ABSTRACT
Avoid co-administration of phenothiazines, amisulpride, pimozide or sertindole with adenosine. Monitor the ECG closely when adenosine is co-administered with atypical antipsychotics
ADENOSINE BRONCHODILATORS – THEOPHYLLINE
↓ efficacy of adenosine Theophylline and other xanthines are adenosine receptor antagonists
Watch for poor response to adenosine; higher doses may be required
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CARDIOVASCULAR DRUGS ANTIARRHYTHMICS Amiodarone
AMIODARONE DRUGS THAT PROLONG THE Q-T INTERVAL
AMIODARONE 1. ANTIARRHYTHMICS – disopyramide, procainamide, propafenone 2. ANTIBIOTICS – macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinolones (especially moxifloxacin), quinupristin-dalfopristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS – arsenic trioxide 4. ANTIDEPRESSANTS – TCAs, venlafaxine 5. ANTIEMETICS – dolasetron 6. ANTIFUNGALS – fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES – terfenadine, hydroxyzine, mizolastine 8. ANTIMALARIALS – artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine, quinine 9. ANTIPROTOZOALS – pentamidine isetionate 10. ANTIPSYCHOTICS – atypical agents, phenothiazines, pimozide 11. BETA-BLOCKERS – sotalol 12. BRONCHODILATORS – parenteral bronchodilators 13. CNS STIMULANTS – atomoxetine
Risk of ventricular arrhythmias, particularly torsades de pointes
Additive effect; these drugs cause prolongation of the Q-T interval. In addition, procainamide levels may be ≠ by amiodarone (uncertain mechanism). Also, amiodarone inhibits CYP2C9 and CYP2D6, which have a role in metabolizing TCAs
Avoid co-administration
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Mechanism Precautions Uncertain Avoid co-administration
depressant effects of inhalational anaesthetics
Additive effect Monitor PR, BP and ECG closely
AMIODARONE ANAESTHETICS – LOCAL Risk of ↓ BP Additive myocardial depression Particular care should be taken to avoid inadvertent intravenous administration during bupivacaine infiltration; monitor PR, BP and ECG during epidural administration of bupivacaine
AMIODARONE ANTIARRHYTHMICS
AMIODARONE ANTIARRHYTHMICS Risk of bradycardia and ↓ BP Additive myocardial depression Monitor PR and BP closely AMIODARONE FLECAINIDE ≠ plasma levels of flecainide Amiodarone is a potent inhibitor
of the CYP2D6-mediated metabolism of flecainide
↓ the dose of flecainide (by up to 50%)
AMIODARONE ANTIBIOTICS
AMIODARONE CO-TRIMOXAZOLE Risk of ventricular arrhythmias Uncertain Avoid co-administration
AMIODARONE RIFAMPICIN ↓ levels of amiodarone Uncertain, but rifampicin is a known enzyme inducer and therefore may ≠ metabolism of amiodarone
Watch for a poor response to amiodarone
AMIODARONE ANTICANCER AND IMMUNOMODULATING DRUGS
AMIODARONE CICLOSPORIN Ciclosporin levels may be ≠ by amiodarone; risk of nephrotoxicity
Uncertain; ciclosporin is metabolized by CYP3A4, which is markedly inhibited by amiodarone. Amiodarone also interferes with renal elimination of ciclosporin and inhibits intestinal P-gp, which may ≠ the bioavailability of ciclosporin
Monitor renal function closely; consider reducing the dose of ciclosporin when co-administering amiodarone
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CARDIOVASCULAR DRUGS ANTIARRHYTHMICS Amiodarone
Attributed to additive effects Avoid exposure of skin and eyes to direct sunlight for 30 days after porfimer therapy
AMIODARONE ANTICOAGULANTS – ORAL Cases of bleeding within 4 weeks of starting amiodarone in patients previously stabilized on warfarin. The effect was seen to last up to 16 weeks after stopping amiodarone
Amiodarone inhibits CYP2C9-and CYP3A4-mediated metabolism of warfarin
↓ the dose of anticoagulant by 30-50% and monitor INR closely for at least the first month of starting amiodarone and for 4 months after stopping amiodarone. If the INR suddenly ≠ after being initially stabilized, check TSH level
AMIODARONE ANTIDEPRESSANTS
AMIODARONE LITHIUM 1. Rare risk of ventricular arrythmias, particularly torsades de pointes 2. Risk of hypothyroidism
1. Additive effect; lithium rarely causes Q-T prolongation 2. Additive effect; both drugs can cause hypothyroidism
1. Manufacturer of amiodarone recommends avoiding co-administration 2. If co-administration is thought to be necessary, watch for symptoms/ signs of hypothyroidism; check TFTs every 3-6 months
AMIODARONE SSRIs – SERTRALINE Sertraline may ≠ amiodarone levels Sertraline may inhibit CYP3A4mediated metabolism of amiodarone
Watch for amiodarone toxicity; for those taking high doses of amiodarone, consider using an alternative SSRI with a lower affinity for CYP3A4
AMIODARONE ANTIEPILEPTICS – PHENYTOIN
