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Muhammad Uwais Ashraf1, Mohd. Aslam1, Asif Hasan1, Juwairia Ashraf2
1Department of Medicine, JN Medical College, AMU, Aligarh-202002, UP, India.
2Department of Moalajat, Ajmal Khan Tibbiya College, AMU, Aligarh-202002, UP, India.

Volume 2, Issue 3, Page 178-188, September-December 2014.

Article history
Received: 1 August 2014
Revised: 20 August 2014
Accepted: 28 August 2014
Early view: 29 August 2014

*Author for correspondence
Mobile/Tel: +91 9760159391


Ranolazine is a relatively new drug having effects on cardiac metabolic pathways and it is known to improve cardiac functions by favourably inhibiting fatty acid oxidation. Ranolazine inhibits free fatty acid oxidation and improves glucose metabolism in the heart. The mechanism of action is not fully known. It is thought that this drug acts via selective inhibition of the late inward sodium current (INa) in cardiac muscle cells. A unique feature of ranolazine is that it does not have any effects on hemodynamic parameters.

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Ranolazine is an active piperazine derivative, which is available in an oral and intravenous form. This drug was patented in 1986. It has effects on cardiac metabolic pathways and improves cardiac functions by favourably inhibiting fatty acid oxidation. During myocardial ischemia, increases in fatty acid metabolism are known to be detrimental to cardiac function. Ranolazine inhibits free fatty acid oxidation and improves glucose metabolism in the heart. This shift towards improved glucose oxidation generates more adenosine triphosphate (ATP) per oxygen molecule consumed and thus reduces myocardial oxygen demand. It has also been shown that ranolazine decreases the variability of the action potential duration in single myocytes (Song et al., 2004). Recent studies completed with the help of myocardial perfusion imaging techniques have demonstrated that ranolazine improves coronary perfusion and oxygen supply in humans (Venkataraman et al., 2009).
A recent study on diabetic patients showed that treatment with ranolazine significantly improved glycated haemaoglobin (HbA1c) levels and it abrogated the risk of recurrent ischemia (Morrow et al., 2009). Lovelock and coworkers have recently shown that ranolazine also has a direct effect on the contractile functions due to the modulation of myofilament Calcium sensitivity (Lovelock et al., 2012).

Figure 1. Structure of ranolazine.
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Mechanism of action
The mechanism of action is not fully known. It is thought that this drug acts via selective inhibition of the late inward sodium current (INa) in cardiac muscle cells (Antztlevitch et al., 2004, Song et al., 2004). This mechanism reduces intracellular accumulation of sodium and also reduces calcium overload. Thus it improves myocardial relaxation and decreases the left ventricular diastolic dysfunction (Morrow et al., 2007). An added advantage is that, this drug has no/minimal haemodynamic side effects (It decreases mean heart rate by <2 bpm and mean systolic blood pressure by <3 mmHg. However, it has been observed that patients treated with ranolazine may have dose-dependent and plasma concentration-dependent increases in the QTc interval (about 6 ms at 1,000 mg twice daily) and there may be reductions in T wave amplitude. Notched T waves have also been observed in patients treated with ranolazine. These effects may be because of inhibition of the fast-rectifying potassium current. As discussed earlier, a unique feature of ranolazine is that it does not have any effects on hemodynamic parameters. Beta-blockers decrease heart rate and reduce blood pressure and myocardial contractility. Therefore these parameters have to be closely monitored in patients taking beta-blockers. Calcium channel blockers dilate coronary arteries, and also reduce the blood pressure. The non dihydropyridine calcium channel blockers (diltiazem and verapamil) also decrease heart rate and myocardial contractility. Short-acting dihydropyridine calcium channel blockers have been found to increase the risk of adverse cardiac events when used as antianginals. Ranolazine is superior because it is free from these effects. Continuous administration of nitrates can rapidly lead to the development of nitrate tolerance. This can be avoided by providing a 10-14 hour nitrate free interval. This limitation of using nitrates with a 10-14 hour nitrate free interval leaves the patient without any anti-aginal support during this period. Important clinical trials on ranolazine

Monotherapy assessment of ranolazine in stable angina (MARISA)
MARISA was a study that tested a 3-fold dose range of ranolazine (Chaitman et al., 2004). This study was a double-blind, randomised, placebo-controlled, crossover type of study. This trial revealed that exercise duration (based on exercise tolerance tests, ETT) increased with increment in plasma concentrations of ranolazine. But this benefit with increasing drug doses was attenuated at dosage >1000 mg twice daily (Chaitman et al., 2004).

