Journal of Pharmacy And Bioallied Sciences
Journal of Pharmacy And Bioallied Sciences Login  | Users Online: 1638  Print this pageEmail this pageSmall font sizeDefault font sizeIncrease font size 
    Home | About us | Editorial board | Search | Ahead of print | Current Issue | Past Issues | Instructions | Online submission




 
 Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 5  |  Issue : 4  |  Page : 253-256  

Effects of moxonidine on sympathetic nervous system activity: An update on metabolism, cardio, and other target-organ protection


1 Department of Internal Medicine, AHEPA Hospital, Thessaloniki, Greece
2 Department of Internal Medicine-Propaedeutic, Gastroenterology Division, Laikon General Hospital, University of Athens, Athens, Greece
3 Department of Biochemistry, Medical School, Aristotles University of Thessaloniki, Thessaloniki, Greece

Date of Submission09-Oct-2012
Date of Decision23-Dec-2012
Date of Acceptance10-Jun-2013
Date of Web Publication19-Oct-2013

Correspondence Address:
Christos G Savopoulos
Department of Internal Medicine, AHEPA Hospital, Thessaloniki
Greece
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-7406.120067

Rights and Permissions
   Abstract 

Moxonidine is the newest, second-generation, centrally acting antihypertensive agent. It has selective agonist activity at imidazoline I1 receptors and less adverse effects than the other centrally acting drugs. This fact authorizes the frequent use of moxonidine in clinical practice, as monotherapy or in combination with other antihypertensive agents. Also, moxonidine has beneficial effects in obese and metabolic syndrome and in target-organs, such as heart and kidneys.

Keywords: Moxonidine, organ protection, sympathetic nervous system


How to cite this article:
Karlafti EF, Hatzitolios AI, Karlaftis AF, Baltatzi MS, Koliakos GG, Savopoulos CG. Effects of moxonidine on sympathetic nervous system activity: An update on metabolism, cardio, and other target-organ protection. J Pharm Bioall Sci 2013;5:253-6

How to cite this URL:
Karlafti EF, Hatzitolios AI, Karlaftis AF, Baltatzi MS, Koliakos GG, Savopoulos CG. Effects of moxonidine on sympathetic nervous system activity: An update on metabolism, cardio, and other target-organ protection. J Pharm Bioall Sci [serial online] 2013 [cited 2020 Jul 15];5:253-6. Available from: http://www.jpbsonline.org/text.asp?2013/5/4/253/120067

Moxonidine is a second-generation centrally acting antihypertensive drug [Figure 1]. [1] It has selective agonist activity at imidazoline I 1 receptors and only minor activity at imidazoline α-2 adrenoceptors. [2] Moxonidine reduce the activity of the sympathetic nervous system (SNS), because activates I 1 imidazoline receptors in the rostal ventrolateral medulla (RVLM). [3] The result is the inhibition of peripheral alpha-adrenergic tone, and the decrease of blood pressure, due to a fall in systemic vascular resistant. [4] Moxinidine is used in patients with mild to moderate hypertension, as monotheraphy, or in combination with other antihypertensive agents. [2],[5],[6] A plenty of studies demonstrate that moxonidine acts on heart, a target-organ. This effect is achieved through the activation of cardiac I 1 imidazoline receptors. [7] Through this mechanism, moxonidine produces clinically relevant sympatholysis, with beneficial effects on hemodynamics, coronary circulation, and neurohumoral parameters. [8] Also, studies indicated that moxonidine has antiarrhythmic reaction, [9] suppresses the activation of myocardial infarction, and reacts on postmyocardial infarction remodeling. [10]
Figure 1: Chemical structure of moxonidine

Click here to view


Additional, moxonidine attenuates sympathetic tone [11] and improves the hemodynamic profile in patients with congestive heart failure. [12]

