Biomedical Engineering Reference
In-Depth Information
monoamine oxidase A and B [
79
] and reduction of neuronal K
v
1.1 potassium and
sodium currents [
80
]. It has been suggested that fluoxetine might inhibit the K
+
-
induced serotonin release by decreasing the voltage-dependent Ca
2+
entry into nerve
terminals [
81
]. Furthermore, it had been demonstrated that delayed rectifier K
+
channels and Na
+
channels in human corneal epithelium are blocked by fluoxetine
[
82
] and, finally, inhibitory effects of fluoxetine on cardiac Ca
2+
and Na
+
channels.
Selective serotonin reuptake inhibitor antidepressant drugs are generally believed to
cause fewer proarrhythmic side effects compared with tricyclic antidepressants [
83
].
However, serious concerns have been raised by case reports of tachycardia and
syncope associated with fluoxetine treatment [
84
]. In addition, a patient with mark-
edly prolonged QTc interval due to fluoxetine has been reported, whereas previous
experimental and clinical studies did not reveal any prolongation of the QTc interval
[
85
]. But still the QTc prolongation seen during application of fluoxetine suggests
that cardiac repolarization might be affected by this drug. Repolarization of cardiac
ventricular myocyte is mainly due to outward potassium currents [
86
].
Grepafloxacin: It is well known to prolong cardiac repolarization and has been
reported to increase the QT interval by an average of 10 ms in clinical trials at
therapeutic doses (Table
2
). Grepafloxacin was withdrawn from the market because
of concerns over QT interval prolongation and rare cases of ventricular arrhythmia,
including torsades de pointes, in patients receiving the drug [
87
,
88
].
Ketoconazole: Ketoconazole is a synthetic antifungal drug and blocker of
potassium rectifier current, which prolongs the QT interval (Table
2
). It has been
associated with QT prolongation and
Tdp
when co-administered with QT interval
prolonging drugs (e.g., astemizole, terfenadine). Oral dose of 50 mg/kg terfenadine
with ketoconazole 200 mg/kg combination results in immediate QT prolongation
but none of them alone increased QT prolongation in telemetred conscious guinea
pigs orally [
63
]. There is a pharmacokinetic component, both compounds use the
same cytochrome-P450 metabolic pathway, resulting in an increase in plasma
concentration of terfenadine. The voltage- and time-dependent characteristics of
hERG
blockade by ketoconazole indicated dependence of block on channel gating,
ruling out a significant role for closed-state channel inhibition. Thus, ketoconazole
accesses
hERG
channel pore-cavity on channel gating and S6 residue F656 is an
important determinant of ketoconazole binding [
63
,
89
,
90
]. However, ketocona-
zole can block potassium currents mediated by
hERG
and K
v
1.5, another cardiac
potassium channel. The IC
50
were reported 15.5-49
M in Xenopus oocytes and
m
approximately 2.5
M in cat ventricular myocytes [
90
].
Levacetylmethadol: Opioids have capability to block
hERG
current in patients
with or without any cardiac abnormalities and are responsible for QT interval
prolongation (Table
2
). Levacetylmethadol is a metabolite of methadone, causes
Tdp
, and its use requires electrophysiographic screening before treatment and
during titrations. It is indicated as a second-line regimen drug for the treatment
and management of opioid dependence if patients fail to respond to drugs such as
methadone or buprenorphine [
91
].
Macrolides (erythromycin): Macrolides are a group of closely related com-
pounds characterized by a macrocyclic lactone ring to which sugars are attached.
m
