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IVABRADINE-If INHIBITOR: AN OVERVIEW
Indermeet S. Anand1*, Niki Vinodkumar Modi1
1
Shri Sarvajanik Pharmacy College, Mehsana
*Address for Correspondence
Dr. Indermeet S. Anand
Department of Pharmacology,
Shri Sarvajanik Pharmacy College,
Mehsana-384001
Phone-9426383239/(02762) 247711
Email: [email protected]
ABSTRACT
Ivabradine is the first representative of the new class of exclusive heart rate-reducing agents,
it selectively inhibit If current in the sinoatrial node. Ivabradine reduce the heart rate & act by
selective and specific inhibition of the cardiac pacemaker. This pharmacological inhibition of
the If current with the new drug Ivabradine, preserve coronary vasodilatation upon exercise,
which is myocardial perfusion, with no negative ionotropic effect & maintenance of cardiac
contractility. This new class drug Ivabradine, also protects myocardium during ischaemia,
and improves left ventricular function in congestive heart failure. Numbers of trails have
shown that it is benefits in stable angina and can be used when β-blockers and calcium
channel antagonist are contraindicated. This review is attempted to give an overview of some
aspect of Ivabradine.
Key words: ivabradine, If current, heart rate
INTRODUCTION
Manifestations of coronary artery disease (CAD) include myocardial infarction (MI), angina
pectoris, heart failure, and death. CAD is a large public health burden. According to the
Framingham study, the lifetime risk of CAD for individuals at age 40 was 49% in men and
32% in women. Furthermore, the World Health Organization prediction is that CAD will
remain the leading cause of death for the next 20 years, accounting for 13.4% of total deaths
in 2030[14].
The most common cause of angina pectoris is myocardial ischemia, which results from a
disturbance between myocardial blood flow and oxygen demand. Increased heart rate is a
major determinant of myocardial ischemia principally through increased myocardial oxygen
demand and reduced diastolic perfusion & it has been a major target for pharmacologic
intervention. So in this condition a new drug ivabradine reduces the rate of spontaneous
diastolic depolarization through selective If current inhibition in sinoatrial node cells, which
increases the time taken to reach the voltage threshold required for initiation of action
potential.[1] Lowering heart rate reduces cardiac work, thereby diminishing myocardial
oxygen demand. This mechanism is the primary basis for the anti-ischaemic and anti-anginal
effects of heart rate-lowering drugs. Heart-rate lowering might also increase coronary blood
flow and, thus, myocardial oxygen supply, mitigating ischaemia by increasing diastolic
perfusion time, during which coronary flow proceeds against relatively low resistance. Heartrate modulation is part of standard angina prevention strategies[5]. It has been postulated that
the heart rate may be the marker of sympathetic nervous system activation, which may lead to
insulin resistant states if over - stimulated in the long term, so increasing the metabolic risk
factor for cardiovascular disease. An elevated heart rate is the independent predictor of
cardiovascular morbidity & mortality. In coronary artery disease, elevated heart rates are
associated with greater atherosclerosis & plaque disruption, probably due to the increased
wall stress. On opposite side, the lower heart decrease myocardial oxygen demand by
reduction in overall cardiac work & it also increase the length of the diastole , so it increase
diastole perfusion time. So the pure heart rate reduction is potentially highly advantageous[8].
There is spontaneous electrical pacemaking activity in many regions of heart; it includes
sinoatrial node, atrinoventricular node, bundle of his & purkinje fibres.
