A korszerű centrális antitenzív kezelés szerepe a kiemelt cardiovascularis kockázatú metabolikus szindrómás, Hypertoniás – Obes - Diabeteses betegcsoportokban 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 Pest Megyei Orvosnapok Gödöllő 2006. április 22. dr. Oláh Csaba

H.O.D. Hypertonia Obesitas Diabetes 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

A tünetek különböző mértékű szimpatikus túlsúlyt tükröznek1 Metabolikus szindróma A hypertonia gyakran társul obezitással, inzulinrezisztenciával és dyslipidaemiával Ez a tünetegyüttes alkotja a metabolikus szindrómát, mely a diabetes és a cardiovascularis betegségek kialakulása szempontjából fokozott rizikót jelent 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 A tünetek különböző mértékű szimpatikus túlsúlyt tükröznek1 1. Rahn KH et al. J Hypertens 1999;17(suppl 3):S11-S14

Szimpatikus túlsúly A fokozott szimpatikus tónus egy központi tényező, mely összekapcsolja a hypertoniát és a metabolikus szindróma egyéb komponenseit Sympathetic overactivity may be a central feature linking hypertension with other components of the metabolic syndrome.

SNSO kapcsolata az MS komponenseivel I. Hypertonia: Állatkísérletekben a szimpatikus túlsúly előidézi és fenntartja a magas vérnyomást3 Hypertoniás betegekben a plasma noradrenalin szintje szignifikánsan magasabb, mint a normotenziv kontrollokban (p<0.05)4 A hypertonia korai szakaszában is kimutatható a fokozott szimpatikus aktivitás és egyes esetekben megelőzheti a hypertonia manifesztálódását!5 A szimpatikus aktivitás magasabb lehet fiatal, borderline-hypertoniásokban A fokozott szimpatikus aktivitás oka és nem következménye a vérnyomás emelkedésnek!2 Obesitás Nagyobb BMI növekvő szimpatikus tónus fokozódással jár együtt a vázizomzatban6 A BMI, testzsír-eloszlás és a vizelet NA-kiválasztás között korreláció mutatható ki7 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 2. Rahn KH et al. J Hypertens 1999;17(suppl 3):S11-S14 3. Mancia G et al. J Hum Hypertens 1997;11(suppl 1):S3-S8., 4. Goldstein DS. Hypertension 1981;3:48-52., 5. Julius S, Valentini M. Blood Press 1998;7(suppl 3):5-13, 6. Scherrer U et al. Circulation 1994;89:2634-2640., 7. Landsberg L. Cardiovasc Risk Factors 1993;3:153-158

SNSO kapcsolata az MS komponenseivel II. Inzulin rezisztencia és diabetes Klinikai kísérletekben8 és 2-es típusú diabeteses betegekben9 a szimpatikus aktivitás az inzulinrezisztencia fő komponense Cardiopathia(autonom dysfunctio) előfordulása - a diabeteses betegek 30-50%-ában, - a nem diabeteses, obes betegek 40%-ában10 Egyéb rizikó faktorok Fokozott szimpatikus aktivitás jelen van mind vesebetegségekben, LVH és CHF-el járó esetekben11,12,13 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 8. Jamerson KA et al. Hypertension 1993;21:618-623., 9. Huggett RJ et al. Circulation 2003;108:3097-3101., 10. Valensi P et al. ESC 2004 (www.solvaycardio.com) 11. Ritz E et al. Blood Press 1998;7(suppl 3):14-19., 12. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65., 13. Lanfranchi A et al. Blood Press 1998;7(suppl 3):40-45

Szimpatikus túlsúly, inzulin rezisztencia és diabetes Klinikai kísérletekben7 és 2-es típusú diabetesben8 szenvedő betegek körében a szimpatikus aktivitás az inzulinrezisztencia kialakulásának fő komponense Kardiális autonóm diszfunkció - a diabeteses betegek 30-50%-ában, - a nem diabeteses, obes betegek 40%-ában fordul elő 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;21:618-623 8. Huggett RJ et al. Circulation 2003;108:3097-3101 9. Valensi P et al. ESC 2004(www.solvaycardio.com) 7. Jamerson KA et al. Hypertension 1993;21:618-623., 8. Huggett RJ et al. Circulation 2003;108:3097-3101., 9. Valensi P et al. ESC 2004 (www.solvaycardio.com)

