Savvy Psychopharmacology

Drug interactions with tobacco smoke: Implications for patient care

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References

Practice Points
  • Tobacco smokers often are treated with medications that are metabolized by hepatic cytochrome (CYP) 1A2 enzymes. Starting or stopping tobacco smoking may cause drug interactions because polycyclic aromatic hydrocarbons in cigarette smoke induce CYP1A2 enzymes.
  • Drugs that are significantly metabolized by CYP1A2 (major substrates) are more likely to be impacted by changes in tobacco smoking compared with minor substrates.
  • Induction of hepatic CYP1A2 enzymes may be greater in heavy or moderate smokers compared with light smokers (eg, <10 cigarettes per day).
  • Evidence-based approaches for treating tobacco use in health care settings should address the risk of CYP1A2 drug interactions in tobacco smokers and how this impacts their clinical care.

Mrs. C, age 51, experiences exacerbated asthma and difficulty breathing and is admitted to a non-smoking hospital. She also has chronic obstructive pulmonary disease, type 2 diabetes mellitus, hypertension, hypercholesterolemia, hypothyroidism, gastroesophageal reflux disease, overactive bladder, muscle spasms, fibromyalgia, bipolar disorder, insomnia, and nicotine and caffeine dependence. She takes 19 prescribed and over-the-counter medications, drinks up to 8 cups of coffee per day, and smokes 20 to 30 cigarettes per day. In the emergency room, she receives albuterol/ipratropium inhalation therapy to help her breathing and a 21-mg nicotine replacement patch to avoid nicotine withdrawal.

In the United States, 19% of adults smoke cigarettes.1 Heavy tobacco smoking and nicotine dependence are common among psychiatric patients and contribute to higher rates of tobacco-related morbidity and mortality.2 When smokers stop smoking or are admitted to smoke-free facilities and are forced to abstain, nicotine withdrawal symptoms and changes in drug metabolism can develop over several days.3-5

Smokers such as Mrs. C are at risk for cytochrome (CYP) P450 drug interactions when they are admitted to or discharged from a smoke-free facility. Nine of Mrs. C’s medications are substrates of CYP1A2 (acetaminophen, caffeine, cyclobenzaprine, diazepam, duloxetine, melatonin, olanzapine, ondansetron, and zolpidem). When Mrs. C stops smoking while in the hospital, she could experience higher serum concentrations and adverse effects of these medications. If Mrs. C resumes smoking after bring discharged, metabolism and clearance of any medications started while she was hospitalized that are substrates of CYP1A2 enzymes could be increased, which could lead to reduced efficacy and poor clinical outcomes.

Pharmacokinetic effects

Polycyclic aromatic hydrocarbons in tobacco smoke induce hepatic CYP1A1, 1A2, and possibly 2E1 isoenzymes.6-12 CYP1A2 is a hepatic enzyme responsible for metabolizing and eliminating several classes of substrates (eg, drugs, hormones, endogenous compounds, and procarcinogens).6,13 Genetic, epigenetic, and environmental factors such as smoking impact the expression and activity of CYP1A2 and result in large interpatient variability in pharmacokinetic drug interactions.6,12,13 CYP1A2 enzymes can be induced or inhibited by drugs and substances, which can result in decreased or increased serum concentrations of substrates, respectively. When individuals stop smoking and switch to other nicotine products or devices, CYP1A2 induction of hepatic enzymes will revert to normal metabolism over several weeks to a month.10 Besides tobacco smoke, other CYP1A2 inducers include charbroiled food, carbamazepine, omeprazole, phenobarbital, primidone, and rifampin.4,5 Nicotine replacement products—such as gum, inhalers, lozenges, patches, and nasal spray—and nicotine delivery devices such as electronic cigarettes do not induce hepatic CYP1A2 enzymes or cause the same drug interactions as cigarette smoking.

Table 13-11 and Table 23-11 list commonly prescribed CYP1A2 substrates that could be affected by tobacco smoke. There are no specific guidelines for how to assess, monitor, or manage pharmacokinetic drug interactions with tobacco smoke.6-13 Induction of hepatic CYP1A2 enzymes by cigarette smoke may require increased dosages of some psychotropics—such as tricyclic antidepressants, duloxetine, mirtazapine, and some first- and second-generation antipsychotics (SGAs)—to achieve serum concentrations adequate for clinical efficacy. Serum concentrations may increase to toxic levels and result in adverse effects when a person quits smoking cigarettes or if a CYP1A2 inhibitor, such as amlodipine, cimetidine, ciprofloxacin, diclofenac, fluoxetine, fluvoxamine, or nifedipine, is added.5

Table 1

Common major cytochrome P450 (CYP) 1A2 substrates

DrugClass
Alosetron3,5,6Irritable bowel syndrome: serotonin 3 antagonist
Aminophylline3,5Bronchodilator: theophylline derivative
Betaxolol3,5β-1 selective adrenergic receptor blocking agent
Caffeine3-9Stimulant
Clomipramine3-11Tricyclic antidepressant
Clozapine3-10Second-generation antipsychotic
Cyclobenzaprine3-7Skeletal muscle relaxant
Doxepin3,7,10,11Tricyclic antidepressant
Duloxetine3-6Serotonin-norepinephrine reuptake inhibitor
Estradiol3,5-8Estrogen (active)
Estrogens: conjugated and estropipate3,5; estrone3,7Estrogen (derivatives)
Fluvoxamine3,8,9Selective serotonin reuptake inhibitor
Guanabenz3,5-7α-2 adrenergic agonist
Mirtazapine3-7Antidepressant: α-2 antagonist/serotonin 2A, 2C antagonist
Olanzapine3-11Second-generation antipsychotic
Pimozide3,5,7First-generation antipsychotic
Propranolol3-11β-adrenergic blocker
Ramelteon3,5,10Melatonin receptor agonist
Rasagiline3,5Antiparkinson: type B monoamine oxidase inhibitor
Riluzole3-7,10Glutamate inhibitor
Ropinirole3,5-7Antiparkinson: dopamine agonist
Theophylline3-6,8-11Bronchodilator: methylxanthine
Thiothixene3,5First-generation antipsychotic
Trifluoperazine3,5,9First-generation antipsychotic
Several classes of CYP1A2 substrates are not included and may cause toxicity with smoking cessation or require dosage increases in tobacco smokers (eg, antiarrhythmic, antifungal, antimalarial, antineoplastic, antiretroviral, and anthelmintic agents and the antibiotic quinolone). Clinicians should be most concerned about drugs with a narrow therapeutic index and those that may be toxic with smoking cessation (eg, bleeding from warfarin and clopidogrel; high serum concentrations of caffeine, clozapine, olanzapine, propranolol, and theophylline)

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