21. Schaefer HG, Toublanc N, Weimann H-J. The pharmacokinetics of moxonidine. Rev Contemp Pharmacol 1998;9:481-90.
22. Küppers H, Jäger B, Hughes PR, et al. Placebo-controlled comparison of the efficacy and tolerability of once-daily moxonidine and enalapril in mild to moderate essential hypertension. J Hypertens 1997;15:93-7.
23. Mitrovic V, Patyna W, Hüting J, Schlepper W. Haemodynamic and neurohormonal effects of moxonidine in patients with essential hypertension. Cardiovasc Drugs Ther 1991;5:967-72.
24. Eichstädt H, Richter W, Bäder M, et al. Demonstration of hypertrophy regression with magnetic resonance tomography under the new adrenergic inhibitor moxonidine. Cardiovasc Drugs Ther 1989;3(suppl 2):583-7.
25. Motz W, Vogt M, Scheler S, Strauer BE. Hypertensive coronary microcirculation-effects of the imidazoline-receptor-agonist moxonidine. Cardiovasc Risk Factors 1995;5(suppl 1):28-32.
26. Trieb G, Jäger B, Hughes PR, et al. Long-term evaluation of the antihypertensive efficacy and tolerability of the orally-acting imidazoline I1 receptor agonist moxonidine in patients with mild to moderate essential hypertension. Eur J Clin Res 1995;7:227-40.
27. Schäfers RF, Löw-Kröger A, Philipp T. Wirksamkeit und Verträgichkeit des neuen zentralwirksamen antihypertensivums moxonidin im vergleich zu enalapril. Nieren Hochdruck 1994;23:221-4.
28. Lotti G, Gianrossi R. Moxonidin vs. Captopril bei leicher bis mittelschwerer hypertonie. Doppelblindstudie zur wirksamkeit und verträglichkeit [in German]. Fortschr Med 1993;111:429-32.
29. Kraft K, Vetter H. 24-Hour blood pressure profiles in patients with mild-to-moderate hypertension: moxonidine versus captopril. J Cardiovasc Pharmacol 1994;24(suppl 1):S29-35.
30. Prichard BNC, Simmons R, Rooks J, et al. A double-blind comparison of moxonidine and atenolol in the management of patients with mild to moderate hypertension. J Cardiovasc Pharmacol 1992;20(suppl 4):S45-9.
31. Wolf R. The treatment of hypertensive patients with a calcium antagonist or moxonidine: a comparison. J Cardiovasc Pharmacol 1992;20(suppl 4):S42-4.
32. Frei M, Kuster L, Gardosch von Krosigk P-P, et al. Moxonidine and hydrochlorothiazide in combination: a synergistic antihypertensive effect. J Cardiovasc Pharmacol 1994;24(suppl 1):S25-8.
33. Waters J, Ashford J, Wonnacott S, Verboom CN, for the TOPIC Investigators. Use of moxonidine as initial therapy and in combination in the treatment of essential hypertension. Results of the TOPIC (Trial Of Physiotens In Combination) Study. J Hum Hypertens 2000; in press.
34. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755-62.
35. Wenzel RR, Spicker L, Qui S, et al. I1-imidazoline agonist moxonidine decreases sympathetic nerve activity and blood pressure in hypertensives. Hypertension 1998;32:1022-7.
36. Webster J, Koch H-F. Aspects of tolerability of centrally acting antihypertensive drugs. J Cardiovasc Pharmacol 1996;27(suppl 3):S49-54.
37. Schachter M, Luszick J, Jäger B, et al. Safety and tolerability of moxonidine in the treatment of hypertension. Drug Safety 1998;19:191-203.
38. Kaan EC, Brückner R, Frohly P, et al. Effects of agmatine and moxonidine on glucose metabolism: an integrated approach to pathophysiological mechanisms in cardiovascular metabolic disorders. Cardiovasc Risk Factors 1995;5(suppl 1):19-27.
39. Lithell H. Oral presentation. XVIIII Congress European Society of Cardiology. Stockholm, Sweden, 29 August 1997.
40. Messerli FH. Implications of discontinuation of doxazosin arm of ALLHAT. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Lancet 2000355:863-864.

Section Description

Proceedings of a Satellite Symposium to the 20th Congress of the European Society of Cardiology; Vienna, Austria; August 25, 1998

Copies of this supplement were made possible by an educational grant from Solvay Pharmaceuticals and Eli Lilly & Company

Keywords:

Imidazoline receptor; Moxonidine; Essential hypertension; Antihypertensive therapy; Sympathetic nervous system; Metabolic syndrome; Insulin resistance

© 2000 Lippincott Williams & Wilkins, Inc.