Biomedical Engineering Reference
In-Depth Information
recommended dose; by restricting the dose in patients with pre-existing heart
disease or other risk factors; and by avoiding concomitant administration of drugs
that inhibit drug metabolism or excretion, prolong the QT interval, or produce
hypokalaemia [
121
]. When the patient develops
Tdp
, the offending drug should be
stopped and electrolyte abnormalities corrected [
60
].
Sertindole: Sertindole is a new indolylpiperidine antipsychotic agent, which has
nanomolar affinities for dopamine D
2
, serotonin 5-HT
2
and
-1 adrenergic
receptors (Table
2
). Sertindole blocked the
hERG
currents on two cloned human
cardiac potassium channels,
hERG
and K
v
1.5, in a stably transfected mammalian
cell lines with an IC
50
value at 14 nM. Sertindole enhanced the rate of current decay
during these prolonged voltage steps and displayed a positive voltage dependence.
Sertindole was approximately 1,000-fold less active at blocking K
v
1.5 displaying
an IC
50
value of 2.1
a
M. Sertindole is a high affinity antagonist of the human
cardiac potassium channel
hERG
and blockade underlies the prolongation of QT
interval [
122
].
Terfenadine: It
m
is a second generation of histamine receptor antagonists
(IC
50
ΒΌ
56.0 nmol/l), widely used as non-sedating antihistamines that differ phar-
macologically from first-generation antihistamines by having preferential affinity
for peripheral H
1
receptors versus the brain H
1
and cholinergic receptors (Table
2
)
[
123
]. Terfenadine at 0.3 mg/kg (IV) produced no effect on QT interval, but at
1 and 3 mg/kg, it significantly prolonged QT interval in dogs [
124
]. In guinea pig,
10 mg/kg IV infusion also results in QT prolongation.
Terodiline: Terodiline is used to treat urinary incontinence (Table
2
). It was
removed from the market in 1991 for proarrhythmia. Terodiline depresses the
action potential plateau and induces triangulation without affecting action potential
duration (APD
90
). The triangulation ratios (normalized ratio of APD
50
over APD
90
)
for terodiline were 0.94 and 0.59 for 1.0 and 10
M. However, at supratherapeutic
concentrations, preclinical data predict risk of QT prolongation. It is suggested that
hERG
block and triangulation are among multiple factors that must be considered
in preclinical cardiac safety assessments [
125
,
126
].
In addition to
hERG
inhibitors discussed above, several other drugs including
chloroquine, chlorpromazine, disopyramide, dofetilide, droperidol, halofentrine,
haloperidol, ibutilide, pentamidine, probucol, procainamide, quinidine, sotalol,
thioridazine, and sparfloxacine have potential to produce QT prolongation.
m
5 Cardiovascular Safety and Guidelines
Accurately assessing the pro-arrhythmic potential of drug candidates should be
done early in preclinical development to avoid the economic and public health
consequences of late-stage failures of drug candidates, unfavorable labeling, and
withdrawals of approved products. Regulatory authorities are focusing on safety
issues associated with drugs where there is evidence of QT interval prolongation
risk. The underlying basis for this stance is the observation that most drugs
