Antipsychotic toxicity

Amisulpride

• QT prolongation and Torsades
• >4g should be monitored for at least 16 hours and until ECG intervals are normal
• Risk assessment
  • <4g usually benign but may show mild-moderate sedation and mild anticholinergic features
  • >4g poses risk of QT prolongation, Torsades, bradycardia, hypotension and CNS depression
    • Usually delayed several hours from ingestion (5-20 hours)
  • All paediatric ingestions require hospital assessment

Amisulpride

• Toxic mechanism
  • Atypical antipsychotic D2/3 antagonist
• Toxicokinetics
  • Absorption: Bioavailability 50% with two absorption peaks at 1 and 4 hours
  • Distribution: 5.8L/kg (large)
  • Metabolism: Minimal metabolism to inactive metabolites
  • Excretion: Mostly unchanged via faecal and renal routes with half-life 12 hours (therapeutic doses)

Amisulpride

• Investigations

• Screening ECG, BSL, paracetamol
• Serial ECG’s for minimum 16 hours if >4g and continuous monitoring if QT prolonged
• Serum electrolytes
• Management

• Resus – ABC, Mg/overdrive pacing (electrical or chemical)
  • Hypotension usually responds well to fluids
• Decontamination – Oral activated charcoal appropriate if ingestion <4 hours ago
• Enhanced elimination N/A
• Antidote – None

Amisulpride

• Disposition
  • <4g and normal ECG – D/C
  • >4g – Observe 16 hours as above
• Handy tips
  • After large ingestions may be mildly symptomatic before sudden deterioration
  • Bradycardia seen in 25% of cases and strongly associated with higher risk of QT prolongation and Torsades
• Pitfall
  • Failure to closely examine ECG intervals

Clozapine

• Uncommon due to restricted availability
• Risk assessment
  • Threshold for severe poisoning may be as low as 100mg
  • Clinical manifestations of toxicity more likely if not on clozapine normally
  • Children: Single tablet usually causes toxicity, <2.5mg/kg causes sedation, hypersalivation, tachycardia, ataxia and agitation. EPSE over the following days

Clozapine

• Toxic mechanism
  • Tricycle dibenzodiazepine atypical antipsychotic
  • D1/2 antagonist, 5-HT antagonist and peripheral alpha 1 antagonist
  • M1/H1/GABA antagonist
• Toxicokinetics
  • Absorption – Rapid
  • Vd – 0.5-3L/kg. Highly protein bound
  • Metabolism – Hepatic oxidation CytP450 1A2, 2D6 to metabolites excreted in urine and faeces
  • Significant first-pass

Clozapine

• Clinical features

• Onset of intoxication occurs within 4 hours
• CNS depression may occur early
• Lethargy, confusion, sedation, tachycardia and orthostatic hypotension
• Anticholinergic effects – agitation, ileus, urinary retention
• Both mydriasis and miosis are seen
• Hypersalivation is characteristic and pathognomonic
• Seizures in 5-10%
• EPSE more common in children
• QT prolongation is rare
• Usually resolves over 24 hours

Clozapine

• Investigations

• Screening ECG, BSL, paracetamol
• Serial ECG’s q6h
• Monitor if QT prolonged >450ms
• Clozapine levels only useful to confirm diagnosis
• Management

• Resus
  • ABC, treat seizures with benzos, fluid balance, supportive cares
• Decontamination – Activated charcoal only if airway secure
• Enhanced elimination N/A
• Antidotes – None

Clozapine

• Disposition
  • Well at 6 hours can be discharged
  • EPSE may occur up to 7 days later in children
• Handy tips
  • Consider in sedated patients with anticholinergic features but small pupils and prominent hypersalivation
  • Agranulocytosis and myocarditis ARE NOT features of acute overdose
• Pitfall
  • Failure to recognise and correct urinary retention