Phenytoin levels may be ≠ by amiodarone; conversely, amiodarone levels may be ↓ by phenytoin
Uncertain; amiodarone inhibits CYP2C9, which plays a role in phenytoin metabolism while phenytoin is a known hepatic enzyme inducer. Also, amiodarone inhibits intestinal P-gp, which may ≠ the bioavailability of phenytoin
↓ phenytoin dose by 25-30% and monitor levels; watch for amiodarone toxicity. Note that phenytoin and amiodarone share similar features of toxicity, such as arrhythmias and ataxia
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Mechanism Precautions
↓ ↓ absorption of amiodarone Watch for poor response to amiodarone
AMIODARONE ANTIVIRALS Amiodarone levels may be ≠ by protease inhibitors
Uncertain, but postulated to be due to ↓ metabolism of amiodarone
Watch closely for amiodarone toxicity; for those taking high doses of amiodarone, consider reducing the dose when starting protease inhibitor anti-HIV therapy
AMIODARONE BETA-BLOCKERS Risk of bradycardia (occasionally severe), ↓ BP and heart failure. Also, ≠ plasma levels of metoprolol
Additive negative inotropic and chronotropic effects. In addition, high-dose amiodarone is associated with ≠ plasma levels of metoprolol due to inhibition of CYP2D6
For patients on beta-blockers, monitor BP closely when loading with amiodarone
AMIODARONE BRONCHODILATORS – THEOPHYLLINE
Theophylline levels may be ≠ by amiodarone (single case report of theophylline levels doubling)
Uncertain; amiodarone probably inhibits the metabolism of theophylline
Watch for theophylline toxicity; monitor levels regularly until stable
AMIODARONE CALCIUM CHANNEL BLOCKERS
Risk of bradycardia, AV block and ↓ BP when amiodarone coadministered with diltiazem or verapamil
Additive negative inotropic and chronotropic effect. Also, amiodarone inhibits intestinal P-gp, which ≠ the bioavailability of diltiazem and verapamil
Monitor PR, BP and ECG closely; watch for heart failure
AMIODARONE CARDIAC GLYCOSIDES
AMIODARONE DIGOXIN Amiodarone may ≠ plasma levels of digoxin (in some cases up to fourfold)
Uncertain; thought to be due to inhibition of P-gp-mediated renal clearance of digoxin. Amiodarone is also known to inhibit intestinal P-gp, which may ≠ the bioavailability of digoxin
↓ digoxin dose by one-third to one-half when starting amiodarone. Monitor digoxin levels; watch for digoxin toxicity, especially for 4 weeks after initiating or adjusting amiodarone therapy
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CARDIOVASCULAR DRUGS ANTIARRHYTHMICS Amiodarone
Uncertain; thought to be due to inhibition of P-gp-mediated renal clearance of digoxin
Watch for digitoxin toxicity
AMIODARONE DIURETICS
AMIODARONE CARBONIC ANHYDRASE ANTAGONISTS, LOOP DIURETICS, THIAZIDES
Risk of arrhythmias Cardiac toxicity directly related to hypokalaemia
Monitor potassium levels every 4-6 weeks until stable, then at least annually
AMIODARONE POTASSIUM-SPARING DIURETICS
Risk of ≠ levels of eplerenone with amiodarone; risk of hyperkalaemia directly related to serum levels
Calcium channel blockers inhibit CYP3A4-mediated metabolism of eplerenone
Restrict dose of eplerenone to 25mg/day. Monitor serum potassium concentrations closely; watch for hyperkalaemia
AMIODARONE DRUG DEPENDENCE THERAPIES – BUPROPION
≠ plasma concentrations of amiodarone, with risk of toxic effects
Bupropion and its metabolite hydroxybupropion inhibit CYP2D6
Initiate therapy of these drugs at the lowest effective dose
AMIODARONE GRAPEFRUIT JUICE Possibly ↓ effect of amiodarone Inhibition of CYP3A4-mediated metabolism of amiodarone to its active metabolite
Warn patients to avoid grapefruit juice; if amiodarone becomes less effective, ask the patient about grapefruit juice ingestion
AMIODARONE H2 RECEPTOR BLOCKERS Cimetidine may ≠ amiodarone levels
Uncertain Monitor PR and BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.). Consider alternative acid suppression therapy
AMIODARONE IVABRADINE Risk of arrhythmias Additive effect Monitor ECG closely
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Effect Mechanism Precautions
Colestyramine binds amiodarone, reducing its absorption and interrupting its enterohepatic circulation
Avoid co-administration
AMIODARONE SIMVASTATIN ≠ risk of myopathy with high doses (40 mg daily) of simvastatin
Uncertain; amiodarone inhibits intestinal P-gp, which may ≠ the bioavailability of statins
Avoid20 mg daily doses of simvastatin in patients taking amiodarone; if higher doses are required, switch to an alternative statin
AMIODARONE OXYGEN Risk of pulmonary toxicity (adult respiratory distress syndrome) in patients on amiodarone who were ventilated with 100% oxygen during surgery
