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Pharmacologic agents associated with QT interval prolongation.

KEY POINTS

Diverse classes of medications are associated with QT interval prolongation and expose patients to the risk of potentially fatal ventricular arrhythmias.

Clinicians can minimize adverse events by avoiding prescription of multiple medications associated with QT interval prolongation in high-risk patients.

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Certain classes of medications that are commonly used in clinical practice are associated with risk for QT interval prolongation and its complications. (1,2) The most serious yet rare of these potential complications is torsades de pointes (TdP), a polymorphic form of ventricular tachycardia that may result in sudden cardiac arrhythmia leading to death. Detection of QT interval prolongation (commonly calculated with a correction for heart rate and reported as QTc) and TdP is challenging during preclinical testing and in clinical trials, even though drug development includes several screening methods that may be used to predict these adverse events (AEs). Thus, clinicians should be aware of the potential safety risks associated with QT interval prolongation. In particular, avoiding combinations of 2 or more medications associated with QT interval prolongation in the same patient should be a consideration in daily practice.

Screening methods for drug-induced QT interval prolongation

Preclinical evaluation of new drug compounds includes the effects on the rapid potassium ion channel (IKr) encoded by the human cardiac ether-a-go-go-related (HERG) gene. (3) Inhibition of the IKr channel delays repolarization (measured as QT interval prolongation) and increases the risk of developing arrhythmias by blocking outward flow of potassium ions from myocytes. Screening for inhibition of the HERG gene is relatively inexpensive and can be performed for many drugs. It is often used early in drug development to identify or eliminate candidate compounds for further evaluation. Studies in animals allow in vivo assessment of QT interval prolongation and other cardiac functions associated with new drugs. (3) However, as in humans, TdP is an extremely rare event that may not be detected at all, and small changes in QTc values are difficult to interpret. Thus, both preclinical and clinical evaluations of the potential for TdP associated with any drug present challenges for drug development.

Monitoring for QT interval prolongation and torsades de pointes

Torsades de pointes is a rare event in the general population, with an estimated 8.6 cases per 10 million individuals. (4) In subjects receiving any medication, the incidence of TdP is 40 cases per 10 million population. (4) The frequency of TdP associated with medication use cannot be reliably predicted from clinical trials, so postmarketing surveillance and reporting of AEs during use in the general population are important mechanisms for overcoming the limitations of clinical trials in this regard. (3,5-7) In the 1990s, QT interval prolongation associated with TdP was the most common cause of the withdrawal or restriction of marketed medications by the Food and Drug Administration. (8) Nine noncardiac medications were affected, including terfenadine, astemizole, grepafloxicin, terodiline, droperidol, lidoflazine, sertindole, levomethadyl, and cisapride. (8) This broad range of medications highlights the difficulty in accurately predicting risk for drug-induced TdP.

Postmarketing surveillance has demonstrated that even small drug-induced increases in QTc values may increase the risk for TdP when sufficient numbers of patients are exposed. (9,10) For example, in 1 clinical trial, terfenadine was associated with mean increases in QTc values of only 6 msec in normal subjects and 12 msec in patients with cardiovascular disease (CVD). (9) Yet terfenadine was withdrawn from the market because of unacceptable rates of TdE Similarly, cisapride treatment caused a mean increase in QTc values of only 15 msec in a clinical trial but was also withdrawn because of TdP. (10) Conversely, medications such as amiodarone and verapamil cause significant QT interval prolongation, yet are rarely associated with TdP. (6) Thus, these findings complicate the interpretation of the relationship between QT interval prolongation and TdP.

Medication interactions and effect on QTc values

Medication interactions are one of the most important considerations for evaluating the risk of QT interval prolongation and serious cardiac events. (2,11) Drug interactions may be classified as pharmacodynamic effects, which result from use of 2 or more agents that prolong QTc values. Alternatively, drug interactions may be due to pharmacokinetic effects, which result from use of 1 drug that prolongs QTc values and concomitant therapy that interferes with its hepatic metabolism (a cytochrome P450 isozyme inhibitor, for example), causing increased serum concentrations of the first drug and higher rates of AEs (FIGURE 1). (2,11) Clinicians must consider both of these mechanisms and whether the potential benefit associated with prescribing 1 or more QT interval-prolonging agents outweighs the risks associated with the treatment regimen.

