Current Drug Safety, 2010, 5, 73-78 73

Prokinetic Agents and QT Prolongation: A Familiar Scene with New

Actors
Guillermo Alberto Keller* and Guillermo Di Girolamo

Pharmacovigilance Unit, Second Chair of Pharmacology, School of Medicine, Universidad de Buenos Aires, Argentina
and Department of Physiological, Biochemistry and Pharmacological Sciences, School of Medicine, Universidad
Favaloro, Buenos Aires, Argentina

Abstract: Prokinetic agents are a very large family of drugs with different mechanisms of action. Only QT prolongation by cisapride has
made notable impact and deserved its partial restriction and/or withdrawal from the market. Postmarketing surveillance initially showed
that cisapride was generally safe and well tolerated, but in the past decade, more recent data have shown some risk in the patient
populations. QT prolongation by prokinetic agents can raised from different mechanisms: some involve increased plasma concentrations
of cisapride due to increased bioavailability by inhibiting P glycoprotein, and inhibition of metabolism or deficit in the elimination. On
the other hand, pharmacodynamic interactions can also enhance the arrhythmogenic effect of cisapride. The present article presents the
mechanisms and reviews the main interactions studied so far, and the role of pharmacovigilance in the detection of rare clinical events.
We emphasize the need for physicians to look for conditions (either clinical or not) prone to increase the risk of QT interval prolongation.
Keywords: Prokinetic agents, cisapride, mosapride, torsades de pointes, long QT syndrome, pharmacovigilance.

INTRODUCTION spontaneous reports pooled from reports received world-wide [6]

Prokinetic agents are a very large family of drugs. Its members
are in different chemical groups with different mechanisms of
action (Table 1). Though several have been implicated in serious
arrhythmia related to QT interval prolongation, only cisapride, has
had significant impact and deserved its limitation and/or partial
withdrawal from the market. Other members of this category seem
to have a minimal risk that is expressed only in certain cases,
related to interactions with other drugs to which they are not
frequently associated. Despite their different chemical structures, in
many cases they share a partial common structure: substituted
benzamide (substituted benzoic acid amide) like the known
antiarrhythmic procainamide.
The extensive use of prokinetic agents to treat symptoms of
diverse severity in all cases of high prevalence, turn them into drugs
to which the population has a large exposure. The past years have
been characterized by a better understanding of their mode of action
as well as their ability to induce relevant side-effects.
CISAPRIDE: PRE-MARKETING RESEARCH AN D
DETECTION OF ADVERSE EVENTS
Cisapride was approved in UK in 1989 and in US in 1993 for
the treatment of gastro-esophageal reflux, dyspepsia and impaired
gastric motility [1]. It is a partial 5-HT4 agonist, structurally related
to procainamide. Interestingly, since early 80’s, procainamide is
known to be associated with Torsades de pointes (TdP) when
plasma levels of its active metabolite are high [2, 3].
Following marketing approval, cisapride had been the subject
of standard continuous pharmacovigilance. In this phase of clinical
research, different pharmacovigilance centers of all the countries
received notifications of all suspected adverse drug reactions
through the ‘Yellow card’ spontaneous reporting scheme [4].
Summaries of adverse drug reactions (ADRs) were sent to the
World Heath Organization (WHO) [5]. The WHO Uppsala
Monitoring Centre (UMC) in Sweden maintains a database of
*Address correspondence to this author at the Pharmacovigilance Unit,
Second Chair of Pharmacology, School of Medicine, Universidad de
Buenos Aires, Paraguay 2155 – Piso 16, (C1121ABG), Buenos Aires,
Argentina; Tel/Fax: 54 11 4961-0943;
E-mail: catedra2@farmaco-vigilancia.com.ar
and uses three index cases to represent a signal [7, 8]. The WHO
researchers were the first to report the cisapride related risk of
arrhythmia [7, 9] from seven reports received from national centers
in Australia, Belgium, Netherlands and UK between 1989 and
1991. They concluded that cisapride may induce tachycardia and
recommended further pharmacological studies.
Cisapride was withdrawn or restricted in most countries in 2000
because it caused serious ventricular arrhythmias [10]. In
Argentina, the ANMAT (Administración Nacional de
Medicamentos, Alimentos y Tecnología Médica) has developed
progressive regulatory measures with regard to this drug. In
November 1998 ANMAT had changed the product information file,
in February 2000 added warnings about its use, and finally in 2004
all presentations except pediatric drops dosage were withdrawn.
The evidence for arrhythmogenicity comes from
electrophysiological studies [3], adverse drug events obtained
through spontaneous reporting [11], and its structural similarity to
other benzamides (procainamide) [12]. Initial controlled
epidemiological studies at the time of withdrawal were failed to
demonstrate association [13] because they had been too small to
identify a significant difference of cisapride treatment with the low
baseline incidence of ventricular arrhythmia which is less than 2 per
thousand person-years [13-17]. Indeed, subsequent studies with
larger population size have shown a high rate of arrhythmia
associated with cisapride [14, 15]. In our days, we can assume that
cisapride is associated with an approximate doubling to tripling of
the risk of hospitalization for ventricular arrhythmia and sudden
cardiac death [18]. This risk is more marked in the initial
prescription period in which it can be eightfold [18]. These data are
consistent with the finding that 61% of cases of QT prolongation
and ventricular arrhythmia reported to FDA in association with
cisapride were produced within 30 days of initiation of therapy
[11].
MECHANISM OF QT PROLONGATION BY PROKI-
NETIC AGENTS
5-HT4 receptors are distributed throughout the body. In the
central nervous system (especially in the limbic areas) [20] they
appear to play an important role in the regulation of mood and
pathogenesis of depression. In blood vessels, 5-HT4 receptors are
involved in muscle relaxation, whereas in the heart they exert a

