clinical toxicology & pharmacology, newcastle mater misericordiae hospital poisoning with newer...
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Poisoning with newer Poisoning with newer antidepressants, diagnosis antidepressants, diagnosis
and management. and management. AH Dawson, IM Whyte, GK IsbisterDepartment of Clinical Toxicology, Newcastle Mater Hospital, Australia
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
The new antidepressantsThe new antidepressants
Classes– SSRI– Selective MAOI– NSSRI– Nefazodone
Patterns of Use
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
ToxicityToxicity
Direct extension of therapeutic effect– Serotonin Toxicity
Non-therapeutic effects – CNS, Cardiac, other
Differences– between drug class– within drug class
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
PharmacologyPharmacology
High lipid solubility P450 drug metabolism
– Saturable metabolism– Drug interactions
High volume of distribution
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Mechanism Mechanism
©Jacob L. Driesen, Ph.D., 2000, 2001 http://www.driesen.com/index.html
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotinergic Toxicity:Serotinergic Toxicity: an extension of therapeutic effect.an extension of therapeutic effect.
Dose studies in therapeutic trials Hergyl et al. The serotonin syndrome scale:
first results on validity. Eur Arch Psychiatry Clin Neurosci. 1998; 248:96-103
– Grouping of symptoms into 9 items– Auditory evoked potentials
Correlation with concentration
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotinergic Toxicity:Serotinergic Toxicity: an extension of therapeutic effect.an extension of therapeutic effect.
Diagnosis
Prediction
Treatment
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotonin Syndrome: Sternbach criteriaSerotonin Syndrome: Sternbach criteria Mental status changes (confusion, hypomania) Agitation Myoclonus Hyperreflexia Diaphoresis Shivering Tremor Diarrhoea Incoordination Fever
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Redefining the Clinical Syndrome Redefining the Clinical Syndrome of Serotonin Toxicityof Serotonin Toxicity
Incidence of signs in serotinergic drug poisoning vs other drugs– diagnostically useful
Examination of signs may assist in deciding who we treat
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Sternbach criteria in HATSSternbach criteria in HATSTreated(n = 45)
Untreated(n = 351)
Other drug(n = 2033)
Hyperreflexia 93.3 % 38.7 % 11.3 %Agitation 55.6 % 16.0 % NRTremor 44.4 % 5.4 % NRConfusion/hypomania 15.6 % 7.1 % 4.4 %Fever 28.9 % 7.7 % 3.4 %Diaphoresis 17.8 % 5.1 % 0.7 %Ataxia/incoordination 13.3 % 8.5 % NRShivering 20.0 % 4.0 % NRDiarrhoea 11.1 % 5.7 % NRMyoclonus 11.1 % 2.3 % 0.2 %
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Other clinical featuresOther clinical featuresTachycardia 55.6 %Mydriasis 35.6 %Inducible clonus 55.6 %Spontaneous clonus 64.4 %Hypertonia/rigidity 31.1 %Ocular clonus/oscillations 44.4 %Coma 15.6 %Nystagmus 28.9 %Flushed 20.0 %Seizures 13.3* (4.4) %Rhabdomyolysis 8.9 %Akathisia 0Lacrimation 0Oculogyric crisis 0Opisthotonus 0
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Major Features
Ocular clonus/oscillations 30.4 (11.6 – 82.7)Hyperreflexia 22.1 (6.8 – 113.1)Spontaneous clonus 20.9 (9.6 – 46.0)Inducible clonus 19.6 (8.8 – 43.6)Tremor 14.0 (6.1 – 31.5)Agitation/restlessness 6.6 (3.2 – 13.4)Hypertonia/rigidity 6.2 (2.6 – 13.8)Shivering 6.0 (2.1 – 16.1)Myoclonus 5.4 (1.3 – 19.5)Flushing 5.2 (1.9 – 13.6)
Odds Ratio of signs:Odds Ratio of signs:SSRI vs nonSSRISSRI vs nonSSRI
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Minor Features
Odds Ratio of signs:Odds Ratio of signs:SSRI vs nonSSRISSRI vs nonSSRI
Fever 4.9 (2.1 – 10.9)Nystagmus 4.5 (1.9 – 10.0)Diaphoresis 4.0 (1.4 – 10.5)Coma 3.4 (1.1 – 9.2)Tachycardia 2.3 (1.2 – 4.5)
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Non-features
Odds Ratio of signs:Odds Ratio of signs:SSRI vs nonSSRISSRI vs nonSSRI
Rhabdomyolysis 4.2 (0.9 – 16.4)Seizures 4.0 (0.4 – 29.0)Confusion/hypomania 2.4 (0.8 – 6.2)Diarrhoea 2.1 (0.6 – 6.1)Ataxia/incoordination 1.6 (0.5 – 4.4)Mydriasis 1.4 (0.7 – 2.8)Akathisia –Lacrimation –Oculogyric crisis –Opisthotonus –
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Who do we treatWho do we treat
Hunter Area Toxicology Service (HATS)– over last 4 years (1995–1999)
2429 admissions 396 (16.3 %) primary serotinergic
drug overdose 45 (11.4 %) of those admissions were
treated with a serotonin blocker
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Odds of Clinical Sign being Odds of Clinical Sign being present in treated patients present in treated patients
Clonus (any) 28.8 (10.5 – 78.7)Flushing 8.8 (2.4 – 32.9)Tremor/shivering 8.7 (3.5 – 21.6)Nystagmus 4.4 (1.5 – 12.6)Fever 3.7 (1.3 – 10.8)
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotinergic Symptom Serotinergic Symptom ScoreScore
3 – Clonus Inducible/spontaneous/ocular
2 – Flushing 2 – Tremor/shivering 1 – Nystagmus 1 – Fever
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
0123456789
10
Pati
en
ts (
%)
0 1 2 3 4 5 6 7 8 9
Score
Untreated Treated
61%
Application of Score to Application of Score to Serotinergic PoisoningsSerotinergic Poisonings
61%
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Predicting Serotonin ToxicityPredicting Serotonin Toxicity
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Rate of SS slideRate of SS slide
Single ingestions Synergistic combinations
– MAOI serotinergic drugs
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Synergistic EffectsSynergistic Effects
Coingestion Inadequate washout Serotinergic nonpharmaceuticals
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Poor PrognosisPoor Prognosis
SS due to combination therapy Fever Respiratory Failure Spontaneous clonus.