A metabolikus szindróma incidenciája1 a normál éhomi vércukorral rendelkezők 10-15%-ában az IGT/IFG-s betegek 42-64%-ában a 2-es típusú diabeteses betegek 78-84%-ában fordul elő Metabolikus szindróma esetén a coronariabetegség és a stroke rizikója, valamit a cardiovascularis mortalitás magasabb (p<0.001) Metabolic syndrome is a frequent condition. An epidemiological study of 4,483 subjects aged 35-70 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;24:683-689 A metabolikus szindróma tünetei különböző mértékű szimpatikus túlsúlyt tükröznek2 1. Isomaa B et al. Diabetes Care 2001;24:683-689 *4483 - 35-70 év közötti – beteg vizsgálata 2. Rahn KH et al. J Hypertens 1999;17(suppl 3):S11-S14

A cardiovascularis tünetek kialakulása10 Életmód Elhízás INZULIN REZISZTENCIA / METABOLIKUS SZINDRÓMA - Szabad zsírsavak - oxidativ stress - gyulladás Relatív szimpatikus túlsúly Endothel dysfunctio Artériás rigiditás hypertonia 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 Arrhythmia LVH Cardiovascularis szövődmények 10. Valensi P et al. Presented at a satellite symposium at the ESC Congress 2004, Munich, Germany.

Diabeteses/prediabeteses hypertoniás betegek A prediabeteses állapot jellemzője az inzulin rezisztencia, hyperinsulinaemia és a hyperglycaemia Az antihypertensiv kezelés hosszútávú hasznát veszélyeztetheti ha a választott gyógyszerek kedvezőtlenül befolyásolják az inzulin érzékenységet! Hypertoniás betegekben a moxonidin csökkenti a plazma glucose szintjét és fokozza az inzulin érzékenységet 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 SENSITIVITÁS INDEX (ISI) GLUCOSE INFUSIO SEBESSÉGE Moxonidin hatásai inzulin rezisztencia esetén16 8 hetes moxonidin kezelés (0.4mg/nap) hatása hypertoniás, csökkent inzulin érzékenységű betegekben - kettősvak, placebo-kontrollált, randomizált, parallel csoportos vizsgálat - INSULIN SENSITIVITÁS INDEX (ISI) GLUCOSE INFUSIO SEBESSÉGE p=0.026 p=0.056 25 - 20 - 15 - 10 - 5 - 0 - - 5 - -10 - % változás a kiindulási értékhez képest p=0.004 p=0.027 moxonidin (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. 16. Haenni A, Lithell H. J Hypertens 1999;17(Suppl 3):S29-S35 ISI meghatározása: hyperinsulinaemiás- euglycaemiás clamp teszttel. ISI = glucose infusio sebesség/átlag inzulin konc. „steady-state”-nél

Normal glucose toleranciás hypertoniások17 30, enyhe-középsúlyos hypertoniás, normál glucose toleranciájú egyén Az inzulin szenzitivitást a moxonidin kezelés (0,2mg-0,6mg/nap) 6. hónapja után vizsgálták Az OGTT során a 2 órás plasma insulin szintet a moxonidin kezelés szignifikánsan csökkentette (18%-al, p<0.05) összehasonlítva a kezelést megelőző értékkel Almazov et al (2000)[32] evaluated the influence of six months of treatment with moxonidine (0.2-0.6mg/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 17. Almazov VA et al. J Hypertens 2000;18(suppl 2):12

Inzulin-rezisztens hypertoniás betegek18 202 inzulin rezisztens, túlsúlyos, enyhe hypertoniás beteg, nyílt, randomizált vizsgálata 16 hetes moxonidin (2x0.2mg) vagy metformin (2x500mg) kezelés naponta OGTT során az inzulin AUC 14.7%-kal alacsonyabb volt moxonidin kezelés mellett, mint metformin esetén (p=0.052) A magas szimpatikus aktivitással bíró betegek között a két kezelési csoportban az AUC különbsége 23.8% volt (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 (www.solvaycardio.com) 18. Betteridge J. ESC 2004 (www.solvaycardio.com) Fokozott szimpatikus aktivitás = >80/min pulzus