Uncertain Manufacturers recommend that, for patients on amiodarone undergoing surgery, the lowest possible oxygen concentrations to achieve adequate oxygenation should be given
AMIODARONE THYROID HORMONES Risk of either under-or overtreatment of thyroid function
Amiodarone contains iodine and has been reported to cause both hyper-and hypothyroidism
Monitor triiodothyronine, thyroxine and TSH levels at least 6 monthly
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CARDIOVASCULAR DRUGS ANTIARRHYTHMICS Disopyramide
DISOPYRAMIDE 1. ANTIARRHYTHMICS – amio-
darone, procainamide, propafenone 2. ANTIBIOTICS – macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinolones (especially moxifloxacin), quinupristin/dalfopristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS – arsenic trioxide 4. ANTIDEPRESSANTS – TCAs, venlafaxine 5. ANTIEMETICS – dolasetron 6. ANTIFUNGALS – fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES – terfenadine, hydroxyzine, mizolastine 8. ANTIMALARIALS – artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine, quinine 9. ANTIPROTOZOALS – pentamidine isetionate 10. ANTIPSYCHOTICS – atypicals, phenothiazines, pimozide 11. BETA-BLOCKERS – sotalol 12. BRONCHODILATORS – parenteral bronchodilators 13. CNS STIMULANTS – atomoxetine
Risk of ventricular arrhythmias, particularly torsades de pointes
Additive effect; these drugs prolong the Q-T interval. Also, macrolides ≠ the levels of disopyramide by inhibiting its metabolism (probably CYP3A mediated)
Avoid co-administration
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Mechanism Precautions
2. ANTIARRHYTHMICS – propafenone 3. ANTIDEPRESSANTS – TCAs 4. ANTIEMETICS – cyclizine 5. ANTIHISTAMINES – chlorphenamine, cyproheptadine, hydroxyzine 6. ANTIMUSCARINICS – atropine, benzatropine, cyclopentolate, dicycloverine, flavoxate, homatropine, hyoscine, orphenadrine, oxybutynin, procyclidine, propantheline, tolterodine, trihexyphenidyl, tropicamide 7. ANTIPARKINSON’S DRUGS – dopaminergics 8. ANTIPSYCHOTICS – phenothiazines, clozapine, pimozide 9. MUSCLE RELAXANTS – baclofen 10. NITRATES – isosorbide dinitrate
effects. NB å efficacy of sublingual nitrate tablets
Additive effect; both drugs cause antimuscarinic side-effects. Antimuscarinic effects å salivary production, which å dissolution of the tablet
Warn patient of this additive effect. Consider changing the formulation to a sublingual nitrate spray
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CARDIOVASCULAR DRUGS ANTIARRHYTHMICS Disopyramide
BP Additive myocardial depression Particular care should be taken to avoid inadvertent intravenous administration during bupivacaine infiltration; monitor PR, BP and ECG during epidural administration of bupivacaine
DISOPYRAMIDE ANALGESICS Disopyramide may slow the onset of action of intermittent dose paracetamol
These drugs have anticholinergic effects that include delayed gastric emptying. This will delay absorption
Warn patients that the action of paracetamol may be delayed. This will not be the case when paracetamol is taken regularly
DISOPYRAMIDE ANTIARRHYTHMICS Risk of bradycardia and ↓ BP Additive effects; antiarrhythmics are myocardial depressants
Monitor PR, BP and ECG closely
DISOPYRAMIDE ANTIBIOTICS – RIFAMPICIN Disopyramide levels are ↓ by rifampicin
Rifampicin induces hepatic metabolism of disopyramide
Watch for poor response to disopyramide; check serum levels if necessary
DISOPYRAMIDE ANTIDIABETIC DRUGS ≠ risk of hypoglycaemic episodes, particularly in patients with impaired renal function. Hypoglycaemic attacks may occur even when plasma levels of disopyramide are within the normal range (attacks occurring with plasma disopyramide levels of 1-4 ng/mL)
Disopyramide and its metabolite mono-isopropyl disopyramide ≠ secretion of insulin (considered to be due to inhibition of potassiumATP channels). Suggestion that disopyramide causes an impairment of the counterregulatory (homeostatic) mechanisms that follow hypoglycaemia
In patients receiving antidiabetic drugs, start with the lowest dose of disopyramide if there is no alternative. Measure creatinine clearance. If creatinine clearance is 40 mL/min or less, the dose of disopyramide should not exceed 100 mg and should be administered once daily if creatinine clearance is less than 15 mL/min ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia
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Mechanism Precautions
PHENYTOIN
Phenobarbital and primidone induce the hepatic metabolism of disopyramide
Watch for poor response to disopyramide; check serum levels if necessary
DISOPYRAMIDE ANTIVIRALS Disopyramide levels may be ≠ by protease inhibitors
