Phenothiazines and butyrophenones

Phenothiazines and butyrophenones are the antipsychotic (neuroleptic) agents. Commonly used agents are chlorpromazine, prochlorperazine, droperidol and haloperidol. Other unfamiliar agents include fluphenazine, Pericyazine, Pipothiazine and Trifluoperazine. If you think how you use these drugs in an aggressive patient you will understand their effects in overdose for a spectrum of CNS depression, orthostatic hypotension, anticholinergic effects and rarely dystonia.

Toxic Mechanism:

These drugs antagonise central dopamine (D2), serotonin, histamine the muscarninic M1 and peripheral alpha 1 and alpha 2 receptors. This causes an anticholinergic effect (muscarinic receptors) in overdose and drowsiness (histamine receptor blockade). Cardiotoxicity can occur from sodium and potassium blockading effects on the myocardium.

Toxicokinetics: 

• Rapidly absorbed but in overdose absorption can be slow and erratic.
• Large volume of distribution and lipid soluble
• Extensive first pass effect with variable bioavailability.
• Hepatic metabolism to multiple active metabolites that have varying elimination half-lives.

Resuscitation:

• Reduced GCS: Prompt intubation and ventilation
• Hypotension: Give 10 – 20 ml/kg of IV crystalloid, if response is not adequate start noradrenaline (adrenaline is contraindicated due to paradoxical hypotension from beta 2 mediated vasodilatation). Noradrenaline dose: 0.15mg/kg in 50ml D5W at 1-10ml/hr (0.05 – 0.5 mcg/kg/min)
• Seizures (rare)/agitation: IV benzodiazepines incrementally dosed every 5 minutes to effect.
  • Check the patient is not in a dysrhythmia
  • Can be managed with benzodiazepines (varying doses in the textbooks, easy method is 0.1mg/kg IV for lorazepam (max 4mg) / midazolam (max 10mg) / diazepam (max 10mg). Or…
  • Lorazepam 0.1mg/kg max 4mg
  • Diazepam 0.15mg/kg max 10mg
  • Midazolam 0.2mg/kg max 10mg

Risk Assessment

• They all cause dose-dependent CNS depression, tachycardia, hypotension and anticholinergic effects.
• Chlorpromazine causes a coma in doses > 5 grams.
• Seizures are uncommon.
• Children: Ingestion of one tablet requires hospital assessment. Delayed extrapyramidal effects can occur in children days later.
• Clinical features should manifest within 2 – 4 hours and may last 24 hours (coma usually lasts 18 – 48 hours)
  • Sedation, ataxia, mydriasis, fluctuating mental status.
  • Tachycardia and orthostatic Hypotension
  • Mild to moderate anticholinergic syndrome
  • Urinary retention is common
  • Seizures and extrapyramidal effects are rare.

Supportive Care

• Controlling the delirium can be difficult, things to consider include
  • Titrated doses of benzodiazepines e.g. diazepam 2.5 – 5 mg every 5 minutes IV until gentle sedation is achieved (doses used may necessitate intubation).
  • Physical restraint
  • Bladder scan and a catheter for urinary retention (no amount of benzodiazepines will fix this agitation)

Investigations

• Screening: 12 lead ECG, BSL, Paracetamol level
• Specific:
  • ECG monitoring, do an ECG at presentation and 6 hours, if this is normal then cardiac monitoring may stop. If intubated then the patient will need ECG every 4 hours until clinical symptoms or cardiac abnormalities resolve. Minor QT prolongation but no Torsades de pointes has been reported since thiorodiazine was taken off the market.

Decontamination:

• Activated charcoal is only intoxicated post intubation via a nasogastric tube as patients recover with good supportive care. The utility of using charcoal post intubation is to reduce the anticholinergic effects on extubation that may make management difficult.

Enhanced Elimination

• Not clinical useful

Antidote

• None available
• Acute dystonic reactions however, have the following management:
  • Benztropine
  • Benzodiazepines:
    • Second line treatment
    • help relieve muscle spasm and anxiety
    • best used for  acute dystonic reactions that are slow to resolve following benztropine administration — early use may lead to diagnostic confusion
    • Midazolam dose 1-2mg IV/IM
    • Diazepam dose 5-10mg IV/PO
  • Antihistamines (H1 receptor antagonists) with anticholinergic activity:
    • Can be used if benztropine not available.
    • e.g. promethazine 25-50mg IV/IM or diphenhydramine 50mg IV/IM or 1 mg/kg in children)

Disposition

• Patients should be observed for 6 hours, if asymptomatic with a normal baseline ECG, no hypotension, eating and drinking can be medically cleared
• Patients with any clinical features should be observed or treated as required until symptoms have resolved. Depending on severity patients may stay in an overnight observation ward or may need ICU.

References and Additional Resources:

Additional Resources:

• CCC – Neuroleptic Malignant Syndrome
• Tox conundrum 046 – A fumbling, Mumbling Mess
• Tox conundrum 030 – Stiff and twisted
• Anticholinergic song
• Tox Flashcards – Anticholinergic Toxidrome

References:

• James LP, Abel K, Wilkinson J, Simpson PM, Nichols MH. Phenothiazine, butyrophenone, and other psychotropic medication poisonings in children and adolescents. Clinical Toxicology 2000; 38(6):615–623.
• Strachan EM, Kelly CA, Bateman DN. Electrocardiogram and cardiovascular changes in thioridazine and chlorpromazine poisoning. European Journal of Clinical Pharmacology 2004; 60:541-545.