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Pharmacologic Agents and QT interval
Prolongation: An emphasis on
psychotropics
Babatunde Idowu Ogundipe M.D. M.P.H.
Washington DC VA Medical Center
Monday August 20 2012
Torsades De Pointes
http://heart.bmj.com/content/89/11/1363.full
• History: Francois Dessertenne.
• Many conditions can cause prolonged or abnormal repolarisation = QT
interval prolongation and/or abnormal T or T/U wave morphology,
which is associated with Torsades de Pointes (TdP).
• Rapid/prolonged TdP can  ventricular fibrillation and sudden cardiac
death.
• TdP is caused by either: (1) Congential Long QT syndrome or (2)
Acquired Long QT syndrome.
Drug
TdP (n)
Fatal (n)
Total (n)
TdP/total (%)
Sotalol
Cisapride
Amiodarone
Erythromycin
Ibutilide
Terfenadine
Quinidine
Clarithromycin
Haloperidol
Fluoxetine
Digoxin
Procainamide
Terodiline
Fluconazole
Disopyramide
Bepridil
Furosemide
Thioridazine
Flecainide
Loratidine
130
97
47
44
43
41
33
33
21
20
19
19
19
17
16
15
15
12
11
11
1
6
1
2
1
1
2
0
6
1
0
0
0
0
1
0
0
0
2
1
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
http://heart.bmj.com/content/89/11/1363.full
TdP (n), total number of adverse drug reaction reports which named TdP associated with this drug; Fatal (n):
number of adverse drug reaction reports which named TdP with fatal outcome; Total (n): total number of
adverse drug reaction reports for the drug.
What is the meaning of Sudden Cardiac Death?
• Caused by loss of heart function (sudden cardiac arrest).
Sudden i.e. within a short period, generally < 1 hour, from the
onset of symptoms, unexpected i.e in a person without any
prior condition that would appear fatal.
• Sudden cardiac death is the largest cause of natural death in
the United States, causing about 325,000 adult deaths in the
United States each year.
• Sudden cardiac death is responsible for half of all heart
disease deaths.
• Sudden cardiac death occurs most frequently in adults in their
mid-30s to mid-40s, and affects men twice as often as it does
women. It is rare in children, affecting only 1 to 2 per 100,000
children each year.
drsvenkatesan.wordpress.com
How do Drugs cause QT prolongation and Torsades De Pointes?
• Repolarisation phase
myocytes driven by outward
movement of potassium
ions.
• Variety of different K+
channels subtypes in heart:
Ikr & Iks.
• Blockade of either of these
outward potassium currents
may prolong the action
potential.
• Blockade of Ikr by these drugs
in part responsible for their
pro-arrhythmic effect.
• Blockade Ikr manifests
clinically as a prolonged QT
interval + emergence of
other T or U wave
abnormalities on ECG.
http://rudylab.wustl.edu/images/Research/Cell/Publications/Single/zengikriks.gif
Rhythm strip in a patient with drug induced
TdP.
Arrhythmogenesis of torsades de pointes.
Yap Y G , Camm A J Heart 2003;89:1363-1372
Copyright © BMJ Publishing Group Ltd & British Cardiovascular Society. All rights reserved.
What is the QT interval and when is it prolonged?
• QT interval measured from
beginning of QRS complex to
the end of the T wave.
• QT interval prolongation:
• Men QTc > 440ms.
• Women QTc > 460ms.
• Extent of QT prolongation +
risk of Torsades not linearly
related to the dose/plasma
concentration of the drug as
patient & metabolic factors
also important i.e electrolyte
imbalances.
• There is no simple relation
between degree of drug
induced QT prolongation and
likelihood development
Torsades.
http://lifeinthefastlane.com/wp-content/uploads/2011/01/waves-of-the-ecg.gif
Which Drugs cause QT prolongation and Torsades De Pointes?
• Antiarrhythmics:
• Torsades been found to occur at low therapeutic/subtherapeutic with class 1a
drugs.i.e. quinidine, disopyramide & procainamide.
• Others such as d,l,-sotalol prolong QT and induce TdP at incidence directly
proportionate to their concentration until potassium ch’s completely blocked.
Risk increases with female patients, patients with reduced creatinine
clearance, CHF, or sustained ventricular tachycardia.
