Ranolazine is a new antianginal drug that represents a new class of drugs. It partially inhibits fatty acid oxidation and shifts energy production to a more efficient carbohydrate oxidation during ischemia. It also inhibits late inward sodium currents, reducing calcium overload and improving diastolic function and myocardial perfusion. Ranolazine has been shown to reduce angina frequency and improve exercise ability with no effects on blood pressure or heart rate. Its benefits and mechanisms of action were discussed along with its indications, studies, and potential role in other conditions such as diabetes and cardioplegia.

1. Ranolazine An update

2. Agenda for today What we know What we need to know What we may not know What we do not know

3. Ranolazine What we know

4. Understanding ECG

5. Understanding ECG leads

6. Understanding ECG leads

7. Spectrum of CAD Silent ischemia Stable angina Acute coronary syndromes Unstable angina AMI NSTEMI STEMI Partial occlusion / early recanalization / rich collaterals leads to NSTEMI (non-ST elevation MI) Total occlusion of infarct related artery leads to ST elevation (STEMI) and subsequent evolution of Q waves

8. Spectrum of CAD

9. What do you see?

10. What do you see?

11. What do you see?

12. Spectrum of Coronary Artery Disease Diagnose by ECG changes! Silent ischemia Stable angina Unstable angina AMI NSTEMI STEMI Endocardial damage

13. New approaches to myocardial ischaemia Rho kinase inhibition (Fasudil) Metabolic modulation ( Trimetazidine ) Preconditioning ( Nicorandil ) Sinus node inhibition ( Ivabradine ) Late Na+ current inhibition (Ranolazine)

14. Ranolazine Ranolazine represents a new class of antianginal drugs. It is a compound with a structure similar to trimetazidine. Ranolazine is a partial inhibitor of fatty acid oxidation [ pFOX ].

15. What are the benefits of pFOX? Ranolazine has been shown to: What?: How?: When?: Where?: shift ATP production from fatty acid to more oxygen efficient carbohydrate oxidation by stimulating glucose oxidation during the elevated plasma free fatty acid levels associated with myocardial ischemia

16. What else does Ranolazine do? Ranolazine has also been shown to be capable of : Inhibiting the late inward sodium entry, thus Decreasing the calcium overload, thus Reducing diastolic stiffness, and Improving myocardial perfusion.

17. Basis of pFOX 1. Myocardial ischemia is associated with sudden increase in fatty acid levels resulting in enhanced oxidation of long chain fatty acids 2. Oxidation of fatty acids needs more ATPs and also an increased oxygen demand for their breakdown than oxidation of carbohydrates 3. Moreover this may lead to accumulation of free fatty acids and lactic acid increasing the acidosis and affecting heart performance. 4. These mechanisms have harmful effects on the contractility and efficiency of the heart. 5. Treatment must aim to shift myocardial substrate utilisation to glucose metabolism as this will then provide benefits to ischemic patients. 6. This is achieved by drugs which suppress fatty acid oxidation. Trimetazidine Ranolazine

18. Late sodium inward entry Let us have a closer look at that!

19. Ranolazine – the background In the ischaemic myocardium, late inward Na+ currents occur. This contributes to an ↑ in intracellular Na+, This leads to an increase in intracellular Ca++ [ through the sodium-calcium exchanger] ?? Calcium overload in ischaemic cells leads to impaired relaxation. This is called diastolic stiffness.

20. Outcome of diastolic stiffness End result 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.

21. Ranolazine - benefits Ranolazine blocks late inward sodium currents in cardiomyocytes By blocking late inward sodium currents, there is reduction in calcium overload and diastolic wall stress- This, in turn, reduces diastolic stiffness and improves myocardial perfusion. This, along with pFOX, contributes to superior anti-anginal efficacy of ranolazine.

22. Ranolazine - summary Ischaemia ↑ Late I Na Na + Overload Diastolic relaxation failure (Increased diastolic tension) Extravascular compression Ca ++ Overload Ranolazine: Inhibits the late inward Na current Ranolazine prevents the diastolic stiffness and thereby preserves myocardial blood flow Intramural small vessel compression ( ↓ O2 supply) and ↑ O2 demand

23. Ranolazine What we need to know

24. Ranolazine - Indications Ranolazine was approved by the FDA in 2006 as an extended release oral compound for treatment of chronic angina. Dosing should be initiated at 500 mg bid and increased to 1000 mg bid, as needed, based on clinical symptoms The maximum recommended daily dose of ranolazine is 1000 mg bid Ranolazine should be used in combination with amlodipine,Beta-blockers or nitrates

25. Ranolazine – Drug interactions Inhibitors of CYP3A Increase ranolazine plasma levels and QTc prolongation and should not be coadministered with ranolazine: Ketoconazole and other azole antifungals Diltiazem Verapamil Macrolide antibiotics HIV protease inhibitors Grapefruit juice or grapefruit-containing products Inducers of CYP3A Reduce the plasma concentration of ranolazine to subtherapeutic levels and thus should not be given together: Rifampin, Rifabutin, Rifapentin Phenytoin Phenobarbital Carbamazepine St. John's wort

26. Ranolazine – Drug interactions Reduce doses of the following drugs: Simvastatin Digoxin [Coadministration of Ranolazine and digoxin increases the plasma concentrations of digoxin by approx. 1.5-fold]; Tricyclic antidepressants & some antipsychotics Ranolazine prolongs the QT-interval. Hence, it is contradicted in patients with prolonged QT-intervals.

27. Ranolazine – the studies MARISA = Monotherapy Assessment of Ranolazine In Stable Angina CARISA = Combination Assessment of Ranolazine In Stable Angina ERICA = Evaluation of Ranolazine in Chronic Angina MERLIN-TIMI = Metabolic Efficiency with Ranolazine for Less Ischemia in Non ST elevation acute coronary syndromes

28. Ranolazine – Summary Additional, well-tolerated antianginal efficacy in patients who remain symptomatic despite maximal anti-anginal therapy Metabolic modulation Reduces late INa Does not affect BP Does not affect heart rate Extends exercise ability Reduces angina frequency Reduces nitrate consumption

29. Ranolazine What we may not know

30. Ranolazine does not affect heart rate or BP * *

31. 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.

32. How does trimetazidine work? Anginal patients accumulate FFAs, which the cardiac muscles oxidise for their energy requirements, LCFA oxidation demands more ATP to break down the FFAs than glucose oxidation. This demands more O2 and more blood supply from the anginal heart, adding to the load on the compromised heart. This is prevented by trimetazidine which shifts metabolism from LCFAs to glucose.

33. Trimetazidine & ranolazine - Difference 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.

34. How does late inward sodium entry influence angina? In the normal diastolic phase, sodium ions usually move from the intracellular space of the cardiac cells to the extracellular space. However, in anginal patients, the late phase of diastolic relaxation is prolonged and there is inward entry of sodium during this late phase. Inward entry of sodium increases sodium overload, Sodium overload leads to calcium overload through the sodium-calcium exchange pump. Intracellular calcium promotes cardiac muscle contraction, leading to incomplete or partial diastolic relaxation – also called as diastolic stiffness.

35. What happens in diastolic stiffness to worsen angina? Diastolic stiffness = ↓ filling of blood in the heart due to the restricted availability of space -> great stress on the heart muscle walls,. This increased pressure on the muscle walls squeezes the intramural blood vessels, decreasing the endothelial perfusion. This adds in a small way to the ischaemia of angina instead of preventing the same.

36. Role of ranolazine on diastolic stiffness Such ischaemia of diastolic stiffness-induced angina, occuring due to the late sodium inward entry; is prevented by ranolazine as it blocks late inward sodium entry and thus helps to avoid diastolic stifness.

37. Ranolazine What we do not know

38. New indication for ranolazine In the European Union, the drug remains indicated for stable angina as an add-on therapy when symptoms aren't controlled with first-line agents. Basis for such change As seen in the MERLIN-TIMI 36 trial and in clinical practice, patients with ischemia and angina can be at increased risk for arrhythmias and also often have diabetes. Considering its mechanism of action, established cardiovascular safety, and observed reductions in arrhythmias and [glycosylated hemoglobin], ranolazine now becomes an even more important drug in the treatment of chronic angina.

