Drug induced TdP Vietnam 2010 tài liệu, giáo án, bài giảng , luận văn, luận án, đồ án, bài tập lớn về tất cả các lĩnh vự...
Drug induced Torsades de Pointes: Therapy & Prevention Razali Omar MD, FHRS, FACC Director, Electrophysiology and Pacing Unit National Heart Institute, Kuala Lumpur Vietnam Congress of Cardiology 18-19 Oct 2010 QT Prolongation & Torsades de Pointes Congenital LQTS Acquired LQTS Drugs Bradycardia Hypokalemia CHF & LVH Drug Induced Torsades de Pointes (TdP) Low frequency event Estimated at 1:10,000 to 1:100,000 Potentially life threatening Not highly predictable despite known risk factors More likely to occur in hospitalized patients as they are a sicker group QT Intervals in Drug Induced TdP Percent of Patients with QTc or QT> 500 msec (%) 100 89.5 89.5 80.2 75.5 QTc 75 50 QT 25 Antiarrhythmic Drugs (N= 332) Makkar et al JAMA 1993; 270: 2590-2597 Non-Antiarrhythmic Drugs (N=189) Increase in QTc Each 10 ms increase in QTc contributes an exponential increase of -7% for TdP E.g pt with QTc 540 ms has a 63 -97% higher risk for TdP than a pt with QTc 440ms No threshold of QT increase at which TdP is certain to occur Cut off point of 500ms usually used Circ 1991;84 NEJM 1998;339 NEJM 2003;348 Characteristic Pattern of TdP 1.Change in the amplitude and morphology (twisting) of the QRS around the isoelectric line Usually starts with short-longshort pattern of R-R cycles This short-long-short cycles promote TdP by increasing heterogeneity of repolarization across the myocardial wall TdP episodes have a warm up phenomenon with the first few beats of VT having longer CL Frequently terminates spontaneously Drugs Which Prolong the QTc Anticonvulsants Antihistamines Anti-Infectives Fosphenytoin; Felbamate Azelastine; Clemastine Amantadine; Clarithromycin; Chloroquine; Foscarnet; Erythromycin; Halofantrine; Mefloquine; Moxifloxacin; Pentamidine; Sparfloxacin; Quinine; TrimethoprimSulfamethoxazole, Ketoconazole Antineoplastics Tamoxifen Cardiovascular: Antiarrhythmics Amiodarone; Bretylium; Disopyramide; Flecainide; Ibutilide; Procainamide; Quinidine; Sotalol; Dofetilide Calcium Channel Blockers Bepridil; Israpidine; Nicardipine Diuretics Indapamide; Moexipril/HCTZ Hormones Octreotide; Vasopressin Immunosuppressives Tacrolimus Migraine: Serotonin Receptor Agonists Zolmitriptan; Naratriptan; Sumatriptan Muscle Relaxant Tizanidine Narcotic Detoxification Levomethadyl Psychotherapeutics: Antidepressants Amitriptyline; Desipramine; Fluoxetine; Imipramine; Venlafaxine Antipsychotic Chlorpromazine; Haloperidol; Pimozide; Quetiapine; Risperidone; Thioridazine Antianxiety Doxepin Antimanic Lithium Respiratory: Sympathomimetics Salmeterol Sedative/Hypnotics Chloral hydrate http://www.dml.georgetown.edu/depts/pharmacology/torsades.html http://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/publicat/adrv8n1_e.html Twenty most commonly reported drugs associated with torsades de pointes (TdP) between 1983 and 1999 Drug Sotalol Cisapride Amiodarone Erythromycin Ibutilide Terfenadine Quinidine Clarithromycin Haloperidol Fluoxetine Digoxin Procainamide Terodiline Fluconazole Disopyramide Bepridil Furosemide Thioridazine Flecainide Loratidine TdP (n) Fatal (n) Total (n) Tdp/total (%) 130 