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Savvy Psychopharmacology


Drug interactions with tobacco smoke: Implications for patient care

Vol. 12, No. 01 / January 2013

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

Drug

Class

Alosetron3,5,6

Irritable bowel syndrome: serotonin 3 antagonist

Aminophylline3,5

Bronchodilator: theophylline derivative

Betaxolol3,5

β-1 selective adrenergic receptor blocking agent

Caffeine3-9

Stimulant

Clomipramine3-11

Tricyclic antidepressant

Clozapine3-10

Second-generation antipsychotic

Cyclobenzaprine3-7

Skeletal muscle relaxant

Doxepin3,7,10,11

Tricyclic antidepressant

Duloxetine3-6

Serotonin-norepinephrine reuptake inhibitor

Estradiol3,5-8

Estrogen (active)

Estrogens: conjugated and estropipate3,5; estrone3,7

Estrogen (derivatives)

Fluvoxamine3,8,9

Selective serotonin reuptake inhibitor

Guanabenz3,5-7

α-2 adrenergic agonist

Mirtazapine3-7

Antidepressant: α-2 antagonist/serotonin 2A, 2C antagonist

Olanzapine3-11

Second-generation antipsychotic

Pimozide3,5,7

First-generation antipsychotic

Propranolol3-11

β-adrenergic blocker

Ramelteon3,5,10

Melatonin receptor agonist

Rasagiline3,5

Antiparkinson: type B monoamine oxidase inhibitor

Riluzole3-7,10

Glutamate inhibitor

Ropinirole3,5-7

Antiparkinson: dopamine agonist

Theophylline3-6,8-11

Bronchodilator: methylxanthine

Thiothixene3,5

First-generation antipsychotic

Trifluoperazine3,5,9

First-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)

Table 2

Common minor cytochrome P450 (CYP) 1A2 substrates

Drug

Class

Acetaminophen3-9

Analgesic

Almotriptan6

Antimigraine: serotonin 1B, 1D receptor agonist

Amitriptyline3-7,9-11

Tricyclic antidepressant

Asenapine9

Second-generation antipsychotic

Carvedilol5-7

β and α adrenergic blocking activity

Chlorpromazine3,4,7-9,11

First-generation antipsychotic

Chlorzoxazone4,7

Skeletal muscle relaxant

Clopidogrel5

Antiplatelet

Desipramine4,7,10,11

Tricyclic antidepressant

Diazepam4,7,9,10

Benzodiazepine

Diclofenac5,7

Nonsteroidal anti-inflammatory drug

Diphenhydramine6

Antihistamine

Febuxostat5

Xanthine oxidase inhibitor

Fluphenazine3,9

First-generation antipsychotic

Frovatriptan3

Antimigraine: serotonin 1 agonist

Haloperidol3,4,6,8,9

First-generation antipsychotic

Imipramine3,4,6-11

Tricyclic antidepressant

Maprotiline6

Tetracyclic antidepressant

Melatonin3,4,6,7

Sleep-regulating hormone

Metoclopramide3

Antiemetic: prokinetic gastrointestinal agent

Nabumetone6

Nonsteroidal anti-inflammatory drug

Naproxen3,4,6,7

Nonsteroidal anti-inflammatory drug

Naratriptan10

Antimigraine: serotonin 1B, 1D receptor agonist

Nicardipine3,7

Calcium channel blocker

Nortriptyline4,6,7,9-11

Tricyclic antidepressant

Ondansetron3,4,6,7

Antiemetic: serotonin 3 antagonist

Palonosetron5

Antiemetic: serotonin 3 antagonist

Perphenazine3,7

First-generation antipsychotic

Progesterone5,7

Progestin

Propofol4,6,7

General anesthetic

Ranitidine5,7

H2 antagonist

Rivastigmine10

Acetylcholinesterase inhibitor

Selegiline6,7

Antiparkinson: type B monoamine oxidase inhibitor

Thioridazine3,4,6

First-generation antipsychotic

Tizanidine3-6

Skeletal muscle relaxant: α-2 adrenergic agonist

Trazodone6,9

Serotonin reuptake inhibitor and antagonist

Triamterene6

Diuretic: potassium sparing

Verapamil3,4,6,7,10

Calcium channel blocker

Warfarin3,4,6-10

Anticoagulant: coumarin derivative

Zileuton3,4,6,7

Asthma agent: 5-lipoxygenase inhibitor

Ziprasidone3,4

Second-generation antipsychotic

Zolmitriptan3,6,7

Antimigraine: serotonin 1B, 1D receptor agonist

Zolpidem4,6,7

Nonbenzodiazepine hypnotic

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)

