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

Tail

Cu

rren

t (N

orm

ali

zed

)

Ranolazine Concentration (mM/L)

IKr – rapidly activating component of delayed rectifier current

2 6Ranolazine Concentration (mM/L)

I Na l

ate

no

rmal

ized

cu

rren

t

2 6

Late INa – late sodium current

No

rmal

ized

cu

rren

t

Late ICa – late calcium current

2 6

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

Antzelevitch C, 2004

Canine ventricular myocytes

Effects of ranolazine on epicardial and M cell Action Potential Duration – APD50/90: 50/90% repolarization

Ranolazine Concentration (mM/L)

AP

D50

(m

s)

K+ Concentration: 4 mM/L

Antzelevitch C, 2004

AP

D90

(m

s)Control 1 5 10 50 100

Ranolazine Concentration (mM/L)

Control 1 5 10 50 100

*: P<0.05 vs Control

M cell (N=5)

Epicardial cell (N=4)

M cell (N=5)

Epicardial cell (N=5)

Rapid pacing

2-4 different waveforms

Rapid pacing

Persisting VF

DC Shock

VF + Ranolazine 10mM

VF interruption(12+6 s)

Progressive reduction of waveformsIsolated Rat Hearts (N=8)

Morita N, 2011

VF

Ranolazine 10mM

VF interruption

1.1+0.4 m

Isolated Rat Hearts (N=8) Morita N, 2011

Pseudo-ECG

Micro-Electrode EADs

H2O2

(0.1 mM)

Multifocal activation

VF

H2O2

(0.1 mM)

EADs

Ranolazine stop

VF36+10 min

Nu

mb

er o

f F

oci

per

100

ms

1 second

H2O2

(0.1 mM)

VF termination

(SR)

Ranolazine 10mM

Morita N, 2011

VF SR

Time course of the reduction in the number of foci after ranolazine perfusion.

Inci

den

ce o

f P

AC

s (%

)In

cid

ence

of

PA

Cs

(%)

Term

inat

ion

of

PA

Cs

(%)

Vehicle Ranolazine Vehicle RanolazineIso

-in

du

ced

PA

Cs

Ca2+

-in

du

ced

PA

Cs

Sossalla S, 2010

Term

inat

ion

of

PA

Cs

(%)

Lat

e I N

a in

teg

ral

(ms•

A/F

)

Baseline

Pea

k I N

a (A

/F)

Sinus rhythm Atrial Fibrillation

Frequency (Hz) Frequency (Hz) Frequency (Hz)

*: P<0.05 vs Vehicle* / #: P<0.05 vs Vehicle / Baseline*: P<0.05 vs SR

Sossalla S, 2010

Eff

ecti

ve r

efra

cto

ry p

erio

d (

ms)

Time (min)

Right ventricle

Right Atrium

Vehicle

Ranolazine

Vehicle

Ranolazine

*: P<0.05 vs Baseline

+57

Ranolazine 50 mg (2mL) - Intra-pericardial injection

N=7 - closed-chest anesthetized pigs

N=6 - closed-chest anesthetized pigs

Carvas M, J Cardiovasc Pharmacol 2010

*: P<0.05 vs Baseline

Carvas M, J Cardiovasc Pharmacol 2010

Ranolazine 50 mg (2mL) - Intra-pericardial injectionIn

ten

sity

(m

A)

Time (min)

Right Atrium

5

29Atrial Fibrillation Threshold

N=6 - closed-chest anesthetized pigs

Inte

nsi

ty (

mA

)

Right ventricle

24

29 Ventricular Fibrillation Threshold

Control Rano(5mM)

ChronicAmio

ChronicAmio & Rano

Control Rano(5mM)

ChronicAmio

ChronicAmio & Rano

ERP

APD90

*: P<0.01 vs APD75

ERP

APD75

Atria Ventricle

ERP: effective refractory period

APD75/90: action potential duration at 75/90% of repolarizaion

PRR: post-repolarization refractoriness

Sicouri S, Circ Arrhythm Electrophysiol 2010

Control Rano(5mM)

ChronicAmio

ChronicAmio & Rano

Control Rano(5mM)