Olanzapine

• Risk assessment
  • <40mg – Therapeutic sedation and antipsychotic effects
  • 40-100mg – Mild-to-moderate sedation +- anticholinergic
  • 100-300mg – Sedation with intermittent marked agitation
  • >300mg
    • Increasing sedation progressing to coma and likely intubation. Hypotension secondary to peripheral alpha blockade
  • Miosis often seen despite anticholinergic syndrome
  • In children, >0.5mg/kg carries risk of lethargy, agitation, tachycardia and extrapyramidal side effects

Olanzapine

• Toxic mechanism
  • D2, 5-HT2, H1, M1 and alpha antagonist
• Toxicokinetics
  • Absorption – Rapid absorption
  • Distribution – 10-20L/kg
  • Metabolism – Hepatic by oxidative (cytP450 1A2 and 2D6) and conjugation (glucuronidation) to inactive water-soluble metabolites
    • Large first-pass effect after oral dosing
  • Excretion – Inactive metabolites excreted in urine

Olanzapine

• Clinical features
  • Within 2-4 hours
  • Sedation, ataxia, miosis, orthostatic hypotension and tachycardia
  • Fluctuating conscious level with agitated delirium usually lasts <24 hours
  • Urinary retention is common
  • Coma lasts up to 48 hours
  • Non-specific ST-T wave changes are seen in 15% of cases
  • QT prolongation is rare
  • EPSE are uncommon
  • Seizures are rare

Olanzapine

• Resus

• Usual care and monitor for urinary retention
• Benzo’s to manage agitation +- seizure – may warrant intubation
• Decontamination
• Not indicated as onset of sedation is rapid and supportive care ensures good outcome

• Enhanced elimination N/A
• Antidotes – None

Olanzapine

• Disposition

• If children well without sedation at 4 hours – safely d/c with advice that EPSE may occur up to 3 days later
• Medical discharge once mobilising, eating, drinking, passing urine and clinically well
• Handy tips
• Always monitor for urinary retention
• Controversy
• Physostigmine of unclear role as delirium not solely anticholinergic in origin. May also reverse coma

Phenothiazines and butyrophenones

• Phenothiazines: Chlorpromazine (Largactil), prochlorperazine (Stemetil), thioridazine (N/A)
• Butyrophenones: Droperidol, Haloperidol
• Risk assessment

• Dose-dependent CNS depression, tachycardia, hypotension and anticholinergic effects
• Chlorpromazine may cause coma if >5g
• Cardiac dysrhythmias are very uncommon
  • Although chlorpromazine and haloperidol can both prolong the QT with risk of Torsades de pointes
• Seizures are very uncommon
• In children, even one tablet warrants hospital assessment abd EPSE can occur up to 72 hours post-ingestion

Phenothiazines/butyrophenones

• Toxic mechanism

• Central D2 antagonism + H1/GABA-A/M1/Alpha1-2/5-HT antagonism
• Cardiotoxicity due to K and Na channel blocking activity
• Toxicokinetics

• Absorption – Rapid with extensive first-pass metabolism. Can be slow and erratic with massive ingestions.
• Distribution – Lipid soluble, large Vd
• Metabolism – Extensive CytP450 metabolism in liver with active metabolites and prolonged half-lives
• Chlorpromazine has early (2-3hrs), intermediate (11-15 hours) and late elimination (up to 60days) phases

Phenothiazines/butyrophenones

• Clinical features
  • Onset of intoxication within 2-4 hours
  • Sedation, ataxia, orthostatic hypotension and tachycardia
  • Fluctuating mental status and intermittent agitated delirium lasting <24 hours
  • Urinary retention is common
  • Coma can occur with chlorpromazine lasting 18-48 hours
  • Anticholinergic delirium
  • QT prolongation are not clinically significant
  • Seizures and EPSE are uncommon

Phenothiazines/butyrophenones

• Resus – as normal
• Decontamination
• AC only if intubated as coma can occur rapidly and good outcome is expected if not requiring intubation anyway

