Ranolazine

history,mechanism of action, uses and evidence supporting ranolazine

1. RANOLAZINE

2. INTRODUCTION chronic angina, a condition that impairs quality of life and is associated with decreased life expectancy, affects 6.4 million Americans Over the period, number of pharmacological measures such as nitrates, beta-Blockers, calcium channel blockers and revascularisation strategies such as CABG and Coronary Angioplasty have been introduced but still many patients continue to experience angina despite being on optimal medical therapy Considerable progress has been made over the last 30 years in understanding its pathogenesis

3. Several new investigational drugs are being tested for the treatment of chronic angina. In addition there are a number of patients particularly elderly patients who are unsuitable for revascularisation procedures or they do not tolerate higher doses of conventional anti- anginal drugs. In such cases a novel medical treatment with different mechanism of action would be particularly beneficial in relieving the symptoms.

4. HISTORY OF ANTI ANGINALS 1867 - nitrates 1962 - b blocker 1981 - CCBs 2006 - ranolazine 2015 - ivabradine

5. Why must the newer anti anginals be used? Despite the current use of drugs for CAD like beta blockers, CCBs, nitrates, and satisfying response to current treatments, patients still continue to get recurring pain ( chronic angina or refractory angina). These anginal patients have 2 abnormalities which are not effectively controlled by current antianginals / revascularization therapies: - Beta oxidation of FFAs and - Late inward sodium entry.

6. RANOLAZINE

7. Ranolazine is an active piperazine derivative. Ranolazine is a unique anti-ischaemic drug that was initially thought to act purely through metabolic mechanisms. On 27th January, 2006, Ranolazine was approved in the USA – FDA for use in patients with chronic angina who continue to be symptomatic on β-Blockers, Ca antagonists or Nitrates.

8. MECHANISM OF ACTION P FOX inhibitor Late Na + channel inhibitor

9. BASIS FOR pFOX Myocardial ischemia is associated with sudden increase in fatty acid levels resulting in enhanced oxidation of long chain fatty acids. Oxidation of fatty acids needs more ATPs and also an increased oxygen demand for their breakdown than oxidation of carbohydrates. Moreover this may lead to accumulation of free fatty acids and lactic acid increasing the acidosis and affecting heart performance. These mechanisms have harmful effects on the contractility and efficiency of the heart. Treatment must aim to shift myocardial substrate utilisation to glucose metabolism as this will then provide benefits to ischemic patients. This is achieved by drugs which suppress fatty acid oxidation.

10. Metabolic modulation ( pFOX ) Clinical trials showed ranolazine SR 500–1000 mg bid (~2–6 µmol/L) reduced angina Experimental studies demonstrated that ranolazine 100 µmol/L achieved only 12% pFOX inhibition Ranolazine does not inhibit pFOX substantially at clinically relevant doses Fatty acid oxidation Inhibition is not a major antianginal mechanism for ranolazine . J Cardiovasc Pharmacol Therapeut . 2004;9( suppl 1):S65-83 . .

11. LATE Na+ CHANNEL INHIBITION The passage of sodium ions through sodium channels and into a myocardial cell generates the rapid depolarization or ‘upstroke ’ of the action potential. Sodium channel ‘openings ’ are very brief and, after opening, channels inactivate rapidly and stay closed during the plateau phase of the action potential. Channel inactivation appears to involve a ‘plugging’ of the channel pore by a cytoplasmic loop of the channel

12. Upon repolarization of the cell membrane, sodium channels transform from the inactivated to a resting state and do not open again until the next membrane depolarization. A small fraction of sodium channels may not fully inactivate after opening. These channels may continue to open and close spontaneously throughout the plateau phase of the action potential at a time when sodium channels typically remain closed . Na+ channels that exhibit slow or delayed inactivation in phase 2 and 3 of cardiac action potential – late Na+ Comprised of ~1% of all Na+ channels in a healthy cardiomyocyte

13. The late openings of these channels allow a sustained/persistent current of sodium ions (referred to as late INa ) to enter the myocardial cell throughout systole. late INa is increased in myocytes exposed to hypoxia, ischaemia , heart failure, reactive oxygen species, and it is increased in post ischaemic ‘remodelled’ ventricular myocytes .

