Arterijska hipertenzija 2007: ocekujuci nove smjernice

1. Arterijska hipertenzija 2007: ocekujuci nove smjernice V. Gerc, M.Buk�a Klinika za bolesti srca i reumatizam KCU Sarajevo

2. HIPERTENZIJA  Esencijalna hipertenzija se danas smatra jednom od najva�nijih bolesti na�e civilizacije i time ona postaje socijalno-medicinski problem prvoga reda.

4. Hipertenzija se cesto javlja u razvijenim zemljama, tako da 32.3% osoba u SAD i 44% osoba u Evropi boluje od hipertenzije. Prevalencija hipertenzije raste sa godinama. Problem hipertenzije ce biti sve veci zbog niza faktora ukljucujuci sve veci broj starijih osoba kao i povecanje prevalencije kardiovaskularnih faktora rizika

5. Znacaj i problem hipertenzije Lijecenje i efikasna kontrola hipertenzije je nedostatna, na primjer u Evropi: Otprilike 73% osoba sa hipertenzijom nije lijeceno Otprilike 70% onih koji su lijeceni, kod njih se ne postignu ciljne vrijednosti

6. Znacaj i problem hipertenzije Nedovoljno i neadekvatno lijecenje hipertenzije predstavlja veliki zdravstveni i ekonomski problem za dru�tvo

7. Procjena problema hipertenzijeProjekcija hipertenzije 2025 godine 2000. godina 26,4% odrasle populacije ima hipertenziju Najveca prevalencija je u razvijenim zemljama 600 miliona ima hipertenziju 2025. godina 29,2% odrasle populacije ce imati hipertenziju Ukupno 1 mil i 560 miliona (60% ukupno; 24% u razvijenim zemljama; 80% u zemljama u razvoju) Najveca prevalencija bice u Aziji i Africi : 75% od ukupne svjetske populacije hipertonicara

8. Hipertenzija danas u Kanadi i SAD

9. Hipertenzija danas u Evropi

10. Hipertenzija Primarna prevencija hipertenzije je u cijelom svijetu nezadovoljavajuca Ni u jednoj zemlji na svijetu nije do�lo do smanjenja prevalencije hipertenzije

11. Korist antihipertenzivnog lijecenja dobro je dokazana rezultatima studija! smanjenje ucestalosti: mo�danog udara 35-40 % srcanog zatajivanja 50 % srcanog infarkta 20-25% KV- smrti 21 % Najvi�e koristi imaju bolesnici s najvecim kardio-vaskularnim rizikom!

13. Momenti koji doprinose neadekvatnoj kontroli arterijskog pritiska Mnogobrojni vodici za hipertenziju Ne odabere se odgovarajuci lijek Cijena lijeka Sporedni efekti lijekova Lo�a suradljivost pacijenta Nedovoljna motiviranost ljekara � Rezistentna � hipertenzija

14. HIPERTENZIJA PREVALENCIJA HIPERTENZIJE RASTE SA STARO�CU SISTOLNI PRITISAK BOLJE KORELIRA S O�TECENJIMA CILJNIH ORGANA NEGO DIJASTOLNI PRITISAK

15. Bei Hypertonikern unterscheidet man abh�ngig davon, ob beide oder nur einer der Blutdruckwerte erh�ht sind, verschiedene Subtypen. Die H�ufigkeit der einzelnen Subtypen �ndert sich altersbedingt deutlich. W�hrend bis etwa zum 40. Lebensjahr am h�ufigsten eine isolierte diastolische Hypertonie zu beobachten ist, findet sich bei 40 bis 50-j�hrigen meist die kombiniert systolisch-diastolische Hypertonie mit Erh�hung beider Blutdruckwerte �ber 140 bzw. 90 mmHg. Hypertoniker �ber 50 Jahren hingegen weisen meist eine isolierte systolische Hypertonie auf, die ab dem 60. Lebensjahr zum absolut dominierenden Subtyp wird. � � Franklin SS, Jacobs MJ, Wong N et al.: Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives. Analysis based on national health and nutrition examination survey (NHANES) III. Hypertension 2001; 37: 869-874 Bei Hypertonikern unterscheidet man abh�ngig davon, ob beide oder nur einer der Blutdruckwerte erh�ht sind, verschiedene Subtypen. Die H�ufigkeit der einzelnen Subtypen �ndert sich altersbedingt deutlich. W�hrend bis etwa zum 40. Lebensjahr am h�ufigsten eine isolierte diastolische Hypertonie zu beobachten ist, findet sich bei 40 bis 50-j�hrigen meist die kombiniert systolisch-diastolische Hypertonie mit Erh�hung beider Blutdruckwerte �ber 140 bzw. 90 mmHg. Hypertoniker �ber 50 Jahren hingegen weisen meist eine isolierte systolische Hypertonie auf, die ab dem 60. Lebensjahr zum absolut dominierenden Subtyp wird. � � Franklin SS, Jacobs MJ, Wong N et al.: Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives. Analysis based on national health and nutrition examination survey (NHANES) III. Hypertension 2001; 37: 869-874

