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Chapter 8: Psychopharmacology

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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

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a. increased GI absorption of clozapine.

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b. decreased renal excretion of clozapine.

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c. a decrease in his blood-brain barrier function.

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d. decreased metabolism of clozapine.

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e. a pharmacy mistake.

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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).

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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 ...

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