1. Acquired Long QT Syndrome by Antiarrhythmic Drugs Chen Liying MD – Cardiology Department An Zhen Hospital Beijing CHINA. NASPE-Heart Rhythm Association International fellow. Bologna 2004. Franco Naccarella MD – Cardiology Department Azienda USL Città di Bologna ITALY Stefano Sdringola Maranga MD – Cardiology Division Hermann Memorial Hospital Houston TX USA CHINA 1-16/11/2005 CARDIOSTIM 2004 – June 16-19 Nice, France

6. GENETIC FACTOR CONGENITAL ACQUIREDLONG QT SYNDROME (" FORME FRUSTE ") - IT SHOULD BE REMEMBERED THE LOW PENETRANCE OF GENETIC DISORDERS - BETWEEN ENVIRONMENTAL FACTORS THE MOST IMPORTANT SEEMS TO BE THE CONCOMITANT HYPOKALEMIA FIGURE 1 - SCHEMATIC REPRESENTATION OF DIFFERENT FACTORS BEING INVOLVED IN TDP INDUCTION TRIGGER (DRUGS) ENVIRONMENTAL FACTORS

7. Genetic characterization of congenital LQT syndrome

8. Mechanims of Drug-induced QT Prolongation and TdP 1 The blockade of I kr current by antiarrhythmic drugs that are capable of prolonging the action potential duration is at least in part responsible for their proarrhythmic effect. The blockade of I kr current by antiarrhythmic drugs that are capable of prolonging the action potential duration is at least in part responsible for their proarrhythmic effect. It is interesting to note that many other drugs that cause the development of early afterdepolarizations and TdP block the I kr channel. It is interesting to note that many other drugs that cause the development of early afterdepolarizations and TdP block the I kr channel. The incidence of TdP remain low, however, and not all drugs that block I kr have the same arrhythmogenic potential. The precise reason for the different effects of I kr blocker is unknown. The incidence of TdP remain low, however, and not all drugs that block I kr have the same arrhythmogenic potential. The precise reason for the different effects of I kr blocker is unknown.

9. Mechanims of Drug-induced QT Prolongation and TdP 2 Thus, in an ordinary situation, the administration of an I kr blocker might not prolong the QT interval. Thus, in an ordinary situation, the administration of an I kr blocker might not prolong the QT interval. However in the presence of an otherwise subclinical lesion in the repolarization mechanisms (i.e. reduced repolarization reserve), the same I kr blocker may precipitate marked QT prolongation and TdP. However in the presence of an otherwise subclinical lesion in the repolarization mechanisms (i.e. reduced repolarization reserve), the same I kr blocker may precipitate marked QT prolongation and TdP.

10. Mechanims of Drug-induced QT Prolongation and TdP 3 The causes for these lesions may be acquired (e.g. myocardial infarction, congestive heart failre, ischemia, etc.) or congenital (formes frustes of congenital long QT syndrome). The causes for these lesions may be acquired (e.g. myocardial infarction, congestive heart failre, ischemia, etc.) or congenital (formes frustes of congenital long QT syndrome). The extent of QT prolongation and risk of TdP associated with a given drug may not be linearly related to the dose of plasma level of the drug, because patient and metabolic factors are also important (e.g. gender, electrolyte levels, etc) The extent of QT prolongation and risk of TdP associated with a given drug may not be linearly related to the dose of plasma level of the drug, because patient and metabolic factors are also important (e.g. gender, electrolyte levels, etc) There is not a simple relationship of drug-induced QT prolongation and the likelihood of the development of TdP which can sometimes occur without any noticeable prolongation of the QT interval. There is not a simple relationship of drug-induced QT prolongation and the likelihood of the development of TdP which can sometimes occur without any noticeable prolongation of the QT interval.

11. Torsades de Pointes

12. Factors Modulate the Effects of Drugs That Block I Kr Hypokalemia and hypomagnesemia Hypokalemia and hypomagnesemia Hypertrophy and heart failure Hypertrophy and heart failure Gender Gender Metabolic factors Metabolic factors Sympathetic activity Sympathetic activity Multiple actions of drugs that block I Kr Multiple actions of drugs that block I Kr “Forme fruste” of the congenital long QT syndrome “Forme fruste” of the congenital long QT syndrome

13. Part 1: Cardiac Drugs able to induce QT Prolongation and TdP

14. Class І Antiarrhythmics Quinidine Quinidine Blocks the delayed rectifier I kr as well as I Ks Blocks the delayed rectifier I kr as well as I Ks Quinidine Syncope Quinidine Syncope Causes QT prolongation early during therapy, usually within 1 week Causes QT prolongation early during therapy, usually within 1 week QT prolongation — 1.5% QT prolongation — 1.5% TdP— 1% ~ 8.8%, especially when QT interval ≥520ms, hypokalemia and bradycardia TdP— 1% ~ 8.8%, especially when QT interval ≥520ms, hypokalemia and bradycardia

15. Li Kui: rude and rush by nature. Quinidine

16. Class III Antiarrhythmic Drugs 1 d, l – Sotalol Blocks the delayed rectifier I kr potassium current Blocks the delayed rectifier I kr potassium current No effect on the slow component I ks current No effect on the slow component I ks current Additional β-blocking effect Additional β-blocking effect Incidence of TdP increases with dose and the baseline values of the QT interval. Incidence of TdP increases with dose and the baseline values of the QT interval. TdP occurred early even with low doses of oral d,l-sotalol, especially in patients with congestive heart failure and low ejection fraction. TdP occurred early even with low doses of oral d,l-sotalol, especially in patients with congestive heart failure and low ejection fraction.

