LA RANOLAZINA UN NUOVO FARMACO CON UN’AZIONE DI CLASSE /
RANOLAZINE, A NEW DRUG WITH A CLASS ACTION
L’azione antiaritmica – The Anti-Arrhythmic Action
Stefano Fumagalli
SOD Cardiologia e Medicina
Geriatrica
AOU Careggi e Università di Firenze
2 6
Late ICa – late calcium current
Late INa – late sodium current
INa late normalized current
Tail Current (Normalized)
IKr – rapidly activating component
of delayed rectifier current
2
6
Ranolazine Concentration (mM/L)
Normalized current
Canine ventricular myocytes
Ranolazine Concentration 2-6 mM/L:
therapeutic range
Inhibition of IKr by ranolazine prolongs
APD, and its effect to inhibit late INa
and late ICa,L abbreviates APD
2 6
Ranolazine Concentration (mM/L)
Antzelevitch C, 2004
Effects of ranolazine on epicardial and M cell Action Potential Duration –
APD50/90: 50/90% repolarization
M cell (N=5)
Epicardial cell (N=5)
APD90 (ms)
APD50 (ms)
M cell (N=5)
Epicardial cell (N=4)
Control 1
5
10
50
100
Ranolazine Concentration
(mM/L)
Control 1
5
10
50
100
Ranolazine Concentration
(mM/L)
K+ Concentration: 4 mM/L
*: P<0.05 vs Control
Antzelevitch C, 2004
Rapid pacing
DC Shock
2-4 different
waveforms
Persisting VF
Rapid pacing
VF
+ Ranolazine 10mM
VF interruption
(12+6 s)
Isolated Rat Hearts (N=8)
Progressive
reduction of
waveforms
Morita N, 2011
VF
Pseudo-ECG
MicroElectrode
EADs
H2O2
VF
(0.1 mM)
interruption
1.1+0.4 m
H2O2
Ranolazine
10mM
(0.1 mM)
EADs
Ranolazine
stop
VF
36+10 min
Multifocal
activation
Isolated Rat Hearts (N=8)
VF
Morita N, 2011
Number of Foci per 100 ms
Time course of the reduction in the number of
foci after ranolazine perfusion.
H2O2
(0.1 mM)
Ranolazine
10mM
VF
termination
(SR)
1 second
VF
SR
Morita N, 2011
Termination of
PACs (%)
Incidence of
PACs (%)
Incidence of
PACs (%)
Termination of
PACs (%)
Ca2+-induced PACs
Iso-induced PACs
Sossalla S, 2010
Vehicle
Ranolazine
Vehicle
Ranolazine
Sossalla S, 2010
Sinus rhythm
Atrial Fibrillation
Frequency (Hz)
Frequency (Hz)
Frequency (Hz)
Late INa integral
(ms•A/F)
Peak INa (A/F)
Baseline
*: P<0.05 vs SR
* / #: P<0.05 vs Vehicle / Baseline
*: P<0.05 vs Vehicle
Effective refractory period (ms)
Ranolazine 50 mg (2mL) - Intra-pericardial injection
Vehicle
Right ventricle
N=6 - closed-chest
anesthetized pigs
Ranolazine
+57
Ranolazine
Right Atrium
N=7 - closed-chest
anesthetized pigs
Vehicle
Time (min)
*: P<0.05 vs Baseline
Carvas M, J Cardiovasc
Pharmacol 2010
Ranolazine 50 mg (2mL) - Intra-pericardial injection
Intensity (mA)
Intensity (mA)
Right ventricle
29
Ventricular Fibrillation
Threshold
24
*: P<0.05 vs Baseline
29
Right Atrium
Atrial Fibrillation
Threshold
N=6 - closed-chest
anesthetized pigs
5
Time (min)
Carvas M, J Cardiovasc
Pharmacol 2010
Atria
Ventricle
ERP
ERP
APD75
APD90
*: P<0.01 vs APD75
Control
Rano
(5mM)
Chronic Chronic
Amio
Amio &
Rano
ERP: effective refractory period
APD75/90: action potential duration at
75/90% of repolarizaion
Control
Rano
(5mM)
Chronic Chronic
Amio
Amio &
Rano
PRR: post-repolarization refractoriness
Sicouri S, Circ Arrhythm
Electrophysiol 2010
Right Atrial preparations
