TOXICOLOGY: ANTIDEPRESSANTS &ANTIPSYCHOTICS

May 26, 2011Jason MitchellJoe McLellan

Phil Ukrainetz

INTRODUCTION

18 yo F 1/52 Fever, otalgia, chills, myalgia, arthralgia Tooth extraction 2/52 ago Meds: Percodan (ASA/Oxycodone)

Chlorphenamine Erythromycin

“Something for stress”

Frequent marijuana, denies cocaine or other rec drugs

INTRODUCTION O/E: 39.7oC, 120, 110/75 supine 95/60 standing, 20, 4.7

CNS: Appears distressed Intermittent writhing/agitation/confusion ?volitional “Strange jerking movements” and shivering noted Hyper-reflexic, nystagmus

HEENT: Hyperemic R TM

CV: II/VI LLSB diastolic murmur

Resp: Clear to bases

Integument: Petechial rash to R thigh

INTRODUCTION

Ix:

CBC/Lytes: WBC 18

CXR: Normal

ECG: Sinus tach

INTRODUCTION

Dx: Tentative diagnosis of “viral syndrome NYD with hysterical symptoms”

Admitted to hospital, routine vitals Agitation persists 25mg Demerol IM Rx for agitation and

shivering

INTRODUCTION

Agitation and confusion worsens Pt thrashing in bed, ripped out IVs Hypertense, tachycardic, ongoing fever Resident notified by telephone

Physical restraints 1 mg haloperidol

Agitation initially resolves, but shortly returns

Axillary temp. 420C Cold compresses and cooling blanket

applied Progresses to respiratory arrest and unable

to resuscitate Pt dies 7 hours after presentation to

hospital

ANTIDEPRESSANTS

Multiple Classes SSRIs (Citalopram, Fluoxatine, Fluvoxamine, Paroxetine,

Sertraline) MAOIs (Isocarboxacid, Phenelzine, Moclobemide) TCAs (Amitriptyline, Clomipramine, Imipramine, Desipramine) SNRIs (Desvenlafaxine, Venlafaxine, Duloxetine) NaSSAs (Mirtazapine) NRIs (Strattera) NDRIs (Bupropion) SSREs (Tianeptine) NDDIs (Agomelatine)

ANTIDEPRESSANTS

Multiple Classes SSRIs (Citalopram, Fluoxatine, Fluvoxamine, Paroxetine,

Sertraline) MAOIs (Isocarboxacid, Phenelzine, Moclobemide) TCAs (Amitriptyline, Clomipramine, Imipramine, Desipramine) SNRIs (Desvenlafaxine, Venlafaxine, Duloxetine) NaSSAs (Mirtazapine) NRIs (Strattera) NDRIs (Bupropion) SSREs (Tianeptine) NDDIs (Agomelatine)

ANTIDEPRESSANTS

PHYSIOLOGY

Mechanism of depression incompletely understood

Proposed consequence of low [monoamines]: serotonin (5-HT), norepinephrine (NE),

dopamine (DA)

ANTIDEPRESSANTS

PHYSIOLOGY SSRI:

Prevents 5-HTreuptake

MAOI:Prevents 5-HTdeamination

Increasessynaptic [5-HT]

MAOIs

PHARMACODYNAMICS Peak plasma concentrations 0.5-2.5 hours

Hepatic metabolism

Minimal urinary excretion

MAOIs

TOXICITY MAOI Overdose

MAOI-food/beverage interactions

MAOI-drug interactions

MAOIs

TOXICITY MAOI Overdose

Excessive MAOI-food/beverage interactions Sympathetic

Activity

MAOI-drug interactions

MAOIs

MAOI OVERDOSE Four phases

Asymptomatic/Latent

CV/CNS excitation with sympathetic hyperactivity

CNS depression and CV collapse

Secondary complications

MAOIs

MAOI-FOOD/BEVERAGE INTERACTIONS Foods high in tyramine

Tyramine leads to catecholamine release

May potentiate hypertensive crisis

MAOIs

MAOI-FOOD/BEVERAGE INTERACTIONS

FOOD BEVERAGEAged/Fermented Meats Ales

Aged Cheese BeersBeans Wines

Sauerkraut SherryYeast Vermouth

ChocolateFigs

RaisinsBananas

MAOIs MOAI-DRUG INTERACTIONS

Occur minutes to hours after co-ingestion

May cause sympathetic storm/serotonin syndrome Production of excessive concentrations of monoamines

Examples: SSRIs TCAs Sympathomimetics Opiates Lithium

MAOIs

MANAGEMENT Recall ABCDEFs of toxicology

ABCs primarily supportive Sinus tachycardia does not usually require

treatment β Blockers and CCBs relatively contraindicated

Hypertension Nitroprusside 0.3 mcg/kg/min titrated to effect (max

10 mcg/kg/min) Nitroglycerine 20 mcg/min titrate q5min to effect Phentolamine 5 mg bolus q5-10min

MAOIs

MANAGEMENT ABCs primarily supportive

Bradycardia Compensatory response to hypertension Treat if associated with hypotension

Hypotension IV crystalloid Atropine if associated with bradycardia Vasopressors not contraindicated

Avoid dopamine

MAOIs

MANAGEMENT DEFs

May consider AC

Forced diuresis, hemoperfusion ineffective

No antidote available

MAOIs

DISPOSITION Onset of symptoms may be delayed

Recommended 24 hour observation for asymptomatic pts with MAOI overdose

Recommended 6 hour observation for food interaction

ICU/MTU admit depending on symptom severity

SSRIs

PHARMACODYNAMICS Peak plasma concentration: 3 – 10 hours

Liver metabolism: Elimination half-life 15hours – 4days

Small amount of urinary excretion

SSRIs

TOXICITY Not as pronounced as TCA toxicity

High ingested dosages required

Toxic Spectrum Mild serotonin-related symptoms Serotonin syndrome Toxic states

Radomski JW, Dursun SM, Reveley MA, Kutcher SP. An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria Pages 218-224

SSRIs

TOXICITY

SSRIs

GI TOXICITY Abdominal cramps

Nausea

Vomiting

Diarrhea

Salivation

SSRIs

CV TOXICITIY Cutaneous flushing

Hypertension/Hypotension

Tachycardia/Bradycardia

QT Prolongation (rare) Fluoxetine, Citalopram

Ventricular tachycardia (rare)

SSRIs

CNS TOXICITY (RARE) Agitation Akathisia Anxiety Clonus Coma Confusion Delirium Headache Hyper-reflexia Hyperthermia

Hypomania Insomnia Mania Mydriasis Myoclonus Nystagmus Rigidity Seizures Sedation

SSRIs

CNS and CV TOXICITY

Hoffman RS, Nelson LS, Howland MA, et al. Goldfrank's Manual of Toxicologic Emergencies. McGraw-Hill Companies, 2007.

SSRIs

DIAGNOSIS Primarily clinical History important

SSRI dosage increase Known ingestion Co-ingestion of drugs that potentiate [synaptic

serotonin] Eg – Cocaine, DM, amphetamines, MAOIs, TCAs,

Carbamazepine, Lithium, Sumatriptan Urine/Blood tox screens not useful

Unless coingestion suspected.

SSRIs

MANAGEMENT

Recall the ABCDEFs of toxicology

SSRI overdose is generally mild and rarely life-threatening

Treatment is largely supportive

SSRIs

MANAGEMENT ABCs – Mainly supportive

Hypertension Not usually indicated Consider sodium nitroprusside

Hypotension IV crystalloid +/- norepinephrine or dopamine

VTach/Bradycardia As per ACLS algorithms

Neurologic complications treated with benzodiazepines

SSRIs

MANAGEMENT Decontamination and Elimination

AC may be considered Forced diuresis not indicated

Minimal amounts of SSRI excreted in urine Hemodialysis not indicated

Large volumes of distribution, high protein-binding Find an Antidote

No specific antidote exists for SSRIs

SSRIs

DISPOSITION 6-hour monitoring for asymptomatic patients

Psychiatric consultation if intentional ingestion

Citalopram OD warrants 12-24 hour observation

DISCONTINUATION SYNDROME

Observed with cessation of TCAs, MAOIs, and SSRIs Pts complain of:

Dizziness Lethargy Paresthesia Nausea Depressed mood

Occur ~5 days post-cessation; can last up to 3 weeks Supportive treatment and re-initiation of stopped

drug

SEROTONIN SYNDROME

Clinically recognizable signs and symptoms Pathophysiology incompletely understood,

unpredictable Severe disease manifested by

Hyperpyrexia Hypertension Tachycardia Muscle rigidity Clonus

SEROTONIN SYNDROME

STERNBACH’S DIAGNOSTIC CRITERIA Addition or increased dose of a serotinergic agent 3 or more of:

A neuroleptic has not been given Other etiologies ruled out

Agitation HyperthermiaAtaxia Altered LOC

Diaphoresis MyoclonusDiarrhea Shivering

Hyper-reflexia Tremor

Sternbach H. The serotonin syndrome. Am J Psychiatry 1991; 148: 705-713

SEROTONIN SYNDROME

HUNTER SEROTONIN TOXICITY CRITERIA

Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003 Sep;96(9):635-42

SEROTONIN SYNDROME

INVESTIGATIONS Serum/Urine Tox Screen Serum CK Urine myoglobin Blood gas (metabolic acidosis) LFTs Blood/CSF cultures DIC Panel βHCG ECG

SEROTONIN SYNDROME

MANAGEMENT Primary supportive

Aggressive cooling

Aggressive use of benzodiazepines

Consider neuromuscular blockade and RSI

Consider cyproheptadine/chlorpromazine

SEROTONIN SYNDROME

MANAGEMENT Cyproheptadine 8mg followed by 4 mg q1-4g

max 32mg/day

Non-specific antihistamine with anti-serotinergic properties

Case reports support use in mild symptoms

Efficacy not known in severe serotonin toxicityLappin RI, Auchincloss EL. Treatment of the serotonin syndrome with cyproheptadine. NEJM 1994;13(15):1021-2.Graudins A, Stearman A and Betty Chan B. Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med 1998;16(4):615– 619

SEROTONIN SYNDROME

DISPOSITION Generally favourable prognosis

MTU/ICU admission for supportive management

Symptoms generally resolve after 24 hours Delirium may persist

ANTIPSYCHOTICS

PHARMACOLOGY Three Classes:

Low Potency Typicals Chlorpromazine, Hydroxyzine, Promethazine

High Potency Typicals Droperidol, Haloperidol, Loxapine

Atypicals Aripriprazole, Clozapine, Olanzepine Quetiapine, Risperidone, Ziprazadole

ANTIPSYCHOTICS

PHARMACOLOGY Dopamine antagonists

Dopamine receptors found in the mesolimbic and nigrostriatal brain areas Nigrostriatal dopamine blockade results in EPS

and TD

Atypical antipsychotics more selective for mesolimbic dopamine antagonism

ANTIPSYCHOTICS

TOXICITY Exaggerated clinical effects CNS depression universal

Mild sedation to coma (dose dependent) Airway reflexes may be impaired Concomitant respiratory depression Low-potency typicals can cause anticholinergic

delirium Seizures rare

Exception: Clozapine

ANTIPSYCHOTICS

TOXICITY Cardiovascular Effects

Most commonly sinus tach

QRS prolongation rare?

