1. L’azione antiaritmica – The Anti-Arrhythmic Action
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. IKr – rapidly activating component of delayed rectifier current
Late INa – late sodium current
INa late normalized current
Tail Current (Normalized) 2 6 2 6
Ranolazine Concentration (mM/L)
Late ICa – late calcium current
Canine ventricular myocytes
Ranolazine Concentration 2-6 mM/L: therapeutic range
Normalized current
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

3. Ranolazine Concentration (mM/L)
Effects of ranolazine on epicardial and M cell Action Potential Duration – APD50/90: 50/90% repolarization
M cell (N=5)
M cell (N=5)
Epicardial cell (N=4)
Epicardial cell (N=5)
APD50 (ms)
APD90 (ms)
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

4. Progressive reduction of waveforms
Rapid pacing
DC Shock
2-4 different waveforms
Persisting VF
Rapid pacing VF
+ Ranolazine 10mM
VF interruption
(12+6 s)
Progressive reduction of waveforms
Isolated Rat Hearts (N=8)
Morita N, 2011

5. Multifocal activationVF
Pseudo-ECG
Ranolazine 10mM
VF interruption m
Micro-Electrode
EADs
H2O2
(0.1 mM)
H2O2
(0.1 mM)
EADs
Ranolazine stop VF
36+10 min
Multifocal activation VF
Isolated Rat Hearts (N=8)
Morita N, 2011

6. Time course of the reduction in the number of foci after ranolazine perfusion.
H2O2
(0.1 mM)
Ranolazine 10mM
Number of Foci per 100 ms
VF termination
(SR)
1 second VF SR
Morita N, 2011

7. Termination of PACs (%) Termination of PACs (%)
Sossalla S, 2010
Incidence of PACs (%)
Ca2+-induced PACs
Termination of PACs (%)
Incidence of PACs (%)
Termination of PACs (%)
Iso-induced PACs
Vehicle
Ranolazine
Vehicle
Ranolazine

8. Late INa integral (ms•A/F)
Sossalla S, 2010
Baseline
Sinus rhythm
Atrial Fibrillation
Frequency (Hz)
Frequency (Hz)
Frequency (Hz)
Peak INa (A/F)
Late INa integral (ms•A/F)
*: P<0.05 vs SR
* / #: P<0.05 vs Vehicle / Baseline
*: P<0.05 vs Vehicle

9. Effective refractory period (ms)
Ranolazine 50 mg (2mL) - Intra-pericardial injection
Right ventricle
Vehicle
N=6 - closed-chest anesthetized pigs
Ranolazine
+57
Ranolazine
Effective refractory period (ms)
Right Atrium
N=7 - closed-chest anesthetized pigs
Vehicle
Time (min)
Carvas M, J Cardiovasc Pharmacol 2010
*: P<0.05 vs Baseline

10. Intensity (mA) Intensity (mA) Time (min)
Ranolazine 50 mg (2mL) - Intra-pericardial injection
Intensity (mA)
Right ventricle 24 29
Ventricular Fibrillation Threshold
*: P<0.05 vs Baseline
Intensity (mA)
Time (min)
Right Atrium 5 29
Atrial Fibrillation Threshold
N=6 - closed-chest anesthetized pigs
Carvas M, J Cardiovasc Pharmacol 2010

11. Atria Ventricle ERP ERP APD75 APD90 *: P<0.01 vs APD75 Control Rano
(5mM)
Chronic
Amio
Chronic
Amio & Rano
Control
Rano
(5mM)
Chronic
Amio
Amio & Rano
ERP: effective refractory period
APD75/90: action potential duration at 75/90% of repolarizaion
PRR: post-repolarization refractoriness
Sicouri S, Circ Arrhythm Electrophysiol 2010

12. Right Atrial preparations
*: P<0.05 vs Control & Ranolazine
*: P<0.001 vs Control; †: P<0.01 vs Amiodarone & Ranolazine
Control
Rano
(5mM)
Chronic
Amio
Chronic
Amio & Rano
Control
Rano
(5mM)
Chronic
Amio
Chronic
Amio & Rano
Vmax: maximum rate of rise of action potential upstroke
DTE: diastolic threshold of excitation
Sicouri S, Circ Arrhythm Electrophysiol 2010

