ranolazine dr merajuddin shah md dm cardiology al kareem cardiac center srinagar kashmir n.
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RANOLAZINE Dr. Merajuddin shah, MD, DM (Cardiology) Al-Kareem Cardiac Center, Srinagar, Kashmir. METABOLIC MANUPULATION OF ISCHEMIC HEART DISEASE. A NOVEL APPROACH TO TREATMENT -------- Leong Lee , EHJ, 2004. RANOLAZINE A Piperazine Derivative. Chronic Angina.

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slide2

METABOLIC MANUPULATION OF ISCHEMIC HEART DISEASE. A NOVEL APPROACH TO TREATMENT --------Leong Lee , EHJ, 2004

chronic angina
Chronic Angina
  • A condition that impairs quality of life and is associated with decreased life expectancy
  • Current major drug therapies
  • Nitrates
  • ß-blockers,
  • Calcium antagonists

All these affect HR and BP

ranolazine
Ranolazine
  • A drug that reduces angina symptoms, with a mechanism of action different from that of currently available pharmacological therapies.
  • Do not affect HR & BP.

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

slide7

Primary Mechanism of Action: Inhibition of Late Na channel

NCX: Sodium-calcium exchange

Eur Heart J. 2004;6(suppl I):I3–I7.

mechanism of action
Mechanism of action
  • In ischemia, number of late Na channel (I-Na) increases which leads to calcium overload through Na-Ca exchange.
  • Ranolazine block these late Na channel, and hence prevent the calcium overload which in turn decreases mechanical dysfunction, abnormal contraction and relaxation, and diastolic tension.
slide9
Ranolazine (therapeutically conc.up to 10 µmol/L) selectively inhibit late INa (IC50=5 to 21 µmol/L)
  • No effect on either the fast sodium current responsible for the upstroke of the action potential (IC50 value of 244 µmol/L for peak INa) or the Na+-H+ and Na+-Ca2+ exchangers.

Thus, ranolazine is a relatively selective inhibitor for late INa

J Cardiovasc Pharmacol Ther. 2004; 9: S65–S83

ranolazine inhibition of various currents
Ranolazine & inhibition of various currents
  • IC50 values for various currents:
    • Late INa+ 5.9 umol/L
    • IKr 11.5 umol/L
    • Late ICa+ 50 umol/L
    • INa-Ca 91 umol/L
    • Peak ICa+ 296 umol/L
    • IKs (17%) 30 umol/L

Circulation. 2004;110:904-910

pharmacokinetics
Pharmacokinetics
  • Food - no effect on Bioavailability

The absolute bioavailability - 35% to 50%.

Elimination

  • 80% - by cytochrome P450 (CYP) 3A enzymes
  • 10-15% by CYP2D6
  • 5% Glucuronidation
  • 5% Excreted unchanged in Urine.
  • Elimination half-life
  • 7 hrs - ER formulation
drug drug interaction
Drug–Drug Interaction
  • Diltiazem (≥240 mg daily) - ↑ ranolazine plasma levels - 1.5-fold
  • Ranolazine has no significant effect on diltiazem pharmacokinetics
  • Verapamil (≥360 mg daily) - 2.3-fold ↑ in ranolazine plasma levels
  • Ranolazine increases digoxin concentrations 1.4- to 1.6-fold at trough &2-fold at peak plasma levels
  • Ranolazine is contraindicated in patients on potent and

moderately potent CYP3A inhibitors such as ketoconazole, diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors, and grapefruit juice

drug drug interaction1
Drug–Drug Interaction
  • Simvastatin Cmax is ↑ by 2-fold after ranolazine;
  • Simvastatin - no significant effect on ranolazine pharmacokinetics.
  • In phase II studies of ranolazine with patients

on statin drugs, significant increases in creatine kinase, clinical myositis, or elevated liver function tests have not been reported.

  • No interactions with warfarin
  • Antiarrhythmic drugs
    • Class Ia: quinidine
    • Class III: dofetilide, sotalol
    • Certain antipsychotics: Thioridazine, ziprasidone
m onotherapy a ssessment of r anolazine i n s table a ngina marisa
MonotherapyAssessment of RanolazineIn Stable AnginaMARISA
  • Patients withdrawn from other anti-anginals(N = 191 randomized)
  • Randomized, double-blind, 4-period crossover
    • 1-wk treatment periods
    • Placebo vs 500, 1000, and 1500 mg bid
  • Exercise tests after each week of treatment
    • At trough (12 hr after dosing)
    • At peak (4 hr after dosing)

J Am Coll Cardiol 2004;43:1375-82.

monotherapy with ranolazine increases exercise performance at trough and peak marisa

1000 mg bid

Monotherapy With Ranolazine Increases Exercise Performance at Trough and Peak MARISA

Peak

Trough

***

***

***

***

**

***

***

***

***

***

***

***

***

***

***

***

***

**

Placebo

500 mg bid

N = 175, All/Near Completers population; LS means ± SE.

