Introduction

The drug Ivabradine, under trade name Corlanor, is a relatiely novel drug for treatment of chronic
heart failure, inappropriate sinus tachycardia and stable angina pectoris in patients with low
tolerance to β-adrenoceptor antagonists/ β- blockers. Those are mainly patients with chronic
obstructive respiratory disease and asthma, elderly people, while diabetics should be careful with
taking them.

In 2005, European medicines agency approved Ivabradine tablets against angina pectoris, and
later in 2012, it was approved to treat heart failure as well. However, United States followed the
trend 10 years later. Manufactured by Amgen Inc company, i was granted license to be sold under
trade name Corlanor by FDA in April, 2015.

Fig.1.: Ivabradine chemical structure

Photo credit: PubChem

IUPAC name: 3-[3-[[(7S)-3,4-dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl]methyl-

methylamino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-one
Pharmacological drug class: hyperpolarization activated cyclic nucleotide gated channel
blockers
Aim: To provide a brief overview of drug properties, and to desribe its pharmacokinetics and
pharmacodynamics, DDI, dose regime.
Materials and methods: The paper has a narrative character and it contains various information
and clinical trials results from qualified pharmacological websites.
Discussion
The therapeutic effect of Ivabradine is lowering the heart rate acting on sinoatrial node. It is known
as If inward current inhibitor. This current is generated in sinoatrial node myocytes upon
hyperpolarization negative to a threshold of -50 mV in diastole. The negative membrane potential
opens cation channels both permeable to Na+ and K+ influx Na+ to the cell is greater than of K+,
so the current regulates SA node automacity and depolarizes His- Purkinje system.

Ivabradine blocks the specific If channels of HCN family in a dose-dependent manner, thereby
reducing cardiac pacemaker activity, slowing heart rate and allowing longer dyastolic periods. It
does not act on other heart cells, hence intraatrial, atrioventricular or intraventricular conduction
times, myocardial contractility or ventricular repolarisation. It is an ideal choice for patients whose
ejection fraction is <35% and sinus rhythm ≥70 bpm.

Fig 2.: The cardiac action potential phases and currents

Photo credit: Tulane University

Dose regime
As mentioned before, Ivabradine is given in the form of film-coated tablets available with 5 or 7.5
mg of the active substance. In the beginning of the treatment, it is usually given twice a day. The
dose should not exceed 15 mg in 24 hours (7.5 mg twice a day). Tracking of heart rate and blood
pressure is necessary two weeks prior to treatment and during the treatment. Respecting the
prescribed dose, an approximate decrease of heart rate is 10 bpm. To avoid the risk of systemic
drug exposure, the drug should be taken with food. It is not recommended in pregnancy, due to
potential fetal harm. If the benefit outweighs risk, cardiac status of pregnant women should be
closely monitored especially in the first trimester, and taken care of preterm birth. Patients under
18 should not consume Ivabradine.
Metabolism
Ivabradine undergoes the first-pass effect, resulting in its bioavailability around 40% in the liver
and intestines. Renal clearance is about 70ml/min in people with healthy kidneys. It is extensively
oxidized in guts and liver by cytochrome P450 3A4 / CYP3A4 enzyme and decomposed into
several metabolites, with major active N-desmethylated compund (S-18982), that is equipotent to
Ivabradine. The plasma peak concentration is reached within 1 hour under fasting conditions and
half-life is 2 hours, but it is noteworthy that half-life of the N-desmethylated derivative is 11 h.
Tissue distribution is thorough and 70% is bound to plasma proteins. The cases of liver injury due
to Ivabradine use have not been recorded, although in severe hepatic impairment caution has to be
taken.

Drug-drug interactions
CYP3A4 inhibitors increase ivabradine plasma concentrations, while CYP3A4 inducers decrease
plasma concentrations. Azole antifungals (itraconazole, ketoconazole, voriconazole), macrolide
antibiotics (clarithromycine, erithromycine), calcium-channel blockers like verapamil and
amiodarone, are all strong CYP3A4 inhibitors and must not be taken concomitantly. Negative
chronotropes that slow down the heart rate, e.g. digoxin may cause bradycardia. Dexamethasone
will decrease Ivabradine effect. St John's-wort should be avoided in combination.
Side effects:
In the study conducted by European Medicines agency, 14.5% of patients reported luminous
impressions in their eyefields that follow the direction of gaze- called phosphenes. Other side
effects may include: blood pressure less than 90/50 mmHg, headache, dizziness, constipation.
Contraindications: sinoatrial block, 2nd and 3rd degree AV block, sick-sinus syndrome history,
unstable angina, artificial demand pacemaker set to rates ≥ 60 bpm.
Conclusion:
A study conducted by three researchers K. Suresh Babu, Frantisek Gadzik and Stephen T. Holgate
in Southhampton hospital was aimed to evaluate respiratory effects with Ivabradine in patients
with asthma. The study was double-blinded and placebo controlled and it involved 20 patients who
were receiving PO Ivabradine, 5 mg twice a day, 9 doses in total. FEV1 and peak expiratory flow
volume were measured as variables. The differences between values of both variables of placebo
and non-placebo participants were scarce, confirming that Ivabradine has little to no effect on
respiratory system. This makes it a valuable alternative to β-blockers which are known for causing
caugh as a side effect. Another advantage is that it can be taken for a long period of time. It protects
heart from ischemia.
References:
https://pubchem.ncbi.nlm.nih.gov/compound/Ivabradine#section=Computed-Properties

https://www.pharmaceutical-journal.com/news-and-analysis/news-in-brief/fda-fast-tracks-ivabradines-
heart-failure-licence-years-after-europe/20068360.article

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671466/

http://circ.ahajournals.org/content/circulationaha/127/19/1986.full.pdf

http://tmedweb.tulane.edu/pharmwiki/doku.php/introduction_to_cardiac_physiology_electrophysiolog
y

http://www.sciencedirect.com/science/article/pii/S0735109712026915

https://www.omicsonline.org/ivabradine-just-another-new-pharmacological-option-for-heart-rate-
control-2155-9880.S4-001.php?aid=2425#29

https://www.medicines.org.uk/EMC/medicine/17188/SPC/Procoralan/

https://drugs.webmd.boots.com/drugs/drug-253-
andecon+pediatric+oral.aspx?drugid=253&drugname=andecon+pediatric+oral

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2008.03160.x/full

https://www.drugs.com/ppa/ivabradine.html