Inhibition of CYP3A4-mediated metabolism of disopyramide
Watch closely for disopyramide toxicity
DISOPYRAMIDE BETA-BLOCKERS Risk of bradycardia (occasionally severe), ↓ BP, and heart failure
Additive negative inotropic and chronotropic effects
Monitor PR, BP and ECG at least weekly until stable; watch for development of heart failure
DISOPYRAMIDE CALCIUM CHANNEL BLOCKERS
Risk of myocardial depression and asystole when disopyramide is co-administered with verapamil, particularly in the presence of heart failure
Disopyramide is a myocardial depressant like verapamil and can cause ventricular tachycardia, ventricular fibrillation or torsades de pointes
Avoid co-administering verapamil with disopyramide if possible. If single-agent therapy is ineffective, monitor PR, BP and ECG closely; watch for heart failure
DISOPYRAMIDE DIURETICS – CARBONIC ANHYDRASE INHIBITORS, LOOP DIURETICS, THIAZIDES
Risk of ≠ myocardial depression Cardiac toxicity directly related to hypokalaemia
Monitor potassium levels closely
DISOPYRAMIDE GRAPEFRUIT JUICE Possibly ↓ effect of disopyramide Unclear Monitor ECG and side-effects more closely
DISOPYRAMIDE IVABRADINE Risk of arrhythmias Additive effect Monitor ECG closely
FLECAINIDE
FLECAINIDE AMMONIUM CHLORIDE Urinary acidification ↓ flecainide levels
Flecainide excretion is ≠ in the presence of an acidic urine; flecainide exists in predominantly ionic form, which is less readily reabsorbed from the renal tubules
Watch for a poor response to flecainide
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CARDIOVASCULAR DRUGS ANTIARRHYTHMICS Flecainide
BP Additive myocardial depression Particular care should be taken to avoid inadvertent intravenous administration during bupivacaine infiltration; monitor PR, BP and ECG during epidural administration of bupivacaine
FLECAINIDE ANALGESICS
FLECAINIDE NSAIDs Parecoxib may ≠ flecainide levels Parecoxib weakly inhibits CYP2D6mediated metabolism of flecainide
Monitor PR and BP closely. If possible, use only short courses of NSAID
FLECAINIDE OPIOIDS Methadone and tramadol may ≠ flecainide levels
Methadone and tramadol inhibit CYP2D6-mediated metabolism of flecainide
Monitor PR and BP closely
FLECAINIDE ANTIARRHYTHMICS
FLECAINIDE ANTIARRHYTHMICS Risk of bradycardia and ↓ BP Additive myocardial depression Monitor PR and BP closely; watch for flecainide toxicity
FLECAINIDE AMIODARONE ≠ plasma levels of flecainide Amiodarone is a potent inhibitor of CYP2D6-mediated metabolism of flecainide
↓ the dose of flecainide (by up to 50%)
FLECAINIDE ANTICANCER AND IMMUNOMODULATING DRUGS – IMATINIB
Imatinib may cause an ≠ in plasma concentrations of flecainide with a risk of toxic effects, e.g. visual disturbances, dyspnoea, liver dysfunction
Imatinib is a potent inhibitor of CYP2D6 isoenzymes, which metabolize flecainide
Monitor for clinical efficacy and toxicity of flecainide. Monitor liver function and BP, and do FBCs if toxicity is suspected
FLECAINIDE ANTIDEPRESSANTS
FLECAINIDE DULOXETINE Duloxetine may ≠ flecainide levels Duloxetine moderately inhibits CYP2D6, which metabolizes flecainide
Monitor PR and BP at least weekly until stable
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Mechanism Precautions SSRIs inhibit CYP2D6-mediated
metabolism of flecainide Monitor PR and BP closely; watch for flecainide toxicity
FLECAINIDE TCAs Risk of arrhythmias Additive effect; both drugs may be proarrhythmogenic. In addition, amitriptyline and clomipramine may inhibit CYP2D6-mediated metabolism of flecainide
Monitor PR, BP, and ECG closely; watch for flecainide toxicity
FLECAINIDE ANTIEMETICS – 5-HT3ANTAGONISTS
Risk of arrhythmias Additive effect Manufacturers recommend avoiding co-administration of flecainide with dolasetron. Caution with other 5-HT3antagonists; monitor ECG closely
FLECAINIDE ANTIHISTAMINES – TERFENADINE, HYDROXYZINE, MIZOLASTINE
Risk of arrhythmias Additive effect Avoid co-administration
FLECAINIDE ANTIMALARIALS
FLECAINIDE ARTEMETHER/ LUMEFANTRINE
Risk of arrhythmias Additive effect Avoid co-administration
FLECAINIDE QUININE Quinine may ≠ flecainide levels Quinine inhibits CYP2D6-mediated metabolism of flecainide
The effect seems to be slight, but watch for flecainide toxicity; monitor PR and BP closely
FLECAINIDE ANTIPSYCHOTICS – PHENOTHIAZINES, AMISULPRIDE, PIMOZIDE, SERTINDOLE
Risk of arrhythmias Additive effect. Also, haloperidol and thioridazine inhibit CYP2D6mediated metabolism of flecainide
Avoid co-administration
FLECAINIDE ANTIVIRALS – PROTEASE INHIBITORS
Amprenavir, ritonavir and possibly saquinavir and tipranavir with ritonavir ≠ flecainide levels, with risk of ventricular arrhythmias