[FIGURE 1 OMITTED]

Agents associated with QT interval prolongation

Both cardiovascular (CV) and non-CV agents may increase QTc values. Antiarrhythmic agents are the medications most often cited in this regard. Consistent with their activities on cardiac electrophysiology, several have the unintended side effect of QT interval prolongation (TABLE 1). (1,8) These medications inhibit the IKr channel and increase the duration of action potentials, thus prolonging QTc values. The average increase in QTc values associated with antiarrhythmic agents is > 50 msec; TdP occurs in 1% to 8% of patients who receive these medications. (8) Class 1A and class III antiarrhythmic agents that may be involved in these events include amiodarone, azimilide, bepridil, bretylium, disopyramide, dofetilide, D-sotalol, flecainide, ibutilide, procainamide, propafenone, quinidine, and tedisamil. (1,8)

Many non-CV medications with diverse structures and functions are also associated with QT interval prolongation (TABLE 2). (1,8) The most commonly prescribed classes that may produce QT interval prolongation are macrolide antibiotics, fluoroquinolones, antipsychotic agents, and tricyclic antidepressants. (1,8)

Macrolide antibiotics. This group of anti-infective agents includes azithromycin, clarithromycin, erythromycin, and telithromycin. Erythromycin causes QT interval prolongation and blocks potassium channels encoded by the HERG gene. (12,13) Furthermore, erythromycin prolongs QTc values by participating in pharmacokinetic drug interactions through inhibition of cytochrome P450 3A4 enzymes. (12-14) Similarly, clarithromycin has been shown to inhibit rapid potassium channels that are encoded by the HERG gene. It is also reported to cause QT interval prolongation and increase the risk of TdP. (1,13) Azithromycin demonstrates less QT interval-prolonging activity than erythromycin and clarithromycin in a rabbit model of proarrhythmia. (15) Cases of TdP have been associated with use of erythromycin, clarithromycin, and azithromycin. (16) The effect of telithromycin on arrhythmia has not vet been determined.

The significance of QT interval prolongation associated with erythromycin was shown in a recent population-based study of a Medicaid cohort that included 1.25 million person-years of follow-up and 1476 cases of sudden death from cardiac causes. (17) Participants had a mean age of 45 years; 25% were 65 years or older. The population was 70% female and 58% white. In this large cohort, the rate of cardiac death was 2.01 times higher in patients treated with erythromycin vs patients with no antibiotic use (P = .03). Patients who received erythromycin concurrently with a P450 3A4 enzyme inhibitor had a rate of cardiac death that was 5.35 times higher than patients who received no antibiotic or cytochrome P450 3A4 inhibitor (P = .004) (FIGURE 2). (17) The CYP3A inhibitors included in the analysis were nitroimidazole antifungal agents, diltiazem, verapamil, and troleandomycin. These studies suggest that simultaneous use of erythromycin and inhibitors of cytochrome P450 3A4 enzymes should be avoided. (17)

Fluoroquinolones. Members of the fluoroquinolone class of antibiotics that are currently available include ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin. In general, fluoroquinolones do not interact with cytochrome P450 3A4 enzymes, so the risk of drug interactions through this mechanism is low. (7) However, some fluoroquinolones inhibit HERG rapid potassium channels and may increase the risk of QT interval prolongation. A recent study showed that the extent of HERG inhibition is variable in this group. Sparfloxacin and grepafloxacin were the most potent inhibitors of the HERG channel, with 50% inhibitory concentration ([IC.sub.50]) values of 18 [micro]M and 50 [micro]M, respectively. (18) Moxifloxacin and gatifloxacin exhibited intermediate inhibition, with [IC.sub.50] values of 129 [micro]M and 130 [micro]M, respectively. (18) Levofloxacin, ciprofloxacin, and ofloxacin were the least potent inhibitors, with [IC.sub.50] values of 915 [micro]M, 966 [micro]M, and 1420 [micro]M, respectively. (18) In clinical trials, fluoroquinolones have been associated with QT interval prolongation, and postmarketing surveillance includes reports of torsades de pointes for sparfloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin therapy. (7) Sparfloxacin and grepafloxacin have been withdrawn from the market due to the increased risk of cardiac-related fatalities, including TdP.

