Mar, 2005

The Rx Files: Q&A Summary S. Downey BSP, B. Jensen BSP, L.Regier BSP, BA

QT PROLONGATION and TORSADES DE POINTES: DRUGS and SUDDEN DEATH

What is Torsades de Pointes (TdP)?
w TdP or “twisting of the points” refers to a polymorphic ventricular tachycardia
w It is associated with a prolonged QTc interval and bradycardia; patients may also report shortness of breath or syncope
w TdP is thought to be caused by early after-depolarizations during prolonged repolarization1
w It is often self-limiting but may be potentially fatal, sometimes leading to syncope and/or sudden death
w TdP can be either 1° (congenital) or 2° (acquired) due to metabolic disturbances, medical conditions, or most commonly, drugs 1,10
w Recent USA black box FDA WARNINGS due to QT prolongation: amiodarone, cisapride, droperidol, itraconazole & thioridazine 13
w Recent drug FDA REMOVALS due to QT prolongation: astemizole (Hismanal), grepafloxacin (Raxar) & terfenadine (Seldane). 13

Who is at risk?1-6,14
w The “multiple hit” theory suggests that a culmination of several factors is required to induce TdP 2
w Generally, these factors promote early after-depolarizations or prolongation of the action potential 1
Table 1: Risk Factors for QT interval Prolongation and TdP 1-6 * greatest significance
Cardiac Metabolic Other
Bradycardia < 50 bpm Altered nutritional status: *Age - á risk with á age
*Cardiomyopathy: Alcoholism Cerebrovascular disease
Heart failure Anorexia, starvation *Female sex –sex hormones
Left ventricular hypertrophy Diabetes regulate channel expression
*Myocardial infarction Electrolyte disturbances: Hypothyroidism
*Congenital long QT interval Hypokalemia Obesity
(incidence ~ 1/5000)8 Hypomagnesemia Pituitary insufficiency
Hypertension Hypocalcemia Poisoning –arsenic, organophosphates, nerve gas
Ischemic heart disease Hypoglycemia Renal disease
Hypothermia *DRUGS (see Table 2)

Which drugs are implicated?

w Many drugs from a variety of therapeutic classes have been associated with QT interval prolongation and/or TdP (see table)
w All of these drugs have in common their ability to block the I kr potassium channel; this results in increased repolarization time and a
prolonged QT interval (beginning of QRS complex to end of T wave) on ECG.1 Inward Na+ and Ca+ influx channels may also be affected 8
w Prolongation of the QT interval is thought to be dose-related and can occur within therapeutic range for some agents
(eg amiodarone) but only at supra-therapeutic concentrations for others (eg. clarithromycin)
w Effects of different drugs can be additive
w Since many of these drugs are also metabolized by the cytochrome P450 system, serious and sometimes lethal drug
interactions can occur when combined with drugs which inhibit or compete for binding to these isoenzymes (see table)

How to avoid trouble: 2,6

wIdentify those at risk (Table 1); be aware however, that individuals’ vulnerability can vary greatly due to a complexity of
genetic and environmental factors which are not completely understood
wFor patients with major or multiple risk factors, obtain a baseline ECG and determine the QTc interval (corrected for
heart rate – equation described elsewhere7)
• Short 2 QTc < 0.41 sec ..........................VERY LOW RISK
-may not require ECG monitoring after initiating a QT-prolonging agent but should have if additional risk factors
develop or if a drug interaction is likely
• Intermediate QTc 0.42-0.44 sec .........LOW - MODERATE RISK
- repeat ECG after initiating any QT prolonging agent, again at steady state, weekly for 1st month, then q6months and
when any other QT prolonging agent is added or if a drug interaction is likely
- if QTc >0.45 sec, reduce dosages or avoid these agents and use alternatives
• Prolonged QTc >0.45 sec ...................MODERATE - HIGH RISK
- repeat ECG after initiating any QT prolonging agent, again at steady state, weekly for 1st month, then q6months and
when any other QT prolonging agent is added or if a drug interaction is likely
- if QTc >0.50 sec avoid these agents and use alternatives
- regular monitoring of serum K+ and Mg+ also advised
Rule of thumb 8: A QTc change of < 10msec is acceptable as long as there are no other significant risk factors;
If the QTc change is >10msec, reduce dosage or eliminate the drug(s), monitor more closely.

PROMOTING OPTIMAL DRUG THERAPY www.RxFiles.ca

 Mar, 2005
The Rx Files: Q&A Summary S. Downey BSP, B. Jensen BSP, L.Regier BSP, BA

How to treat TdP:

Emergency: 9
w Do not use standard antiarrhythmic agents
w Give magnesium sulphate 2 grams IV over 2 minutes. If ineffective, consider isoproterenol , dobutamine, or atropine IV
w Consider giving potassium if serum K+ is low; bicarbonate for TCP (phencyclidine) or quinidine poisoning
w Lidocaine & phenytoin have also been used
Later:
w Stop the offending agent w Maintain normal K+ , Mg++ and HCO3_ w Keep out of trouble as above

