Antiarrhythmic drugs

Drug interaction

Classification of antiarrhythmic drugs

Class IA: Ajmaline, Disopyramide, Procainamide, Quinidine
Class IB: Lidocaine, Mexiletine
Class IC: Flecainide, Propafenone
Class II: Acebutolol, Atenolol, Bisoprolol, Carteolol, Esmolol, Metoprolol, Nadolol, Nebivolol, Oxprenolol, Propranolol
Class III: Amiodarone, Dofetilide, Dronedarone, Ibutilide, Sotalol
Class IV: Diltiazem, Verapamilo
Other: Adenosine, Atropine, Digoxin, Magnesium sulfate, Vernakalant

 

See other sections for drug interactions involving other cardiovascular drugs. Use of this content is subject to our disclaimer.

 

General interactions

DrugPharmacodynamic interactionsPharmacokinetic interactions Cautions
Antiarrhythmic drugsCombination of antiarrhythmic drugs increases the risk of proarrhythmia and decreases cardiac contractilityAvoid the combinations if possible
Hypo/hyperkalemiaMay increase the cardiodepressant effectsMonitor serum potassium levels
QTc-prolonging drugsIncrease the risk of proarrhythmia (torsades de pointes)Avoid the combination

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Adenosine

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
CarbamazepineIncrease the degree of heart block produced adenosine Monitor the ECG

- Digoxin
- Diltiazem
- Verapamil
Produce synergistic depressing effects on the SA and AV nodesMonitor the ECG
DipyridamoleInhibits the uptake of adenosine and may potentiate its effects (risk of hypotension, bradycardia and AV block)Inhibits the uptake and metabolism of adenosine and increases its plasma levelsReduce the dose of adenosine
Methylxantines:
- Aminophylline
- Caffeine
- Theophylline
Inhibit the hemodynamic effects of adenosine. Aminophylline can terminate persistent adverse effects of adenosine infusionsPatients may require higher doses of adenosine. Xanthines should be withheld 12 to 24 hours prior to the administration of adenosine
Nicotine-containing drugsIt appears to increase the effects of adenosineAvoid smoking

Due to the possibility of transient cardiac arrhythmias arising during conversion of the SVT to normal sinus rhythm, adenosine should only be used in a hospital setting  and cardio-respiratory resuscitation equipment available