There are four ionic currents work to produce spontaneous diastolic depolarisation:
1) The decay of the outward potassium current(I k)
2) The activation of the time dependent inward current If
3) The activation of two calcium currents, ICaL(long – lasting ) &
4) ICaT(transient)
The If current determines the slope of diastolic on depolarisation curve towards the threshold
level, which control the time interval between the successive action potential & so it play
important role in the process of pacemaking. The If current is directly activated by the
intracellular cyclic adenosine monophosphate (cAMP), & it is not linked to cAMP –
dependent phosphorylation activity & it is carried by the hyperpolarisation- activated cyclic
nucleotide – gated family on ion channel. The If channels open & close in response to both
ambient voltage & local intracellular cAMP concentration. Adrenergic agonist activate
adenylate cyclase, increasing local cAMP concentration & so it increasing cAMP binding to
the If channel. On apposite side cholinergic transmitter decrease local cAMP concentration by
inhibiting adenylate cyclase, so decreasing cAMP binding to the If channel. An If channel
bound more to cAMP is more likely to open, increasing the rate of slow diastolic
depolarisation , whereas an unbound channel is more likely to remain closed, & it lowers the
heart rate[3,5,27]. β- blocker leads to intolerance & even worsens airway disease caused by
bronchospasm, hypotension, erectile dysfunction & symptomatic deterioration in peripheral
vascular disease. Calcium antagonist are contraindicated with the left ventricular
impairment[8].
HISTORY OF IVABRADINE
On Nov. 15, the European Commission approved ivabradine (Procoralan film-coated tablets,
made by Servier Laboratories, Inc.) for the symptomatic treatment of chronic stable angina
pectoris in patients with normal sinus rhythm who have a contraindication or intolerance to
β-blockers. The approval allows use of the drug in 27 member states of the European
Union[2,9,15].
CHEMISTRY
Figure 1: Structure of Ivabradine
(S)-3-(3-(((3,4-dimethoxybicyclo(4.2.0)octa-1,3,5-trien-7-yl)methyl)methylamino)
propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one[27,28]
Molecular formula: C27H36N2O5
Molecular weight: 468.585 g/mol
INDICATION
Ivabradine is used to treat the symptoms of long-term stable angina (pains to the chest, jaw
and back, brought on by physical effort and due to problems with the blood flow to the heart).
It is used in adults (aged 18 years or over) with coronary artery disease (obstruction of the
blood vessels that supply the heart) who have a normal sinus rhythm (heartbeat). It can be
used in patients who cannot take or tolerate β-blockers (another type of medicine to treat
angina) and in patients whose disease is not controlled with β-blockers and whose heart rate
is above 60 beats per minute. It is used in combination with β-blockers in these patients.
Apart from angina, it is also being used off-label in the treatment of tachycardia[2,6,9].
DOSE
Starting Dose is 5 mg twice daily. After 3-4 weeks of treatment, increase to 7.5 mg twice
daily for the recommended dosage. If, during treatment, heart rate decreases persistently <50
beats/min (bpm) at rest or the patient experiences symptoms related to bradycardia eg,
dizziness, fatigue or hypotension, titrate downward to 2.5 mg twice daily (one-half 5-mg tab
twice daily). Discontinue the treatment if heart rate is <50 bpm or symptoms of bradycardia
persist.
Dose adjustment in particular population
No dose adjustment is required in patients with renal insufficiency and mild hepatic
impairment. Creatinine clearance >15 mL/min.No data are available in patients with
creatinine clearance <15 mL/min. Ivabradine should therefore be used with caution in this
population. Caution should be exercised when using ivabradine in patients with moderate
hepatic impairment. Ivabradine is contraindicated for use in patients with severe hepatic
insufficiency, since it has not been studied in this population and a large increase in systemic
exposure is anticipated. Ivabradine is not recommended in children and adolescents as the
efficacy and safety of ivabradine have not been studied in these populations. Since ivabradine
has been studied in a limited number of patients ≥75 years, a lower starting dose should be
considered for these patients (2.5 mg twice daily ie, one-half 5-mg tab twice daily) before uptitration if necessary. If you miss a dose, take the next dose at the usual time. Do not double
the dose to catch up[6,9,35].
MECHANISM OF ACTION
Ivabradine reduce the heart rate & act by selective and specific inhibition of the cardiac
pacemaker If current that controls the spontaneous diastolic depolarisation in the sinus node
and regulates heart rate. The cardiac effects are specific to the sinus node with no effect on
intra-atrial, atrioventricular or intraventricular conduction times, nor on myocardial
contractility or ventricular repolarisation[3,5.8].
