Vol. V, No. VI
November/December 2002
Mandy C. Leonard,
Pharm.D., BCPS
and
Michael A. Militello,
Pharm.D., BCPS
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Pharmacotherapy
Update Index
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5-HT3 Receptor Antagonists and ECG Effects
Introduction:
The 5-HT3 receptor antagonists have resulted in a major
advancement in the management of chemotherapy-induced (CINV), radiation-induced
(RINV), and post-operative nausea and vomiting (PONV), as they exhibit
a high level of antiemetic activity with a low incidence of adverse effects.
Comparative clinical trials among the three agents have not demonstrated
any clinically relevant differences in efficacy or safety for the prevention
of CINV or PONV. However, questions have been raised about minor electrocardiographic
changes caused by each of the currently available 5-HT3 receptor antagonists.
Nausea & Vomiting:
Many patients experience CINV, RINV, and PONV.
Nausea is defined
as a subjectively unpleasant sensation associated with flushing, tachycardia,
and an awareness of the urge to vomit.
Vomiting is
the contraction of the abdominal muscles, descent of the diaphragm, and
opening of the gastric cardia, resulting in the expulsion of stomach contents
from the mouth.
Retching is defined as a spasmodic contraction of the diaphragm, thoracic and abdominal
walls without expulsion of gastric contents.
The incidence of CINV
varies depending on the emetogenic potential of the chemotherapy. Nausea
and vomiting associated with radiation is dependent on radiation field
size, site, and dose per fraction. And the incidence of PONV depends on
multiple risk factors, such as type of surgery, sex, and concomitant medications.
Pharmacotherapy:
Because of the potentially serious nature of CINV, RINV, and PONV, extensive
research has been undertaken to find successful approaches for prevention
and treatment. The 5-hydroxytryptamine type three (5-HT3) receptor
antagonists are effective therapies for the management of CINV, RINV,
and PONV and offer significant benefits over traditional treatments such
as phenothiazines (eg, prochlorperazine [Compazine®], promethazine
[Phenergan®]), benzamides (eg, metoclopramide [Reglan®]), trimethobenzamides
(Tigan®), butyrophenones (eg, haloperidol [Haldol®], droperidol
[Inapsine®]), and benzodiazepines (eg, lorazepam [Ativan®]). Currently,
there are three 5-HT3 receptor antagonists available in the
United States: dolasetron (Anzemet®), granisetron (Kytril™),
and ondansetron (Zofran®).
Each agent is approved for the prevention of nausea and vomiting associated with initial and
repeat courses of emetogenic cancer chemotherapy and for the prevention
of PONV. Additionally, no 5-HT3 receptor antagonist is currently
indicated for treating CINV; however, dolasetron and granisetron are approved
for treating PONV. Granisetron and ondansetron are indicated for the prevention of RINV.
Members of this class produce their antiemetic effects by selectively blocking 5-HT3
receptors in the gut and the brain stem, receptors that, when stimulated,
lead to initiation of the emetic response.
Safety Profiles:
The 5-HT3 receptor antagonists are well tolerated. The most
common adverse events experienced by patients are headache, diarrhea,
constipation, and fever. The 5-HT3 receptor antagonists are
not associated with sedation or extrapyramidal side effects. Furthermore,
the 5-HT3 receptor antagonists exhibit no significant drug
interactions with common anesthetic agents and have little or no affinity
for receptor sites other than the 5-HT3 receptors.
Although the 5-HT3 receptor antagonists have favorable and similar safety profiles, some
minor ECG changes have been reported with this class of agents, including
prolongations of the PR interval, the QRS complex, and the QT interval
in healthy volunteers and in patients undergoing cancer chemotherapy or
surgery. These potential changes have been the source of some concern
with regard to their clinical significance.
When evaluating literature regarding the 5-HT3 receptor antagonists and ECG
effects, it is important to understand the cardiac action potential and
ECG parameters.
Cardiac Action Potential:
The cardiac action potential, the basic unit of electrical activity in
the heart, produces cardiac contractions. Cardiac myocytes, like other
types of muscle cells, have a negative potential difference (-90 mV) at
rest between the cell membrane and extra-cellular space (ie, they are
polarized). Under the influence of trigger events, potassium, sodium,
and calcium ions cross the cell membrane, thereby generating discrete
ion currents (See Figure 1).
Electrocardiogram:
The ECG represents a summation of action potentials across the entire
heart. The ECG reading includes interpretation of the following: P wave,
PR interval, QRS complex, QT interval, and ST segment. (See Table 1 and Figure 2).
The QT interval and corrected QT interval (QTc):
Torsades de pointes. Even a small change in ion currents may be
detrimental to the cardiac myocytes and may produce cardiac arrhythmias.
If the action potential is prolonged during the repolarization phase,
the membrane potential may abruptly reverse course and depolarize instead.
An early after-depolarization may occur resulting in a second action potential,
which has the potential to produce ventricular arrhythmias. Torsades de
pointes ("twisting of the points"), a potentially life-threatening,
polymorphic ventricular arrhythmia, may develop if this process is repetitive and self-sustaining.
Congenital or acquired prolongation of the QT interval has been associated with a risk of developing
torsades de pointes, and there is some evidence that QT interval prolongation
may also be a risk factor for sudden death. Other risk factors for torsades
de pointes include electrolyte imbalance, bradycardia, and certain medications.