Uncertain; possibly inhibition of CYP3A4-and CYP2D6-mediated metabolism of flecainide
Manufacturers recommend avoiding co-administration of flecainide with amprenavir, ritonavir and saquinavir
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CARDIOVASCULAR DRUGS ANTIARRHYTHMICS Flecainide
↓ described bradycardia when timolol eye drops given to a patient on flecainide
Additive negative inotropic and chronotropic effects
Monitor PR, BP and ECG closely; watch for development of heart failure
FLECAINIDE CALCIUM CHANNEL BLOCKERS
Risk of heart block and ↓ BP when flecainide is co-administered with verapamil. A single case of asystole has been reported
Additive negative inotropic and chronotropic effect
Monitor PR, BP and ECG at least weekly until stable; watch for heart failure
FLECAINIDE DIURETICS – CARBONIC ANHYDRASE INHIBITORS, LOOP DIURETICS, THIAZIDES
Risk of arrhythmias Cardiac toxicity directly related to hypokalaemia
Monitor potassium levels closely; watch for hypokalaemia
FLECAINIDE DRUG DEPENDENCE THERAPIES – BUPROPION
≠ levels of flecainide Bupropion may inhibit CYP2D6mediated metabolism of flecainide
Monitor PR and BP closely; start flecainide at the lowest dose for patients taking bupropion
FLECAINIDE H2 RECEPTOR BLOCKERS Cimetidine may ≠ flecainide levels Cimetidine inhibits CYP2D6mediated metabolism of flecainide. Ranitidine is a much weaker CYP2D6 inhibitor
Monitor PR and BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.). Consider alternative acid suppression therapy
FLECAINIDE SODIUM BICARBONATE Urinary alkalinization ≠ flecainide levels
Flecainide excretion is ↓ in the presence of an alkaline urine; flecainide exists in predominantly non-ionic form, which is more readily reabsorbed from the renal tubules
Monitor PR and BP closely
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Mechanism Precautions Uncertain; postulated that hepatic
metabolism ≠ by a component of tobacco smoke
Watch for poor response to flecainide and ≠ the dose accordingly (studies have suggested that smokers need up to 20% higher doses)
MEXILETINE
MEXILETINE ANAESTHETICS – LOCAL
MEXILETINE BUPIVACAINE, LEVOBUPIVACAINE
Risk of ↓ BP Additive myocardial depression Particular care should be taken to avoid inadvertent intravenous administration during bupivacaine infiltration; monitor PR, BP and ECG during epidural administration of bupivacaine
MEXILETINE LIDOCAINE Mexiletine ≠ lidocaine levels (with cases of toxicity when lidocaine is given intravenously)
Mexiletine displaces lidocaine from its tissue-binding sites; it also seems to ↓ its clearance but the exact mechanism is uncertain at present
Watch for the early symptoms and signs of lidocaine toxicity (perioral paraesthesia, ≠ muscle tone)
MEXILETINE ANALGESICS – OPIOIDS 1. Absorption of oral mexiletine is ↓ by co-administration with morphine or diamorphine 2. Methadone may ≠ mexiletine levels
1. Uncertain, but thought to be due to opioid-induced delay in gastric emptying 2. Methadone inhibits CYP2D6-mediated metabolism of mexiletine
1. Watch for a poor response to mexiletine; consider starting at a higher dose or using the intravenous route 2. Monitor PR, BP and ECG closely; watch for mexiletine toxicity
MEXILETINE ANTIARRHYTHMICS
MEXILETINE ANTIARRHYTHMICS Risk of bradycardia and ↓ BP; however, mexiletine ↓ the Q-T prolongation of other antiarrhythmics so is often beneficial
Additive effect; antiarrhythmics are all myocardial depressants
Monitor PR, BP and ECG closely
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CARDIOVASCULAR DRUGS ANTIARRHYTHMICS Mexiletine
Propafenone inhibits CYP2D6mediated metabolism of mexiletine; no case reports of adverse clinical effects but is potential for proarrhythmias
Monitor ECG closely
MEXILETINE ANTIBIOTICS Rifampicin ↓ mexiletine levels Uncertain; postulated that rifampicin ≠ mexiletine metabolism
Watch for poor response to mexiletine
MEXILETINE ANTICANCER AND IMMUNOMODULATING DRUGS – IMATINIB
Imatinib may cause an ≠ in plasma concentrations of mexiletine and a risk of toxic effects, e.g. nausea, vomiting, constipation, taste disturbances, dizziness and confusion
Imatinib is a potent inhibitor of CYP2D6 isoenzymes, which metabolize mexiletine
Mexiletine is used for life-threatening ventricular arrhythmias. Close monitoring of BP and ECG is mandatory, and watch for signs and symptoms of heart failure
MEXILETINE ANTIDEPRESSANTS
MEXILETINE SSRIs SSRIs may ≠ mexiletine levels SSRIs inhibit CYP2D6-mediated metabolism of mexiletine
Monitor PR and BP closely; watch for mexiletine toxicity