PHARMACOKINETICS & PHARMACODYNAMIC PROPERTIES
Pharmacokinetic properties
ADME of ivabradine suggest that, it is rapidly and almost completely absorbed after oral
administration with a peak plasma level reached in about 1 hour under fasting condition. The
absolute bioavailability of the film-coated tablets is around 40%, due to first-pass effect in the
gut and liver. Food delayed absorption by approximately 1 hour, and increased plasma
exposure by 20 to 30 %. The intake of the tablet during meals is recommended in order to
decrease intra-individual variability in exposure. Ivabradine is approximately 70% plasma
protein bound. The maximum plasma concentration following chronic administration at the
recommended dose of 5 mg twice daily is 22 ng/ml. The average plasma concentration is 10
ng/ml at steady-state. Ivabradine is extensively metabolised by the liver and the gut by
oxidation through cytochrome P450 3A4 (CYP3A4) only. The major active metabolite is the
N-desmethylated derivative with an exposure about 40% of that of the parent compound. The
metabolism of this active metabolite also involves CYP3A4. Ivabradine has low affinity for
CYP3A4, shows no clinically relevant CYP3A4 induction or inhibition and is therefore
unlikely to modify CYP3A4 substrate metabolism or plasma concentrations. Ivabradine is
eliminated with a main half-life of 2 hours (70-75% of the AUC) in plasma and an effective
half-life of 11 hours. The total clearance is about 400 ml/min and the renal clearance is about
70 ml/min. Excretion of metabolites occurs to a similar extent via faeces and urine. About 4%
of an oral dose is excreted unchanged in urine[6,9].
Pharmacodynamic properties
The main pharmacodynamic property of ivabradine in humans is a specific dose dependent
reduction in heart rate. Analysis of heart rate reduction with doses up to 20 mg twice daily
indicates a trend towards a plateau effect which is consistent with a reduced risk of severe
bradycardia below 40 bpm. At usual recommended doses, heart rate reduction is
approximately 10 bpm at rest and during exercise. This leads to a reduction in cardiac
workload and myocardial oxygen consumption. Ivabradine does not influence intracardiac
conduction, contractility (no negative inotropic effect) or ventricular repolarisation:
- in clinical electrophysiology studies, ivabradine had no effect on atrioventricular or
intraventricular conduction times or corrected QT intervals;
- in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF)
between 30 and 45%), ivabradine did not have any deleterious influence on LVEF
In experimental studies, it has been shown that ivabradine does have some unfavorable
pharmacodynamic properties, such as the block of all four hyperpolarization-activated cyclic
nucleotide-gated channels and block of other ion channels at high concentrations.[6,9,36,37]
BENEFITS
Considering the patient oriented benefits of ivabradine, it was that Ivabradine reduces the
frequency of angina attacks at least as effectively as atenolol and amlodipine, also it reduces
the need for short-acting nitrate consumption as well as atenolol and amlodipine, ivabradine
7.5 mg bid is as effective as atenolol 100 mg od and amlodipine 10 mg od in increasing time
to angina onset and time to limiting angina during exercise, no rebound effect (unlike β
blockers) and no drug tolerance (unlike nitrates)were found with ivabradine[29].
COST EFFECTIVE ANALYSIS
One of the draw back with Ivabradine is the cost, Ivabradine on dose of 5/7.5 mg bd for 28
days cost about £ 39 on the other hand diltiazam(180mg od), amlodipine (10mg od),
metoprolol (100 mg bd), and atenolol (100 mg od) cost for days are £8.34, £7.69, £3.44,
£1.32 respectively[30]. However ivabradine significantly reduced the risk of death from heart
failure by 26% and the risk of hospitalisation was also significantly reduced by 26%. The
benefits were seen even though the heart failure patients were already taking currently
recommended treatment. Based on conservative preliminary analysis, ivabradine is cost
effective in heart failure patients. The cost-effectiveness ratio of ivabradine in a UK setting is
£14,458 per QALY (cost value 2006), well below the £20,000 per QALY threshold
considered by NICE. Ivabradine costs less than £10 per week, compared to a hospital
admission which cost nearly £4,000[31].
