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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 -induced QT effect • Prescribing advice for ‘QT ’ • 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. . 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 (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 Uroxatral® Pertofrane® and others Corvert® Symmetrel® and others Precedex® and others Fanapt® and others Cordarone® and others Dihydroartemisinin+piperaquine Eurartesim® (melipramine) Tofranil® Solian® and others Benadryl® and others Lozol® and others Elavil® (Discontinued 6/13) Norpace® Dynacirc® and others Tikosyn® Sporanox® and others Asendin® and others Anzemet® Ivabradine (Not on US mkt) Procoralan® and others Anagrelide Agrylin® and others (Not on US mkt) Motilium® and others Nizoral® and others Apokyn® and others Sinequan® and others Lapatinib Tykerb® and others Abilify® and others Multaq® Levofloxacin Levaquin® and others Arsenic trioxide Trisenox® Inapsine® and others Levomethadyl (Off US mkt) Orlaam® (Off US mkt) Hismanal® Eribulin Halaven® Eskalith® and others Reyataz® E.E.S.® and others (Off US mkt) Serentil® Azithromycin Zithromax® and others Cipralex® and others Methadone Dolophine® and others Sirturo® Famotidine Pepcid® and others Metronidazole Flagyl® and many others (Off US mkt) Vascor® Felbamate Felbatol® Mifepristone Korlym® and others Bortezomib Velcade® and others Fingolimod Gilenya® Myrbetriq® Bosutinib Bosulif® Tambocor® and others Remeron Aquachloral® and others Fluconazole Diflucan® and others Moexipril/HCTZ Uniretic® and others Chloroquine Aralen® Prozac® and others Avelox® and others Thorazine® and others Foscarnet Foscavir® Nelfinavir Viracept® Ciprofloxacin Cipro® and others Cerebyx® and others Cardene® (Off US mkt) Propulsid® (Frusemide) Lasix® and others Nilotinib Tasigna® Celexa® and others Galantamine Reminyl® and others Norfloxacin Noroxin® and others Biaxin® and others Gatifloxacin (Off US mkt) Tequin® Pamelor® and others Anafranil® Gemifloxacin Factive® Ofloxacin Floxin® Clozaril® and others Kytril® and others Zyprexa® and others Cocaine Halofantrine Halfan® Zofran® and others Crizotinib Xalkori® Haldol® (US & UK) and others Pitocin® and others Dabrafenib Tafinlar® Apo-Hydro® and others 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 Paxil® and others Sorafenib Nexavar® basis to assure that the available evidence supports their Pasireotide Signifor® 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® (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 Orap® Tacrolimus Prograf® and others listed on this form. (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® (Oral off Telithromycin Ketek® information about health-related matters. It is not intended Pronestyl® and others US mkt) (Off US mkt) Seldane® for any other purpose, including but not limited to medical Phenergan® (Orphan advice and/or treatment, nor is it intended to substitute for Nitoman® and others Vivactil® drug in US) the users relationships with their own health care Seroquel® Mellaril® and others providers. To that extent, by use of this website and the Quinaglute® and others Zanaflex® and others information it contains, the user affirms the understanding Quinine sulfate Qualaquin® Detrol® and others of the purpose and releases AZCERT, Inc. from any Ranexa® and others Toremifene Fareston® Rilpivirine Edurant® and others Desyrel® (discontinued claims arising out of his/her use of the website and its lists. 6/13) and others 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 Surmontil® and others (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. (Not on US Vemurafenib Zelboraf® Serdolect® and others mkt) Effexor® and others Zoloft® and others Voriconazole VFend® Ulane® and others Vorinostat Zolinza® VESIcare® 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 (e.g. terfenadine and astemizole) • Macrolide • Some psychotropic • 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 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) encoded by the KCNH2 gene • This potassium ion channel is responsible for the repolarisation in the cardiac action potential But has a role in anti-arrhythmics… • The risk of antiarrhythmic drug-induced TdP is thought to be related an inverse correlation between the heart rate and QT interval: – The QT interval decreases as the heart rate increases and… – Lengthens as the heart rate slows • This explains why drug-induced torsades de pointes is more commonly seen with bradycardia Some help for determining risk of drug-induced TdP

• In essence, a greater risk of SCD is identified by:

– Longer QT prolongation – Combination of conditions or – Combination of QT drugs

As a rule……

• Normal QTc < 440 msec • Abnormal (the 99th percentile): QTc of >470 msec (men) and >480 msec (women)* • Clinically significant >500 msec • Drug induced QT prolongation is usually dose related • Roughly for every 10 msec increase in QTc, there is a 5% increase in the risk of TdP

*2011 AHA/ACC scientific statement Further data

• Investigators measured: – The plasma concentrations of QT drugs achieved during usual clinical use: the effective free therapeutic plasma concentration (ETCP) – The in-vitro concentration of the drug that inhibits 50% of potassium ion channels (IC50). • The ratio of these values (ETCP/IC50) is thought to be a measure of the therapeutic/toxic window • The following findings in about 50 drugs were reported: • The ETCP/IC50 ratio ranged from 0.00003 for to 29.7 for thioridazine • There was a linear relationship between the ETCP/IC50 ratio and the reported incidence of a composite end point of cardiac arrest, sudden death, TdP, ventricular tachycardia, and ventricular fibrillation.