Large, population-based analyses of the association between fluoroquinolones, QT interval prolongation, and cardiac death have not been conducted. However, several recent clinical trials have evaluated QT interval prolongation with fluoroquinolones in both critically ill patients and healthy adults (TABLE 3). (19-24) In critically ill patients, moxifloxacin was associated with a significantly greater mean increase in QTc values and discontinuation rate than ciprofloxacin. (19) Prolonged QT intervals were observed at a similar rate with moxifloxacin and the antiarrhythmic agents haloperidol and amiodarone. (20) In healthy adults, ciprofloxacin, levofloxacin, and moxifloxacin were associated with QT interval prolongation compared with placebo in a dose-dependent manner. (21-24) In dose escalation trials, moxifloxacin was associated with prolonged QTc values 2 hours after administration of both the prescribing dose (400 mg) and twice the prescribing dose (800 mg). (22) In contrast, levofloxacin was not associated with prolonged QTc values 2 hours after administration of the prescribing dose (500 mg) or twice the prescribing dose (1000 mg). (21) Moxifloxacin was associated with the greatest mean increase in QTc values in comparative trials. (23,24) The mean increase in QTc values were 16.3 to 17.8 msec for moxifloxacin, 800 mg; 3.5 to 4.9 msec for levofloxacin, 1000 mg; and 2.3 to 4.9 msec for ciprofloxacin, 1500 mg. (23) Although comparison among different trials is inherently difficult because of differences in trial design, these results suggest that the magnitude of QT interval prolongation varies among the fluoroquinolones in both critically ill patients and healthy adults. Future clinical trials should address the association among fluoroquinolone use, QT interval prolongation, and the risk for sudden cardiac death in a large patient population.

Antipsychotic medications. Psychiatric patients have higher rates of sudden cardiac death than does the general population, but the reasons for this phenomenon are not fully understood. (25) The effects of antipsychotic medications and other risk factors on QT interval prolongation were evaluated in 495 psychiatric patients, 93 % of whom were receiving antipsychotic agents. (26) The population was 60% male with an average age of 45 years. QTc values in this group were compared with those in 101 healthy control patients. This study showed that increasing doses of antipsychotic agents were associated with increased risk for abnormal QTc values. Prolongation of QTc values was defined from the control population as 456 msec or greater. High medication doses (chlorpromazine 1001 to 2000 mg or an equivalent dose of another medication) were associated with an odds ratio (OR) of 5.4 (P = .03) for QTc interval prolongation and very high doses (chlorpromazine > 2000 mg or an equivalent dose of another medication) were associated with an OR of 8.2 (P = .01) for increased QTc values. (26) The highest risk of QTc interval prolongation associated with individual agents was observed with droperidol (OR 6.7; P = .004) and thioridazine (OR 5.3; P = .001). (26) Thus, this study demonstrated a dose-related correlation between QT prolongation and use of antipsychotic medications.

In addition to this analysis, a population-based analysis of a Medicaid cohort that included 1.28 million person-years of follow-up and 1487 cases of confirmed cardiac death was performed to evaluate the association between use of antipsychotic agents and risk of sudden death. (27) In this large population, 70% of participants were female and 59% were white. This study demonstrated that the risk for sudden death for individuals who were currently receiving moderate doses of antipsychotic medications (thioridazine, 100 mg, or an equivalent dose of another antipsychotic medication) was 2.39 times higher than for nonusers (P < .001). (27) In participants with severe CVD, the rate of cardiac death was 3.53 times higher in those who received moderate doses of thioridazine than in nonusers (P < .001). (27) Other members of this class associated with QT interval prolongation include haloperidol, mesoridazine, pimozide, quetiapine, risperidone, and sertindole. (1,26)

