ReviewAntiarrhythmic properties of ranolazine: A review of the current evidence
Introduction
Ranolazine {Ranexa, Gilead Sciences, Foster City, Calif., USA; N-(2,6 dimethylphenyl)-4(2-hydroxy-3-{2-methoxyphenoxy}-propyl)-1-piperazine acetamide dihydrochloride}, a sustained-release, hemodynamically inert anti-anginal drug was approved by the Food and Drug Administration in 2006 for use in patients with chronic stable angina pectoris [1], [2], [3], [4], [5], [6], [7], [8]. Although initially developed as an antianginal agent, it was found to additionally exert antiarrhythmic actions [9], [10], [11], [12], [13]. Ranolazine has been shown to inhibit a number of ion currents that play a role in the genesis of the transmembrane cardiac action potential [14], [15], [16], [17], [18], [19]. Table 1 reviews the IC50 (concentration that causes 50% inhibition) values of ranolazine for the various ion currents. In the ventricles, ranolazine exercises its antiarrhythmic effects mainly through inhibition of the late phase of the inward sodium current (late INa) and the rapidly activating delayed rectifier potassium current (IKr). In atria, in addition to the blockade of late INa and IKr, inhibition of the early or peak sodium channel current (peak INa) by ranolazine plays an important role [14]. This review discusses the electrophysiological basis of the antiarrhythmic actions of ranolazine and summarizes the relevant preclinical and clinical data on its use as an antiarrhythmic agent.
Section snippets
Study selection
Relevant peer-reviewed literature was selected in Pubmed, Google Scholar and Cochrane Library using terms ‘ranolazine’, ‘arrhythmia’, and ‘late sodium channel inhibitors’. The search was limited to English language publications, without date limitation.
Effect of ranolazine on peak and late INa, other ion channel currents and cardiac action potential
The late INa was first described by Coraboeuf et al. in 1979, when they found that tetrodotoxin reduces action potential (APD) in dog Purkinje fibers at concentrations lower than those at which the maximum rate of rise of action potential upstroke (Vmax) decreases. They concluded that “this current, which is more sensitive to tetrodotoxin than the normal rapid (or peak) sodium current, flows through a background sodium conductance and/or a small proportion of sodium channels with no activation
Ranolazine in atrial arrhythmias
Rhythm control still remains an important strategy in the treatment of symptomatic atrial fibrillation (AF). However, the currently available antiarrhythmic drugs are associated with potentially severe cardiac and extra-cardiac side effects such as ventricular proarrhythmia, hypotension, and lung toxicity [48]. Also, in the setting of heart failure with reduced ejection fraction, antiarrhythmic therapy is more or less limited to amiodarone, as other class III agents as well as class I agents
Ranolazine in ventricular arrhythmias
Ventricular arrhythmias associated with reduced repolarization reserve due to an increased late INa, reduced IKr or a combination of both, are effectively suppressed by ranolazine. An increase in late INa is associated with prolongation of APD and destabilization of repolarization. Also, enhanced late INa increases sodium influx, and therefore, increased intracellular calcium via the INCX. Intracellular calcium overload leads to spontaneous release of calcium from sarcoplasmic reticulum,
Conclusion
In recent years, there has been an increased interest in the electrophysiological effects of ranolazine. This article summarizes the current evidence for the therapeutic role of ranolazine in treatment of atrial and ventricular arrhythmias in addition to its current antianginal role. The drug has been studied in several small clinical studies. The only multicenter randomized-control data supporting its use as an antiarrhythmic agent comes from the MERLIN-TIMI 36 trial. However, this study was
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