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FARMACI DEL SISTEMA RENINA-ANGIOTENSINA-ALDOSTERONE ANTAGONISTI DELLA RENINA

Corso di Farmacologia 2005. FARMACI DEL SISTEMA RENINA-ANGIOTENSINA-ALDOSTERONE ANTAGONISTI DELLA RENINA INIBITORI DELL’ENZIMA DI CONVERSIONE (ACE-Inibitori) ANTAGONISTI DEI RECETTORI AT-1 (Sartani) DIURETICI ANTI-ALDOSTERONICI. FARMACI DEL SISTEMA RENINA-ANGIOTENSINA-ALDOSTERONE.

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FARMACI DEL SISTEMA RENINA-ANGIOTENSINA-ALDOSTERONE ANTAGONISTI DELLA RENINA

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  1. Corso di Farmacologia 2005 • FARMACI DEL SISTEMA • RENINA-ANGIOTENSINA-ALDOSTERONE • ANTAGONISTI DELLA RENINA • INIBITORI DELL’ENZIMA DI CONVERSIONE • (ACE-Inibitori) • ANTAGONISTI DEI RECETTORI AT-1 • (Sartani) • DIURETICI ANTI-ALDOSTERONICI

  2. FARMACI DEL SISTEMA RENINA-ANGIOTENSINA-ALDOSTERONE Angiotensin Converting Enzyme -ACE ACE-inibitori Inibitori della renina Angiotensinogeno Angiotensina I Angiotensina II renina Beta-bloccanti AT1-antagonisti (Sartani) recettore AT1 Spironolattone Canrenone aldosterone vasocostrizione

  3. Sviluppo degli inibitori della renina Enalkiren Remikiren J.Clin.Pharmacol. 1994, 34: 873

  4. INIBITORI DELLA RENINA Gli inibitori della renina sono molecole “modellate” sull’angiotensinogeno umano che bloccano l’azione della renina sul substrato legandosi in maniera competitiva al sito attivo della renina al quale rimangono legati senza subire alcun attacco enzimatico (falsi substrati). Enalkiren Ramikiren Aliskiren Zankiren

  5. TEPROTIDE – BRADYCHININ POTENTIATING FACTOR (Ferreira) The 1998 National Medal of Technology, Scientific American, March 1999

  6. Angiotenin II receptor antagonists. Lancet 355, 637, 2000

  7. O SH N OH O Legame del Captopril all’ACE Zn++ Zn++ O Angiotensin I C Captopril

  8. O HO O O O N H Enalapril ACE-I carbossilici ACE Zn++ Esterasi plasmatiche Enalaprilat

  9. O O P N O O HO O ACE-I fosforilici ACE Zn++

  10. Principali caratteristiche farmacocinetiche degli ACE inhibitori

  11. Heart Brain Adrenal gland Kidney Karl T. Weber, M.D. NEJM 345,1689, 2001

  12. Angiotensinogen NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser- Renin Angiotensin I Bradykinin NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-COOH Converting enzyme (ACE) (Chimase) Angiotensin II NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-COOH Inactive Fragments Aminopeptidase Angiotensin III NH2-Arg-Val-Tyr-Ile-His-Pro-Phe-COOH

  13. Vascular wall Kidney Heart Brain ACE-I  ANG II Adrenal gland ALDOSTERONE INOTROPIC, CHRONOTROPIC ACTIONS SYMPATHETIC TONE VASODILATATION Na+ excretion  BLOOD PRESSURE

  14. Sistema renina-angiotensina (RAS) Ditribuzione dell‘ACE nell‘organismo: R A S 10 % 90 % circolante (plasma) locale (tessuto) Effetti immediati cardiovascolari/ omeostasi renale Effetti a lungo termine „adattamento“ locale dell‘organo Attivazione rene-indipendente mod. sec Dzau V, Arch Intern Med 153 (1993)

  15. Effetti farmacodinamici degli ACE-I Effetti ormonali Effetti emodinamici

  16. ACE-Inibitori ed ipertensione sistema adrenergico ACE-I aldosterone dilatazione arteriole bradichinina prostaglandine vasorilascianti resistenze vascolari sistemiche  pressione arteriosa

  17. L’effetto ipotensivo degli ACE-I è potenziato in condizioni di elevata renina

  18. L’effetto ipotensivo degli ACE-I e potenziato dall’associazione con diuretici tiazidici Captopril o Idroclorotiazide da soli Captopril o Idroclorotiazide da soli Terapia combinata Terapia combinata

  19. Change in left ventricular mass (LVM) with antihypertensive treatment Hydrochlorothiazide Enalapril Modified from Dahlof, Hansson J Hypertens 1992, 10:1513-24

  20. Ang II-induced signal varies from seconds (e.g. activation of phospholipase C (PLC), generation of inositol phosphate and Ca2+ release) to minutes (e.g. mitogen-activated protein (MAP) kinase activation) to hours (e.g. activation of Janus kinase (JAK) and signal transducers and activators of transcription (STAT) pathway).