What is a normal QTc interval? Interpretation of the QT interval
can be challenging since QT varies inversely with heart rate (ie, QT interval
decreases as heart rate increases). Consequently, the corrected QT interval
(QTc) is used when heart rate exceeds 60 beats per minute (bpm) to investigate
possible effects of treatment or pathologic processes on the intrinsic
duration of the QT interval. Bazett's formula calculates a QTc that accountsfor individual variations in heart rate and is useful when the heart rate is >60 bpm:
QTc = QT/(RR)0.5
(where RR is the mean interval in
seconds between QRS complexes)
A QTc interval of 440 ms is considered by many to be the upper limit of
normal. In patients with no evidence of cardiac dysfunction, a QTc of >
440 ms can be associated with a 2.3 times higher risk for sudden death compared
with a QTc of < 440 ms.
The most common type of acquired QTc interval prolongation is caused by drugs. Torsades de
pointes occur in 2% to 8% of patients receiving quinidine and in 2% to
4% of patients receiving sotalol (Betapace®). However, it is well
recognized that non-cardiac medications, including certain anti-infectives,
antidepressants, anti-histamines, anti-psychotics, antineoplastics, and
gastro-intestinal agents, also can adversely affect ECG parameters. In
some cases, these effects have led to withdrawals of drugs from the market,
or significant changes in their use. For instance, cisapride (Propulsid®)
can increase the QT interval, particularly when prescribed in combination
with medications that inhibit its hepatic metabolism by the cytochrome
(CYP) 450 3A4 isoenzyme. Because of the risk of cardiac arrhythmias, the
use of cisapride has been voluntarily withdrawn from the market in July
2000; however, there is a restricted access program.
The antihistamines, terfenadine (Seldane®) and astemizole (Hismanal®), were removed
from the US market due to the potential for QT prolongation and cardiac
arrhythmias when used concomitantly with certain medications that inhibited
their metabolism. The withdrawal of these drugs, because of concerns over
cardiac safety, has raised awareness of the potential for drug-induced
ECG effects, including QT interval prolongation.
Effects on ECG Parameters:
Ondansetron, granisetron, and dolasetron have all been associated with
minor cardiovascular and ECG changes. Clinically relevant cardiovascular
effects have not been reported to date; however, there have been rare
reports of hypotension, angina, tachycardia, bradycardia, atrial fibrillation,
syncope, and small, transient, reversible changes in ECG parameters with
all of the available 5-HT3 receptor antagonists. Alterations
in ECG intervals appear to be a class effect. Specific data about cardiovascular
changes associated with this class of drugs are limited; the most detailed
information that is available relates to dolasetron. As dolasetron was
the last of the three agents in clinical development, most of the trials
involving dolasetron included specific ECG monitoring, resulting in more
detailed ECG data for this compound.
In models:
Sodium channels were blocked in a frequency dependent manner by each of
the 5-HT3 receptor antagonists, with granisetron having the
most potent effect followed by dolasetron and ondansetron.Ondansetron
displayed the most potent blockade of the rapid-delayed rectifier potassium
ion channel, followed by granisetron, then dolasetron. None of the drugs
displayed high-affinity block (ie, minimal effect) of the slow-delayed
rectifier potassium channel. Specifically, dolasetron caused acute effects
on the ECG via sodium channel blockade to delay ventricular depolarization,
manifested as prolonged PR and QRS duration, without a substantial effect
on ventricular repolarization (QT interval). Ondansetron primarily blocks
potassium channels, prolonging the QT interval. Granisetron blocks both
sodium and potassium channels, potentially affecting both depolarization
and repolarization through its prolongation of PR, QRS, and QT intervals.
These data help to clarify the molecular mechanisms by which some of the
ECG changes (particularly QT and QRS prolongation) associated with this
class of agents occur.
Clinical Trials:
The propensity of these agents to prolong the QT interval has been studied
in clinical trials in healthy volunteers, in cancer patients receiving
chemotherapy and in surgical patients (See Table 2 and Table 3).
As a class, they may induce some statistically significant changes in QT intervals, but these
changes are acute, transient, reversible, and not clinically relevant.
In clinical trials to date, ECG interval increases have not resulted in
clinically relevant cardiovascular events. It is important to note, however,
that these clinical trials have generally excluded the participation of
patients with cardiovascular disease. Computer-generated ECG analysis
was used in the majority of trials because it more accurately determines
ECG intervals than visual inspection of ECG tracings.
Summary:
Agents with the potential to prolong QT intervals, characterized by prolonged
ventricular repolarization with QT intervals exceeding 500 ms, pose a
serious and clinically relevant complication in general practice, as they
may ultimately give rise to a potentially fatal arrhythmia, torsades de
pointes. The 5-HT3 receptor antagonists have been associated
with QT interval prolongation, but have a low proarrhythmic risk which
is not associated with the occurrence of potentially lethal arrhythmias.
To date, no cases of torsades de pointes associated with 5-HT3 receptor
antagonist administration have been reported in the medical literature.
Typically, the QT interval changes with the 5-HT3 receptor
antagonists do not exceed 15 milliseconds.
Both the American Society of Health-System Pharmacists (ASHP) Therapeutic Guidelines on
the Pharmacologic Management of Nausea and Vomiting in Adult and Pediatric
Patients Receiving Chemotherapy or Radiation Therapy or Undergoing Surgery
and the Recommendations for the Use of Antiemetics published by the American
Society of Clinical Oncology (ASCO) state that there are no differences
in the safety profiles of the available 5-HT3 receptor antagonists,
including ECG effects.
Conclusions:
The 5-HT3 receptor antagonists are effective in the prevention
and treatment of nausea and vomiting associated with chemotherapy, radiation
therapy, and surgery. Dolasetron, ondansetron, and granisetron also have,
as a class, some effects on ECG intervals. Reversible, transient changes
in the PR, QRS, and QT intervals have been consistently observed in noncomparative
and comparative trials. Ondansetron, granisetron, and dolasetron all have
a similar propensity to affect ECG intervals; however, clinically relevant
ECG changes have not been reported or documented.
References available upon request
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