Ranolazine is a second-line antianginal drug that inhibits late inward sodium currents, reducing calcium overload and improving myocardial perfusion. It has shown efficacy in reducing angina in clinical trials. Ranolazine also partially inhibits fatty acid oxidation, shifting metabolism from fatty acids to glucose. Common side effects include dizziness and constipation. It has potential utility for various conditions including microvascular coronary disease and post-operative atrial fibrillation, though evidence is limited for others such as acute coronary syndrome.

1. DR. DEBABRATA HALDER
NICVD, DHAKA
RANOLAZINE

2. Introduction
 Ranolazine, a piperazine derivative, represents a
second-line antianginal drug in the management of
chronic stable angina pectoris(CSAP), was approved in
the United States(2006) and Europe(2008).

3. Pharmacodynamics
 In the ischaemic myocardium, late inward Na+ currents
occur.
 This contributes to an increase in intracellular Na+,
 This leads to an increase in intracellular Ca++(through
sodium-calcium exchanger)
 Calcium overload in ischaemic cells leads to impaired left
ventricular diastolic relaxation(called diastolic stiffness).

4.  Elevated left ventricular diastolic wall tension
compromises coronary blood flow even further.
 Additionally, calcium overload has adverse effects on
myocardial electrical activity predisposing to
ventricular tachycardia.

5.  Ranolazine inhibits the late phase of the inward
sodium current during cardiac repolarization .Thus
- Decreasing the calcium overload,thus
- Reducing diastolic stiffness, and
- Improving myocardial perfusion.

6. summery

7. Metabolic Properties
 Myocardial ischemia is associated with sudden
increase in fatty acid levels resulting in enhanced
oxidation of LCFA.
 LCFA oxidation needs more ATPs & also an increased
O2 demand for their breakdown than glucose
oxidation.

8.  Moreover this may lead to accumulation of FFAs &
lactic acid increasing the acidosis & affecting heart
performance.
 This is prevented by Ranolazine(partial inhibitor of
fatty acid oxidation-pFOX ) which shifts metabolism
from fatty acid beta oxidation to glucose oxidation.

9.  Ranolazine also inhibits the delayed rectifier
potassium current (IKr) at clinically therapeutic level,
which prolongs the ventricular action potential
duration (prolongation of QTc by 2 to 6 ms).

10. Pharmacokinetics
 Route : Oral
 Onset of Action : 2 to 6 hours and steady state within 3
days of twice-daily dosing.
 Plasma Half Life(t ½ ): about 7 hours
 Metabolism : Liver
 Excretion : Kidney(75%)

11. Tolerability
 Extended-release ranolazine has been well tolerated.
 The most frequent adverse events- dizziness (11.8%),
constipation (10.9%), and peripheral edema (8.3%).
 Plasma levels increase up to 50% to 60% in patients with
moderate hepatic or renal impairment. Therefore, caution
in these groups.
 Contraindication: creatinine clearance of ≤30 mL/min,
renal dialysis, cirrhosis of liver.

12. Interaction/Precaution
 Ranolazine undergoes hepatic metabolism by CYP3A4.
 Ranolazine is contraindicated with potent inhibitors of the
CYP3A4 pathway including
- antifungals (ketoconazole and other azole),
- antibiotics (macrolides, clarithromycin),
- HIV protease inhibitors,
- Diltiazem,
- Grapefruit juice.

13. Interaction/Precaution
 Although ranolazine prolongs QT interval, in a recent
large trial no proarrhythmic effects were noted.
 However, it should still be avoided in those with prior
QT prolongation, or with other drugs that prolong QT
interval.
 It is recommended that an ECG be performed 1 to 2
weeks after initiation.

14. Dose
Extended release tablet : 500mg & 1000mg.
 Starting dose: 500mg BID
 Maximum dose: 1000mg BID

15. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI Guideline
for the Diagnosis and Management of Patients
With Stable Ischemic Heart Disease
 Ranolazine can be useful as a substitute for beta blockers if
initial treatment with beta blockers leads to unacceptable
side effects or is ineffective or if initial treatment with beta
blockers is contraindicated. (LOE: B)
 Ranolazine in combination with beta blockers can be
useful when initial treatment with betablockers is not
successful . (LOE: A)

16. 2013 ESC guidelines on the management of
stable coronary artery disease
Second line antianginal drug(COR-IIa, LOE-B).
Ref:Ranolazine:A contemporary Review;J AM Heart Asso.march 15,2016

17.  MARISA study
 CARISA study
 ERICA study
-Provide the clinical basis for use of ranolazine as
an antianginal therapy in chronic stable angina.