Also, moxonidine acts on other target-organs, like kidney and eye and on metabolism, with neutral or favorable effect on lipid parameters, improvement of insulin resistance in obese, and reduction of catecholamines. This may be due to the fact that moxonidine lowers leptin plasma levels and reduces weight in obese patients, through its action on SNS. [13]

Influence of moxonidine on target-organ protection and metabolism

During the last few years, a great number of studies involving moxonidine have been published. Most of them involve obesity, insulin resistance, and metabolic syndrome. Moxonidine reduces blood pressure in patients with metabolic syndrome while simultaneously reducing body weight in obese patients, as it has been showed in the postmarketing surveillance study CAMUS. [14] Also, Chazova et al., [15] showed through a multicenter, prospective, randomized, open-label study that moxonidine improves insulin sensitivity in response to glucose challenge in patients with evidence of metabolic syndrome. This is the result of the reduction in plasma insulin levels. Moreover, several research groups independently found an improvement of insulin sensitivity in animals models too (mainly Zucker rats). [16]

Sanjuliani et al., [17] showed that after 24 weeks of moxonidine treatment, plasma arterial adrenaline and noradrenaline were significantly reduced. This fact confirms the decrease of plasma catecholamines and, moreover, proves the action of the drug in conditions of sympathetic overactivity.

A double-blind, placebo-controlled crossover study demonstrate that moxonidine reduces exercise and mental stress-induced SNS activation and seems to be considered as an alternative to b-adrenoceptor blockers-in combination therapy-, when patients bothered by the exercise limitations of b-adrenoceptor blockers. [18] This antihypertensive agent lowers intraocular pressure, suggesting a possible benefit in glaucoma. [1]

The study of Krespi et al., [19] suggests that in hypertensive patients with microalbuminuria, moxonidine reduces urine albumin excretion, thrombomodulin, and Plasminogen activator inhibitor-1 (PAI-1) levels. These results demonstrate an effect on renal function and endothelial homeostatic mechanisms. Also, a 3-year trial showed that treatment with standard antihypertensive therapy and adjunctive moxonidine in patients with advanced renal failure was predicted to reduce the number of new end-stage renal disease cases compared to adjunctive nitrendipine. The model showed that adjunctive moxonidine seems to increase life-years lived. [20]

Furthermore, moxonidine is used in the treatment of obese patients with metabolic syndrome, because this antihypertensive agent reduces leptin levels in plasma and reduces weight in obese patients, through the action of the SNS. [13]

Effects of imidazoline receptor activation by moxonidine in heart function

A lot epidemiological studies have shown that increased activity of SNS leads to an increase in cardiovascular morbidity and mortality. Considering that moxonidine decrease the SNS activity, it is safe to administrate that the drug has a place in cardiovascular protection and reversal of metabolic disorders due to SNS overactivity. [21]

Moxonidine is a selective imidazoline receptor (I 1 ) agonist with central antihypertensive effects. [1] Imidazoline I 1 receptors have been localized in the brainstem RVLM, and in peripherical nervous system, including heart-mainly in cardiac atria. [22] The atria are the primary site of atrial natriuretic peptide (ANP) production. The ANP is involved in blood pressure reduction and volume regulation. [23] The chronic hypotensive effect of ANP is mediated by attenuation of cardiovascular sympathetic tone. [24] Moxonidine can stimulate ANP release from heart. [25] The increase in ANP may be explained in part by moxonidine SNS inhibition in heart. [22]

A study, in spontaneously hypertensive rats, demonstrates that cardiac I 1 receptors are upregulated and normalized by chronic antihypertensive treatment with moxonidine. [26]

Also, an other study contends the acute hemodynamic effects of moxonidine. These are the reduction in right atrial pressure, pulmonary artery pressure, and cardiac index. [27]

Additional, moxonidine seems to attenuate tachyarrhythmias [28] and increase left ventricular ejection fraction, in patients with chronic heart failure. [29] Also, moxonidine pretreatment provides a beneficial effect, during reperfusion-induced arrhythmias that appear after a brief period of myocardial ischemia. [30]

