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- 1. Predavanje je potpomognuto od strane kompanije Abbott Laboratories S.A., u skladu sa Pravilnikom o načinu oglašavanja leka, odnosno medicinskog sredstva Službeni glasnik RS br 79/2010 Prim. dr Miloš Prtenjak Kardiolog Opšta bolnica Čačak Mesto centralnih antihipertenziva u terapiji hipertenzije i uloga simpatikusa u patogenezi kardiometaboličkih oboljenja
- 2. ESH/ESC Guidelines for the management of arterial hypertension 2013 Journal of Hypertension 2013, 31:1281–1357 Guidelines for the management of arterial hypertension
- 3. 5.2.1 Izbor antihipertenzivnog leka Osnovna dobit od antihipertenzivne terapije je snižavanje KP samo po sebi i u velikoj meri je nezavisna od klase upotrebljenih AH lekova. Najveće raspoložive meta-analize ne pokazuju klinički relevantne razlike između klasa lekova.[284,394,395]. Vodiči potvrđuju da su diuretici (uključujući tiazide, hlortalidon i indapamid), beta- blokeri, kalcijum antagonisti, ACE inhibitori i blokatori angiotensinskih receptora pogodni za pokretanje i održavanje antihipertenzivne terapije, bilo kao monoterapija ili u kombinaciji. 5.2.1.6 Ostali antihipertenzivni lekovi Antihipertenzivni lekovi centralnog delovanja i blokatori alfa receptora su takođe efikasni antihipertenzivni lekovi. Danas se najčešće koriste u kombinovanoj terapiji. ESH/ESC Guidelines for the management of arterial hypertension 2013 Journal of Hypertension 2013, 31:1281–1357 Guidelines for the management of arterial hypertension
- 4. Uključimo mozak …… Snizimo pritisak
- 5. Moksonidin 0,2 mg i 0,4 mg • Antihipertenzivi centralnog delovanja - C02A • Agonisti imidazolinskog receptora (selektivan) C02AC • Lečenje blage do umerene esencijalne ili primarne hipertenzije • Lista A1: I 10 • Lek se u terapiju uvodi na osnovu mišljenja interniste ili kardiologa • početna dnevna doza: 0,2 mg jendom dnevno • maksimalna dnevna doza: 0,6 mg, dato u dve podeljene doze • maksimalna pojedinačna doza: 0,4 mg • dozu treba individualno podesiti u skladu sa reagovanjem pacijenta na lek Sažetak karakteristika leka moksonidin, Avgust 2014 5
- 6. Mehanizam delovanja - Moksonidin smanjuje prekomernu aktivnost simpatikusa a2 – adrenoreceptor centralno delovanje Sušenje usta snižavanje krvnog pritiska stimulacija (agonist) I1 - imidazolinskog receptor Metildopa Pljuvačne žlezde Nucleus coeruleus Nucleus tractus solitarii MoksonidinKlonidin (selektivan) Rostralno ventro lateral medulla (RVLM) redukcija simpatičke nervne aktivnosti inhibicija oslobađanja norepinefrina smanivanje sistemskog vaskularnog otpora (ne-selektivan) Sedacija van Zwieten PA. The renaissance of centrally acting antihypertensive drugs. J Hypertens 1999;17(suppl 3):S15-S21 Doksazosin a1 -adrenoreceptor periferno delovanje oblasti kritičnoj za centralnu kontrolu perifernog simpatičkog nervnog sistema periferna vazodilatacija centralno delovanje Sažetak karakteristika leka moksonidin, Avgust 2014
- 7. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620 13% nedelja 3 % pacijenata koji su prijavili neželjene efekte 20 - 15 - 10 - 5 - 0 - Suva usta Nesvestica 3% 2% nedelja 12 nedelja 52 5% nedelja 3 0% 0% nedelja 12 nedelja 52 Tokom 12 meseci studije, kod 137 od 141 pacijenata (97%), jedini neželjeni događaji koji su se pojavili sa ukupnom incidencom većom od 2% su suva usta i umor. Uglavnom su bili prijaviljeni tokom ranih nedelja terapije, a posle tri meseca lečenja, jedini neželjeni događaj sa incidencom većom od 2% ostala su suva usta. Takođe: Podaci o podnošljivosti upotrebe moksonidina postoje kod 91,170 hipertenzivnih pacijenata (>18,500 pacijent-godina), oko 2/3 pcijenata je primalo monoterapiju. Više od 7,000 pacijenata praćeno je 6 i više meseci, a preko 15,000 pacijenata (16.5%) imalo je pridruženi dijabetes. Neželjena dejstva su prijavljeni u 9,4% bolesnika, a najčešći neželjeni događaj bila su suva usta (3.6%). Terapija je prekinuta za 1,8% bolesnika zbog neželjenih događaja. Bezbednosni profil open-label study
