Clozapine smoking

Cigarette smoking induces CYP1A2 increasing the metabolism of clozapine may need to increase usual clozapine dose when a patient begins to smoke, or decrease clozapine dose if smoking is stopped or nicotine replacement is used instead of smoking. 

Clozapine 1A2 3A3/4, 2D6, 2C19 Fluvoxamine, ciprofloxacin, paroxetine Cigarette smoking... 

Smoking cessation, with or without nicotine substitutes, may alter response to concomitant medication in ex-smokers. Smoking may affect alcohol, benzodiazepines, beta-adrenergic blockers, caffeine, clozapine, fluvoxamine, olanzapine, tacrine, theophylline, clorazepate, lidocaine (oral), estradiol, flecanide, imipramine, heparin, insulin, mexiletine, opioids, propranolol, catecholamines, and cortisol. 

Substrates Inhibitors Inducers CYP1A2 Acetaminophen, caffeine, clozapine, imipramine, theophylline, propranolol Most fluoroquinolone antibiotics, fluvoxamine, cimetidine Tobacco smoking, charcoal-broiled foods, cruciferous vegetables, omeprazole... 

Clozapine is metabolized by hepatic CYP 1A2 and, to a lesser degree, CYP 3A3/4 therefore, the drug is subject to changes in serum concentration when combined with medications that inhibit or induce these enzymes. Serum clozapine levels increase with coadministration of fluvoxamine or erythromycin and decrease with coadministration of phenobarbital or phenytoin and with cigarette smoking (Byerly and DeVane 1996). These pharmacokinetic interactions are particularly important because of the dose-dependent risk of seizures. 

Clozapine is principally metabolized to N -desmethylclozapine (norclozapine). It is also metabolized to and n-oxide, other hydroxyl metabolites, and a protein-reactive metabolite. The n-oxide can be converted back to clozapine. The enzyme responsible for the metabolism of clozapine to norclozapine is the cytochrome P450 1A2 enzyme (325). This is consistent with a study showing that caffeine, a marker for 1A2, is cleared in relationship to the conversion of clozapine to norclozapine ( 326). Discontinuation of coffee intake can decrease the clozapine plasma levels by more than 50%, and increasing caffeine intake can produce a reemergence of the side effects (e.g., drowsiness, excess salivation). Additionally, smoking, which induces 1A2, lowers clozapine plasma levels. Fluvoxamine, an inhibitor of 1A2, dramatically increases plasma levels, and on occasion, adverse effects are seen ( 327). This phenomenon can lead to clozapine intoxication in patients on high doses of fluvoxamine. 

On the other hand, when an inducer of 1A2 is given concomitantly with either of the two antipsychotic substrates of 1A2, the level of the antipsychotic may fall. This happens when a patient begins to smoke, because smoking induces 1A2, and this would cause levels of olanzapine and clozapine to fall (Fig. 11—45). Theoretically this might cause patients stabilized on an antipsychotic dose to relapse if the levels fell too low. Also, cigarette smokers may require higher doses of these atypical antipsychotics than nonsmokers. 

Smoking could lower clozapine and olanzapine plasma levels. True or False. 

Such approaches have been used successfully to demonstrate the induction of CYP1A2 by smoking (42). In addition, this study showed that oral contraceptives produce a small but significant inhibition of CYP1A2. Urinary metabolic ratios have also been used to show that oral AUC of clozapine was correlated with caffeine N-3-demethylation (59), a finding supported by some recent in vitro data, which has shown that clozapine N-demethylation is mediated by CYP1A2 (60). 

George TP, Serynak MJ, Ziedonis DM, Woods SW. 1997. Effects of clozapine on smoking in chronic schizophrenic outpatients. J Clin Psychiatry 56 344-346. 

McEvoy JP, Freudenreich O, Wilson W. 1999. Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol Psychiatry 46 125-129. 

Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Int Clin... 

Fatal pulmonary embolism occurred in a 29-year-old man who was not obese, did not smoke, and had not had recent surgery, after he had taken clozapine 300 mg/day... 

A 35-year-old schizophrenic man successfully treated with clozapine 700-725 mg/day for more than 7 consecutive years abruptly stopped chronic heavy cigarette smoking and 2 weeks later suddenly developed tonic-clonic seizures followed by stupor and coma. After recovery, he successfully reduced the daily dose by about 40% before he stopped smoking. 

The plasma concentrations of clozapine and its metabolite norclozapine (N-desmethylclozapine) have been measured in samples from 3775 patients (2648 men, 1127 women) (308). Step-wise backward multiple regression analysis (37% of the total sample) of log plasma clozapine concentration against log clozapine dose (mg/day), age (years), sex (male = 0, female = 1), cigarette smoking (non-smokers = 0, smokers = 1), body weight (kg), and plasma clozapine/norclozapine ratio (MR) showed that these co-variates explained 48% of the observed variation... 

Skogh E, Bengtsson F, Nordin C. Could discontinuing smoking be hazardous for patients administered clozapine medication A case report. Ther Drug Monit 1999 21(5) 580-2. 

Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol 2004 24 70-8. 

Fluvoxamine under steady-state conditions increases the systemic availability of olanzapine and inhibits the metabolism of clozapine, as shown in 21 male non-smoking Chinese volunteers (mean age 27 years) (277). This could be related to the different metabolic pathways and secretion rates of the two drugs it would be advisable to reduce the dosage of olanzapine and to extend the dosing interval of clozapine when they are combined with fluvoxamine. 

Zullino DF, Delessert D, Eap CB, Preisig M, Baumann P. Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Int Clin Psychopharmacol 2002 17(3) 141-3. 

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