Antianginal drugs

Drug interaction

1. Nitrates Nitroglycerin (glyceryl trinitrate), isosorbide dinitrate, isosorbide mononitrate

2. Beta-adrenergic antagonists: a) Non-selective b1/b2: Carvedilol, Nadolol, Propranolol, Sotalol, Timolol. b) b1-selective: Atenolol, Bisoprolol, Metoprolol, Nebivolol

3. Calcium channel blockers: a) dihydropyridines: Amlodipine, Felodipine, Isradipine, Nicardipine, Nifedipine, Nimodipine, Nitrendipine. b) Non-dihydropyridines: diltiazem, verapamil

4. Ivabradine

5. Nicorandil

6. Perhexiline

7. Ranolazine

8. Trimetazidine

Ivabradine

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
β-blockers Increases the risk of bradycardiaIncreases ivabradine exposureMonitor ECG
Calcium channel blockers:
- Diltiazem
- Verapamil
Increases the risk of bradycardiaIncreases ivabradine exposureMonitor ECG
Grapefruit juiceInhibits the CYP 3A4 drug-metabolizing enzyme and increases ivabradine exposureGrapefruit juice should be avoided
Moderate CYP3A4 inhibitors:
- Diltiazem
- Fluconazole
- Verapamil
Starting dose of 2.5 mg bid if resting heart rate is above 70 bpm. Monitor heart rate
Potassium-depleting diuretics (thiazide diuretics and loop diuretics)They cause hypokalemia and ivabradine bradycardia. Both effects increase the risk of arrhythmiaConcomitant use with precaution
Potent CYP3A4 inhibitors:
- Azole antifungals: Itraconazole, Ketoconazole
- HIV-protease inhibitors: Nefazone, Nelfinavir, Ritonavir
- Macrolide antibiotics: Clarithromycin, Erythromycin, Josamycin, Telithromycin
Increase ivabradine plasma levelsAvoid the combination
Potent CYP3A4 inducersDecreases ivabradine plasma levelsAvoid the combination
QT prolonging drugs:
- Cardiovascular drugs: class I and III AADs
- Non-cardiovascular drugs: Erythromycin, Halofantrine, Mefloquine, Pentamidine, Pimozide, Sertindole, Ziprasidone
QT prolongation may be exacerbated by heart rate reductionAvoid the combination

No interactions with proton pump inhibitors (omeprazole, lansoprazole), ACEIs, ARBs, sildenafil, statins, dihydropyridine CCBs, digoxin, warfarin or aspirin

Tablets contain lactose; avoid ivabradine in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.


Nicorandil

Drug Pharmacodynamic interactionsPharmacokinetic interactionsCautions
AntihypertensivesRisk of hypotensionMonitor BP
CorticosteroidsIncreased risk of gastrointestinal ulceration
MetforminIt can antagonise the effects of nicorandilAvoid the combination
Vasodilators:
- Alcohol
- Dipyridamole
- Riociguat
- Tricyclic antidepressants
Risk of hypotensionMonitor BP

No interactions have been observed with angiotensin converting enzyme inhibitors, angiotensin II antagonists, antialdosterone agents, β-blockers, calcium channel blockers (amlodipine, lacidipine), digoxin, diuretics, fibrates, nitrates, oral antidiabetics, proton pump inhibitors (omeprazole, lansoprazole), sildenafil, simvastatin and warfarin.


Perhexiline

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Antiabetic drugs:
- Insulin
- Sulphonylureas
Perhexiline increases the riesk of hypoglycemia in diabetic patients receiving insulin or sulphonylureasMonitor blood glucose levels
CYP2D6 inhibitorsThey increase perhexiline exposureMonitor increase perhexiline exposure
DoxorubicinPerhexiline can increase dpxorubicin-induced ttoxicity.

Ranolazine

DrugPharmacodynamic interactionsPharmacokinetic interactions Cautions
AntipsychoticsRanolazine is a mild inhibitor of CYP2D6 and can increase the exposute to these drugsCareful dose titration is recommended
AtorvastatinRanolazine increases exposure to amlodipineReduce the dose of atorvastatin and appropriate clinical monitoring
CYP3A4 substrates:
- Atorvastatin
- Ciclosporin
- Everolimus
- Lovastatin
- Simvastatin
- Sirolimus
- Tacrolimus
Increase the exposure to ranolazineDose adjustment is required when coadministered with ranolazine.
It is recommended to monitor the plasma levels of ciclosporin, everolimus, sirolimus and tacrolimus and dosage adjusted accordingly.
DigoxinRanolazine increases the plasma levels of digoxinDigoxin levels should be monitored following initiation and termination of ranolazine therapy.
MetforminPlasma exposure of metformin increasesThe dose of metformin should not exceed 1700 mg/day
Moderate CYP3A4 or P-gp inhibitors
- Diltiazem
- Erythromycin
- Fluconazole
Increase the plasma concentrations of ranolazineCareful dose titration is recommended
P-gp inhibitors:
- Ciclosporin
- Verapamil
Increase plasma levels of ranolazineReduce the dose of ranolazione may be required
Moderate CYP3A4 inhibitors:
- Diltiazem
- Erythromycin
- Fluconazole
Reduce the dose of ranolazione may be required
ParoxetineIncrease the plasma concentrations of ranolazineCareful dose titration is recommended
Potent CYP3A4 and P-gp inducers:
- Carbamazepine
- Phenytoin
- Phenobarbital
- Rifampicin
- St. John's Wort
Decrease ranolazine plasma levelsAvoid the combination
Potent CYP3A4 and P-gp inhibitors:
- Azole antifungals: Itraconazole, Ketoconazole, Posaconazole Voriconazole
- HIV-protease inhibitors
- Macrolides: Clarithromycin, Telithromycin
- Nefazodone
- Grapefruit juice
Markedly increases ranolazine exposureAvoid the combination
Potent CYP3A4 inhibitorsIncrease the exposure to ranolazineThis combination should be avoided. The dose of ranolazine should be limited to 500 mg bid in patients treated with moderate CYP3A inhibitors.
QT-prolonging drugs:
- Histamine H1-receptor antagonists: Mizolastine, Terfenadine
- Antipsychotics: Thioridazine, Ziprasidone
- Antidepressants: amitriptyline, Imipramine
- Class IA and class III AADs
- Erythromycin
Risk of ventricular arrhythmia may be increasedAvoid the combination of ranolazine with Class I or Class III (except amiodarone) anti-arrhythmic drugs.
Ranolazine should be used with caution in patients with known QT prolongation, taking QT-prolonging drugs
However, ranolazine shorten the QT interval in patients with long QT syndrome
SimvastatinRisk of myopathyRanolazine increases plasma levels of simvastatinThe maximum daily dose of simvastatin is 20 mg daily. Patients should be told to report any signs of myopathy or weakness

Trimetazidine

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
MetoclopramideEnhances the adverse/toxic effect of trimetazidine. Extrapyramidal symptoms may be enhancedAvoid the combination

There are no interactions between trimetazidine and b-blockers, CCBs, digoxin, heparin, hypolipidemic agents or nitrates


Abbreviations

AADs: antiarrhythmic drugs
ACEIs: angiotensin-converting enzyme inhibitors
ARBs: angiotensin receptor blockers
bid: twice daily
BP: blood pressure
bpm: beats per minute
CCBs: calcium channel blockers
CYP: Cytochrome P450 family
ECG: electrocardiogram
HIV: human immunodeficiency virus
P-gp: P glycoprotein.