Tricyclic antidepressants. The potential association of these agents with sudden cardiac death was evaluated in the same large Medicaid cohort mentioned above that included 1.28 million person-years of follow-up and 1487 cases of sudden cardiac death. (28) Risk of sudden cardiac death with tricyclic antidepressants increased in a dose-dependent manner. Patients who were currently taking tricyclic antidepressants at doses [greater than or equal to] 300 mg had a 2.53 times higher risk than nonusers (P = .03 for dose response) (FIGURE 3). (28) Among patients who were taking amitriptyline [greater than or equal to] 100 mg or an equivalent dose of another medication, the risk of sudden death was 1.41 times higher compared with nonusers (P = .038) and 1.5 times higher in patients with treated CVD compared with those without CVD (P = .02). Other antidepressants associated with QT interval prolongation include desipramine, doxepin, fluoxetine, imipramine, paroxetine, sertraline, and venlafaxine. (1)

Other classes. Antiretroviral agents, antifungal agents, and tamoxifen may increase QTc values and the risk of TdP either directly or through inhibition of cytochrome P450 enzymes. (11,29) In addition, some medications of unrelated classes, such as arsenic trioxide, cisapride, dolasetron, foscarnet, halofantrine, indapamide, ketoconazole, moexipril, octreotide, pentamidine, tacrolimus, and tizanidine, have been implicated in reports of QT interval prolongation (TABLE 2). (1,8) Updated lists of individual medications that have been associated with increased risk of TdP can be found on the Internet at http://www.torsades.org.

Patterns of prescribing QT interval-prolonging medications

The risk of TdP and sudden cardiac death associated with QT prolongation requires physicians to use caution in prescribing concomitant therapy with medications that may produce this effect. High rates of concomitant therapy with 2 or more QT interval-prolonging medications were found in a retrospective cohort analysis of a large prescription claims database that included 4.8 million patients. (30) The analysis included 50 medications associated with QT interval prolongation and 26 agents that inhibit hepatic or renal clearance of these medications. In this study, 22.8% of patients (n = 1.1 million) had a prescription for at least 1 medication associated with QT interval prolongation, of which 47.4% were for erythromycin or clarithromycin and 40% were for antidepressants. (30) Among all patients with prescriptions for at least 1 QT interval-prolonging agent, 103,119 (9.4%) filled overlapping prescriptions for at least 1 other QT interval-prolonging medication or for at least 1 agent that inhibits its clearance. Of these patients, 7249 (0.7%) filled overlapping prescriptions for 3 or more potentially interacting medications (TABLE 4). (30)

Among 103,119 patients who filled 2 or more prescriptions for medications that may prolong QTc values, 74% were women and 22% were 65 years or older. (30) Among 445,668 patients who filled prescriptions for antidepressants associated with QT interval prolongation, 26.9% also filled an overlapping prescription for a potentially interacting medication. (30) Thus, medications that may increase QTc values, especially macrolide antibiotics and antidepressants, are frequently prescribed for concomitant therapy in the general outpatient population. Because of the potential for serious cardiac events associated with these practices, clinicians should determine that the benefits of these regimens outweigh the risks and avoid, if possible, concurrent prescription of these agents in patients with multiple risk factors for QT interval prolongation.