Combination Assessment of Ranolazine in Stable Angina (CARISA)
This was the main clinical study of ranolazine in severe chronic angina (El-Bizri et al., 2011). This was a randomised, double-blind, placebo-controlled trial. The CARISA trial has shown that the efficacy was not dose-related.

The Metabolic Efficiency with ranolazine for less ischemia in non–ST-elevation acute coronary syndrome (MERLIN TIMI 36) study
The MERLIN-TIMI 36 trial was conducted to evaluate the efficacy and safety of ranolazine in reducing cardiovascular death, MI or recurrent ischaemia in acute coronary syndrome (ACS) patients (Morrow et al., 2007). The results of this trial have elucidated that there is no benefit of ranolazine on cardiovascular deaths in acute NSTEMI or STEMI. A potential anti-arrhythmic effect was demonstrated, which required further investigations.

The ERICA trial evaluated the effects of sustained-release ranolazine preparations in patients with stable angina who were also receiving conventional antianginals (Stone et al., 2006). 45% of the patients assessed in this trial, were using long acting nitrates. The effects of ranolazine were consistent irrespective of gender and age. ranolazine had no significant effects on heart rate or blood pressure.

Dosage and side effects
The starting dose of ranolazine is 500 mg two times a day. The dose can be increased to 1000 mg twice a day, if needed. The maximum dose has been shown to be 1000 mg twice daily. Electrocardiograms (ECG) should be obtained to examine any adverse effects of the drug on the QT interval. Ranolazine may be taken irrespective of intake of meals. The tablet should not be broken, crushed or chewed and should be swallowed as a whole.
Ranolazine is a well tolerated drug with only mild to moderate adverse effects. The most common side effects reported by patients taking ranolazine were constipation, nausea and asthenia. Headache, syncope and prolongation of QTc have also been reported in various clinical trials.

Treatment with ranolazine was shown to be associated with small dose-related increase in QTc from baseline (European Public Assessment Report). In some clinical studies, mean changes from baseline in QTcF (Fridericia’s correction) after doses of 500 mg and 750 mg twice daily were shown to be 1.9 and 4.9 ms, respectively. However, an increased risk of torsades de pointes has not been demonstrated in any of the trials.

Drug interactions
Ranolazine must be given with caution to patients already taking drugs that prolong the QTc. Following drugs have an interaction with ranolazine and co-administration of these drugs with ranolazine should be done cautiously:
– Azole antifungals: Ketoconazole (Morrow et al., 2009, Chaitman, 2002), Itraconazole, Posaconazole, Voriconazole
– HIV Protease Inhibitors–e.g. Azatanavir, Ritonavir
– Other CYP34A Inhibitors-Grapefruit Juice
– CYP3A4 Inducers (Jerling, 2006): Rifampicin, Phenytoin, Phenobarbital, Carbamazepine
– Macrolide Antibiotics: Clarithromycin, Telithromycin, Erythromycin.
– Nefazodone
– Antiarrythmics–Class Ia and III antiarrythmics should be avoided including disopyramide, sotalol, quinidine. Amiodarone can be used in combination.
Dose adjustment may be required with following drugs:
– Antiarrythmics/cardiac drugs-digoxin, diltiazem, flecainide,
– Metoprolol, Verapamil
– Antidepressants–paroxetine, tricylic antidepressants
– Antipsychotics
– Antihistamines which prolong QTc interval–mizolastine, rupatadine
– Bupropion-Cyclosporine
– Cyclophosphamide
– Efarvirenz
– Erythromycin
– Fluconazole
– Simvastatin
– Any other drugs with the potential to prolong QTc interval

