Drugs and the QT Adrian Stanley PhD FRCP Senior Clinical Teaching Fellow Honorary Cardiovascular Physician University of Leicester Introduction • QT prolongation and the ECG • The clinical significance of QT prolongation • Causes of QT prologation • Mechanism of drug-induced QT effect • Prescribing advice for ‘QT Drugs’ • Managing QT prolongation / TdP • Summary Interpreting an ECG • Rhythm • Rate • P wave • P-R interval • QRS interval • QRS complex • ST segment • T wave • U wave • Q-T duration Normal ECG Long QT Syndrome QT R-R Bazzett’s Formula: QTc = QT/ √R-R Bazett HC. An analysis of the time relationships of electrocardiograms. Heart. 1920;7:355-70. Online QT Calculator http://www.medcalc.com/qtc.html http://en.ecgpedia.org/wiki/QTc_Calculator Or just google ‘QT calc’ Online QT Calculator http://www.medcalc.com/qtc.html http://en.ecgpedia.org/wiki/QTc_Calculator Or just google ‘QT calc’ Torsade de Pointes (TdP) or polymorphic ventricular tachycardia Causes of Long QT Syndrome Causes of Long QT Syndrome COMBINED LIST OF DRUGS THAT PROLONG QT AND/OR CAUSE TORSADES DE POINTES (TDP) Crediblemeds.org is your trusted partner providing reliable information on medicines. This is a composite list of drugs that CredibleMeds has concluded either 1) have a risk of TdP, 2) prolong QT and therefore have a possible risk of TdP or 3) have a risk of TdP under certain conditions such as overdose, drugdrug interactions or when administered to certain high-risk individuals (e.g. congenital long QT syndrome). Generic Name Brand Name Generic Name Brand Name Generic Name Brand Name Alfuzosin Uroxatral® Desipramine Pertofrane® and others Ibutilide Corvert® Amantadine Symmetrel® and others Dexmedetomidine Precedex® and others Iloperidone Fanapt® and others Amiodarone Cordarone® and others Dihydroartemisinin+piperaquine Eurartesim® Imipramine (melipramine) Tofranil® Amisulpride Solian® and others Diphenhydramine Benadryl® and others Indapamide Lozol® and others Elavil® (Discontinued 6/13) Disopyramide Norpace® Isradipine Dynacirc® Amitriptyline and others Dofetilide Tikosyn® Itraconazole Sporanox® and others Amoxapine Asendin® and others Dolasetron Anzemet® Ivabradine (Not on US mkt) Procoralan® and others Anagrelide Agrylin® and others Domperidone (Not on US mkt) Motilium® and others Ketoconazole Nizoral® and others Apomorphine Apokyn® and others Doxepin Sinequan® and others Lapatinib Tykerb® and others Aripiprazole Abilify® and others Dronedarone Multaq® Levofloxacin Levaquin® and others Arsenic trioxide Trisenox® Droperidol Inapsine® and others Levomethadyl (Off US mkt) Orlaam® Astemizole (Off US mkt) Hismanal® Eribulin Halaven® Lithium Eskalith® and others Atazanavir Reyataz® Erythromycin E.E.S.® and others Mesoridazine (Off US mkt) Serentil® Azithromycin Zithromax® and others Escitalopram Cipralex® and others Methadone Dolophine® and others Bedaquiline Sirturo® Famotidine Pepcid® and others Metronidazole Flagyl® and many others Bepridil (Off US mkt) Vascor® Felbamate Felbatol® Mifepristone Korlym® and others Bortezomib Velcade® and others Fingolimod Gilenya® Mirabegron Myrbetriq® Bosutinib Bosulif® Flecainide Tambocor® and others Mirtazapine Remeron Chloral hydrate Aquachloral® and others Fluconazole Diflucan® and others Moexipril/HCTZ Uniretic® and others Chloroquine Aralen® Fluoxetine Prozac® and others Moxifloxacin Avelox® and others Chlorpromazine Thorazine® and others Foscarnet Foscavir® Nelfinavir Viracept® Ciprofloxacin Cipro® and others Fosphenytoin Cerebyx® and others Nicardipine Cardene® Cisapride (Off US mkt) Propulsid® Furosemide (Frusemide) Lasix® and others Nilotinib Tasigna® Citalopram Celexa® and others Galantamine Reminyl® and others Norfloxacin Noroxin® and others Clarithromycin Biaxin® and others Gatifloxacin (Off US mkt) Tequin® Nortriptyline Pamelor® and others Clomipramine Anafranil® Gemifloxacin Factive® Ofloxacin Floxin® Clozapine Clozaril® and others Granisetron Kytril® and others Olanzapine Zyprexa® and others Cocaine Cocaine Halofantrine Halfan® Ondansetron Zofran® and others Crizotinib Xalkori® Haloperidol Haldol® (US & UK) and others Oxytocin Pitocin® and others Dabrafenib Tafinlar® Hydrochlorothiazide Apo-Hydro® and others Paliperidone Invega® and others Dasatinib Sprycel® If list is printed, check website for updates: www.crediblemeds.org •Please see Disclaimer and list continued COMBINED LIST OF DRUGS THAT PROLONG QT AND/OR CAUSE TORSADES DE POINTES (TDP) Crediblemeds.org is your trusted partner providing reliable information on medicines. This is a composite list of drugs that CredibleMeds has concluded either 1) have a risk of TdP, 2) prolong QT and therefore have a possible risk of TdP or 3) have a risk of TdP under certain conditions