14. Sodium Current Late Peak Late Peak Sodium Current Na + Impaired Inactivation Na + Ischemia Myocardial ischemia causes enhanced late INa Eur Heart J Suppl. 2006:A10-13 .

15. coupled exchange of sodium and calcium that is facilitated by the cell membrane Na+/Ca2+ exchanger (NCX), an elevation of the intracellular sodium concentration leads to an increased exchange of intracellular sodium for extracellular calcium ( NCX in the reverse mode , with sodium exit and calcium entry ) a reduced exchange of intracellular calcium for extracellular sodium (i.e. activity of NCX in the forward mode, with calcium exit and sodium entry).

16. Na+/Ca2+ overload and ischemia  Late Na + current  Diastolic wall tension (stiffness) Intramural small vessel compression ( O 2 supply)  O 2 demand Na + overload Ca 2+ overload Myocardial ischemia

17. Diastolic relaxation failure increases oxygen consumption and reduces oxygen supply - Impaired coronary blood collection during diastole due to the diastolic stiffness - Increased ventricular diastolic wall stress and end-diastolic pressure. - Mechanical compression of the microcirculation within the wall of the ventricle, - Worsening of ischaemia , particularly in the sub- endocardial regions. 

18. Consequences associated with dysfunction of late sodium current Diseases ( eg , ischemia, heart failure) Pathological milieu (reactive O 2 species, ischemic metabolites) Toxins and drugs ( eg , ATX-II, etc.) Na + channel (Gating mechanism malfunction) Increase ATP consumption Decrease ATP formation Oxygen supply and demand Abnormal contraction and relaxation ↑ diastolic tension ( ↑ LV wall stiffness) Mechanical dysfunction Early after potentials Arrhythmias (VT) Electrical instability

19. In radioligand binding studies of rat hearts and guinea-pig lungs , ranolazine exhibits negligible affinity for a1,b1 and b2 adrenoreceptors and weak 1- and 2-antagonist activity in the rat cardiovascular system . It has weak calcium channel antagonist activity

20. TRIMETAZIDINE VS RANOLAZINE Like trimetazidine , ranolazine also stimulates glucose metabolism and shifts the metabolism from beta oxidation to glucose. But , ranolazine has one additional MOA. In addition to metabolic modulation, ranolazine prevents late inward sodium entry. In this way, the dual MOA of ranolazine acts on the 2 hidden causes of chronic angina in angina patients to provide better efficacy in terms of - survival rates, - angina free duration periods , - exercise ability and - nitrate dose reduction.

21. MYOCARDIAL ISCHEMIA: Sites of action of anti-ischemic medication Consequences of ischemia Ca 2+ overload Electrical instability Myocardial dysfunction ( ↓ systolic function/ ↑ diastolic stiffness) Ischemia ↑ O 2 Demand Heart rate Blood pressure Preload Contractility ↓ O 2 Supply Development of ischemia Traditional anti-ischemic medications: β -blockers Nitrates Ca 2+ blockers Ranolazine

22. METABOLISM Oral bioavailability is in the range of 30% to 55 % Plasma protein binding (mainly to 1-acid glycoprotein) is 65 %. metabolism - Cytochrome P450 (CYP) 3A4 (65%) - CYP2D6 (10% to 15%), - Glucuronidation (5 %), and - excretion of unchanged ranolazine by the kidneys (5 %) There are no gender differences in ranolazine pharmacokinetics, nor are pharmacokinetics significantly altered by diabetes mellitus or heart failure

23. Medication Class Impact on HR Impact on BP Physiologic Mechanism Beta Blockers Decrease pump function Calc Channel Blockers Decrease Pump function + Vaso-dilitation Nitrates Vaso-dilitation Ranolazine O O Reduced Cardiac Stiffness Pharmacologic Classes for Treatment of Angina

24. USES Ranolazine was approved on January 27, 2006, in the United States for use in patients with chronic angina who continue to be symptomatic on -blockers, calcium antagonists, or nitrates

25. MARISA trail randomized, double-blind, placebo-controlled , 4 weeks (n=191 ) age ≥21 years, chronic stable angina ≥3 months relieved by anti- anginal therapy ranolazine 500 mg or 1,000 mg or 1,500 mg twice daily, or placebo; all other anti- anginals discontinued except sublingual nitroglycerin as needed

