Drug Interactions With Smoking

Lisa A. Kroon, Pharm.D

Disclosures

Am J Health Syst Pharm. 2007;64(18):1917-1921. 

In This Article

Pharmacokinetic Drug Interactions

Figure 1 lists the pharmacokinetic drug interactions with smoking. The most clinically significant interactions appear in the shaded rows and are discussed below.

Pharmacokinetic and pharmacodynamic interactions with smoking. Reprinted, with permission, from the Regents of the University of California, University of Southern California, and Western University of Health Sciences. All rights reserved.

Caffeine is >99% metabolized by CYP1A2 and often used in studies as a marker for CYP1A2 activity.[7] Its clearance is increased by 56% in smokers.[3] After controlling for caffeine intake, since smokers consume more caffeine, the median caffeine concentrations are twofold to threefold higher in nonsmokers.[8] When a patient quits smoking, the patient's caffeine intake should be reduced by half to avoid excessive caffeine levels. Symptoms of caffeine toxicity, such as irritability and insomnia, can mimic those of nicotine withdrawal and may confound the assessment of whether a person is experiencing nicotine withdrawal. Careful evaluation of a patient's total daily caffeine intake is important, so all sources of caffeine, such as nonprescription drugs and dietary supplements, should be examined.

Clozapine, an atypical antipsychotic drug with a narrow therapeutic range, is metabolized primarily by CYP1A2 but also by CYP2C19 and possibly CYP3A4.[7,9] One study found that at a given dose, the average plasma clozapine levels of smokers were 81.8% of those of nonsmokers (p = 0.022).[10] In male smokers, the plasma clozapine levels were only 67.9% of the concentrations of nonsmokers (p = 0.0083).[10] Another study found that nonsmokers had 3.2-fold higher plasma clozapine levels compared with smokers.[7] Heavy smoking (30 or more cigarettes daily) significantly affected mean intraindividual variation in plasma clozapine concentrations at a daily dose of 100 mg. The mean coefficient of variation for clozapine concentrations was significantly higher for heavy smokers than non-heavy-smokers (32% ± 3% versus 19% ± 8%, p = 0.03).[9] There were no significant differences observed between smokers and nonsmokers receiving the 300- and 600-mg doses.

Olanzapine, a widely used atypical antipsychotic, is extensively metabolized by direct N-glucuronidation, with CYP1A2 and CYP2D6 being minor metabolic pathways.[11,12] Smokers have been found to have an approximate fivefold-lower dose-corrected steady-state plasma olanzapine concentration compared with nonsmokers.[11] Another study found the dose-corrected plasma concentrations of olanzapine to be 12% lower in patients who smoke. Olanzapine's clearance is increased by 98% in smokers.[13]

De Leon[14] recommended an average dosage-correction factor of 1.5 for clozapine and olanzapine in smokers. For example, if a patient is taking clozapine and starts smoking, the clozapine dosage may need to be increased by 1.5 within two to four weeks.[14] Clozapine levels should be monitored in this situation or if the patient quits smoking. Of note, smoking does not affect the metabolism of quetiapine, a more widely used atypical antipsychotic.[15]

Fluvoxamine is extensively metabolized by CYP1A2 and polymorphic CYP2D6 and is a potent inhibitor of CYP1A2.[16,17] Fluvoxamine's maximum serum concentration, steady-state serum concentration (Css), and area under the concentration-time curve are significantly lower (32%, 39%, and 31%, respectively) in smokers than in nonsmokers.[16,18] Another study found no significant difference in the Css of smokers compared with nonsmokers.[17] These inconsistent findings may be explained by the small sample sizes, possible saturation of CYP1A2 in smokers, and CYP2D6 genotype differences.[17] While dosage modification is not routinely recommended, smokers may require higher dosages of this infrequently used antidepressant.

Tacrine, an infrequently used drug for the treatment of Alzheimer's disease, significantly interacts with smoking. The half-life of tacrine is decreased by 50%,[3] and serum tacrine concentrations are threefold lower in patients who smoke.[19]

Theophylline's clearance is increased by 58-100% and its half-life is decreased by 63% in smokers compared with nonsmokers.[3] This is because it is highly metabolized by CYP1A2. One week after a patient quit smoking, theophylline's clearance was decreased by 38% and its half-life was increased by 36%.[20] After only 24-36 hours of smoking cessation, theophylline's pharmacokinetics are not significantly changed.[21] However, Faber and Fuhr[6] found that CYP1A2 activity was reduced by 20% after only two days of smoking cessation. Theophylline's clearance increases by 51% in children exposed to the secondhand smoke of parents who smoke at least 20 cigarettes daily. Further, when receiving the same i.v. dose of aminophylline, the Css was approximately 25% lower in children exposed to secondhand smoke compared with children not exposed to tobacco smoke.[22] Theophylline, while used much less frequently for the outpatient management of asthma, is still used in the inpatient setting. Plasma theophylline levels should be routinely monitored in smokers, and dosages should be adjusted accordingly.

Inhaled insulin is contraindicated for use in smokers and in patients who have stopped smoking for less than six months. Inhaled insulin peaks faster and reaches higher concentrations in smokers compared with nonsmokers.[23,24] This leads to a systemic exposure that is twofold to fivefold higher in smokers, thus increasing the risk of hypoglycemia.[25] If a person resumes smoking, an alternative form of insulin delivery (i.e., subcutaneous injection) must be used.

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