About this Journal Submit a Manuscript Table of Contents
Case Reports in Neurological Medicine
Volume 2013 (2013), Article ID 451206, 3 pages
http://dx.doi.org/10.1155/2013/451206
Case Report

A Rare Neurological Complication of Ranolazine

1VA Western New York Healthcare System, Division of Critical Care and Pain Medicine, Department of Anesthesiology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14215, USA
2University of Iowa, Mason City Cardiology, Mason City, IA 50401, USA
3Director of Mercy North-Iowa Neurology and Sleep Laboratory, University of Iowa, Mason City Neurology, Mason City, IA 50401, USA

Received 24 May 2013; Accepted 19 June 2013

Academic Editors: T. K. Banerjee, P. Berlit, J. L. González-Gutiérrez, R. Koide, and Y. Wakabayashi

Copyright © 2013 Jahan Porhomayon et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Myoclonus is not a known side effect of ranolazine. We report a case of myoclonus in a 72-year-old female who underwent cardiac catheterization for angina and was started on ranolazine after the procedure. Two days after ranolazine therapy on 1000 mg per day in divided doses, myoclonus developed, which severely impaired her normal activity. Her symptoms resolved 2 days after discontinuation of ranolazine. Ranolazine was resumed after discharge from hospital with recurrent myoclonus after two days of therapy. The causal relationship between ranolazine and myoclonus was suggested by cessation of myoclonus after ranolazine was discontinued.

1. Introduction

Chronic angina is a debilitating condition affecting nearly 6 million Americans. Current standard therapy includes beta-blockers, calcium channel blockers, and long acting nitrates. Some patients may be intolerable to standard therapy due to their side effects [1]. Ranolazine is new agent introduced into clinical practice in 2006. It is an extended release antianginal drug and is intended to act without reducing heart rate or blood pressure. Ranolazine is specifically indicated for the treatment of chronic angina in patients that failed previous anti-ischemic therapy [2]. It is contraindicated in patients with QT prolongation [3]. It has a piperazine compound that belongs to a group known as partial fatty-acid oxidation inhibitors [4]. Initially, the main anti-anginal effects of ranolazine were thought to be related to the actions of ranolazine to shift adenosine triphosphate (ATP) production away from fatty-acid oxidation toward glycolysis [5, 6]. Recent evidence suggests that ranolazine is an inhibitor of the late sodium current which results in a reduction of the intracellular sodium and calcium overload in ischemic cardiac myocytes [79].

2. Case Report

This is a 72-year-old female who presented to the emergency department with history of chest pain and non-ST-segment elevation myocardial infarction (NSTEMI). Her past medical history was significant for intermittent chest pain. She underwent cardiac catheterization with placement of 2 drug eluding stents and was started on ranolazine for symptomatic relief of NSTEM with angina.

Her medication list included atorvastatin 20 mg daily, clopidogrel 75 mg daily, aspirin 162 mg daily, diltiazam 60 mg four times a day, and ranolazine 500 mg twice daily. She presented 2 days after discharge with myoclonic jerks in her upper and lower extremities. She was readmitted in the hospital for evaluation of myoclonus. At the time of her hospitalization, ranolazine was discontinued and she did not have any further myoclonus. Brain MRI (magnetic resonance imaging) and blood works including liver enzymes, renal function, and electrolytes all were within normal limits. She was discharged home, and ranolazine was resumed as part of her discharge medication list. She had another episode of generalized myoclonus involving face, arms, and legs that started on the second day of her discharge. Myoclonic jerks progressively got worse; therefore, she presented to emergency room. After readmission and discontinuing ranolazine, her myoclonic jerks disappeared again.

3. Discussion

Current studies evaluating the safety and side effects of ranolazine alone or in combination with other agents have not revealed myoclonus as a known side effect [1013]. Ranolazine is usually well tolerated, and the most common adverse effects include dizziness, constipation, nausea, asthenia, syncope, headache, and abdominal pain. Ranolazine is a relatively new drug, released in early 2006, and the total experience with it is relatively limited.

In the monotherapy assessment of ranolazine in stable angina (MARISA) trial [14], 191 patients were randomized to 500 mg, 1000 mg and 1500 mg of ranolazine, and most adverse events occurred in the 1500 mg dose range. In the combination assessment of ranolazine in stable angina (CARISA) trial [14], five cases of syncope were reported when 1000 mg twice daily dose was used; all cases involved patients on concurrent medications known to raise ranolazine plasma concentrations. However, there were no reported cases of syncope in the efficacy of ranolazine in chronic angina (ERICA) [15] trial. In the ranolazine open label experience (ROLE) trial [16], 746 patients were followed up to almost 3 years with 72 patients discontinuing ranolazine due to dizziness (11.8%) and constipation (10.9%). None of the trials mentioned above reported myoclonus as a side effect.

Ranolazine is extensively metabolized by CYP3A enzymes and, to a lesser extent, by CYP2D [10]. Due to its principal CYP3A-mediated metabolism, multiple drug-drug interactions are seen with ranolazine. Moderate to potent inhibitors of the CYP3A4 enzyme such as ketoconazole, diltiazem, verapamil, macrolide antibiotics, and protease inhibitors can increase plasma ranolazine concentrations by 2.0- to 4.5-fold. Additionally, because ranolazine also blocks persistent sodium (Na) channels both in cardiac and neuronal channels [17], it has been investigated as a promising agent for treatment of conditions resulting from neuronal excitation. Although ranolazine mainly targets persistent Na channels, it can interact with broad spectrum of Na and central nervous system channels. We believe that myoclonic reaction may have occurred as a result of ranolazine interaction with other Na channels as well as persistent resurgent sodium currents [18] leading to increased neural sensitivity. Our current understanding and knowledge regarding Na channels properties are increasing but are currently incomplete. More research is needed to improve selective targeting of Na channels in order to limit side effects of newer agents.

