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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. REFERENCE 1. Silva R, Fox K. Ivabradine for treatment of stable angina pectoris. Nature Reviews Cardiology 2009, 6, 339-340. 2. European medicines agency, science medicine health, http://www.ema.europa.en/ema/439046.html [accesed on 2011 Apr. 23]. 3. 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