Biomedical Engineering Reference
In-Depth Information
In contrast, little is known about the effects of these macrolides on the
hERG
channel [
92
]. They have been widely used as effective antibiotics against gram-
positive organisms [
93
]. In fact, it is also the most thoroughly characterized with
respect to effects on cardiac repolarization that seems to be mediated by cardiac
potassium channel blockade [
94
-
96
]. The cardiac adverse effects of macrolides,
especially erythromycin (Table
2
) have been reported elsewhere [
93
]. It is also the
most thoroughly characterized with respect to the effects on cardiac repolarization
that seems to be mediated by cardiac potassium channel blockade [
94
-
96
]. With
increasing reports of QT prolongation and arrhythmias associated with these drugs
is by inhibiting
hERG
channels [
97
,
98
].
Mesoridazine: Mesoridazine is used to treat the symptoms of schizophrenia and
reduce restlessness, anxiety and tension. It can also reduce hyperactivity and
uncooperativeness. Mesoridazine has been shown to prolong the QT interval in a
dose-related manner which increases the risk of life-threatening arrhythmias such
as
Tdp
and sudden death consequently its use in schizophrenia has been restricted
(Table
2
). Its use in other psychiatric disorders was abandoned after it was felt that
there was an unacceptable balance of risks and benefits as a result of its cardiotoxic
potential and it is no longer available in many countries [
99
].
Methadone: It is a synthetic opioid, used medically as an analgesic, antitussive
and maintenance antiaddictive for use in patients on opioids (Table
2
). Methadone
inhibits the cardiac potassium channel
hERG
and can cause a prolonged QT interval.
Methadone is chiral but its therapeutic activity is mainly due to (R)-methadone.
Whole-cell patch-clamp experiments using cells expressing
hERG
showed that (S)-
methadone blocked the
hERG
current 3.5-fold more potently than (R)-methadone
[
100
-
102
].
Mibefradil: It is a calcium channel blocker that selectively blocks T-type
calcium channel, useful in cardiovascular conditions such as hypertension, angina,
or heart pain and congestive heart failure. It is also reported to cause QT
prolongation and
Tdp
by blocking
hERG
potassium channel in concentration-
dependent manner [
103
]. Also, K
v
LQT1 is inhibited by bepridil and mibefradil,
explains that Ikr is that sensitive target to most of the calcium channel blockers,
which further depicts the proarrhythmic effect of these drugs (Table
2
). Shortly
following its introduction, mibefradil was withdrawn from the US market because
of potentially harmful interactions with other drugs (e.g., amiodarone, quinidine,
sotalol, erythromycin, desimipramine and thioridazine), which collectively prolong
QT interval [
104
].
Nelfinavir: It is a potent HIV protease inhibitor class of antiretroviral drug that
causes unpredicted adverse effects by changing elements of normal cellular metab-
olism (Table
2
). Drug-induced QT prolongation is usually caused by block
of
hERG
potassium channels and nelfinavir shown to cause dose-dependent block-
ade as heterologously expressed in HEK293 cells
in vitro
. Block by lopinavir of
repolarizing IKr channels in neonatal mouse cardiac myocytes suggests that prote-
ase inhibitors could predispose individuals to QT prolongation and
Tdp
[
105
].
Pimozide: It is well another known antipsychotic which causes QT prolongation
and
Tdp
. Forty cases (16 deaths) of serious cardiac reactions (predominantly