International Drug Monitoring Program of the World Health Organization (2005) Effects of oral anti-psychotic therapy on the QT interval Mean Incr. % >60 msec • Thioridazine 35.8 msec 29% • Ziprasidone 20.6 msec 21% • Quetiapine 14.5 msec 11% • Risperidone 10 msec 4% • Olanazipine 6.4 msec 4% • Haloperidol 4.7 msec 4% Cardiology Examples

• Quinidine has been the most frequently implicated cause of drug-induced TdP, with an incidence of 0.6 -1.5%. Most cases occur within 48 hours of initiating drug therapy; associated factors are hypokalemia and excessive bradycardia, rather than dose level. • Sotalol causes QT prolongation and TdP in ~2% men and 4% women. Tthese complications usually are related to the dose. • Amiodarone markedly prolongs the QT interval, but is rarely associated with TdP, except when used concomitantly with a class IA agent or when hypokalemia is present. Mental Health Examples

• Haloperidol: QT prolongation and TdP have been observed in patients receiving haloperidol, especially when given IV or in higher doses than recommended. • In vitro studies have shown that haloperidol is a high-potency blocker of the potassium ion channel.

• Methadone is a cause of TdP. Erythromycin Interactions

• Taking erythromycin led to a 2-fold increase in SCD. • There is added caution of concomitant prescribing with drugs that inhibit CYP3A4 • In an analysis of over one million patient-years of follow-up data, those taking , , or azole antifungal drugs had a 5-fold increase in sudden cardiac death risk when taking erythromycin Risk Factors……1

• Unmodifiable factors: – Occult (latent) congenital LQTS – Underlying heart disease, particularly , , and left ventricular hypertrophy – Advanced age – Female sex about 70% of cases: oestrogen potentiates QT prolongation induced by bradycardia

• Electrolyte disturbances: – hypokalemia and hypomagnesemia and less often hypocalcemia – Impaired hepatic and/or renal function

Risk Factors……2

• Drug Treatment: – High drug doses of QT drug – Rapid intravenous infusion of QT drug – Concurrent use of more than one drug that can prolong the QT – Diuretic treatment may lead to hypokalaemia

• ECG factors: – Baseline QT prolongation – The development of marked QT during therapy – Bradycardia or premature complexes

• Recent conversion from

Prescribing Advice

• Be aware of risk factors! • Alternative agents should be considered • Use of more than one QT prolonging drug should be avoided, if possible. • Baseline ECGs and FU ECGs • Patient advice regarding symptoms of palpitation etc, changes to other therapy or illness e.g. diarrhoea Treatment of TdP

• If cardiac arrest: – Treat as pulse-less VT/VF

• If haemodynamically compromised: – Emergency cardioversion

• If not compromised: – Preference: IV – Second line: Temporary cardiac pacing – as bridge to pacing – Others: IV Lignocaine Summary

• 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 Drugs to be avoided in Congenital Prolonged QT

Albuterol Clarithromycin Ketoconazole Ondansetron Alfuzosin Clomipramine Flecainide Levalbuterol Paroxetine Solifenacin Amantadine Clozapine Fluconazole Levofloxacin Pentamidine Sotalol Amiodarone Cocaine Fluoxetine Levomethadyl Phentermine Sparfloxacin Amitriptyline Desipramine Foscarnet Lithium Tacrolimus

Amoxapine Dextroamphet. Fosphenytoin Mesoridazine Phenylpropanol. Tamoxifen Amphet./dextro Disopyramide Galantamine Metaproterenol Pimozide Telithromycin Ampicillin Gatifloxacin Methadone Procainamide Arsenic trioxide Dofetilide Gemifloxacin Methylphenidate Protriptyline Thioridazine Dolasetron Granisetron Tizanidine Azithromycin Domperidone Halofantrine Quetiapine Tolterodine Bepridil Haloperidol Moexipril/HCTZ Quinidine Trimethoprim-Sul Chloral hydrate Doxepin Ibutilide Moxifloxacin Ranolazine Trimipramine Chloroquine Droperidol Imipramine Nicardipine Risperidone Vardenafil Chlorpromazine Indapamide Venlafaxine Ciprofloxacin Epinephrine Isoproterenol Nortriptyline Roxithromycin* Voriconazole Cisapride Erythromycin Isradipine Ziprasidone Citalopram Felbamate Itraconazole Ofloxacin Sertraline