Olanzapine
Olanzapine is a solid option for sedation in ICU patients with psychosis and delirium. It has never appeared in any of the CICM exams, and perhaps never will. This is not a statement about its utility or importance in our practice; only that there is likely never going to be a reasonable thing to ask about it, which would reveal something interesting about the exam candidate. Neither are the pharmacokinetics of olanzapine especially unique or instructive, nor its mechanism of action especially unique, nor the complications of its use important enough to the public for examiners to insist on making it an example. So for First Part Exam questions, it seems like a poor choice. And it is pretty terrible for the Second Part Exam because there are no controversies to explore, and little evidence to critically evaluate. As such, it remains underexplored.
| Class | Antipsychotic |
|---|---|
| Chemistry |
Thienobenzodiazepine - grouped with the "atypical" antipsychotics, but they are all very chemically different
|
| Routes of administration |
Oral, IV, IM |
| Absorption |
Rapidly and completely absorbed; oral bioavailability is about 60%
|
| Solubility |
pKa 7.78; minimally water-soluble, highly lipophilic
|
| Distribution |
VOD=10-20L/kg; 90% protein-bound
|
| Metabolism |
Hepatic metabolism into inactive metabolites
|
| Elimination |
Inactive metabolites are renally cleared (60%) and 30% via the faeces, with about 10% of the drug eliminated unchanged
|
| Time course of action |
Elimination half-life of about 33 hours
|
| Target receptor |
D2 receptors, as well as muscarinic cholinergic receptors, histamine receptors and alpha-adrenergic receptors (but less so than "typical" agents). Compared to other antipsychotics, olanzapine:
|
| Mechanism of action |
Antipsychotic effects are mediated mainly by the D2 antagonist effect on the dopaminergic neurons in the mesolimbic system |
| Clinical effects |
|
| Literature reference |
Petersen, A. B., et al. "Adverse effects associated with high-dose olanzapine therapy in patients admitted to inpatient psychiatric care." Clinical Toxicology 52.1 (2014): 39-43. Gannon, Louisa, et al. "High-dose olanzapine in treatment-resistant schizophrenia: a systematic review." Therapeutic Advances in Psychopharmacology 13 (2023): 20451253231168788. |
| CICM details of understanding | Level 3 |
| Mentioned around Deranged Physiology | |
| Related SAQs |
Question 16 from the second paper of 2021 (classification of antipsychotics, but mainly about haloperidol). |
The list of adverse effects presented here might make it sound like a dangerous substance, but in fact olanzapine toxicity is remarkably rare even in populations chronically exposed to truly heroic doses. Consider that high dose olanzapine is considered to be a well-tolerated alternative to clozapine in patients who do not tolerate clozapine (or cannot adhere to the fastidious self-maintenance it requires).
What do they call "high dose", and "well tolerated"? More than 20mg/day was classified as "a lot" by the authors of Gannon et al (2023), but others went further. One terrifying case series (Petersen et al, 2014) reported people getting up to 160mg, with "serious adverse effects". 
However, looking closely at these serious adverse effects, the majority weere extrapyramidal side effects (from long term use, about 50 days) and sedation (which some might consider a desirable effect in ICU). The others were "weight gain (14%), hypotension (2%), neuroleptic malignant syndrome (2%) and corrected QT-interval (QTc) prolongation (1%)". These adverse events, though concerning for psychiatric inpatients, are fairly benign when compared to what goes on in the ICU.