MOXONIDINE ® ® A review of moxonidine in essential hypertension, with emphasis on metabolic syndrome and other conditions associated with sympathetic overactivity.

MOXONIDINE A review of moxonidine in essential hypertension, with emphasis on metabolic syndrome and other conditions associated with sympathetic overactivity © 2005 Solvay Pharmaceuticals GmbH ® registered trademark Date of preparation: December 2005 Material Code:

Summary of Product Characteristics before prescribing moxonidine
Please see Summary of Product Characteristics before prescribing moxonidine Details of formulations and dosage recommendations may vary between countries Trade names include: Physiotens®, Cynt®, Fisiotens®, Moxon®, Norcynt® and Normatens® References cited in this slide set are numbered to correspond with those in the companion moxonidine e-monograph

They may all reflect varying degrees of sympathetic overactivity1
Metabolic syndrome Elevated blood pressure is often associated with obesity, insulin resistance and dyslipidaemia Clustering of these symptoms has given rise to the concept of the ‘metabolic syndrome’ (with high risk of diabetes and CVD) Hypertension is an important cause of mortality and morbidity. It is now widely recognised that elevated blood pressure is frequently associated with obesity, insulin resistance and dyslipidaemia. The clustering of these symptoms has given rise to the concept of the ‘metabolic syndrome’, which carries a high risk of diabetes and cardiovascular disease. One of the explanations for the association between raised blood pressure and co-morbidities of the metabolic syndrome is that they all reflect varying degrees of sympathetic overactivity.[1] Ref 1. Rahn KH et al. J Hypertens 1999;17(suppl 3):S11-S14 They may all reflect varying degrees of sympathetic overactivity1 1. Rahn KH et al. J Hypertens 1999;17(suppl 3):S11-S14

Sympathetic overactivity
Sympathetic overactivity may be a central feature linking hypertension with other components of the metabolic syndrome Sympathetic overactivity may be a central feature linking hypertension with other components of the metabolic syndrome.

Link with hypertension
In animal models, sympathetic overactivity can initiate and maintain elevated blood pressure2 In humans, plasma norepinephrine levels in hypertensive patients are significantly higher than in normotensive controls (p<0.05)3 Sympathetic activation is seen in early phases of hypertension and may precede blood pressure elevation in some patients4 It has been demonstrated in several animal models of hypertension that sympathetic overactivity can initiate and maintain elevated blood pressure.[2] In humans, a meta-analysis of a large number of studies showed that plasma norepinephrine levels in hypertensive patients were significantly higher than in normotensive controls (p<0.05).[3] Sympathetic activation has been repeatedly documented in early phases of hypertension and may precede actual blood pressure elevation in some patients.[4] Refs 2. Mancia G et al. J Hum Hypertens 1997;11(suppl 1):S3-S8 3. Goldstein DS. Hypertension 1981;3:48-52 4. Julius S, Valentini M. Blood Press 1998;7(suppl 3):5-13 2. Mancia G et al. J Hum Hypertens 1997;11(suppl 1):S3-S8., 3. Goldstein DS. Hypertension 1981;3:48-52., 4. Julius S, Valentini M. Blood Press 1998;7(suppl 3):5-13

Link with hypertension
Sympathetic activity can be high in young subjects with borderline hypertension This suggests that increased sympathetic activity is the cause, rather than the consequence, of blood pressure elevation1 The observation that sympathetic activity can be high in young subjects with borderline hypertension supports the idea that increased sympathetic activity is the cause rather than the consequence of blood pressure elevation.[1] Ref 1. Rahn KH et al. J Hypertens 1999;17(suppl 3):S11-S14 1. Rahn KH et al. J Hypertens 1999;17(suppl 3):S11-S14

Link with obesity Raised BMI is associated with an increased rate of sympathetic nerve discharge in skeletal muscle5 There is a correlation between BMI, body fat distribution and urinary norepinephrine excretion6 Overactivity of the sympathetic nervous system appears to be a pivotal factor in several coronary risk factors. For example, an increase in body mass index (BMI) is associated with an increased rate of sympathetic nerve discharge in skeletal muscle,[5] and there is a correlation between BMI, body fat distribution and urinary norepinephrine excretion.[6] Refs 5. Scherrer U et al. Circulation 1994;89: 6. Landsberg L. Cardiovasc Risk Factors 1993;3: 5. Scherrer U et al. Circulation 1994;89: , 6. Landsberg L. Cardiovasc Risk Factors 1993;3:

Link with insulin resistance and diabetes
Sympathetic activation is a major component of insulin resistance in clinical experiments7 and in humans with type 2 diabetes8 Cardiac autonomic dysfunction occurs in: % of patients with diabetes - 40% of obese patients without diabetes9 An association of diabetes and hypertension has long been recognised. Elevated plasma insulin is a strong predictor of future diabetes, and sympathetic activation has been shown to be a major component of insulin resistance, both in clinical experiments[7] and in humans with type 2 diabetes.[8] Cardiac autonomic dysfunction (measured as abnormal heart rate variation to standardised tests) has been reported to occur in 30-50% of patients with diabetes, but also in 40% of obese patients without diabetes, indicating relative sympathetic overactivity both in diabetic and prediabetic states.[9] Refs 7. Jamerson KA et al. Hypertension 1993;21: 8. Huggett RJ et al. Circulation 2003;108: 9. Valensi P et al. ESC 2004( 7. Jamerson KA et al. Hypertension 1993;21: , 8. Huggett RJ et al. Circulation 2003;108: , 9. Valensi P et al. ESC 2004 (

Link with other risk factors
Sympathetic overactivity is also implicated in: - renal disease10 - left ventricular hypertrophy11 - congestive heart failure12 Sympathetic overactivity is also implicated in renal disease, left ventricular hypertrophy and congestive heart failure.[10-12] Refs 10. Ritz E et al. Blood Press 1998;7(suppl 3):14-19 11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65 12. Lanfranchi A et al. Blood Press 1998;7(suppl 3):40-45 10. Ritz E et al. Blood Press 1998;7(suppl 3):14-19., 11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65., 12. Lanfranchi A et al. Blood Press 1998;7(suppl 3):40-45

Incidence of metabolic syndrome13
In a study of 4,483 subjects aged years, metabolic syndrome was present in: 10-15% with normal fasting blood glucose 42-64% with impaired glucose tolerance/ impaired fasting glucose 78-84% with type 2 diabetes Metabolic syndrome is a frequent condition. An epidemiological study of 4,483 subjects aged years showed that 10-15% of people with normal fasting blood glucose had metabolic syndrome, and that the prevalence increased to 42-64% in those with impaired glucose tolerance/impaired fasting glucose. In people with type 2 diabetes the incidence of metabolic syndrome was 78-84%.[13] The risk of coronary heart disease and stroke was increased three-fold in subjects with metabolic syndrome (p<0.001), and cardiovascular mortality was markedly increased (12.0% versus 2.2%, p<0.001). In this study, metabolic syndrome was defined as the presence of at least two of: obesity, hypertension, dyslipidaemia, microalbuminuria. Ref 13. Isomaa B et al. Diabetes Care 2001;24: Risk of CHD, stroke and CV mortality was higher in people with metabolic syndrome (p<0.001) 13. Isomaa B et al. Diabetes Care 2001;24: Metabolic syndrome was defined as the presence of at least two of: obesity, hypertension, dyslipidaemia, microalbuminuria

Origin of cardiovascular symptoms9
Lifestyle Adiposity inflammation INSULIN RESISTANCE / METABOLIC SYNDROME - free fatty acids - oxidative stress Relative sympathetic overactivity Endothelial dysfunction Arterial rigidity hypertension A framework has been suggested in which insulin resistance and metabolic syndrome contribute to cardiovascular complications through two main mechanisms: autonomic dysfunction (relative sympathetic overactivity) and endothelial dysfunction.[9] Both mechanisms are also capable of aggravating metabolic syndrome and insulin resistance. Ref 9. Valensi P et al. Presented at a satellite symposium at the ESC Congress 2004, Munich, Germany. Atherothrombosis Arrhythmias LVH Cardiovascular complications 9. Valensi P et al. Presented at a satellite symposium at the ESC Congress 2004, Munich, Germany.

Treatment strategy Autonomic dysfunction appears to have an important role in many patients with metabolic syndrome Given the important role of autonomic dysfunction in patients with metabolic syndrome, it would be rational that management of patients with hypertension should not be confined simply to lowering blood pressure, but should also take account of associated metabolic conditions [14] 14. Hansson L. Blood Press 1998;7(suppl 3):20-22 Treatment of patients with hypertension should take account of associated metabolic conditions14 14. Hansson L. Blood Press 1998;7(suppl 3):20-22

thus reducing peripheral sympathetic activity
Rationale for moxonidine Sympathetic tone is regulated centrally in the rostral ventrolateral medulla (RVLM)15 This region contains imidazoline I1-receptors and a2-adrenoceptors which regulate sympathetic activity Sympathetic tone is regulated centrally by the cardiovascular control centres in the brainstem, of which one of the most important appears to be the rostral ventrolateral medulla (RVLM).[15] This area contains several types of neuroreceptors, including alpha-2-adrenoceptors and imidazoline I1-receptors, which exert a regulating influence on sympathetic activity. Moxonidine binds selectively and with high affinity to imidazoline I1-receptors in the RVLM of the brainstem,[16] bringing about a reduction in peripheral sympathetic activity. This offers the opportunity to treat raised blood pressure whilst at the same time having beneficial effects on the metabolic syndrome. Refs 15. Hamilton CA. In: van Zwieten PA et al (eds). The I1 Imidazoline Receptor Agonist Moxonidine. 2nd Ed, London: Roy Soc Med,1996:7-30 16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S1-S10 Moxonidine binds selectively and with high affinity to I1-receptors in the RVLM16 thus reducing peripheral sympathetic activity 15. Hamilton CA. In: van Zwieten PA et al (eds). The I1 Imidazoline Receptor Agonist Moxonidine. 2nd Ed, London: Roy Soc Med,1996:7-30., 16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S1-S10