17. Bao Zheng: a clean political career and a man of justice. Sotalol

18. Drug induced TDP: comparison between Quinidine and Sotalol

19. Class III Antiarrhythmic Drugs 2 Amiodarone Amiodarone Unique drug which possesses pharmacological properties from all four antiarrhythmic classes Unique drug which possesses pharmacological properties from all four antiarrhythmic classes Has the same potent effects on QT prolongation as other Class III agents, but the associated incidence of TdP is very low. Has the same potent effects on QT prolongation as other Class III agents, but the associated incidence of TdP is very low. TdP usually occurs during concomitant therapy with other QT prolonging drugs or in the context of severe electrolyte disturbance. TdP usually occurs during concomitant therapy with other QT prolonging drugs or in the context of severe electrolyte disturbance. Intravenous amiodarone is also safe and effective for the treatment of ventricular tachyarrhythmias. Intravenous amiodarone is also safe and effective for the treatment of ventricular tachyarrhythmias.

20. Meng Liang: a good general. Amiodaron

21. d- Sotalol d- Sotalol Ibutilide Ibutilide Azimilide Azimilide Tedisamil Tedisamil Ersentilide Ersentilide Dofetilide Dofetilide Dronedarone Dronedarone Almokalant Almokalant New Class III drugs

27. Part 2: Acquired Long QT Syndrome by Non- Antiarrhythmic Drugs

29. Part 3 Drug – Drug Interaction

30. Cytochrome P450(CYP) enzymes are divided into two classes on the basis of the fundamental characteristics of their substrates Those primarily involved in the metabolism of drugs and other xenobiotics Those primarily involved in the metabolism of drugs and other xenobiotics Those involved in the biosynthesis and metabolism of steroid hormones and other endobiotics Those involved in the biosynthesis and metabolism of steroid hormones and other endobiotics Metabolic factors

32. Part 4 How to Avoid Drug- Induced Torsades de Pointes

37. Flow chart for Sotalol administration

38. Conclusions 1 The discordance between QT prolongation and the incidence of TDP among antiarrhythmic drugs that prolong ventricular refractoriness has stimulated immense interest in separating the salutary terapeutic effects from the adverse proarrhythmic action of antiarrhytmic drugs. The discordance between QT prolongation and the incidence of TDP among antiarrhythmic drugs that prolong ventricular refractoriness has stimulated immense interest in separating the salutary terapeutic effects from the adverse proarrhythmic action of antiarrhytmic drugs. Rapidly expanding knowledge of ion channel kinetics and structure, will aid the development of new drugs with specific profiles of channel blocking properties which have an effective antiarrhythmic action with minimal proarrhythmic potential. Rapidly expanding knowledge of ion channel kinetics and structure, will aid the development of new drugs with specific profiles of channel blocking properties which have an effective antiarrhythmic action with minimal proarrhythmic potential.

39. Conclusions 2 For non antiarrhythmic drugs wich prolongs QT interval, dose, duration of treatment, route of administration and magnitude of liver and kidney clearances will affect the intensity and duration of the exposure to the drug. For non antiarrhythmic drugs wich prolongs QT interval, dose, duration of treatment, route of administration and magnitude of liver and kidney clearances will affect the intensity and duration of the exposure to the drug. The most suitable raccomandation for a prescribing physician for both antiarrhythmic and non cardiac drugs is to consult the drug information sheets, the reference books, national formularies, and other drug compendia, to avoid unwanted drug interactions and additive effects on I kr channels. The most suitable raccomandation for a prescribing physician for both antiarrhythmic and non cardiac drugs is to consult the drug information sheets, the reference books, national formularies, and other drug compendia, to avoid unwanted drug interactions and additive effects on I kr channels.

40. Conclusions 3 The overall incidence of TdP in patients who use drugs that block I kr is low (<3%), and not all drugs that block I kr have the same arrhythmogenic potential. The extact reasons for this are unknown but there are many factors which physicians must know and monitor when using drugs that block I kr The overall incidence of TdP in patients who use drugs that block I kr is low (<3%), and not all drugs that block I kr have the same arrhythmogenic potential. The extact reasons for this are unknown but there are many factors which physicians must know and monitor when using drugs that block I kr Hypokalemia and hypomagnesemia Hypokalemia and hypomagnesemia Hypertrophy and heart failure Hypertrophy and heart failure Female gender Female gender Metabolic factors and drug interactions Metabolic factors and drug interactions Symphatethic activity and β- stimulation Symphatethic activity and β- stimulation Multiple actions of drugs thab block I kr (the low incidence of TdP due to Amiodarone may be due to its blocking effects of calcium and sodium currents, thus suppressing the development of early afterdepolarizations, and preventing reentry. Multiple actions of drugs thab block I kr (the low incidence of TdP due to Amiodarone may be due to its blocking effects of calcium and sodium currents, thus suppressing the development of early afterdepolarizations, and preventing reentry. Formes frustes of the congenital long QT syndrome. Formes frustes of the congenital long QT syndrome.