Presentation by

Dr Muhammad Burhan Pasha

Topics to be covered
 Electrical System of Heart and
Conduction of cardiac impulse

 Action Potential of SA node

 Ivabradine
 CONDUCTION OF CARDIAC IMPULSE
SA node Atrial muscles

Internodal pathways

AV node

Common bundle HIS

Right and left bundle branches

Purkinje fibers Ventricular muscles

1

4
SA node is the pacemaker of Heart
IONIC BASIS OF ACTION
POTENTIAL IN SA NODE
RMP (-55 to -60mV)

+ + + + + + + + ++ + + + + + + + + + + + + + + + + + + + + +

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - -- - - - - - - - - - - - - - - - - - - -

K+
- - - - - - - - - - - - - - - - - --- - -- -- ---- - - - - - - - - - - - - - - - - - - - - - - - - - - -

+++++++++++++++++++++++++++++++++++

Na+ Ca++
 an outward K+ current (iK)

 an inward Na current induced by

hyperpolarization

 an inward Ca++ current (ICa)

 CHANNELS IN SA NODE MUSCLE FIBRES

1. SLOW / LEAK Na+ + K CHANNELS

2. SHORT LASTING VOLTAGE GATED Ca++ CHANNELS

( T- TYPE CALCIUM CHANNELS)

3. LONG LASTING VOLTAGE GATED Ca++ CHANNELS

( L- TYPE CALCIUM CHANNELS)

4. VOLTAGE GATED K+ CHANNELS

 SEQUENCE OF EVENTS

RAPID &

RAPID
LONG Ca++ K+ EFFLUX
INFLUX

SLOW

K+EFFLUX

SLOW Na+ INFLUX SLOW Ca++ INFLUX

IVABRADINE
Mechanism of Action

 Blocks the hyperpolarization-activated cyclic

nucleotide-gated (HCN) channel responsible for the
cardiac pacemaker I(f) ‘funny’ current, which
regulates heart rate

 the cardiac effects most pronounced in the sinoatrial

(SA) node

 No effect on ventricular repolarization and no effects

on myocardial contractility
 AnginaPactoris
Angina Pectoris

Unique mechanism of action

If Channel

Control RR
Coralan 0.3 µM

0 mV

-40 mV

-70 mV
Delay of diastolic depolarization
in the sinus node

DiFrancesco D, Camm JA. Drugs. 2004;64:1757-1765.

 AnginaPactoris
Angina Pectoris

Unique pharmacological properties

 Negative chronotropic effect

 No impact on the inotropism and dromotropism of the hea

 No coronary constriction

 Increases stroke volume

 Preserves cardiac output

Clinical Uses
 heart failure with reduced ejection
fraction

 Ivabradine is a second-line drug for

systolic heart failure and chronic
stable angina (after BB or when BB
are contraindicated)
 for the treatment of inappropriate
sinus tachycardia
Pharmacokinetics
 Food delays absorption by ~1 hr and
increases plasma exposure by 20-40% so
should be taken with meals

 Protein bound: 70%

 Extensively metabolized in the liver by

CYP3A4-mediated oxidation

 Major metabolite: N-desmethylated

derivative (S 18982), which is equipotent to
ivabradine
Elimination

 Distribution half-life: 2 hr
 Effective half-life: ~6 hr
 Excretion: 4% unchanged in urine;
excretion of metabolites occurs to a
similar extent via feces and urine
 The MOST tested antianginal
agent

Coralan1-3

1. Werdan K. et al. Clin Res Cardiol. 2012;101:365-373. 2. Amosova E et al. Cardiovasc Drugs Ther. 2011;25:531-537. 3. Fox
K et al. Eur Heart J. 2009;30:2337-2345. 4. Wei J et al. Int J Cardiol. 2011;146(1):4-12. 5. Ezekowitz MD, Hossack K, Mehta
JL, et al. Amlodipine in chronic stable angina: results of a multicenter double-blind crossover trial. Am Heart J. 1995;129:527-
535. 6. Nissen SE et al. JAMA. 2004;292:2217-2225. 7. Poole-Wilson PA et al. Lancet. 2004;364:849-857. 8. Stone PH et al. J
Am Coll Cardiol. 2006;48(3):566-575. 9. Chaitman BR et al. JAMA. 2004;291(3):309-316. 10. Morrow DA et al. JAMA.
 Heart Failure

Effective and safe

for patients with associated conditions
RIGHT PATIENT ACEi / ARB β-Blocker MRA Ivabradine
&
RIGHT TREATMENT1-2

Renal dysfunction

Hypotension

Asthma/COPD

Hyperkalemia

Bradycardia
1. Maggioni AP et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with ESC
guidelines? Evidence from ESC Heart Failure Long-Term Registry.
Eur J Heart Fail. 2013;15(7):1173-1184. 2. Coralan Summary of Product Characteristics (European Medicines Agency -
Contraindications

 Ac.MI, USA
 Cardiogenic shock, hypotension
 congenital LQT
 HR<70
 Ac. CVA
 PPM dependent AV blocks
 SSS (severe)
 Unstable or acute HF
 A.Fib
 Pregnancy
 Severe renal failure
Adverse Effects
 Severe bradycardia, hypotension,
syncope

 Atrial Fibrillation

 Hypertension

 Visual brightness/ visual impairment

 Drug Interactions overview

 Coadministration of verapamil or
diltiazem increases ivabradine systemic
exposure and should be avoided

 Concomitant use with negative

chronotropes (eg, digoxin, amiodarone,
beta-blockers) may increase the risk of
bradycardia
 For angina and heart failure patients

INITIATE UPTITRATE

*2.5 mg bid for patients over 75 years old

1. Coralan Summary of Product Characteristics (European Medicines Agency - latest update of December 2013)