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

R-R

QT

Bazzett’s Formula: QTc = QT/ √R-R

Bazett HC. An analysis of the time relationships of

electrocardiograms. Heart. 1920;7:355-70.

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’

Online QT Calculator

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

Alfuzosin Uroxatral®

Amantadine Symmetrel® and others

Amiodarone Cordarone® and others

Amisulpride Solian® and others

AmitriptylineElavil® (Discontinued 6/13)

and others

Amoxapine Asendin® and others

Anagrelide Agrylin® and others

Apomorphine Apokyn® and others

Aripiprazole Abilify® and others

Arsenic trioxide Trisenox®

Astemizole (Off US mkt) Hismanal®

Atazanavir Reyataz®

Azithromycin Zithromax® and others

Bedaquiline Sirturo®

Bepridil (Off US mkt) Vascor®

Bortezomib Velcade® and others

Bosutinib Bosulif®

Chloral hydrate Aquachloral® and others

Chloroquine Aralen®

Chlorpromazine Thorazine® and others

Ciprofloxacin Cipro® and others

Cisapride (Off US mkt) Propulsid®

Citalopram Celexa® and others

Clarithromycin Biaxin® and others

Clomipramine Anafranil®

Clozapine Clozaril® and others

Cocaine Cocaine

Crizotinib Xalkori®

Dabrafenib Tafinlar®

Dasatinib Sprycel®

Generic Name Brand Name

Desipramine Pertofrane® and others

Dexmedetomidine Precedex® and others

Dihydroartemisinin+piperaquine Eurartesim®

Diphenhydramine Benadryl® and others

Disopyramide Norpace®

Dofetilide Tikosyn®

Dolasetron Anzemet®

Domperidone (Not on US mkt) Motilium® and others

Doxepin Sinequan® and others

Dronedarone Multaq®

Droperidol Inapsine® and others

Eribulin Halaven®

Erythromycin E.E.S.® and others

Escitalopram Cipralex® and others

Famotidine Pepcid® and others

Felbamate Felbatol®

Fingolimod Gilenya®

Flecainide Tambocor® and others

Fluconazole Diflucan® and others

Fluoxetine Prozac® and others

Foscarnet Foscavir®

Fosphenytoin Cerebyx® and others

Furosemide (Frusemide) Lasix® and others

Galantamine Reminyl® and others

Gatifloxacin (Off US mkt) Tequin®

Gemifloxacin Factive®

Granisetron Kytril® and others

Halofantrine Halfan®

Haloperidol Haldol® (US & UK) and others

Hydrochlorothiazide Apo-Hydro® and others

Generic Name Brand Name

Ibutilide Corvert®

Iloperidone Fanapt® and others

Imipramine (melipramine) Tofranil®

Indapamide Lozol® and others

Isradipine Dynacirc®

Itraconazole Sporanox® and others

Ivabradine (Not on US mkt) Procoralan® and others

Ketoconazole Nizoral® and others

Lapatinib Tykerb® and others

Levofloxacin Levaquin® and others

Levomethadyl (Off US mkt) Orlaam®

Lithium Eskalith® and others

Mesoridazine (Off US mkt) Serentil®

Methadone Dolophine® and others

Metronidazole Flagyl® and many others

Mifepristone Korlym® and others

Mirabegron Myrbetriq®

Mirtazapine Remeron

Moexipril/HCTZ Uniretic® and others

Moxifloxacin Avelox® and others

Nelfinavir Viracept®

Nicardipine Cardene®

Nilotinib Tasigna®

Norfloxacin Noroxin® and others

Nortriptyline Pamelor® and others

Ofloxacin Floxin®

Olanzapine Zyprexa® and others

Ondansetron Zofran® and others

Oxytocin Pitocin® and others

Paliperidone Invega® and others

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

Paroxetine Paxil® and others

Pasireotide Signifor®

Pazopanib Votrient®

Pentamidine Pentam®

Perflutren lipid

microspheresDefinity®

Pimozide Orap®

Pipamperone (Not on

US Mkt)

Dipiperon (E.U) and

others

Posaconazole Noxafil® and others

Probucol (Off US mkt) Lorelco®

Procainamide (Oral off

US mkt)Pronestyl® and others

Promethazine Phenergan®

Protriptyline Vivactil®

Quetiapine Seroquel®

Quinidine Quinaglute® and others

Quinine sulfate Qualaquin®

Ranolazine Ranexa® and others

Rilpivirine Edurant® and others

Risperidone Risperdal®

Ritonavir Norvir®

Roxithromycin (Not on

US Mkt)Rulide® and others

Saquinavir Invirase®(combo)