Overview of moxonidine - 1
Lowers peripheral arterial resistance without significant effects on cardiac output17 Relatively little affinity for a2-receptors in the brainstem (adverse events such as sedation and dry mouth are infrequently reported during prolonged therapy)28 Low potential for drug interactions Moxonidine is a centrally acting agent which binds selectively and with high affinity to imidazoline I1-receptors in the rostral ventrolateral medulla of the brainstem.[16] Occupation of the imidazoline binding site by moxonidine reduces peripheral sympathetic activity, culminating in lowered peripheral arterial resistance without significant adverse change in cardiac output.[17] Unlike older centrally-acting agents (clonidine and methyldopa), moxonidine has relatively little affinity for alpha-2-receptors in the brainstem.[16] As a result, adverse events such as sedation and dry mouth, which are in part mediated by alpha-2-receptor interactions, are infrequently reported during prolonged therapy with moxonidine.[28] There is a low potential for drug interactions. Refs 16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S1-S10 17. Mitrovic V et al. Cardiovasc Drugs Ther 1991;5: 28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620 16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S1-S10., 17. Mitrovic V et al. Cardiovasc Drugs Ther 1991;5: , 28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620

Overview of moxonidine - 2
Effective when used as monotherapy An effective adjunct to other first-line therapies such as diuretics and ACE-inhibitors Linear dose-response effect allows dose titration Improves glucose metabolism / insulin resistance Neutral effect on the lipid profile Renal protective effect Several placebo-controlled studies have demonstrated that moxonidine is as effective as other classes of antihypertensives when given as monotherapy. Clinical studies have also indicated that moxonidine can be used as an adjunct to other first-line therapies such as diuretics and ACE-inhibitors, giving significant additional blood pressure lowering effects compared with monotherapy. There is a clear dose-response effect, allowing titration of dosage to optimise the therapeutic response. Moxonidine appears to be of particular benefit for hypertensive patients with metabolic syndrome. It has been shown to give significant improvement in glucose metabolism and insulin resistance, with a neutral effect on the lipid profile. Clinical studies also indicate that moxonidine has a renal protective effect. The above studies are described in later slides

Efficacy studies reviewed in this slide set
Monotherapy versus active comparators Dose response Long-term efficacy Combination with other antihypertensives Diabetic / prediabetic hypertensive patients Obese hypertensive patients Postmenopausal hypertensive women Hypertensive patients with LVH Role in renal protection This slide set reviews efficacy studies in the following areas: - Monotherapy versus active comparators - Dose response - Long-term efficacy - Combination with other antihypertensives - Diabetic/prediabetic hypertensive patients - Obese hypertensive patients - Postmenopausal hypertensive women - Hypertensive patients with LVH - Role in renal protection

Moxonidine versus active comparators
Moxonidine has been found to be similarly effective to other first-line antihypertensive agents in reducing blood pressure including: Diuretics (hydrochlorothiazide - HCTZ) Beta-blockers (atenolol) ACE inhibitors (captopril and enalapril) Calcium-channel blockers (nifedipine) Moxonidine has been found to be similarly effective to other first-line antihypertensive agents in reducing blood pressure, including diuretics (hydrochlorothiazide - HCTZ), beta-blockers (atenolol), ACE inhibitors (captopril and enalapril) and calcium-channel blockers (nifedipine).

Moxonidine versus hydrochlorothiazide19
Double-blind, placebo-controlled parallel group, randomised study in general practice (n=160) Moxonidine (0.4mg/day) compared with HCTZ (25mg /day) in mild-to-moderate hypertension After 8 weeks of monotherapy, moxonidine and HCTZ both gave significant reductions in BP compared with placebo (p<0.05) No significant differences between the drugs Frei et al (1994)[19] compared monotherapy with moxonidine (0.4mg once-daily) versus hydrochlorothiazide (25mg once-daily) in patients with newly diagnosed or unsatisfactorily controlled mild-to-moderate hypertension in a double-blind, placebo-controlled parallel group, prospectively randomised study in general practice. The intent-to-treat patient sample consisted of 160 patients. After eight weeks of monotherapy with moxonidine or hydrochlorothiazide there were statistically significant reductions in blood pressure compared with placebo (p<0.05), with no significant differences between the two active treatments. This study also evaluated blood pressure response when using the two active agents in combination with each other; these results are described later. Ref 19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28 19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28 Results using the two active agents in combination are described on a later slide

Moxonidine versus atenolol20
Response after 8 weeks of moxonidine or atenolol in a randomised, double-blind study in mild-moderate hypertension N.S. % responders 100 - 80 - 60 - 40 - 20 - 0 - 68% (17/25) 71% (20/28) Prichard, Simmons, Rooks, et al (1992)[20] reported that moxonidine was as effective as atenolol in a multicentre, randomised, double-blind, parallel groups study in general practice. A total of 79 patients aged years were enrolled; patients were eligible for inclusion if they had mild-to-moderate hypertension with sitting diastolic blood pressure mmHg. After a 4-week placebo run-in period, patients were randomised to eight weeks of treatment with moxonidine (0.2mg once-daily) or atenolol (50mg). The dosage was doubled if diastolic pressure did not fall below 90 mmHg within the first two weeks of treatment. Efficacy data were available for analysis in 25 patients on moxonidine and 28 on atenolol. On an intent-to-treat basis at the end of active treatment, mean sitting blood pressure decreased in the moxonidine group from 166/100 to 149/90 mmHg, compared with a reduction from 169/101 to 149/87 mmHg with atenolol. Responder rates, defined as diastolic pressure becoming <90 mmHg, were similar for both treatment groups (68% moxonidine vs 71% atenolol, per protocol analysis). No alterations in blood pressure were observed in moxonidine-treated patients during the 2-week washout phase of the study, whereas blood pressure increased in the atenolol group. Ref 20. Prichard BNC et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S45-S49 moxonidine mg/day atenolol 50-100mg/day 20. Prichard BNC et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S45-S49 Response was defined as DBP <90 mmHg

Moxonidine versus captopril21
Mean sitSBP and sitDBP during 4 weeks of treatment with moxonidine ( mg/day) or captopril (25-50mg/day) in a randomised, double-blind study moxonidine (n=25) Mean blood pressure (mmHg) 200 - 160 - 120 - 80 - captopril (n=25) systolic Lotti & Gianrossi (1993)[21] reported the results of a randomised, double-blind study comparing four weeks of treatment with moxonidine ( mg daily; n=25) versus the ACE inhibitor captopril (25-50mg daily; n=25). Outpatients aged years (mean 57 years) were included in the study if their diastolic blood pressure was mmHg when measured after a 1-week washout phase and a 1-week placebo baseline period. Other antihypertensive agents had previously been taken by 19/25 moxonidine patients and 17/25 captopril patients (but patients did not take any other antihypertensive agents during the study). In the moxonidine group, sitting blood pressure was reduced from 176/101 to 155/91 mmHg after four weeks of therapy, compared with a reduction from 170/99 to 150/89 mmHg in the captopril group (each p<0.01 compared with baseline). There was no statistically significant difference between the treatment groups. The global judgement of efficacy was excellent in 72% of the moxonidine group and 68% of the captopril group (‘excellent’ was defined as diastolic blood pressure <90 mmHg at the end of treatment). There was no evidence of rebound effects on drug withdrawal. Ref 21. Lotti G, Gianrossi R. Fortschr Med 1993;111(27): diastolic week 1 week 2 week 3 week 4 21. Lotti G, Gianrossi R. Fortschr Med 1993;111(27):

Moxonidine versus captopril22
A randomised, double-blind, 4-week study compared moxonidine (0.2mg bd) versus captopril (25mg bd) 26 patients with mild-to-moderate hypertension (over 80% also had evidence of endocrine or metabolic diseases) Both drugs reduced BP by similar amounts No evidence of rebound hypertension with moxonidine on withdrawal of therapy Kraft & Vetter(1994)[22] used 24-hour ambulatory blood pressure monitoring (ABPM) to evaluate the antihypertensive efficacy of moxonidine (0.2mg bd) in comparison with captopril (25mg bd) in outpatients with mild-to-moderate hypertension. Twenty six patients aged years with an average 24-hour diastolic blood pressure of mmHg were enrolled in this randomised, double-blind, comparative study lasting four weeks. Over 80% of patients had evidence of endocrine/metabolic diseases in addition to hypertension. Sitting and standing blood pressures recorded on days 0, 14, 28 and post-study were reduced by similar amounts in both study groups. After withdrawal of active treatment, blood pressure increased towards baseline levels, but there was no evidence of a rebound blood pressure ‘overshoot’ with moxonidine. Ref 22. Kraft K, Vetter H. J Cardiovasc Pharmacol 1994;24(suppl 1):S29-S33 22. Kraft K, Vetter H. J Cardiovasc Pharmacol 1994;24(suppl 1):S29-S33

Moxonidine versus enalapril23
8-week, double-blind, placebo-controlled study of moxonidine ( mg/day, n=47) versus enalapril (5-10mg/day, n=47) in outpatients with mild-to-moderate hypertension Both drugs were significantly superior to placebo at week 8 for sitBP (p<0.001), 24hr SBP (p=0.002) and 24hr DBP (p<0.001) Response rates were comparable between moxonidine and enalapril (66% vs 60%) Küppers, Jäger, Luszick, et al (1997)[23] compared the efficacy of moxonidine versus enalapril in an 8-week, double-blind, randomised, placebo-controlled study involving 140 outpatients with mild-to-moderate hypertension. Patients with severe concomitant diseases were excluded, as were those patients known to be resistant to two or more other antihypertensives. Following a 4-week placebo phase, treatment was commenced at a dose of 0.2mg/day for moxonidine and 5mg/day for enalapril; these doses were doubled after two weeks of treatment. Results were evaluable on an intent-to-treat basis in 47 patients on moxonidine, 47 on enalapril, and 45 on placebo. After eight weeks of treatment, the mean reduction in office sitting blood pressure with moxonidine was comparable to that with enalapril, and both were significantly superior to placebo (p<0.001). Response rates (defined as diastolic blood pressure <90 mmHg or >10 mmHg reduction) were comparable between moxonidine and enalapril (66% vs 60%, respectively). Both drugs produced comparable reductions in the mean systolic and diastolic 24-hour blood pressures, each being significantly superior to placebo at week 8 (systolic p=0.002; diastolic p<0.001). There was no evidence of rebound hypertension in either group at the end of the treatment. Ref 23. Küppers HE et al. J Hypertens 1997;15:93-97 23. Küppers HE et al. J Hypertens 1997;15:93-97 Response was defined as DBP <90 mmHg or >10 mmHg reduction