Table. Summary of randomized clinical trials with ranolazine.
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Future roles of ranolazine

Effect on HbA1c and glucose levels
Ranolazine lowers fasting plasma glucose and HbA1c levels in patients with poorly controlled diabetes. It is a unique finding which points towards the added benefits of ranolazine in diabetic patients. A recent study, published in The Journal of Pharmacology and Experimental Therapeutics (JPET), has demonstrated that ranolazine Increases β-Cell Survival and improves glucose homeostasis in low-dose streptozotocin-induced diabetes in mice (Ning et al., 2011).

Role in Skeletal Disorders
Ranolazine has been shown to have beneficial effects in some skeletal disorders. In a study recently, it has been shown that ranolazine is useful in reducing the sustained action potential firing in patients of paramyotonia congenita (El-Bizri et al., 2011). It has also been hypothesized that ranolazine inhibits the paramyotonia congenita Na(v) 1.4 gain-of-function mutations, R1448C, R1448H, and R1448P which are associated with repetitive action potential firing.

Role in peripheral vascular disease
Ranolazine has been shown to have a role in the treatment of peripheral arterial disease, particularly in the management of intermittent claudication. It allows maintenance of energy output by muscle cells under hypoxic conditions (Jones, 1998).

Role in neuropathic pain
Ranolazine also targets neuronal [Na(v) 1.7 and 1.8] isoforms of sodium channels which have been implicated in neuropathic pain. In a recent study, the analgesic efficacy of ranolazine in an animal model of neuropathic pain was determined (Mark-Estacion, 2010). Ranolazine inhibited the mechanical and cold allodynia associated with spared nerve injury, without producing ataxia or other behavioural side effects. These data support the potential use of ranolazine in the treatment of neuropathic pain.

Role in leukaemia
Some researchers have found that inhibition of fatty acid oxidation (FAO) by ranolazine inhibits human leukaemia cell proliferation in vitro. Fatty acid oxidation (FAO) regulates the activity of Bak-dependent mitochondrial permeability transition. It is hypothesizd that, ranolazine decreases the number of quiescent leukaemia progenitor cells in approximately 50% of primary human acute myeloid leukaemia samples and, when it was combined with a chemotherapy agent (cytosine arabinoside), provided substantial therapeutic benefit in a murine model of leukaemia. These results support the theory of fatty acid oxidation (FAO) inhibitors emerging as a therapeutic strategy for haematological malignancies.

Role of ranolazine in diastolic dysfunction
In recent studies, it was demonstrated that, ranolazine reduces the frequency-dependent increase in diastolic pressure without causing any negative inotropic effect on the contractility of myocytes (Sossalla, 2008). Also, in rabbit myocytes the increases in late I(Na), [Na(+)](i) and [Ca(2+)](i) caused by ATX-II, were abrogated by ranolazine. These findings point towards a beneficial role of ranolazine in diastolic dysfunction due to elevated [Na(+)](i) and diastolic [Ca(2+)](i).

Anti-arrhythmic properties of ranolazine
Ranolazine inhibits a number of ion currents that are important for the genesis of transmembrane action potentials in the heart. It thus exerts antiarrhythmic actions, due to its multichannel-blocking properties. In recent years, many studies have demonstrated the beneficial effects of ranolazine in both atrial and ventricular arrhythmias, such as atrial fibrillation, ventricular premature beats, ventricular tachycardia, torsades de pointes, and ventricular fibrillation. A study completed recently examined the electrophysiological effects of ranolazine in isolated canine ventricular myocytes, tissues, and arterially perfused left ventricular wedge preparations. In this study, the beneficial effects of ranolazine on transmural dispersion of repolarization (TDR) suggest that, in addition to its antianginal properties, this drug also possesses antiarrhythmic activities (Antzelevitch et al., 2004).


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