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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
Angiotensin Converting Enzyme -ACE
Inibitori della renina
Angiotensinogeno
ACE-inibitori
Angiotensina I
Angiotensina II
renina
Beta-bloccanti
AT1-antagonisti
(Sartani)
recettore AT1
Spironolattone
Canrenone
aldosterone
vasocostrizione
Sviluppo degli inibitori della renina
Enalkiren
Remikiren
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
TEPROTIDE – BRADYCHININ POTENTIATING FACTOR (Ferreira)
The 1998 National Medal of Technology, Scientific American, March 1999
Angiotenin II receptor antagonists. Lancet 355, 637, 2000
Legame del Captopril all’ACE
Zn++
O
C
Zn++
SH
O
N
OH
O
ACE-I carbossilici
ACE
Zn++
Esterasi plasmatiche
Enalapril
Enalaprilat
ACE-I fosforilici
ACE
Zn++
O
O
P
N
O
O
HO
O
Principali caratteristiche farmacocinetiche degli ACE inhibitori
Captopril
Enalapril Lisinopril
Ramipril 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
0.25-0.5
1-4
1-2
0.5-2
1-2
1-2
3-12
12-30
18-30
24
24
24
b.(t.)d.
o.(b.)d.
o.d.
o.d.
o.(b.)d.
o.d.
Peak effect (h)
Duration
Frequency
Heart
Brain
Adrenal gland
Kidney
Karl T. Weber, M.D. NEJM 345,1689, 2001
Angiotensinogen
NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-SerRenin
Angiotensin I
NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-COOH
Angiotensin II
Bradykinin
Converting enzyme (ACE)
(Chimase)
NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-COOH
Aminopeptidase
Angiotensin III
NH2-Arg-Val-Tyr-Ile-His-Pro-Phe-COOH
Inactive Fragments
ACE-I
 ANG II
Vascular wall
Kidney
Adrenal gland
VASODILATATION
ALDOSTERONE
Na+ excretion
Heart
Brain
INOTROPIC,
SYMPATHETIC
CHRONOTROPIC
TONE
ACTIONS
 BLOOD PRESSURE
Sistema renina-angiotensina (RAS)
Ditribuzione dell‘ACE nell‘organismo:
10 %
RAS
90 %
circolante (plasma)
locale (tessuto)
Effetti immediati
Effetti a lungo termine
cardiovascolari/
omeostasi renale
mod. sec Dzau V, Arch Intern Med 153 (1993)
„adattamento“ locale dell‘organo
Attivazione rene-indipendente
Effetti farmacodinamici degli ACE-I
Effetti ormonali
Diminuzione
Aumento
Angiotensina II plasmatica
Angiotensina I
Aldosterone plasmatico
Renina
Kallicreina urinaria
Kinine urinarie
Effetti emodinamici
Diminuzione
Aumento
Resistenze periferiche
Gettata cardiaca
Pressione arteriosa
Flusso ematico regionale
Flusso ematico renale
ACE-Inibitori ed ipertensione
sistema adrenergico
ACE-I
aldosterone
dilatazione
arteriole
bradichinina
prostaglandine
vasorilascianti
resistenze
vascolari
sistemiche
 pressione arteriosa
L’effetto ipotensivo degli ACE-I è potenziato
in condizioni di elevata renina
L’effetto ipotensivo degli ACE-I e potenziato
dall’associazione con diuretici tiazidici
Captopril o
Idroclorotiazide
da soli
Terapia combinata
Captopril o
Idroclorotiazide
da soli
Terapia combinata
Change in left ventricular mass (LVM) with antihypertensive treatment
0
Hydrochlorothiazide
Change in LVM (g)
-10
-20
-30
Enalapril
-40
-50
-60
10
100
1000
Duration of treatment (days)
Modified from Dahlof, Hansson J Hypertens 1992, 10:1513-24
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
Altered
Peripheral
Resistance
1. Direct Vasoconstriction
2. Enhancement of peripheral
noradrenergic
neurotransmission
3. Increased sympathetic
discharge
4. Release of catecholamines
from adrenal medulla
Rapid Pressor Response
Altered
Renal
Function
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
Slow Pressor Response
Altered
Cardiovascular
Structure
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
Vascular and cardiac
hypertrophy and remodeling
L’angiotensina II è un fattore umorale co-responsabile dei processi di
rimodellamento patologico
Central role of myocardial remodeling in the
pathophysiology of heart failure
Hemodynamic
overload
Secondary
biologic response
Myocardial remodeling
Myocardial dysfunction
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
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.
Normal
Compensatory
hypertrophy
Dilated
cardiomyopathy
 ANG II
RIMODELLAMENTO
VASCOLARE
ACE-I
RIMODELLAMENTO
CARDIACO
ACE-I SURVIVAL
0.8
0.7
Placebo
0.6
PROBABILITY 0.5
OF
0.4
DEATH
p< 0.001
p< 0.002
0.3
Enalapril
0.2
0.1
CONSENSUS
N Engl J Med 1987;316:1429
0
0
1
2
3
4
5
6
7
8
MONTHS
9
10 11 12
ACE-I SURVIVAL
n = 2589
CHF
- NYHA II-III
- EF < 35
%
MORTALITY
50
p = 0.0036
Placebo
n=1284
40
30
Enalapril
20
n=1285
10
0
SOLVD (Treatment) 0
N Engl J M 1991;325:293
6
12
18 24 30
Months
36 42
48
Prostaglandina E2
Evoluzione della velocità di
filtrazione 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 receptors
MECHANISM OF ACTION
RENIN
Angiotensinogen
Other paths
AT1
RECEPTOR
BLOCKERS
AT1
Vasoconstriction
Angiotensin I
ACE
ANGIOTENSIN II
RECEPTORS
Proliferative
Action
AT2
Physio-pathological role ?
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
DIFFERENZE FRA ANTAGONISTI DEI RECETTORI AT1
Unger T. Am. J. Cardiol. 84, 95, 1999
DIFFERENZE FRA ANTAGONISTI DEI RECETTORI AT1
Unger T. Am. J. Cardiol. 84, 95, 1999
Trial
ELITE 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-inibitori
Am. J. Hypert. 13, 214, 2000
Diuretici risparmiatori di potassio
Cellula Principale
LUME
INTERSTIZIO
Na+
Na+
Na+
ATP
K+
Amiloride
Triamterene
Aldosterone
NEFRONE
DISTALE
H+
H+
K+
ATP
Recettore
Spironolattone
Canrenone
Canrenoato di K
H+
HCO3-
HCO3-
Cl-
H2CO3
ATP
A.C.
CO2+H2O
Cellula intercalare A
INIBITORI DELL’ALDOSTERONE
ALDOSTERONE
Spironolattone
antagonista competitivo dei
recettori dell’aldosterone nel
miocardio, parete vasale e
rene
• Ritenzione di NA+
• Ritenzione di H2O
Edema
•Escrezione di K+
•Escrezione di
Mg2+
Aritmie
Deposizione di
collagene
Fibrosi
- miocardio
- vasi
PRODUZIONE DI ALDOSTERONE da parte delle cellule endoteliali e
muscolari lisce dell’arteria coronarica intramiocardica
Angiotensin II
Karl T. Weber, M.D. NEJM 345,1689, 2001
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
Probability of survival
0.80
0.75
0.70
Placebo
P<0.001
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).