- 8. Promene u prosečnom sedećem SKP i DKP tokom dve godine lečenja moksonidinom Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620., Prichard BNC. In: van Zwieten PA et al, editors. The I1 Imid. Rec. Agonist Moxonidine. 2nd Ed. London: Roy Soc Med, 1996:49-75 promene u prosečnom krvnom pritisku (mmHg) 180 - 160 - 140 - 120 - 100 - 80 - 2 godina (n=49) 1 godina (n=141) 26 52 78 1040 nedelje na terapiji moksonidinom open, multicenter, 12-24 month study 3 sistolni diastolni Tokom 12 meseci, 97% pacijenata bilo je zadovoljavajuće kontrolisano na dnevnoj dozi od 0.4mg ili manje Dugotrajna efikasnost 3 nedelja = kraj titriranja doze od 0.2 do 0.8mg (sa 172/103 na 151/88) no evidence of a rebound effect
- 9. Moksonidin snižava KP smanjujući sistemski vaskularni otpor, a zadržava minutni volumena srca i puls Mitrovic V et al. Cardiovasc Drugs Ther 1991;5:967-972 dyn.sec/cm5 2000 - 1800 - 1600 - 1400 - 1200 - 1 2h 3 4h0 minutni volumen srca sistemski vaskularni otpor - 8 - 6 - 4 - 2 - 0 Vreme (sati nakon primene) L/min * * * * p<0.01 Hemodinamski efekat significant fall in mean BP no significant change око 16% smanjenje sistemskog vaskularnog otpora 176/105 to 158/95 mmHg (p<0.01)
- 10. Povišena simpatička aktivnost može biti uzrok različitih patoloških stanja
- 11. Grassi G et al., Exp Physiol 2009 95.5; 581-585 Aktivnost simpatikusa je povišena kod sledećih bolesnika Hipertenzivni Kontrolna grupa MSNA*(bursts/minute) *Muscle Sympathetic Nerve Activity Gojazni saMetaboličkimsindromom bolesnicisaoštećenjembubrega p < 0.05 p < 0.05 MSNA represents the centrally generated postganglionic sympathetic activity to the human skeletal muscle circulation, which is an important determinant of blood pressure!
- 12. Hipertoničari, metabolički sindrom Povećana simpatička aktivnost • Pacijenti sa Hipertenzijom • Gojazni pacijenti • Pacijenti sa Metaboličkim sindromom6 5. Pharmacol. Properties of the Central Antihyper. Agent, Moxonidine Cardiovascular Therapeutics 30 (2012) 199–208 Hipertenzija Gojaznost abdominalana Insulinska rezistencija 6. MERSY Study, Int J Hypertens. 2013;2013:541689 Waist circumference +94/80 cm leptin, FFA insulin visok KP, norepinefrin
- 13. Osetljivost na insulin Efekti moksonidina 0.4mg/dan tokom 8 nedelja kod hipertenzivnih pacijenata sa smanjenom insulinskom osetljivošću % Promene u odnosu na stanje pre terapije GLUCOSE INFUSION RATE INSULIN SENSITIVITY INDEX 25 - 20 - 15 - 10 - 5 - 0 - - 5 - -10 - - 6.0% p=0.004 N.S. p=0.026 +21% - 6.0% p=0.027 +21% p=0.056 N.S. Placebo (n=13) Moksonidin (n=25) Prospektivna, duplo slepa, placebo kontrolisana, randomizovana, paralelna studija n=77 gojaznih pacijenata 9. 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
- 14. Efikasan kao monoterapija i u kombinaciji sa ostalim AH N= 5603; Multinational study: 13 countries; Male/Female:50.2/49.8%; 18-65 years (73.9%); diabetes was present for 47.1% Open label, observational study, follow up: 6 months, routine medical practice, either as monotherapy or as adjunct therapy to current antihypertensive treatment Uncontrolled essential HT and MS (Lack of eff. (n=3885); Intolerance (n=286); New dg. (n=866)...) Primary objective: Efficacy and safety of moxonidine 0.2-0.4 mg, once daily in hypertensive patients, mean BP 158/94 mmHg at base line; (respond: BP reduction < 140/90 mmHg) Secondary objective: Effect of moxonidine on lab. parameters associated with MS FPG↓; TG↓; Cho↓; LDL ↓; HDL↑... International Journal of Hypertension 2013; 2013:541689. doi: 10.1155/2013/541689.
