Farmaci Calcio Antagonisti26 Marzo 2004

Farmaci Calcio Antagonisti26 Marzo 2004

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

CCB binding to Ca++ channel

DHP alone BZT + DHP PAA + BZTDHP alone BZT + DHP PAA + BZT

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.