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IntroductionDrug-induced prolongation of the QT interval has been
known to occur after administration of antiarrhythmics for
more than 20 years.1 Recently, drug-induced long QT
syndrome (LQTS) has been observed after administration of
non-antiarrhythmic medications.1 The additional attention
paid to the mechanisms of hereditary QT prolongation has
led to numerous advances in our understanding of how drugs
produce QT prolongation.1
Torsades de Pointes (TdP) is a concern in any patient
receiving a drug with QT prolonging potential. TdP is a
polymorphic ventricular arrhythmia which may result from
LQTS and can lead to cardiac arrest. At least nine drugs have
been withdrawn from the market world-wide because of their
propensity to cause TdP. In fact, more drugs have been
removed from the market within the past 10 years in the
United States for increased risk for TdP than any other
reason.2 Fortunately, the risk of developing TdP is small
(<0.01% in the absence of risk factors)3 despite prolongation
of the QT interval. This is because the etiology of TdP is
more complex than simple QT prolongation.2 This review
will discuss the pathophysiology, causes and management of
drug-induced QT prolongation.
PathophysiologyThe length of the QT interval is inversely related to the
heart rate. The faster the heart rate the shorter the QT
interval. The most common method to eliminate the effect of
the heart rate is the Bazett formula for the QTc, which
divides the QT interval by the square root of the RR interval.
The QT interval is equal to the QTc interval when the heart
rate is 60 bpm.1 Normal QTc intervals are less than 430 ms
for males and less than 450 ms for females. It is not
considered prolonged until it exceeds 450 ms in males and
470 ms in females. Lengthening of the QT interval occurs
when cardiac repolarization is delayed.
A Program of the University of Utah College of Pharmacy
tox pdateU T A H P O I S O N C O N T R O L C E N T E R
2005VOLUME 7
ISSUE 3
Drug-Induced QT ProlongationDepolarization occurs when positive ions (mostly sodium)
flow into the ventricular myocyte and repolarization when
positive ions (potassium) flow out. The action potential is
lengthened when there is an augmentation of inward
depolarizing currents or inhibition of outward repolarizing
potassium currents in ventricular myocytes.2 Most types of
congenital LQTS are a result of genetic mutations in the ion
channels active during the ‘plateau’ phase (phase 2) of the
action potential responsible for the delicate balance between
depolarization and repolarization. Drugs that prolong the QT
interval (drug-induced LQTS) almost universally interfere
with potassium outflow through the rapidly activating
delayed rectifier potassium channels (IKr).1 The IKr
channels are coded for by the human Ether-à-go-go Related
Gene (hERG) and are also called hERG channels. Other
potassium channels may also be implicated in drug-induced
QT prolongation.2
Recent studies have shown variability in the sensitivity of
cardiac myocytes to pharmacologic interference with
repolarization based on location within the myocardium.2
Myocytes within the endocardium and epicardium are less
susceptible to QT prolongation by certain pharmacologic
agents than are mid-myocardium cells (M cells) found in the
deep structures of the ventricular myocardium. This
difference in susceptibility is due to ion flow through
membrane channels (smaller IKs and a larger late INa and
sodium-calcium exchange current (INa-Ca)). Agents known
to cause TdP (quinidine, sotalol, etc.) do so through a
transmural dispersion of repolarization. Repolarization is
delayed in one region of the myocardium (M cells) more than
in another region (endocardium and epicardium). The end
result is a lengthened T-wave on the surface ECG. TdP
develops in experimental models when the time difference in
repolarization between the M cells and other regions of the
ventricular myocardium approaches 90 ms. When
endocardial and epicardial depolarization occur before M
cell repolarization is complete, TdP results.4 This premature
depolarization is also called early afterdepolarization (EAD).5
Table 3. Drugs in OverdoseAssociated with TdP7
methadone
thioridazine
quetiapine
venlafaxine
amitriptyline
desipramine
fluoxetine
sertraline
propoxyphene
haloperidol
lithium
risperidone
ziprasidone
nortriptyline
imipramine
paroxetine
arsenic
fluoride
classes associated with QTc prolongation and specific drugs
of concern. A more complete list can be found elsewhere.7
QT prolongation and risk for TdP is most likely to occur
during therapeutic administration of medications. However,
QT prolongation may also occur after an acute overdose.
Table 3 lists drugs commonly associated with QT
prolongation in overdose.
