Seizures, Sedation and Saliva

Clozapine is an atypical anti-psychotic agent.

Clozapine is commonly prescribed for treatment-refractory schizophrenia. Given this indication, it is not often used and is usually administered under supervision so overdose with this drug is rare. Clozapine is a tricyclic dibenzodiazepine atypical antipsychotic that acts at multiple receptors with antagonism of D₁ and D₂ as well as serotonin (5HT₂), muscarinic (M₁), histaminic (H₁), peripheral alpha-adrenoreceptors and gamma-aminobutryic acid (GABA) receptors.

Like other anti-psychotics, the observed action of clozapine at multiple receptors also accounts for the clinical presentation seen in overdose.

Clozapine is available as 25, 50, 100 and 200mg tablets in either packets of 28 or 100 tablets.

Toxicokinetics of clozapine:

• Absorption: Rapidly absorbed following oral administration. Intoxication occurs within 4 hours of ingestion.
• Distribution: Moderate volume of distribution (0.5-3L/kg). Highly protein-bound.
• Metabolism: Metabolised in the lliver by oxidation (cytochrome P450 1A2, 2D6) to its metabolites with significant first pass effect.
• Excretion: Mainly in the urine and faces as metabolites

Clozapine, like many other anti-psychotics, has multiple potential toxicological properties owing to its actions at multiple receptors. Toxicity usually resolves within 24 hours.

Effects include:

CNS effects

• Lethargy, confusion, sedation, coma (the latter requiring intubation is rare)
• Seizures occur in ~5-10% of patients
• Extra-pyramidal side-effects are more common in children

Cardiovascular effects

• Sinus tachycardia, hypotension (due to alpha2-adrenoreceptor blockade)
• QT prolongation is rare

Anti-muscarinic effects

• Agitation, restlessness, delirium, mydriasis (big pupils) but often have miosis (small pupils due to alpha-bloackade), dry, warm skin, tachycardia, ileus, urinary retention (don’t forget an IDC with an agitated patient post overdose with an anticholinergic!)

Hypersalivation is a characteristic and seemingly paradoxical effect of clozapine toxicity. The mechanism is poorly understood and likely multifactorial

There are two tests that are incredibly useful in Toxicology (not only my opinion but that of many smarter people too):

1. ECG
2. paracetamol level

Whilst some patients present to the Emergency Department whilst conscious and clearly volunteer how much and what they have taken, many do not (as in this case). Paracetamol poisoning is often clinically silent initially and, if not treated, can lead to serious morbidity or even mortality. However, it is easily detected via a simple blood test, and has a safe and effective antidote that is widely available. Similarly, the ECG is a cheap, useful non-invasive test useful for identifying otherwise occult cardiotoxicity.

Whilst clozapine overdose is usually considered to be benign and any accompanying hypotension can be resolved with intravenous fluids alone, this patient has significant hypotension despite adequate filling.

As clozapine is known to act as a peripheral alpha-adrenoreceptor antagonist, commencing an inotrope is suggested. Noradrenaline, an alpha-agonist, is the preferred choice. Alternatives could include other alpha-adrenergic agents such as metaraminol or phenylephrine. In refractory cases, vasopressin has been used with good effect in a previous published case report.

Both agranulocytosis and myocarditis are known complications of chronic therapeutic clozapine use, however they are not features of acute overdose.

An echocardiogram may be appropriate if there were concerns about response to inotropes in the setting of hypotension.

Using the Resus-RSI-DEAD approach as all good toxicologists do…

Resuscitation

• Attention to airway, breathing and circulation always takes precedent. Basic resuscitative measures ensure a good outcome in the vast majority of patients.
• Treat seizures with benzodiazepines
• If intravenous fluid does not improve hypotension, consider the use of an inotrope (noradrenaline is generally preferred)

Supportive care and monitoring

• Supportive care will suffice for most cases so ensure it is done well!
• Secure appropriate IV access
• Ensure adequate hydration with IV fluids
• Remember FASTHUGS IN BED Please especially pressure care, bladder care and DVT prophylaxis
• Cardiac monitoring should continue until toxicity is reversed if ECG changes are present

Investigations

• ECG, paracetamol and blood glucose levels should be performed as recommended for all intentional overdoses
• Consider possible co-ingestants

Decontamination

• Clozapine is rapidly absorbed and usually benign. Activated charcoal is therefore not indicated on these grounds.

Antidotes

• None available

Enhanced elimination

• Not useful

Disposition

• Haemodynamically stable patients that are symptomatic (i.e. drowsy) can be managed as inpatients in an appropriate ward (e.g. observation unit) until medically cleared (awake, able to walk, has passed urine independently and has tolerated oral intake)
• Patients requiring inotropic support require HDU/ICU but this is likely to be for a short period of time (~24 hours)
• Psychiatric review and possible inpatient management

• Burns MJ. The pharmacology and toxicology of atypical antipsychotic agents. J Toxicol Clin Toxicol. 2001;39(1):1-14. [PMID 11327216.]
• Rotella JA, Zarei F, Frauman AG, Greene SL. Refractory hypotension treated with vasopressin after intentional clozapine overdose. Eur J Emerg Med. 2014 Aug;21(4):319-20 [PMID 24983646]