Chapter 8: Psychopharmacology
A 56-year-old man who has a 30-year history of smoking cigarettes is being treated for schizophrenia with clozapine. He is hospitalized for an acute exacerbation of his psychoses; his clozapine therapy is continued. During the third week of his hospital stay, he has a seizure that is thought to be due to clozapine toxicity. The clozapine toxicity in this patient is likely due to
a. increased GI absorption of clozapine.
b. decreased renal excretion of clozapine.
c. a decrease in his blood-brain barrier function.
d. decreased metabolism of clozapine.
Answer is d. Changes in smoking status can be especially problematic for clozapine-treated patients and will alter serum levels by 50% or more. Within 2 weeks of smoking discontinuation (eg, hospitalization in nonsmoking environment), the absence of aryl hydrocarbons will cause upregulated CYP1A2 activity to return to baseline levels, with a concomitant rise in serum clozapine concentrations (see Table 8-5).
Table 8-5. Metabolism of Common Antipsychotic Drugs
|AGENT ||METABOLIC PATHWAYS ||EFFECT OF CYP INHIBITION ||EFFECT OF CYP INDUCTION |
|Atypical Antipsychotic Agents |
|Aripiprazole ||2D6 and 3A4 convert aripiprazole to active metabolite dehydro-aripiprazole. Metabolite has longer t1/2 (75 vs. 94 hours) and represents 40% of AUC at steady state. || |
2D6 PMs experience 80% ↑ in aripiprazole AUC, and 30% ↓ in metabolite AUC (net effect is 60% ↑ in AUC for active moiety). Aripiprazole t1/2≈ 146 hrs in PM.
2D6 inhibitors ↑ aripiprazole AUC by 112% and ↓ metabolite AUC by 35%.
Ketoconazole (a potent 3A4 inhibitor) with a 15-mg single dose of aripiprazole ↑ the AUC of aripiprazole and its active metabolite by 63% and 77%, respectively.
|3A4 induction ↓ maximum concentration and AUC of aripiprazole and metabolite by 70%. |
|Asenapine ||Primarily glucuronidation (UGT 1A4), and limited oxidation via CYP 1A2, and to a lesser extent 2D6 and 3A4. No active metabolites. ||Fluvoxamine, 25 mg twice daily for 8 days, ↑ Cmax by 13% and AUC 29%. Paroxetine ↓ both Cmax and AUC by 13%. Valproate, a UGT 1A4 inhibitor, ↑ Cmax 2%, and ↓ AUC 1%. ||Smoking had no effect on clearance or other kinetic parameters. Carbamazepine ↓ both Cmax and AUC by 16%. |
|Clozapine ||Multiple enzymes convert clozapine to active metabolite N-desmethylclozapine. The mean contributions of CYPs 1A2, 2C19, 3A4, 2C9, and 2D6 are 30%, 24%, 22%, 12%, and 6%, respectively. CYP1A2 is the most important form at low concentrations, which is in agreement with clinical findings. ||Fluvoxamine ↑ Cp 5-10 fold. 2D6 inhibition may ↑ levels as much as 100%. ||Loss of smoking-related 1A2 induction ↑ serum ...|