The QT interval on the ECG, measured from the beginning of the Q wave to the end of the T wave, represents the interval from the beginning of depolarization to the end of repolarization of the ventricular myocardium.
WHY THE REGULATORY CONCERNS ON
DRUG-INDUCED QT INTERVAL PROLONGATION?
The
QT interval on the ECG, measured from the beginning of the Q wave to the end of
the T wave, represents the interval from the beginning of depolarization to
the end of repolarization of the ventricular myocardium. Prolongation of QT
interval is most frequently associated with prolonged repolarization following
administration of class III antiarrhythmic drugs. This class of antiarrhythmic
drugs is intended to act by blocking the repolarizing current mediated by potassium
channels and produce their desired ther-apeutic effect by a moderate and
controlled prolon-gation of ventricular repolarization, and therefore an
increase in the myocardial refractory period.
However,
excessive prolongation of ventricular repolarization, and therefore of the QT
interval, can be proarrhythmic and degenerate into torsade de pointes, a
ventricular tachyarrhythmia with a unique twist-ing morphology on the ECG. It
is usually transient and self-terminating, lasting only a few seconds, and therefore
is often asymptomatic. When sustained, however, the clinical manifestations of
torsade de pointes include palpitation, syncope, blackouts, dizzi-ness and/or
seizures. Torsade de pointes can subse-quently degenerate into ventricular
fibrillation in about 20% of cases (Salle et
al., 1985) and, not uncommonly, cardiac arrest and sudden death may be the
outcome. The overall mortality associated with torsade de pointes is of the
order of 10–17% (Salle et al., 1985;
Fung et al., 2000). Clearly, the
balance between the therapeutic
antiarrhythmic and the poten-tially fatal proarrhythmic prolongation of QT
interval is a very delicate one, and depends not only on the drug concerned and
its plasma concentration, but also on a number of host factors. These include
electrolyte imbalance (especially hypokalaemia), bradycardia, cardiac disease
and pre-existing prolongation of QT interval. Females are at a greater risk,
and the risk is further enhanced during the menstrual period.
Unfortunately,
however, a number of non-antiarrhythmic drugs are found to possess this class
III electrophysiological activity as part of their secondary (undesirable in
this instance) pharmacological prop-erties. The number of drugs with
‘QT-liability’, and by inference a potential to induce torsade de pointes,
continues to increase inexorably (Shah, 2002). The clinical and public health
concerns on the potential of non-cardiac drugs to prolong QT interval and
induce torsade de pointes have been eloquently summarized in an editorial
(Priori, 1998). Concerns have legiti-mately been expressed that:
·
Almost every week a new agent is added to the list of drugs
associated with acquired long QT syndrome (LQTS) and torsades de pointes (TdP).
Despite this impressive number of reports, the awareness of this subject is
still limited among medical professionals and
·
It is likely that prevention of drug-induced TdP will never
be fully successful, because it is a moving target. A patient may not be at
risk when therapy is initiated, and may become at risk 5 days later because
·
It is intuitive that when two or more agents sharing
potassium-channel-blocking activity are simultane-ously administered, the risk
of excessive prolongation of repolarisation is substantially increased.
·
The exclusion of potassium-channel-blocking proper-ties
might be considered in the future as a requirement before new molecules are
approved for marketing, and more strict warnings in the package insert of drugs
with known repolarisation prolonging activity could be enforced.
Apart
from the number of drug classes implicated, additional concerns arise from the
size of the popu-lation at risk. The expression of IKr and other
potas-sium channels is under the control of genes that are known to carry
mutations responsible for expression of channels with diminished or
dysfunctional capac-ity – the so-called ‘diminished cardiac repolarization
reserve’. IKr channels with
mutations of the hERG β-subunit (encoded by the KCNH2 gene located on chromosome 7) or the MiRP1 β-subunit (encoded by the KCNE2 gene located on chromosome 21)
very frequently conduct a repolarizing current of smaller amplitude, and
in consequence the
repolarization process is delayed in individuals carrying these
muta-tions (giving rise to congenital long QT syndromes of types 2 and 6
respectively). The most familiar clinical phenotypes of patients with potassium
channel muta-tions are the Romano–Ward or Jervell–Lange-Neilsen syndromes, with
ECG evidence of QT interval prolon-gation, and the propensity to develop
potentially fatal cardiac arrhythmias including torsade de pointes. However,
there is now abundant evidence that in view of the low penetration of many of
the mutations of potassium channel genes, the size of the population carrying
these mutations may be substantially larger than that diagnosed by ECG evidence
of a prolonged QT interval. Relatively large numbers of individu-als who carry
these ‘silent’ mutations of long QT syndrome genes have been identified, and
despite a diminished repolarization reserve, they have a normal ECG phenotype
(Priori, Napolitano and Schwartz, 1999). Nevertheless, because of the
compromised repolarization reserve, they are at a greater risk of cardiac
arrhythmias following administration of QT-prolonging drugs, even at doses that
are clinically safe in non-carriers (Yang et
al., 2002; Paulussen et al.,
2004; Shah, 2004). It has been postulated that drug-induced long QT syndrome
might represent a ‘forme fruste’ of the long QT syndrome.
It
may be speculated whether some of the 12 patients with terodiline-induced
proarrhythmias referred to earlier, and in whom there were no obvi-ous risk
factors, might be carriers of potassium chan-nel mutations (clinically silent
congenital long QT syndrome with a normal ECG phenotype). Genetic factors may
also operate remotely through other mechanisms. For example, cardiac failure is
the end result of many genetically (and non-genetically) determined cardiac
diseases. Cardiac failure is typi-cally associated with down-regulation of
potas-sium channels (Tomaselli and Zipes, 2004), and this will also increase
the susceptibility of these patients to QT interval prolongation and
proar-rhythmias. It is interesting to note that despite urinary incontinence,
27 of the 69 patients with terodiline-induced proarrhythmias discussed earlier
were receiving diuretics, and 33 were in receipt of other cardioactive
medications. Hypokalaemia induced by the diuretics, or electrophysiological
activ-ities of the cardioactive medications, further potentiate the
pharmacodynamic susceptibility of the patients concerned. In addition, patients
with a wide range of non-cardiac diseases have a pre-existing prolonga-tion of
QT interval, and therefore have an increased susceptibility to torsade de
pointes by QT-prolonging drugs. These conditions include those associated with
autonomic failure (as in diabetes or Parkinson’s disease), hypoglycaemia,
cirrhosis and infection with human immunodeficiency virus.
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