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  1. 1.  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 2
  2. 2.  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- induced cardiotoxicity  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 abnormalities 3
  3. 3.  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. 4
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  5. 5.  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 channel blockade. 6 • 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.
  6. 6.  There’s a chance of drug-induced cardiotoxicity other than the hERG channel. There are drugs do not inhibit hERG that do cause QT prolongation  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 7
  7. 7.  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) b) OncoLogic c) HazardExpert d) COMPACT (Computer Optimized Molecular Parametric Analysis of Chemical Toxicity e) CASE/Multi CASE/MCASE-ES (Computer automated structure evolution) f) TOPKAT (TOxicity Prediction by komputer Assisted Technology) g) Other software applications like QSARIS and TOXSYS 8
  8. 8.  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. 9