- 15. 44,3% responder rate in pts <65 years; 33,4% responder rate in pts > 65 years; Average weight -2,1↓; Heart rate 79,6 74,1 beats/min; FPG↓ -0.8; TG↓-0.6; Cho↓-0.7; LDL↓-0.5; HDL↑ 0.1 Patients’ assess. of treatment were “excellent“,44.4%,“good“,48.3% “tolerable“, or “bad” 0.9% 195 SADRs were recorded in 132 patients (2,2%); dry mouth (48 events in 47 subjects); dizziness (16 events in 16 subjects) or headache (13 events in 13 subjects) -24.5 ± 14.3 -12.6 ± 9.1 -23 -24.8 (N= 5603)
- 17. O kojim pacijentima treba još misliti? • Pacijenti sa oštećenjem (ishemija) ili bolestima bubrega7 • Pacijenti pod stresom angiotensin II povećana aktivnost aferentntnih nervnih vlakana bubrega 7. Blankestijn P, Rupp H. Cardiovasc Hematol Agents Med Chem 2008;8:191–6
- 18. Hvala na pažnji!
Hinweis der Redaktion
- Antihipertenzivi centralnog delovanj
- Also, beta-blockers tend to increase body weight [401] and, particularly when used in combination with diuretics, to facilitate new-onset diabetes in predisposed patients [402]. Diuretics have remained the cornerstone of antihypertensive treatment since at least the first Joint National Committee (JNC) report in 1977 [412] and the first WHO report in 1978 [413], and still, in 2003, they were classified as the only first-choice drug by which to start treatment, in both the JNC-7 [264] and the WHO/International Society of Hypertension Guidelines [55,264]. It has also been argued that diuretics such as chlorthalidone or indapamide should be used in preference to conventional thiazide diuretics, such as hydrochlorothiazide [271]. Calcium antagonists have been cleared from the suspicion of causing a relative excess of coronary events by the same authors who had raised the question. Both classes are among those most widely used in antihypertensive therapy. Aliskiren, a direct inhibitor of renin at the site of its activation, is available for treating hypertensive patients, both as monotherapy and when combined with other antihypertensive agents. To date, available evidence shows that, when used alone, aliskiren lowers SBP and DBP in younger and elderly hypertensive patients [428]; that it has a greater antihypertensive effect when given in combinationwith a thiazide diuretic, a blocker of the RAS at other sites, or a calcium antagonist [429,430]; and that prolonged administration in combination treatment can have a favourable effect (i) on asymptomatic OD, such as urinary protein excretion [431] or (ii) on prognostic biomarkers for heart failure, such as B-type natriuretic peptides [432]. The alphablocker doxazosin has effectively been used as third-line therapy in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). This will be further discussed in the section on resistant hypertension (6.14).
- Also, beta-blockers tend to increase body weight [401] and, particularly when used in combination with diuretics, to facilitate new-onset diabetes in predisposed patients [402]. Diuretics have remained the cornerstone of antihypertensive treatment since at least the first Joint National Committee (JNC) report in 1977 [412] and the first WHO report in 1978 [413], and still, in 2003, they were classified as the only first-choice drug by which to start treatment, in both the JNC-7 [264] and the WHO/International Society of Hypertension Guidelines [55,264]. It has also been argued that diuretics such as chlorthalidone or indapamide should be used in preference to conventional thiazide diuretics, such as hydrochlorothiazide [271]. Calcium antagonists have been cleared from the suspicion of causing a relative excess of coronary events by the same authors who had raised the question. Both classes are among those most widely used in antihypertensive therapy. Aliskiren, a direct inhibitor of renin at the site of its activation, is available for treating hypertensive patients, both as monotherapy and when combined with other antihypertensive agents. To date, available evidence shows that, when used alone, aliskiren lowers SBP and DBP in younger and elderly hypertensive patients [428]; that it has a greater antihypertensive effect when given in combinationwith a thiazide diuretic, a blocker of the RAS at other sites, or a calcium antagonist [429,430]; and that prolonged administration in combination treatment can have a favourable effect (i) on asymptomatic OD, such as urinary protein excretion [431] or (ii) on prognostic biomarkers for heart failure, such as B-type natriuretic peptides [432]. The alphablocker doxazosin has effectively been used as third-line therapy in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). This will be further discussed in the section on resistant hypertension (6.14).