such as overdose, drugdrug interactions or when administered to certain high-risk individuals (e.g. congenital long QT syndrome). Generic Name Brand Name Generic Name Brand Name Note: Medicines on this list are reviewed on an ongoing Paroxetine Paxil® and others Sorafenib Nexavar® basis to assure that the available evidence supports their Pasireotide Signifor® Sotalol Betapace® and others continued placement on this list. The list changes regularly Pazopanib Votrient® Sparfloxacin (Off US mkt) Zagam® and we recommend checkingthe website at Pentamidine Pentam® Sulpiride (Not on US Dogmatil® and others Mkt.) crediblemeds.org for the most up-todate information. Perflutren lipid Definity® microspheres Sunitinib Sutent® There may be many additional brand names that are not Pimozide Orap® Tacrolimus Prograf® and others listed on this form. Pipamperone (Not on Dipiperon (E.U) and Nolvadex®(discontinued Tamoxifen US Mkt) others 6/13) and others Disclaimer and Waiver: The information presented is Posaconazole Noxafil® and others Telaprevir Incivek® and others intended solely for the purpose of providing general Probucol (Off US mkt) Lorelco® Telavancin Vibativ® Procainamide (Oral off Telithromycin Ketek® information about health-related matters. It is not intended Pronestyl® and others US mkt) Terfenadine (Off US mkt) Seldane® for any other purpose, including but not limited to medical Promethazine Phenergan® Tetrabenazine (Orphan advice and/or treatment, nor is it intended to substitute for Nitoman® and others Protriptyline Vivactil® drug in US) the users relationships with their own health care Quetiapine Seroquel® Thioridazine Mellaril® and others providers. To that extent, by use of this website and the Quinidine Quinaglute® and others Tizanidine Zanaflex® and others information it contains, the user affirms the understanding Quinine sulfate Qualaquin® Tolterodine Detrol® and others of the purpose and releases AZCERT, Inc. from any Ranolazine Ranexa® and others Toremifene Fareston® Rilpivirine Edurant® and others Desyrel® (discontinued claims arising out of his/her use of the website and its lists. Trazodone 6/13) and others Risperidone Risperdal® The absence of drugs from these lists should not be Trimethoprim-Sulfa Septra® and others Ritonavir Norvir® considered an indication that they are free of risk of QT Trimipramine Surmontil® and others Roxithromycin (Not on prolongation or TdP. Many medicines have not been Rulide® and others US Mkt) Vandetanib Caprelsa® tested for this risk in patients, especially those with Saquinavir Invirase®(combo) Vardenafil Levitra® congenital long QT syndrome. Sertindole (Not on US Vemurafenib Zelboraf® Serdolect® and others mkt) Venlafaxine Effexor® and others Sertraline Zoloft® and others Voriconazole VFend® Sevoflurane Ulane® and others Vorinostat Zolinza® Solifenacin VESIcare® Ziprasidone Geodon® and others Generated: June 2, 2014. List last revised: May 31, 2014 Major classes of drugs that prolong the QT interval • Anti-arrhythmics • Some non-sedating antihistamines (e.g. terfenadine and astemizole) • Macrolide antibiotics • Some psychotropic medications • Some gastric motility agents (e.g. cisapride) Risk of Sudden Death from non-cardiac QT Drugs • In 775 patients with SCD, 24 (3.1%) were taking a QT prolonging drug • Current use of any non-cardiac QT prolonging drug was associated with a significantly increased risk of SCD (adjusted OR 2.7) • The highest risk was associated with antipsychotic drugs (adjusted OR 5.0). • The risk was higher in women and in people who had recently started a QT prolonging drug Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. Straus SM, Sturkenboom MC, Bleumink GS, Dieleman JP, van der Lei J, de Graeff PA, Kingma JH, Stricker BH Eur Heart J. 2005;26(19):200 USA Data • Among 761 cases of drug-induced TdP reported to the World Health Organization Drug Monitoring Centre (1983 and 1999), the most common drugs were sotalol and cisapride (17 and 13 percent) • In a review of 92 patients from the United States with drug-induced TdP, anti-arrhythmics were responsible in 71 (77%) 1. Drug induced QT prolongation and torsades de pointes. Yap YG, Camm AJ. Heart. 2003;89(11):1363 2. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, Hohnloser SH, Shimizu W, Schwartz PJ, Stanton M, Murray KT, Norris K, George AL Jr, Roden DM. Circulation. 2002;105(16):1943 But data health warning….. • Most available data comes from case reports or small observational series • Thus determining the risk of SCD with drugs associated with QT prolongation is difficult Mechanism • Almost all of the drugs that prolong the QT act by blocking the potassium current (IKr) ion channel encoded by the KCNH2 gene • This potassium