Moxonidine versus enalapril24 – high dose
Change in DBP at week 8 with moxonidine (n=51) and enalapril (n=53) in a randomised, double-blind, placebo-controlled study in mild-to-moderate hypertension moxonidine 0.6mg/day enalapril 20mg/day placebo Mean change in DBP from baseline (mmHg) - 0 - - 4 - - 8 - - 12 - - 16 - - 2.3 Prichard et al (2002)[24] reported the results of a double-blind, randomised, placebo-controlled study comparing moxonidine (0.6mg/day, n=51) versus the ACE inhibitor enalapril (20mg/day, n=53) in patients with mild-to-moderate hypertension treated in primary care. After eight weeks of treatment, both moxonidine and enalapril gave statistically significant reductions in systolic and diastolic blood pressure compared with placebo (p<0.001), with no significant difference between the active treatments. There was also no significant difference between moxonidine and enalapril in the proportion of patients attaining a diastolic pressure <90 mmHg (56.9% and 58.5% respectively, each p<0.001 versus placebo). Ref 24. Prichard BNC et al. Blood Press 2002;11: -11.9 - 13.2 p<0.001 p<0.001 24. Prichard BNC et al. Blood Press 2002;11:

Moxonidine versus enalapril25 – low dose
8-week, double-blind, randomised, placebo-controlled study in mild-to-moderate hypertension Moxonidine 0.2mg/day (n=54) versus enalapril 5mg/day (n=59) Both gave significant reductions in DBP versus placebo (p<0.001) No significant difference between moxonidine and enalapril in their effects on blood pressure Prichard et al (2003)[25] investigated the effect of low doses of moxonidine (0.2mg/day, n=54) and enalapril (5mg/day, n=59) in an 8-week, double-blind, randomised, placebo-controlled study in patients with mild-to-moderate hypertension. Both drugs gave statistically significant reductions in diastolic blood pressure compared with placebo (p<0.001) with no significant difference between the active treatments. Results of these three comparative studies with moxonidine and enalapril were subsequently analysed to determine a dose-relationship of blood pressure reduction with moxonidine. These results are described later. Ref 25. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51 25. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51

Moxonidine versus nifedipine26
Mean SBP and DBP after 0.2-4mg/day moxonidine (n=116) and 20-40mg/day nifedipine (n=113) in a double-blind study moxonidine Mean blood pressure (mmHg) 180 - 160 - 140 - 120 - 100 - 80 - systolic nifedipine diastolic Wolf (1992)[26] compared moxonidine with a sustained-release formulation of nifedipine in a multicentre, double-blind, parallel group study. Following a 3-week placebo run-in phase, 229 patients (mean age 56 years, diastolic blood pressure mmHg) were randomly allocated to receive 26 weeks of once-daily treatment with moxonidine (0.2mg/day, n=116) or sustained-release nifedipine (20mg/day, n=113). The dose was doubled if diastolic blood pressure remained greater than 90 mmHg after four weeks of treatment. Mean blood pressure decreased from 168/102 to 147/86 mmHg with moxonidine, and from 168/102 to 140/83 mmHg with nifedipine. Response rate was defined as diastolic blood pressure <90 mmHg or a reduction in diastolic pressure >10 mmHg. The response rate with the lower doses of each drug was 70% for moxonidine and 68% for nifedipine. Doubling the dose increased the response rate to over 80% in both groups. Ref 26. Wolf R. J Cardiovasc Pharmacol 1992;20(suppl 4):S42-S44 4 8 12 19 week 26 26. Wolf R. J Cardiovasc Pharmacol 1992;20(suppl 4):S42-S44

Moxonidine versus nifedipine27
4-week, randomised, double-blind study in patients aged years Compared moxonidine ( mg/day) versus sustained-release nifedipine (20-40mg/day) Mean BP reductions after 4 weeks: - moxonidine ... from 167/100 to 132/83 mmHg - nifedipine ... from 167/99 to 134/83 mmHg Mangiameli et al (1992)[27] reported similar findings in a controlled, randomised, double-blind study comparing four weeks of treatment with moxonidine ( mg/day) versus sustained-release nifedipine (20-40mg/day) in 60 patients aged years (mean 60 years). There was a reduction in mean blood pressure from 167/100 to 132/83 mmHg with moxonidine, compared with a reduction from 167/99 to 134/83 mmHg in the nifedipine-treated patients. Ref 27. Mangiameli S et al. Z Allg Med 1992;68:862866 27. Mangiameli S et al. Z Allg Med 1992;68:862866

Dose-response with moxonidine
Percentage of patients requiring a moxonidine dose increase from 0.2mg to 0.4mg daily after two weeks of treatment in four clinical trials 20,21,26,27 % patients requiring dose doubling 100 - 80 - 60 - 40 - 20 - 0 - 56% (14/25) 42% (49/116) 28% (8/29) 10% (3/30) A number of controlled clinical trials started dosing with 0.2mg/day and allowed doubling of this dosage after two weeks if there was insufficient response.[20,21,26,27] The percentage of patients taking 0.4mg/day is shown in this diagram, which demonstrates that 10-56% of patients needed the higher dosage. Refs 20. Prichard BNC et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S45-S49 21. Lotti G, Gianrossi R. Fortschr Med 1993;111(27): 26. Wolf R. J Cardiovasc Pharmacol 1992;20(suppl 4):S42-S44 27. Mangiameli S et al. Z Allg Med 1992;68: Prichard 1992 Lotti 1993 Wolf 1992 Mangiameli 1992 20. Prichard BNC et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S45-S49., 21. Lotti G, Gianrossi R. Fortschr Med 1993;111(27): , 26. Wolf R. J Cardiovasc Pharmacol 1992;20(suppl 4):S42-S44., 27. Mangiameli S et al. Z Allg Med 1992;68:

moxonidine dosage (mg/day)
Linear dose-response25 Dose-response of moxonidine in reducing office sitDBP at trough from three double-blind, placebo-controlled trials Mean placebo-adjusted reduction in sitDBP (mmHg) 15 - 10 - 5 - 0 - 10.5 7.01 4.65 Prichard et al (2003)[25] examined the dose-relationship for moxonidine across the range of currently approved dosages ( mg/day) using data from three placebo-controlled, double-blind, comparative studies versus enalapril. The three studies were based on a standardised protocol involving eight weeks of double-blind treatment, with a primary efficacy variable of office sitting diastolic blood pressure at trough. Patients enrolled in the three studies were broadly similar in their baseline demographics. The blood pressure responses to moxonidine and dose-matched enalapril were statistically significantly greater than placebo in all three trials (p<0.001), and there was no significant difference between the active drugs. There was a clear dose-linearity in the office sitting DBP response to moxonidine. The evidence of a dose-proportionate effect was confirmed by analysis of ABPM measurements. The authors commented that the linear dose-response indicates that dose titration is a practical option with moxonidine, making it a useful and flexible agent for monotherapy or in combination with other antihypertensive drugs. Ref 25. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51 0.2mg 0.4mg 0.6mg moxonidine dosage (mg/day) 25. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51

Long-term efficacy of moxonidine28
Change in mean sitSBP and sitDBP during up to two years of treatment with moxonidine (week 3 = end of dose titration) 1 year (n=141) Change in mean blood pressure (mmHg) 180 - 160 - 140 - 120 - 100 - 80 - systolic 2 years (n=49) diastolic Long term efficacy was studied in an open, multicentre, 12-month clinical trial in 141 ambulant hypertensive patients with mean sitting diastolic pressure >95 mmHg[28]. The dosage was started at 0.2mg/day, and was individually titrated over a period of three weeks up to a maximum of 0.8mg/day in divided doses. The median age of the patients was 57 years (range years). A subgroup of 49 patients from one trial centre in this study continued moxonidine treatment for a second year.[44] The mean sitting blood pressure fell over a period of three weeks on moxonidine from 172/103 to 151/88 mmHg and these reductions were maintained throughout the study. The reductions in standing blood pressure were of similar magnitude. At 12 months, 97% of patients were satisfactorily controlled on daily doses of 0.4mg or less. On discontinuation of treatment, blood pressure gradually increased towards baseline with no evidence of a rebound effect. Ref 28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620 44. Prichard BNC. In: van Zwieten PA et al, editors. The I1 Imidazoline Receptor Agonist Moxonidine. 2nd Edition. London: Roy Soc Med, 1996:49-75 26 52 78 104 weeks of moxonidine treatment 28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620., 44. Prichard BNC. In: van Zwieten PA et al, editors. The I1 Imidazoline Receptor Agonist Moxonidine. 2nd Edition. London: Roy Soc Med, 1996:49-75