- Antihipertenzivi centralnog delovanj
- 500 – 755 din u slobodnoj prodaji (02 jeftiniji za -85 din a 04 za -160 din) Moksonidin je noviji lijek, antihipertenziv, i spada u skupinu blokatora imidazolinskih receptora. Po kemijskoj strukturi je vrlo sličan klonidinu, ali za razliku od klonidina manje djeluje na alfa-adrenergičke receptore, a više na imidazolinske receptore. Mjesto antihipertenzivnog djelovanja moksonidina jest središnji živčani sustav. U moždanom deblu moksonidin selektivno stimulira I1-imidazolinske receptore. Ovi imidazolinski receptori koncentrirani su u rostralnoj ventrolateralnoj meduli, području odgovornom za centralnu kontrolu perifernih funkcija simpatičkog živčanog sustava. Ukupni učinak blokade I1-imidazolinskih receptorima jest smanjena aktivnost simpatikusa. Moksonidin se razlikuje od prve generacije antihipertenziva s centralnim djelovanjem (metildopa, klonidin) po tome što pokazuje znatno niži afinitet vezanja za moždane alfa-2-adrenoreceptore u usporedbi sa I1-imidazolinskim receptorima; smatra se da je stimulacija alfa 2-adrenoreceptora odgovorna za sedaciju i suha usta, kao najčešće neželjene učinke prve generacije centralno djelujućih antihipertenziva. Moksonidin dovodi do širenja krvnih žila i do sniženja arterijskog tlaka. Osim toga, nakon šestomjesečne terapije dolazi do smanjenja prethodno postojeće hipertrofije lijevog ventrikula srca. Koristi se u liječenju hipertenzije u obliku tableta. Liječenje treba započeti najnižom dozom od 0,2 mg dnevno, tj. 1 tableta 0,2 ujutro. Ako terapijski odgovor nije dovoljan, nakon tri tjedna se može povećati na 0,4 mg, kao pojedinačna doza ili podijeliti u dvije doze. Ako terapijski odgovor nije dovoljan niti nakon slijedeća tri tjedna, doza se može povećati na max 0,6 mg. Ukoliko se moksonidin uzima istodobno s beta-blokatorom, a liječenje treba prekinuti, prvo treba prekinuti uzimanje beta - blokatora, a tek nakon toga uzimanje moksonidina. Kontraindikacije: preosjetljivost na neki sastojak lijeka, sindrom bolesnog sinusnog čvora, bradikardija (frekvencija srca u mirovanju&lt;50 otkucaja/min), teška disfunkcija bubrega (GFR &lt; 30 ml/min, koncentracija kreatinina u serumu &gt; 160 mcmol/l). Na početku liječenja se obično prijavljuju suha usta, glavobolja, i pospanost. Povremeno su prijavljivani umor i omaglica. Međutim, učestalost i jačina navedenih simptoma često se smanjuju tijekom liječenja. Rijetko su prijavljeni slučajevi alergijskih kožnih reakcija i/ili edema.
- Mesto i mehanizam delovanja: centralni nervni sistem (CNS - moždano stablo) je mesto anhipertenzivnog delovanja moksonidin selektivno stimuliše imidazolinske I1 receptore, koncentrisane u rostralnoj ventrolateralnoj meduli (RVLM), oblasti kritičnoj za centralnu kontrolu perifernog simpatičkog nervnog sistema stimulacija imidazolinskih receptora očigledno redukuje simpatičku aktivnost i snižava krvni pritisak; (dovodi do smanjivanja sistemskog vaskularnog otpora) !!! Centralni nervni sistem (CNS) mesto anhipertenzivnog delovanja moksonidina. Pokazalo se da, unutar moždanog stabla, moksonidin selektivno stimuliše imidazolinske receptore. Ovi receptori su koncentrisani u rostralnoj ventrolateralnoj meduli, oblasti kritičnoj za centralnu kontrolu perifernog simpatičkog nervnog sistema. Stimulacija imidazolinskih receptora očigledno redukuje simpatičku aktivnost i snižava krvni pritisak. Dovodi do smanjivanja sistemskog vaskularnog otpora i, samim tim, do sniženja arterijskog krvnog pritiska. Metildopa: Alpha-adrenergic agonist (selective for α2-adrenergic receptors) - sympatholytic or antihypertensive - Gestational hypertension (or pregnancy-induced hypertension) and pre-eclampsia - relatively safe in pregnancy compared to many other antihypertensives which may affect the fetus. Methyldopa is capable of inducing a number of adverse side effects, which range from mild to severe. Nevertheless, they are generally mild when the dose is less than 1 gram per day. Doxazosin: α1-selective alpha blocker used to treat high blood pressure and urinary retention associated with benign prostatic hyperplasia (BPH). Inhibits the binding of norepinephrine (released from sympathetic nerve terminals) to the alpha-1 receptors on the membrane of vascular smooth muscle cells. The primary effect of this inhibition is relaxed vascular smooth muscle tone (vasodilation), which decreases peripheral vascular resistance, leading to decreased blood pressure.