Magnesium Treatment for ProlongedQTc and TdP
Prolongation of the QTc is harmless by itself, but patients
have increased risk of developing TdP and resultant cardiac
arrest when their QTc exceeds 500 ms.6 Magnesium chloride
has been shown to prevent depolarization at action potentials
larger than -70 mV (the usual trigger point) and suppress early
afterdepolarizations in canine cardiac myocytes.5 However,
magnesium sulfate failed to correct QTc intervals lengthened
by haloperidol overdose in a canine model.8 In a case series of
12 patients with QTc in intervals ranging from 540 to 720 ms
who developed TdP, intravenous magnesium sulfate (2-4
grams IV bolus) successfully reversed TdP and prevented its
recurrence.9 No significant changes in the QTc interval were
observed after treatment. The mechanism by which
magnesium functions to reverse and prevent TdP without
shortening a prolonged QTc interval remains uncertain.
Current theories include acting as a cofactor to enhance
sodium-potassium ATPase function, stabilizing the membrane
potential and correcting dispersed repolarization.8
There are no published guidelines for magnesium
administration in the setting of QTc prolongation that are
based on prospective studies. However, it is reasonable to
administer magnesium intravenously to every patient with a
QTc exceeding 500 ms. Patients who possess any of the
Drugs causes of QTc prolongation The occurrence of TdP in patients not taking class IA, 1C,
and III antiarrhythmics is due to an idiosyncratic reaction.
Several reviews have identified female gender as the most
common risk factor in patients who developed TdP.1 A
variety of other risk factors have also been identified and are
listed in Table 1.
More than 70 commercially available and investigational
drugs have been implicated in QTc prolongation.2 The
University of Arizona maintains a list of currently available
medications that cause QTc prolongation
(www.torsades.org).7 Table 2 lists examples of general drug
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Table 1. Risk Factors for TdP with QTcProlongation6
Female gender
Heart disease (heart failure,
cardiomyopathies,hypertrophy)
Hypokalemia
Concomitant administration of multiple QT-prolonging
drugs
Bradycardia
Familial history of LQTS
Recent conversion of atrial fibrillation with a QT-
prolonging drug
Hypocalcemia
Hypomagnesemia
High levels of a QT-prolonging drug
Table 2. Drug Classes and Specific DrugsAssociated with TdP7
Drug Class Specific Examples
Macrolide erythromycin, clarithromycin
antibiotics
Antifungals voriconazole
Fluoroquinolone gemifloxacin, sparfloxacin,
antibiotics gatifloxacin, levofloxacin
Antipsychotics haloperidol, chlorpromazine,
thioridazine
Antiemetics cisapride, promethazine, dolasetron,
droperidol
Antiarrhythmics ibutilide, amiodarone, dofetilide,
quinidine, sotalol, disopyramide,
procainamide
Miscellaneous methadone
A Publication for Health Professionals Page 3
common risk factors (see Table 1) may also benefit from
magnesium administration when their QTc is > 450 ms in
males or > 470 ms in females.
ManagementThe first step in managing patients with QT prolongation
is discontinuation of the offending agent. Maintain serum
potassium concentrations between 4 and 4.5 mmol/L as
hypokalemia has been associated with LQTS. For
asymptomatic patients, magnesium sulfate 1-2 gm over 2
minutes is appropriate. For symptomatic patients, or those
with TdP, administer a 2 gm IV bolus of magnesium sulfate
infused over 30-60 seconds and repeat every 5-15 minutes as
needed. Continuous magnesium sulfate infusions of 2-4
mg/min may be required. Monitor the serum magnesium
concentrations and for clinical signs of magnesium toxicity
(depressed deep tendon reflexes, muscle weakness,
bradycardia). Large doses of magnesium sulfate may result
in hypotension and cardiac arrest. Patients refractory to
magnesium administration or those with long pauses after
premature ventricular contractions may require cardiac
pacing to prevent development of TdP.1
QT prolongation after tricyclic antidepressant (TCA)
overdose will usually present with QRS widening as well.
Sodium bicarbonate infusion is the therapy of choice for
these patients.10
SummaryQT prolongation may occur following therapeutic and
toxic doses of a number of drugs. Magnesium sulfate is a
viable therapeutic option in the treatment of patients with
QTc prolongation or TdP. The UPCC is available for
consultation regarding the management of overdose patients
with drugs that prolong the QTc interval.
Joshua Walsh, PharmD
References1. Abriel H, Schlapfer J, Keller DI, Gavillet B, Buclin T, Biollaz J, Stoller R,
Kappenberger L. Molecular and clinical determinants of drug-induced
long QT syndrome: an iatrogenic channelopathy. Swiss Med Wkly.
2004;134:685-94.
2. Antzelevitch C. Arrhythmogenic mechanisms of QT prolonging drugs: is
QT prolongation really the problem? J Electrocardiol. 2004;37 Suppl:15-
24.
3. Frothingham, R. Rates of torsades de pointes associated with
ciprofloxacin, ofloxacin, levoflocacin, gatifloxacin, and moxifloxacin.
Pharmacology 2001;21:1468-72.