16. HIPERTENZIJA O esencijalnoj hipertenziji, koja obuhvaca 90-95% populacije hipertonicara, danas moramo govoriti i razmi�ljati kao o metabolicko � hipertenzivno �ateroskleroticnom sindromu

19. �Zacarani krug�

20. Sindrom inzulinske rezistencije Prepared by PhocusPrepared by Phocus

21. Inzulinska rezistencija i faktori rizika Prepared by PhocusPrepared by Phocus

25. Hipertenzija 2007 Pristup u lijecenju hipertenzije u svjetlu revidiranih Engleskih smjernica i u svjetlu novih antihipertenzivnih lijekova

26. Beta blokatori i hipertenzija Da li beta blokatori imaju jo� mjesta u lijecenju hipertenzije, odnosno da li mogu i dalje da budu lijek prvog reda ?

27. Engleske smjernice za hipertenziju Beta blokatori nisu vi�e lijek prvog reda Ne preporucuje se kombinacija beta blokatora i diuretika Kod mladih pacijenata lijek izbora su ACEI i antagonisti angiotenzina II

30. Beta blokatori i hipertenzija Sredinom �ezdesetih godina pro�log stoljeca poceo se je propranolol primijenjivati u lijecenju hipertenzije u Engleskoj ; u SAD 1976 godine. 1984 zavr�ene su bile velike studije sa beta blokatorima kod hipertenzije.

31. Beta blokatori i hipertenzija Shodno preporukama JNC III � 1984 godine, lijecenje hipertenzije se je zapocinjalo sa beta blokatorom ili diuretikom.

32. Indikacije za primijenu betablokatora Ishemijska bolest srca Sekundarna prevencija infarkta miokarda Insuficijencija srca Supraventrikularne i ventrikularne aritmije

33. Beta blokatori i hipertenzija Beta blokatori nisu tako efikasni u smanjivanju kardiovaskularnih dogadaja, pogotovo kada je u pitanju mo�dani udar.

39. Beta blokatori i atenolol Atenolol, pogotovo kod starijih pacijenata, slabo smanjuje rizik od kardiovaskularnih incidenata Ne popravlja vaskularnu komplijansu Ne smanjuje efikasno centralni aortalni tlak Ne dovodi do regresije HLV

41. CAFE STUDIJA Rezultati studije pokazuju da lijekovi koji djeluju raznim mehanizmima mogu podjednako da smanje pritisak na nivou brahijalne arterije, ali da razlicito djeluju na centralni pritisak.

42. CAFE STUDIJA Periferni sistolni pritisak je nakon aplicirane terapije bio podjednak i u skupini �antagonist kalcija � kao i u skupini �beta blokator �. Medutim, centralni sistolni pritisak je bio signifikantno ni�i u skupini �antagonist kalcija � u poredenju sa skupinom �beta blokator �.