Conclusion

A large and diverse group of medications is associated with the potential for QT interval prolongation and exposes patients to the risk of ventricular arrhythmias and TdP. Because detection and prediction of these AEs in clinical trials is challenging, they are frequently revealed after a medication has entered the market and many patients have been treated. To increase timely recognition of medication-induced cardiac problems in the community, health care professionals should report any AE suggestive of cardiac arrhythmias to drug safety authorities and to drug manufacturers. In addition, clinicians should be aware of the risks associated with these agents and take appropriate precautions to minimize those risks, particularly by avoiding prescription of multiple medications associated with QT prolongation in high-risk patients. Periodic review of recent literature or changes to prescribing recommendations is warranted to monitor updates in QT safety precautions.
TABLE 1

Antiarrhythmic Agents Associated
With QT Interval Prolongation. (1,8)

Amiodarone
Azimilide
Bepridil
Bretylium
Disopyramide
Dofetilide
D-sotalol
Flecainide
Ibutilide
Procainamide
Propafenone
Quinidine
Tedisamil

TABLE 2
Noncardiac Medications Associated With QT Interval Prolongation (1,8)

Macrolide Antibiotics   Fluoroquinolones       Antidepressants

Azithromycin            Ciprofloxacin          Amitriptyline
Clarithromycin          Gatifloxacin           Desipramine
Erythromycin            Levofloxacin           Doxepin
                        Moxifloxacin           Fluoxetine
                                               Imipramine
                                               Paroxetine
                                               Sertraline
                                               Venlafaxine

Antipsychotic
Agents                  Other Agents

Droperidol              Arsenic trioxide, tamoxifen
Haloperidol               (antineoplastic)
Mesoridazine            Cisapride (gastrointestinal adjunct)
Pimozide                Dolasetron, domperidone
Quetiapine                (antiemetic agents)
Risperidone             Foscarnet (antiviral)
Sertindole              Halofantrine (antimalarial)
Thioridazine            Indapamide, moexipril
Chlorpromazine            (antihypertensive)
                        Ketoconazole (antifungal)
                        Octreotide (multiple indications,
                          including antidiarrheal and
                          antihemorrhagic)
                        Pentamidine (antiprotozoal)
                        Tacrolimus (immunosuppressant)
                        Tizanidine (antispastic)

TABLE 3
Clinical Trials Evaluating QT Interval
Prolongation With Fluoroquinolones

QT Interval Prolongation in Critically III Patients (19,20)

Number        Mean Age
of Patients   (y)        Medication               Outcomes

25            70.1       Moxifloxacin,            Mean increase in QTc
                         400 mg IV                value: 85.3 msec with
                         Ciprofloxacin,           moxifloxacin vs 47.1
                         200 to 400 mg IV         msec with
                                                  ciprofloxacin
                                                  (P = .039)
                                                  Discontinuation rate
                                                  due to QTc value >
                                                  500 msec: 41% with
                                                  moxifloxacin vs 13%
                                                  with ciprofloxacin

267           64         Several prespecified     Highest rate of QTc
                         QT interval              value > 500, increase
                         prolonging medications   in QTc > 60 msec over
                                                  baseline, and new
                                                  onset ventricular
                                                  ectopy:
                                                  Moxifloxacin (48.1%)
                                                  Haloperidol (45.9%)
                                                  Amiodarone (45.1%)

QT Interval Prolongation in Healthy Adults (21-24)

Number        Mean Age                            Mean QTc Value
of Patients   (y)        Medication               at 2 H (msec)

47            47.1       Placebo                  NS
                         Levofloxacin, 500 mg     NS
                         Levofloxacin, 1000 mg    NS
                         Levofloxacin, 1500 mg    414 msec *

18            23.8       Placebo                  NS
                         Moxifloxacin, 400 mg     394 msec ([section])
                         Moxifloxacin, 800 mg     396 msec ([section])

47            47.6       Placebo                  Not reported
                         Moxifloxacin, 800 mg
                         Levofloxacin, 1000 mg
                         Ciprofloxacin, 1500 mg

47            18 to      Placebo                  Not reported
                > 60     Moxifloxacin, 400 mg
                         Moxifloxacin, 800 mg
                         Levofloxacin, 500 mg
                         Levofloxacin, 1000 mg
                         Erythromycin, 1000 mg

Number        Mean Age                            Mean Increase in
of Patients   (y)        Medication               QTc Value (msec)

47            47.1       Placebo                  NS
                         Levofloxacin, 500 mg     NS
                         Levofloxacin, 1000 mg    1.5 to 3.9 ([dagger])
                         Levofloxacin, 1500 mg    6.4 to 7.7 ([double
                                                    dagger])