39. Ranolazine in cardioplegia Cardioplegia is the temporary cessation of cardiac activity. Results suggest that addition of ranolazine during hyperkalemic ischemic cardioplegic arrest is beneficial and provides further protection against contracture. Ranolazine as an Adjunct to Cardioplegia: A Potential New Therapeutic Application by Hyosook Hwang, PhD et al. Heart Institute, Good Samaritan Hospital, Los Angeles, California, Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 14, No. 2, 125-133 (2009)

40. Ranolazine and infarct size Results suggest that ranolazine was effective in reducing myocardial infarct size, the mechanism by which it did this was independent of improving perfusion during either ischemia or reperfusion, suggesting that ranolazine's effect of reducing infarct size involves alternative mechanisms. . The Antianginal Agent, Ranolazine, Reduces Myocardial Infarct Size but Does Not Alter Anatomic No-Reflow or Regional Myocardial Blood Flow in Ischemia/Reperfusion iby Sharon L. Hale, BS et al, Heart Institute, Good Samaritan Hospital and the Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, sharon.hale@netscape.com, Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 13, No. 3, 226-232 (2008)

41. Ranolazine and diabetes Results from MERLIN-TIMI and other studies suggest that ranolazine was effective in reducing HbA1c. Even in CARISA, though ranolazine did not appear to significantly lower fasting glucose levels in diabetic patients, there was a statistically significant reduction of HbA1c. Ranolazine’s effect on HbA1c levels may be speculated by its action on cell membrane or its metabolic action; but could possibly be due to a ranolazine-induced decrease in anginal symptoms leading to increased physical activity, with a resultant increase in insulin sensitivity.

42. Understanding nicorandil Nicorandil acts by relaxing the smooth muscle of the blood vessels, especially those of the venous system. It does this by 2 ways- Firstly, by activating K+ channels, and Secondly, by donating nitric oxide to activate the enzyme guanylate cyclase. Guanylate cyclase activation leads to both arterial and venous vasodilatation. Although it can dilate the coronary vessels, it dilates the venous system, instead, thus reducing preload and the work of the heart. Peri-anal, ileal and peri-stomal ulceration is a side effect limiting its use.

43. Understanding Fasudil Fasudil Hydrochloride is a potent Rho-kinase inhibitor and vasodilator. Rho-kinase proteins are involved in a variety of biochemical signalling in the cells.. Fasudil is used for cerebral vasospasm treatment , as well as to improve the memory decline seen in stroke victims and in Alzheimer’s pts.

44. Understanding Fasudil in CAD Increased activity of Rho-kinase causes hypercontraction of vascular smooth muscle This has been implicated as playing a pathogenetic role in divergent cardiovascular diseases such as coronary artery spasm. Inhibition of Rho-kinase helps blood vessels to relax and increases the blood supply of cardiac tissue. This forms the basis of use in CAD, but spasm is not always present in CAD.

45. Understanding Ivabradine Ivabradine acts on the If ion current, which is highly expressed in the sinoatrial node. (f is for "funny", so called because it had unusual properties compared with other current systems known at the time of its discovery) It is one of the most important ionic currents for regulating activity in the SA node. Ivabradine selectively inhibits the pacemaker If current in a dose-dependent manner.

46. Understanding Ivabradine Blocking this channel reduces cardiac activity, slowing the heart rate & allowing more time for blood flow to myocardium. Hence, it is indicated for the symptomatic treatment of stable angina pectoris in patients with normal sinus rhythm, who have a contraindication to or intolerance to beta blockers.

47. Understanding Ivabradine It has been shown to be non-inferior to the beta-blocker atenolol for this indication 3 and amlodipine. Apart from angina, it is also being used off-label in the treatment of inappropriate sinus tachycardia. Reduction in heart rate with ivabradine does not improve cardiac outcomes in all patients with stable coronary artery disease and left-ventricular systolic dysfunction, but could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater . The Lancet, Volume 372, Issue 9641, Pages 807 - 816, 6 September 2008, Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL).

48. Conclusion In chronic angina Ranolazine is the most effective and valuable. Acts on cell membrane Acts on metabolism Acts on HbA1c. Ranolazine confers the following benefits- Decreases angina frequency, Increases exercise tolerance, No deleterious effects on hemodynamics Reduces nitrate dosage

49. Ranolazine What you must not know?

50. Nothing