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

Corso di Farmacologia 2005

Angiotensinogeno Angiotensina I

renina

Angiotensina II

Angiotensin Converting Enzyme -ACE

vasocostrizione

FARMACI DEL SISTEMA RENINA-ANGIOTENSINA-ALDOSTERONE

aldosterone

ACE-inibitori

Beta-bloccantiAT1-antagonisti

(Sartani)

SpironolattoneCanrenone

recettore AT1

Inibitori della renina

Enalkiren

Remikiren

Sviluppo degli inibitori della renina

J.Clin.Pharmacol. 1994, 34: 873

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

The 1998 National Medal of Technology, Scientific American, March 1999

TEPROTIDE – BRADYCHININ POTENTIATING FACTOR (Ferreira)

Angiotenin II receptor antagonists. Lancet 355, 637, 2000

Legame del Captopril all’ACELegame del Captopril all’ACE

Zn++Zn++OO

CC

Zn++Zn++

Angiotensin I

Angiotensin I

Captopril

CaptoprilOO

OO

OHOH

NNSHSH

ACE-I carbossilici

Enalaprilat

Esterasi plasmaticheEsterasi plasmatiche

Zn++Zn++ACEACE

Enalapril Enalapril

OO

OO

OO

OO

HOHO

NH

NH

ACE-I fosforilici

Zn++Zn++ACEACE

OO

OO

OO

PPNN

OO

OOHOHO

Captopril EnalaprilLisinopri

lRamipril

Quinapril

Fosinopril

Binding site -SH -COOH -COOH -COOH -COOH -POOH

Prodrug No Yes Yes Yes Yes Yes

Protein Binding %

25 50 10 56 97 96

Elimination GF/TS GF/TS GF GF/TS R R/H

Dose 50-150 5-40 5-40 5-20 5-40 10-40

tmax (h) 0.5-1.5 3-4 6-7 1.5-3 1.5-2 3

tslow (h) - 30-50 30 110 - 12

Peak effect (h)

0.25-0.5 1-4 1-2 0.5-2 1-2 1-2

Duration 3-12 12-30 18-30 24 24 24

Frequency b.(t.)d. o.(b.)d. o.d. o.d. o.(b.)d. o.d.

Principali caratteristiche farmacocinetiche degli ACE inhibitori

Karl T. Weber, M.D. NEJM 345,1689, 2001

Kidney

Adrenal gland

BrainHeart

NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser-

NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-COOH

NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-COOH

NH2-Arg-Val-Tyr-Ile-His-Pro-Phe-COOH

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin I

Angiotensin IIAngiotensin II

Angiotensin IIIAngiotensin III

ReninRenin

Converting enzyme (ACE)Converting enzyme (ACE)

AminopeptidaseAminopeptidase

(Chimase)(Chimase)

Bradykinin

Inactive FragmentsInactive Fragments

SYMPATHETIC

TONE

SYMPATHETIC

TONE

ANG II ANG II

Na+ excretionNa+ excretion

INOTROPIC,

CHRONOTROPIC

ACTIONS

INOTROPIC,

CHRONOTROPIC

ACTIONS

ACE-IACE-I

Vascular wallVascular wall KidneyKidneyAdrenal glandAdrenal gland

HeartHeart BrainBrain

VASODILATATIONVASODILATATION

BLOOD PRESSURE BLOOD PRESSURE

ALDOSTERONEALDOSTERONE

Ditribuzione dell‘ACE nell‘organismo:

Sistema renina-angiotensina (RAS)

mod. sec Dzau V, Arch Intern Med 153 (1993)

R A S

circolante (plasma) locale (tessuto)

10 % 90 %

Effetti immediaticardiovascolari/

omeostasi renale

Effetti a lungo termine„adattamento“ locale dell‘organoAttivazione rene-indipendente

Effetti farmacodinamici degli ACE-I

Diminuzione Aumento

Angiotensina II plasmatica Angiotensina I

Aldosterone plasmatico Renina

Kallicreina urinaria Kinine urinarie

Effetti ormonali

Effetti emodinamici

Diminuzione Aumento

Resistenze periferiche Gettata cardiaca

Pressione arteriosa Flusso ematico regionale

Flusso ematico renale

ACE-I

sistema adrenergico

aldosterone

bradichininaprostaglandinevasorilascianti

dilatazione arteriole

resistenze vascolari

sistemiche

pressione arteriosa

ACE-Inibitori ed ipertensione

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

Terapia combinataCaptopril oIdroclorotiazide

da soli

Captopril oIdroclorotiazide

da soli

Terapia combinata

L’effetto ipotensivo degli ACE-I e potenziato dall’associazione con diuretici tiazidici

10 100 1000-60

-50

-40

-30

-20

-10

0

Cha

nge

in L

VM

(g)

Duration of treatment (days)

EnalaprilEnalapril

HydrochlorothiazideHydrochlorothiazide

Modified from Dahlof, Hansson J Hypertens 1992, 10:1513-24

Change in left ventricular mass (LVM) with antihypertensive treatment

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).  

ANGIOTENSIN II

AlteredPeripheralResistance

AlteredRenal

Function

AlteredCardiovascular

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-oncogenesB. Release of Growth FactorsC. Synthesis of extracellular

matrix

2. Hemodinamically mediated effects:

A. Increased afterloadB. Increased preload

Rapid Pressor Response Slow Pressor Response Vascular and cardiachypertrophy and remodeling

L’angiotensina II è un fattore umorale co-responsabile dei processi dirimodellamento patologico

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

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

Hemodynamic overload

Secondary biologic response

Myocardial remodeling

Myocardial dysfunction

Central role of myocardial remodeling in the pathophysiology of heart failure

Central role of myocardial remodeling in the pathophysiology of heart failure

NormalNormal Compensatory hypertrophy

Compensatory hypertrophy

Dilated cardiomyopathy

Dilated cardiomyopathy

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 hypertrophy has evolved as a powerful predictor of sudden death.