ChronicAmio

ChronicAmio & Rano

Vmax: maximum rate of rise of action potential upstroke

DTE: diastolic threshold of excitation

*: P<0.05 vs Control & Ranolazine

*: P<0.001 vs Control; †: P<0.01 vs Amiodarone & Ranolazine

Right Atrial preparations

Sicouri S, Circ Arrhythm Electrophysiol 2010

C Rano(5mM)

WO Dron& Ran

Dron(10mM) C Rano

(5mM)Dron

& RanDron

(10mM)

C Rano(5mM)

WO Dron& Ran

Dron(10mM)

Th

e sh

ort

est

CL

wit

h 1

:1

acti

vati

on

(m

s)

ER

P a

nd

AP

D7

0 (

ms)

Vm

ax (

% o

f C

on

tro

l)V

ma

x

(% o

f C

on

tro

l at

500

0 m

s C

L)

Atria

ERP

APD70

Atria

Ventricle

Atria

Ventricle

Pulmonary veins

Pulmonary veins

*: P<0.05 vs Control#: P<0.05 vs ERP

*: P<0.05 vs Control

*: P<0.05 vs Control*: P<0.05 vs Control

Burashnikov A, 2010

Canine preparations

ACh(1 mM/L)

Rano(5 mM/L)

Dron& Ran

Dron(10 mM/L)

Ind

uct

ion

of

per

sist

ent

AF

(%

)Burashnikov A, 2010

N=10 N=7 N=6 N=10

ACh(1 mM/L)

Rano(5 mM/L)

Dron& Ran

Dron(10 mM/L)

Term

inat

ion

of

per

sist

ent

AF

(%

)

N=10 N=5 N=6 N=10

Effects of Ranolazine, Dronedarone, and Their Combination on ACh-Mediated Persistent AF in the Isolated Canine Coronary-Perfused Right Atria

Inci

den

ce (

%)

Du

rati

on

(s)

Sotalol Lido Rano Control Sotalol Lido Rano Control

P<0.05P=0.01

P<0.05P<0.05

Ventricular arrhythmias VT episodes

Lido: LidocaineRano: Ranolazine

Dogs (N=20 per group) - 5’ proximal LAD occlusion; 5’ reperfusion

Kloner RA, J Cardiovasc Pharmacol Ther 2010

First Direct Comparison of the Late Sodium Current Blocker Ranolazine to Established Antiarrhythmic Agents in an Ischemia/Reperfusion Model

Scirica BM, 2007

Inci

den

ce (

%)

Supraventricular Arrhythmias

p=0.08

AF SVT >3 b >4 b >8 b

Ventricular Tachycardia

P<0.001

P<0.001

P<0.001

P<0.001

Bradycardia<45 bpm

Pause>3 s

P<0.001

P=0.01

PlaceboN=3189 - Age: 63 years

RanolazineN=3162 - Age: 63 years

Continuous ECG monitoring duration: 6.8 days

Inci

den

ce (

%)

Hours from randomization

2.3%

3.4%

3.1%

4.7%RR=0.67 p=0.008

RR=0.65 p<0.001

RR=0.63 p<0.001

Placebo – 8.3%N=3189 - Age: 63 years

Ranolazine – 5.3%N=3162 - Age: 63 years

P<0.001

Scirica BM, 2007

Incidence of VT >8 beatsContinuous ECG monitoring duration: 6.8 days

Hospital admission

30 day Mortality

Atrial fibrillation

P=NS

P=0.035

P=NS(%)

Post-CABG events

Ranolazine – 1000 mg bidage: 67 years; LVEF: 58%; n=182

Amiodarone – 200 mg bidage: 65 years; LVEF: 55%; n=211

Ranolazine versus Amiodarone for atrial fibrillation prophylaxis following coronary bypass surgery

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

0 2 4 6 8 10

Chinidina

FlecainidePropafenone

Classe IC

AmiodaroneSotalolo

Classe IIIAmiodarone vs. Classe IAmiodarone vs. Sotalolo

NS

P=0.002

P=0.02

NS

P<0.001

P=0.004

P<0.001

NS

OR Effetti collaterali –Abbandono dello studio entro 12 mesi

Lafuente-Lafuente C, Arch Int Med 2006

42.9

13.7

1

P=0.005

NNH

9

17§

27

27

27

NNH: number needed to harm§: solo eventi pro-aritmici

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

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

Sossalla S, 2010

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