1574-8863/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.

74 Current Drug Safety, 2010, Vol. 5, No. 1 Keller and Di Girolamo

Table 1. Pharmacodynamic Profile of Prokinetic Agents

Pharmacological Affinity Clinical Profile

HERG Therapeutic
Drug Dopamine Receptors Serotonin Receptors Utility IC50 IC50
QT –Interval (μmol/L) (μmol/L)
D1 D2 5-HT3 5-HT4 Prolongation Antiemetic

Low Antiemetic,
Potent Potent
Metoclopramide potency Low potency agonist Very low risk 5.4
4.69
Antagonism Antagonism Prokinetic
agonist

Potent Antiemetic,
Domperidone - - - Low risk 0.162
0.049
Antagonism Prokinetic
Low
Cisapride - - potency High potency Agonist High Risk Prokinetic 0.009 0.14
agonist
Mosapride - - - High potency Agonist Very low risk Prokinetic 4 0.98
Tegaserod - - - High potency Agonist Low risk Prokinetic 50
10
Low
Cinitapride - potency - High potency Agonist Very low risk Prokinetic >10
0.74
Antagonism
IC50 : concentration of half-maximum block.

positive chronotropic effect by an action on the atrium [20-22]. In
the adrenal glands, they stimulate steroid hormone release [23, 24]
and in urinary bladder they facilitate cholinergic excitatory
transmission of human detrusor urinae muscle [25, 26]. In the
clinical setting, the 5-HT4 receptor agonists are used for their
gastrointestinal action. Thus, other effects in different target organs
are considered as adverse effects. The principal locations of these
events are the lower urinary tract and the cardiovascular system.
Cisapride produces polyuria and urinary incontinence [27-29].
However, the most potentially dangerous effects of 5-HT4 agonists
are found in the cardiovascular system. These may be due to: (i)
stimulation of cardiac 5-HT4 receptors causing atrial dysrhythmia,
with a very low frequency [21, 22, 30], and (ii) Class III-
antiarrhythmic properties displayed by some compounds. This last
feature seems to be the main reason for the ability of cisapride to
prolong the QT interval and induce potentially fatal arrhythmias
[31, 32].
The initial hypothesis tested was that cisapride produced these
cardiovascular effects via stimulation of 5-HT4 receptors. However,
the absence of these receptors in the ventricle, and the lack of
efficacy to produce similar effects by other more specific agonists
of 5-HT4 receptor, have ruled out this hypothesis [33]. Cisapride
has class III antiarrhythmic properties [33-34] at slightly over
therapeutic concentration (100 to 200 nmol/l,) whereas other
prokinetic agents require very large concentration to show similar
effect (metoclopramide, levosulpiride, mosapride, tegaserod,
prucalopride, cinitapride) (Table 1) [33-42]. This property can be
attributed to the blockade of potassium currents, which increases
the duration of the action potentials originating from cardiac muscle
cells [3, 41] like Class III antiarrhythmic agents [42, 43]. Cisapride,
like other benzamide derivates (amisulpride, sultopride, metoclopr-
amide) [33, 44-47], prolongs the duration of action potential of
ventricular muscle in a dose dependent manner by blocking the
human ether-a-go go- related gene (HERG), and reducing the rapid
component of cardiac delayed rectifier K+ current (IKr) [3, 41, 48-
50].
RISK FACTORS
Postmarketing surveillance initially showed that cisapride was