Long-term efficacy of moxonidine29
Open, multicentre study of 223 outpatients with mean sitBP >160/95 to <240/114 mmHg Moxonidine ( mg/day) was given for 12 months, with a supplementary diuretic if required Mean sitBP was reduced by 25/15 mmHg at week 12 and by 27/16 mmHg at week 52 Response was 82% at week 12 and 85% at week 52 Trieb, Jäger, Hughes, et al (1995)[29] demonstrated the long-term efficacy of moxonidine in an open, multicentre study of 223 outpatients with mild-to-moderate hypertension who were treated with moxonidine ( mg/day) for 12 months. Supplementary use of diuretics was permitted in patients who did not respond adequately to moxonidine 0.6mg/day. Patients were eligible for enrolment if they had mean sitting blood pressure in the range >160/95 to <240/114 mmHg. Per protocol analysis showed that 12 weeks of moxonidine therapy reduced mean sitting blood pressure by 25/15 mmHg. Similar reductions were maintained for the subsequent 40 weeks of the study; the reduction in mean blood pressure at 52 weeks was 27/16 mmHg. Blood pressure reduction in a subgroup of patients aged 65 years or more was at least as great as in a younger group at 52 weeks. Satisfactory response to therapy (defined as diastolic blood pressure <90 mmHg or a reduction in diastolic blood pressure of >10 mmHg) was observed in 82% of patients at week 12 and in 85% of patients at week 52. There was no clinically significant change in heart rate during the study. Rebound hypertension was not observed on termination of moxonidine therapy. Ref 29. Trieb G et al. Eur J Clin Res 1995;7: 29. Trieb G et al. Eur J Clin Res 1995;7: Response defined as DBP <90 mmHg or a reduction of >10 mmHg

moxonidine + HCTZ (0.4/25mg/day)
Moxonidine in combination with HCTZ19 Mean reduction in sitDBP after 8 weeks of moxonidine and HCTZ as monotherapy or in combination in a double-blind study moxonidine + HCTZ (0.4/25mg/day) moxonidine (0.4mg/day) HCTZ 25mg/day placebo Mean reduction in diastolic blood pressure from baseline (mmHg) - 0 - - 10 - - 20 - 9mmHg (n=41) Frei et al (1994)[19] evaluated the efficacy of moxonidine and hydrochlorothiazide as monotherapy or in combination in a placebo-controlled study in 160 patients with mild-to-moderate hypertension. This was a double-blind, parallel group, prospectively randomised study in general practice, with a 4-week placebo run-in and an 8-week treatment period. Patients were newly diagnosed or had unsatisfactorily controlled blood pressure; their mean age was 55 years (range years). Monotherapy results were described in an earlier slide. Using the two drugs in combination gave a more marked reduction in blood pressure than either of the monotherapies (p<0.05). Ref 19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28 12mmHg n=37 * 13mmHg (n=40) * 16mmHg (n=42) ** *p<0.05 vs placebo **p<0.05 vs placebo and monotherapies 19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28

moxonidine + HCTZ (0.4/25mg/day)
Moxonidine in combination with HCTZ19 Percentage response for all patients after 8 weeks of moxonidine and HCTZ as monotherapy or in combination in a double-blind study 88% (n=42) % patients with response 100 - 80 - 60 - 40 - 20 - 0 - 70% (n=37) 70% (n=40) 44% (n=41) In the Frei study, overall response (defined as diastolic blood pressure <90 mmHg or >10 mmHg decrease in blood pressure) was 70% with monotherapy, 88% with combination therapy, and 44% with placebo. After cessation of treatment, rebound hypertension did not occur in any group. placebo moxonidine (0.4mg/day) moxonidine + HCTZ (0.4/25mg/day) HCTZ (25mg/day) 19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28 Intent-to-treat analysis. Response defined as DBP <90 mmHg or >10 mmHg decrease

Combination therapy – TOPIC study30
Mean change in SBP and DBP after 4 weeks of combination therapy in patients who had not responded to previous moxonidine monotherapy moxonidine 0.4mg + amlodipine 5mg (n=81) moxonidine 0.4mg + enalapril 10mg (n=82) moxonidine 0.4mg + HCTZ 12.5mg (n=90) 0 - - 4 - - 8 - - 12 - - 16 - - 20 - Change in mean BP from baseline (mmHg) -5.5 -3.2 -4.8 -4.4 -7.3 * Waters et al (1999)[30] reported the results of the TOPIC study (Trial Of Physiotens In Combination) which included patients aged years with mild-to-moderate hypertension and a mean baseline BMI of 28.6 kg/m2. A 4-week placebo run-in phase was followed by eight weeks of monotherapy with moxonidine mg/day. Patients not responding to monotherapy were randomised to double-blind treatment with a daily dose of 0.4mg moxonidine plus either amlodipine 5mg, enalapril 10mg or HCTZ 12.5mg for a further four weeks. In total, 253 patients were included in the double-blind ‘combination’ efficacy analysis. Reductions in blood pressure were seen in all three combination groups, but the combination of moxonidine with amlodipine reduced sitting DBP (primary endpoint) and SBP to a significantly greater extent (p<0.05) than other combination therapies. Response to therapy (sitting DBP normalisation or a reduction of >10 mmHg) occurred in significantly more moxonidine/amlodipine patients (46.9%) than moxonidine/HCTZ (21.1%) or moxonidine/enalapril (26.8%) patients (both p<0.05). Ref 30. Waters J et al. J Clin Basic Cardiol 1999;2: -7.9 -10.7 * sitSBP sitDBP * p<0.05 versus the other combinations 30. Waters J et al. J Clin Basic Cardiol 1999;2:

Diabetic/prediabetic hypertensive patients
Prediabetic conditions include insulin resistance, hyperinsulinaemia and hyperglycaemia Long-term benefits of antihypertensive therapy may be compromised if the drugs chosen have adverse effects on insulin sensitivity In hypertensive patients, moxonidine has been shown to reduce plasma glucose levels and increase insulin sensitivity Prediabetic conditions such as insulin resistance, hyperinsulinaemia and hyperglycaemia may increase overall cardiovascular risk in patients with hypertension, especially when there are other risk factors associated with metabolic syndrome. Long-term benefits of antihypertensive therapy may be compromised if the drugs chosen have adverse effects on insulin sensitivity. In hypertensive patients, moxonidine has been shown to reduce plasma glucose levels and increase insulin sensitivity.

INSULIN SENSITIVITY INDEX
Effects on insulin resistance31 Effects of moxonidine (0.4mg/day for 8 weeks) in hypertensive patients with reduced insulin sensitivity in a double-blind, placebo-controlled, randomised, parallel group study GLUCOSE INFUSION RATE INSULIN SENSITIVITY INDEX p=0.026 p=0.056 % change from baseline 25 - 20 - 15 - 10 - 5 - 0 - - 5 - -10 - p=0.004 p=0.027 moxonidine (n=25) 21% 21% Haenni and Lithell (1999)[31] reported the results of a prospective, double-blind, placebo-controlled, randomised, parallel group study of 77 overweight patients with mild essential hypertension. A placebo run-in period of 1-3 weeks was followed by 8-9 weeks of double-blind treatment with moxonidine 0.4mg/day or placebo. Insulin sensitivity was evaluated by hyperinsulinaemic euglycaemic clamp test; the insulin sensitivity index (M/I ratio) was calculated by dividing the glucose infusion rate by the mean insulin concentration during the steady-state phase. In a subgroup of patients with insulin resistance at baseline (M/I ratio <3.6), moxonidine gave statistically significant improvements in the glucose infusion rate and insulin sensitivity index (21% change in each parameter, p=0.004 and p=0.027 versus baseline, respectively). Differences between moxonidine and placebo were statistically significant for glucose infusion rate (p=0.026), but did not quite attain statistical significance for insulin sensitivity index (p=0.056). There was a statistically significant fall in fasting plasma glucose with moxonidine (3% fall, p=0.009 versus baseline). No significant changes were observed in patients who were not insulin resistant at baseline (M/I ratio >3.6). Therefore, in practice, moxonidine would not be expected to cause unwanted hypoglycaemia in patients with normal blood glucose concentrations. Ref 31. Haenni A, Lithell H. J Hypertens 1999;17(Suppl 3):S29-S35 placebo (n=13) - 6.0% - 6.0% N.S. N.S. 31. Haenni A, Lithell H. J Hypertens 1999;17(Suppl 3):S29-S35 Insulin sensitivity evaluated by hyperinsulinaemic euglycaemic clamp test. Insulin sensitivity index = glucose infusion rate/mean insulin concentration at steady-state

Patients with normal glucose tolerance32
30 patients with mild-to-moderate hypertension and normal glucose tolerance Insulin sensitivity was studied after 6 months of treatment with moxonidine ( mg/day) Following oral GTT, the 2-hour plasma insulin level was statistically significantly reduced by moxonidine compared with pretreatment (18% reduction, p<0.05) Almazov et al (2000)[32] evaluated the influence of six months of treatment with moxonidine ( mg/day) on insulin sensitivity in 30 patients with mild-to-moderate hypertension and normal glucose tolerance. Following oral glucose tolerance tests, the 2-hour plasma insulin level was statistically significantly reduced by moxonidine compared with pretreatment (18% reduction, p<0.05). Ref 32. Almazov VA et al. J Hypertens 2000;18(suppl 2):12 32. Almazov VA et al. J Hypertens 2000;18(suppl 2):12

Insulin-resistant hypertensive patients33
Open, randomised study of 202 mildly hypertensive, insulin-resistant, overweight patients Moxonidine (0.2mg bd) or metformin (500mg bd) for 16 weeks Insulin AUC after OGTT was 14.7% lower with moxonidine than metformin (p=0.052) Difference in AUC between treatments was 23.8% in patients with high sympathetic activity at baseline (p<0.05) Betteridge (2004)[33] summarised the results of the ALMAZ study. This was an open, randomised, parallel group study in which moxonidine was compared with metformin (a standard first-line oral hypoglycaemic agent) in mildly hypertensive, insulin-resistant, overweight patients with impaired glucose tolerance or early type 2 diabetes. In total, 202 patients were randomised to receive either moxonidine (0.2mg twice-daily) or metformin (500mg twice-daily) for a 16-week treatment period. The area-under-the-curve (AUC) for insulin after a standard oral glucose tolerance test (the primary endpoint) was 14.7% lower in the moxonidine group than in the metformin group (p=0.052) on an intent-to-treat analysis. The difference between moxonidine and metformin was greater (23.8%, p<0.05 between treatments) in patients with high sympathetic activity at baseline (heart rate of >80 beats per minute). The insulin sensitivity index increased significantly to a similar extent in both treatment groups. Ref 33. Betteridge J. ESC 2004 ( 33. Betteridge J. ESC 2004 ( High sympathetic activity was defined as heart rate of >80 beats per minute

Hypertensive diabetic patients34
12-week study in hypertensive patients with type 2 diabetes Moxonidine ( mg/day as an adjunct to stable antihypertensive therapy) versus metoprolol Moxonidine significantly improved fasting plasma glucose levels compared with metoprolol No significant differences between treatments in the change in insulin sensitivity from baseline In a 12-week study reported by Jacob et al (2004)[34] in patients with hypertension and type 2 diabetes, moxonidine mg/day significantly improved fasting plasma glucose levels compared with metoprolol. There were no statistically significant differences between treatments in the change in insulin sensitivity from baseline. In this study, moxonidine was used as an adjunct to stable antihypertensive therapy, mostly ACE inhibitors, AIIAs, diuretics or calcium-channel blockers. Ref 34. Jacob S et al. Exp Clin Endocrinol Diabetes 2004;112(6): A large, double-blind, prospective study is currently in progress, which is designed to evaluate the effects of moxonidine and ramipril either as monotherapy or in combination in overweight patients with mild-to-moderate hypertension and impaired fasting glycaemia. The MARRIAGE study (Moxonidine and Ramipril Regarding Insulin and Glucose Evaluation) has blood pressure responses as the primary endpoint, with a range of indices of glucose homeostasis as secondary endpoints. 34. Jacob S et al. Exp Clin Endocrinol Diabetes 2004;112(6):

