Transcript SITI DI AZIONE DEI FARMACI ANTIIPERTENSIVI

Farmaci Calcio Antagonisti
26 Marzo 2004
CENTRALI
a Stimolanti
•Metildopa
•Clonidina
Altri
•Reserpina
b bloccanti?
SITI DI AZIONE DEI FARMACI ANTIIPERTENSIVI
Inibitori delle
catecolamine
b
a
sinapsi
VASODILATATORI
DIRETTI
•Idralazina
a-BLOCCANTI
Bloccanti
•Prazosina
Diuretici
CALCIOANTAGONISTI
vasodilatazione
•Nifedipina
Renina
•Verapamil
Angio vasocostrizione
tensina
II
•Diltiazem
Formule chimiche dei calcio antagonisti
N
O
N
O
O
O
O
Verapamil
S
O
H
N
N
O
-
O O
O
O
N
O
+
O
N
O
Diltiazem
Nifedipine
Role of Calcium Antagonists in Heart Failure
 Because of the lack of evidence supporting efficacy, calcium antagonists should not be used
for the treatment of heart failure. Large scale trials of newer agents have not provided
persuasive evidence that long-term treatment with these drugs can improve the symptoms of
heart failure or prolong survival.
 Because of concerns about safety, most calcium antagonists should be avoided in patients
with heart failure, even when used for the treatment of angina or hypertension. Of the
available agents, clinical trials have provided long-term safety data only for amlodipine and
felodipine. There is persuasive evidence that amlodipine does not adversely affect survival.
 The possibility that amlodipine might have a favourable effect on survival in patients with a
nonischemic cardiomyopathy requires further study (and confirmation) before such a finding is
apllied to the care of patients with heart failure
Ca2+antagonisti modalità d’azione
Chemistry of the Ca
2+
Phenylalkylamine-derivatives
Verapamil
Gallopamil
Dihydropyridine-derivatives
Nifedipine
Nisoldipine
Nicardipine
Benzothiazepine- derivatives
Diltiazem
T-channel blocking drugs
Mibefradil
antagonists
Characteristic properties of the L, N and T-type Ca2+ channels
Channel type
L
N
T
Sensitivity to organic
calcium antagonists
Channel conductance
(picosiemens)
Activation threshold
+
-
-
High (25)
Moderate (13)
Low (9)
Weak
Strong
Strong
depolarisation
depolarisation depolarisation
-70 mv
-10 mv
-10 mv
Activation voltage
+ denotes the presence, and – the absence of sensitivity to the organic
calcium antagonists- such as verapamil, nifedipine or diltiazem
Struttura del canale del calcio
I
II
+
+
+
S
6
IV
+
+
+
+
+
+
S4
+
SSS+ S
12 3+5
III
Top view
N
III
II
I
IV
I
IV
C
CCB binding to Ca++ channel
DHP alone BZT + DHP PAA + BZT
State dependent affinity for dihydropyridines
100
Ca current (%)
0.36 nM
730 nM
EH= -15 mV
50
EH= -80 mV
0
10-10
10-9
10-8
10-7
Nitrendipine (M)
10-6
10-5
State dependent binding
Depolarized
-60
+40
Repolarized
Resting
Activated
Inactivated
+ drug
Activated *
- drug
Inactivated*
Prolonged recovery
time course
Ca channel shape action potential
Cardiac pacemaker
0
Cardiac ventricle
EM (mV)
0
-50
-80
100 ms
250 ms
Central neuron
0
0
EM (mV)
Vascular smooth
muscle
50
30
20 ms
500 ms
Excitation-contraction coupling mechanisms