• Antihistamines:
• Certain nonsedating antihistamines (second generation antihistamines) mainly
terfenadine and astemizole reported to cause QT prolongation and in some
cases Torsades De Pointes.
• Evidence so far shows potential to cause Torsades De Pointes not a class effect
non-sedating antihistamines. Low risk: azelastine, mizolastine. No association
with QT prolongation/Torsades/other ventricular arrhythmias: loratidine,
cetirizine, ebastine, fexofenadine.
• Incidence cardiotoxicity with antihistamines very low in view of widespread
use of these drugs.
Yap Y G , Camm A J Heart 2003;89:1363-1372
Which Drugs cause QT prolongation and Torsades De Pointes?
• Antimicrobials:
• Macrolides(erythromycin, clarithromycin), fluoroquinolones, antifungals, and
antimalarials implicated in predisposing to TdP as a result of QT prolongation.
(few reports).
• Evidence thus far suggests that there are significant differences in potency to
prolong QT interval among fluoroquinolones, & risk arrhythmias varies
between drugs.
Which Drugs cause QT prolongation and Torsades De Pointes?
• Antimicrobials:
• Antimalarials Quinine, quinidine, & halofantrine prolong QT
interval.
• Cardiotoxicity of antimalarials increased in patients with acute
renal failure, especially after 3 days of treatment. ECG monitoring
during infusion quinidine.
• Antifungals Ketoconazole & itraconazole prolong the QT interval
via blockade Ikr channels.
• Antifungals Ketoconazole & itraconazole also inhibit the hepatic
cytochrome P450 CYP3A4 isoenzyme. Co-administration with
another QT prolonging drug metabolised by cytochrome P450
CYP3A4 isoenzyme(i.e. terfenadine) will  prolonged QT interval
+ increased risk of Torsades De Pointes.
Which Drugs cause QT prolongation and Torsades De Pointes?
• Prokinetics:
• Cisapride, gastrointestinal prokinetic agent used in treatment
Gastroesophageal Reflux Disease, Gastroparesis, & Childhood
chronic intestinal pseudo-obstruction.
• U.S.A. Cisapride marketed from 1993-1999. During this time FDA
received reports of 341 patients with serious adverse cardiac
effects: 117 developed QT prolongation; 107 TdP; 16 polymorphic
VT; 27 VT(ventricular tachycardia); 18 VF (ventricular fibrillation);
25 cardiac arrest; 16 serious(unspecified) arrhythmia; & 15 sudden
death. 80(23%) of 341 patients died.
http://dailymed.nlm.nih.gov/dailymed/archives/image.cfm
?archiveid=13266&type=img&name=propulsid-02.jpg
Psychotropics, QT prolongation and Torsades De Pointes?
• Tricyclic Antidepressants:
• Amitriptyline, doxepin, desipramine, imipramine, and
clomipramine associated with prolonged QT interval.
• Nueroleptics:
• Phenothiazines, thioridazine, haloperidol, chlorpromazine,
trifluoperazine, pericyline, prochlorperazine, and fluphenazine
reported to cause QT prolongation & Torsades at therapeutic
doses or in overdose.
• Thioridazine most potent in causing QT prolongation and
arrhythmia.
• Sertindole. Off market in U.S & U.K.
• Pimozide can cause QT prolongation and TdP been described after
acute poisoning. Now with restricted use in the U.K.
Methadone & QTc
• Most widely used agent for opioid maintenance,
may prolong rate-corrected QT interval(QTc) and
result in Torsade de Pointes.
• Methadone potent inhibitor hERG
channelinhibition/blockade cardiac ion channel
Ikr.
• Methadone metabolized by cytochrome P450
system, thus inhibitors increase its plasma
concentrations.
• Risk Torsades enhanced in bradycardia &
methadone exhibits negative chronotropic effects
via 2 mechanisms:
• (1)Calcium channel antagonism
• (2)Anticholinesterase properties.
heroinaddictionhelp.blogspot.com
Ann Intern Med. 2009;150(6):387-395. doi:10.7326/0003-4819-150-6-200903170-00103
erowid.org
Citalopram & QTc
• As of march 28 2012:
• (1)Citalopram  dose-dependent QT – prolongation, Torsades de Pointes, ventricular
tachycardia, or sudden death.
• (2)Citalopram is not recommended in patients with: congenital long QT syndrome;
bradycardia; hypokalemia; hypomagnesemia; recent acute myocardial infarction;
uncompensated heart failure; concomitant use of drugs that prolong the QT interval.
