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Ivabradine

Ivabradine

Overview
Ivabradine (icon) is a novel medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

 used for the symptomatic management of stable angina pectoris. It is marketed under the trade name Procoralan (Servier
Servier Laboratories
Servier Laboratories is a privately owned French pharmaceutical company that specialises in medication for cardiological and rheumatological conditions, as well as for diabetes and clinical depression. The consolidated turnover for the 2005/2006 financial year was €3.5 billion...

), Coralan in India (Servier), Australia or such as in Italy Corlentor (Servier
Servier Laboratories
Servier Laboratories is a privately owned French pharmaceutical company that specialises in medication for cardiological and rheumatological conditions, as well as for diabetes and clinical depression. The consolidated turnover for the 2005/2006 financial year was €3.5 billion...

), and was also known as S-16257 during its development. Ivabradine acts by reducing the heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....

 in a mechanism different from beta blocker
Beta blocker
Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...

s and calcium channel blocker
Calcium channel blocker
A calcium channel blocker is a chemical that disrupts the movement of calcium through calcium channels.CCB drugs devised to target neurons are used as antiepileptics. However, the most widespread clinical usage of calcium channel blockers is to decrease blood pressure in patients with...

s, two commonly prescribed antianginal
Antianginal
An antianginal is any drug used in the treatment of angina pectoris, a symptom of ischaemic heart disease.-Nitrates:Nitrates cause vasodilation of the venous capacitance vessels by stimulating the endothelium-derived relaxing factor...

 drugs.
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Encyclopedia
Ivabradine (icon) is a novel medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

 used for the symptomatic management of stable angina pectoris. It is marketed under the trade name Procoralan (Servier
Servier Laboratories
Servier Laboratories is a privately owned French pharmaceutical company that specialises in medication for cardiological and rheumatological conditions, as well as for diabetes and clinical depression. The consolidated turnover for the 2005/2006 financial year was €3.5 billion...

), Coralan in India (Servier), Australia or such as in Italy Corlentor (Servier
Servier Laboratories
Servier Laboratories is a privately owned French pharmaceutical company that specialises in medication for cardiological and rheumatological conditions, as well as for diabetes and clinical depression. The consolidated turnover for the 2005/2006 financial year was €3.5 billion...

), and was also known as S-16257 during its development. Ivabradine acts by reducing the heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....

 in a mechanism different from beta blocker
Beta blocker
Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...

s and calcium channel blocker
Calcium channel blocker
A calcium channel blocker is a chemical that disrupts the movement of calcium through calcium channels.CCB drugs devised to target neurons are used as antiepileptics. However, the most widespread clinical usage of calcium channel blockers is to decrease blood pressure in patients with...

s, two commonly prescribed antianginal
Antianginal
An antianginal is any drug used in the treatment of angina pectoris, a symptom of ischaemic heart disease.-Nitrates:Nitrates cause vasodilation of the venous capacitance vessels by stimulating the endothelium-derived relaxing factor...

 drugs. It is classified as a cardiotonic agent.

Medical uses


Ivabradine was approved by the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...

 in 2005. It is indicated for the symptomatic treatment of chronic stable angina pectoris in patients with normalsinus rhythm
Sinus rhythm
In medicine, sinus rhythm is the normal beating of the heart, as measured by an electrocardiogram . It has certain generic features that serve as hallmarks for comparison with normal ECGs.- ECG structure :...

, who have a contraindication to or intolerance to beta blocker
Beta blocker
Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...

s.
It is also indicated in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose and whose heart rate is superior to 60 bpm.

It has been shown to be non-inferior to the beta-blocker atenolol for this indication and amlodipine
Amlodipine
Amlodipine is a long-acting calcium channel blocker used as an anti-hypertensive and in the treatment of angina...

.

Apart from angina, it is also being used off-label in the treatment of inappropriate sinus tachycardia
Inappropriate sinus tachycardia
Inappropriate Sinus Tachycardia is a rare type of cardiac arrhythmia, within the category of supraventricular tachycardia , although doctors believe it stems from dysautonomia, a disturbance and/or failure of the autonomic nervous system....

.

Adding ivabradine to heart-failure medication decreases cardiovascular death or heart-failure hospitalization.

Contraindications


Ivabradine is contraindicated in sick sinus syndrome
Sick sinus syndrome
Sick sinus syndrome, also called sinus node dysfunction, is a group of abnormal heart rhythms presumably caused by a malfunction of the sinus node, the heart's primary pacemaker...

