are the most life-threatening. The risk of cardiovascular toxicity is greater in patients with https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 12/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate structural heart disease and in those treated for ventricular rather than supraventricular arrhythmias [74,75]. The relation between propafenone dose, concentration, clinical response, and toxicity is complex. The main metabolic route of propafenone is via the cytochrome P450 2D6 isoenzyme. This metabolic pathway, known to have genetic polymorphisms, is functionally absent in approximately 7 percent of White and African Americans. In these "slow metabolizers," the extent of first-pass hepatic metabolism is much less than in "extensive metabolizers," and increased plasma concentration may be more likely to cause side effects. Moreover, because the oxidative elimination of propafenone is saturable, small dose increases may cause a rapid and disproportionate increase in plasma concentrations, thus augmenting its potential for causing toxicity. (See 'When to measure drug concentrations' above.) Cardiovascular effects Inotropic effects In patients with a normal or minimally decreased LVEF ( 40 percent), oral propafenone can decrease the ejection fraction without causing symptoms of HF [77]. However, overt HF may be induced in patients with preexisting ventricular systolic dysfunction [78]. The negative inotropic effect of propafenone is associated with significant increases in pulmonary capillary wedge pressure and in systemic and pulmonary vascular resistance and a decline in cardiac output. Propafenone should therefore be avoided in patients with overt HF. However, propafenone can be administered cautiously to patients with mildly reduced LVEF who have no clinical signs or symptoms of HF, with close monitoring over one to two weeks for the development of HF symptoms following the initiation of therapy. Chronotropic effects Propafenone has a variety of effects that can lead to bradycardia including its Class IC activity and its beta-blocker and calcium channel blocker properties. As a result, patients with known sinus node dysfunction, including the sinus node dysfunction, should not receive propafenone in the absence of a permanent pacemaker [79]. Alternatively, because potential variations in propafenone metabolism may exist and remain undetected in everyday practice, some authors have suggested a heart rate challenge, such as exercise testing, for patients using chronic propafenone [80]. Conduction disturbances Propafenone slows atrioventricular conduction and causes prolongation of the PR and QRS intervals. Prolongation of the PR interval ranges from 15 to 25 percent; it is a common finding and is not necessarily regarded as a sign of toxicity. However, on rare occasions propafenone has been associated with the development of atrioventricular block. Patients on propafenone who develop second or third degree AV block should have their dose of propafenone reduced or discontinued. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 13/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Propafenone has been associated with QRS prolongation, new left bundle branch block, and new right bundle branch block [81,82]. These conduction disturbances usually occur in patients with underlying heart disease and appear to be dose-dependent. No specific dose adjustments are required in this setting. Proarrhythmia Like other antiarrhythmic agents, propafenone has a proarrhythmic effect that can trigger sustained ventricular tachycardia (VT) [29]. The proarrhythmic effect of propafenone may be somewhat reduced by its beta-blocking activity. The potential for proarrhythmia is greater with the class IC agents, such as flecainide or propafenone, compared with the IA or IB drugs ( table 1) [83]. The two most powerful predictors of proarrhythmia are previous VT and decreased LVEF. CNS side effects A variety of adverse central nervous system (CNS) effects have been reported in association with propafenone, with dizziness being the most common along with nausea, unusual taste, and blurred vision. Ataxia caused by propafenone has also been reported [84]. Although the side effects of the drug are usually dose-related, the precise mechanism is not fully understood. Blockade of beta-adrenergic receptors may be partly responsible, because this action can in itself cause CNS symptoms including sleep disturbance, depression, drowsiness, fatigue, lethargy, hallucination, delirium, paranoia, and amnesia. In patients who develop CNS effects from propafenone, it is reasonable to consider lowering the dose in an effort to reduce side effects. If CNS side effects persist, propafenone should be discontinued. Gastrointestinal side effects Gastrointestinal side effects from propafenone, usually mild in nature, are among the most commonly reported adverse effects. Up to 20 percent of patients receiving propafenone report an unusual taste , and up to 10 percent develop nausea. The frequency of side effects may be reduced when medication is taken with food. Propafenone intoxication HF, conduction disturbances, and seizures are major clinical signs of intoxication. While adverse reactions to propafenone are relatively common, reports of death secondary to propafenone intoxication are comparatively rare [85]. Propafenone intoxication is associated with ingested doses from 1800 to 9000 mg and serum concentrations as high as 12,000 ng/mL have been reported (normal therapeutic and toxic ranges for propafenone are 400 to 1100 ng/mL and 1100 to 2000 ng/mL, respectively) [85,86]. