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

6. 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.

7. RANOLAZINE

8. • 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.

9. MECHANISM OF ACTION
1) P FOX inhibitor
2) Late Na + channel inhibitor

10. 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.

11. 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.
.

12. 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

14. • 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

15. • 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.

16. Sodium
Current
0
Late
Peak
0
Late
Peak
Sodium
Current
Na+
Impaired
Inactivation
Na+
Ischemia
Myocardial ischemia causes enhanced late
INa
Eur Heart J Suppl. 2006:A10-13.

17. • 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).

18. Na+/Ca2+ overload and ischemia
 Late Na+ current
 Diastolic wall tension (stiffness)
Intramural small vessel compression
( O2 supply)
 O2 demand
Na+ overload
Ca2+ overload
Myocardial
ischemia

19. 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.

20. Consequences associated with
dysfunction of late sodium current
• Diseases
(eg, ischemia, heart
failure)
• Pathological milieu
(reactive O2 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

21. • 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

22. 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.

23. MYOCARDIAL ISCHEMIA: Sites of action of
anti-ischemic medication
Consequences of ischemia
Ca2+ overload
Electrical instability
Myocardial dysfunction
(↓systolic function/
↑diastolic stiffness)
Ischemia
↑ O2 Demand
Heart rate
Blood pressure
Preload
Contractility
↓ O2 Supply
Development of ischemia
Traditional
anti-ischemic
medications:
β-blockers
Nitrates
Ca2+ blockers
Ranolazine

24. 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

25. 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

26. 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

28. 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

29. 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

31. 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

32. 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

37. 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

41. • 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.

42. 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

43. 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

44. • 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

45. • 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.

46. 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

47. • 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

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

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

50. ROLE IN AF

51. 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

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

53. • 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.

54. • 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

55. • 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)

56. • 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)

57. VT

58. • 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 INa, has anti-
arrhythmic effects as assessed by Holter monitoring

60. • 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 1st 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

61. 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.

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

63. 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.

64. 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 HbA1c levels.

65. • 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

66. 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