, and cannot be used concominantly with inhibitors of CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...

 such as azole antifungals
Antifungal drug
An antifungal medication is a medication used to treat fungal infections such as athlete's foot, ringworm, candidiasis , serious systemic infections such as cryptococcal meningitis, and others...

 (such as ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...

), macrolide
Macrolide
The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...

 antibiotics, nefazodone
Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...

 and the anti-HIV drugs nelfinavir
Nelfinavir
Nelfinavir is an antiretroviral drug used in the treatment of the human immunodeficiency virus . Nelfinavir belongs to the class of drugs known as protease inhibitors and like other PIs is generally used in combination with other antiretroviral drugs.Nelfinavir mesylate is a potent and orally...

 and ritonavir
Ritonavir
Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....

.

Adverse effects


14.5% of all patients taking ivabradine experience luminous phenomena
Phosphene
A phosphene is a phenomenon characterized by the experience of seeing light without light actually entering the eye. The word phosphene comes from the Greek words phos and phainein...

 (by patients described as sensations of enhanced brightness in a fully maintained visual field). This is probably due to blockage of I h ion channels in the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...

 which are very similar to cardiac If. These symptoms are mild, transient, fully reversible and non-severe. In clinical studies about 1% of all patients had to discontinue the drug because of these sensations, which occurred on average 40 days after commencement of the drug.

Bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...

 (unusually slow heart rate) occurs at 2% and 5% for doses of 7.5 and 10 mg respectively (compared to 4.3% in atenolol). 2.6-4.8% reported headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...

s. Other common adverse drug reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

s (1–10% of patients) include first-degree AV block
Heart block
A heart block can be a blockage at any level of the electrical conduction system of the heart .* Blocks that occur within the sinoatrial node are described as SA nodal blocks....

, ventricular extrasystoles
Premature ventricular contraction
A premature ventricular contraction , also known as a premature ventricular complex, ventricular premature contraction , ventricular premature beat , or extrasystole, is a relatively common event where the heartbeat is initiated by the heart ventricles rather than by the sinoatrial node, the...

, dizziness and/or blurred vision.

Mechanism of action


Ivabradine acts on the If (f is for "funny
Funny current
Funny current refers to a specific current in the heart....

", so called because it had unusual properties compared with other current systems known at the time of its discovery) ion current, which is highly expressed in the sinoatrial node
Sinoatrial node
The sinoatrial node is the impulse-generating tissue located in the right atrium of the heart, and thus the generator of normal sinus rhythm. It is a group of cells positioned on the wall of the right atrium, near the entrance of the superior vena cava...

. If is a mixed Na+–K+ inward current activated by hyperpolarization and modulated by the autonomic nervous system. It is one of the most important ionic currents for regulating pacemaker activity in the sinoatrial (SA) node. Ivabradine selectively inhibits the pacemaker If current in a dose-dependent manner. Blocking this channel reduces cardiac pacemaker
Cardiac pacemaker
right|thumb|350px|Image showing the cardiac pacemaker which is the SA nodeThe contraction of heart muscle in all animals with hearts is initiated by chemical impulses. The rate at which these impulses fire controls the heart rate...

 activity, slowing the heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....

and allowing more time for blood to flow to the myocardium.

Coronary artery disease


The BEAUTIFUL study has shown that in coronary patients with a heart rate more than 70 bpm, ivabradine significantly reduces the risk of
  • Coronary events by 22% (P=0.023)
  • Fatal and nonfatal myocardial infarction by 36% (P=0.001)
  • Coronary revascularization by 30% (P=0.016).

Chronic heart failure


In the SHIFT study, ivabradine significantly reduced the risk of the primary composite endpoint of hospitalization for worsening heart failure or cardiovascular death by 18% (P<0.0001) compared with placebo on top of optimal therapy. These benefits were observed after 3 months of treatment.
SHIFT also showed that administration of ivabradine to heart failure patients significantly reduced the risk of death from heart failure by 26% (P=0.014) and hospitalization for heart failure by 26% (P<0.0001).
The improvements in outcomes were observed throughout all prespecified subgroups: female and male, with or without beta-blockers at randomization, patients below and over 65 years of age, with heart failure of ischemic or non-ischemic etiology, NYHA class II or class III, IV, with or without diabetes, and with or without hypertension.

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