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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 Citt di Bologna ITALY Stefano Sdringola Maranga MD Cardiolo
2、gy Division Hermann Memorial Hospital Houston TX USA CHINA 1-16/11/2005 CARDIOSTIM 2004 June 16-19 Nice, France,GENETIC FACTOR CONGENITAL ACQUIRED LONG QT SYNDROME LONG QT SYNDROME (“ FORME FRUSTE “) - IT SHOULD BE REMEMBERED THE LOW PENETRANCE OF GENETIC DISORDERS - BETWEEN ENVIRONMENTAL FACTORS TH
3、E MOST IMPORTANT SEEMS TO BE THE CONCOMITANT HYPOKALEMIA,FIGURE 1 - SCHEMATIC REPRESENTATION OF DIFFERENT FACTORS BEING INVOLVED IN TDP INDUCTION,TRIGGER (DRUGS),ENVIRONMENTAL FACTORS,Genetic characterization of congenital LQT syndrome,Mechanims of Drug-induced QT Prolongation and TdP 1,The blockade
4、 of Ikr 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 Ikr channel.
5、 The incidence of TdP remain low, however, and not all drugs that block Ikr have the same arrhythmogenic potential. The precise reason for the different effects of Ikr blocker is unknown.,Mechanims of Drug-induced QT Prolongation and TdP 2,Thus, in an ordinary situation, the administration of an Ikr
6、 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 Ikr blocker may precipitate marked QT prolongation and TdP.,Mechanims of Drug-induced QT Prolongation and TdP 3,The
7、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 l
8、evel 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 in
9、terval.,Torsades de Pointes,Factors Modulate the Effects of Drugs That Block IKr,Hypokalemia and hypomagnesemia Hypertrophy and heart failure Gender Metabolic factors Sympathetic activity Multiple actions of drugs that block IKr “Forme fruste” of the congenital long QT syndrome,Part 1: Cardiac Drugs
10、 able to induce QT Prolongation and TdP,Class Antiarrhythmics,Quinidine Blocks the delayed rectifier Ikr as well as IKs Quinidine Syncope Causes QT prolongation early during therapy , usually within 1 week QT prolongation 1.5% TdP 1% 8.8%, especially when QT interval 520ms, hypokalemia and bradycard
11、ia,Li Kui: rude and rush by nature. Quinidine,Class III Antiarrhythmic Drugs 1,d, l Sotalol Blocks the delayed rectifier Ikr potassium current No effect on the slow component Iks current Additional -blocking effect Incidence of TdP increases with dose and the baseline values of the QT interval. TdP
12、occurred early even with low doses of oral d,l-sotalol, especially in patients with congestive heart failure and low ejection fraction.,Bao Zheng: a clean political career and a man of justice. Sotalol,Drug induced TDP: comparison between Quinidine and Sotalol,Class III Antiarrhythmic Drugs 2,Amioda
13、rone 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. TdP usually occurs during concomitant therapy with other QT prolonging drugs or
14、in the context of severe electrolyte disturbance. Intravenous amiodarone is also safe and effective for the treatment of ventricular tachyarrhythmias.,Meng Liang: a good general. Amiodaron,d- Sotalol Ibutilide Azimilide Tedisamil Ersentilide Dofetilide Dronedarone Almokalant,New Class III drugs,Part
15、 2: Acquired Long QT Syndrome by Non- Antiarrhythmic Drugs,Part 3 Drug Drug Interaction,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 involv
16、ed in the biosynthesis and metabolism of steroid hormones and other endobiotics,Metabolic factors,Part 4 How to Avoid Drug-Induced Torsades de Pointes,Flow chart for Sotalol administration,Conclusions 1,The discordance between QT prolongation and the incidence of TDP among antiarrhythmic drugs that
17、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 profil
18、es of channel blocking properties which have an effective antiarrhythmic action with minimal proarrhythmic potential.,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 th
19、e 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 inte
20、ractions and additive effects on Ikr channels.,Conclusions 3,The overall incidence of TdP in patients who use drugs that block Ikr is low (3%), and not all drugs that block Ikr have the same arrhythmogenic potential. The extact reasons for this are unknown but there are many factors which physicians
21、 must know and monitor when using drugs that block Ikr Hypokalemia and hypomagnesemia Hypertrophy and heart failure Female gender Metabolic factors and drug interactions Symphatethic activity and -stimulation Multiple actions of drugs thab block Ikr (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.,THANK YOU,