  21. ANGIOTENSIN II Altered Peripheral Resistance Altered Renal Function Altered Cardiovascular Structure 1. Direct Vasoconstriction 2. Enhancement of peripheral noradrenergic neurotransmission 3. Increased sympathetic discharge 4. Release of catecholamines from adrenal medulla • 1. Direct increase of Na reasbsorption in prox tubule • 2. Release of aldosterone from adrenal cortex • 3. Altered hemodynamics: • vasoconstriction • Increased NA control on kidney 1. Non-hemodinamically mediated effects: A. Expression of proto-oncogenes B. Release of Growth Factors C. Synthesis of extracellular matrix 2. Hemodinamically mediated effects: A. Increased afterload B. Increased preload Rapid Pressor Response Slow Pressor Response Vascular and cardiac hypertrophy and remodeling

  22. L’angiotensina II è un fattore umorale co-responsabile dei processi di rimodellamento patologico

  23. Hemodynamic overload Secondary biologic response Myocardial remodeling Myocardial dysfunction Central role of myocardial remodeling in the pathophysiology of heart failure Hemodynamic overload (e.g., due to myocardial injury) serves as the primary stimulus for myocardial remodeling. With the development of myocardial dysfunction, there is an activation of secondary biologic responses, including the stimulation of systemic neurohormonal systems (e.g., renin-angiotensin and sympathetic nervous systems) and expression of myocardial peptides (e.g., endothelin, angiotensin, inflammatory cytokines) that can act directly on the myocardium to cause further remodeling

  24. Dilated cardiomyopathy Compensatory hypertrophy Normal Initially, cardiac hypertrophy represents a beneficial adaptative process, allowing the myocardial wall stress to be kept constant despite increased afterload caused by long-standing hypertension. With time, however, the hypertrophic response becomes deleterious and cardiomyopathy progressively develops, as reflected by aa reduced myocardial contractility ….. Left ventricular hypertrophyhas evolved as a powerful predictor of sudden death.

  25. ACE-I  ANG II RIMODELLAMENTO CARDIACO RIMODELLAMENTO VASCOLARE

  26. ACE-I SURVIVAL 0.8 0.7 Placebo 0.6 PROBABILITYOFDEATH p< 0.001 0.5 0.4 p< 0.002 0.3 Enalapril 0.2 0.1 0 CONSENSUS N Engl J Med 1987;316:1429 0 1 2 3 4 5 6 7 8 9 10 11 12 MONTHS

  27. 50 40 30 20 10 0 ACE-I SURVIVAL n = 2589 CHF - NYHA II-III - EF < 35 p = 0.0036 Placebo n=1284 % MORTALITY Enalapril n=1285 48 0 6 12 18 24 30 36 42 SOLVD (Treatment)N Engl J M 1991;325:293 Months

  28. Prostaglandina E2

  29. Evoluzione della velocità di filtrazione glomerulare e della proteinuria in pazienti ipertesi non diabetici dopo instaurazione di terapia con ACE-Inibitori

  30. Principali indicazioni degli ACE-Inibitori • Ipertensione • Scompenso cardiaco • Post-infarto • Nefropatia diabetica e ipertensiva • (microalbuminuria)

  31. Effetti indesiderabili degli ACE-I • Ipotensione • Iperkaliemia • Edema angioneurotico • Tosse secca e stizzosa • Insufficienza renale

  32. ACE-ICONTRAINDICATIONS Renal artery stenosis Renal insufficiency Hyperkalemia Arterial hypotension Intolerance (due to side effects)

  33. ANTAGONISTS OF AT-1 receptors MECHANISM OF ACTION RENIN Angiotensin IANGIOTENSIN II Angiotensinogen ACE Other paths AT1 RECEPTOR BLOCKERS RECEPTORS AT1 AT2 Vasoconstriction Proliferative Action Physio-pathological role ?

  34. Antagonisti dei Recettori AT-1 dell’Angiotensina II • SARTANI • Antagonisti competitivi e selettivi dei recettori AT-1 • Losartan • Valsartan • Irbesartan • Eprosartan • Candesartan cilexetil • Olmesartan medoxomil

  35. DIFFERENZE FRA ANTAGONISTI DEI RECETTORI AT1 Unger T. Am. J. Cardiol. 84, 95, 1999

  36. DIFFERENZE FRA ANTAGONISTI DEI RECETTORI AT1 Unger T. Am. J. Cardiol. 84, 95, 1999

  37. Trial ELITE II Lancet 355, 1582, 2000

  38. EFFECT OF IRBESARTAN ON THE DEVELOPMENT OF DIABETIC NEPHROPATHY IN PATIENTS WITH TYPE 2 DIABETES Parving et al., NEJM 345:870 2001

  39. INCIDENZA DI TOSSE Studio clinico in pazienti ipertesi con storia di tosse da ACE-inibitori Am. J. Hypert. 13, 214, 2000

  40. Diuretici risparmiatori di potassio Cellula Principale INTERSTIZIO LUME Na+ Na+ Na+ ATP K+ Amiloride Triamterene Aldosterone Spironolattone Canrenone Canrenoato di K NEFRONE DISTALE Recettore H+ HCO3- HCO3- H+ ATP Cl- H2CO3 H+ ATP A.C. K+ CO2+H2O Cellula intercalare A

  41. INIBITORI DELL’ALDOSTERONE ALDOSTERONE Spironolattone antagonista competitivo dei recettori dell’aldosterone nel miocardio, parete vasale e rene • Ritenzione di NA+ • Ritenzione di H2O • Escrezione di K+ • Escrezione di Mg2+ Deposizione di collagene Fibrosi - miocardio - vasi Edema Aritmie

  42. Angiotensin II PRODUZIONE DI ALDOSTERONE da parte delle cellule endoteliali e muscolari lisce dell’arteria coronarica intramiocardica Karl T. Weber, M.D. NEJM 345,1689, 2001

  43. Kaplan–Meier Analysis of the Probability of Survival among Patients in the Placebo Group and Patients in the Spironolactone Group. 1.00 0.95 0.90 Spironolactone 0.85 0.80 0.75 Placebo 0.70 P<0.001 Probability of survival 0.65 0.60 0.55 0.50 0.45 0 3 6 9 12 15 18 21 24 27 30 33 36 Months The risk of death was 30 percent lower among patients in the spironolactone group than among patients in the placebo group (P<0.001).

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