• Enhanced elimination N/A
• Antidotes – None
• Disposition
• Medical discharge at 6 hours if well, normal ECG, normal vital signs
• Handy tips
• Hypotension is usually due to peripheral vasodilation and IV fluids usually suffice

Quetiapine

• Risk assessment

• <3g: Mild-moderate sedation and sinus tachycardia (120)
• >3g: CNS depression, coma, hypotension, delirium and seizures
• Minor QT prolongation but no reports of Torsades
• Children: >100mg carries risk of sedation, tachy and delirium
• Hugely wide therapeutic window so risk assessment difficult based on dose alone
• Toxic mechanism
• D2, 5-HT2A, H1, M1, Alpha-1 antagonist
• Toxicokinetics

• Absorption – Rapidly but incompletely absorbed
• Distribution – 10L/kg. Lipid soluble and protein bound
• Metbaolism – Almost completely metabolised to active metabolite 7-hydroxyquetiapine via hepatic CytP450 3A4

Quetiapine

• Clinical features
  • Usually within 2-4 hours and lasting 24-72 hours
  • Coma, if it occurs, usually lasts 18-48 hours
  • Seizures in <5%
• Management
  • Treat hypotension with fluids
  • Severe agitated delirium – IV diazepam
  • Decontamination – AC if intubated only
  • Enhanced elimination N/A
  • Antidotes N/A

Quetiapine

• Disposition

• Children well at 4 hours (or 8 hours if SR) can be discharged with advice that EPSE may occur up to 3 days later
• Adult patients who took <3g and well with no sedation and normal ECG at 4 hours (or 8 hours if SR) can be discharged
• If >3g or symptomatic, require admission for observation
• Handy tips

• Sinus tachy >120/min is usual and no specific intervention is required
• Adrenaline infusion may paradoxically exacerbate hypotension due to excessive beta-2 mediated vasodilatation. Noradrenaline is the preferred agent
• Role of physostigmine not defined yet

Risperidone

• Risk assessment

• Dose-effect profile not well defined
• Sinus tachycardia seen in 50% and acute dystonia in 10%
• CNS depression is rare if taken alone
• Children: >1mg is associated with toxicity. Acute dystonic reactions are more common in children and can be delayed
• Toxic mechanism

• D2, 5-HT2A, M1, Alpha-1 antagonist
• Much lower affinity for M1 and H1 than other antipsychotics
• Toxicokinetics

• Absorption – Rapidly and well absorbed orally
• Distribution – 1.5L/kg
• Metabolism – Hepatic via CytP450 2D6 to active 9-hydroxyrisperidone
• Excretion – Active metabolite excreted in urine

Risperidone

• Clinical features

• Onset within 4 hours
• Sinus tachycardia common
• Mild sedation rare
• Miosis and mydriasis both reported
• Acute dystonias frequent
• QT prolongation may occur but no reports of TdeP
• Resolves within 24 hours
• Management

• Resus as normal
• Decontamination not indicated
• Enhanced elimination not useful
• Antidote – Benztropine 1-2mg IV by slow injection for acute dystonic reactions (0.02mg/kg in children)

Risperidone

• Decontamination
  • AC within 2 hours of immediate-release and 4 hours in cause of SR preparations
• Extrapyramidal 
  • Benztropine 1-2mg IV/PO PRN
• Disposition
  • Asymptomatic 6 hours following IR preparation
  • Asymptomatic at 10 hours for SR preparations
  • If symptomatic -> Observe until all resolved
  • If benztropine required, short course of 2mg BD PO provided for 3 days post-discharge, especially in the case of risperidone

Risperidone

• Disposition
  • Clinically well, not sedated, normal ECG at 4 hours – D/C
  • Admit symptomatic patients until above
  • Cardiac monitoring not required beyond 4 hours unless QT prolonged
  • EPSE may occur up to 3 days later
• Handy tip
  • Coma, seizures or significant alteration in vital signs suggests an alternative agent
• Pitfall
  • Failure to warn patients of delayed EPSE

Last Updated on October 14, 2020 by Andrew Crofton