ACE-IACE-I

RIMODELLAMENTO RIMODELLAMENTO VASCOLAREVASCOLARE

RIMODELLAMENTO RIMODELLAMENTO CARDIACOCARDIACO

ANG II

Placebo

Enalapril

12111098765

PROBABILITYOFDEATH

MONTHSMONTHS

0.1

0.8

0

0.2

0.3

0.7

0.4

0.5

0.6p< 0.001

p< 0.002

CONSENSUSN Engl J Med 1987;316:1429

ACE-I SURVIVAL

43210

50

40

30

20

10

0

Months0 6 12

p = 0.0036

%MORTALITY

2418 30 36 42 48

Enalapriln=1285

Placebon=1284

SOLVD (Treatment)N Engl J M 1991;325:293

ACE-I SURVIVAL

n = 2589CHF

- NYHA II-III- EF < 35

Prostaglandina E2

Evoluzione della velocità difiltrazione glomerulare e della

proteinuria in pazienti ipertesi

non diabetici dopo instaurazione

di terapia con ACE-Inibitori

Principali indicazioni degli ACE-Inibitori

Ipertensione

Scompenso cardiaco

Post-infarto

Nefropatia diabetica e ipertensiva(microalbuminuria)

Effetti indesiderabili degli ACE-I

Ipotensione Iperkaliemia

Edema angioneurotico Tosse secca e stizzosa

Insufficienza renale

ACE-I

CONTRAINDICATIONS

Renal artery stenosis

Renal insufficiency

Hyperkalemia

Arterial hypotension

Intolerance (due to side effects)

ANTAGONISTS OF AT-1 receptorsMECHANISM OF ACTION

RENIN

Angiotensinogen Angiotensin I

ANGIOTENSIN II

ACEOther paths

Vasoconstriction Proliferative Action

AT1 AT2

AT1 RECEPTOR BLOCKERS

RECEPTORS

Physio-pathological role ?

Antagonisti dei Recettori AT-1 dell’Angiotensina IISARTANI

Antagonisti competitivi e selettivi dei recettori AT-1

Losartan Valsartan Irbesartan Eprosartan

Candesartan cilexetilOlmesartan medoxomil

Unger T. Am. J. Cardiol. 84, 95, 1999

DIFFERENZE FRA ANTAGONISTI DEI RECETTORI AT1

DIFFERENZE FRA ANTAGONISTI DEI RECETTORI AT1

Unger T. Am. J. Cardiol. 84, 95, 1999

TrialELITE II

Lancet 355, 1582, 2000

EFFECT OF IRBESARTAN ON THE DEVELOPMENT OF DIABETIC NEPHROPATHY IN PATIENTS WITH TYPE 2

DIABETES

Parving et al., NEJM 345:870 2001

INCIDENZA DI TOSSE

Studio clinico in pazienti ipertesi con storia di tosse da ACE-inibitoriAm. J. Hypert. 13, 214, 2000

Diuretici risparmiatori di potassioDiuretici risparmiatori di potassio

NaNa++

KK++

NaNa++

NaNa++

ATPATP

ATPATP

ATPATP

HCOHCO33-- HCOHCO33

--

ClCl--

HH22COCO33

KK++

HH++

HH++ HH++

A.C.A.C.COCO22+H+H22OO

Cellula intercalare ACellula intercalare A

Cellula PrincipaleCellula PrincipaleLUMELUME INTERSTIZIOINTERSTIZIO

AmilorideAmilorideTriamtereneTriamterene

SpironolattoneSpironolattoneCanrenoneCanrenone

Canrenoato di KCanrenoato di K

AldosteroneAldosterone

RecettoreRecettoreNEFRONEDISTALE

ALDOSTERONE

• Ritenzione di NA+

• Ritenzione di H2O

•Escrezione di K+

•Escrezione di Mg2+

Deposizione di

collagene

Fibrosi - miocardio

- vasi

Spironolattoneantagonista competitivo deirecettori dell’aldosterone nelmiocardio, parete vasale e

rene

Edema

Aritmie

INIBITORI DELL’ALDOSTERONE

Angiotensin II

Karl T. Weber, M.D. NEJM 345,1689, 2001

PRODUZIONE DI ALDOSTERONE da parte delle cellule endoteliali e muscolari lisce dell’arteria coronarica intramiocardica

PRODUZIONE DI ALDOSTERONE da parte delle cellule endoteliali e muscolari lisce dell’arteria coronarica intramiocardica

Kaplan–Meier Analysis of the Probability of Survival among Patients in Kaplan–Meier Analysis of the Probability of Survival among Patients in the Placebo Group and Patients in the Spironolactone Group.the Placebo Group and Patients in the Spironolactone Group.

The risk of death was 30 percent lower among patients in the spironolactone The risk of death was 30 percent lower among patients in the spironolactone group than among patients in the placebo group (P<0.001). group than among patients in the placebo group (P<0.001).

3 6 9 12 15 18 21 24 27 30 33 363 6 9 12 15 18 21 24 27 30 33 36

P<0.001P<0.001

Pro

bab

ility

of

su

rviv

alP

rob

abili

ty o

f s

urv

ival

MonthsMonths

Spironolactone

PlaceboPlacebo

0.500.50

0.550.55

00

0.450.45

0.600.60

0.650.65

0.700.70

0.750.75

0.800.80

0.850.85

0.900.90

0.950.95

1.001.00