Acquired Long QT Acquired Long QT Syndrome by Syndrome by

Antiarrhythmic DrugsAntiarrhythmic DrugsChen Liying MD Chen Liying MD – – Cardiology Department An Zhen Cardiology Department An Zhen Hospital Beijing CHINA. NASPE-Heart Rhythm Hospital Beijing CHINA. NASPE-Heart Rhythm Association International fellow. Bologna 2004.Association International fellow. Bologna 2004.

Franco Naccarella MDFranco Naccarella MD – – Cardiology Department Cardiology Department Azienda USL Città di Bologna ITALYAzienda USL Città di Bologna ITALY

Stefano Sdringola Maranga MDStefano Sdringola Maranga MD – – Cardiology Cardiology Division Hermann Memorial Hospital Houston TX USADivision Hermann Memorial Hospital Houston TX USACHINA 1-16/11/2005CHINA 1-16/11/2005CARDIOSTIM 2004 – June 16-19 Nice, FranceCARDIOSTIM 2004 – June 16-19 Nice, France

GENETIC FACTOR

CONGENITAL ACQUIREDLONG QT SYNDROME LONG 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

Genetic characterization of Genetic characterization of congenital LQT syndromecongenital LQT syndrome

Mechanims of Drug-induced QT Mechanims of Drug-induced QT Prolongation and TdP 1Prolongation and TdP 1

The blockade of The blockade of IIkr kr current by antiarrhythmic drugs that acurrent by antiarrhythmic drugs that are capable of prolonging the action potential duration is at re capable of prolonging the action potential duration is at least in part responsible for their proarrhythmic effect. least in part responsible for their proarrhythmic effect.

It is interesting to note that many other drugs that cause tIt is interesting to note that many other drugs that cause the development of early afterdepolarizations and TdP blohe development of early afterdepolarizations and TdP block the ck the IIkr kr channel. channel. The incidence of TdP remain low, however, and not all druThe incidence of TdP remain low, however, and not all drugs that block gs that block IIkr kr have the same arrhythmogenic potential. have the same arrhythmogenic potential.

The precise reason for the different effects of The precise reason for the different effects of IIkr kr blocker is blocker is unknown.unknown.

Mechanims of Drug-induced QT Mechanims of Drug-induced QT Prolongation and TdP 2Prolongation and TdP 2Thus, in an ordinary situation, the administration of aThus, in an ordinary situation, the administration of an n IIkr kr blocker might not prolong the QT interval.blocker might not prolong the QT interval.However in the presence of an otherwise subclinical lHowever in the presence of an otherwise subclinical lesion in the repolarization mechanisms (i.e. esion in the repolarization mechanisms (i.e. reduced reduced repolarization reserverepolarization reserve), the same ), the same IIkr kr blocker may preblocker may pre

cipitate marked QT prolongation and TdP.cipitate marked QT prolongation and TdP.

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

Torsades de PointesTorsades de Pointes

Factors Modulate the Effects of Factors Modulate the Effects of Drugs That Block IDrugs That Block IKrKr• Hypokalemia and hypomagnesemiaHypokalemia and hypomagnesemia• Hypertrophy and heart failureHypertrophy and heart failure• GenderGender• Metabolic factorsMetabolic factors• Sympathetic activitySympathetic activity• Multiple actions of drugs that block IMultiple actions of drugs that block IKrKr• ““Forme fruste” of the congenital long QT syndrForme fruste” of the congenital long QT syndromeome

Part 1: Cardiac Drugs able tPart 1: Cardiac Drugs able to induce QT Prolongation ao induce QT Prolongation and TdPnd TdP

Class Class ІІ Antiarrhythmics Antiarrhythmics QuinidineQuinidine Blocks the delayed rectifierBlocks the delayed rectifier I Ikr kr as well asas well as I IKsKs Quinidine SyncopeQuinidine Syncope Causes QT prolongation early during tCauses QT prolongation early during therapy , usually within herapy , usually within 1 1 weekweek QT prolongation — 1.5%QT prolongation — 1.5% TdP— 1% ~ 8.8%, especially when QT interval TdP— 1% ~ 8.8%, especially when QT interval ≥520ms, hypokalemia and bradycardia≥520ms, hypokalemia and bradycardia

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

Class IIIClass III Antiarrhythmic Antiarrhythmic Drugs 1Drugs 1d, l – Sotalold, l – Sotalol

• Blocks the delayed rectifier IBlocks the delayed rectifier Ikr kr potassium currentpotassium current• No effect on the slow component INo effect on the slow component Iks ks currentcurrent• Additional Additional ββ-blocking effect -blocking effect • Incidence of TdP increases with dose and the baseliIncidence of TdP increases with dose and the baseline values of the QT interval. ne values of the QT interval. • TdP occurred early even with low doses of oral d,l-sTdP occurred early even with low doses of oral d,l-sotalol, especially in patients with congestive heart otalol, especially in patients with congestive heart failure and low ejection fraction. failure and low ejection fraction.