13. The shortest CL with 1:1 activation (ms)
Burashnikov A, 2010
Atria
*: P<0.05 vs Control
#: P<0.05 vs ERP
ERP
APD70
ERP and APD70 (ms)
Vmax (% of Control)
Atria
*: P<0.05 vs Control
Ventricle C
Rano
(5mM) WO
Dron
(10mM)
Dron
& Ran
Atria
Canine preparations
Ventricle
Pulmonary veins
Pulmonary veins
The shortest CL with 1:1 activation (ms)
(% of Control at 5000 ms CL)
Vmax
*: P<0.05 vs Control
*: P<0.05 vs Control C
Rano
(5mM) WO
Dron
(10mM)
Dron
& Ran C
Rano
(5mM)
Dron
(10mM)
Dron
& Ran

14. Induction of persistent AF (%) Termination of persistent AF (%)
Burashnikov A, 2010
Effects of Ranolazine, Dronedarone, and Their Combination on ACh-Mediated Persistent AF in the Isolated Canine Coronary-Perfused Right Atria
N=10
N=7
N=6
N=10
N=10
N=5
N=6
N=10
Induction of persistent AF (%)
Termination of persistent AF (%)
ACh
(1 mM/L)
Rano
(5 mM/L)
Dron
(10 mM/L)
Dron
& Ran
ACh
(1 mM/L)
Rano
(5 mM/L)
Dron
(10 mM/L)
Dron
& Ran

15. Ventricular arrhythmias
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
P<0.05
Incidence (%)
Duration (s)
Sotalol
Lido
Rano
Control
Sotalol
Lido
Rano
Control
Lido: Lidocaine
Rano: Ranolazine
Dogs (N=20 per group) - 5’ proximal LAD occlusion; 5’ reperfusion
Kloner RA, J Cardiovasc Pharmacol Ther 2010

16. Supraventricular Arrhythmias Ventricular Tachycardia
Scirica BM, 2007
Ranolazine
N= Age: 63 years
Placebo
N= Age: 63 years
Supraventricular Arrhythmias
p=0.08 AF
SVT
>3 b
>4 b
>8 b
Ventricular Tachycardia
P<0.001
Continuous ECG monitoring duration: 6.8 days
P<0.001
Incidence (%)
P=0.01
Bradycardia
<45 bpm
Pause
>3 s

17. Hours from randomization
Incidence of VT >8 beats
Continuous ECG monitoring duration: 6.8 days
RR=0.63 p<0.001
Placebo – 8.3%
N= Age: 63 years
RR=0.65 p<0.001
Ranolazine – 5.3%
N= Age: 63 years
RR=0.67 p=0.008
4.7%
Incidence (%)
3.4%
3.1%
P<0.001
2.3%
Hours from randomization
Scirica BM, 2007

18. Ranolazine versus Amiodarone for atrial fibrillation prophylaxis following coronary bypass surgery
(%)
P=NS
Amiodarone – 200 mg bid
age: 65 years; LVEF: 55%; n=211
P=NS
Ranolazine – 1000 mg bid
age: 67 years; LVEF: 58%; n=182
Hospital admission
30 day Mortality
Atrial fibrillation
Post-CABG events
Murdock D et al, ACC, 60th Annual Scientific Sessions, 2011

19. 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

20. OR Effetti collaterali – Abbandono dello studio entro 12 mesi
NNH: number needed to harm
§: solo eventi pro-aritmici
OR Effetti collaterali –
Abbandono dello studio entro 12 mesi
NNH
Chinidina NS 9
42.9
Flecainide
P=0.005
17§
Propafenone
P=0.02 27
Classe IC
P=0.002
13.7
Amiodarone
P<0.001 27
Sotalolo NS 27
Classe III
P<0.001
Amiodarone vs. Classe I
P=0.004
Amiodarone vs. Sotalolo NS
Lafuente-Lafuente C, Arch Int Med 2006 1 2 4 6 8 10

21. 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

22. Late INa was significantly greater as well as Nav1.1 expression
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 pro-arrhythmogenic 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

23. Both agents have rapid unbinding kinetics from the Na+ channel
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 a- and 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