• (3)20mg/day is maximum recommended dose patients: with hepatic impairment; who
are greater than 60 years of age; who are CYP 2C19 poor metabolizers; who taking
concomitant cimetidine (Tagamet) or other CYP2C19 inhibitor agents. Such factors 
increased blood levels citalopram  increased risk QT interval prolongation & Torsades
de Pointes.
• (4)Perform ECG monitoring in patients initiating or maintained on citalopram but who
have relative contraindications as # (2). Discontinue if QTc >500ms.
• (5)Measure baseline potassium & magnesium levels in patients at risk electrolyte
disturbances. Correct hypokalemia &/or hypomagnesemia before initiation citalopram
& monitor periodically while maintained on citalopram.
• (6)Educate patients on signs & symptoms abnormal heart rate/rhythm(dizziness,
palpitations, syncope) & to notify provider if experience these symptoms.
Antiarrhythmic drugs
Type 1A (TdP reported in all)
Quinidine (TdP reported)
Procainamide (TdP reported)
Disopyramide (TdP reported)
Ajmaline (TdP reported)
Type 1C (increase QT by prolonging QRS
interval)
Psychiatric drugs
Encainide
Flecainide
Type 3 (TdP reported in all)
Amiodarone
Sotalol
d-Sotalol
Bretylium
Ibutilide
Dofetilide
Amakalant
Semantilide
Thioridazine (TdP reported)
Mesoridazine
Chlorpromazine (TdP reported)
Haloperidol (TdP reported)
Droperidol (TdP reported)
Amitriptyline (TdP reported)
Nortriptyline
Imipramine (TdP reported)
Desipramine (TdP reported)
Clomipramine
Maprotiline (TdP reported)
Doxepin (TdP reported)
Lithium (TdP reported)
Chloral hydrate
Sertindole (TdP reported, withdr in UK)
Pimozide (TdP reported)
Ziprasidone(TdP reported)
Olanzapine(TdP reported)
Methadone
Citalopram
Antihistamines
the USA)
Terfenadine (TdP reported, withdrawn in
Astemizole (TdP reported)
Diphenhydramine (TdP reported)
Hydroxyzine
Ebastine
Loratadine
Mizolastine
Antimicrobial and antimalarial drugs
Erythromycin (TdP reported)
Clarithromycin (TdP reported)
Ketoconazole
Pentamidine (TdP reported)
Quinine
Chloroquine (TdP reported)
Halofantrine (TdP reported)
Amantadine (TdP reported)
Sparfloxacin
Grepafloxacin (TdP reported, withdrawn in
the UK and USA)
Pentavalent antimonial meglumine
Serotonin agonists/antagonists Ketanserin (TdP reported)
Cisapride (TdP reported, withdrawn in the
UK and USA)
Immunosuppressant
Tacrolimus (TdP reported)
Antidiuretic hormone
Vasopressin (TdP reported)
Antiemetics
Domperidone
Droperidol
Calcium channel blockers
Prenylamine (TdP reported, withdrawn)
Bepridil (TdP reported, withdrawn)
Terodiline (TdP reported, withdrawn)
Other agents
Adenosine
Organophosphates
Probucol (TdP reported)
Papaverine (TdP reported)
Cocaine
Yap Y G , Camm A J Heart 2003;89:1363-1372
Other Factors Increasing Prolongation of Ventricular Repolarisation or
Predicting Torsades.
•
•
•
•
•
•
•
•
•
•
•
•
•
Organic Heart Disease:
Congenital Long QT syndrome
Ischemic Heart Disease
Congestive Heart Failure
Dilated Cardiomyopathy
Hypertrophic Cardiomyopathy
Myocarditis
Kawasaki Syndrome
Metabolic Abnormalities:
Hypokalemia(most common)
Hypocalcemia
Hypomagnesemia
Bradycardia, Atrioventricular &
Sinoatrial blocks.
• Recent conversion from Atrial
Fibrillation especially with QTprolonging drug.
• Drug related factors:
• Narrow therapeutic window
• Multiplicity of pharmacological
actions
• Inhibition & induction of cytochrome
P450 enzymes
• Polypharmacy
• Female Preponderence.
• Hepatic Impairment.