SIDE EFFECTS
Eyesight problems which include blurred vision and having brief moments of increased
brightness, most often caused by sudden changes in light intensity, slowing down of your
heart rate, headache, dizziness, awareness of your heart beat (palpitations) , changes in heart
rhythm, feeling sick, constipation, diarrhoea, feeling giddy (vertigo), shortness of breath,
muscle cramps, eosinophilia are side effects related to ivabradine[6,9,35].
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Special warning
Ivabradine is not recommended in patients with atrial fibrillation or other cardiac arrhythmias
that interfere with sinus node function as it is likely to lose its efficacy when a
tachyarrhythmia occurs (eg. ventricular or supraventricular tachycardia). Also in patient with
AV-block of 2nd degree, and in stroke (because there is no data available in this situation)
Ivabradine is not recommended. Ivabradine must not be initiated in patients with a pretreatment resting heart rate below 60 beats per minute. The use of ivabradine is contraindicated in heart failure patients with NYHA functional classification III-IV and should be
used with caution in heart failure patients with NHYA functional classification I-II.
Concomitant use of ivabradine with heart rate reducing calcium channel blockers such as
verapamil or diltiazem is not recommended. No safety issue has been raised on the
combination of ivabradine with nitrates and dihydropyridine calcium channel blockers such
as amlodipine. Additional efficacy of ivabradine in combination with dihydropyridine
calcium channel blockers has not been established. Ivabradine influences on retinal function.
To date, there is no evidence of a toxic effect of ivabradine on the retina, but the effects of
long-term ivabradine treatment beyond one year on retinal function are currently not known.
Cessation of treatment should be considered if any unexpected deterioration in visual
function occurs. Caution should be exercised in patients with retinitis pigmentosa and in
elderly, patients with symptoms of tiredness or shortness of breath, chronic retinal (eye)
disease, chronic heart failure, moderate liver disease, severe renal disease, mild to moderate
low blood pressure[6,29,35].
Precaution for use
Limited data are available in patients with mild to moderate hypotension, and ivabradine
should therefore be used with caution in these patients. Ivabradine is contra-indicated in
patients with severe hypotension (blood pressure < 90/50 mmHg). There is no evidence of
risk of (excessive) bradycardia on return to sinus rhythm when pharmacological
cardioversion is initiated in patients treated with ivabradine. However, in the absence of
extensive data, non urgent DC-cardioversion should be considered 24 hours after the last dose
of ivabradine. Also ivabradine is unsafe to use during pregnancy and during breast feeding.
Overdose of ivabradine may cause breathlessness and tiredness [6,29,35].
CONTRAINDICATION
Ivabradine is contraindicated if resting heart rate below 60 beats per minute prior to
treatment, cardiogenic shock, acute myocardial infarction, severe hypotension (< 90/50
mmhg), severe hepatic insufficiency, sick sinus syndrome, sino-atrial block, heart failure
patients with NYHA functional classification III-IV , pacemaker dependent, unstable angina,
rd
AV-block of 3 degree, combination with strong cytochrome P450 3A4 inhibitors such as
azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin,
erythromycin telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone pregnancy, lactation[6,9,35].
DRUG INTERACTION
Pharmacodynamic interaction
The concomitant use of cardiovascular(e.g. quinidine, disopyramide, bepridil, sotalol,
ibutilide, amiodarone) and non cardiovascular(e.g. pimozide, ziprasidone, sertindole,
mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin) QT prolonging
medicinal products with ivabradine should be avoided since QT prolongation may be
exacerbated by heart rate reduction. If the combination appears necessary, close cardiac
monitoring is needed[6].
Pharmacokinetic interactions
Ivabradine is metabolised by CYP3A4 only and it is a very weak inhibitor of this
cytochrome. The concomitant use of potent CYP3A4 inhibitors such as azole antifungals
(ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os,
josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone is
contra-indicated. The potent CYP3A4 inhibitors ketoconazole (200 mg once daily) and
josamycin (1 g twice daily) increased ivabradine mean plasma exposure by 7 to 8 fold.