43. Centralni pritisak Centralni pritisak ima vrlo va�nu ulogu u nastanku kardiovaskularnih komplikacija.

49. Nacrt studije

50. Novi slucajevi diabetes mellitusa

52. Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI): Mechanisms of action ACE-inhibitors cause arteriovenous vasodilatation. Venodilation is accompanied by reduction in PAD, PCWP, and LVEDP. Arterial vasodilatation decreases SVR and MAP and increases cardiac output, ejection fraction, and exercise tolerance. Heart rate and contractility do not change, and, thus, double product and myocardial oxygen demand are decreased. These effects are more noticeable in patients with low sodium levels, in whom there is an increased plasma renin activity. Vasodilatation is seen in various vascular territories: renal, coronary, cerebral, and musculoskeletal (increasing exercise capacity). Additionally, ACE-inhibitors cause diuretic and natriuretic effects that are a consequence of the inhibition of angiotensin II and aldosterone synthesis, as well as the increase in cardiac output and renal perfusion. It is now known that the magnitude and duration of blood pressure reduction correlates better with the activity of ACE in certain tissues (heart, vessels, kidney, adrenal, etc.) than with its plasma levels, which indicates that ACE-inhibitors act by inhibiting local tissue production of angiotensin II. Plasma levels of ACE are not good predictors of the magnitude of hemodynamic effects of ACE-inhibition. Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI): Mechanisms of action ACE-inhibitors cause arteriovenous vasodilatation. Venodilation is accompanied by reduction in PAD, PCWP, and LVEDP. Arterial vasodilatation decreases SVR and MAP and increases cardiac output, ejection fraction, and exercise tolerance. Heart rate and contractility do not change, and, thus, double product and myocardial oxygen demand are decreased. These effects are more noticeable in patients with low sodium levels, in whom there is an increased plasma renin activity. Vasodilatation is seen in various vascular territories: renal, coronary, cerebral, and musculoskeletal (increasing exercise capacity). Additionally, ACE-inhibitors cause diuretic and natriuretic effects that are a consequence of the inhibition of angiotensin II and aldosterone synthesis, as well as the increase in cardiac output and renal perfusion. It is now known that the magnitude and duration of blood pressure reduction correlates better with the activity of ACE in certain tissues (heart, vessels, kidney, adrenal, etc.) than with its plasma levels, which indicates that ACE-inhibitors act by inhibiting local tissue production of angiotensin II. Plasma levels of ACE are not good predictors of the magnitude of hemodynamic effects of ACE-inhibition.

57. Prednosti kombinovane a i � blokade

60. Kojim beta blokatorimatreba dati prednost Karvedilol Nebivolol Bisoprolol Dilevalol

62. Beta blokatori ihipertenzija Ima li raison d�etre da beta blokatori ne budu vi�e lijek prvog reda ? Ustvari, odgovor zavisi �to se podrazumjeva da jedan antihipertenzivni lijek ispunjava kriterije da bude lijek prvog reda.

63. GEMINI STUDYMetabolic Effects of Carvedilol vs Metoprolol in Patients with Type 2 Diabetes Mellitus and HypertensionA Randomized Controlled Trial

66. Kojim beta blokatorimatreba dati prednost Karvedilol Nebivolol Bisoprolol Dilevalol

67. Noviji farmakoterapijskipristupi u lijecenju hipertenzije Exforge Aliskiren

68. Nedovoljna efikasnost lijeka sa jednim mehanizmom djelovanja Preporuka za kombinovanu terapiju Prednosti vi�estrukog djelovanja lijekova Efikasnost i sigurnost Dobra suradljivost

69. 70 % pacijenata ne posti�e ciljne vrijednosti sa monoterapijom

71. Prosjecan broj antihipertenzivnih lijekova koji supotrebni da bi se postigle ciljne vrijednosti SP Major clinical trials have demonstrated that patients typically needed treatment with multiple antihypertensive agents to get to, and stay at, BP goal. The number of antihypertensive agents required for BP control in many patients typically averages at 2?4, with co-morbid conditions (such as kidney disease or diabetes mellitus) imposing greater drug requirement.1,2 For example, in the Hypertension Optimal Treatment (HOT) study, an average of 3.3 drugs were required to attain a diastolic BP goal of <80 mmHg, and in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA), most patients were taking at least two antihypertensive agents by the end of the trial.2,3 References Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension. The cycle repeats. Drugs 2002;62:443?62. Bakris GL, et al. The importance of blood pressure control in the patient with diabetes. Am J Med 2004;116(5A):30S�8S. Dahlof B, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895?906. Major clinical trials have demonstrated that patients typically needed treatment with multiple antihypertensive agents to get to, and stay at, BP goal. The number of antihypertensive agents required for BP control in many patients typically averages at 2?4, with co-morbid conditions (such as kidney disease or diabetes mellitus) imposing greater drug requirement.1,2 For example, in the Hypertension Optimal Treatment (HOT) study, an average of 3.3 drugs were required to attain a diastolic BP goal of <80 mmHg, and in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA), most patients were taking at least two antihypertensive agents by the end of the trial.2,3 References Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension. The cycle repeats. Drugs 2002;62:443?62. Bakris GL, et al. The importance of blood pressure control in the patient with diabetes. Am J Med 2004;116(5A):30S�8S. Dahlof B, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895?906.