generally safe and well tolerated [51], but in 90’s, data showed risk
in some patient populations. The first group included conditions
that may lead, through different mechanisms to increase plasma
concentrations of cisapride. The mechanisms involved are:
increased bioavailability by inhibiting P glycoprotein, inhibition of
metabolism, and deficit in the elimination. Other group involves
pharmacodynamic interactions that enhance the arrhythmogenic
effect of cisapride. As a practical approach, the highest risk of
arrhythmia by QT prolongation should be assessed in special
population like newborns or children which can have an immature
metabolic system [52, 53], patients with congenital or acquired long
QT interval, patients under treatment with Class III antiarrhythmics,
phenothiazines, tricyclic antidepressants or other new drugs that
demonstrate an ability for QT-prolongation, patients with
comorbidities such as renal or liver function impairment, or patients
treated with known CYP3A4 inhibitors such as azoles
(ketoconazole, itraconazole) [3, 48, 52, 54, 55], some macrolides
(erythromycin, clarithromycin and troleandomycin) [56-63] and
protease inhibitors [64].
CISAPRIDE AND CYPs: REPEATING THE HISTORY OF
ANTIHISTAMINES
Cisapride is mainly metabolized by CYP3A4 oxidative
metabolism to the major metabolite norcisapride [65], N-oxide of
cisapride by N- oxidation at the piperidine nitrogen, 2-hydroxy-
cisapride and 3-fluoro-4-hydroxy-cisapride by aromatic
hydroxylation at the fluorophenoxy moiety, and other minor
metabolites by O-dealkylation [66]. Over the therapeutic range (1.1
± 3 mM), the metabolism of cisapride have shown a linear kinetics.
Cisapride is unlikely to inhibit the metabolism of co-
administered drugs, however it is possible that cisapride itself may
influence the pharmacokinetics of other drugs through accelerated
gastric-emptying or increased absorption in the small intestine.
Cisapride was shown to increase the absorption rate of H2-
antagonists such as cimetidine [7] and ranitidine [67], diazepam
[68] and ethanol [56].
Interactions of cisapride with known 3A4 inhibitors have been
studied to identify the clinical situations that may increase the
concentrations of cisapride [66]. Among the antifungal CYP3A4
inhibitors in decreasing order of potency rank are ketoconazole,
miconazole, hydroxyitraconazole, itraconazole and fluconazole. All
of them generate significant inhibition of metabolism of cisapride at
concentrations that are reached under standard dosage of antifungal
drugs, generating interactions of clinical relevance. Ketoconazole is
able to increase plasma concentrations of cisapride by eight fold.
The antidepressant nefazodone, the macrolide antibiotic
Prokinetic Agents and QT Prolongation Current Drug Safety, 2010, Vol. 5, No. 1 75

Table 2. Confidence Criteria of Prolonged QT

Confidence Criteria

Electrocardiographic documentation of prolonged QT interval (QTc > 460 ms) plus TdP.

High Sudden death, cardiac arrest, ventricular tachycardia or TdP with measurements, statements, or ECGs indicating prolonged QT interval.

Syncope with polymorphic ventricular extrasystoles and statements, measurements, or ECGs indicating prolonged QT interval with
resolution of arrhythmia and prolonged QT interval when LQTS factors were removed.