Hypertoniás - diabeteses betegek19 2-es típusú diabeteses hypertoniás betegek 12 hetes vizsgálata Antihypertensiv terápiát kiegészítő moxonidin kezelés (0.2-0.6mg/nap) vs. metoprolol A moxonidin szignifikánsan jobban javította az éhomi plazma glucose szintet mint a metoprolol A kiindulási értékhez képest egyik csoportban sem változott szignifikánsan az inzulin érzékenység! In a 12-week study reported by Jacob et al (2004)[34] in patients with hypertension and type 2 diabetes, moxonidine 0.2-0.6mg/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):315-322 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. 19. Jacob S et al. Exp Clin Endocrinol Diabetes 2004;112(6):315-322

Obesitás és hypertonia Obes betegekben a hypertonia, a renalis szimpatikus idegek aktivációjával és a RAAS rendszer stimulációjával mutat összefüggést 20,21 Az emelkedett BMI, fokozott vizelet NA szinttel jár együtt22 Az normo,- és hypertoniás obes betegek többségében emelkedett a leptin szint23,24 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;304:930-933 49. Landsberg L. J Cardiovasc Pharmacol 1994;23(suppl 1):S1-S8., 50. Barroso SG et al. Trace Elem Electrolytes 2003;20:134-139 51. Masuo K et al. Am J Hypertens 2001;14:530-538 20. Hall JE. Am J Hypertens 1997;10: S49-S55., 21. Tuck ML et al. N Engl J Med 1981;304:930-933., 22. Landsberg L. J Cardiovasc Pharmacol 1994;23(suppl 1):S1-S8., 23. Barroso SG et al. Trace Elem Electrolytes 2003;20:134-139., 24. Masuo K et al. Am J Hypertens 2001;14:530-538

Moxonidin obes hypertoniásokban25 A moxonidin 0.2-0.4mg/nap és az amlodipin 5mg/nap hatása a rendelői RR diast. értékekre 12 és 24 hetes kezelés során - 40 obes, enyhe-középsúlyos hypertoniás beteg nyílt vizsgálata - moxonidin amlodipin 12.hét 24.hét 12.hét 24.hét ülő RR diast. változása (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 27-63 years old. Patients were eligible for inclusion if sitting blood pressure was in the range 140-180/90-120 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 kiindulási értékhez képest (kezelések között nincs szignifikáns különbség) 25. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25 A vérnyomás moxonidin mellett 58%-ban, amlodipin mellett 52%-ban volt kontrollált

Moxonidin metabolikus hatásai obes hypertoniásokban25 24 hetes moxonidin kezelés (0.2-0.4mg/nap) hatása - alcsoport analízis a vérnyomáscsökkenés függvényében - álló helyzetben mért NA (pg/ml) plazma leptin csökkenés (pg/ml) éhomi inzulin csökkenés (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). reagálók ** p<0.003 reagálók vs nem reagálók * p<0.05 reagálók vs nem reagálók nem reagálók 25. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25 Reagálók=rendelői RR<140/90Hgmm

Moxonidin obes - hypertoniásokban26 112 obes, nem-kontrollált hypertoniás és 25, 2-es tip. diabeteses antitensiv kezelésének kiegészítése moxonidinnel (0.4mg/nap) nyílt, multicentrikus vizsgálatában 6 hónapos kezelés után átlagos RRsyst. csökkenés 23.0 Hgmm, RRdiast. csökkenés 12.9 Hgmm Összességében a systolés vérnyomást a betegek 63%-ban, a diasztolés vérnyomást 86%-ban sikerült kontrollálni 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 26. Abellán J et al. Kidney Int 2005;67(suppl 93):S20-S24