72. Monoterapija v.s. kombinirana terapija i krvni tlak(HOT studija- 27 zemalja, 19193 bolesnika)

73. Monoterapija vrs kombinirana terapija HOT studija

74. Hypertension Optimal Treatment (HOT) Study: smanjenje velikih kardiovaskularnih dogadaja za 30% The Hypertension Optimal Treatment (HOT) study was a Prospective, Randomized, Open-Blinded Endpoint (PROBE) trial comparing the effect of 3 different target diastolic blood pressure (DBP) levels (? 90 mm Hg, n = 6,264; ? 85 mm Hg, n = 6,264; ? 80 mm Hg, n = 6,262) in 18,790 patients with hypertension and DBP between 100 mm Hg and 105 mm Hg. A PROBE trial has been proposed as a novel, simplified study design for medical intervention trials, which more closely mimics actual clinical practice compared with double-blind, randomized, controlled trials. In the HOT study, antihypertensive therapy started with the long-acting calcium channel blocker felodipine, with the addition of other agents according to a five-step regimen. Patients were followed for an average period of 3.8 years (Hansson et al, 1998). The primary objective of HOT was to assess 1) major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) for each of the target DBP groups during treatment, and 2) major cardiovascular events for the DBP achieved during treatment. In the overall HOT study population, intensive lowering of blood pressure (BP) substantially reduced the incidence of major cardiovascular events including fatal and nonfatal myocardial infarction, fatal and nonfatal stroke, and cardiovascular death, although the differences among the 3 groups did not reach statistical significance. The greatest risk reduction (30%) was observed in those who achieved a diastolic blood pressure of 83 mm Hg. Additional lowering of BP did not produce further reduction in events, but was not harmful; there was no evidence of a J-shaped curve for the relation of cardiovascular events with the achieved blood pressures in the HOT study. The Hypertension Optimal Treatment (HOT) study was a Prospective, Randomized, Open-Blinded Endpoint (PROBE) trial comparing the effect of 3 different target diastolic blood pressure (DBP) levels (? 90 mm Hg, n = 6,264; ? 85 mm Hg, n = 6,264; ? 80 mm Hg, n = 6,262) in 18,790 patients with hypertension and DBP between 100 mm Hg and 105 mm Hg. A PROBE trial has been proposed as a novel, simplified study design for medical intervention trials, which more closely mimics actual clinical practice compared with double-blind, randomized, controlled trials. In the HOT study, antihypertensive therapy started with the long-acting calcium channel blocker felodipine, with the addition of other agents according to a five-step regimen. Patients were followed for an average period of 3.8 years (Hansson et al, 1998). The primary objective of HOT was to assess 1) major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) for each of the target DBP groups during treatment, and 2) major cardiovascular events for the DBP achieved during treatment. In the overall HOT study population, intensive lowering of blood pressure (BP) substantially reduced the incidence of major cardiovascular events including fatal and nonfatal myocardial infarction, fatal and nonfatal stroke, and cardiovascular death, although the differences among the 3 groups did not reach statistical significance. The greatest risk reduction (30%) was observed in those who achieved a diastolic blood pressure of 83 mm Hg. Additional lowering of BP did not produce further reduction in events, but was not harmful; there was no evidence of a J-shaped curve for the relation of cardiovascular events with the achieved blood pressures in the HOT study.