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 14/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Treatment for propafenone intoxication centers on hemodynamic support and includes intravenous glucagon (to reverse any toxicity due to the beta blocker effects), hypertonic sodium bicarbonate, hypertonic saline, and inotropic agents [86]. A temporary pacemaker may be required for patients with high-degree AV block related to the overdose. Routine blood testing for propafenone concentrations should be performed in patients following resuscitation, particularly in patients undergoing treatment for arrhythmias. (See "General approach to drug poisoning in adults", section on 'Poisoning management'.) SUMMARY AND RECOMMENDATIONS Quinidine side effects Gastrointestinal These are the most frequent adverse effects with oral quinidine. Nausea, diarrhea, and abdominal bloating and discomfort can occur. Central nervous system toxicity This is associated with high-dose therapy and subsequent high plasma quinidine concentrations. The constellation of symptoms is called cinchonism and includes tinnitus, hearing loss, confusion, delirium, disturbances in vision, and psychosis. Cardiac toxicities These include proarrhythmia with lengthening of the QT interval (potentially resulting in polymorphic ventricular tachycardia), slowed atrioventricular (AV) nodal conduction (potentially leading to heart block), and hypotension. (See 'Quinidine' above.) Disopyramide side effects Anticholinergic symptoms These include dry mouth, urinary hesitancy, and constipation. Cardiac effects These include negative inotropic activity (potentially resulting in heart failure) and proarrhythmia with lengthening of the QT interval (potentially resulting in polymorphic ventricular tachycardia). (See 'Disopyramide' above.) Procainamide side effects Gastrointestinal disturbances. Central nervous system dysfunction. Fever, rash, and myalgias. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 15/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Positive antinuclear antibody titer This is seen in almost all patients with chronic administration of procainamide. This is particularly seen in slow acetylators, with symptoms similar to those in systemic lupus erythematosus (eg, arthritis, arthralgias, and pleuritis) in 15 to 20 percent of patients. Serious and potentially lethal cardiac effects These are more common at toxic plasma concentrations (above 30 mg/L for procainamide plus its major metabolite N- acetylprocainamide versus a therapeutic range of 4 to 12 mg/L for procainamide alone), including conduction delay (with PR prolongation or QRS widening), QT prolongation, ventricular tachyarrhythmias, increased AV nodal conduction, and depressed left ventricular function. (See 'Procainamide' above.) Lidocaine side effects When administered intravenously in the treatment of ventricular arrhythmias, lidocaine is generally well tolerated. Central nervous system These include tremor, insomnia or drowsiness, lightheadedness, ataxia, and agitation. Gastrointestinal These include nausea, vomiting, and anorexia. Cardiovascular system These include sinus node slowing, asystole, hypotension, and shock. (See 'Lidocaine (intravenous)' above.) Mexiletine side effects The side effects of mexiletine are generally dose and concentration dependent. Gastrointestinal tract These are the most common adverse effects and include nausea, vomiting, or heartburn. Central nervous system These include dizziness, lightheadedness, tremor, nervousness, difficulty with coordination, change in sleep habits, paresthesias, and numbness. Cardiac A proarrhythmic effect can contribute to ventricular tachyarrhythmias. (See 'Mexiletine' above.) Flecainide side effects This is generally well tolerated, though it can induce a variety of generally mild and tolerable side effects. Noncardiac These include dizziness, blurred vision or difficulty in focusing, headache, and nausea, each of which occurs in 10 to 20 percent of patients. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 16/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Cardiac Proarrhythmia and the potential for fatal ventricular arrhythmias can occur in persons with structural heart disease. Conversely, flecainide does not appear to increase mortality when used for the treatment of supraventricular arrhythmias in persons with structurally normal hearts. (See 'Flecainide' above.) Propafenone side effects Approximately 15 to 20 percent of patients taking propafenone will have side effects that require drug discontinuation. Gastrointestinal These are the most common and include nausea and an unusual taste sensation. Central nervous system Most commonly, dizziness occurs. 