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Amiodarone

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Anesthetics, generalAmiodarone may increase the risk of complications (atropine-resistant bradycardia, hypotension, decreased cardiac output) during general anesthesia.Patients on amiodarone who require general anesthesia should be carefully monitored for potential cardiovascular complications
AntihypertensivesThey increase the risk of hypotension, particularly following the IV administration of amiodaroneMonitor BP
Antiviral drugs:
- Daclasvir
- Sofosbuvir
Severe bradycardia with this combination Monitor heart rate during the first 48 hours.
Beta-blockers
- Metoprolol
- Propranolol
- Sotalol
Increase the incidence of hypotension, bradycardia, ventricular fibrillation and asystoleThe combination can be beneficial, but increases the risk of bradycardia or ventricular arrhythmias. Atenolol does not appear to interact with amiodarone. Reduce the dose of these beta-blockers
Bile acid sequestrants:
- Cholestyramine
- Colestipol
Reduces amiodarone efficacyReduce the absorption of amiodarone Patients may require higher doses of amiodarone to control arrhythmias. Take amiodarone 1 hour before or 4 hours after the sequestrant
Calcium channel blockers:
- Diltiazem
- Verapamil
Additive depressant effects on sinoatrial and atrioventricular nodesMonitor the ECG. The combination increases the risk of bradycardia and AV block
CimetidineIncreases the adverse effects of amiodaroneMay inhibit the metabolism of amiodarone and increases its serum levelsDecrease the dose of amiodarone.
Replace cimetidine for another proton pump inhibitor
Class I AADs:
- Disopyramide
- Procainamide
- Quinidine
Additive depressant effects on intracardiac conduction Amiodarone inhibits the metabolism of procainamide and reduces the clearance of quinidine. Increases the plasma levels of class IA AADsMonitor the ECG for excessive QT interval prolongation and proarrhythmic effects. Avoid the combination with class IA AADs
Class IV AADs:
- Diltiazem
- Verapamil
Increase the risk of bradycardia, hypotension and HFAmiodarone inhibits the metabolism of procainamide and reduces the clearance of quinidine. Increases the plasma levels of both drugsMonitor the ECG and blood pressure
ClopidogrelAmiodarone may decrease the antiplatelet activity of clopidrogel.Inhibit CYP activation of clopidogrelPrescribe an alternative platelet P2Y12 receptor inhibitor
CiclosporinrinAmiodarone reduces the clearance and increases the plasma levels of CiclosporinMonitor for possible Ciclosporin toxicity (renal, hypertension)
DextromethorphanAmiodarone inhibits CYP2D6 and increases the plasma levels of dextromethorphanDecrease the dose of dextromethorphan. Monitor for possible dextromethorphan toxicity (nausea, headaches, insomnia, tremors)
DigoxinIncreases the risk of bradycardia, AV block, AV block and digitalis toxicityAmiodarone increases the bioavailability and decreases the clearance of digoxin. Increases digoxin plasma levels.Monitor the digoxin plasma levels. The dose of digoxin needs to be reduced (50%) when amiodarone is added
Disopyramide Additive depressant effects on intracardiac conductionMonitor the ECG for excessive QT/QRS interval prolongation and proarrhythmic effects
FlecainideAdditive cardiodepressant effectsAmiodarone inhibits the clearance increases plasma levels of flecainideReduce (30-50%) the dose of flecainide and monitor the ECG carefully
General anesthesiaIncreased risk of bradycardia, hypotension, disturbances of conduction, decreased cardiac outputMonitor blood pressure and ECG
Grapefruit juiceInhibits the metabolism of amiodarone and increases its exposure (50-80%).Avoid drinking grapefruit
HIV-Protease inhibitors:
- Indinavir
- Nefinavir
- Ritonavir
Increase the risk of adverse effects.Increase amiodarone serum levelsMonitor the patient
LidocaineAdditive effect of the sinoatrial nodeMonitor the ECG to avoid bradycardia
LithiumReported cases of hypothyroidismAmiodaorne and lithium can produce hypothyroidismMonitor thyroid function. Avoid the combination
Macrolides antibiotics:
- Azithromycin
- Erythromycin
Increase the QT intervalMonitor the ECG. QT prolongation occurred when some macrolides were added to established amiodarone therapy.
MethotrexateAmiodarone increases its adverse effects.Amiodarone decreases the metabolism of methotrexateMonitor for the adverse effects of methotrexate
OrlistatReduces the absorption of amiodaroneMonitor the ECG
PhenytoinReduces the antiarrhythmic efficacy of amiodaroneAmiodarone inhibits hepatic metabolism of phenytoin and phenytoin increases the metabolism of amiodaroneThe phenytoin dosage should be reduced (50%). The interaction can take several weeks to become apparent
Positive inotropic drugs:
- Dobutamine
- Dopamine
Amiodarone exhibits β-adrenergic blocking effects Higher IV doses of dopamine and dobutamine are needed in patients receiving amiodarone.
QT-prolonging drugsIncreases the risk of QT prolongation and torsades de pointesThe use of these drugs should be avoided
Quinolones:
- Levofloxacin
- Gatifloxacin
- Moxifloxacin
- Sparfloxacin
QT prolongation and increase the risk of arrhythmiaClose monitoring of the ECG; avoid as possible the combination
RifampicinDecrease the serum levels of amiodarone and its metabolite N-desethylamiodarone
SotalolIncreases the risk of hypotension and bradycardiaMonitor the hemodynamic response; avoid combination
SSRIs:
- Sertraline
Increase the cardiodepressant effects of amiodaroneMay increase the serum levels of amiodaroneIncrease the risk of bradycardia, AV block and ventricular dysfunction.
Statins:
- Atorvastatin
- Rosuvastatin
- Simvastatin
Increased risk of myopathy and rhabdomyolisisDoses of lovastatin and simvastatin should not exceed 40 mg/day and 20 mg/day, respectively
St.John´s wortDecrease the plasma levels of amiodaroneAvoid the combination
TheophyllineIncreases the risk of theophylline toxicityAmiodarone inhibits the metabolism of theophyllineMonitor the development of theophylline toxicity (nausea, tremor, tachycardia, nervousness)
VardenafilIncreases the risk of serious ventricular arrhythmiasAvoid the combination
WarfarinIncreases the prothrombin time and the risk of bleedingAmiodarone reduces the metabolism and displaces warfarin from plasma proteinsThe dose of warfarin should be reduced (30-50%). Monitor the INR

Due to its long t½, the interactions may last several months after drug discontinuation

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Atropine

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Anticholinergic drugs:
- Antispasmodics
- Disopyramide
- Mequitazine
- Phenothiazines
- Quinidine
Increased risk of atropinic adverse effects (urinary retention, constipation, dry mouthMonitor the adverse effects. They can be reversed with pyridostigmine, an acetylcholinesterase inhibitor
Monoamine oxidase inhibitors Potential to precipitate hypertensive crisis.Avoid the combination if possible

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Disopyramide

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Antiacids (aluminium phosphate)Aluminium phosphate may cause a small reduction in the absorption of disopyramideClinical importance is uncertain
Atropine and other anticholinergic drugsPotentiate the anticholinergic effectsAvoid the combination. Pyridostigmine reduces these anticholinergic effects
BarbituratesInduce the metabolism and decrease the serum levels of disopyramide, decrease the antiarrhythmic effects and increase the anticholinergic effect of disopyramideMonitor the ECG. Decrease the dosage of disopyramide
Beta-blockersRisk of bradycardia, hypotension and negative inotropic effects. Some patients given iv sotalol develop asystole Administer disopyramide with caution. Avoid iv co-administration
Calcium channel blockers:
- Diltiazem
- Verapamil
Increases the risk of hypotension, bradycardia, AV block and heart failureAvoid the combination
Class I and III AADsAdditive cardiodepressant effectsRisk of bradycardia, heart failure and QT prolongation. Avoid the combination with other antiarrhythmic drugs
DigoxinDisopyramide reduces the inotropic effect of digoxin. Increases the risk of bradycardia and AV blockMonitor the hemodynamic effect of digoxin and the ECG
Drugs that induce hypokalemiaIncrease the risk of proarrhythmiaMonitor serum potassium levels
Histamine H2-receptor antagonists Cimetidine can slightly increase the serum levels of disopyramideRanitidine does not appear to interact
HIV-protease inhibitorsThey are substrates of CYP3A4 and can compete with disopyramide for metabolism increasing its plasma levelsMonitor the patient for an increase in disopyramide-induced adverse effects
Macrolides:
- Clarythromycin
- Erythomycin
- Josamycin
Prolong the QTc interval and may induce cardiac arrhythmiasIncrease the plasma levels of disopyramideMonitor the ECG. It has been reported QT prolongation, torsades de pointes and ventricular fibrillation. Avoid if possible the combination
PhenytoinLoss of antiarrhythmic activity may occurPhenytoin increases the metabolism of disopyramide and decreases the serum levels of disopyramideMonitor the response to disopyramide. Avoid the combination.
QuinidineAdditive cardiodepressant effectsIncreases the serum levels of disopyramideMonitor the ECG. Both drugs prolong the QT interval and the risk of bradycardia, AV block and arrhythmias. Avoid the combination
RifampicinIncreases the metabolism of disopyramide and decreases the serum levels of disopyramideMonitor the effects of disopyramide
QT prolonging drugsIncrease the QT prolongation and the risk of proarrhythmiaWith caution. Avoid the combination if possible

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Dofetilide

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
CimetidineIncreases the QT prolongationMarkedly increases plasma dofetilide levelsQT prolongation and the risk of torsade de pointes arrhythmias. Dofetilide appears not to interact with ranitidine
Diuretics:
- Hydrochlorothiazide
- Hydrochlorothiazide/triamterene
A slight increase in the QT intervalSlightly increase dofetilide plasma levelsRisk of QT prolongation. Monitor the ECG
HIV-protease inhibitorsRitonavir markedly increases plasma dofetilide levelsQT prolongation and the risk of torsade de pointes arrhythmias. Dofetilide appears not to interact with ranitidine
KetoconazoleIncreases the QT prolongationMarkedly increases dofetilide plasma levelsQT prolongation and the risk of torsade de pointes arrhythmias. This combination is contraindicated
Macrolide antibioticsMarkedly increases dofetilide plasma levelsQT prolongation and the risk of torsade de pointes arrhythmias. This combination is contraindicated
QT-prolonging drugsIncreases the risk of QT prolongation and torsades de pointesThe use of these drugs should be avoided
TrimethoprimIncreases the risk of QT prolongation and torsade de pointesMarkedly increases dofetilide plasma levelsThis combination is contraindicated
VerapamilIncreases QT prolongationIncreases dofetilide plasma levelsThis combination increases the risk of torsades and is contraindicated