MEXILETINE TCAs Risk of arrhythmias Additive effect; both drugs may be proarrhythmogenic. In addition, amitriptyline and clomipramine may inhibit CYP2D6-mediated metabolism of mexiletine, while mexiletine inhibits CYP1A2mediated metabolism of amitriptyline, clomipramine and imipramine
Monitor PR, BP and ECG closely
MEXILETINE ANTIEMETICS – 5-HT3ANTAGONISTS
Risk of arrhythmias with dolasetron Additive effect Manufacturers recommend avoiding co-administration. Also caution with tropisetron; monitor ECG closely
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Mechanism Precautions
Phenytoin induces CYP1A2-mediated metabolism of mexiletine
Watch for poor response to mexiletine
MEXILETINE ANTIHISTAMINES – MIZOLASTINE
Risk of arrhythmias Additive effect Avoid co-administration
MEXILETINE ANTIMALARIALS – QUININE
Quinine may ≠ mexiletine levels Quinine inhibits CYP2D6-mediated metabolism of mexiletine
Monitor PR and BP closely
MEXILETINE ANTIMUSCARINICS – ATROPINE
Delayed absorption of mexiletine Anticholinergic effects delay gastric emptying and absorption
May slow the onset of action of the first dose of mexiletine, but this is not of clinical significance for regular dosing (atropine does not ↓ the total dose absorbed)
MEXILETINE ANTIVIRALS Mexiletine levels may be ≠ by ritonavir
Inhibition of metabolism via CYP2D6, particularly in rapid metabolizers (90% of the population)
Monitor PR, BP and ECG closely
MEXILETINE BETA-BLOCKERS Risk of bradycardia (occasionally severe), ↓ BP and heart failure
Additive negative inotropic and chronotropic effects. Also, mexiletine is known to inhibit CYP1A2-mediated metabolism of propanolol
Monitor PR, BP and ECG closely; watch for development of heart failure
MEXILETINE BRONCHODILATORS – THEOPHYLLINE
Theophylline levels may be ≠ by mexiletine; cases of theophylline toxicity have been reported
Mexiletine inhibits CYP1A2mediated metabolism of theophylline
↓ the theophylline dose (by up to 50%). Monitor theophylline levels and watch for toxicity
MEXILETINE CNS STIMULANTS – MODAFINIL
May cause ↓ mexiletine levels if CYP1A2 is the predominant metabolic pathway and alternative metabolic pathways are either genetically deficient or affected
Modafinil is a moderate inducer of CYP1A2 in a concentrationdependent manner
Be aware
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CARDIOVASCULAR DRUGS ANTIARRHYTHMICS Moracizine
THIAZIDES
Uncertain Normalize potassium levels before starting mexiletine
MEXILETINE H2 RECEPTOR BLOCKERS Cimetidine may ≠ plasma concentrations of mexiletine
Cimetidine inhibits CYP2D6mediated metabolism of mexiletine. Ranitidine is a much weaker CYP2D6 inhibitor
Monitor PR and BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.). Consider alternative acidsuppression therapy
MORACIZINE
MORACIZINE BRONCHODILATORS – THEOPHYLLINE
↓ plasma concentrations of theophylline and risk of therapeutic failure
Due to induction of microsomal enzyme activity
May need to ≠ dose of theophylline by 25%
MORACIZINE CALCIUM CHANNEL BLOCKERS
Co-administration is associated with ≠ bioavailability of moracizine and ↓ availability of diltiazem
Postulated that diltiazem inhibits metabolism of moracizine, while moracizine ≠ metabolism of diltiazem; the precise mechanism of interaction is uncertain at present
Monitor PR, BP and ECG; adjust doses of each drug accordingly
MORACIZINE CARDIAC GLYCOSIDES – DIGOXIN
Case reports of heart block when moracizine is co-administered with digoxin
Uncertain at present Monitor PR and ECG closely
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Effect Mechanism Precautions
PROCAINAMIDE 1. ANTIARRHYTHMICS – amiodarone, disopyramide, propafenone 2. ANTIBIOTICS – macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinolones (especially moxifloxacin), quinupristin/dalfopristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS – arsenic trioxide 4. ANTIDEPRESSANTS – TCAs, venlafaxine 5. ANTIEMETICS – dolasetron 6. ANTIFUNGALS – fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES – terfenadine, hydroxyzine, mizolastine 8. ANTIMALARIALS – artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine, quinine 9. ANTIPROTOZOALS – pentamidine isetionate 10. ANTIPSYCHOTICS – atypicals, phenothiazines, pimozide 11. BETA-BLOCKERS – sotalol 12. BRONCHODILATORS – parenteral bronchodilators. 13. CNS STIMULANTS – atomoxetine
Risk of ventricular arrhythmias, particularly torsades de pointes
Additive effect; these drugs prolong the Q-T interval. In addition, procainamide levels may be ≠ by amiodarone (uncertain mechanism). Also, amitriptyline, clomipramine and quinine inhibit CYP2D6-mediated metabolism of procainamide
Avoid co-administration
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CARDIOVASCULAR DRUGS ANTIARRHYTHMICS Procainamide
