drugs and the qt - ukmi...• in a review of 92 patients from the united states with drug-induced...
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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 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