Farmaci Calcio Antagonisti 26 Marzo 2004
SITI DI AZIONE DEI FARMACI ANTIIPERTENSIVI CENTRALI Stimolanti Metildopa Clonidina Altri Reserpina b bloccanti? SITI DI AZIONE DEI FARMACI ANTIIPERTENSIVI Inibitori delle catecolamine a b VASODILATATORI DIRETTI Idralazina a-BLOCCANTI Prazosina CALCIOANTAGONISTI Nifedipina Verapamil Diltiazem sinapsi Bloccanti Diuretici vasodilatazione Renina Angio tensina II vasocostrizione
Formule chimiche dei calcio antagonisti Verapamil Diltiazem Nifedipine
Ca2+antagonisti modalità d’azione
Struttura del canale del calcio II III IV +++ +++ +++ +++ S1 S2 S3 S5 S6 S4 Top view N II III IV I I IV C
CCB binding to Ca++ channel DHP alone BZT + DHP PAA + BZT
State dependent affinity for dihydropyridines 100 0.36 nM 730 nM Ca current (%) 50 EH= -15 mV EH= -80 mV 10-10 10-9 10-8 10-7 10-6 10-5 Nitrendipine (M)
State dependent binding Depolarized -60 +40 Repolarized Resting Activated Inactivated + drug Activated * Inactivated* Prolonged recovery time course - drug
Ca channel shape action potential Cardiac pacemaker Cardiac ventricle EM (mV) -50 -80 100 ms 250 ms Vascular smooth muscle Central neuron EM (mV) 50 30 20 ms 500 ms
Excitation-contraction coupling mechanisms in muscle cells Ca2+ Ca2+ Receptor Membrane SR Ca2+ Ca2+ Ca2+ SR Ca2+ SR Ca2+ Activator Ca2+ Activator Ca2+ Activator Ca2+ SKELETAL CARDIAC SMOOTH
Ca2+ ANTAGONISTS: COMPARATIVE PROPERTIES V=D=N Diltiazem (Verapamil) Spasm - - SA LAD AV ecg - contractility Verapamil Diltiazem Peripheral arteriole - - N > V > D Variable effect: Usually cancelled by Afterload reduction Especially for N - - Opie. 1985 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 LAD AV ecg Peripheral arteriole - Experimentally V=D >N Clinically ? V=D ? V >D - contractility - N > V > D experimentally V >N, D clinically Nifedipine >V > D Or N >V=D Opie. 1987 RATIO NEG INOTROPIC TO VASCULAR EFFECT: V >D >N
Pharmacokinetics of Ca2+ antagonists
Half- life of some of the second generation calcium antagonists
Effetti collaterali dei calcio antagonisti