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Dronedarone

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
β-blockersIncreases the depressant effects on SA and AV nodesMonitor the ECG
Class I and III AADsIncrease the risk of proarrhythmiaAvoid the combination
Class IV AADs:
- Diltiazem
- Verapamil
Increases the depressant effects on SA and AV nodesReduce the starting dose. Monitor the ECG
CYP2D6 substrates:
- Metoprololol
- Propranolol
- Selective serotonin reuptake inhibitors
- Tricyclic antidepressants
Dronedarone inhibits CYP2D6 and slightly increases the exposure of CYP2D6 substrates Dronedarone increases the exposure to propranolol, metoprolol, selective serotonin reuptake inhibitors and tricyclic antidepressants
DabigatranDronedarone inhibits P-gp and increases the maximum plasma concentrations of dabigatran (70%)Avoid the combination
DigoxinThe combination increases the risk of bradycardia, AV block, arrhythmic or sudden death. In patients with permanent AF this combination increased the risk of arrhythmic or sudden deathDronedarone inhibits P-gp and increases the maximum digoxin plasma levelsConsider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin and monitor serum levels closely
Immunosuppressant drugs:
- Ciclosporinrin
- Everolimus
- Sirolimus
- Tacrolimus
Dronedarone increases the plasma levels of these drugsMonitor their plasma concentrations and adjust doses of the immunosuppressant as appropriate
MAO inhibitors Decrease the clearance of the active metabolite of dronedaroneUse with caution
Moderate CYP3A4 inhibitors:
- Diltiazem
- Sirolimus
- Tacrolimus
- Verapamil
- Grapefruit juice
Additive bradycardia and cardiac depression when combined with diltiazem or verapamilIncrease the plasma levels of dronedaroneLower doses of concomitant drugs should be used. Clinical and ECG (bradycardia, AVB) monitoring is recommended
Potent CYP3A4 inhibitors:
- Azole antifungals: Itraconazole, Ketoconazole, Voriconazole
- Ciclosporinrin
- Macrolides: Clarithromycin, Telithromycin
- Nefazodone
- HIV-protease inhibitors: Ritonavir
Dronedarone is primarily metabolised by CYP3A4. They increase the plasma levels of dronedaroneAvoid the combination
Potent CYP3A4 inducers:
- Carbamazepine
- Phenytoin
- Rifampin
- St John's wort
Potent CYP3A inducers markedly decrease dronedarone exposurePotent CYP3A4 inhibitors should be avoided. When co-administered with moderate CYP3A4 inhibitors, lower doses of concomitant drugs should be used. CYP3A inducers are not recommended
QT-prolonging drugsIncreases the risk of QT prolongation and torsades de pointesThe combination should be avoided
StatinsIncreases the risk of the risk of myopathyDronedarone increases lovastatin and simvastatin plasma levelsThe dose of lovastatin and simvastatin should be limited to 20 mg/day and 10 mg/day, respectively
Vitamin K antagonistsIncreases the exposure to S-warfarinINR should be monitored
  • Dronedarone is a moderate inhibitor of CYP 3A4, a mild inhibitor of CYP 2D6 and a potent inhibitor of P-gp. It can interact with substrates of P-gp, CYP 3A4 or CYP 2D6 substrates, inhibitors and inducers
  • There are no interactions between dronedarone and theophylline, metformin, omeprazole, pantoprazole, clopidogrel

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Flecainide

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AmiodaroneAdditive cardiodepressant effectsAmiodarone inhibits the clearance of flecainideReduce (30-50%) the dose of flecainide.
Antiepileptics:
- Carbamazepine
- Phenobarbital
- Phenytoinn
They are enzymatic inducers and decrease flecainide plasma levels Monitor the response to flecainide
Beta-blockers:
- Propanolol
Possible additive cardiac depressant effectsEach agent inhibits the metabolism of the otherMonitor the effects of both drugs
BupropionDecreases the metabolism of flecainideMonitor the effects of flecainide
CimetidineMay increase the risk of arrhythmiaInhibits the hepatic metabolism of flecainide and increases flecainide plasma levelsMonitor the effects of flecainide. Decrease the dosage of flecainide
Class I AADsIncrease the risk of bradycardia, intracardiac blockades and decreased cardiac contractilityMonitor carefully the ECG. Avoid the combination
Class IV AADs:
- Diltiazem
- Verapamil
The cardiac depressant effects of these drugs can be additive (negative inotropic and AV nodal depressant effects)Monitor the blood pressure and the ECG
ClozapineIncreases the risk of proarrhythmiaMonitor the ECG
DigoxinFlecainide increases digoxin plasma levelsMonitor digoxin serum levels and the ECG
Drugs that inihibit CYP2D6:
- Antivirals:
- Indinavir, Lopinavar,
- Ritonavir
- Clozapine
- Fluoxetine
- Paroxetine
- Tricyclic antidepresssants
Increase the risk of proarrhythmiaIncrease the plasma levels of flecainideMonitor the effects of flecainide (ECG)
FoodThe absorption of flecainide is decreased by milk in infantsDose adjustment is needed in milk-fed infants
HIV-protease inhibitorsRitonavir inhibits CYP2D6 and increases flecainide plasma concentrationsRitonavir and tipranavir should not be coadministered with flecainide
ParoxetineParoxetine inhibits CYP2D6 and increases flecainide plasma levelsReduce the dose of flecainide
QT-prolonging drugsIncreased risk of torsades de pointesAvoid the combination
QuinidineQuinidine decreases the metabolism of flecainideMonitor the effects of flecainide (ECG). Avoid the combination
TobaccoTobacco smoke inhibits CYP1A2 and increases the metabolism of flecainide Tobacco smokers need higher doses of flecainide
Tricyclic antidepressantsPotentiate the cardiodepressant effects of flecainideMonitor the blood pressure and the ECG
Urinary pHThe urinary clearance of flecainide increases if the urine is made acidic (ammonium chroride) and decreases if the urine is made alkaline (sodium bicarbonate)The clinical relevance of this interaction is unknown, but the response to flecainide should be monitored in patients treated with ammonium chloride, acetazolamide or sodium bicarbonate.