82. EXFORGE Exforge ( amlodipin/valsartan) je fiksna kombinacija dva antihipertenzivna lijeka i to antagonista kalcija i antagonista angiotenzina II Exforge 5/80 mg, 5/160 mg i 10/160 mg

89. Amlo/Val dovodi do signifikantno manje incidencije perifernih edema vs. amlodipin

90. Inhibitori renina Kakva perspektiva ?

92. Patofiziolo�ki efekti angiotenzina II A II has many pathophysiologic effects, mediated by stimulation of the AT1 and AT2 receptors:1 A powerful vasoconstrictor that stimulates the secretion of two other potent vasoconstrictors, vasopressin and endothelin. Increases salt and water retention directly, and indirectly via increased aldosterone secretion. Activates the sympathetic nervous system and has a direct inotropic effect on the myocardium. Stimulates cell growth and hypertrophy, apoptosis, interstitial fibrosis, and collagen synthesis influencing vascular and cardiac remodeling. Causes platelet aggregation, promotes the production of tissue factor, induces the expression of PAI-1, and stimulates the formation of superoxide radicals.1 Reference: 1. Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet. 2000;355:637�645. A II has many pathophysiologic effects, mediated by stimulation of the AT1 and AT2 receptors:1 A powerful vasoconstrictor that stimulates the secretion of two other potent vasoconstrictors, vasopressin and endothelin. Increases salt and water retention directly, and indirectly via increased aldosterone secretion. Activates the sympathetic nervous system and has a direct inotropic effect on the myocardium. Stimulates cell growth and hypertrophy, apoptosis, interstitial fibrosis, and collagen synthesis influencing vascular and cardiac remodeling. Causes platelet aggregation, promotes the production of tissue factor, induces the expression of PAI-1, and stimulates the formation of superoxide radicals.1 Reference: 1. Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet. 2000;355:637�645.

94. Novi inhibitori renina stvoreni su na osnovu kristalografije i rekonstrukcijom aktivne strane  IC50 Razvoj (nM) Novartis (aliskiren) 0.6 Faza III Speedel (nekoliko spojeva) predkl.-faza I Actelion/MSD <100 predkl. Pfizer 0.2 predkl. GSK NA NA

95. ALISKIREN Aliskiren je jedan od najjacih inhibitora renina. On pokazuje znatno manji afinitet za renin kod psa, �takora, zeca i macke nego kod covjeka.

96. Biolo�ki profil nakon akutne i produljene blokade RASsa aliskirenom ili enalaprilom kod normotenzivnih osoba

99. Inhibicija renina smanjuje PRA i druge komponente RAS

105. In an 8-week dose-ranging study, the blood pressure-lowering efficacy and safety of aliskiren was compared with that of the starting dose of irbesartan. This was a randomised, multicenter, double-blind, placebo-controlled, active comparator study in 652 patients with mild-to-moderate hypertension. Eligible patients were =18 years of age, with mean trough sitting diastolic blood pressure (SeDBP) =95 and <110 mm Hg. After a 2-week washout and a 2- to 4-week, single-blind placebo run-in, patients were randomised to receive aliskiren 150 mg, 300 mg or 600 mg, irbesartan 150 mg, or placebo, once daily, for 8 weeks. The primary efficacy endpoint was the change from baseline in mean trough Seated DBP. References Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides antihypertensive efficacy and placebo-like tolerability similar to an AT1-receptor blocker in hypertensive patients. Am J Hypertens. 2004;17:108A. Abstract P-204.In an 8-week dose-ranging study, the blood pressure-lowering efficacy and safety of aliskiren was compared with that of the starting dose of irbesartan. This was a randomised, multicenter, double-blind, placebo-controlled, active comparator study in 652 patients with mild-to-moderate hypertension. Eligible patients were =18 years of age, with mean trough sitting diastolic blood pressure (SeDBP) =95 and <110 mm Hg. After a 2-week washout and a 2- to 4-week, single-blind placebo run-in, patients were randomised to receive aliskiren 150 mg, 300 mg or 600 mg, irbesartan 150 mg, or placebo, once daily, for 8 weeks. The primary efficacy endpoint was the change from baseline in mean trough Seated DBP. References Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides antihypertensive efficacy and placebo-like tolerability similar to an AT1-receptor blocker in hypertensive patients. Am J Hypertens. 2004;17:108A. Abstract P-204.