Postmenopausalis hypertonia Menopausa után a systolés vérnyomás emelkedése jellemző Menopausa után hölgyekben a hypertonia prevalenciája megegyezik a férfiakéval!27 A „Menopausalis Metabolikus Szindróma” (MMS) a hypertonia, abdominalis obesitas, inzulin rezisztencia, 2-es típusú diabetes és a dyslipidaemia együttese28,29 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;25:305-313 53. Tong PL et al. Atherosclerosis 2002;161(2):409-415 54. Mercuro G et al. Ital Heart J 2001; 2(10):719-727 27. Burt VL et al. Hypertension 1995;25:305-313., 28. Tong PL et al. Atherosclerosis 2002;161(2):409-415., 29. Mercuro G et al. Ital Heart J 2001; 2(10):719-727

Regionális zsír metabolizmus Menopausalis Metabolikus Szindróma30 MENOPAUSA Oestrogen hiány Regionális zsír metabolizmus Energia felhasználás Centrális elhízás Inzulin Rezisztencia Hypertonia és Endothel Dysfunctio Metabolikus Szindróma 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 Vascularis gyulladás Csökkent Glucose Tolerancia 2-típusú diabetes Atherosclerosis 30. Sjoberg L et al. Int J Clin Pract 2004;suppl 139:4-12

*p<0.01 vs. kezelés előtti állapot Intention to treat analysis Moxonidin postmenopauzás nőkben31 I. A plazma glucose változása a kiindulási értékhez képest OGTT során moxonidin (0.6mg/nap) és atenolol (50mg/nap) kezelést követően 109 postmenopauzás, obes, hypertoniás nőbeteg kettősvak vizsgálata Plazma glucose (mmol/l) 0.2 - 0 - - 0.2 - - 0.4 - - 0.6 - - 0.8 - - 1.0 - * * 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 0 óra 1 óra 2 óra * OGTT után eltelt idő AUC *p<0.01 vs. kezelés előtti állapot moxonidin atenolol 31. Kaaja R et al. Int J Clin Pract 2004;suppl 139:26-32 Intention to treat analysis

Moxonidin postmenopauzás nőkben31 II. A plazma inzulin változása a kiindulási értékhez képest OGTT során moxonidin (0.6mg/nap) és atenolol (50mg/nap) kezelést követően 109 postmenopauzás, obes, hypertoniás nőbeteg kettősvak vizsgálata Plazma inzulin (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 0 óra 1 óra 2 óra OGTT után eltelt idő AUC moxonidin atenolol 31. Kaaja R et al. Int J Clin Pract 2004;suppl 139:26-32

Centrális antitensivumok hatásmechanismusa* a-methyldopa clonidine MOXONIDIN (non-selective) selective a2 - adrenoreceptor I1 - imidazolin receptor Nucleus tractus solitarii Rostralis ventrolateralis medulla (RVLM) Nyálmirigy Nucleus coeruleus Symp. idegrendszer aktivitásának gátlása 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. NA felszabadulás gátlása Peripheriás vasodilatio Szájszárazság Álmosság vérnyomáscsökkenés *van Zwieten. J Hypertens 1999;17(suppl 3):S15-S21

Kedvező hatás a lipid profilra 20 hypertoniás beteg vizsgálata során a HDL, LDL és TC, és TG szintekben, a moxonidin nem okozott statisztikailag szignifikáns változást14 Különböző placebo-kontrollált vizsgálatok eredményeinek analízise során nem volt szignifikáns változás a lipid profilban15 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;13:781-785 14. Elisaf MS et al. J Hum Hypertens 1999;13:781-785, 15. Data on file, Solvay Pharmaceuticals GmbH.

Összefoglalás A moxonidin csökkenti a vérnyomást és kedvezően befolyásolja a metabolikus paramétereket az alábbi kórállapotok / társbetegségek esetén Hypertonia Obesitas Diabetes IGT / IR PMMS(postmenop.met. syndr.) A moxonidin kedvezően befolyásolja a balkamra hypertrophiát, renoprotectív hatása van Kombinációban történő alkalmazás előnyei (ritka a gyógyszer- interakció, lineáris dózis-hatás összefüggés. napi 1x adható)

Egy „sympathicus” üzenet Az autonom dysfunctio fontos szerepet játszik a metabolikus szindrómás betegek többségében 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 A hypertoniás betegek kezelés során a kísérő metabolikus eltéréseket is szem előtt kell tartani32 32.Hansson L. Blood Press 1998;7(suppl 3):20-22