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Topic 86747 Version 24.0 https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 23/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 24/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 25/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Side effects induced by quinidine Side effect Relative frequency Cardiovascular Proarrhythmia +++ Torsades de pointes +++ Prolonged QT interval ++ Hypotension ++ Sinus arrest + Heart failure + AV block Gastrointestinal Diarrhea +++ Nausea, abdominal pain ++ Hepatotoxicity + Central nervous system Cinchonism ++ Psychosis ++ Depression + Blurred vision + Hematologic Thrombocytopenia +++ Agranulocytosis + Hemolytic anemia + Hypoprothrombinemia Other Fever + Lupus-like syndrome + Major side effects induced by quinidine and their relative frequency. Graphic 65568 Version 1.0 https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 26/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Cytochrome P450 3A (including 3A4) inhibitors and inducers Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers Adagrasib Amiodarone Apalutamide Bexarotene Atazanavir Aprepitant Carbamazepine Bosentan Ceritinib Berotralstat Enzalutamide Cenobamate Clarithromycin Cimetidine Fosphenytoin Dabrafenib Cobicistat and Conivaptan Lumacaftor Dexamethasone cobicistat- Crizotinib Lumacaftor- ivacaftor Dipyrone containing coformulations Cyclosporine Efavirenz Mitotane Diltiazem Elagolix, estradiol, and norethindrone Darunavir Phenobarbital Duvelisib Idelalisib therapy pack Phenytoin Dronedarone Indinavir Eslicarbazepine Primidone Erythromycin Itraconazole Etravirine Rifampin Fedratinib Ketoconazole (rifampicin) Lorlatinib Fluconazole Levoketoconazole Mitapivat Fosamprenavir Lonafarnib Modafinil Fosaprepitant Lopinavir Nafcillin Fosnetupitant- palonosetron Mifepristone* Pexidartinib Nefazodone Rifabutin Grapefruit juice Nelfinavir Rifapentine Imatinib Nirmatrelvir- ritonavir Sotorasib Isavuconazole (isavuconazonium St. John's wort Ombitasvir- paritaprevir- sulfate) Lefamulin ritonavir Letermovir Ombitasvir- Netupitant paritaprevir- Nilotinib ritonavir plus dasabuvir Ribociclib Schisandra Posaconazole Verapamil Ritonavir and ritonavir-containing coformulations Saquinavir Telithromycin Tucatinib Voriconazole https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 27/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation. These classifications are based upon US Food and Drug Administration (FDA) guidance. [1,2] Other sources may use a different classification system resulting in some agents being classified differently. Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug interaction program such as the Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 28/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial ischemia or GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy infarction, especially with Hypocalcemia Diuretic therapy via electrolyte disorders Starvation particularly hypokalemia and hypomagnesemia prominent T-wave inversions Anorexia nervosa Herbs Liquid protein diets Cinchona (contains quinine), iboga Intracranial disease Hypothyroidism (ibogaine), licorice extract in overuse via electrolyte disturbances Bradyarrhythmias HIV infection Sinus node Hypothermia dysfunction Toxic exposure: Organophosphate AV block: Second or third degree insecticides Medications* High risk Adagrasib Cisaparide Lenvatinib Selpercatinib (restricted availability) Ajmaline Levoketoconazole Sertindole Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine Vandetanib Dofetilide (intracoronary) Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab Propafenone ozogamacin Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 29/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Certinib Escitalopram Levofloxacin Risperidone (systemic) Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine Clarithromycin Flecainide Sparfloxacin antimoniate Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil Terbutaline Nilotinib (systemic) Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > Gabobenate dimeglumine Dasatinib Vemurafenib oral) Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole Romidepsin Anagrelide Foscarnet (systemic) Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine Nortriptyline Benperidol (rare reports) Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus Olodaterol (systemic) Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 30/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- norethindrone Periciazine Tropisetron Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide in Eliglustat Primaquine Vorinostat overdose Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM [1,2] 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 31/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews.