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Cardiotoxicity is the occurrence of heart electrophysiology
dysfunction or muscle damage
Some drugs may affect the heart as toxic effects,then heart
becomes weaker and is not as efficient in pumping
It is the major concern during drug development, with increased
pro arrhythmic potential being the main culprit
Ion channels- Action potentials in cardiac cells by sodium, calcium, and
potassium ion channels. Drug-mediated alteration of any of these can cause
either pro- or anti-arrhythmic condition
Population variability— in terms of age, gender, genetics, ethnicity,
renal/hepatic function, and electrolyte homeostasis— can leads drug-
Drug-drug interactions- can play a role in drugs proarrhythmic effects due to
changes in pharmacokinetics. One of the best known examples of QT
prolongation is the combination of terfenadine and ketoconazole
Ketaconazole inhibits CYP3A4 that causes a substantial increase in the
concentration of terfenadine this can result in ECG repolarization
Heart rate is influenced by QT interval
It is a measure of the total duration of ventricular activation
and recovery (depolarization and repolarization). During
depolarization sodium and calcium inflow that exceeds
potassium outflow. When potassium outflow exceeds sodium
and calcium inflow, then repolarization occurs.
Potassium current mediated by the hERG channel.
QT interval prolongation can result from pharmacological inhibition of the
hERG ion channel results in cardiac arrhythmias.
Most, if not all drugs which induce QT interval prolongation have been
reported by inhibition of delayed repolarizing current (IKr) due to hERG
• The most important component of
phase3 repolariza -tion is K+ current
which is conducted by hERG channels
• At negative membrane potentials (for
example 80 mV), hERG channels are in
a non-conducting closed state.
There’s a chance of drug-induced cardiotoxicity other than the hERG
channel. There are drugs do not inhibit hERG that do cause QT
long QT syndrome (LQTS), an abnormality of cardiac muscle
repolarization that is characterized by the prolongation of the QT
interval in ECG , was implicated as reason for torsades de pointes(TdP)
TdP is defined as polymorphic ventricular tachycardia with a twist of the
QRS complex around the isoelectric baseline on the ECG
Toxicity prediction systems uses a knowledge based rules collected
from human experts as the basis for the toxicity predictions.
Some examples are:
a) DEREK (Deductive Estimation of Risk from Existing Knowledge)
d) COMPACT (Computer Optimized Molecular Parametric Analysis of
e) CASE/Multi CASE/MCASE-ES (Computer automated structure
f) TOPKAT (TOxicity Prediction by komputer Assisted Technology)
g) Other software applications like QSARIS and TOXSYS
Many molecular modeling studies focused on hERG block
prediction have been published, covering QSAR,
pharmacophores, structure-based studies employing
homology models, machine learning, And computational
approaches describing the physiology of the electrical wave
propagation in the heart.