Q: 57 year old male with 100 PPY of smoking history is admitted to ICU with COPD exacerbation. Patient developed mild delirium & psychosis in ICU though recovering from his COPD exacerbation and is now extubated.. Olanzapine was initiated by service but delirium and psychosis continue to get worse. What could be the reason?  

Answer: Olanzapine is metabolized by the cytochrome P450 system, principally by isozyme 1A2. By these mechanisms more than 40% of the oral dose is removed by the hepatic first-pass effect. Agents that increase the activity of CYP1A2, notably tobacco smoke significantly increase hepatic first-pass clearance of Olanzapine and decreases its effect