chapter
Antiarrhythmics
Pages 26

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