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Drug-induced
QT prolongation syndrome
In
these days of polypharmacy where a patient is likely to take several
medications it is imperative that pharmaceutical companies take
advantage of in-vitro methodologies available to rule out fatal
adverse side effects of widely used drugs, says Dr V Sudarsanam
Ion
channels are magnificent molecular machines that play critical roles
in the generation of cellular responses to a wide variety of informational
inputs. Under physiologic conditions ion channels permit the orderly
movement of ions across cell membranes, both plasma and intracelular.
Under
pathologic conditions, the disorderly movement of ions through these
same channels contributes to a number of disease states and cell
death. Some have likened the constant movements of ion through their
cellular channels as the music of life - played, of course, by the
ionic ensemble.
Ions
are asymmetrically distributed across cell membranes and this asymmetry
is mantained because membranes are selectively permeable and because
cells possess energy-driven ion pumps that maintains and restore
ionic gradients dissipated through leaks or during cell stimulation.
Ion channels, permeate the cations Na+ K+ Ca++ and the anion Cl-
in response to diverse cell stimuli including light, heat, pressure
and changes in chemical and electrical potential.
Voltage-dependent
ion channels are responsible for generating electrical activity
of the human heart. Na+, Ca++ and K+ channels are the most important
channels for determining the shape and duration of cardiac action
potential. Activation of Na+ and Ca++ channels leads to the influx
of these positively charged ions into individual cardiac cells causing
depolarisation of heart. Conversely the opening of K+ channels allows
the flow of positive charge out of cells and terminates the action
potential and repolarises the myocardium (European J: Pharmacol
375, 311, 1999; Trends in cardivoasc Med I, 118, 1997).
Any
intervention that changes these channels can alter the cardiac potential
and may be detected clinically on the ECG. One such intervention
is the problem of drug-induced long QT syndrome. In this situation,
a drug, usually as a result of side effect, prolongs the action
potential in individual cardiac cells and may trigger ventricular
arrhythmias including the life-threatening ‘Torsade de pointes.’
In practice, a specific class of potassium channels is of major
significance in regulating a potassium current component of the
cardiac action potential and whose misbehaviour because of the influence
of a number of drugs is responsible for the serious cardiac arrhythmias.
A vast majority of these drugs preferentially interact with a single
type of K+ channel known as HERG. In fact, there is a growing list
of drugs that are known to produce acquired long QT syndrome through
an interaction with HERG
A
typical example is the antihistamine terfenadine which causes QT
prolongation particularly when co-administered with the antifungal
ketoconazole. Ketoconazole inhibits the first pass metabolism of
terfenadine by blocking a specific cytochrome P450 isoform, greatly
elevating plasma terfenadine levels resulting in high affinity for
HERG and QT syndrome. This resulted in the withdrawal of terfenadine
from the market (JAMA 269, 1513, 1993). A similar interaction with
HERG involved cardiotoxicity caused the withdrawal of astemizole
(J. cardiovasc Electrophyisol 10, 836, 1999). Another HERG-interacting
problem drug is the gastric motility agent cisapride.
In
this connection, it is pertinent to note that there are several
structural types which interact with HERG. Several methanesulfonanilide
compounds like dofetilide, sotalol, MK 499 interact with HERG in
the myocardium. In fact, dofetilide which has two methane sulfonoanilide
moeities in its structure is much more potent in its interaction
than d-sotalol which has one such structural feature.
Structural
features
It
is well known in medicinal research that certain structural features
can give rise to certain property. For example, a nitro containing
heterocycles can undergo bioactivation and can be mutagenic (nitrofurans,
nitroimidazoles etc). A structural feature of benzyl thiazolidine
dione is likely to be peroxisomal proliferator activator receptor
(PPARr) agoinst. A alpha, alpha dimethyl phenoxy acetic acid (eg;
clofibrate) can be PPAR alpha agonists.
Even
though other factors such as plasma/cardiac levels, pharmacokinetic,
polypharmacology, repolarisation, complexity etc have a role in
the extent of QT prologation by drugs the question, whether drugs
which are in current use and which incorporate structural features
which are present in compounds which are known to inhibit HERG channel
activity, should also be checked for HERG channel activity remains
to be answered. If such a study has not been done earlier in such
drugs currently in wide use, it is necessary to resolve such questions
to avoid any serious side effects. The candidate for such an exercise
can be a currently widely used drug incorporating a methanesulfoanilide
moiety.
In
view of the growing list of drugs such as haloperiodol, pimozide,
seratindole, ondansetron, erythromycin etc causing long QT syndrome,
particularly when co-administered with drugs which can suppress
hepatic metabolism, and in view of the fact that modern day polygenic
diseases are often treated with a battery of different drugs, perhaps
there is a case for the office of the Drugs Controller to insist
on in vitro HERG channel inhibition studies for many of the widely
used drugs and for drugs which are to be introduced for the first
time in India.
[Other
References on this topic are: J. Gen. Physiol 115, 229, 2000; Eur.
J. Pharmacol 392, 137, 2000; J. Pharmacol Exp. Ther 286, 788, 1998;
J. Cardiovasc. Electrophysiol 10, 836, 1999].
It
is imperative that pharmaceutical companies and drug discovery establishments
take advantage of such in-vitro methodologies available to rule
out fatal adverse side effects of widely used drugs in these days
of polypharmacy in which a patient is likely to be taking several
medications.
This
is again brought out well in other situations also. Two closely
related orphan nuclear hormone receptors - the pregnane X receptor
(PXR) and the constitutive androstane receptor (CAR)- have emerged
as transcriptional regulators of heam containing monoxygenase cytochrome
P 450 expression that couple xenobiotic exposure to oxidative metabolism.
The
discovery of PXR as the primary regulator of inducible CYP 3A expression
in the liver and intestine has important implications for the drug
development process (J. Clin. Invest, 102, 1016, 1998) CYP 3A metabolises
most drugs and the inadvertant activation of PXR in humans can lead
to undesirable drug-drug interactions or generation of toxic levels
of drug metabolite (Clin. Pharmcokinet 38, 493, 2000).
The
antidiabetic drug, troglitazone was withdrawn from market due to
rare incidences of fatal hepatotoxicity (N. Engl. J.Med 338, 916,
1998; Drug Metab. Dispo 27, 1260, 1999). Troglitazone activates
PXR at therapeutic doses and is metabolised by CYP3A to a potentially
toxic quinone. Even though PXR screening has not been used routinely
earlier in drug discovery, the availability of PXR assays gives
an access to an early identification of CyP 3A inducers before human
clinical trials. (Toxicology 153, 1, 2000).
The
writer is a accomplished scientist and a research consultant
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