Obesity and hypertension
Hypertension in obese patients may be related to activation of renal sympathetic nerves and stimulation of the renin-angiotensin system45,46 Urinary norepinephrine levels increase with rising BMI49 Most obese subjects and obese hypertensive patients have high circulatory levels of the hormone leptin50,51 Obesity is a major risk factor for the development of hypertension. It is one of the cluster of cardiovascular, renal, metabolic and neuro-endocrine disorders which make up the metabolic syndrome. Hypertension in obese patients appears to be related mainly to activation of renal sympathetic nerves and stimulation of the renin-angiotensin system.[45,46] It has been suggested that over-eating activates the sympathetic nervous system to try and stabilise weight, but with the consequence of raised blood pressure due to sympathetic activation in the heart, kidneys and vasculature. Over-eating in humans increases sympathetic nervous activity. In obese hypertensive patients, urinary norepinephrine levels increase with rising body mass index (BMI) and also with increasing abdominal fat distribution.[49] Another factor may be increased levels of the hormone leptin in obese hypertensive patients. Most obese subjects and obese hypertensive patients have high circulatory leptin levels, even when leptin is corrected for BMI.[50,51] Moxonidine may have particular benefits for obese hypertensive patients. This is because activation of the sympathetic nervous system not only contributes to elevated blood pressure but may also lead to unwanted metabolic and cardiovascular effects in these patients. Refs 45. Hall JE. Am J Hypertens 1997;10: S49-S55 ., 46. Tuck ML et al. N Engl J Med 1981;304: 49. Landsberg L. J Cardiovasc Pharmacol 1994;23(suppl 1):S1-S8., Barroso SG et al. Trace Elem Electrolytes 2003;20: 51. Masuo K et al. Am J Hypertens 2001;14: 45. Hall JE. Am J Hypertens 1997;10: S49-S55., 46. Tuck ML et al. N Engl J Med 1981;304: , 49. Landsberg L. J Cardiovasc Pharmacol 1994;23(suppl 1):S1-S8., 50. Barroso SG et al. Trace Elem Electrolytes 2003;20: , 51. Masuo K et al. Am J Hypertens 2001;14:

Moxonidine in obese hypertensives37
Effects of moxonidine mg/day and amlodipine 5mg/day on office sitDBP after 12 and 24 weeks in an open study of 40 obese patients with mild-to-moderate hypertension moxonidine amlodipine week 12 week 24 week 12 week 24 Change in sitDBP from baseline (mmHg) - 0 - - 10 - - 20 - -10.2 * -12.7 * Sanjuliani et al (2004)[37] reported the results of a randomised, parallel, open study comparing the effects of moxonidine with those of the calcium-channel blocker amlodipine in 40 obese hypertensive men and women aged years old. Patients were eligible for inclusion if sitting blood pressure was in the range / mmHg and BMI was 30kg/m2 or over. Following a 2-week washout period, patients were randomised to receive 0.2mg moxonidine once-daily or amlodipine 5mg once-daily. This initial dosage was doubled if blood pressure remained above 140/90 mmHg after one month of treatment. Patients whose blood pressure exceeded 180/110 mmHg on two consecutive visits were excluded from the study. The total duration of active therapy was 24 weeks. Subjects maintained a usual intake of sodium and were not on a calorie-restricted diet. Blood pressure was controlled in 58% of patients receiving moxonidine and 52% on amlodipine. Both drugs reduced office BP to a similar degree, and there was no statistically significant difference between them on 24-hour blood pressure measurements. Neither drug was associated with any significant changes in heart rate during daytime or overnight. Ref 37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25 -14.7 * -15.9 * *p<0.05 vs baseline (no significant difference between active treatments) 37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25 BP was controlled in 58% patients on moxonidine and 52% on amlodipine

Metabolic effects in obese hypertensives37
Effect of 24 weeks of moxonidine mg/day. Subgroup analysis according to blood pressure response (response was defined as achieving office BP <140/90mmHg) reduction of standing norepinephrine (pg/ml) reduction of plasma leptin (pg/ml) reduction of fasting insulin (U/ml) 100 - 50 - 0 - 6 - 3 - 0 - 10 - 5 - 0 - ** * * 90.7 5.5 9.6 4.3 57.3 4.7 This slide shows the effects of moxonidine on plasma catecholamines, fasting plasma insulin and plasma leptin in a subgroup of patients whose blood pressure was controlled (defined as office blood pressure <140/90 mmHg) compared with those whose blood pressure remained uncontrolled. There was a statistically significantly greater reduction in all these parameters in responders versus non-responders (p<0.003 for catecholamines and p<0.05 for insulin and leptin). This finding probably reflects the heterogeneity of sympathetic activity in obese hypertensive patients. The authors commented that the differences between drug treatments were seen despite using only a mid-range dose of moxonidine (up to 0.4mg/day) and a full dose of amlodipine (up 10mg/day). responders ** p<0.003 responders vs non-responders * p<0.05 responders vs non-responders non-responders 37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25

Moxonidine in obese hypertensives38
Moxonidine (0.4mg/day) was added to the current antihypertensive treatment of 112 obese patients with uncontrolled hypertension Open, multicentre study in primary care, which included 25 patients with type 2 diabetes After 6 months of treatment, there were mean decreases in SBP and DBP of 23.0 and mmHg, respectively Overall, SBP and DBP were controlled in 63% and 86% of patients, respectively Abellán et al (2005)[38] investigated the effects of adding moxonidine (0.4mg/day) to the current antihypertensive treatment of 112 obese patients whose hypertension was not adequately controlled. This was an open, multicentre, observational study in primary care and included 25 patients with type 2 diabetes. Patients also received a low calorie diet and were recommended to exercise daily. After six months of treatment, there were mean decreases in SBP and DBP of 23.0 and 12.9 mmHg, respectively (approximately 14% of the baseline values). Overall, SBP and DBP were controlled in 63% and 86% of patients, respectively. Creatinine clearance was significantly decreased in hyperfiltrating obese patients (p<0.0001), without any significant change in patients with normal or slightly decreased renal function. Ref 38. Abellán J et al. Kidney Int 2005;67(suppl 93):S20-S24 38. Abellán J et al. Kidney Int 2005;67(suppl 93):S20-S24

Postmenopausal hypertension
SBP tends to increase in women after the menopause The prevalence of hypertension in women after the menopause is similar to that in men52 ‘Menopausal metabolic syndrome’ describes comorbidities such as hypertension, abdominal obesity, insulin resistance, type 2 diabetes, and changes in the lipid profile53,54 After the menopause, systolic blood pressure increases such that the prevalence of hypertension in postmenopausal women is similar to, or higher than, in men.[52] The presence of several interlinked cardiovascular risk factors after the menopause has led to the concept of the ‘menopausal metabolic syndrome’, with comorbidities such as hypertension, abdominal obesity, insulin resistance, type 2 diabetes, and changes in the lipid profile.[53,54] Refs 52. Burt VL et al. Hypertension 1995;25: 53. Tong PL et al. Atherosclerosis 2002;161(2): 54. Mercuro G et al. Ital Heart J 2001; 2(10): 52. Burt VL et al. Hypertension 1995;25: , 53. Tong PL et al. Atherosclerosis 2002;161(2): , 54. Mercuro G et al. Ital Heart J 2001; 2(10):

Regional fat metabolism
Menopausal metabolic syndrome55 MENOPAUSE Estrogen deficiency Regional fat metabolism Energy expenditure Central adiposity Insulin resistance Hypertension and endothelial dysfunction This slide shows some of the factors associated with the menopausal metabolic syndrome[55]. The contribution of hormonal changes to increased blood pressure in postmenopausal women is unclear, but may include reduced elasticity of the arteries, reduced sensitivity of angiotensin II receptors, increased plasma renin activity, reduced nitric oxide activity, and increased sympathetic activity. After the menopause there is a shift in the autonomic control of the cardiovascular system towards an increased sympathetic tone which is, in part, independent from changes in body weight and glucose metabolism, but is in the long-term heightened by these metabolic changes. The prevalence of metabolic syndrome in postmenopausal hypertensive women has important implications for therapy, as some antihypertensive drugs may worsen the already altered metabolic profile of these patients while others may have a beneficial effect. The profile of moxonidine, with its desirable effects on sympathetic outflow and glucose metabolism, suggests it should be particularly useful in treating hypertension in postmenopausal women with metabolic syndrome. Ref 55. Sjoberg L et al. Int J Clin Pract 2004;suppl 139:4-12 Metabolic syndrome Vascular inflammation Impaired glucose tolerance Type 2 diabetes Atherosclerosis 55. Sjoberg L et al. Int J Clin Pract 2004;suppl 139:4-12

Moxonidine in postmenopausal women35
Change from baseline in plasma glucose during OGTT following treatment with moxonidine (0.6mg/day) and atenolol (50mg/day) (n=109): double-blind study in hypertensive, obese, postmenopausal women Plasma glucose (mmol/L) 0.2 - 0 - * * Kaaja et al (2004)[35] reported the results of a multicentre, double-blind, prospectively randomised study comparing monotherapy with moxonidine (0.3mg twice-daily, n=57) versus atenolol (50mg once-daily, n=55) in hypertensive postmenopausal women who were not taking hormone replacement therapy. Mean body mass index was 29.3 kg/m2 (moxonidine) and 30.9 kg/m2 (atenolol). A 4-week placebo run-in phase was followed by a double-blind 8-week therapy period. Statistically significant reductions in systolic and diastolic blood pressure occurred in both treatment groups during the course of treatment, with the beta-blocker having a slightly more potent effect overall. Atenolol was associated with a significant decrease in heart rate (-8.1 beats per minute, p=0.035), whereas there was no significant change in heart rate in the moxonidine group. Moxonidine demonstrated a beneficial effect on several metabolic parameters, in contrast to atenolol. This slide shows that moxonidine produced statistically significant reductions in AUC and mean plasma glucose levels at one and two hours after an oral glucose tolerance test (p<0.01 versus pretreatment). Changes with atenolol were less marked and were not statistically significant from pretreatment values. Ref 35. Kaaja R et al. Int J Clin Pract 2004;suppl 139:26-32 0hr 1hr 2hr * Hours after oral glucose tolerance test AUC *p<0.01 versus pretreatment moxonidine atenolol 35. Kaaja R et al. Int J Clin Pract 2004;suppl 139:26-32 Intention to treat analysis