QT prolongation Clinical significance unknown Risk of torsades development unknown

ANTIPSYCHOTICS

TOXICITIY Anticholinergic Effects

Tachycardia Hyperthermia Blurred vision Dry mouth Urinary retention Ileus Toxic psychosis

ANTIPSYCHOTICS

ACUTE EXTRAPYRAMIDAL SYNDROMES Acute Dystonia

ANTIPSYCHOTICS

ACUTE EXTRAPYRAMIDAL SYNDROMES Akasthisia

ANTIPSYCHOTICS

ACUTE EXTRAPYRAMIDAL SYNDROMES Parkinsonian syndrome

ANTIPSYCHOTICS

TARDIVE DYSKINESIA

ANTIPSYCHOTICS

MANAGEMENT Primarily supportive

Remember your ABCDEFs

ANTIPSYCHOTICS

MANAGEMENT ABCs

Support airway and breathing with intubation as required

Hypotension usually responds to crystalloids

Vasopressors not contraindicated

Correct metabolic abnormalities

MgSO4 for torsades

ANTIPSYCHOTICS

MANAGEMENT DEFs

Consider AC but no proven benefit Forced diuresis, hemodialysis ineffective EPS:

Anticholinergic agents: Diphenhydramine 25-50 mg Benztropine 1-2 mg

Propanolol Benzos

ANTIPSYCHOTICS

DISPOSITION Recommended 4-6 hour observation for

asymptomatic or mild overdose

24 hours if ongoing symptoms or ECG abnormalities

ICU/MTU for more severe overdoses

NMS

Abrupt change in available dopamine Observed with both typical and atypical

agents Cardinal Features

Altered metal status Muscle rigidity Hyperthermia Autonomic nervous system instability

NMS

DIAGNOSTIC CRITERIA Severe muscle rigidity and fever associated

with neuroleptic Two ore more of:

Alternative causes ruled out

Diaphoresis Motor dysfunctionDysphagia Tachycardia

Tremor HTN/Labile BPIncontinence LeukocytosisAltered LOC Elevated CK

NMS

MANAGEMENT Primarily supportive Aggressive benzos (first line therapy) RSI if required Consider:

Bromocriptine 5mg q8h PO/NG Amantadine 200mg q12h PO/NG Dantrolene 0.8-3 mg/kg IV q6h max

10mg/kg/d May prolong course of illness and may be

associated with a greater incidence of sequelaeSchneider SM. Neuroleptic malignant syndrome: controversies in treatment. Am J Emerg Med. 1991 Jul;9(4):360-2Rosebush PI, Stewart T, Mazurek MF. he treatment of neuroleptic malignant syndrome. Are dantrolene and bromocriptine useful adjuncts to supportive care? Br J Psychiatry. 1991;159:709.

NMS

PROGNOSIS Symptoms of NMS can last for days – weeks

7-10 days post cessation oral antipsychotics 21 days for depot antipsychotics (fluphenazine)

Mortality ~10% Increased to 50% with renal failure

NMS

DISPOSITION Most NMS to ICU Overdose patients with

Hypotension Coma Torsades Airway compromise

Less severe: Observe for 4-6 hours +/- hospital admission

SS vs. NMSSS NMS

CAUSE Serotonin Agonism Dopamine Antagonism

ONSET/DURATION Minutes-Hours Days-WeeksMORTAILITY Low HighAUTONOMIC INSTABILITY

+++ +++

FEVER +++ +++ALTERED LOC

(Depressed/Confusion)+++ +++

ALTERED LOC (Agitation/

Hyperactivity)

+++ +

LEAD PIPE RIGIDITY + +++TREMOR/HYPER-

REFLEXIA/CLONUS+++ +

SHIVERING +++ -BRADYKINESIA - +++

SEIZURES + -

BACK TO THE CASE

18 yo F febrile, agitated Exam significant for hyper-reflexia,

myoclonus, clonus, confusionDDx Hot and Altered?

BACK TO THE CASE

DDx Hot and AlteredSEROTONIN SYNDROME ANTICHOLINERGIC

TOXIDROME

NEUROLEPTIC MALIGNANT SYNDROME

COCAINE OVERDOSE

SEPSIS MDMA OVERDOSE

MENINGITIS/ENCEPHALITIS ASA TOXICITY

HEAT STROKE WITHDRAWAL STATES

MALIGNANT HYPERTHERMIA THYROID STORM

BACK TO THE CASE

Libby Zion Rx’d phenelzine (MAOI)

for depression and stress Most agree cause of death

was serotonin syndrome MAOI and Demerol

QUESTIONS?