Additive myocardial depression Particular care should be taken to avoid inadvertent intravenous administration during bupivacaine infiltration; monitor PR, BP and ECG during epidural administration of bupivacaine
PROCAINAMIDE LIDOCAINE Case report of neurotoxicity when intravenous lidocaine is administered with procainamide. No significant interaction is expected when lidocaine is used for local anaesthetic infiltration
Likely to be an additive effect; both may cause neurotoxicity in overdose
Care should be taken when administering lidocaine as an infusion for patients taking procainamide
PROCAINAMIDE ANALGESICS – OPIOIDS Methadone may ≠ flecainide levels Methadone inhibits CYP2D6mediated metabolism of flecainide
Monitor PR and BP closely
PROCAINAMIDE ANTIARRHYTHMICS Risk of bradycardia and ↓ BP Additive effect; antiarrhythmics are all myocardial depressants
Monitor PR, BP and ECG closely
PROCAINAMIDE ANTIBIOTICS – TRIMETHOPRIM Procainamide levels are ≠ by trimethoprim
Trimethoprim is a potent inhibitor of organic cation transport in the kidney, and elimination of procainamide is impaired
Watch for signs of procainamide toxicity; ↓ the dose of procainamide, particularly in the elderly
PROCAINAMIDE ANTIDEPRESSANTS – SSRIs SSRIs may ≠ procainamide levels SSRIs inhibit CYP2D6-mediated metabolism of procainamide
Monitor PR and BP closely; watch for procainamide toxicity
PROCAINAMIDE ANTIHYPERTENSIVES AND HEART FAILURE DRUGS – ACE INHIBITORS
Possible ≠ risk of leukopenia Uncertain at present Monitor FBC before starting treatment, 2-weekly for 3 months after initiation of therapy, then periodically thereafter
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Mechanism Precautions
↓ Additive negative inotropic and chronotropic effects
Monitor PR, BP and ECG closely; watch for development of heart failure
PROCAINAMIDE CARDIAC GLYCOSIDES – DIGITOXIN
Single case report of toxicity in a patient taking both digitoxin and procainamide
Uncertain at present Watch for digitoxin toxicity
PROCAINAMIDE H2 RECEPTOR BLOCKERS Cimetidine may ≠ plasma concentrations of procainamide
Cimetidine is a potent inhibitor of organic cation transport in the kidney, and elimination of procainamide is impaired. Cimetidine also inhibits CYP2D6mediated metabolism of procainamide. Ranitidine is a much weaker CYP2D6 inhibitor
Monitor PR and BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.). Consider alternative acid-suppression therapy
PROCAINAMIDE MUSCLE RELAXANTS – DEPOLARISING
Possibility of ≠ neuromuscular blockade
Uncertain; procainamide may ↓ plasma cholinesterase levels
Be aware of the possibility of a prolonged effect of suxamethonium when administered to patients taking procainamide
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CARDIOVASCULAR DRUGS ANTIARRHYTHMICS Propafenone
PROPAFENONE 1. ANTIARRHYTHMICS – disopyramide, procainamide 2. ANTIBIOTICS – macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinolones (especially moxifloxacin), quinupristin/ dalfopristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS – arsenic trioxide 4. ANTIDEPRESSANTS – TCAs, venlafaxine 5. ANTIEMETICS – dolasetron 6. ANTIFUNGALS – fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES – terfenadine, hydroxyzine, mizolastine 8. ANTIMALARIALS – artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine, quinine 9. ANTIPROTOZOALS – pentamidine isetionate 10. ANTIPSYCHOTICS – atypicals, phenothiazines, pimozide 11. BETA-BLOCKERS – sotalol 12. BRONCHODILATORS – parenteral bronchodilators 13. CNS STIMULANTS – atomoxetine
Risk of ventricular arrhythmias, particularly torsades de pointes
Additive effect; these drugs prolong the Q-T interval. Also, amitriptyline, clomipramine and desipramine levels may be ≠ by propafenone. Amitriptyline and clomipramine may ≠ propafenone levels. Propafenone and these TCAs inhibit CYP2D6-mediated metabolism of each other
Avoid co-administration
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Mechanism Precautions
2. ANTIARRHYTHMICS – disopyramide 3. ANTIDEPRESSANTS – TCAs 4. ANTIEMETICS – cyclizine 5. ANTIHISTAMINES – chlorphenamine, cyproheptadine, hydroxyzine 6. ANTIMUSCARINICS – atropine, benzatropine, cyclopentolate, dicycloverine, flavoxate, homatropine, hyoscine, orphenadrine, oxybutynin, procyclidine, propantheline, tolterodine, trihexyphenidyl, tropicamide 7. ANTIPARKINSON’S DRUGS – dopaminergics 8. ANTIPSYCHOTICS – phenothiazines, clozapine, pimozide 9. MUSCLE RELAXANTS – baclofen 10. NITRATES – isosorbide dinitrate
effects. NB å efficacy of sublingual nitrate tablets
Additive effect; both drugs cause antimuscarinic side-effects. Antimuscarinic effects å salivary production, which å dissolution of the tablet