Conflict of Interests

The authors do not have any financial or personal relationships with other people or organizations that could inappropriately influence (bias) their work. Examples of potential conflict of interests include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other fundings.

References

  1. B. R. Chaitman, “When should ranolazine be considered for the treatment of chronic angina?: commentary,” Nature Clinical Practice Cardiovascular Medicine, vol. 3, no. 11, pp. 590–591, 2006. View at Publisher · View at Google Scholar · View at Scopus
  2. I. Bonadei, E. Vizzardi, F. Quinzani et al., “Effects of ranolazine on cardiovascular system,” Recent Patents on Cardiovascular Drug Discovery, vol. 6, no. 3, pp. 215–221, 2011. View at Scopus
  3. G. Schram, L. Zhang, K. Derakhchan, J. R. Ehrlich, L. Belardinelli, and S. Nattel, “Ranolazine: ion-channel-blocking actions and in vivo electrophysiological effects,” British Journal of Pharmacology, vol. 142, no. 8, pp. 1300–1308, 2004. View at Publisher · View at Google Scholar · View at Scopus
  4. W. C. Stanley, “Partial fatty acid oxidation inhibitors for stable angina,” Expert Opinion on Investigational Drugs, vol. 11, no. 5, pp. 615–629, 2002. View at Publisher · View at Google Scholar · View at Scopus
  5. B. Clarke, K. M. Wyatt, and J. G. McCormack, “Ranolazine increases active pyruvate dehydrogenase in perfused normoxic rat hearts: evidence for an indirect mechanism,” Journal of Molecular and Cellular Cardiology, vol. 28, no. 2, pp. 341–350, 1996. View at Publisher · View at Google Scholar · View at Scopus
  6. J. G. McCormack, W. C. Stanley, and A. A. Wolff, “Ranolazine: a novel metabolic modulator for the treatment of angina,” General Pharmacology, vol. 30, no. 5, pp. 639–645, 1998. View at Publisher · View at Google Scholar · View at Scopus
  7. B. R. Chaitman, “Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions,” Circulation, vol. 113, no. 20, pp. 2462–2472, 2006. View at Publisher · View at Google Scholar · View at Scopus
  8. C. Antzelevitch, L. Belardinelli, A. C. Zygmunt et al., “Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties,” Circulation, vol. 110, no. 8, pp. 904–910, 2004. View at Publisher · View at Google Scholar · View at Scopus
  9. S. Sicouri, J. Blazek, L. Belardinelli, and C. Antzelevitch, “Electrophysiological characteristics of canine superior vena cava sleeve preparations: effect of ranolazine,” Circulation, vol. 5, no. 2, pp. 371–379, 2012.
  10. M. Jerling, B.-L. Huan, K. Leung, N. Chu, H. Abdallah, and Z. Hussein, “Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects,” Journal of Clinical Pharmacology, vol. 45, no. 4, pp. 422–433, 2005. View at Publisher · View at Google Scholar · View at Scopus
  11. H. Abdallah and M. Jerling, “Effect of hepatic impairment on the multiple-dose pharmacokinetics of ranolazine sustained-release tablets,” Journal of Clinical Pharmacology, vol. 45, no. 7, pp. 802–809, 2005. View at Publisher · View at Google Scholar · View at Scopus
  12. M. Jerling, “Clinical pharmacokinetics of ranolazine,” Clinical Pharmacokinetics, vol. 45, no. 5, pp. 469–491, 2006. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Jerling and H. Abdallah, “Effect of renal impairment on multiple-dose pharmacokinetics of extended-release ranolazine,” Clinical Pharmacology and Therapeutics, vol. 78, no. 3, pp. 288–297, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. R. Jones, “Ranolazine roche bioscience,” IDrugs, vol. 2, no. 12, pp. 1353–1362, 1999. View at Scopus
  15. N. K. Wenger, B. Chaitman, and G. W. Vetrovec, “Gender comparison of efficacy and safety of ranolazine for chronic angina pectoris in four randomized clinical trials,” American Journal of Cardiology, vol. 99, no. 1, pp. 11–18, 2007. View at Publisher · View at Google Scholar · View at Scopus
  16. M. J. Koren, M. R. Crager, and M. Sweeney, “Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE),” Journal of the American College of Cardiology, vol. 49, no. 10, pp. 1027–1034, 2007. View at Publisher · View at Google Scholar · View at Scopus
  17. S. Rajamani, J. C. Shryock, and L. Belardinelli, “Block of tetrodotoxin-sensitive, NaV1.7 and tetrodotoxin-resistant, NaV1.8, Na+ channels by ranolazine,” Channels, vol. 2, no. 6, pp. 449–460, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. B. W. Jarecki, A. D. Piekarz, J. O. Jackson II, and T. R. Cummins, “Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents,” Journal of Clinical Investigation, vol. 120, no. 1, pp. 369–378, 2010. View at Publisher · View at Google Scholar · View at Scopus