- 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 (&gt;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
- Long term efficacy was studied in an open, multicentre, 12-month clinical trial in 141 ambulant hypertensive patients with mean sitting diastolic pressure &gt;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 16-79 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
- Uticaj mokonidine o minutnog volumena i sistemske vaskularne rezistencije 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&lt;0.01). This was accompanied by an approximately 16% decrease in systemic vascular resistance from 1695 to 1427 dyn.sec/cm5 (p&lt;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;5:967-972
- Figure 3. Behaviour of muscle (MSNA) and skin sympathetic nerve activity (SSNA) in healthy subjects and in patientswith hypertension (HT), obesity (OB), congestive heart failure (CHF), metabolic syndrome (MS) or renal failure (RF) Norepinephrine that appears in the plasma is the net result of discharge, reuptake, metabolism, and clearance, and as a consequence is not suitable as marker for activity. True sympathetic nerve activity can be assessed by the microneurographic technique, which was developed by Vallbo et al [3]. The intraneural recording is made with a tungsten microelectrode with a shaft of 0.2mmand a tip of a few micrometers placed in a peripheral nerve, generally the peroneal or radial nerve (muscle sympathetic nerve activity) (MSNA). Usually, nerve recordings cause minimal discomfort and negligible, transient after-effects, when studies are done by an experienced technician. However, the technique is not suitable for routine use, because it is laborious, timeconsuming, and technically difficult
- Povećana simpatička aktivnost može da bude centralna karika povezivnja hipertenzije sa drugim komponentama metaboličkog sindroma Vazokonstrikcija i (retencija natrijuma) zadržavanje soli ***Cilj terapije nije samo smanjiti pritisak, već delovati na druga oboljenja i stanja! ***Metabolički sindrom je kombinacija faktora rizika za nastanak koronarne, periferne arterijske i cerebrovaskularne bolesti. Povećana simpatička aktivnost je uzrok, a ne posledica, povišenog krvnog pritiska1 Viši BMI je povezan sa povećanom stopom simpatičkog nervnog pražnjenja u skeletnim mišićima5 Postoji korelacija između BMI, distribucije telesnih masti i izlučivanja norepinefrina* u mokraći6 Nivo norepinefrina* u plazmi hipertenzivnih bolesnika znatno više nego kod normotenzivnih (p&lt;0.05)3 Simpatički aktivacija je glavna komponenta insulinske rezistencije u kliničkim istraživanjima7 i kod ljudi sa diabetesom tipa 28 Already minimal kidney damage, not necessarily affecting kidney function, results in area(s) of ischemia. Increased plasma levels of Ang II and/or increased afferent renal nerve activity stimulates the central nervous system to increase central sympathetic outflow, which results in sodium retention and vasoconstriction which are meant to restore kidney perfusion. Već minimalna oštećenja bubrega, koja ne moraju da utiče na rad bubrega, dovode do ishemije odredjenih delova. Povećani nivoi Ang II u plazmi i/ili povećana aktivnost aferentntnih nerava bubrega stimuliše centralni nervni sistem da poveća centralno kontrolisan simpaticki tonus, koji dovodi do zadržavanja soli i vazokonstrikcije, što je namenjeno vraćanju perfuzije bubrega. 