Biomedical Engineering Reference
In-Depth Information
and astemizole cause equipotent block of
hERG
channels and these are among the
most potent
hERG
channel antagonists so far. Because desmethylastemizole becomes
a dominant compound in serum, it is confirmed that it becomes the principal cause
of long QT syndrome observed in patients following astemizole ingestion.
Norastemizole block of
hERG
channels is comparatively weaker; thus the risk of
producing ventricular arrhythmias may be lower [
27
]. IC
50
for astemizole on
hERG
expressed in Xenopus oocytes is 69 nM to 0.33
M; in HEK cell; 0.9-22 nM and in
the guinea pig/ventricular myocytes approximately 1.5 nM were reported [
68
].
Bepridil: It is a non-selective calcium channel blocker used to treat angina
pectoris. It improves left ventricular performance and is found to be effective as
monotherapy for treatment of patients with exertional angina. Its use is associated
with increased exercise capacity and decreased angina frequency and nitroglycerine
consumption as well as improved LV systolic and diastolic performance at rest
and during peak exercise (Table
2
). Bepridil produces prominent bradycardia-
dependent QT prolongation with special attention in patients having structural
heart disease [
69
].
Cisapride: Cisapride (IC
50
, 0.02
m
M) is a widely used prokinetic agent and has
attracted much recent attention because of reports of QT prolongation and
Tdp
(Table
2
). Approximately 23 cases of QT prolongation associated with cisapride
were reported to the Food and Drug Administration from 1993 to 1996 with four
deaths and 16 resuscitated cardiac arrests [
48
]. Many of the patients were also
taking imidazole or a macrolide antibiotic, which could inhibit the P-450 CYP3A4
isoenzyme responsible for cisapride metabolism [
70
-
72
].
Domperidone: Several cases of QT prolongation and ventricular tachyarrhyth-
mia have been reported with domperidone, a gastrokinetic and antiemetic agent
available worldwide but still under investigation in the USA (Table
2
). Although
electrolyte disturbances such as hypokalemia could account for some of these
events, it possesses cardiac electrophysiological effects predisposing some patients
to proarrhythmia. These effects are observed at clinically relevant concentrations of
the drug [
73
,
74
].
E-4031: It is a methanesulfonanilide, class III antiarrhythmic drug that was
initially reported to prolong cardiac action potential duration and block I
Kr
in
ventricular cells at submicromolar concentration (Table
2
). E-4031 is a specific
blocker of
hERG
K
+
channels in heterologous systems, cardiac cells and cardiac
preparations [
75
].
Fluconazole: Fluconazole, a commonly used azole antifungal drug, can induce
QT prolongation, which may lead to
Tdp
and sudden death (Table
2
). It is indicated
that fluconazole may cause acquired LQTS and ventricular arrhythmia through
a direct inhibition of
hERG
current and by disrupting
hERG
protein trafficking
and the mutations Y652 and F656 may be obligatory determinants in inhibition of
hERG
current for fluconazole [
76
,
77
].
Fluoxetine
:
Fluoxetine, a selective serotonin reuptake inhibitor, is widely used as
an antidepressant compound (Table
2
)[
78
]. Recent studies revealed that the complex
pharmacological profile of fluoxetine includes various additional effects, such as
inhibition of muscular and neuronal nicotinic acetylcholine receptors, blockade of
m
