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been withdrawn from the market world-wide because of their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

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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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The Utah Poison Control Center expresses its sincere thanks to

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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 poison@hsc.utah.edu

*CSPI denotes Certified Specialist in

Poison Information.

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Employment OpportunitiesThe UPCC has an open position available. You can find out more about

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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.