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SITI DI AZIONE DEI FARMACI ANTIIPERTENSIVISITI DI AZIONE DEI FARMACI ANTIIPERTENSIVI
Inibitori delle catecolamine
CENTRALI Stimolanti•Metildopa•Clonidina
Altri•Reserpina
bloccanti?
Bloccanti
Diuretici
vasodilatazione
sinapsi
Renina
AngioAngio
tensinatensina
IIII
vasocostrizione
VASODILATATORI DIRETTI
•Idralazina
-BLOCCANTI
•Prazosina
CALCIOANTAGONISTI
•Nifedipina
•Verapamil
•Diltiazem
Formule chimiche dei calcio antagonistiFormule chimiche dei calcio antagonisti
N
N
O
O
O
O
HN
O
O
O
ON+
-O
O
N
ON
O
O
S
O
Verapamil
Nifedipine
Diltiazem
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
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
CaCa2+2+antagonisti modalità d’azioneantagonisti modalità d’azione
Chemistry of the Ca2+ antagonists
Phenylalkylamine-derivatives Verapamil Gallopamil
Dihydropyridine-derivatives
Nifedipine Nisoldipine Nicardipine
Benzothiazepine- derivatives
Diltiazem T-channel blocking drugs
Mibefradil
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
Activation voltage
+
High (25)
Strong depolarisation
-10 mv
-
Moderate (13)
Strong depolarisation
-10 mv
-
Low (9)
Weak depolarisation
-70 mv + denotes the presence, and – the absence of sensitivity to the organic calcium antagonists- such as verapamil, nifedipine or diltiazem
+++
Struttura del canale del calcioStruttura del canale del calcio
II
II
IIII IIIIII IVIV
S1
S2
S3
S5
S6
II
IIII IIIIII
IVIVIVIV
S4
+++
+++
+++
N
C
Top view
State dependent affinity for dihydropyridinesState dependent affinity for dihydropyridines
Ca
cu
rren
t C
a c
urr
ent
(%)
(%)
0
50
100
1010-10-10 1010-9-9 1010-8-8 1010-7-7 1010-6-6 1010-5-5
0.36 nM 730 nM
EH= -15 mV EH= -80 mV
Nitrendipine (M)Nitrendipine (M)
State dependent binding
Resting Activated Inactivated
Inactivated*
Prolonged recovery time course- drug
+ drug
Activated *
Depolarized
Repolarized
-60 +40
Ca channel shape action potentialCa channel shape action potential
Cardiac pacemakerCardiac pacemaker Cardiac ventricleCardiac ventricle
Vascular smooth muscle
Vascular smooth muscle
Central neuronCentral neuron
20 ms
100 ms
500 ms
250 ms
0
30
EM (
mV
)E
M (m
V)
0
50
0
-80
0
-50
Excitation-contraction coupling mechanismsExcitation-contraction coupling mechanismsin muscle cellsin muscle cells
ExcitationExcitationExcitationExcitation ExcitationExcitationExcitationExcitation ExcitationExcitationExcitationExcitation
MembraneMembraneReceptorReceptor
CaCa2+2+ CaCa2+2+
CaCa2+2+ CaCa2+2+SR
CaCa2+2+
SR
CaCa2+2+
SR
CaCa2+2+
Activator Ca2+Activator Ca2+ Activator Ca2+Activator Ca2+ Activator Ca2+Activator Ca2+
SKELETAL CARDIAC SMOOTH
Selectivity of the calcium antagonists
Drug Myocardium Vasculature Conducting and nodal tissue
Skeletal muscle
Verapamil Diltiazem Nifedipine Nimodipine Amlodipine
+ + + + +
+ +
++ ++++ ++++
+ + - - -
- - - - -
Electrophysiologic effects of calcium channel blockers
SA node automaticity
Direct effect Clinical effect AV node conduction
Verapamil
Nifedipine
Diltiazem
Nicardipine
Isradipine
Nitrendipine
Bepridil
, increased; , decreased; no significant change
N > V > DN > V > D
Variable effect: Usually cancelled Variable effect: Usually cancelled by Afterload reduction Especially for Nby Afterload reduction Especially for N
CaCa2+2+ ANTAGONISTS: COMPARATIVE PROPERTIES ANTAGONISTS: COMPARATIVE PROPERTIES
ecgecg
Peripheral arteriolePeripheral arteriole
Nifedipine >V > DNifedipine >V > D
V=D=NV=D=N
SpasmSpasm
--
--
DiltiazemDiltiazem
(Verapamil)(Verapamil)
SASA
AVAV
--
--
VerapamilVerapamil
DiltiazemDiltiazem
--
-- --contractilitycontractility
LADLAD
Opie. 1985Opie. 1985
N > V > D experimentallyN > V > D experimentally
V >N, D clinicallyV >N, D clinically
CaCa2+2+ ANTAGONISTS: COMPARATIVE PROPERTIES ANTAGONISTS: COMPARATIVE PROPERTIES
ecgecg
Peripheral arteriolePeripheral arteriole
Nifedipine >V > DNifedipine >V > D
SpasmSpasm
--
--SASA
AVAV
--
--ExperimentallyExperimentally
V=D >NV=D >N
Clinically ? V=DClinically ? V=D
? V >D? V >D--
contractilitycontractility
LADLAD
Opie. 1987Opie. 1987
V =N=D clinicallyV =N=D clinically
N >V=D experimentallyN >V=D experimentally
Or N >V=DOr N >V=D
ClinicallyClinically
D >V >ND >V >N
Or D =V >NOr D =V >N
RATIO NEG INOTROPIC TO VASCULAR EFFECT: V >D >N
Pharmacokinetics of CaPharmacokinetics of Ca2+2+ antagonists 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 Half- life of some of the second generation calcium antagonistscalcium antagonists
Drug T ½ (hours)
Amlodipine Felodipine Isradipine Nisoldipine Nitrendipine
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
Effetto Diltiazem Nifedipina Verapamil
Ipotensione Vampate Cefalea Edemi alle caviglie Palpitazioni/dolore toracico Disturbi della conduzione Insufficienza cardiaca Bradicardia Nausea Stipsi Diarrea
+ - + + + + - + +
(+) -
+ ++ ++ + + -
(+) - - - +
+ + + + -
++ +
++ + + -
Da Krebs R. 24.
Effetti collaterali dei calcio antagonistiEffetti collaterali dei calcio antagonisti
INDICAZIONI CARDIOLOGICHE DIFFERENZIALI DEI CALCIO-ANTAGONISTI(1)
Indicazioni VERAPAMIL(2) NIFEDIPINA
(2) DILTIAZEM(2)
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
++ ++ ++ +/- ++ ++ + +
++ ++
++ ++
(3) ++ ++ - -
++ ++ ++ +
++ ++ ++ + +
++ + +
++ +
(1) 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.
INDICAZIONI CARDIOLOGICHE DIFFERENZIALI DEI CALCIO-ANTAGONISTI(1)
Indicazioni VERAPAMIL(2) NIFEDIPINA
(2) DILTIAZEM(2)
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
++ ++ ++ +/- ++ ++ + +
++ ++
++ ++
(3) ++ ++ - -
++ ++ ++ +
++ ++ ++ + +
++ + +
++ +
(1) 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.