18            23.8       Placebo                  Not reported
                         Moxifloxacin, 400 mg
                         Moxifloxacin, 800 mg

47            47.6       Placebo                  --
                         Moxifloxacin, 800 mg     16.3 to 17.8
                                                    ([parallel])
                         Levofloxacin, 1000 mg    3.5 to 4.9 ([section])
                         Ciprofloxacin, 1500 mg   2.3 to 4.9 ([section])

47            18 to      Placebo                  --
                > 60     Moxifloxacin, 400 mg     13.1 ([paragraph])
                         Moxifloxacin, 800 mg     16.3 ([paragraph])
                         Levofloxacin, 500 mg     2.1 ([paragraph])
                         Levofloxacin, 1000 mg    7.3 ([paragraph])
                         Erythromycin, 1000 mg    2.2 ([paragraph])

                                                  Episodes of QTc
                                                  > 450 msec (men)
Number        Mean Age                            and > 470 msec
of Patients   (y)        Medication               (women)

47            47.1       Placebo                  Not reported
                         Levofloxacin, 500 mg
                         Levofloxacin, 1000 mg
                         Levofloxacin, 1500 mg

18            23.8       Placebo                  4 (females)
                         Moxifloxacin, 400 mg
                         Moxifloxacin, 800 mg

47            47.6       Placebo                  3
                         Moxifloxacin, 800 mg     6

                         Levofloxacin, 1000 mg    2
                         Ciprofloxacin, 1500 mg   1

47            18 to      Placebo                  Not reported
                > 60     Moxifloxacin, 400 mg
                         Moxifloxacin, 800 mg
                         Levofloxacin, 500 mg
                         Levofloxacin, 1000 mg
                         Erythromycin, 1000 mg

NS = not significant. All QTc values reported
are calculated from Bazett's formula.
Levofloxacin 500 mg, 1000 mg, and 1500 mg is equivalent to the
prescribing dose, 2 times the prescribing dose, and 3 times the
prescribing dose, respectively. Moxifloxacin, 400 mg and 800 mg
are equivalent to the prescribing dose and twice the prescribing
dose, respectively. Ciprofloxacin 1500 mg and erythromycin 1000
mg are equivalent to 2 times the prescribing dose.

* P [less than or equal to] .05 vs placebo.

([dagger]) P [less than or equal to] .05 vs placebo.

([double dagger]) P [less than or equal to] .001 vs placebo.

([section]) P <.05 vs placebo; ([parallel]) P <.001 vs placebo.

([paragraph]) Mean increase in QTc from baseline at [C.sub.max].

TABLE 4
Overlapping Prescriptions of Medications
Associated with QT Interval Prolongation (30)

                           Number of Patients
Number of Prescriptions     (N = 4.8 million)

1 or more                     1,097,871
2 or more                       103,119
3 or more                          7249

FIGURE 2
Risk of Sudden Cardiac Death Increases
With Use of Erythromycin
and a CYP3A Inhibitor (17)

                      Risk for Sudden Cardiac Death

Concur erythromycin
and CYP3A inhibitor              5.35 *

Erythromycin                     2.01 ([dagger])

Amoxicillin                      1.18

CYP3A inhibitor                  0.93

* P = .004 vs no antibiotic or CYP3A inhibitor therapy; ([dagger]) P =
.03 vs no antibiotic or CYP3A inhibitor therary.

Note: Table made from bar graph.

FIGURE 3
Risk of Sudden Cardiac Death With Use
of Tricyclic Antidepressants (28)

Tricyclic antidepressant dose (mg)   Risk of Sudden Cardiac Death

<100                                             0.97
200                                              1.25
300                                              1.67
[greater than or equal to] 300                   2.53

P = .03 for trend

Note: Table made from bar graph.


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Keith M. Olsen, PharmD, FCCE FCCM

University of Nebraska Medical Center

Omaha, NE
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Date:Jun 1, 2005
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