Sudden death, ventricular fibrillation, ventricular tachycardia, or syncope with no plausible cause and without documented or stated
prolonged QT interval, subsiding after removal of LQTS factors.
Medium Ventricular tachycardia or ventricular fibrillation without documented or stated prolonged QT interval, subsiding after removal of LQTS
factors.
Syncope without documented or stated ventricular tachycardia but with documented prolonged QT interval.

Sudden death, ventricular fibrillation, ventricular tachycardia, or syncope with plausible cause and normal QT interval.
Low
Syncope without documented ventricular tachycardia and with normal QT interval.

troleandomycin, the calcium channel blocker mibefradil and the
HIV-1 protease inhibitors ritonavir and indinavir also showed
interactions with cisapride that were probably clinically relevant,
because their IC50 values were lower than their therapeutic plasma
levels, therefore they are able to inhibit cisapride metabolism.
Indeed they have been implicated in several cases [58-64].
Clarithromycin and erythromycin showed no metabolic
interaction with cisapride in vitro. However, they are able to
increase the risk of QT prolongation in vivo by different
mechanisms. First, clarithromycin alone associates with a minimal
increase in QT intervals that can cause pharmacodynamic
synergism with cisapride. Second, to inhibit CYP mediated
metabolism, clarithromycin and erythromycin need to be
metabolized by CYP3A4. The resultant metabolite binds to
cytochrome P-450 causing an inactivation of CYP3A4 [69].
Therefore, combination of cisapride and clarithromycin caused an
average QT-increase of 25 ms above pre-treatment values and 3
fold increase in cisapride concentrations.
Indinavir and ritonavir are strong inhibitors of CYP3A4, and
interaction with cisapride metabolism is to be expected. However,
other protease inhibitors, such as saquinavir, will most likely not
affect the metabolism of cisapride.
Ofloxacin, paroxetine, and diltiazem do not inhibit the cisapride
metabolism [66]. The grapefruit flavonoid naringenin has shown
50% inhibition of cisapride metabolism in vitro, and in vivo data
show that grapefruit juice increases the oral bioavailability of
cisapride [70].
LESSONS ABOUT IMPORTANCE OF PHARMACO-
VIGILANCE
Beyond the pharmacokinetics and pharmacodynamic
characteristics of cisapride, the history of this drug enables us to
highlight the role of pharmacovigilance. Even when all the pre-
clinical tests are conducted properly, certain risks cannot be ruled
out. Very rare incidence events cannot be assessed in stages 1 to 3.
When a medicine is released into the market there is still a great
deal that is unknown about the safety of the product. For example,
at least 30,000 people are needed to use a medication in order to
identify, with 95 per cent power, and an adverse reaction with an
incidence of one in 10,000. Once marketed, the medicines are used
by the patients who have many different diseases, are using several
other drugs and have different traditions and diets which may affect
the way in which they react to a medicine. Different brands of
medicines may differ in the manner in which they are produced and
the ingredients that are used. The adverse drug reactions and
poisonings associated with traditional and herbal remedies also
need to be monitored in each country. The information we receive
on the adverse effects of drugs in other countries may not be
relevant or applicable to our country’s citizens.
In some cases pharmacovigilance through, for example,
spontaneous ADR reporting or large scale databases, is used to
generate hypotheses and signals about potential hazards of
marketed drugs that require further investigation. Spontaneous
reporting of suspected ADRs is particularly useful in identifying
rare or delayed reactions; such a system enables us to monitor the
medicines throughout their lifetime.
Spontaneous reporting systems are the only systems available
for signal generation of rare events, and represent the most used
source of information used to withdraw a drug from the market for
safety reasons [71, 72].
In addition to contribute to the safety profiles of existing drugs,
pharmacovigilance activities help to improve the knowledge set and
contribute to the breadth of epidemiological data.
Pharmacovigilance is, therefore, vital for the advancement of future
research, medical understanding, drug development and
epidemiological studies. Large-scale databases containing
longitudinal patient or prescription data reflect routine usage of
medications in the general population and provide denominator data
which can be used to identify trends.
However it’s very important to realize that spontaneous
reporting systems have limitations such as under-reporting and
advantages, such as being an effective system for signal generation,