106. All doses of aliskiren significantly reduced mean trough sitting diastolic blood pressure (SeDBP), compared with placebo. Reductions in SeDBP were similar in the aliskiren 150-mg and irbesartan 150-mg groups; aliskiren 300 mg and 600 mg were significantly more effective in reducing SeDBP than was irbesartan. Once-daily aliskiren 150 mg, 300 mg, and 600 mg reduced mean trough SeDBP by 9.5 mm Hg, 12.0 mm Hg, and 11.7 mm Hg, respectively, compared with a 6.5 mm Hg reduction in the placebo group (P<0.005 for each dose vs placebo). Irbesartan 150 mg reduced mean trough SeDBP by 9.0 mm Hg, which was comparable to that with aliskiren 150 mg and significantly greater than that with placebo (P<0.02). Aliskiren 300 mg and 600 mg reduced SeDBP significantly more than did irbesartan (P=0.005 and P=0.01, respectively). References Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides antihypertensive efficacy and placebo-like tolerability similar to an AT1-receptor blocker in hypertensive patients. Am J Hypertens. 2004;17:108A. Abstract P-204.All doses of aliskiren significantly reduced mean trough sitting diastolic blood pressure (SeDBP), compared with placebo. Reductions in SeDBP were similar in the aliskiren 150-mg and irbesartan 150-mg groups; aliskiren 300 mg and 600 mg were significantly more effective in reducing SeDBP than was irbesartan. Once-daily aliskiren 150 mg, 300 mg, and 600 mg reduced mean trough SeDBP by 9.5 mm Hg, 12.0 mm Hg, and 11.7 mm Hg, respectively, compared with a 6.5 mm Hg reduction in the placebo group (P<0.005 for each dose vs placebo). Irbesartan 150 mg reduced mean trough SeDBP by 9.0 mm Hg, which was comparable to that with aliskiren 150 mg and significantly greater than that with placebo (P<0.02). Aliskiren 300 mg and 600 mg reduced SeDBP significantly more than did irbesartan (P=0.005 and P=0.01, respectively). References Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides antihypertensive efficacy and placebo-like tolerability similar to an AT1-receptor blocker in hypertensive patients. Am J Hypertens. 2004;17:108A. Abstract P-204.

107. All doses of aliskiren also significantly reduced mean trough sitting systolic blood pressure (SeSBP), compared with placebo. Reductions in SeSBP were similar in the aliskiren 150-mg and irbesartan 150-mg groups. Once-daily aliskiren 150 mg, 300 mg, and 600 mg reduced mean trough SeSBP by 10.8 mm Hg, 15.5 mm Hg, and 15.6 mm Hg, respectively, compared with a 5.1-mm Hg reduction with placebo (P<0.001 for each dose vs placebo). Irbesartan 150 mg reduced mean trough SeSBP by 12.5 mm Hg, which was comparable to that with aliskiren 150 mg and significantly greater than that with placebo (P<0.001). Aliskiren 300 mg and 600 mg trended toward greater reductions in SeSBP compared with irbesartan (P= 0.052 and P=0.055, respectively). References Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides antihypertensive efficacy and placebo-like tolerability similar to an AT1-receptor blocker in hypertensive patients. Am J Hypertens. 2004;17:108A. Abstract P-204.All doses of aliskiren also significantly reduced mean trough sitting systolic blood pressure (SeSBP), compared with placebo. Reductions in SeSBP were similar in the aliskiren 150-mg and irbesartan 150-mg groups. Once-daily aliskiren 150 mg, 300 mg, and 600 mg reduced mean trough SeSBP by 10.8 mm Hg, 15.5 mm Hg, and 15.6 mm Hg, respectively, compared with a 5.1-mm Hg reduction with placebo (P<0.001 for each dose vs placebo). Irbesartan 150 mg reduced mean trough SeSBP by 12.5 mm Hg, which was comparable to that with aliskiren 150 mg and significantly greater than that with placebo (P<0.001). Aliskiren 300 mg and 600 mg trended toward greater reductions in SeSBP compared with irbesartan (P= 0.052 and P=0.055, respectively). References Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides antihypertensive efficacy and placebo-like tolerability similar to an AT1-receptor blocker in hypertensive patients. Am J Hypertens. 2004;17:108A. Abstract P-204.