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Ibutilide

DrugPharmacodynamic interactionsPharmacokinetic interactionCautions
AmiodaroneA further QT prolongation is expectedIncreases serum flecainide levels Monitor the ECG
Class I and III antiarrhythmics Increased risk of proarrhythmiaAvoid the combination
QT-prolonging drugsIncreases the risk of QT prolongation and torsades de pointesThe use of these drugs should be avoided

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Lidocaine

DrugPharmacodynamic interactionsPharmacokinetic interactions Cautions
AmiodaroneAdditive effect of the sinoatrial nodeReduces the hepatic clearance of lidocaineMonitor the ECG and reduce the dose of lidocaine
AminoglycosidesEnhances neuromuscular blockadeMonitor respiration in patients receiving lidocaine and aminoglycosides
BarbituratesBarbiturates induce the metabolism of lidocaine The dose of lidocaine must be increased
Beta-blockers:
- Metoprolol
- Nadolol
- Propranolol
Additive cardiodepressant effectsReduce the hepatic blood flow and the metabolism of lidocaine increasing its plasma levelsDecrease the loading dose of lidocaine. Atenolol does not appear to interact
CimetidineReduces the metabolism of lidocaine and increases its plasma levelsLidocaine toxicity may occur if the dosage is not reduced. Ranitidine appears to interact minimally
Class I and III AADsAdditive depressant effects on intracardiac conductionMonitor de ECG for excessive QRS/QT interval prolongation and proarrhythmic effects. Reduce the dosage of lidocaine
DisopyramideIncreases the risk of bradycardiaIt can increase the plasma levels of unbound lidocaineRisk of bradycardia, heart failure and QT prolongation
HalothaneReduce the hepatic clearance of lidocaineReduce the dose of lidocaine (50%)
HIV protease inhibitorsRitonavir inhibits CYP3A4 and increases the plasma levels of lidocaineReduce the lidocaine dose as necessary
MacrolidesErythromycin inhibits CYP3A4 and increases the plasma levels of lidocaineReduce the lidocaine dose as necessary
MexiletineIncreases the toxicity of lidocaineAvoid the combination
Neuromuscular blocking drugsLidocaine may prolong neuromuscular blockade of alcuronium and suxamethoniumCaution should be observed
PhenytoinThe incidence of central toxic side-effects may be increased. Increases serum lidocaine levelsReduce the dosage of lidocaine
PropafenoneIncrease the severity and duration of the CNS adverse effectsMonitor the patients for side effects and efficacy
RifampicinSerum lidocaine levels may be slightly reducedIncrease the dose of lidocaine
ZiprasidoneA further QT prolongation is expectedMonitor the ECG

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Mexiletine

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AmiodaroneAdditive depressant effects on intracardiac conductionIncreases the plasma levels of mexiletineMonitor the ECG for excessive QT interval prolongation and proarrhythmic effects. Reduce the dosage of mexiletine
Beta-blockersMexiletine may reduce the QT prolonging effects of sotalolThe use of mexiletine and beta-blockers can be clinically useful
CimetidineIt can reduce the gastric side-effects of mexiletineDecreases the metabolism and increases the plasma concentrations of mexiletineReduce the dosage of mexiletine
CiprofloxacinIt slightly reduces the clearance of mexiletine
HIV protease inhibitorsRitonavir inhibits CYP3A4 and increases the plasma levels of mexiletineReduce the lidocaine dose as necessary
MorphineThe oral absortion of mexiletine is reduces after myocardial infarction and morphine also reduces the absorption of mexiletineIncrease the oral dose of mexiletine during the first few hours following a myocardial infarction
PhenytoinEnhances the metabolism and reduces the plasma levels of mexiletineAn increase in the dosage of mexiletine may be necessary. Monitor the response of mexiletine.
PropafenoneIncreases mexiletine serum levels in extensive metabolisers of CYP2D6Avoid the combination
QuinidineAdditive antiarrhythmic activity. Mexiletine limits quinidine-induced QT prolongationQuinidine inhibits the metabolism of mexiletine and increases mexiletine plasma levels in extensive metabolisers of CYP2D6Monitor the effects of mexiletine when quinidine is added. Avoid the combination if possible
RifampicinIncreases the metabolism of mexiletineThe dosage of mexiletine may need to be increased when rifampicin is added
SSRIs:
- Fluoxetine
- Fluvoxamine
- Paroxetin
Inhibit CYP2D6 and markedly increases the AUC of mexiletineMonitor the effects of mexiletine (ECG). Sertraline does not seem to interact
TheophyllineIncreases the risk of GI upset and the cardiodepressant effectsMexiletine inhibits CYP1A2 and increases the plasma levels of theophyllineMonitor for theophylline toxicity (tachycardia, GI upset, seizures) and reduce the dose (50%) of theophylline
Urinary pHAcidification of the urinary increases its excretion, while alkalinization slows its eliminationThe clinical relevance of this interaction is unknown