particularly for rare adverse drug reactions. Subsequent
pharmacoepidemiological studies show the incidence of particularly
rare adverse reactions using large number of patients, yet cohort
sizes may be insufficient to detect very rare ADRs.
Other interesting features are the events in question. These need
to be easily recognizable by physicians and documented in patients
records. In this connection, there is a criteria for determining the
reliability of the information related to the events associated with
the use of cisapride [73] (Table 2). In the post-marketing phase, we
continue to rely on the vigilance by health professionals to
recognize potential rare adverse drug reactions such as QT
prolongation. However, if the physician is unaware of the QT-
prolongation risk, ECG monitoring is unlikely for most non-
cardiovascular medications.
WHAT ABOUT OTHER PROKINETIC AGENTS?
After worldwide discontinuation of cisapride, the focus was on
the other prokinetic agents [35, 36, 74]. The first question to answer
was whether an individual or class effect was present in QT
76 Current Drug Safety, 2010, Vol. 5, No. 1
prolongation by cisapride. While this question began to be
answered, the use of other prokinetic agents presumably safer drugs
such as domperidone was increased. This situation was followed by
questions about prokinetic agents that act via different mechanisms
of stimulation of serotonergic receptors.
Mosapride is also a benzamide derivative, structurally related to
cisapride. Using isolated Langerndoff-perfused rabbit hearts,
mosapride did not prolong the duration of monomorphic action
potential or induce early after-depolarization and triggered activity
in isolated rabbit Purkinje fibers. Mosapride blocked the IKr current
but at markedly higher concentration than cisapride. Mosapride was
approximately 1000-fold less potent than cisapride in blocking the
Ikr current with an IC50 of 4 μmol/L [36].
Tegaserod did not prolong the QT interval at a concentration
between 0.5 and 10 μmol/L, but the QT interval was significantly
increased by 12% if the concentration of tegaserod was increased to
50 μmol/L (1000X the plasma concentration obtained following
recommended clinical dosages) [35]. Tegaserod metabolites had no
effect on the QT interval. However, In March 2007, Novartis
voluntarily discontinued tegaserod, based on new data from FDA
indicating that the benefits of therapy do not outweigh the risks.
This decision was based on a new data showing that patients treated
with tegaserod have an increased risk of serious cardiovascular side
effects including myocardial infarction, stroke, and unstable angina.
In July 2007, the FDA allowed restricted access to tegaserod under
a treatment investigational new drug (IND) protocol for women less
than age 55 to treat irritable bowel syndrome with constipation or
chronic idiopathic constipation. However, On April 2, 2008, after
more than eight months of availability, Novartis has re-assessed the
program and has made a decision to close it.
Domperidone is a prokinetic dopamine-receptor antagonist.
Due to the proarrhytmic risk of cisapride, domperidone has been
felt to be a safer alternative to cisapride, because its apparent
favorable safety profile. However, QT prolongation, life-thretening
ventricular tachyarrhytmias and cardiac arrest have been reported
after the use of intravenous domperidone [75-82]. Underlying
electrolyte disturbances such as hypokalemia and not a drug
specific effect were assumed as the physiopathologic mechanism
involved in cardiac domperidone-related adverse events. However
attention must be given because domperidone is an IKr blocker and
prolongs cardiac repolarization. IKr blocking concentrations for
domperidone are lower than those required by other prokinetic
agents and slighty higher than those obteined with standard
therapeutic regimen. Domperidone is actually less potent than
cisapride, but is currently the most potent prokinetic IKr blocker
present in market [38].
CONCLUSION
The benzamide gastrointestinal prokinetic agents such as
cisapride, are widely used gastroenterology compounds that can
induce cardiac adverse effects such as QT prolongation and risk for
life threatening arrhythmias through the potential to block HERG
potassium channels. The most frequent clinical circumstances that
may promote these events are known. Given the widespread use of
these drugs, all doctors should know these risk factors in detail to
prevent unfortunate events. The experience of recent years with
antihistamines and prokinetic agents should teach us about the
importance of pharmacovigilance, the need to report all the adverse
events to the national centers, and to actively seek out new possible
adverse reactions, since what never had been sought, can never be
found.
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Accepted: July 22, 2009