Table 2: Drugs which can prolong QT Interval 1,3,6,9,12,13,14 -see also www.torsades.org
Cardiovascular CNS Agents / Anti-Infective Miscellaneous Cytochrome P450
Agents Psychotropics Agents Agents Inhibitors
Anti-arrhythmics Anticonvulsants Antibiotics Alfuzosin CYP3A4
Amiodarone Felbamate Cotrimoxazole Amantidine amiodarone
(low risk of TdP Fosphenytoin Fluoroquinolones Arsenic trioxide Azole antifungals:
compared to other Lithium Gatifloxacin Cisapride(Special Access) Fluconazole
class III agents such as Gemifloxacin Cocaine
sotalol; however Itraconazole
Antipsychotics Levofloxacin Cyclosporin Ketoconazole
potential for DIs)
Clozapine Moxifloxacin Foscarnet
Bepridil Calcium channel blocker:
Phenothiazines (PZs) Ofloxacin Hydroxyzine
Bretylium Diltiazem
Chlorpromazine Macrolides Indapamide
Disopyramide Verapamil
Perphenazine Azrithromycin Methadone
Dofetilide Cimetidine
Mesoridazine Clarithromycin Midodrine
Flecainide Ciprofloxacin
Thioridazine Erythromycin 11 Octreotide
Ibutilide Grapefruit juice
Butyrophenones Roxithromycin Phenylephrine
Procainamide HIV: protease inhibitors
Haloperidol Probucol
Propafenone
Thioxanthines Azole Antifungals Pseudoephedrine Macrolides:
Quinidine
Pimozide Fluconazole Ritodrine Erythromycin
Sotalol
Quetiapine Itraconazole Tacrolimus Clarithromycin
Risperidone Ketoconazole Tamoxifen Troleandomycin
Dobutamine (not with Azithromycin)
Ziprasidone Voriconazole Tizanidine
Dopamine Methadone
Triptans(Recently off QT list)
Isradipine
Chloral Hydrate Antimalarials Vardenafil SSRI's:
Moexipril/HCTZ
Chloroquine Antihistamines Fluvoxamine
Nicardipine
SSRIs Halofantrine Diphenhydramine Norfluoxetine
Norepinephrine
Fluoxetine Mefloquine Clemastine Nefazodone
Paroxetine Quinine Loratidine Paroxetine
Sertraline (proposed but no reports)
CYP2D6
Pentamidine Withdrawn:
-------------------------- Astemizole & terfenadine
Beta Blockers (BBs)
SNRI
Haloperidol
Venlafaxine Appetite suppressant
ADHD agents Phenothiazines
Ephedrine
Amphetamine TCAs Quinidine
Fenfluramine
Atomoxetine
Amitriptyline Phentermine SSRIs (not interact with citalopram)
Dextroamphetamine Terbinafine
Amoxapine Sibutramine
Methylphenidate TCAs
Clomipramine Bronchodilators
Desipramine Epinephrine
--------------------------
Antiemetics Doxepin
less significant

Dolasetron Isoproterenol
Imipramine Levalbuterol CYP1A2
Domperidone Maprotiline Fluoroquinolones
Metaproterenol
Droperidol Nortriptyline Fluvoxamine
Salbutamol/albuterol
Granisetron Grapefruit juice
Salmeterol
Ondansetron
Terbutaline
AVOID COMBINATIONS of PHENOTHIAZINES with TCAs, BETA BLOCKERS, and ANTICONVULSANTS
Some drugs (eg. erythromycin & amiodarone) prolong the QT Interval AND act as inhibitors to potentially increase levels or QT effects of concomitant medications.
BOLD=major significance (well-documented) REGULAR=low-moderate significance (fewer case reports) ITALIC=minor significance (theoretical, few if any case reports)
References:
1. Wolbrette D. Drugs that cause TdP & increase the risk of sudden cardiac death. Curr Card Reports 2004; 6: 379-84. 8. Brown et al. Cardiovascular effects of anti-psychotics. Clin Pharmacokinet 2004; 43(1): 38-56
2. Wojciech Z & Lin D. Antipsychotic drugs and QT interval prolongation. Psychiatr Q 2003; 74(3): 291-306. 9. Gowda RM, et al. Torsade de pointes: the clinical considerations. Int J Cardiol. 2004;96:1
3. Taylor D. Antipsychotics and QT prolongation. Acta Psychiatr Scand 2003;107:85-95. 10. Sudden Arrhythmia Death Syndromes Foundation The long QT syndrome. SADS Foundation
4. Vieweg W. New generation antipsychotic drugs abd QTc interval prolongation. http://www.sads.org/LQTflyer.pdf (Cardiac Arrhythmia Reasearch & Education Foundation www.longqt.org)
Prim Care Companion J Clin Psychiatry 2003;5 (5):205-15. 11. Ray WA, et al. Oral erythromycin & the risk of sudden death from cardiac causes. N Engl J Med. 2004 Sep
5. Roden D. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350: 1013-22. 9;351(11):1089-96.
6. Crouch M et al. Clinical relevance & management of drug-related QT interval prolongation. Pharmacotherapy 2003; 12. Liu BA, Juurlink DN. Drugs and the QT interval - caveat doctor. N Engl J Med. 2004 Sep 9;351(11):1053-6.
23(7):881-908. 13. Woeffel JA. Drug-Induced Long QT Interval & Sudden Cardiac Death. Pharmacist's Letter Nov 2004;20:201111
7. Witchel H et al. Psychotropic drugs, cardiac arrhythmia, & sudden death. J Clin Psychopharmacol 2003; 23(1):58-77. 14. Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA. 2003
Apr 23-30;289(16):2120-7. Review. Erratum in: JAMA. 2003 Sep 10;290(10):1318.

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