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

Drug induced TDP: Drug induced TDP: comparison between comparison between Quinidine and SotalolQuinidine and Sotalol

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

Meng Liang: a good general. AmiodaronMeng Liang: a good general. Amiodaron

• d- Sotalold- Sotalol• IbutilideIbutilide• AzimilideAzimilide• TedisamilTedisamil• ErsentilideErsentilide• DofetilideDofetilide• DronedaroneDronedarone• AlmokalantAlmokalant

New Class New Class IIIIII drugs drugs

Part 2: Acquired Long QT Part 2: Acquired Long QT Syndrome by Non- Syndrome by Non-

Antiarrhythmic DrugsAntiarrhythmic Drugs

Part 3 Drug – Drug InteractionPart 3 Drug – Drug Interaction

Cytochrome P450(CYP) enzymes are Cytochrome P450(CYP) enzymes are divided into two classes on the basis divided into two classes on the basis of the fundamental characteristics of of the fundamental characteristics of their substratestheir substrates Those primarily involved in the metabolism Those primarily involved in the metabolism of drugs and other xenobioticsof drugs and other xenobiotics Those involved in the biosynthesis and metaThose involved in the biosynthesis and metabolism of steroid hormones and other endobibolism of steroid hormones and other endobioticsotics

Metabolic factorsMetabolic factors

Part 4 How to Avoid Drug-IndPart 4 How to Avoid Drug-Induced Torsades de Pointesuced Torsades de Pointes

Flow chart for Sotalol Flow chart for Sotalol administrationadministration

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

Conclusions 2Conclusions 2

For non antiarrhythmic drugs wich prolongs QT inteFor non antiarrhythmic drugs wich prolongs QT interval, dose, duration of treatment, route of administrrval, dose, duration of treatment, route of administration and magnitude of liver and kidney clearances ation and magnitude of liver and kidney clearances will affect the intensity and duration of the exposure will affect the intensity and duration of the exposure to the drug. to the drug. The most suitable raccomandation for a prescribing The most suitable raccomandation for a prescribing physician for both antiarrhythmic and non cardiac dphysician for both antiarrhythmic and non cardiac drugs is to consult the drug information sheets, the rerugs is to consult the drug information sheets, the reference books, national formularies, and other drug ference books, national formularies, and other drug compendia, to avoid unwanted drug interactions ancompendia, to avoid unwanted drug interactions and additive effects ond additive effects on IIkrkr channels.channels.

Conclusions 3Conclusions 3The overall incidence of TdP in patients who use drThe overall incidence of TdP in patients who use drugs that blockugs that block I Ikr kr is low (<3%), and not all drugs thais low (<3%), and not all drugs that blockt block IIkr kr have the same arrhythmogenic potential. have the same arrhythmogenic potential. The extact reasons for this are unknown but The extact reasons for this are unknown but there there are many factors which physicians must know and are many factors which physicians must know and monitor when using drugs that block monitor when using drugs that block IIkr kr

Hypokalemia and hypomagnesemiaHypokalemia and hypomagnesemia Hypertrophy and heart failureHypertrophy and heart failure Female genderFemale gender Metabolic factors and drug interactionsMetabolic factors and drug interactions Symphatethic activity and Symphatethic activity and ββ--stimulationstimulation Multiple actions of drugs thab block Multiple actions of drugs thab block IIkr kr (the low incidence (the low incidence of TdP due to Amiodarone may be due to its blocking effecof TdP due to Amiodarone may be due to its blocking effects of calcium and sodium currents, thus suppressing the dts of calcium and sodium currents, thus suppressing the development of early afterdepolarizations, and preventing evelopment of early afterdepolarizations, and preventing reentry.reentry. Formes frustes of the congenital long QT syndrome.Formes frustes of the congenital long QT syndrome.