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Treatment of Serotonin Treatment of Serotonin ToxicityToxicity
Supportive Care Specific Antagonists?
– Theory– Animal models– Case Reports– Absence of Clinical Trials
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Benzodiazepineslorazepamdiazepamclonazepam
Drugs used for NMSdantrolenebromocriptine
Neurolepticschlorprothixenechlorpromazinehaloperidol
Non–specific blocking agents
methysergidecyproheptadine
–blockerspropranololpindolol
Miscellaneouschlormethiazolenitroglycerine
Drugs used to treat Drugs used to treat serotonin syndromeserotonin syndrome
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Which 5–HT receptor?Which 5–HT receptor?
Originally thought to be 5–HT1A mediated
Evidence implicating 5-HT2
– failure of propranolol (5-HT1A blocker)
– 5-HT2 antagonists apparent efficacy
– 5-HT2 agonists produce hyperthermia
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Kapur, S et al. (1997). Cyproheptadine: a potent in vivo serotonin antagonist.American Journal of Psychiatry, 154, 884
Affinity=10-7 x 1/Kd.
CyproheptadineCyproheptadine
Case reports Oral preparation Safe 20-30mg required to
achieve 90% blockade of brain 5-HT2 receptors (Kapur et al., 1997).
Sertindole 260Chlorprothixene 233Ketanserin 178Risperidone 170Cyproheptadine 100Chlorpromazine 71Clozapine 62Olanzapine 25Methysergide 14Haloperidol 2.8
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
ChlorpromazineChlorpromazine
5-HT2 antagonist
PET scans avid 5-HT2 binding
Case reports (mostly old) Oral or parenteral medication Sedating and a potent vasodilator.
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Rat model: Rat model: Nisijima K et al. Brain research 890 (2001) 23-31.Nisijima K et al. Brain research 890 (2001) 23-31.
Nisijima K et al. Psychopharmacology (2000) 150:9-14 Nisijima K et al. Psychopharmacology (2000) 150:9-14
Clorgyline & 5-HTP
(5-hydroxy-L-tryptophan)
Outcomes– Rectal Temperature
– hypothalamic [NA]
– mortality
Dose mg/kg
Deaths/Total
Saline 6/6WAY 100635 1 5/5Propranolol 10 5/5Ritanserin 3 0/5Pipamperone 20 0/6Chlorpromazine 20 6/6
40 0/5Cyproheptadeine 5 5/5
10 0/5Dantroline 20 6/6Risperidone 0.5 0/6Ketanserin 5 0/6Haloperidol 0.5 6/6
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
TherapyTherapy
when oral therapy suitable– cyproheptadine 8-12 mg stat & review
when oral therapy unsuitable or cyproheptadine fails– chlorpromazine 50-100 mg IVI stat & review
if respiratory failure or fever > 39oC– barbiturate anaesthesia, muscle relaxation ±
active cooling
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
ConclusionConclusion
Serotonin toxicity not the syndrome requires treatment
More rigorous case definition is required
The pharmacology and clinical evidence for a number of agents appears promising and should be subject to clinical trial.