108. Plasma renin activity (PRA) decreased in all aliskiren groups, and increased with irbesartan therapy. Each dose of aliskiren reduced PRA compared with baseline and compared with placebo. By contrast, PRA rose dramatically with irbesartan 150 mg. References Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides antihypertensive efficacy and placebo-like tolerability similar to an AT1-receptor blocker in hypertensive patients. Am J Hypertens. 2004;17:108A. Abstract P-204.Plasma renin activity (PRA) decreased in all aliskiren groups, and increased with irbesartan therapy. Each dose of aliskiren reduced PRA compared with baseline and compared with placebo. By contrast, PRA rose dramatically with irbesartan 150 mg. References Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides antihypertensive efficacy and placebo-like tolerability similar to an AT1-receptor blocker in hypertensive patients. Am J Hypertens. 2004;17:108A. Abstract P-204.

109. Aliskiren demonstrated a safety and tolerability profile similar to that of placebo and irbesartan, with no evidence of a dose-dependent increase in the incidence of adverse events (AEs). The percentage of patients reporting an AE was 26.8%, 36.2% and 33.1% with aliskiren 150 mg, 300 mg, and 600 mg, respectively, compared with 36.6% for irbesartan and 32.1% for placebo. The number of patients discontinuing therapy due to AEs was similar in all groups (range 2.2�3.9%). No serious AEs were reported in patients receiving aliskiren, and no deaths occurred in the study. References Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides antihypertensive efficacy and placebo-like tolerability similar to an AT1-receptor blocker in hypertensive patients. Am J Hypertens. 2004;17:108A. Abstract P-204.Aliskiren demonstrated a safety and tolerability profile similar to that of placebo and irbesartan, with no evidence of a dose-dependent increase in the incidence of adverse events (AEs). The percentage of patients reporting an AE was 26.8%, 36.2% and 33.1% with aliskiren 150 mg, 300 mg, and 600 mg, respectively, compared with 36.6% for irbesartan and 32.1% for placebo. The number of patients discontinuing therapy due to AEs was similar in all groups (range 2.2�3.9%). No serious AEs were reported in patients receiving aliskiren, and no deaths occurred in the study. References Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides antihypertensive efficacy and placebo-like tolerability similar to an AT1-receptor blocker in hypertensive patients. Am J Hypertens. 2004;17:108A. Abstract P-204.

116. Potencijalna va�nost prorenina Otprilike 90% od �ukupnog renina� u krvnoj plazmi je prorenin, inaktivni biosintetski preteca renina1 Prorenin se otpu�ta stalno a ne akutno Lokalna sinteza prorenina se odigrava u adrenalki, u ocima, ovariju i testisima Povecane vrijednosti prorenina nalazimo kod : diabeticne nefropatije i retinopatije2 tokom trudnoce i poticu iz ovarija Kod transgenetskih glodara i sa ekspresijom prorenina u jetri, nalazi se kardijalna hipertrofija i/ili vaskularno o�tecenje3,4 Prorenin is a biosynthetic precursor of renin. In humans, as much as 90% of circulating renin exists in its enzymatically inactive form. Tissue, however, predominantly contains renin. The physiological and possible pathophysiological role of prorenin remains unclear. Kawazu et al. measured prorenin in sera from normal subjects and type 2 diabetic patients, using an antibody-activating direct enzyme kinetic assay. It was shown that: The levels of antibody-activating direct prorenin (AAD-PR) were significantly higher in males than in females, and in diabetic patients than in normal subjects AAD-PR levels were higher in diabetic patients with microalbuminuria, and even higher in those with macroalbuminuria In normoalbuminuric diabetic patients, AAD-PR levels were higher in those with retinopathy There was a significant positive correlation between the AAD�PR levels and hemoglobin A1C in normoalbuminuric diabetic subjects without retinopathy References Muller D, Hilgers. K, Mathews S et al. Hypertension 1999;33:312�317. Kawazu S, Minagawa S, Yazawa M et al. J Diabetes Complications 2004;18(5): 275�81. Prorenin is a biosynthetic precursor of renin. In humans, as much as 90% of circulating renin exists in its enzymatically inactive form. Tissue, however, predominantly contains renin. The physiological and possible pathophysiological role of prorenin remains unclear. Kawazu et al. measured prorenin in sera from normal subjects and type 2 diabetic patients, using an antibody-activating direct enzyme kinetic assay. It was shown that: The levels of antibody-activating direct prorenin (AAD-PR) were significantly higher in males than in females, and in diabetic patients than in normal subjects AAD-PR levels were higher in diabetic patients with microalbuminuria, and even higher in those with macroalbuminuria In normoalbuminuric diabetic patients, AAD-PR levels were higher in those with retinopathy There was a significant positive correlation between the AAD�PR levels and hemoglobin A1C in normoalbuminuric diabetic subjects without retinopathy References Muller D, Hilgers. K, Mathews S et al. Hypertension 1999;33:312�317. Kawazu S, Minagawa S, Yazawa M et al. J Diabetes Complications 2004;18(5): 275�81.

