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Assessing Risk of QTC Prolongation

Assessing Risk of QTC Prolongation

Certain psychotropic medications and somatic medications can increase the

risk of lethal torsade de pointes through a mechanism of blocking cardiac

conduction channels (e.g., Na+, K+ and/or Ca++). The best available parameter

for assessing risk of torsade de pointes is measuring the rate-corrected QT

interval (QTC) on electrocardiogram (Labellarte et al., 2003a; Tisdale et al.,

2001).

While it is necessary to identify whether or not a psychotropic medication

can prolong QTC alone or in combination with other medications, the list of

marketed medications that are known to prolong QTC is incomplete (Labellarte et

al., 2003a). Available QTC safety data are a hodgepodge of post-marketing

clinician case reports, animal and human myocyte conduction studies using

proprietary technology, and treatment studies screening for QTC prolongation. Of

the medications known to prolong QTC, some are more dangerous than others at

clinical doses, in overdose or in combination with other medications.

Few of the studies reporting cardiac safety of psychotropic medications have

involved children and adolescents. Three practical guidelines discuss

conservative screening and monitoring of children and adolescents who require

treatment with psychotropics known or suspected to cause QTC prolongation

(Labellarte et al., 2003a) (Table) .

Medications That Prolong QTC

The most comprehensive and easily accessed reference source for somatic and

psychotropic medications known or suspected to cause QTC prolongation is at

<www.Qtdrugs.org>. This Web site is maintained by the University of Arizona Center

for Education and Research on Therapeutics in Tucson, Ariz. It lists cautious

medication combinations by identifying which medications could cause additive

pharmacodynamic risk when combined with psychotropics that prolong QTC.

A more concise list of psychotropics that can contribute to QTC prolongation

is inspired by earlier recommendations from the American Heart Association

(Gutgesell et al., 1999). The list contains no surprises: older medications

(e.g., tricyclic antidepressants, phenothiazines, butyrophenones and pimozide

[Orap]) that have been known for decades to cause QTC prolongation/torsade de

pointes. The only newer medication on the list is ziprasidone (Geodon), which

has caused a mild but measurable QTC prolongation in a comparison study (~21

msec) (Harrigan et al., 2004) but has not caused cardiac events in clinical or

research settings (Daniel, 2003). In contrast to the old-school medications,

ziprasidone's potential impact on ion channels has not been studied.

The older medications have not compared well in QTC monitoring studies of

adults. Droperidol (Inapsine) caused the highest documented QTC prolongation

(~59 msec) (Lischke et al., 1994) and also has the highest relative risk of

causing QTC duration >450 msec (Reilly et al., 2000). Thioridazine

(Mellaril) had the next highest relative risk (Reilly et al., 2000), and also

caused noteworthy QTC prolongation (~30 msec to 36 msec) compared to

haloperidol's (Haldol) minimal QTC prolongation (8 msec) in the comparison study

by Harrigan and colleagues (2004). The impact of haloperidol on QTC

duration/torsade de pointes has debatable clinical relevance (Di Salvo and

O'Gara, 1995; Hatta et al., 2001), but haloperidol merits ECG monitoring in

light of emerging data that its active metabolites may have different patterns

of toxicity (Kalgutkar et al., 2003).

Important Drug Interactions

The most comprehensive and easily accessed reference source for

pharmacokinetic interactions is maintained at <www.drug-interactions.com> by the

Indiana University Department of Medicine.

While the Web site does not focus specifically on interactions that

contribute to QTC prolongation, it is easy to extrapolate a working list of

important medications that could cause worrisome metabolic inhibition and

potentially increased risk of QTC prolongation.

In addition, protein-binding competition can potentially cause increased

serum levels of medications that prolong QTC when combined with seemingly benign

medications that are highly protein-bound (e.g., aspirin, valproic acid

[Depakene], herbal preparations). Unclear pharmacokinetic mechanisms also result

in increased exposure to psychotropics that prolong QTC with a few identified

medication combinations, e.g., pimozide plus sertraline (Zoloft) (Zoloft package

insert).

Pretreatment Risk Factors

Pretreatment risk factors of QTC prolongation are rare but can be easily

screened. Screening includes pertinent medical history for signs/symptoms of

cardiac events, including syncope-like events and pertinent family history for

cardiac events such as syncope-like events, sudden death or congenital deafness

(which can be associated with an inherited variant of long QT syndrome) (Ocal

et al., 1997). Pretreatment laboratory test screening, when appropriate, would

test serum for hyponatremia, hypokalemia or hypermagnesemia.

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