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Procainamide

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Amiodarone The QT interval prolonging effects are increasedSerum levels of procainamide and N-acetylprocainamide (NAPA) are increased (60% and 30%, respectively)Avoid this combination. If the combination is used, the dosage of procainamide should be reduced
Antacids and AntidiarrhealsMay reduce the effects of procainamideAluminium phosphate and kaolin-pectin appears to reduce bioavailability of procainamideIt can be necessary to increase the dosage of procainamide
Antiarrhythmic drugs:
- Class I
- Class III
Increased risk of bradycardia, intracardiac blockade, and proarrhythmiaAvoid the combination
Anticholinergic drugsAdditive effects on heart rate and AV conductionMonitor the ECG
Anticholinesterase drugsProcainamide has anticholinergic properties and may antagonize the effects of anticholinesterase agents in patients with myasthenia gravisProcainamide should be used with caution, if at all, in patients with myasthenia gravis. Avoid the combination.
Beta-blockers:
- Metoprolol
- Propranolol
They reduce the hepatic blood flow and can increase the plasma levels of procainamideMonitor the ECG
CaptoprilRare cases of neutropenia and/or Stevens–Johnson syndromeReplace by another ACEI
Histamine H2-receptor antagonists May increase procainamide side effectsCimetidine and ranitidine reduce renal tubular secretion of procainamide and increase its plasma levelsThis interaction is more frequent in the elderly. Reduce the dose of procainamide.
QT prolonging drugsIncreased risk of torsades de pointesAvoid the combination
QuinidineAdditive cardiodepressant effects. The combination prolongs the QT intervalIt may increase the plasma levels of procainamideMonitor the ECG. The combination should be avoided because of the increased risk of torsade de pointes
Quinolones:
- Gatifloxacin
- Moxifloxacin
- Ofloxacin
- Sparfloxacin
- Levofloxacin
An increased risk of torsade de pointes would be expected if procainamide is combined with some quinolonesOfloxacin and levofloxacin slightly increase the serum levels of procainamideMonitor the ECG. Quinolones should be generally avoided in patients taking procainamide
SotalolSotalol and procainamide prolong the QT intervalMonitor the ECG. Avoid the combination
Suxamethonium Patients treated with procainamide require lower doses of suxamethonium
TrimethoprimCompetes with the renal excretion of procainamide and NAPA. Markedly increases the plasma levels of procainamide and N-acetylprocainamideMonitor the patients for an increased risk of procainamide toxicity. Avoid the combination