Warn patient of this additive effect. Consider changing the formulation to a sublingual nitrate spray
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CARDIOVASCULAR DRUGS ANTIARRHYTHMICS Propafenone
BP Additive myocardial depression Particular care should be taken to avoid inadvertent intravenous administration during bupivacaine infiltration; monitor PR, BP and ECG during epidural administration of bupivacaine
PROPAFENONE ANALGESICS
PROPAFENONE NSAIDs Serum levels of propafenone may be ≠ by parecoxib
Parecoxib is a weak inhibitor of CYP2D6-mediated metabolism of propafenone
Monitor PR and BP closely. If possible, use only short courses of NSAID
PROPAFENONE OPIOIDS Methadone may ≠ propafenone levels
Methadone inhibits CYP2D6mediated metabolism of propafenone
Monitor PR and BP closely
PROPAFENONE PARACETAMOL Propafenone may slow the onset of action of intermittent-dose paracetamol
Anticholinergic effects delay gastric emptying and absorption
Warn patients that the action of paracetamol may be delayed. This will not be the case when paracetamol is taken regularly
PROPAFENONE ANTIARRHYTHMICS
PROPAFENONE ANTIARRHYTHMICS Risk of bradycardia and ↓ BP with all antiarrhythmics
Additive myocardial depression Monitor PR and BP closely
PROPAFENONE MEXILETINE ≠ serum levels of mexiletine Propafenone inhibits CYP2D6mediated metabolism of mexiletine; no case reports of adverse clinical effects, but is a potential for proarrhythmias
Monitor ECG closely
PROPAFENONE ANTIBIOTICS – RIFAMPICIN Rifampicin may ↓ propafenone levels
Rifampicin may inhibit CYP3A4and CYP1A2-mediated metabolism of propafenone
Watch for poor response to propafenone
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Mechanism Precautions
DRUGS – CICLOSPORIN
≠ Uncertain Watch for signs of ciclosporin toxicity
PROPAFENONE ANTICOAGULANTS – ORAL Warfarin levels may be ≠ by propafenone
Propafenone seems to inhibit warfarin metabolism
Monitor INR at least weekly until stable
PROPAFENONE ANTIDEPRESSANTS
PROPAFENONE DULOXETINE Duloxetine may ≠ propafenone levels
Duloxetine moderately inhibits CYP2D6, which metabolizes propafenone
Monitor PR and BP closely
PROPAFENONE SSRIs Levels of both may be ≠ Both SSRIs and propafenone are substrates for and inhibitors of CYP2D6
Monitor PR and BP closely
PROPAFENONE ANTIEPILEPTICS ↓ serum levels of propafenone with barbiturates
Barbiturates stimulate hepatic metabolism of propafenone
Watch for poor response to propafenone
PROPAFENONE ANTIVIRALS – PROTEASE INHIBITORS
Amprenavir, ritonavir and possibly saquinavir and tipranavir with ritonavir ≠ propafenone levels, with risk of ventricular arrhythmias
Uncertain Manufacturers recommend avoiding co-administration of propafenone and amprenavir, ritonavir or tipranavir
PROPAFENONE BETA-BLOCKERS
PROPAFENONE BETA-BLOCKERS Risk of bradycardia (occasionally severe), ↓ BP and heart failure
Additive negative inotropic and chronotropic effects
Monitor PR, BP and ECG closely; watch for development of heart failure
PROPAFENONE METOPROLOL, PROPANOLOL
≠ plasma levels of propranolol and metoprolol
Propafenone is extensively metabolized by CYP2D6 enzymes and interferes with the metabolism of propranolol and metoprolol
Watch for propranolol and metoprolol toxicity; ↓ doses accordingly
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CARDIOVASCULAR DRUGS ANTIARRHYTHMICS Propafenone
Uncertain at present Watch for signs of theophylline toxicity
by propafenone
Uncertain at present Watch for digoxin toxicity; check digoxin levels if indicated and ↓ digoxin dose as necessary (15-75% suggested by studies)
PROPAFENONE DRUG DEPENDENCE THERAPIES – BUPROPION
Bupropion may ≠ propafenone levels
Bupropion may inhibit CYP2D6mediated metabolism of propafenone
Monitor PR and BP closely; start propafenone at the lowest dose for patients taking bupropion
PROPAFENONE GRAPEFRUIT JUICE Possibly ↓ effect of propafenone Unclear. Metabolism may be altered to CYP3A4 and CYP1A2 in patients with low CYP2D6 activity
Monitor ECG and side-effects more closely
PROPAFENONE H2 RECEPTOR BLOCKERS Cimetidine may ≠ propafenone levels
Cimetidine inhibits CYP2D6mediated metabolism of propafenone. Ranitidine is a weak CYP2D6 inhibitor
Monitor PR and BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.). Consider alternative acidsuppression therapy
PROPAFENONE PARASYMPATHOMIMETICS ↓ efficacy of neostigmine and pyridostigmine
Uncertain; propafenone has a degree of antinicotinic action that may oppose the action of parasympathomimetic therapy for myasthenia gravis
Watch for poor response to these parasympathomimetics and ≠ dose accordingly
SOTALOL ➣ Beta-blockers, below