SGA such as clozapine and olanzapine are major substrates of CYP1A2 and dosages may need to be adjusted when smoking status changes, depending on clinical efficacy and adverse effects.10,14,15 Maximum induction of clozapine and olanzapine metabolism may occur with 7 to 12 cigarettes per day and smokers may have 40% to 50% lower serum concentrations compared with nonsmokers.14 When a patient stops smoking, clozapine and olanzapine dosages may need to be reduced by 30% to 40% (eg, a stepwise 10% reduction in daily dose until day 4) to avoid elevated serum concentrations and risk of toxicity symptoms.15

Tobacco smokers can tolerate high daily intake of caffeinated beverages because of increased metabolism and clearance of caffeine, a major substrate of CYP1A2.11 When patients stop smoking, increased caffeine serum concentrations may cause anxiety, irritability, restlessness, insomnia, tremors, palpitations, and tachycardia. Caffeine toxicity also can mimic symptoms of nicotine withdrawal; therefore, smokers should be advised to reduce their caffeine intake by half to avoid adverse effects when they stop smoking.10,11

Adjusting dosing

Factors such as the amount and frequency of tobacco smoking, how quickly CYP1A2 enzymes change when starting and stopping smoking, exposure to secondhand smoke, and other concomitant drugs contribute to variability in pharmacokinetic drug interactions. Heavy smokers (≥30 cigarettes per day) should be closely monitored because variations in drug serum concentrations may be affected significantly by changes in smoking status.4,9,11 Dosage reductions of potentially toxic drugs should be done immediately when a heavy tobacco user stops smoking.10 For CYP1A2 substrates with a narrow therapeutic range, a conservative approach is to reduce the daily dose by 10% per day for several days after smoking cessation.11,16 The impact on drug metabolism may continue for weeks to a month after the person stops smoking; therefore, there may be a delay until CYP1A2 enzymes return to normal hepatic metabolism.4,8,9,15 In most situations, smoking cessation reverses induction of hepatic CYP1A2 enzymes back to normal metabolism and causes serum drug concentrations to increase.10 Because secondhand smoke induces hepatic CYP1A2 enzymes, those exposed to smoke may have changes in drug metabolism due to environmental smoke exposure.11

Tobacco smokers who take medications and hormones that are metabolized by CYP1A2 enzymes should be closely monitored because dosage adjustments may be necessary when they start or stop smoking cigarettes. An assessment of CYP drug interactions and routine monitoring of efficacy and/or toxicity should be done to avoid potential adverse effects from medications and to determine if changes in dosages and disease state management are required.