26. Figure 4. Symptom-limited exercise duration at trough and peak in MARISA. Exercise duration, time to onset of angina, and time to 1-mm ST-segment depression significantly increased with increased dose. Bernard R. Chaitman Circulation. 2006;113:2462-2472

27. CARISA CARISA (Combination Assessment of Ranolazine in Stable Angina) trial is a randomized , double-blind, placebocontrolled , parallel-group ; 12 weeks two doses of sustained-release ranolazine (750 or 1000 mg b.i.d .) were used in combination with diltiazem , amlodipine , or atenolol in patients with chronic stable angina . The cohort was quite large, with more than 800 patients included. Treadmill exercise was carried out at 12 h after administration and at 2, 6, and 12 weeks treatment in three parallel groups

28. Figure 5. In CARISA, exercise duration, time to onset of angina, and time to 1-mm ST-segment depression significantly increased with each ranolazine dose compared with placebo. Bernard R. Chaitman Circulation. 2006;113:2462-2472

29. ERICA Evaluation of Ranolazine In Chronic Angina (ERICA ) was a clinical randomized trial in patients with continuing angina attacks (more than three attacks per week) already treated with amlodipine at a dose of 10 mg daily, with or without long-acting nitrates. Ranolazine was administered at a dose of 500 mg b.i.d . vs . Placebo for a week, then titrated to 1000 mg b.i.d . for 6 weeks . The primary endpoint was angina frequency during the last 6 weeks, and the secondary endpoints were safety, tolerability, nitroglycerin consumption, and quality of life

30. it was multicentre , randomised, parallel-group, double-blind, placebo-controlled trail done in pts with a history of chronic angina with incomplete revascularisation after percutaneous coronary intervention. Ranolazine did not reduce the composite rate of ischaemia -driven revascularisation or hospitalisation without revascularisation in patients with a history of chronic angina who had incomplete revascularisation after percutaneous coronary intervention. Further studies are warranted to establish whether other treatment could be effective in improving the prognosis of high-risk patients in this population.

31. ADR In controlled clinical trials of angina patients, the most frequently reported adverse reactions dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%). Dizziness may be dose-related. CARISA trail

32. The following additional adverse reactions occurred at an incidence of 0.5 to 4.0% in patients Cardiac Disorders – bradycardia, palpitations Ear and Labyrinth Disorders – tinnitus, vertigo Eye Disorders – blurred vision Gastrointestinal Disorders – abdominal pain, dry mouth, vomiting, dyspepsia General Disorders and Administrative Site Adverse Events – asthenia, peripheral edema Metabolism and Nutrition Disorders – anorexia

33. Nervous System Disorders – syncope (vasovagal ) Psychiatric Disorders – confusional state Renal and Urinary Disorders – hematuria Respiratory, Thoracic, and Mediastinal Disorders – dyspnea Skin and Subcutaneous Tissue Disorders – hyperhidrosis

34. Other (<0.5%) but potentially medically important adverse reactions observed more frequently with Ranolazine than placebo treatment in all controlled studies included: - angioedema , renal failure, eosinophilia , blood urea increased, hypoesthesia , paresthesia , tremor, pulmonary fibrosis , and pancytopenia.

35. QTc Based on CARISA trail the following ECG abnormality were detected 750mg 1000mg QT ms 6.1 9.2 PR ms 1.6 2.1 QRS ms 0.7 1.2

36. An ECG should be acquired at baseline and follow-up to evaluate effects on the QT interval. T-wave notching has been observed at high plasma ranolazine concentrations

37. CONTRAINDICATION Taking strong inhibitors of CYP3A Taking inducers of CYP3A With liver cirrhosis QTc prolongation on ECG

38. OTHER USES atrial fibrillation and other arrhythmias Heart failure Diabetes Long QT syndrome syndrome X

39. ROLE IN AF

40. Comparison of Effectiveness and Safety of Ranolazine versus Amiodarone for Preventing Atrial Fibrillation after Coronary Artery Bypass Grafting Am J Cardiol .  2011 Sep 1;108(5):673-6

41. Indian Pacing and Electrophysiology Journal 9 (5): 260-267 (2009)

42. A 60-year-old mildly hypertensive physician had been diagnosed with HCM in 2004. He developed the first episode of AF in April 2011, which lasted for 6 h. He continued to have paroxysmal AF at a frequency of 3 episodes a month, with each paroxysm lasting 6-7 h. Apart from rapid palpitations (ventricular rate @ 130/ min ), he used to experience uneasiness, exhaustion, occasional dizziness and exertional left arm pain.