Sertindole (Not on US

mkt)Serdolect® and others

Sertraline Zoloft® and others

Sevoflurane Ulane® and others

Solifenacin VESIcare®

Generic Name Brand Name

Sorafenib Nexavar®

Sotalol Betapace® and others

Sparfloxacin (Off US mkt) Zagam®

Sulpiride (Not on US

Mkt.)Dogmatil® and others

Sunitinib Sutent®

Tacrolimus Prograf® and others

TamoxifenNolvadex®(discontinued

6/13) and others

Telaprevir Incivek® and others

Telavancin Vibativ®

Telithromycin Ketek®

Terfenadine (Off US mkt) Seldane®

Tetrabenazine (Orphan

drug in US)Nitoman® and others

Thioridazine Mellaril® and others

Tizanidine Zanaflex® and others

Tolterodine Detrol® and others

Toremifene Fareston®

TrazodoneDesyrel® (discontinued

6/13) and others

Trimethoprim-Sulfa Septra® and others

Trimipramine Surmontil® and others

Vandetanib Caprelsa®

Vardenafil Levitra®

Vemurafenib Zelboraf®

Venlafaxine Effexor® and others

Voriconazole VFend®

Vorinostat Zolinza®

Ziprasidone Geodon® and others

Note: Medicines on this list are reviewed on an ongoing

basis to assure that the available evidence supports their

continued placement on this list. The list changes regularly

and we recommend checkingthe website at

crediblemeds.org for the most up-todate information.

There may be many additional brand names that are not

listed on this form.

Disclaimer and Waiver: The information presented is

intended solely for the purpose of providing general

information about health-related matters. It is not intended

for any other purpose, including but not limited to medical

advice and/or treatment, nor is it intended to substitute for

the users relationships with their own health care

providers. To that extent, by use of this website and the

information it contains, the user affirms the understanding

of the purpose and releases AZCERT, Inc. from any

claims arising out of his/her use of the website and its lists.

The absence of drugs from these lists should not be

considered an indication that they are free of risk of QT

prolongation or TdP. Many medicines have not been

tested for this risk in patients, especially those with

congenital long QT syndrome.

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 ion channel is responsible

for the repolarisation in the cardiac action

potential

But bradycardia 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 nifedipine 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 diltiazem, verapamil, 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 heart failure, myocardial infarction, 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 atrial fibrillation

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 Magnesium

– Second line: Temporary cardiac pacing

– Isoprenaline 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 Fenfluramine Ketoconazole Ondansetron Sibutramine

Alfuzosin Clomipramine Flecainide Levalbuterol Paroxetine Solifenacin

Amantadine Clozapine Fluconazole Levofloxacin Pentamidine Sotalol

Amiodarone Cocaine Fluoxetine Levomethadyl Phentermine Sparfloxacin

Amitriptyline Desipramine Foscarnet Lithium Phenylephrine Tacrolimus

Amoxapine Dextroamphet. Fosphenytoin Mesoridazine Phenylpropanol. Tamoxifen

Amphet./dextro Disopyramide Galantamine Metaproterenol Pimozide Telithromycin

Ampicillin Dobutamine Gatifloxacin Methadone Procainamide Terbutaline

Arsenic trioxide Dofetilide Gemifloxacin Methylphenidate Protriptyline Thioridazine

Atomoxetine Dolasetron Granisetron Mexiletine Pseudoephedrine Tizanidine

Azithromycin Domperidone Halofantrine Midodrine Quetiapine Tolterodine

Bepridil Dopamine Haloperidol Moexipril/HCTZ Quinidine Trimethoprim-Sul

Chloral hydrate Doxepin Ibutilide Moxifloxacin Ranolazine Trimipramine

Chloroquine Droperidol Imipramine Nicardipine Risperidone Vardenafil

Chlorpromazine Ephedrine Indapamide Norepinephrine Ritodrine Venlafaxine

Ciprofloxacin Epinephrine Isoproterenol Nortriptyline Roxithromycin* Voriconazole

Cisapride Erythromycin Isradipine Octreotide Salmeterol Ziprasidone

Citalopram Felbamate Itraconazole Ofloxacin Sertraline