Related Resources

Drug Brand Names

  • Albuterol/ipratropium • Combivent
  • Almotriptan • Axert
  • Alosetron • Lotronex
  • Aminophylline • Phyllocontin, Truphylline
  • Amitriptyline • Elavil
  • Amlodipine • Norvasc
  • Asenapine • Saphris
  • Betaxolol • Kerlone
  • Carbamazepine • Carbatrol, Tegretol
  • Carvedilol • Coreg
  • Chlorpromazine • Thorazine
  • Chlorzoxazone • Parafon Forte
  • Cimetidine • Tagamet
  • Ciprofloxacin • Cipro
  • Clomipramine • Anafranil
  • Clopidogrel • Plavix
  • Clozapine • Clozaril
  • Cyclobenzaprine • Flexeril
  • Desipramine • Norpramin
  • Diazepam • Valium
  • Diclofenac • Voltaren
  • Diphenhydramine • Benadryl
  • Doxepin • Silenor, Sinequan
  • Duloxetine • Cymbalta
  • Estradiol • Estrace
  • Estrogens (conjugated) • Cenestin, Premarin
  • Estropipate • Ogen
  • Febuxostat • Uloric
  • Fluoxetine • Prozac
  • Fluphenazine • Prolixin
  • Fluvoxamine • Luvox
  • Frovatriptan • Frova
  • Guanabenz • Wytensin
  • Haloperidol • Haldol
  • Imipramine • Tofranil
  • Maprotiline • Ludiomil
  • Metoclopramide • Reglan
  • Mirtazapine • Remeron
  • Nabumetone • Relafen
  • Naratriptan • Amerge
  • Nicardipine • Cardene
  • Nifedipine • Adalat, Procardia
  • Nortriptyline • Aventyl, Pamelor
  • Olanzapine • Zyprexa
  • Omeprazole • Prilosec
  • Ondansetron • Zofran
  • Palonosetron • Aloxi
  • Perphenazine • Trilafon
  • Pimozide • Orap
  • Primidone • Mysoline
  • Progesterone • Prometrium
  • Propofol • Diprivan
  • Propranolol • Inderal
  • Ramelteon • Rozerem
  • Ranitidine • Zantac
  • Rasagiline • Azilect
  • Rifampin • Rifadin, Rimactane
  • Riluzole • Rilutek
  • Rivastigmine • Exelon
  • Ropinirole • Requip
  • Selegiline • Eldepryl, EMSAM, others
  • Theophylline • Elixophyllin
  • Thioridazine • Mellaril
  • Thiothixene • Navane
  • Tizanidine • Zanaflex
  • Trazodone • Desyrel, Oleptro
  • Triamterene • Dyrenium
  • Trifluoperazine • Stelazine
  • Verapamil • Calan, Verelan
  • Warfarin • Coumadin, Jantoven
  • Zileuton • Zyflo
  • Ziprasidone • Geodon
  • Zolmitriptan • Zomig
  • Zolpidem • Ambien, Edluar

Disclosure

Ms. Fankhauser reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

References

1. Centers for Disease Control and Prevention (CDC). Vital signs: current cigarette smoking among adults aged ≥18 years—United States 2005-2010. MMWR Morb Mortal Wkly Rep. 2011;60(35):1207-1212.

2. Ziedonis D, Hitsman B, Beckham JC, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008;10(12):1691-1715.

3. Choe JY. Drug actions and interactions. New York NY: McGraw-Hill Medical; 2011.

4. Tatro DS. Drug interaction facts. St. Louis MO: Wolters Kluwer Health; 2011.

5. Lacy CF, Armstrong LL, Goldman MP, et al. eds. Drug information handbook, 20th ed. Hudson, OH: Lexicomp; 2011.

6. Zhou SF, Yang LP, Zhou ZW, et al. Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2. AAPS J. 2009;11(3):481-494.

7. Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002;34(1-2):83-448.

8. Zevin S, Benowitz NL. Drug interactions with tobacco smoking. An update. Clin Pharmacokinet. 1999;36(6):425-438.

9. Desai HD, Seabolt J, Jann MW. Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. CNS Drugs. 2001;15(6):469-494.

10. Schaffer SD, Yoon S, Zadezensky I. A review of smoking cessation: potentially risky effects on prescribed medications. J Clin Nurs. 2009;18(11):1533-1540.

11. Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm. 2007;64(18):1917-1921.

12. Plowchalk DR, Yeo KR. Prediction of drug clearance in a smoking population: modeling the impact of variable cigarette consumption on the induction of CYP1A2. Eur J Pharmacol. 2012;68(6):951-960.

13. Faber MS, Jetter A, Fuhr U. Assessment of CYP1A2 activity in clinical practice: why how, and when? Basic Clin Pharmacol Toxicol. 2005;97(3):125-134.

14. Haslemo T, Eikeseth PH, Tanum L, et al. The effect of variable cigarette consumption on the interaction with clozapine and olanzapine. Eur J Clin Pharmacol. 2006;62(12):1049-1053.

15. Lowe EJ, Ackman ML. Impact of tobacco smoking cessation on stable clozapine or olanzapine treatment. Ann Pharmacother. 2010;44(4):727-732.

16. Faber MS, Fuhr U. Time response of cytochrome P4501A2 activity on cessation of heavy smoking. Clin Pharmacol Ther. 2004;76(2):178-184.

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