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Propafenone

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AmiodaroneIncreased risk of conduction abnormalities and potential arrhythmiasMonitor the ECG. Avoid the combination
AnticholinesterasesIncrease muscular weakness in patients with myasthenia gravisAvoid the combination in patients with myasthenia gravis
BarbituratesIncrease the metabolism and reduce propafenone plasma levelsMonitor the antiarrhythmic response of proprafenone
Beta-blockersPropafenone exhibits beta-adrenergic blocking propertiesInhibit the metabolic clearance and the plasma levels of metoprolol and propranolol Monitor for an increased effect beta blockade. The dosage of beta-blockers should be reduced
CimetidineIncreases the response to propafenoneDecreases the metabolism of propafenone and increases its plasma levels Monitor the response to propafenone
Class I AADsAdditive depressant effects on intracardiac conductionMonitor de ECG for excessive QT interval prolongation and proarrhythmic effects. Avoid the combination
Class IV AADs:
- Diltiazem
- Verapamil
Increase the risk SA and AV node depression Monitor the ECG
CiclosporinProprafenone increases its bioavailability and inhibits its metabolismMonitor Ciclosporinrin plasma levels. Reduce the dose of Ciclosporin
CimetidineIncreases (20%) the plasma levels of propafenone
CYP2D6 inhibitors:
- Desipramine
- Paroxetine
- Ritonavir
- Sertraline
Increase the risk of proarrhythmiaIncrease the plasma levels of propafenoneAvoid the combination
CYP3A4 Inhibitors:
- Rrythromycin
- Ketoconazole
- Ritonavir
- Saquinavir
Increase the risk of proarrhythmiaIncrease the plasma levels of propafenoneAvoid the combination
DesipramineProprafenone increases the plasma levels of desipramineMonitor the ECG and reduce the dose of desipramine
DigoxinReduces the metabolic and renal clearance of digoxin and increases digoxin plasma levels (30-50%)Monitor digoxin plasma concentrations and response
ErythromycinIt may inhibit the metabolism of propafenoneMonitor the ECG
Grapefruit juiceIt may inhibit the metabolism of propafenone
HIV-protease inhibitors:
- Atazanavir
- Cobicistat
- Elvitegravir
- Lopinavir
- Ritonavir
- Tipranavir
Increased risk of proarrhythmiaAvoid the combination
KetoconazoleKetoconazol inhibits CYP2D6 and incresaes the plasma levels of propafenoneReplace ketoconazole for another azole antifungal
LidocainePropafenone increases risk of lidocaine-related CNS side-effects. Avoid the combination if possible
OrlistatAbrupt cessation of orlistat in patients stabilized on propafenone has resulted in severe adverse events Orlistat decreases the absorption of propafenone
QT prolonging drugsIncreased risk of torsades de pointesAvoid the combination
QuinidineIncreases the side effects of propafenoneQuinidine inhibits CYP2D6 and incresaes the plasma levels of propafenone and decreases the levels of its active metaboliteThe dose of propafenone should be reduced. Monitor the toxicity of propafenone when quinidine is added
RifampicinMay cause a loss of antiarrhythmic efficacyReduces propafenone serum levelsMonitor the antiarrhythmic response of propafenone.
SSRIs:
- Citalopram
- Fluoxetine
- Fluvoxamine
- Paroxetine
- Sertraline
Increase the cardiodepressant effects of propafenoneThey inhibit CYP2D6 and the 5-hydroxylation of propafenoneDecrease the dosage of propefenone. Monitor the ECG
TheophyllineMay produce sign of theophylline toxicityPropafenone decreases the clearance of theophylline and increases its plasma levelsMonitor for theophylline toxicity (tachycardia, GI upset, tremor). Reduce the dose of theophylline
Urinary pHAcidification of the urinary increases, while alkalinization slow the excretion of propafenoneThe clinical relevance of this interaction is unknown
WarfarinPropafenone enhances the effects of oral anticoagulantsPropafenone inhibits the metabolism of warfarinMonitor the INR and decrease the dosage of warfarin

Drugs that inhibit CYP2D6, CYP1A2, and CYP3A4, (tropisetron, dolasetron, mizolastine, venlafaxine) may increase the plasma levels of propafenone