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 overactivity4 Hypertension is a central component of this syndrome. Začarani krug - uzrok posledica!!! Nacionalni vodič dobre kliničke prakse za dijagnostikovanje i lečenje Arteriske hipertenzije; Beograd 2012 Kod dve trećine bolesnika nije moguće kontrolisati arterijsku hipertenziju samo jednim lekom, već je neophodna kombinacija najmanje dva leka Započinjanje terapije kombinacijom dva leka povećava se verovatnoća blagovremenog postizanja ciljnih vrednosti krvnog pritiska, manjim dozama lekova Farmakološko lečenje započinje se lekom koji ima najmanje izglede da poveća rizik razvoja dijabetesa melitusa Nacionalni vodič dobre kliničke prakse za dijagnostikovanje i lečenje Gojaznosti ; Beograd 2004 Abdominalna gojaznost udružena je sa metaboličkim i kardiovaskularnim bolestima, a može se proceniti merenjem obima struka Gojaznost je glavni faktor rizika za razvoj hipertenzije Hipertenzija kod gojaznih pacijenata može se povezati sa aktiviranjem simpatičkih nerava u bubrezima i stimulacijom renin-angiotenzin sistema45,46 Nivo norepinephrine* u urinu raste sa porastom BMI i sa povećanjem abdominalne distribucije masti 49 Većina gojaznih osoba i gojaznih hipertenzivnih bolesnika sa imaju visok nivo hormona leptina u cirkulaciji50,51
- 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 &lt;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 &gt;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
- Systolic and diastolic blood pressure (BP) declined by an average of 24.5 + 14.3mmHg and 12.6 + 9.1mmHg, respectively. Documented reasons for initiating moxonidine therapy comprised lack of efficacy of current antihypertensive medication (𝑛 = 3885), intolerance to current antihypertensive medication (𝑛 = 286), or a new diagnosis of hypertension (𝑛 = 886); 138 cases were classified as “other reasons.”
- Systolic and diastolic blood pressure (BP) declined by an average of 24.5 + 14.3mmHg and 12.6 + 9.1mmHg, respectively.
- 500 – 755 din u slobodnoj prodaji (02 jeftiniji za -85 din a 04 za -160 din) Moksonidin je noviji lijek, antihipertenziv, i spada u skupinu blokatora imidazolinskih receptora. Po kemijskoj strukturi je vrlo sličan klonidinu, ali za razliku od klonidina manje djeluje na alfa-adrenergičke receptore, a više na imidazolinske receptore. Mjesto antihipertenzivnog djelovanja moksonidina jest središnji živčani sustav. U moždanom deblu moksonidin selektivno stimulira I1-imidazolinske receptore. Ovi imidazolinski receptori koncentrirani su u rostralnoj ventrolateralnoj meduli, području odgovornom za centralnu kontrolu perifernih funkcija simpatičkog živčanog sustava. Ukupni učinak blokade I1-imidazolinskih receptorima jest smanjena aktivnost simpatikusa. Moksonidin se razlikuje od prve generacije antihipertenziva s centralnim djelovanjem (metildopa, klonidin) po tome što pokazuje znatno niži afinitet vezanja za moždane alfa-2-adrenoreceptore u usporedbi sa I1-imidazolinskim receptorima; smatra se da je stimulacija alfa 2-adrenoreceptora odgovorna za sedaciju i suha usta, kao najčešće neželjene učinke prve generacije centralno djelujućih antihipertenziva. Moksonidin dovodi do širenja krvnih žila i do sniženja arterijskog tlaka. Osim toga, nakon šestomjesečne terapije dolazi do smanjenja prethodno postojeće hipertrofije lijevog ventrikula srca. Koristi se u liječenju hipertenzije u obliku tableta. Liječenje treba započeti najnižom dozom od 0,2 mg dnevno, tj. 1 tableta 0,2 ujutro. Ako terapijski odgovor nije dovoljan, nakon tri tjedna se može povećati na 0,4 mg, kao pojedinačna doza ili podijeliti u dvije doze. Ako terapijski odgovor nije dovoljan niti nakon slijedeća tri tjedna, doza se može povećati na max 0,6 mg. Ukoliko se moksonidin uzima istodobno s beta-blokatorom, a liječenje treba prekinuti, prvo treba prekinuti uzimanje beta - blokatora, a tek nakon toga uzimanje moksonidina. Kontraindikacije: preosjetljivost na neki sastojak lijeka, sindrom bolesnog sinusnog čvora, bradikardija (frekvencija srca u mirovanju&lt;50 otkucaja/min), teška disfunkcija bubrega (GFR &lt; 30 ml/min, koncentracija kreatinina u serumu &gt; 160 mcmol/l). Na početku liječenja se obično prijavljuju suha usta, glavobolja, i pospanost. Povremeno su prijavljivani umor i omaglica. Međutim, učestalost i jačina navedenih simptoma često se smanjuju tijekom liječenja. Rijetko su prijavljeni slučajevi alergijskih kožnih reakcija i/ili edema.