43. Drugs like amiodarone and beta-blockers failed to reduce the episodes of AF . He would take additional propranolol during the episodes. A coronary angiogram was performed and was found to be normal . With a suspicion of microvascular angina, ranolazine was advised. He started taking ranolazine 500 mg twice a day from July 2012. Amazingly, since then he has had no episodes of paroxysmal AF in the last 12 months

44. A Study to Evaluate the Effect of Ranolazine and Dronedarone When Given Alone and in Combination in Patients With Paroxysmal Atrial Fibrillation (HARMONY) Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion  (RAFFAELLO) Safety of Amiodarone and  Ranolazine  Together in Patients With Angina (SARA)

45. analysis of MERLIN-TIMI 36 study28 demonstrates that, in the studied non-ST-elevation ACS population, ranolazine therapy is associated with: - statistically significant lower incidences of supraventricular tachycardia compared to placebo ( ranolazine 44.7% vs. placebo 55%; RR, 0.81; P <0.001 ) - trend toward fewer new-onset AF ( ranolazine 1.7% vs. placebo 2.4%; RR, 0.74; P =0.08 )

46. VT

47. MERLIN TIMI 36 was a randomised placebo controlled trial. 6560 patients hospitalised with NSTEMI were 1:1 randomised to Ranolazine and placebo in addition to standard therapy. Among patients with ACS, ranolazine , an inhibitor of late I Na , has anti-arrhythmic effects as assessed by Holter monitoring

48. In particular, patients treated with ranolazine had fewer episodes of VT > 8 beats, SVT, and ventricular pauses > 3 seconds Consistent effect in several high-risk sub-groups This is the 1 st clinical report of potential anti-arrhythmic actions of ranolazine and supports anti-arrhythmic findings in experimental models There was no evidence for a significant excess risk of polymorphic ventricular tachycardia or sudden cardiac death Studies specifically designed to evaluate the potential role of ranolazine as an anti-arrhythmic agent are warranted

49. HEART FAILURE In animal model Ranolazine significantly decreased left ventricular end-diastolic pressure and increased left ventricular ejection fraction, peak LV dP / dt ,and stroke volume in the absence of any effects on heart rate or blood pressure .

50. Ranolazine improves the LVEDP, PCWP, MPAP after iv infusion. Conclusion - ranolazine acutely improves diastolic parameters in a small randamized placebo controlled trail

51. DIABETES In the CARISA trial, ranolazine reduced glycosylated haemoglobin (HbA1C ) concentrations by almost 0.5%, maybe increasing insulin sensitivity The same effect was also observed in the MERLINTIMI 36 trial, in which ranolazine significantly reduced HbA1C at 4 months, and decreased the incidence of impaired fasting glucose levels.

52. TERISA In 2013, the  Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina (TERISA) study showed that the drug reduced episodes of stable angina in diabetes patients already receiving one or two antianginal drugs. Ranolazine also led to less use of sublingual nitroglycerin . And in that study, the first prospective international randomized controlled study focusing specifically on angina in patients with diabetes, the benefits of ranolazine appeared more prominent in patients with higher rather than lower HbA 1c  levels.

53. The hypothesized mechanisms for such effects could be related to the - effects of the drug on pancreatic islet cells ion channels, in which it seems to increase glucose related insulin secretion. - Recent evidences suggest that insulin could also improve endothelial function. - decreases insulin resistance Vitulano et al. Int J Clin Cardiol 2015, 2:4

54. long QT syndrome long QT syndrome variant 3 (LQT-3) is characterized by mutations in SCN5A, which result in a defect in channel inactivation and persistent late Na+ current ( INaL ) during ventricular depolarization, which cause a transient inward current after repolarization is completed . This inward current could be responsible of malignant arrhythmias in conditions characterized by sarcoplasmic reticulum (SR) calcium Ca2+ overload. Ranolazine has been demonstrated to improve diastolic function in LQT- 3 patients and reduces Ca2+ concentrations, hence malignant VT. Vitulano et al. Int J Clin Cardiol 2015, 2:4