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Defining Other ToxicityDefining Other Toxicity
Citalopram– ? Death– Reports of QT prolongation
Venlafaxine– QRS widening– Reports of arrythmia– Seizures
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Citalopram Controversy Citalopram Controversy BackgroundBackground
Reports of fatal cases and severe cases with survival
Grundemar L, Wohlfart B, Lagerstedt C, et al Symptoms and signs of severe citalopram overdose. Lancet 1997; 349:1602-1602
Case series suggesting reasonable safety in overdose, with no deaths in the study, but a risk of seizures & ECG abnormalities 1,4
Hale AS. Citalopram is safe. BMJ 1998; 316:1825-1825. Personne M, Sjöberg G, Persson H. Citalopram overdose - review of
cases treated in Swedish hospitals. J.Toxicol.Clin.Toxicol. 1997; 35:237-240
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Cardiac toxicity of citalopram & Cardiac toxicity of citalopram & other selective serotonin other selective serotonin
reuptake inhibitors in overdosereuptake inhibitors in overdoseGK Isbister 1,2, IM Whyte 1,3, AH Dawson 1,3
1Department of Clinical Toxicology, Newcastle Mater Hospital, 2Emergency Department, Royal Prince Alfred Hospital, Sydney 3Discipline of Clinical Pharmacology, University of Newcastle
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
MethodsMethods Prospective data from the Hunter Area Toxicology Service
(HATS) was used.
Cases included were :– single SSRI overdoses (SSRI dose > max. daily dose)
– SSRI and co-ingestant with no known effect on the QT or QRS intervals
Control group :– overdoses with medications not known to cause cardiac
toxicity, or effect the QT or QRS interval
– paracetamol, paracetamol/codeine, diazepam and temazepam
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
AnalysisAnalysis Electrocardiograph analysis :
– R-R, QT and QRS were measured manually on ECGs by independent trained persons
– QTc was calculated using Bazett’s formula– QTc > 440 msec was defined as abnormal– An alternate HR correction for QT was used 5 = QT37
QTc =(RR)0.5
QT
QT37 = (RR)0.37
QT Statistical analysis :
– Comparisons were made of QT, QTc, QT37 and QRS– The means of the five groups of SSRIs and controls were
compared using ANOVA– Citalopram was compared to all other SSRIs using either
Welch’s t test or Mann-Whitney for non-parametric data.– Comparison of the proportion of abnormal measurements was
made using Fisher’s Exact Test
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Admission 6 hours after overdose
Discharge 38 hours after overdose
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Mean (+/-SD) QT(msec)
QTc(msec)
QT37
(msec)QRS
(msec)Citalopram (22) 396 49 455 31 439 32 89 17
Sertraline (69) 372 45 429 34 412 29 86 10
Paroxetine (57) 369 43 422 39 407 36 87 14
Fluoxetine (35) 366 40 435 54 418 48 87 9
Fluvoxamine (8) 363 19 425 12 408 9 88 8
SSRI (169) 368 41 428 40 - 87 11
Control (317) 366 41 425 38 409 34 88 14
ResultsResults
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
QT IntervalQT Interval The QT interval in citalopram overdoses was
396 msec (SD 49), significantly different to the 368 msec (SD 41) of all other SSRI overdoses (p=0.02), and to the 366 msec (SD 41) of controls (p= 0.001)
ANOVA comparison of SSRIs and control– 5 SSRIs + control (6 groups) p = 0.06– 3 SSRIs (C,P,S) p = 0.0144 with citalopram
significantly different to paroxetine and sertraline
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
QTc IntervalQTc Interval The QTc interval in citalopram overdoses was 455
msec (SD 31), significantly different to the 428 msec (SD 40) of all other SSRI overdoses (p=0.0008), and to the 425 msec (SD 38) of controls (p= 0.0002)
ANOVA comparison of SSRIs and control– 5 SSRIs + control (6 groups) p = 0.006 : C vs P; and C
vs. controls significantly different– 3 SSRIs (C,P,S) p = 0.003 with citalopram significantly
different to paroxetine, sertraline and controls
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
QTc > 440 msecQTc > 440 msec Proportion of overdoses with QTc > 440 msec was
significantly more for citalopram compared to controls, all other SSRIs, and each group of SSRIs individually.
No significant different between all 5 SSRIs and controls
QTQT3737 Interval IntervalANOVA comparison of SSRIs and control
– 5 SSRIs + control (6 groups) p = 0.004 : Citalopram significantly different to paroxetine, sertraline and controls
QRS IntervalQRS Interval
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
DiscussionDiscussionThis study has demonstrated a significant increase in QT, QTc and QT37 with citalopram overdose compared to overdose of other SSRIs as a group, paroxetine and sertraline overdoses individually, and control overdoses. This supports a previous cases series of citalopram overdoses 2,4 and shows the effect is for citalopram alone and not other SSRIs. There was no significant difference between controls and other SSRIs. There have been previous reports of severe symptomatic sinus bradycardia, with normal QT/QTc, in patients recently started on therapeutic doses of citalopram 6.
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
LimitationsLimitationsThe major limitation in this study was the size of the citalopram group which meant that ANOVA comparisons including controls and SSRIs were limited because nonparametric methods were required. Lengthening of the QT or corrected QT interval is only a surrogate measure for cardiac toxicity, and in some cases may be benign. However until larger data sets are available to demonstrate no cases of torsades de pointes, QT prolongation should be considered an indicator of cardiac toxicity.
RecommendationsRecommendationsAll patients with citalopram overdoses > 60 mg should have serial 12 lead ECGs and be monitored until the QTc < 440 msec. Citalopram should be used with care in patients with a history of cardiac disease or arrhythmias, in particular patients with bradycardia or known long QT syndrome.