Whereas the combination of ivabradine with the heart rate reducing agents diltiazem or
verapamil resulted in an increase in ivabradine exposure (2 to 3 fold increase in AUC) and an
additional heart rate reduction of 5 bpm. The concomitant use of ivabradine with these
medicinal products is not recommended. On the other hand use of moderate CYP3A4
inhibitors (e.g. fluconazole) may be considered at the starting dose of 2.5 mg twice daily and
if resting heart rate is above 60 bpm, with monitoring of heart rate, likewise with Grapefruit
juice ivabradine exposure was increased by 2-fold following the co-administration with
grapefruit juice. Therefore the intake of grapefruit juice should be restricted during the
treatment with ivabradine. CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin,
Hypericum perforatum) may decrease ivabradine exposure and activity. The concomitant use
of CYP3A4 inducing medicinal products may require an adjustment of the dose of
ivabradine.Specific drug-drug interaction studies have shown no clinically significant effect
of the following medicinal products on pharmacokinetics and pharmacodynamics of
ivabradine: proton pump inhibitors (omeprazole, lansoprazole), sildenafil, HMG CoA
reductase inhibitors (simvastatin), dihydropyridine calcium channel blockers (amlodipine,
lacidipine), digoxin and warfarin. In addition there was no clinically significant effect of
ivabradine on the pharmacokinetics of simvastatin, amlodipine, lacidipine, on the
pharmacokinetics and pharmacodynamics of digoxin, warfarin and on the pharmacodynamics
of aspirin. In pivotal phase III clinical trials the following medicinal products were not
restricted and therefore were routinely combined with ivabradine with no evidence of safety
concerns: angiotensin converting enzyme inhibitors, angiotensin II antagonists, diuretics,
short and long acting nitrates, HMG CoA reductase inhibitors, fibrates, proton pump
inhibitors, oral antidiabetics, aspirin and other anti-platelet medicinal products. In pediatric
population no such study have been conducted [6,9] .
PRECLINICAL SAFETY
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. Reproductive
toxicity studies showed no effect of ivabradine on fertility in male and female rats. When
pregnant animals were treated during organogenesis at exposures close to therapeutic doses,
there was a higher incidence of foetuses with cardiac defects in the rat and a small number of
foetuses with ectrodactylia in the rabbit. In dogs given ivabradine (doses of 2, 7 or 24
mg/kg/day) for one year, reversible changes in retinal function were observed but were not
associated with any damage to ocular structures. Other long-term repeat dose and
carcinogenicity studies revealed no clinically relevant changes[9].In one of the study,
conducted on mice, with ivabradine showed significantly reduced heart rate & improved
penile endothelial function by reduction of oxidative stress and penile fibrosis. Beneficial
effects were achieved in prevention and manifest endothelial dysfunction[10].Ivabradine slows
the heart rate by inhibiting an electrical current known as the If current* which is a major
regulator of the activity of the sinoatrial node – better known as the pacemaker. Inhibiting the
If current slows the generation of the electrical impulses by the sinoatrial node that trigger
heart contraction, and therefore slows the heart rate itself. Ivabradine, then known as S16257,
was first developed in the early 1990’s when it was found to be able to block the If current invitro in sinoatrial node tissue from rabbits and guinea pigs, and slowed the generation of
electrical impulses in a manner that was safer than other bradycardic drugs. Ivabradine was
then evaluated in live rats and dogs, where it safely reduced the heart rate, and moreover did
so without reducing the blood pressure[12]. A preclinical research conducted in a pig model of
myocardial ischaemia/reperfusion to check effects of the ivabradine on regional blood flow,
contractile function, and infarct size showed that Ivabradine 15–20 min after the onset of
ischaemia increased regional myocardial blood flow, it also reduced infarct size, heart rate
reduction by β-blockade is associated with negative inotropism and unmasked a-adrenergic
coronary vasoconstriction[13].