Hours after oral glucose tolerance test
Moxonidine in postmenopausal women35 Change from baseline in plasma insulin during OGTT following treatment with moxonidine (0.6mg/day) and atenolol (50mg/day) (n=109): double-blind study in hypertensive, obese, postmenopausal women Plasma insulin (mU/L) 6 - 4 - 2 - 0 - - 2 - - 4 - - 6 - Moxonidine also reduced mean plasma insulin values, whereas atenolol increased mean plasma insulin. The differences between groups did not reach statistical significance, probably because of high variability of the response. The effect of moxonidine on mean plasma insulin levels was even more pronounced in a subgroup of 43 patients with baseline insulin more than 10 mU/L (i.e., insulin-resistant patients); the between-group difference in AUC was not quite statistically significant (p=0.06). There was a significant increase in uric acid after treatment with atenolol (p=0.048) but not with moxonidine. Ref 35. Kaaja R et al. Int J Clin Pract 2004;suppl 139:26-32 0hr 1hr 2hr Hours after oral glucose tolerance test AUC moxonidine atenolol 35. Kaaja R et al. Int J Clin Pract 2004;suppl 139:26-32

LVH and hypertension LVH in hypertensive patients is an adaptation response to try and overcome increased peripheral vascular resistance LVH is a major independent risk factor for cardiovascular morbidity and mortality62,63 Sympathetic overstimulation may play an important role in the development of myocardial hypertrophy64 Left ventricular hypertrophy (LVH) in patients with hypertension occurs as an adaptation response to try and overcome increased peripheral vascular resistance. LVH is a major independent risk factor for cardiovascular morbidity and mortality.[62,63] Sympathetic overstimulation may play an important role in the development of myocardial hypertrophy,[64] and treatment with central sympathomimetic blockers (clonidine and rilmenidine) has been shown to decrease left ventricular mass. Refs 62. Levy D et al. N Engl J Med 1990;322: 63. Koren MJ et al. Ann Intern Med 1991;114: 64. Trimarco B et al. Circulation 1985;72:38-46 62. Levy D et al. N Engl J Med 1990;322: , 63. Koren MJ et al. Ann Intern Med 1991;114: , 64. Trimarco B et al. Circulation 1985;72:38-46

Moxonidine in LVH11 Interventricular septum end-diastolic diameter at baseline and after 3, 6 and 9 months of moxonidine monotherapy ( mg/day) in 20 hypertensive patients with LVF p<0.05 Interventricular septum end-diastolic diameter (cm) 1.8 - 1.6 - 1.4 - 1.2 - 1.0 - p<0.05 p<0.05 Two early studies in patients with hypertension demonstrated that moxonidine treatment gave statistically significant reductions in left ventricular volume compared with pretreatment. More recently, Haczynski et al (2001)[11] reported the results of a non-randomised prospective study investigating the effect of moxonidine ( mg/day) on left ventricular hypertrophy in 20 hypertensive patients. Strict inclusion and exclusion criteria meant that a relatively homogenous group of patients was enrolled. An 8-week dose titration period was followed by 36 weeks of therapy. Systolic and diastolic blood pressures became normal by the 3-month visit, and remained in the normal range during the further treatment period. At the 9-month visit, mean blood pressure had fallen from 154/99 to 136/84 mmHg (p<0.001). After 9 months, transthoracic echocardiography showed a significant decrease in mean interventricular septum thickness from 13.8 to 12.5mm (p<0.05). The decrease in septal wall thickness was statistically significant from the 3-month visit. Ref 11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65 baseline 3 6 9 months 11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65

Moxonidine in LVH11 Left ventricular mass at baseline and after 3, 6 and 9 months of moxonidine monotherapy ( mg/day) in 20 hypertensive patients with LVF p<0.05 Left ventricular mass (g) 400 - 350 - 300 - 250 - 200 - 150 - p<0.05 There was a 14.6% decrease in mean left ventricular mass (from 310 to 265g, p=0.006). The decrease in left ventricular mass was statistically significant from the 6-month visit. There was a tendency towards a relationship between the dose of moxonidine and degree of reduction in left ventricular mass, but statistical significance was not attained. baseline 3 6 9 months 11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65

Renal protection in hypertension
Increased sympathetic activity leads to renal vasoconstriction, stimulation of renin release, and stimulation of sodium reabsorption10 Moxonidine may be renoprotective by: - reducing sympathetic output centrally - direct renal effects (independent of blood pressure lowering) via imidazoline binding sites in the kidney Prevention of chronic kidney disease is multifaceted and includes strict blood pressure control and inhibition of the renin-angiotensin system. There is growing evidence that moxonidine offers strategic advantages when used as an adjunctive therapy in this area. The effects of increased sympathetic activity on the kidney include renal vasoconstriction mediated by alpha-1-adrenergic receptors, stimulation of renin release mediated by beta-1-adrenergic mechanisms, and direct stimulation of sodium reabsorption mediated via alpha-2 and alpha-1 receptors on the tubular membranes. Moxonidine may exert renoprotective effects by reducing sympathetic output centrally, but some effects appear to be independent of blood pressure lowering. Imidazoline binding sites are found in the kidney, and it is possible that direct renal effects may be involved. 10. Ritz E et al. Blood Press 1998;7(suppl 3):14-19

eprosartan + moxonidine
Renal protective effects39 Mean muscle sympathetic nerve activity (MSNA) in nine hypertensive patients with chronic renal failure given eprosartan alone or with moxonidine. Controls were healthy age-matched persons (n=22) Mean MSNA (burst/min) 50 - 40 - 30 - 20 - 10 - 0 - p<0.05 p<0.05 Neumann et al (2004)[39] assessed the effect of moxonidine (0.2mg/day) given in combination with the AIIA eprosartan (600mg/day) for six weeks on blood pressure and sympathetic activity in eleven hypertensive stable patients with chronic renal failure (BP >145/90 mmHg and creatinine clearance ml/min). Sympathetic activity was assessed by measuring muscle sympathetic nerve activity (MSNA) at baseline and during treatment. The rationale for this combination is that moxonidine acts centrally to inhibit sympathetic output whereas eprosartan inhibits local sympathetic effects by blocking presynaptic angiotensin II receptors. In untreated patients, blood pressure, heart rate, plasma renin activity and MSNA were all higher than in matched controls. After six weeks of treatment with eprosartan alone, there were statistically significant reductions in mean arterial pressure (-12%, p<0.001) and in MSNA (-23%, p<0.001). When moxonidine was added to the eprosartan regimen, mean arterial pressure and MSNA became identical to controls. Ref 39. Neumann J et al. J Am Soc Nephrol 2004;15: baseline eprosartan eprosartan + moxonidine healthy controls 39. Neumann J et al. J Am Soc Nephrol 2004;15:

Improved allograft survival40
Predictors of allograft survival were evaluated in 601 renal transplant patients A number of factors increased the relative risk of allograft loss, the most important being renal vascular resistance Another risk factor was high heart rate (pulse>80 beats/min) which suggests increased sympathetic activity The use of moxonidine was associated with an approximately 70% reduction of allograft failure Radermacher et al (2003)[40] investigated predictors of allograft survival in 601 renal transplant patients. A number of factors increased the relative risk of allograft loss, the most important being renal vascular resistance. Another risk factor was high heart rate (pulse >80 beats/min) which suggests increased sympathetic activity in these patients. The use of moxonidine was associated with an approximately 70% reduction of allograft failure (multivariate risk reduction of 0.3). Ref 40. Radermacher J et al. New Engl J Med 2003;349: 40. Radermacher J et al. New Engl J Med 2003;349:

Effect on microalbuminuria
Microalbuminuria is predictive of retinopathy, LVH, CV events and all-cause mortality 12.8% of people with metabolic syndrome are estimated to have microalbuminuria52 Moxonidine reduces urine albumin excretion in: - non-obese hypertensive patients with microalbuminuria (p<0.001 vs baseline)41 - normotensive patients with well controlled type 1 diabetes (p<0.006 vs placebo)42 Microalbuminuria predicts outcome in essential hypertension and is predictive of diabetic retinopathy, LVH, cardiovascular events and all-cause mortality. Data from the United States NHANES-III study indicate that 10.6% of the U.S. adult population has microalbuminuria.[52] The incidence increases with age in patients with and without diabetes. In total, 12.8% of men and women with metabolic syndrome are estimated to have microalbuminuria. Krespi et al (1998)[41] investigated the effect of moxonidine ( mg/day for 6 months) in 58 non-obese hypertensive patients with microalbuminuria. Compared with pretreatment baseline, there was a normalising of blood pressure, together with a statistically significant reduction of the 24-hour urine albumin excretion rate from 32.3 to 24.5mcg/min (p<0.001). Plasma levels of thrombomodulin and plasminogen activator inhibitor-1 (markers of endothelial function) were significantly reduced from baseline over six months of moxonidine treatment (p<0.05). Strojek et al (2000)[42] investigated the effect of moxonidine (0.2mg twice daily for 3 weeks) on albumin excretion rate in a placebo-controlled, crossover study in 15 normotensive patients with well controlled type 1 diabetes. The median albumin excretion rate was significantly lower following treatment with moxonidine compared with placebo (29.0 vs 39.8mcg/min, p<0.006). There was no significant reduction of blood pressure in these normotensive patients, indicating that the effects of moxonidine may at least in part be blood pressure independent. Ref 41. Krespi PG et al. Cardiovasc Drugs Ther 1998;12: , Strojek K et al. 36th Ann Meeting of the EASD (2000), Jerusalem, Israel, September 52. Burt VL et al. Hypertension 1995;25: 41. Krespi PG et al. Cardiovasc Drugs Ther 1998;12: , 42. Strojek K et al. 36th Ann Meeting of the EASD (2000), Jerusalem, Israel, September., 52. Burt VL et al. Hypertension 1995;25:

Effect on serum creatinine43
Effect of moxonidine (0.3mg/day, n=89) and nitrendipine (20mg/day, n=82) on serum creatinine in patients with advanced renal failure moxonidine nitrendipine p<0.05 serum creatinine (µmol/L) 500 - 400 - 300 - 200 - 100 - 0 - Vonend et al (2003)[43] reported the results of a prospective, randomised, double-blind study of 177 patients with advanced renal failure (creatinine clearance <30ml/min). All patients were receiving ‘standard’ renal protection with an ACE inhibitor or AIIA/loop diuretic combination. After a 2-week run-in period, patients were randomised to receive 24 weeks of add-on therapy with moxonidine 0.3mg/day or nitrendipine 20mg/day. Over a 6-month period there was a greater decline in serum creatinine with nitrendipine than with moxonidine, which was statistically significant at the 6-month assessment (p<0.05). Increases of more than 25% in serum creatinine occurred in 28.2% of nitrendipine patients, compared with 6.7% of moxonidine patients (per protocol analysis). Increases of more than 50% in serum creatinine occurred in 7.0% of nitrendipine patients and 1.3% of moxonidine patients. Both treatments were well tolerated, with a drop-out rate due to adverse events of 12.4% for moxonidine and 9.8% for nitrendipine. There were no differences in blood pressure between treatments. Ref 43. Vonend O et al. J Hypertens 2003;21: 1 2 3 4 5 6 months 43. Vonend O et al. J Hypertens 2003;21:

Moxonidine - adverse events24
Treatment-emergent adverse events affecting > 4% patients after monotherapy with moxonidine 0.6mg/day, enalapril 20mg/day, or placebo in an 8-week randomised, double-blind trial moxonidine (n=51) enalapril (n=53) placebo (n=50) % patients reporting adverse events 20 - 10 - 0 - Cumulative exposure to moxonidine worldwide is currently over one million patient years. The clinical safety and adverse events profiles have been well established in approximately 100 clinical trials and a large post-marketing surveillance report. Moxonidine has been generally very well tolerated in controlled clinical studies, either as monotherapy or adjunctive therapy. A low incidence of treatment-emergent adverse events has been reported, most of which were mild or transient, and adverse events only occasionally lead to discontinuation of treatment. In studies versus active comparators, monotherapy with moxonidine was at least as well tolerated as monotherapy with agents from all the main antihypertensive drug classes. This slide shows tolerability results from an 8-week randomised, double-blind, placebo-controlled study versus enalapril, which used the highest recommended daily dose of moxonidine (0.6mg daily).[24] The most common adverse event with moxonidine was dry mouth, which affected 18% of patients. Moxonidine is well tolerated in older patients, with a similar profile of adverse events to that seen in younger patients. Adverse events with moxonidine when used in combination with enalapril, amlodipine or HCTZ in randomised, double-blind, multicentre trials were characteristic of those of the individual component drugs. Ref 24. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51 nausea gastro- enteritis diarrhoea headache dry mouth bronchitis dizziness back pain 24. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51

Tolerability in a 52-week study28
Treatment-emergent adverse events affecting >2% of patients in a long-term, open-label study of moxonidine % patients reporting adverse events 20 - 15 - 10 - 5 - 0 - 13% 5% 3% 2% 0% 0% Moxonidine was considered to be well or very well tolerated in 137/141 patients (97%) who received moxonidine for 12 months in an open-label study.[28] During the 12 months of the study, the only treatment-emergent adverse events with an overall incidence greater than 2% were dry mouth and tiredness, which were mostly reported during the early weeks of therapy. After three months of treatment, the only adverse event with an incidence greater than 2% was dry mouth. Tolerability data are available for the use of moxonidine in 91,170 hypertensive patients (>18,500 patient-years), about two-thirds of whom received monotherapy. Over 7,000 patients were assessed for six months or more, and over 15,000 patients (16.5%) had co-existing diabetes. Adverse events were reported in 9.4% of patients, the most common adverse event being dry mouth (3.6%). Treatment was discontinued by 1.8% of patients because of adverse events. Ref 28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620 week 3 week 12 week 52 week 3 week 12 week 52 DRY MOUTH TIREDNESS 28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620

Moxonidine - contraindications
The following are listed on the Master SmPC for moxonidine:* Known hypersensitivity to any of the components of the product Sick sinus syndrome Bradycardia (resting heart rate <50bpm) This slide shows contraindications listed on the Master SmPC for moxonidine. Please see National Prescribing Information or Summary of Product Characteristics (SmPC), as licence details may vary between countries. Studies have not revealed rebound hypertension with moxonidine, but it would be advisable to withdraw treatment gradually over two weeks. When stopping combined therapy with a beta-blocker, the beta-blocker should be stopped a few days before stopping moxonidine. In renally impaired patients, the dosage should be titrated according to the individual requirements. In patients with moderate-to-severe renal impairment the starting dose is 0.2mg/day. If necessary and well tolerated the dose can be increased to 0.4mg/day. The same dosage recommendations also apply to patients undergoing haemodialysis. Caution should be exercised when prescribing to pregnant women. Lactating women should be advised not to breast feed while on moxonidine, or they should stop treatment with the drug. * Please see National Prescribing Information or SmPC, as licence details may vary between countries

Chemical structure of moxonidine
The coloured area identifies the imidazoline part of the structure OCH3 H N N H3C NH N N The imidazoline moiety of moxonidine is believed to be relevant to its principal pharmacological properties. Cl 71. van Zwieten. J Hypertens 1999;17(suppl 3):S15-S21

Mode of action of moxonidine
The autonomic nervous system is regulated by cardiovascular control centres in the rostral ventrolateral medulla (RVLM) in the brain stem Sympathetic response is mediated through imidazoline binding sites in the RVLM Moxonidine has a highly selective agonist effect on imidazoline I1-receptors in the RVLM16 This causes inhibition of sympathetic activity and reduced peripheral resistance The autonomic nervous system is regulated by cardiovascular control centres in the rostral ventrolateral medulla (RVLM) within the medulla oblongata. The degree of sympathetic response appears to be mediated through imidazoline binding sites in the RVLM. The antihypertensive action of moxonidine can be explained in terms of a highly selective agonist effect on imidazoline I1-receptors in the RVLM, causing inhibition of sympathetic activity and reduced peripheral resistance. 16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992; 20(suppl 4):S1-S10

Acts within the RVLM Microinjection of moxonidine into the RVLM of spontaneously hypertensive rats produces rapid, dose-dependent reductions of arterial blood pressure72 There is no effect on blood pressure if moxonidine is injected into adjacent (non-RVLM) areas of the medulla Microinjection of moxonidine into the RVLM of spontaneously hypertensive rats resulted in rapid, dose-dependent reductions of arterial blood pressure, whereas there was no effect on blood pressure if moxonidine was injected into adjacent (non-RVLM) areas of the medulla.[72] Ref 72. Haxhiu MA et al. J Cardiovasc Pharmacol 1992; 20 (suppl 4):S11S15 72. Haxhiu MA et al. J Cardiovasc Pharmacol 1992; 20 (suppl 4):S11S15

Selective for I1 receptors
The blood pressure-lowering effect of moxonidine is reversed by injection of efaroxan (an I1-receptor antagonist) into the RVLM73 In vitro, moxonidine has an approximately 70-fold greater affinity for I1-receptors compared with a2-receptors16 The blood pressure-lowering effect of systemically administered moxonidine was shown to be reversed by injection of efaroxan (an imidazoline I1-receptor antagonist) into the RVLM.[73] In vitro, moxonidine has been shown to be a highly selective ligand for I1-receptors, having an approximately 70-fold greater affinity for these receptors compared with alpha-2-adrenergic receptors.[16] The selectivity and affinity of moxonidine for I1-receptors has also been confirmed in receptor binding studies in rat renal medulla samples. Refs 16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992; 20(suppl 4):S1-S10 73. Haxhiu MA et al. Cardiovasc Drugs Ther 1993;7(suppl 2):155(Abstr 155) 16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992; 20(suppl 4):S1-S10., 73. Haxhiu MA et al. Cardiovasc Drugs Ther 1993;7(suppl 2):155(Abstr 155)

Moxonidine is highly selective16
Selectivity of moxonidine for imidazoline (I1) and a2-receptors (Ki = affinity constant). Affinity for I1 versus a2-receptors (log Ki at I1 receptors divided by Ki at a2-receptors) -5 -4 -3 -2 -1 1 2 3 moxonidine rilmenidine clonidine norepinephrine epinephrine guanabenz a2 > I1 I1 > a2 16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S1-S10

Actions of centrally-acting agents71
a-methyldopa clonidine MOXONIDINE (non-selective) selective a2 - adrenoceptor I1 - imidazoline receptor Nucleus tractus solitarii Salivary glands Nucleus coeruleus Rostral ventrolateral medulla (RVLM) Inhibition of sympathetic nerve activity Older centrally acting agents such as clonidine and alpha-methyldopa are frequently associated with sedation and dry mouth, which are generally thought to be a result of interactions with alpha-2-receptors. The highly selective action of moxonidine on I1-receptors in the RVLM, with lesser effects on alpha-2-receptors, provides antihypertensive efficacy with a relatively low incidence of adverse events. Inhibition of norepinephrine release Peripheral vasodilation Dry mouth Sedation Lowering of blood pressure 71. van Zwieten. J Hypertens 1999;17(suppl 3):S15-S21

Effects on catecholamine levels
Single oral doses of moxonidine reduce plasma norepinephrine levels in patients with hypertension74 The fall in plasma norepinephrine correlates with the reduction in SBP (p=0.05) and DBP (p=0.02) Reductions in plasma catecholamine levels reported in clinical studies with moxonidine37 Single oral doses of moxonidine have been shown to reduce plasma norepinephrine levels in patients with hypertension.[74] The fall in plasma norepinephrine levels correlated with the reduction in systolic (p=0.05) and diastolic (p=0.02) blood pressures. Reductions in plasma catecholamine levels have also been reported in some clinical studies which evaluated this parameter. For example, 24 weeks of moxonidine treatment in obese hypertensive patients produced statistically significant reductions in plasma arterial levels of epinephrine (-22.5%, p<0.005 versus pretreatment) and norepinephrine (-20.4%, p<0.01 versus pretreatment).[37] There was a statistically significantly greater reduction in patients whose blood pressure was controlled compared with non-responders (p<0.003). Refs 37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25 74. Kirch W et al. J Clin Pharmacol 1990;30: 37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25., 74. Kirch W et al. J Clin Pharmacol 1990;30:

Hours post-administration
Haemodynamic effects of moxonidine17 Effect of moxonidine on cardiac output and systemic vascular resistance dyn.sec/cm5 L/min 2000 - 1800 - 1600 - 1400 - 1200 - - 8 - 6 - 4 - 2 - 0 cardiac output * p<0.01 systemic vascular resistance * The haemodynamic effects of a single oral dose of moxonidine (0.4mg) were investigated in ten patients with mild-to-moderate hypertension.[17] There was a significant fall in mean blood pressure over a 4-hour observation period from 176/105 to 158/95 mmHg (p<0.01). This was accompanied by an approximately 16% decrease in systemic vascular resistance from 1695 to 1427 dyn.sec/cm5 (p<0.01), with no significant change in cardiac output. No significant changes were recorded for either pulmonary artery pressure or pulmonary vascular resistance. The authors concluded that moxonidine lowered blood pressure by reducing systemic vascular resistance while maintaining cardiac output and heart rate. Ref 17. Mitrovic V et al. Cardiovasc Drugs Ther 1991;5: * * 1 2 3 4 Hours post-administration 17. Mitrovic V et al. Cardiovasc Drugs Ther 1991;5:

Neutral effect on lipid profile
In a study of 20 hypertensive patients, moxonidine produced no statistically significant changes in HDL, LDL or total cholesterol, or triglycerides75 There were no significant changes in these lipid parameters in an analysis of pooled results from several placebo-controlled trials70 A study in 20 hypertensive patients looked at the effects of moxonidine on lipid fractions; there were no statistically significant changes in HDL, LDL or total cholesterol, or triglycerides.[75] There were also no significant changes in these parameters in an analysis of pooled results from several placebo-controlled trials.[70] Refs 70. Data on file, Solvay Pharmaceuticals GmbH 75. Elisaf MS et al. J Hum Hypertens 1999;13: 70. Data on file, Solvay Pharmaceuticals GmbH., 75. Elisaf MS et al. J Hum Hypertens 1999;13:

Pharmacokinetics of moxonidine78
Parameter Single dose* Multiple dose Time to peak plasma concentration (hr) 0.74 0.67 Peak plasma concentration (ng/ml) 1.29 1.33 Area under the curve (0-infinity) (ng.hr/ml) 4.18 4.02 Terminal half-life (hr) 2.12 1.97 Total clearance (ml/min) 830 863 Renal clearance (ml/min) 530 522 This slide shows the main pharmacokinetic parameters of moxonidine 78. Weimann H-J, Rudolph M. J Cardiovasc Pharmacol 1992;20(suppl 4):S37-S41 * oral dose 0.2mg bd (n=12)

Pharmacokinetics of moxonidine76,77
80-90% of an oral dose is absorbed Bioavailability = 88% Protein binding = 7% About 10% is metabolised (metabolites have low antihypertensive potency) Peak plasma concentrations reached within 60 min; mean plasma half-life is about 2 hours Of note is the low extent of protein binding (7%) which makes drug interactions with highly protein bound drugs unlikely. 76. Theodor R et al. Eur J Drug Metab Pharmacokinet 1991;16(2): Trenk D et al. J Clin Pharmacol 1987;27:

Pharmacokinetics of moxonidine - 2
Does not accumulate in plasma with repeated dosing77,78 Pharmacokinetics are not significantly affected by food78 No dose adjustment needed in older patients whose renal function is normal for age No evidence of moxonidine accumulation after multiple dosing in older subjects78 Of note here is that older patients can receive the same dose as younger patients. In a parallel-group study, there was no evidence of moxonidine accumulation after five days in older subjects (mean age 71 years, n=12) compared with a younger group (mean age 28 years, n=12). Clinically insignificant changes were observed in tmax, AUC and total apparent clearance. 77. Trenk D et al. J Clin Pharmacol 1987;27: , 78. Weimann H-J, Rudolph M. J Cardiovasc Pharmacol 1992;20 (suppl 4):S37-S41., 79. Kirch Wet al. Clin Pharmacokinet 1988;15:

Time after administration (hours)
Plasma profile of moxonidine77 Plasma concentration-time profile of moxonidine after an oral single dose (0.2mg) and after giving 0.2mg bd for 5 days (n=12) Plasma concentration mcg/L 2000 - single dose 1000 - multiple dose 600 - 300 - Although there is a relatively short plasma half-life, blood pressure control is satisfactory on a once-daily basis. This is probably because moxonidine is compartmentalised in the brain, i.e., an effective concentration is achieved in the RVLM but this is not reflected in the plasma concentration. Excretion is essentially complete within 24 hours after dosing. 100 - 1 2 3 4 5 6 7 8 Time after administration (hours) 77. Trenk D et al. J Clin Pharmacol 1987;27:

Time after administration (hours)
Plasma profile in renal impairment79 Plasma concentration-time profile of moxonidine (0.3mg once-daily for 7 days) in patients with and without renal impairment (n=8 per group) Log plasma concentration mcg/L 4.0 - 1.0 - GFR <30ml/min 0.4 - 0.1 - GFR 30-60ml/min Elimination half-life and area-under-the-curve are increased in patients with renal impairment, and there is a reduction in the total clearance.[79] There was no accumulation in patients with moderate renal dysfunction during seven days of treatment. In patients with moderate to severe renal impairment the recommended starting dose is 0.2mg/day; this may be increased to 0.4mg/day if necessary and well tolerated. Ref 79. Kirch W et al. Clin Pharmacokinet 1988;15: 0.04 - GFR >90ml/min 0.01 - 3 6 9 12 15 18 21 24 Time after administration (hours) 79. Kirch W et al. Clin Pharmacokinet 1988;15:

Low likelihood of drug interactions
Only 7% protein binding - interaction with highly protein bound drugs is unlikely No substantial pharmacokinetic interaction with digoxin, HCTZ or glibenclamide Has been co-administered with hypolipidaemic agents Effect of sedatives/hypnotics may be intensified Avoid use with alcohol or tricyclic antidepressants Moxonidine is likely to be used in conjunction with a variety of drugs including cardiac glycosides, other antihypertensives such as diuretics, and oral hypoglycaemic agents. No evidence of substantial pharmacokinetic interaction has been found in studies conducted with representative agents from each of these three groups (e.g., digoxin, hydrochlorothiazide, glibenclamide). Moxonidine has a low degree of protein binding and interaction with highly protein bound drugs such as warfarin would not be anticipated. The effect of sedatives and hypnotics may be intensified by moxonidine, and the sedative effect of benzodiazepines can be enhanced. Due to lack of therapeutic experience, the use of moxonidine concomitantly with alcohol or tricyclic antidepressants should be avoided. Moxonidine has been co-administered with hypolipidaemic agents (e.g., lovastatin, simvastatin, pravastatin, fenofibrate, gemfibrozil, niacin). Moxonidine has been administered with other antihypertensive drugs, including thiazide diuretics and calcium-channel blockers. Concomitant administration of these and other antihypertensive agents results in an additive effect.

Usual maintenance dose is 0.4mg per day
Dosage of moxonidine 0.2mg, 0.3mg, 0.4mg tablets 0.2mg usual starting dose Can be increased to 0.4mg daily after 2-3 weeks Can be increased to 0.6mg daily after a further 2-3 weeks Moxonidine offers flexible dosing. The usual maintenance dose for most patients is 0.4mg per day. Usual maintenance dose is 0.4mg per day Appearance of pack varies between countries

Administration May be taken with or without food
Stop treatment gradually over two weeks If stopping a combined moxonidine/beta-blocker regimen, stop the beta-blocker a few days before moxonidine is gradually stopped No dose adjustment required in the elderly Starting dose of 0.2mg/day in patients with moderate to severe renal impairment - if necessary and well tolerated the dose can be increased to 0.4mg/day If stopping treatment with moxonidine, this should be carried out gradually over a period of two weeks. Moxonidine may be used alone or in combination with other anti-hypertensives, such as thiazide-type diuretics, calcium-channel blockers, and angiotensin-II receptor antagonists. If used in conjunction with a beta-blocker, in the event of treatment cessation, the patient should stop the beta-blocker a few days before moxonidine is gradually stopped.

Summary - 1 Many patients with hypertension have metabolic syndrome - with one or more conditions such as insulin resistance, impaired glucose tolerance, obesity and altered lipid profile When treating these patients it would be appropriate to select an antihypertensive agent with a beneficial or neutral effect on the other components of the metabolic syndrome

Summary - 2 Moxonidine acts centrally to reduce sympathetic stimulation It is as effective as other classes of antihypertensive agents in reducing SBP and DBP It may be used as monotherapy, but is a good option for adjunctive therapy in patients with the metabolic syndrome

Summary - 3 Moxonidine lowers blood pressure and improves the metabolic profile in several types of hypertensive patients: diabetics impaired glucose tolerance / insulin resistance obese postmenopausal metabolic syndrome

Summary - 4 Beneficial effects have been seen with moxonidine in hypertensive patients with LVH Moxonidine has been shown to have renoprotective properties Moxonidine is well tolerated A low level of drug interactions, once-daily dosing, and linear dose-response are advantageous when using moxonidine in combination regimens

Physiotens Cynt Solvay Pharmaceuticals December 2005

MOXONIDINE ® ® A review of moxonidine in essential hypertension, with emphasis on metabolic syndrome and other conditions associated with sympathetic overactivity.

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MOXONIDINE ® ® A review of moxonidine in essential hypertension, with emphasis on metabolic syndrome and other conditions associated with sympathetic overactivity.

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Presentation on theme: "MOXONIDINE ® ® A review of moxonidine in essential hypertension, with emphasis on metabolic syndrome and other conditions associated with sympathetic overactivity."— Presentation transcript:

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