• Digitalis therapy
• High Drug Concentrations(with
exception of quinidine)
• Rapid rate of IV infusion with QTprolonging drug.
• Base-line QT prolongation
• Subclinical long-QT syndrome
• Ion-channel polymorphisms
What have we learned?
• Drug Induced QT prolongation and Torsades de Pointes are an
increasing public health problem.
• The blockade of Ikr potassium current by these drugs responsible
for their pro-arrhythmic effect.
• Measurement of QT interval should be corrected for Heart Rate.
• Antiarrhythmic drugs, non-sedating antihistamines, macrolide
antibiotics, antifungals, antimalarials, Tricyclic Antidepressants,
Neuroleptics(including Citalopram), Methadone, and Prokinetics
have all been implicated in causing QT prolongation &/or
Torsades De Pointes.
• The risk of QT prolongation is increased in females, patients with
organic heart disease, hypokalemia, and hepatic impairment.
What have we learned?
• We can prevent adverse effects of QT prolonging drugs by:
• (1)Not exceeding the recommended dose.
• (2)Avoiding their use in patients with pre-existing heart disease,
with previous ventricular arrhythmias, &/or electrolyte
imbalance such as hypokalemia, or other risk factors mentioned.
• (4)Avoiding concomitant administration drugs that inhibit
cytochrome P450 (i.e.imidazole, antifungals, macrolide
antibiotics), drugs that prolong the QT interval, or drugs that
cause electrolyte disturbance.
• (5)Checking serum potassium routinely in patients on potassium
wasting diuretics.
• (6)Checking ECG’s routinely before and after initiation/increment
dosage drugs that may prolong the QT interval.
• (7)Stopping an offending drug and correcting electrolyte
abnormalities if patient develops Torsades.
Case #1
• 60 year old veteran with h/o opioid dependence & depression on
105mg methadone daily for maintenance and 40mg citalopram
daily. His ECG shows QT interval 470ms. What is best next step?
• A. Decrease his methadone dose to 55mg daily.
• B. Decrease his citalopram dose to 20mg daily.
• C. Refer him to psychiatry.
• D. Switch to a different SSRI that does not affect the QT interval.
Case #2
• 76 year old female with renal dysfunction treated with sotalol
for atrial fibrillation. What are the risk factors for torsades in
this case?
Case #3
• Mr X, a 61 year old man with Coronary artery disease & Chronic
obstructive pulmonary disease admitted to the ICU for
respiratory failure, intubated and then extubated 3 days later
after his pulmonary function improved. Following extubation he
became delirious and agitated. ECG showed normal rate and
rhythm with QTc=440ms. What is best next step in management?
• A.Administer IV Haloperidol.
• B.Give him wafers of olanzapine or risperidone orally.
• C. Administer any antipsychotic.
• D.Administer IV benzodiazepine.
References:
• Yap YG, Camm AJ. Drug Induced QT Prolongation And Torsades De Pointes. Heart
2003;89:1363-1372.
• Roden DM. Drug-induced prolongation of the QT Interval. The New England Journal of
Medicine. March 2004; 350;10: 1013-1022.
• Alvarez PA, Pahissa J. QT Alterations in Psychopharmacology: Proven Candidates and
Suspects. Current drug Safety. 2010; 5;97-104.
• Krantz MJ, et.al. QTc Interval Screening in Methadone Treatment. Annals of Internal
Medicine. March 2009; 150;6; 387-396.
• National PBM Bulletin. Update: Citalopram Hydrobromide(Celexa) & Dose-Dependent QT
Interval Prolongation. April 17 2012;1-3.
• FDA Drug Safety communication: Abnormal heart rhythms associated with high doses of
Celexa (citalopram hydrobromide). March 28 2012;
• http://my.clevelandclinic.org/heart/disorders/electric/scd.aspx
• Huffman JC, Stern TA. QTc Prolongation and the Use of Antipsychotics: A Case
Discussion. Primary Care Companion Journal of Clinical Psychiatry. 2003;5(6); 278-281.
• Sala M. et al. QT interval prolongation related to psychoactive drug treatment: a
comparison of monotherapy versus polytherapy. Annals of General Psychiatry. 2005; 4:1;
1-6.
• Vieweg WV, Wood MA. Tricyclic Antidepressants, QT Interval Prolongation, and Torsade
de Pointes. Psychosomatics. September-october 2004; 45:5; 371-377.