117. Uloga (Pro)reninskog receptora: izravna uloga renina neovisno od Ang II ? Novi dokazi o postojanju funkcionalnog reninskog receptora Ovaj receptor mo�e da bude odgovoran za stanicne efekte renina, neovisno od stvaranja angiotenzina II Nepoznati patofiziolo�ki odgovori? Nguyen and colleagues reported the identification of a renin receptor by expression cloning. Transfection of the receptor cDNA into cells lacking specific binding of renin resulted in the expression of a 45-kDa membrane protein that specifically binds renin and prorenin. The binding of renin to its receptor induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin I. Furthermore, it induced an intracellular signal with phosphorylation of serine and tyrosine residues associated with an activation of MAP kinases ERK1 and ERK2. Confocal microscopy revealed that the receptor is localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery. In addition, the receptor was shown to be associated with smooth muscle cells and co-localized to renin. Reference Nguyen G, Delarue F, Burckle, C et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Investig 2002;109(11):1417�1427. Nguyen and colleagues reported the identification of a renin receptor by expression cloning. Transfection of the receptor cDNA into cells lacking specific binding of renin resulted in the expression of a 45-kDa membrane protein that specifically binds renin and prorenin. The binding of renin to its receptor induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin I. Furthermore, it induced an intracellular signal with phosphorylation of serine and tyrosine residues associated with an activation of MAP kinases ERK1 and ERK2. Confocal microscopy revealed that the receptor is localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery. In addition, the receptor was shown to be associated with smooth muscle cells and co-localized to renin. Reference Nguyen G, Delarue F, Burckle, C et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Investig 2002;109(11):1417�1427.

119. Teoretske potencijalne koristi od inhibitora renina 5. Specifican supstrat: Angiotensinogen 6. Smanjuju aktivnost RAS Suprimira sve Ang I-derivirajuce peptide Inhibira neovisno od konvertirajuceg enzima stvaranje Ang II Ne stimulira AT2 ili druge ATn receptore Neutralizuje posljedice kontraregulacijonog otpu�tanja renina izazvanog blokadom RAS Potencijalna interakcija sa (pro)reninskim receptorom? 7. Podjednako blokiraju RAS kao i drugi vec prihvaceni lijekovi u lijecenju hipertenzije 8. Dobro se podnose 9. Potencijalne koristi Kod pacijenata sa hronicnom nefropatijom Kod pacijenata sa dijabeticnom nefropatijom i retinopatijom

120. ZAKLJUCAK Aliskiren je podjednako efikasan kao ACEI ili Antag Ang II Podno�ljivost aliskirena je dobra u dozi do 300 mg dnevno Aliskiren se mo�e kombinovati sa diuretikom i Antag Ang II i to sa dodatnim antihipertenzivnim efektom

122. ZAKLJUCAK I tako je aliskiren efikasan, novi antihipertenzivni lijek. Ali, da li je to dovoljno ?