*: P<0.05 vs Control
*: P<0.001 vs Control; †: P<0.01
& Ranolazine
vs Amiodarone & Ranolazine
Control Rano Chronic Chronic
(5mM) Amio Amio &
Rano
Control Rano Chronic Chronic
(5mM) Amio Amio &
Rano
Vmax: maximum rate of rise of action
potential upstroke
DTE: diastolic threshold of excitation
Sicouri S, Circ Arrhythm
Electrophysiol 2010
Burashnikov A, 2010
*: P<0.05 vs Control
Atria
#: P<0.05 vs ERP
Vmax (% of Control)
ERP and APD70 (ms)
ERP
APD70
Atria
Ventricle
The shortest CL with 1:1
activation (ms)
Atria
Ventricle
Pulmonary
veins
*: P<0.05 vs Control
C
Rano
(5mM)
WO
Dron
Dron
(10mM) & Ran
Vmax
(% of Control at 5000 ms CL)
C
*: P<0.05 vs Control
Rano WO Dron Dron
(5mM)
(10mM) & Ran
Pulmonary veins
Canine
preparations
*: P<0.05 vs Control
C
Rano
Dron
(5mM)
(10mM)
Dron
& Ran
Burashnikov A, 2010
Effects of Ranolazine, Dronedarone, and Their Combination on ACh-Mediated
Persistent AF in the Isolated Canine Coronary-Perfused Right Atria
N=7
N=6
ACh
Rano
Dron
N=10
N=10
N=5
N=6
ACh
Rano
Dron
N=10
Induction of persistent AF (%)
Termination of persistent AF (%)
N=10
(1 mM/L)
(5 mM/L)
(10 mM/L)
Dron
& Ran
(1 mM/L)
(5 mM/L)
(10 mM/L)
Dron
& Ran
First Direct Comparison of the Late Sodium Current
Blocker Ranolazine to Established Antiarrhythmic
Agents in an Ischemia/Reperfusion Model
Ventricular arrhythmias
VT episodes
P=0.01
P<0.05
P<0.05
Duration (s)
Incidence (%)
P<0.05
Sotalol
Lido: Lidocaine
Rano: Ranolazine
Lido
Rano
Control
Dogs (N=20 per group) - 5’ proximal
LAD occlusion; 5’ reperfusion
Sotalol
Lido
Rano
Control
Kloner RA, J Cardiovasc
Pharmacol Ther 2010
Scirica BM, 2007
Ranolazine
Placebo
N=3162 - Age: 63 years
N=3189 - Age: 63 years
P<0.001
Continuous ECG monitoring
duration: 6.8 days
P<0.001
Incidence (%)
P<0.001
P<0.001
P<0.001
P=0.01
p=0.08
Bradycardia
<45 bpm
Pause
>3 s
AF
SVT
Supraventricular
Arrhythmias
>3 b
>4 b
>8 b
Ventricular
Tachycardia
Incidence of VT >8 beats
Continuous ECG monitoring duration: 6.8 days
RR=0.63
p<0.001
Placebo – 8.3%
Incidence (%)
N=3189 - Age: 63 years
RR=0.65
p<0.001
RR=0.67
p=0.008
Ranolazine – 5.3%
N=3162 - Age: 63 years
4.7%
3.4%
3.1%
P<0.001
2.3%
Hours from randomization
Scirica BM, 2007
Ranolazine versus Amiodarone for atrial fibrillation
prophylaxis following coronary bypass surgery
(%)
P=0.035
P=NS
Amiodarone – 200 mg bid
age: 65 years; LVEF: 55%; n=211
P=NS
Hospital
30 day
admission Mortality
Ranolazine – 1000 mg bid
age: 67 years; LVEF: 58%; n=182
Atrial
fibrillation
Post-CABG events
Murdock D et al, ACC, 60th
Annual Scientific Sessions, 2011
Conclusioni
 La ranolazina sembra caratterizzata da un importante
effetto antiaritmico …
 … dovuto non solo all’interazione con la corrente tardiva
del sodio, ma al blocco di più canali cellulari
 Questo meccanismo d’azione rende la molecola molto
vicina all’amiodarone in termini di efficacia
 Il miocardio atriale sembrerebbe più sensibile alle azioni
della ranolazina, anche se alcuni dati pre-clinici e clinici
sembrano confermare l’efficacia del farmaco anche nei
confronti delle aritmie ventricolari