Regarding moxonidine and heart, there are studies that support the chronic therapy with this agent, in patients with chronic heart failure. [28] Chronic heart failure is associated with activation of SNS and the degree of this stimulation appears to be a marker for both the severity of the syndrome and the risk of death. [31],[32],[33]

On the contrary, the MOXCON study (MOXonidine CONgestive Heart Failure) demonstrates that the use of moxonidine in patients with advanced heart failure was associated with an early increase in morbidity and mortality in a large cohort of New York Heart Association classes II-IV patient. [34]

The use of moxonidine nowadays

Nowadays, according to the guidelines of ESH-ECS (European Society of Hypertension/European Society of Cardiology), moxonidine, as all centrally acting agents, is not a first-choice agent in antihypertensive treatment. It is mainly used in combination with the other categories of antihypertensive agents. [35]

Also, overweight patients with metabolic syndrome are more likely to be on combination therapy. Despite good blood pressure response to moxonidine and more frequent use of combination therapy, less than 5% of diabetic patients achieve blood pressure target (<130/80 mm Hg). [14]

Furthermore, moxonidine should not be used as treatment in patients when glomerular filtration rate < 30 ml/min. [36]


   Conclusion Top


Moxonidine is the newest, second-generation, centrally acting antihypertensive agent. It is used in therapy of mild to moderate hypertension. Moxonidine has selective agonist activity at imidazoline I 1 receptors and less adverse effects than the other centrally acting drugs. This fact authorizes the frequent use of moxonidine in clinical practice, as monotherapy or in combination with other antihypertensive agents. Also, the beneficial effects of moxonidine in target-organs, such as heart, are very important [Table 1]. Although, a lot of studies have conjecture the role that moxonidine displays in pathophysiological mechanisms, more studies are required, in order to clarify this role.
Table 1: Effects of moxonidine on sympathetic nervous system, metabolism, and on target organs

Click here to view


 
   References Top

1.Ziegler D, Haxhiu MA, Kaan EC, Papp JG, Ernsberger P. Pharmacology of moxonidine, an I1-imidazoline receptor agonist. J Cardiovasc Pharmacol 1996;27 (Suppl 3):S26-37.  Back to cited text no. 1
    
2.Fenton C, Keating GM, Lyseng-Williamson KA. Moxonidine: A review of its use in essential hypertension. Drugs 2006;66:477-96.  Back to cited text no. 2
    
3.Prichard BN, Graham BR, Owens CW. Moxonidine: A new antiadrenergic antihypertensive agent. J Hypertens Suppl 1999;17:S41-54.  Back to cited text no. 3
    
4.Prichard BN, Graham BR. The use of moxonidine in the treatment of hypertension. J Hypertens Suppl 1997;15:S47-55.  Back to cited text no. 4
    
5.Prichard BN, Owens CV, Graham BR. Pharmacology and clinical use of moxonidine, anew centrally acting sympatholytic antihypertensive agent. J Hum Hypertens 1997;11 (Suppl 1):S29-45.  Back to cited text no. 5
    
6.Sica DA. Centrally acting antihypertensive agents: An update. J Clin Hypertens 2007;9:399-405.  Back to cited text no. 6
    
7.Cao Ch, Kang CW, Kim SZ, Kim SH. Augmentation of moxonidine-induced increase in ANP release by atrial hypertrophy. Am J Physiol Heart Circ Physiol 2004;287:H150-6.  Back to cited text no. 7
    
8.Mitrovic V, Hamel M, Miric M, Thormann J, Hamm C. Effect of the imidazoline receptor agonist moxonidine on hemodynamics, coronary circulation, metabolic ischemia markers and the neurohumoral system in patients with essential hypertention. Effects of moxonidine on coronary circulation. Z Kardiol 2001;90:953-63.  Back to cited text no. 8
    