SOME PUBLISHED AND ONGOING CLINICAL STUDIES ON IVABRADINE
STUDY
BEAUTIFUL
trial
[16,22,26]
AIM
CONCLUSION
To evaluate the effects of ivabradine in
Reduction in heart rate does not
patients with coronary artery disease and left
improve cardiac outcome in all
Ventricular dysfunction
patients; ivabradine could be used to
reduce the incidence of coronary
artery disease outcomes in patients
with hight heart rate.
BEAUTIFUL
Echo
substudy [16]
To evaluate the effects of heart rate
Ivabradine may reverse detrimental
reduction with ivabradine on LV size and
LV remodeling in patients with CAD
function and the cardiac biomarker N-
and LV systolic dysfunction
terminal pro-brain natriuretic peptide
INITIATIVE
trial [21,26]
To compare anti-ischemic andanti-anginal
Ivabradine as atenolol is effective in
effects of ivabradine vs atenolol
patients with stable angina
SIGNIfY [17]
Ivabradine’s benefits in terms of morbidity
Result expected in 2013
and mortality in patient with CAD without
heart failure
Fox K [13]
To evaluate the efficacy of ivabradine plus
The results suggest that ivabradine
atenolol was compare with placebo plus
with β blockers is one of the best
atenolol.
evidence-based combination
therapies for angina patients
SHIfT [18,19] To evaluate the role of HR reduction in
Heart-rate reduction with ivabradine
patients with severe LV dysfunction and
showed improvement of clinical
heart failure.
outcomes in heart failure and confirm
the important role of heart rate in the
pathophysiology of this disorder
The
To evaluate the anti-anginal effects of
REDUCTION
ivabradine
Study [20]
Ivabradine has a dose-dependent
improvement in exercise tolerance
and time to development if ischemia
during exercise
Fasullo S et
al.[23]
To compare ivabradine versus metoprolol in
Ivabradine may be administered early
early phases of reperfused anterior
(12hours after PCI) to patients with
myocardial infarction with impaired left
successful PCI for anterior STEMI
ventricular function
with an impaired left ventricular
function and high HR and sinus
rhythm.
Jeffrey S.
Borer [24]
To evaluate the efficacy of the ivabradine in
Ivabradine was effective in
comorbid condition like patient having both
preventing angina in patients with
stable angina pectoris with diabetes
DM and was not associated with
particular safety concerns or adverse
effects on glucose metabolism.
Lage-Gallé E
et al [25]
To evaluate the safety and effectiveness of
Ivabradine is safe, well tolerated, and
the novel I(f) channel antagonist ivabradine
effective in heart transplant recipients
to control heart rate after transplantation
Joannides
[32]
To compare the effects of ivabradine and
Ivabradine, as propanolol, reduced
Lopez-Bscos
et al [33]
propanolol on cardiac haemodynamics at
myocardial oxygen demand but
rest and during exercise
without negative inotropic effects
To evaluate the efficacy and safety of
After adjunction of ivabradine the
combined therapy with ivabradine in patients
number of angina attacks was
treated with nitrates or dihydropiridine
significantly lower
calcium channels blockers
Ruzyllo et al
[34]
To evaluate anti-anginal and anti-ischemic
Ivabradine as amlodipine is effective
effects of ivabradine vs amlodipine
in patients with stable angina
CONCLUSION
Ivabradine is If current inhibitor which reduce heart rate. It is potentially beneficial in patient
having stable angina. Numbers of trails have been performed to check efficacy in patient
having such conditions. There are many trails done to compare the efficacy of ivabradine
with the conventional drug atenolol & metoprolol. The effect of ivabradine is also checked
for patient having diabetes mellitus. It may be good alternative of conventional heart rate
reducing agents. But its safety & efficacy profile are still now under investigation. Results
from the present studies suggest that ivabradine could be a valuable alternative to current
angina therapies. We hope that advanced therapeutic strategies aiming to appropriate control
of heart rate would be available in the future.
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