**p< 0.01 vs placebo; ***p < 0.001 vs. placebo

1500 mg bid

c ombination a ssessment of r anolazine i n s table a ngina carisa
Combination Assessment of RanolazineIn Stable AnginaCARISA
  • Randomization criteria identical to MARISA except for background therapy
    • Atenolol 50 mg qd (n = 354), or
    • Amlodipine 5 mg qd (n = 256), or
    • Diltiazem CD 180 mg qd (n = 213)
  • Three parallel groups for 12 wk of treatment
    • Placebo
    • Ranolazine 750 mg bid
    • Ranolazine 1000 mg bid
  • Exercise testing
    • At trough after 2, 6, and 12 wk of treatment
    • At peak after 2 and 12 wk of treatment

JAMA 2004;291:309-316.

ranolazine with a beta or calcium blocker increases exercise times at trough and peak carisa
Ranolazine With a Beta- or Calcium Blocker Increases Exercise Times at Trough and Peak CARISA

Peak

Trough

*

*

**

**

*

*

***

***

**

*

Change from baseline, sec

N = 791, ITT/LOCF; LS mean ± SE.

*p < 0.05; **p ≤ 0.01; ***p ≤ 0.001 vs placebo.

Placebo

750 mg bid

1000 mg bid

ranolazine decreases weekly angina attacks and nitroglycerin consumption carisa
Ranolazine Decreases Weekly Angina Attacks and Nitroglycerin ConsumptionCARISA

**

***

*

***

Angina attacks

Nitroglycerin consumption

N = 791, ITT/LOCF; LS mean ± SE.

*p < 0.05, **p ≤ 0.01, ***p ≤ 0.001 vs placebo

erica study design
ERICA: Study design

Evaluation of Ranolazine In Chronic Angina

History of CAD* Stable angina (≥3 angina episodes/week)Amlodipine 10 mg/dayN = 565

Ranolazine extended-release 500 mg bid (1 week) then 1000 mg bidn = 281

Placebon = 284

RandomizedDouble-blind

7 weeks

Primary efficacy variable:Angina frequency (weekly average)

*≥60% stenosis, previous MI, and/or stress-induced perfusion defect

Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

erica ranolazine reduces angina frequency and nitrate consumption
ERICA: Ranolazine reduces angina frequency and nitrate consumption

N = 564 on amlodipine 10 mg/day

6

5

P = 0.028

4

Mean number per week

P = 0.014

3

2

1

0

Baseline

Week 7

Baseline

Week 7

Angina episodes

Nitroglycerin use

PlacPlaceboebo

RRannanolazine 1000 mg bid

Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

erica no significant effect on heart rate or bp
ERICA: No significant effect on heart rate or BP

N = 564 on amlodipine 10 mg/day; Supine measurement

Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

ranolazine is at least as effective as atenolol 100 mg daily ran080

p = 0.006

p < 0.001

p < 0.04

Ranolazine IR 400 mg tid

(1741 ± 1026 ng base/mL)

Atenolol 100 mg od

Placebo

Ranolazine Is at Least as Effective as Atenolol 100 mg DailyRAN080

Time to onset of angina

Time to 1-mm ST-depression

Exercise duration

p < 0.001

p = 0.18

p < 0.001

p < 0.001

p = 0.86

LS mean ± SE, sec

p < 0.001

All patients analysis, N = 154.

merlin timi 36
MERLIN-TIMI 36
  • Randomized, placebo controlled tiral.
  • Subjects: 6560 patients hospitalized with NSTEMI were randomized to ranolazine or placebo, in addition to standard therapy.
  • Initially ranolazine was given intravenous infusion followed by oral ranolazine.
  • Median duration of cECG monitoring was 6.8 days.

Circulation 2007;116:1647-1652.

merlin timi 36 summary
MERLIN-TIMI 36: SUMMARY
  • In more than 6300 patients admitted with NSTEMI, treatment with ranolzine resulted in significantly lower incidence of
    • ventricular tachycardia,
    • Supraventricular tachycardia, and
    • Significant ventricular pauses.

Circulation 2007;116:1647-1652.

summary anti anginal and anti ischemic efficacy of ranolazine
Summary—Anti-Anginal and Anti-Ischemic Efficacy of Ranolazine
  • Dose and plasma concentration dependent
  • Consistent throughout a broad population of chronic angina patients
  • Not dependent on decreases in blood pressure or heart rate
  • At least as great asatenolol 100 mg qd (RAN080)
  • In patients on atenolol or diltiazem at doses considered optimal by their physicians (RAN072)
safety
Safety

Common reported adverse events are:-

  • Dizziness:- 6.2%
  • Headache:- 5.5%
  • Constipation:- 4.5%
  • Nausea:- 4.4%

CARISA: the average increase in QTc was 6.1 and 9.2 ms at the ranolazine doses of 750mg and 1000mg twice daily.

NO CASES OF TORSADES DE POINTES HAVE BEEN SEEN IN PATIENTS WHO RECEIVED RANOLAZINE IN CLINICAL TRIALS TO DATE

contraindications
Contraindications
  • Preexisting QT prolongation
  • On drugs that prolong QT interval
  • Hepatic impairment
  • Patients taking drugs which inhibit CYP3A.
  • In patients on potent and moderately potent CYP3A inhibitors such as ketoconazole, diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors, and grapefruit juice.
indications dosage
Indications & Dosage
  • Treatment of Chronic angina.
  • Patients who have not achieved an adequate response with other antianginal drug.
  • It should be used in combination with beta-blockers, amlodipine, or nitrates.
  • 500mg bid initially, can be increased to 1000 mg bid.
  • Max. recommended daily dose is 1000 mg bid.
  • Helps in lowering HbA1c in patients with DM
summary ranolazine efficacy and safety
Summary— Ranolazine Efficacy and Safety
  • Efficacy demonstrated in 5 double-blind, randomized, placebo-controlled trials
  • Safe and well tolerated
  • Adverse events are generally dose dependent and manageable by typical dose titration
  • No evidence for an adverse effect of ranolazine on survival