4. Shimizu W, Antzelevitch C. Cellular basis for the ECG features of the
LQT1 form of the long QT syndrome: Effects of b-adrenergic agonists and
antagonists and sodium channel blockers on transmural dispersion of
repolarization and Torsade de Pointes. Circulation 1998;98:2314-22.
5. Kaseda S, Gilmour RF Jr, Zipes DP. Depressant effect of magnesium on
early afterdepolarizations and triggered activity induced by cesium,
quinidine, and 4-aminopyridine in canine cardiac Purkinje fibers. Am
Heart J. 1989;118:458-66.
6. Roden DM. Drug-Induced Prolongation of the QT Interval. N Engl J Med
2004;350:1013-22.
7. www.torsades.org; accessed April 14, 2005.
8. Satoh Y, Sugiyama A, Tamura K, Hashimoto K. Effect of magnesium
sulfate on the haloperidol-induced QT prolongation assessed in the
canine in vivo model under the monitoring of monophasic action
potential. Jpn Circ J. 2000;64:445-451.
9. Tzivoni D, et al. Treatment of torsade de pointes with magnesium sulfate.
Circulation 1988;77:392–7.
10. Kerr GW, McGuffie AC, Wilkie S. Tricyclic antidepressant overdose: a
review. Emerg Med J 2001;18:236–41.
New EmployeesThe Utah Poison Control Center is pleased to welcome
Remington Johnson as our new customer satisfaction survey
intern. Remington is a senior in the Political Science
Department and the History Department at The University of
Utah. We are also pleased to have Mike Andrus, Chad Condie
and Mike Whipple join us as Poison Information Providers.
Mike, Chad and Mike are all students in the University of
Utah Doctorate of Pharmacy program. Welcome!
Meet the UPCC StaffMarty Malheiro has been the
Outreach Education Provider for the
UPCC since November 2003. She holds
a master’s degree in health education
from the University of Utah, and is a
Certified Health Education Specialist
(CHES). She is a member of the
AAPCC’s Public Education Committee on E-Resource. In her
short time at the center, she has traveled from one end of the
state to the other giving public education presentations on
poison prevention and awareness. Marty’s favorite poison
education topic is senior medication management. She is
married and has two awesome daughters, a dog, and a cat.
She loves to knit and play in the outdoors.
Checkout the UPCC website at
http://uuhsc.utah.edu/poison for public
education updates. The POISON ANITDOTE, our
seasonal newsletter, highlights current prevention
topics. Look for our new plant identification page
coming in September. It will have a searchable
database, as well as color photographs of
common poisonous plants in Utah.
Public Education
Poison antidote
Utah PoisonControl Center
StaffDirectorBarbara Insley Crouch, PharmD, MSPH
Medical DirectorE. Martin Caravati, MD, MPH
Associate Medical DirectorDouglas E. Rollins, MD, PhD
Assistant DirectorHeather Bennett, MPA
Office SupportJulie Gerstner
Specialists in PoisonInformationKathleen T. Anderson, PharmD, CSPI*
Bradley D. Dahl, PharmD, CSPI*
Su Bryner-Brown, RN, BSN
David Evans, PharmD, RPh, CSPI*
Scott Marshall, PharmD, CSPI*
Deborah Melle, RN, BS
Ed Moltz, RN, BSN, CSPI*
Sandee Oliver, RN, BSN
John Stromness, BS Pharm, RPh, CSPI*
Mary Towns, BSN, MS, APRN, CSPI*
Erlynn R. Wallace, RN, CSPI*
Poison Information ProvidersMichael Andrus
Chad Condie
Michael Whipple
Outreach Education ProviderMarty C. Malheiro, MS, CHES
Intern, Community OutreachJoel Arvizo
Survey InternRemington Johnson
UTOX EditorsE. Martin Caravati, MD, MPH
Barbara Insley Crouch, PharmD, MSPH
PublisherHeather Bennett, MPA
Please send comments and suggestions
for future articles to the editor of
UTOX Update at:
585 Komas Dr., Suite 200
Salt Lake City, Utah 84108
Or send e-mail to [email protected]
*CSPI denotes Certified Specialist in
Poison Information.
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UPCC 2004 Annual ReportThe UPCC is pleased to announce the publication of its 2004 Annual
Report. This report provides a summary of the calls received by the UPCC
in 2004. In addition, the report highlights the many and varied outreach
educational activities of the UPCC. The report can be found on the UPCC
website at http://uuhsc.utah.edu/poison. Follow the link for “About us” and
select annual reports. Shortly the 2004 Annual Report of the American
Association of Poison Control Centers Toxic Exposure Surveillance System
will be published. This report characterizes over 2 million poison exposures
reported to over 60 poison centers nationwide. The report can be found at
the AAPCC website at www.aapcc.org. Follow the link for “Poisoning Data-
TESS” and choose annual reports. Alternatively, look for the report
published in the September issue of the American Journal of Emergency
Medicine.