97 47 44 43 41 33 33 21 20 19 19 19 17 16 15 15 12 11 11 1 0 0 0 2758 6489 13725 24776 173 10047 7353 17448 15431 70929 18925 5867 2248 5613 3378 384 15119 6565 3747 5452 4.71 1.49 0.34 0.18 24.86 0.41 0.45 0.19 0.14 0.03 0.10 0.32 0.85 0.30 0.47 3.91 0.10 0.18 0.29 0.20 Tdp (n), total no.of adverse drug reaction reports which named TdP associated with this drug; Fatal (n): no of adverse drug reaction reports which named TdP with fatal outcome; Total(n): total no of adverse drug reaction reports for the drug Action Potential and Ionic Currents TdP mainly from Ikr blockers Reduce net repolarizing current Increase APD and QT Ca++ Na+ IKr IKs Yan & Antzelevitch Circulation 1998;98:1921-1927 Amiodarone QT 621 QTc 747 HR 87 Long-short -> TdP Effect of EC K+ on Drug Induced IKr Block Circulation 1996 Feb 1;93(3):407-11Yang T, Roden DM GAO 01-286R 1/19/01 Drug Induced QT Prolongation Preclinical Screeing In vitro ion channels effects IKr - cloned HERG (HEK or AT-1 cells) I c a & IN a In vitro APD effects Isolated myocytes (dog,rabbit,g pig) Purkinje fibers (dog,rabbit) Papillary muscle (guinea pig) Wide range of concentrations (100-1000X) Wide range of rates Metabolites Drug Induced QT Prolongation Preclinical Screeing Other In vitro models LV wedge (perfused canine) Perfused rabbit heart ( HR & K+) In vivo models Conscious rabbit Anesthetized methoxamine sensitized rabbit Canine chronic AV block Evaluation of New Drugs - Risk Assessment Preclinical profile QT effects in humans Mean & mean max changes c/w PBO Categorical analysis Outliers Special populations Torsades de Pointes VT, VF & cardaic arrest Syncope Sudden death Drug-Induced TdP Drug - drug interactions Pharmacokinetic Pharmacodynamic Drug - gene interactions Genetic polymorphisms Acquired repolarization reserve (CHF) Drug Induced QT Prolongation Preclinical findings QT effects in humans Adverse event profile Therapeutic target(s) Relative efficacy Unique advantages Alternative options Risk:benefit assessment Drugs Which Cause TdP Almost all are IKr blockers Preclinical Many are CYP 450 3A4 substrates Numerous TdP profile cannot exclude risk cofactors enhance risk rarely detected in drug development TdP - Low Risk Drugs (< 0.1%) Therapeutic Effect Is Independent of IKr Block Antihistamines Antibiotics Antiviral agents Psychotropics Many others Drug Induced Torsades de Pointes Drug EP Effects Metabolic Liability Terfenadine Cisapride Mibefradil Erythromycin Astemizole Dofetilide Sotalol IKr blocker IKr blocker IKr blocker IKr blocker IKr blocker IKr blocker IKr blocker 3A4 substrate 3A4 substrate 3A4 inhibitor 3A4 inhibitor 3A4 substrate Renal excretion Renal excretion ... 0.10 0.18 0.29 0.20 Tdp (n), total no.of adverse drug reaction reports which named TdP associated with this drug; Fatal (n): no of adverse drug reaction reports which named TdP with fatal outcome;... are a sicker group QT Intervals in Drug Induced TdP Percent of Patients with QTc or QT> 500 msec (%) 100 89.5 89.5 80.2 75.5 QTc 75 50 QT 25 Antiarrhythmic Drugs (N= 332) Makkar et al JAMA 1993;... Torsades de Pointes Congenital LQTS Acquired LQTS Drugs Bradycardia Hypokalemia CHF & LVH Drug Induced Torsades de Pointes (TdP) Low frequency event Estimated at 1:10,000 to