 L’utilizzo della ranolazina in associazione con
amiodarone e dronedarone potrebbe portare ad una vera
e propria sinergia clinica, permettendo la riduzione delle
dosi degli anti-aritmici e diminuendo l’incidenza di eventi
avversi
NNH: number needed to harm
§: solo eventi pro-aritmici
OR Effetti collaterali –
NNH
Abbandono dello studio entro 12 mesi
Chinidina
NS
42.9
Flecainide
Propafenone
Classe IC
P=0.005 17§
P=0.02
27
P=0.002
13.7
Amiodarone
Sotalolo
Classe III
Amiodarone vs. Classe I
Amiodarone vs. Sotalolo
Lafuente-Lafuente C,
Arch Int Med 2006
9
0 1 2
P<0.001
27
NS
27
P<0.001
P=0.004
NS
4
6
8
10
 The major conclusion of this study is that the late Na current blocking
drug ranolazine demonstrates efficacy against both pacing-induced
re-entrant VF and spontaneous oxidative multifocal VF
 The suppression of multifocal VF is associated with a progressive
reduction in the number of foci
 This finding supports the hypothesis that multifocal VF requires the
constant generation of new interacting foci to maintain themselves
such that when the rate of production of new foci falls below a critical
level, VF terminates
 This is analogous to re-entrant VF, in which a critical mass is
required to ensure that the rate of formation of new wavelets exceeds
the rate of wavelet extinction
 Although H2O2 is an artificial means of inducing oxidative stress,
there are many known triggers … stress in the heart, such as aging,
heart failure, and ischemia–reperfusion, … all conditions associated
with increased risk of VF
Morita N, 2011
Sossalla S, 2010
 The results show that permanent AF is associated with
altered expression and function of Na+ channels
 Late INa was significantly greater as well as Nav1.1
expression
 Ranolazine reduced peak and late INa in SR, but it
preferentially blocked late over peak INa in AF
 Ranolazine restores the physiological relationship between
peak and late INa and consequently suppresses known proarrhythmogenic mechanisms in vitro
 Ranolazine reduced Ca2+- and Iso-induced PACs and caused
a concentration-dependent and reversible negative inotropic
effect associated with an improved diastolic tension
 Amiodarone action includes inhibition of a number of cardiac ionic
currents (IKr, IKs, INa, late INa, Ito, ICa-L, ICa-T, IK1, IK(ACh), IK(ATP)) as well as aand b-adrenoceptor– blocking activity
 Ranolazine has been shown to have a pharmacological profile similar to
that of chronic amiodarone … (and) causes inhibition of INa, IKr, and ICa
 Both agents have rapid unbinding kinetics from the Na+ channel
 Unlike amiodarone, which is an inactivated-state blocker of cardiac Na+
channels, ranolazine is an activated-state blocker
 The actions of amiodarone & ranolazine to produce potent block of the
Na+ channels in the atria are similar to that of class IC antiarrhythmic
agents. However, the effects of the combination are largely restricted to
the atrial myocardium
 The potentiation by ranolazine of the anti-AF effects amiodarone may
permit the use of a lower dose of amiodarone
Sicouri S, Circ Arrhythm
Electrophysiol 2010