in muscle cells
Excitation
Excitation
Excitation
Ca2+
Ca2+
Receptor
Membrane
SR
Ca2+
Ca2+
SR
Ca2+
Activator Ca2+
SKELETAL
Activator Ca2+
CARDIAC
Ca2+ SR
Ca2+
Activator Ca2+
SMOOTH
Drug
Verapamil
Diltiazem
Nifedipine
Nimodipine
Amlodipine
Selectivity of the calcium antagonists
Myocardium Vasculature Conducting and
nodal tissue
+
+
+
+
+
+
+
++
++++
++++
+
+
-
Skeletal muscle
-
Electrophysiologic effects of calcium channel blockers
SA node automaticity
Verapamil
Nifedipine
Diltiazem
Nicardipine
Isradipine
Nitrendipine
Bepridil
Direct effect
Clinical effect
AV node
conduction




















, increased; , decreased;  no significant change
Ca2+ ANTAGONISTS: COMPARATIVE PROPERTIES
V=D=N
Diltiazem
(Verapamil)
Spasm
-
-
SA
LAD
AV
ecg
contractility
Verapamil
Diltiazem
-
-
Peripheral arteriole
N>V>D
Opie. 1985
-
Variable
effect: Usually cancelled
by Afterload reduction Especially for N
Nifedipine >V > D
Ca2+ ANTAGONISTS: COMPARATIVE PROPERTIES
N >V=D experimentally
V =N=D clinically
Clinically
D >V >N
Or D =V >N
Spasm
-
-
SA
AV
Experimentally
LAD
ecg
Peripheral arteriole
-
V=D >N
contractility
Clinically ? V=D
? V >D
Opie. 1987
-
-
N > V > D experimentally
Nifedipine >V > D
V >N, D clinically
Or N >V=D
RATIO NEG INOTROPIC TO VASCULAR EFFECT: V >D >N
Pharmacokinetics of Ca2+ antagonists
Dose
Nifedipine
Verapamil
Oral
Intravenous
Plasma concentration
% protein bound
First pass extraction by liver
Half-life (t1/2)
10-40 mg 8 h-1
5-15 g kg-1
10-75 ng ml-1
95
40-60 %
3-5 h
80-160 mg 8 h-1
100-200 g kg-1
50-250 ng ml-1
90
75-85 %
5-10 h
Half- life of some of the second generation
calcium antagonists
Drug
Amlodipine
Felodipine
Isradipine
Nisoldipine
Nitrendipine
T ½ (hours)
35-40
10
8
8-11
12
T ½ refers to the plasma half-life of these second generation calcium
antagonists in patients with normal kidney and liver function
Effetti collaterali dei calcio antagonisti
Effetto
Ipotensione
Vampate
Cefalea
Edemi alle caviglie
Palpitazioni/dolore toracico
Disturbi della conduzione
Insufficienza cardiaca
Bradicardia
Nausea
Stipsi
Diarrea
Da Krebs R. 24.
Diltiazem
Nifedipina
Verapamil
+
+
+
+
+
+
+
(+)
-
+
++
++
+
+
(+)
+
+
+
+
+
++
+
++
+
+
-
INDICAZIONI CARDIOLOGICHE DIFFERENZIALI DEI CALCIO-ANTAGONISTI(1)
Indicazioni
Angina primaria (vasospastica)
Angina stabile da sforzo
Angina con ipertensione
Angina con insufficienza cardiaca
Tachicardia sopraventricolare
Fibrillazione o flutter
Ipertensione grave
Ipertensione
Fenomeno di Raynaud
Cardiomiopatia ipertrofica
(1)
VERAPAMIL(2) NIFEDIPINA(2)
++
++
++
+/++
++
+
+
++
++
++
++ (3)
++
++
++
++
++
+
DILTIAZEM(2)
++
++
++
+
+
++
+
+
++
+
Da Opie L. H., Singh B.N., Calcium channel antagonists, in “drug for the heart”, a cura di Opie L.H., New York,
Grune & Stratton, 1987, pp. 34-53;modificata.
(2)
Indicazione preferenziale (++), indicazione (+), nessuna indicazione (-)
(3)
Necessaria un’accurata titolazione della dose.