9.Poisson D, Christen MO, Sannajust F. Protective effects of I (1)-antihypertensive agent moxonidine against neurogenic cardiac arrhythmias in halothane-anesthetized rabbits. J Pharmacol Exp Ther 2000;293:929-38.  Back to cited text no. 9
    
10.Van Kerckhoven R, van Veen TA, Boomsma F, Saxana PR, Schoemaker RG. Chronic administration of moxonidine suppresses sympathetic activation in a rat heart failure model. Eur J Pharmacol 2000;397:113-20.  Back to cited text no. 10
    
11.Swedberg K, Bergh CH, Dickstein K, McNay J, Steinberg M. The effects of moxonidine, a novel imidazoline, on plasma norepinephrine in patients with congestive heart failure. J Am Coll Cardiol 2000;35:398-404.  Back to cited text no. 11
    
12.Dickstein K, Manhenke C, Aarsland T, Køpp U, McNay J, Wiltse C. Acute Hemodynamic and neurohumoral effects of moxonidine in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1999;83:1638-44.  Back to cited text no. 12
    
13.Karlafti E, Savopoulos CH, Baltatzi M, Hatzitolios Al. The position of central acting sympatholytic agents on Arterial hypertension therapy. Arterial Hypertens (Greek) 2010;19:32-43.  Back to cited text no. 13
    
14.Sharma AM, Wagner T, Marsalek P. Moxonidine in the treatment of overweight and obese patients with metabolic syndrome: A postmarketing surveillance study. J Hum Hypertens 2004;18:669-75.  Back to cited text no. 14
    
15.Chazova I, Almazov VA, Shlyakhto E. Moxonidine improves glycaemic control in mildly hypertensive, overweight patients: A comparison with metformin. Diabetes Obes Metab 2006;8:456-65.  Back to cited text no. 15
    
16.Keulen L, Henricksen EJ, Jacob S, Lang R. Antihypertensive treatment and cardiovascular risk management in patients with the Metabolic Syndrome-Focus on SNS and insulin resistance. J Clin Basic Cardiol 2001;3:193-5.  Back to cited text no. 16
    
17.Sanjuliani AF, Francischetti EA, Genelhu de Abreu V, Ueleres Braga J, et al. Effects of moxonidine on the Sympathetic Nervous System, Blood Pressure, Plasma Renin Activity, Plasma Aldosterone, Leptin, and Metabolic Profile in Obese Hypertensive Patients. J Clin Basic Cardiol 2004;7:19.  Back to cited text no. 17
    
18.Wenzel RR, Mitchell A, Siffert W, Bührmann S, Philipp T, Schäfers RF. The I 1 -imidazoline agonist moxonidine decreases sympathetic tone under physical and mental stress. Br J Clin Pharmacol 2004;57:545-51.  Back to cited text no. 18
    
19.Krespi PG, Makris TK, Hatzizaxarias AN, Triposkiadis P, Tsoukala C, Kyriaki D, et al. Moxonidine effect on microalbuminuria, thrombomodulin, and plasminogen activator inhibitor-1 levels in patients with essential hypertension. Cardiovasc Drugs Ther 1998;12:463-7.  Back to cited text no. 19
    
20.Littlewood KJ, Greiner W, Baum D, Zoellner Y. Adjunctive treatment with moxonidine versus nitrendipine for hypertensive patients with advanced renal failure: A cost-effectiveness analysis. BMC Nephrol 2007;8:9.  Back to cited text no. 20
    
21.Borchard U. The role of sympathetic nervous system in cardiovascular disease. J Clin Basic Cardiol 2001;4:175-7.  Back to cited text no. 21
    
22.Mukaddam-Daher S, Gutkowska J. Imidazoline receptors in the heart: A novel target and a novel mechanism of action that involves atrial natriuretic peptides. Braz J Med Res 2004;37:1239-45.  Back to cited text no. 22
    
23.Steinheiper ME, Cohrane KL, Field LJ. Hypotension in transgenic mice expressing atrial natriuretic factor fusion genes. Hypertension 1990;16:301-7.  Back to cited text no. 23
    