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Quinidine

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AmiodaroneBoth drugs increase the QT intervalAmiodarone reduces quinidine clearance and increases its plasma levelsMonitor the ECG. Increased risk of torsade de pointes. If the combination (exceptionally) is used, reduce the quinidine dosage appropriately to avoid quinidine toxicity.
Antiacids/urinary alkalinizers:
- Carbonic-anhydrase inhibitors
- Sodium bicarbonate
They may increase quinidine toxicityReduce the renal elimination of quinidineChange the dose of quinidine as appropriate
Anticholinesterase drugsQuinidine has anticholinergic properties and may antagonize the effects of anticholinesterase agents in patients with myasthenia gravisQuinidine should be used with caution, if at all, in patients with myasthenia gravis. The dose of pyridostigmine may have to be increased
Azole antifungals:
- Itraconazole
- Ketoconazole
Increase the plasma levels of quinidineMonitor the ECG and reduce the dosage of quinidine as appropriate
Beta-blockersIncreased risk of bradycardia, AV block, hypotension and decreases cardiac contractilityReduces the metabolism of metoprolol, propranolol and timolol and increases their plasma levels. Propranolol increases peak serum levels and decreases the total clearance of quinidineMonitor the patients for the cardiodepressant effects (bradycardia, AV block, arrhythmias, heart failure)
Anticonvulsants:
- Phenytoin
- Phenobarbital
- Primidone
Reduce serum quinidine levels The dose of quinidine should be increased to avoid the loss of arrhythmia control (under close ECG monitoring)
Calcium channel blockers:
- Diltiazem
- Verapamil
Increased risk of bradycardia, AV block, hypotension and decreases cardiac contractilityNifedipine reduces the plasma levels of quinidine and quinidine inhibits the metabolism of CYP3A4 and increases the plasma levels of nifedipine.
Diltiazem and verapamil reduce the clearance of quinidine and increases its plasma levels
Careful monitoring of the response. Adjustment of quinidine dose is needed when given in combination of nifedipine or verapamil. The levels of quinidine increase when stopping nifedipine. Diltiazem, felodipine and nisoldipine appear not to interact
Class I and III AADs:Additive depressant effects on intracardiac conductionMonitor de ECG for excessive QT interval prolongation, bradicardia, intracardiac blockade, heart failure and proarrhythmic effects. Avoid the combination
CodeineQuinidine inhibits the analgesic effect of codeineQuinidine inhibits the metabolism of codeine in morphineAlternative drugs should be considered for pain control
DextromorphanQuinidine inhibits CYP2D6 and the metabolism of of dextromorphanClinical relevance uncertain
DigoxinIncreases the risk of digitalis toxicityQuinidine inhibits P-gp and increases serum digoxin levelsAvoid the combination. The dose of digoxin should be reduced (50%) and monitor its plasma levels. Use an alternative antiarrhythmic drug
FluvoxamineInhibits the metabolism and clearance of quinidine The clinical relevance is uncertain
Grapefruit juiceDelays the absorption and reduces its metabolism of quinidineUncertain clinical relevance
CimetidineIn some patients may increase quinidine toxicityInhibits the hepatic metabolism and renal clearance of quinidine increasing its plasma levelsAvoid the combination. Famotidine, nizatidine andd ranitidine do not present this interaction.
HaloperidolPotential additive effects on the QTc intervalQuinidine is a potent inhibitor of CYP2D6 and increases the plasma levels of haloperidolAvoid the combination
Kaolin-pectinReduces the absorption of quinidine and lowers its serum levelsMonitor the efficacy of quinidine. Administer kaolin-peptic sevral hours apart from quinidien.
MacrolidesErythromycin increases quinidine plasma levelsMonitor for quinidine adverse effects
Neuromuscular blocking agentsQuinidine inhibits the activity of plasma cholinesterase and potentiates the actions of depolarizing (suxamethonium ) and nondepolarizing (pancuronium) neuromuscular blocking agents.Avoid quinidine administration in the immediate postoperative period.
NifedipineDecreases quinidine plasma levelsAvoid the combination
PhenytoinInduces the metabolism of quinidine and reduces its plasma levelsAdjustments of the quinidine dose may be necessary
QT prolonging drugsIncreased risk of torsades de pointesAvoid the combination
Quinolones:
- Gatifloxacin
- Moxifloxacin
- Sparfloxacin
- Levofloxacin
Increase the risk of torsade de pointesQuinolones may inhibit the metabolism of quinidineMonitor the ECG
RifampicinReduces the therapeutic effects of quinidineInduces the metabolism of quinidine and reduces its plasma levels The dose of quinidine should be increased
Tricyclic antidepressantsAdditive cardiodepressant effectsQuinidine inhibits the metabolism of quinidine and desipraminePatients should be monitored for increased side effects
WarfarinQuinidine has a direct hypoprothrombinemic effect and increases the risk of bleedingDecreases the synthesis of vitamin K dependent clotting factorsReduce the dose of warfarin and monitor the INR
  • Inhibits CYP2D6 and increases the plasma concentrations of tricylic antidepressants, metoprolol, antipsychotics; decreases the efficacy of codeine.
  • Amiodarone, diltiazem, verapamil or cimetidine increase quinidine plasma levels.
  • Quinidine increases the plasma levels of procainamide and haloperidol.
  • Quinidine’s anticholinergic, vasodilating, and negative inotropic actions may be additive to those of other drugs with these effects.

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Sotalol (see β-blockers)

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Antiacids containing aluminum oxide and magnesium hydroxideReduces sotalol exposureAvoid the combination
β2-receptor agonistsThey should be administered at increased dosages in patients treated with sotalol
β-blockersAdditive effects are expectedAvoid the combination
DigoxinIncreases the risk of bradycardia and AV blockWith caution. Monitor the ECG
QT prolonging drugsMarked prolongation of the Qt interval and risk of torsades de pointesAvoid the combination

Interactions. See under β-blockers

Administration of sotalol within 2 h of antacids containing aluminum oxide and magnesium hydroxide reduces sotalol exposure. This interaction can be avoided.

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Vernakalant

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Class I and III AADsAvoid vernakalant in patients who received intravenous AADs (class I and III) in the previous 4 hours
Oral maintenance antiarrhythmic therapy was halted for a minimum of 2 hours after vernakalant administration

No interactions with amiodarone, digoxin, diltiazem, furosemide, propranolol, verapamil, warfarin

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Abbreviations

AADs: antiarrhythmic drugs
ACEI: angiotensin converting enzyme inhibitors
AF: atrial fibrillation
AV: atrio-ventricular
BP: blood pressure
CNS: central nervous system
CYP: cytochrome P450 superfamily
ECG: electrocardiogram
GI: gastrointestinal
HIV: human immunodeficiency virus
HF: heart failure
INR: international normalized ratio
iv: intravenously
MAO: monoamino oxidase
P-gp: P-glycoprotein
SA: sinoatrial
SSRIs: selective serotonin reuptake inhibitors
SVT: supraventricular tachycardia.

Disclaimer: The information contained in these tables is intended for use by medical professionals and is for informational purposes only. The tables do not cover all possible drug interactions. As a medical professional you retain full responsibility and should use your own clinical judgement and expertise. Although we attempt to provide accurate and up-to-date information, no guarantee is made to that effect.

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