18. Acute Coronary Syndrome
 MERLIN-TIMI 36 randomized trial : Effects of
ranolazine in acute non-ST-elevation acute coronary
syndromes
 Study population & period : 6560 ; 348 days
 Study result: No benefit overall on its primary
outcome.
Ref:morrow et al; JAMA,2007

19. Trimetazidine & Ranolazine
 Both drugs stimulate glucose metabolism from beta
oxidation .
 But, ranolazine has one additional benefit by
inhibiting the late phase of inward sodium current
during cardiac repolarization.
 In this way, ranolazine provides better efficacy.

20. Ivabradine & Ranolazine
 Study Name: Comparison of the efficacy and
tolerability of ivabradine and ranolazine in patients of
chronic stable angina pectoris.
 Study popualtion & period: 30; 08 weeks
 Study result: Both appeared equiactive. However,
ranolazine had a better safety and tolerability profile
than ivabradine .
Ref: chaturvedi et al;2013

21. Microvascular Coronary Dysfunction
 Study Name: Ranolazine improves angina in women
with evidence of myocardial ischemia but no
obstructive coronary artery disease.
 Study Type:Pilot randomized,double blind, placebo
controlled trial
 Study popualtion & period: 20; 04 weeks
 Study result: Ranolazine improves angina.
Ref:mehta et al;JACC cardiovasc Imaging.2011

22.  Study Name: Effects of ivabradine and ranolazine in
patients of MVA.
 Study popualtion & period: 46 ;04 weeks
 Study result: significantly improved in both groups
with ranolazine more than ivabradine.
Ref: villano et al.Am J cardiol.2013

23. New onset & Paroxysmal AF
 Study Name: Ranolazine enhances the efficacy of
amiodarone for conversion of recent-onset atrial
fibrillation(<48 hours).
 Study Type: Randomized,prospective,single-blind trial
 Study popualtion : 121
• Study result: A significantly higher conversion rate at 24
hours and at 12 hours in the ranolazine plus amiodarone.
Ref: koskinas et al;Europace.2014

24. Postoperative Cardiac Surgery AF
 Study Name: Efficacy of ranolazine in preventing AF
following cardiac surgery
 Study Type: Meta-analysis(04 studies)
 Study popualtion : 663
• Study result: A significant reduction in POAF with
ranolazine plus standard therapy.
Ref: Chintan trivedi et al,december 5,2016

25.  Study Name: Ranolazine enhances the antiarrhythmic
activity of amiodarone by accelerating conversion of new-
onset atrial fibrillation(<48 hours) after cardiac surgery.
 Study Type: Randomized,single-blind,clinical trial
 Study popualtion : 41
• Study result: amiodarone(IV followed by PO) plus
ranolazine group had a significantly shorter time to sinus
rhythm conversion compared to amiodarone alone.
Ref: Simooulos et al;Angiology.2014

26. Chronic AF
 Study Name: Ranolazine in persistent AF after
successful electrical cardioversion(RAFFAELLO).
 Study popualtion & period : 241 ; 04 months
 Study result: No dose of ranolazine significantly
prolonged time to AF recurrence.
Ref: De ferrari et al; heart rhythm.2015

27. Glycometabolic Effect
 Patients with type 2 diabetes and chronic angina
demonstrated a dose-dependent reduction in HbA1C
in the CARISA trial(Chaitman et al;2004).
 In another RCT, Effect of Ranolazine Monotherapy on
Glycemic Control in 465 patients with Type 2
Diabetes(Eckel et al;2015; over 24 weeks)
-significantly reduce HbA1C.

28. Incomplete Revascularization After PCI
 Study Name: Ranolazine in patients with incomplete
revascularisation after percutaneous coronary intervention
(RIVER-PCI)
 Study Type: multicentre, randomised, double-blind,
placebo-controlled trial.
 Study popualtion & period : 2651 ; 643 days
 Study result: lack of evidence to support the use of
ranolazine.
Ref: Weisz et al;Lancet.2016

29. Take Home Massage
 Ranolazine does not affect heart rate & blood pressure.
 Ranolazine is a second-line agent in refractory angina.
 Ranolazine shows potential role in MCD, post-CABG
AF, and type 2 diabetes.
 Ranolazine has limited evidence in ACS, incomplete
revascularization post-PCI, and chronic AF.