24.Melo LG, Veress AT, Ackermann U, Steinhelper ME, Pang SC, Tse Y, et al. Chronic regulation of arterial blood pressure in ANP transgenic and knockout mice: Role of cardiovascular sympathetic tone. Cardiovasc Res 1999;43:437-44.  Back to cited text no. 24
    
25.Mukaddam-Daher S, Menaouar A, Gutkowska J. Receptors involved in moxonidine-stimulated atrial natriuretic peptide release from isolated normotensive rat hearts. Eur J Pharmacol 2006;541:73-9.  Back to cited text no. 25
    
26.El-Ayoubi R, Menaouar A, Gutkowska J, Mukaddam-Daher S. Imidazoline receptors but not a2-adrenoceptors are regulated in spontaneously hypertensive rat heart by chronic moxonidine treatment. J Pharmacol Exp Ther 2004;310:446-51.  Back to cited text no. 26
    
27.Mobini R, Fu M, Jansson PA, Bergh CH, Scharin Täng M, Waagstein F, et al. Influence of central inhibition of sympathetic nervous activity on myocardial metabolism in chronic heart failure: Acute effects of the imidazoline I1 receptor agonist moxonidine. Clin Sci 2006;110:329-36.  Back to cited text no. 27
    
28.Dickstein K, Manhenke C, Aarsland T, McNay J, Wiltse C, Wright T. The effect of chronic, sustained-release moxonidine therapy on clinical and neurohumoral status in patients with heart failure. Int J Cardiol 2000;75:167-76.  Back to cited text no. 28
    
29.Swedberg K, Bristow MR, Cohn JN, Dargie H, Straub M, Wiltse C, et al. Effects of Substained-Release Moxonidine, an imidazoline Agonist, on plasma Norepinephrine in Patients with Chronic Heart failure. Circulation 2002;105:1797-803.  Back to cited text no. 29
    
30.Lepran I, Papp JG. Effect of moxonidine on arrhythmias induced by coronary artery occlusion and reperfusion. J Cardiovasc Pharmacol 1994;24:S9-15.  Back to cited text no. 30
    
31.Benedict CR, Francis GS, Shelton B, Johnstone DE, Kubo SH, Kirlin P, et al. Effect of long-term enalapril therapy on neurohormones in patients with left ventricular dysfunction. SOLVD Investigators. Am J Cardiol 1995;75:1151-7.  Back to cited text no. 31
    
32.Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819-23.  Back to cited text no. 32
    
33.Swedberg K, Eneroth P, Kiekshus J, Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation 1990;82:1730-6.  Back to cited text no. 33
    
34.Cohn JN, Pfeffer MA, Rouleau J, Sharpe N, Swedberg K, Straub M, et al. MOXCON Investigators. Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail 2003;5:659-67.  Back to cited text no. 34
    
35.Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. ESH-ESC Task Force on the Management of Arterial Hypertension. 2007 ESH-ESC practice guidelines for the management of arterial hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension. J Hypertens 2007;25:1751-62.  Back to cited text no. 35
    
36.Kirch W, Hutt HJ, Planitz V. The influence of renal function on clinical pharmacokinetics of moxonidine. Clin Pharmacokinet 1988;15:245-53.  Back to cited text no. 36
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]


This article has been cited by
1 Investigation of the vasorelaxant effects of moxonidine and its relaxation mechanism on the human radial artery when used as a coronary bypass graft
Bulent Sarac,Ozge Korkmaz,Ahmet Altun,Ihsan Bagcivan,Sabahattin Göksel,Sahin Yildirim,Ocal Berkan
Interactive CardioVascular and Thoracic Surgery. 2015; 21(3): 342
[Pubmed] | [DOI]



 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Conclusion
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed3129    
    Printed64    
    Emailed1    
    PDF Downloaded138    
    Comments [Add]    
    Cited by others 1    

Recommend this journal