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Savvy Psychopharmacology

Drug interactions with tobacco smoke: Implications for patient care

Martha P. Fankhauser, MS Pharm, FASHP, BCPP

rs. C, age 51, experiences exacerbated setron, and zolpidem). When Mrs. C stops asthma and difficulty breathing and smoking while in the hospital, she could M is admitted to a non-smoking hospi- experience higher serum concentrations and tal. She also has chronic obstructive pulmonary adverse effects of these . If Mrs. disease, type 2 diabetes mellitus, hyperten- C resumes smoking after bring discharged, sion, hypercholesterolemia, hypothyroidism, metabolism and clearance of any medica- gastroesophageal reflux disease, overactive tions started while she was hospitalized that Vicki L. Ellingrod, bladder, muscle spasms, fibromyalgia, bipolar are substrates of CYP1A2 enzymes could be PharmD, BCPP, FCCP disorder, insomnia, and and caffeine increased, which could lead to reduced effi- Series Editor dependence. She takes 19 prescribed and over- cacy and poor clinical outcomes. the-counter medications, drinks up to 8 cups of coffee per day, and smokes 20 to 30 cigarettes Pharmacokinetic effects per day. In the emergency room, she receives Polycyclic aromatic hydrocarbons in to- albuterol/ipratropium inhalation therapy to help bacco smoke induce hepatic CYP1A1, 1A2, her breathing and a 21-mg nicotine replacement and possibly 2E1 isoenzymes.6-12 CYP1A2 patch to avoid nicotine withdrawal. is a hepatic enzyme responsible for me-

In the United States, 19% of adults smoke Practice Points cigarettes.1 Heavy tobacco smoking and • Tobacco smokers often are treated with are common among medications that are metabolized by psychiatric patients and contribute to high- hepatic cytochrome (CYP) 1A2 enzymes. er rates of tobacco-related morbidity and Starting or stopping tobacco smoking mortality.2 When smokers stop smoking or may cause interactions because are admitted to smoke-free facilities and polycyclic aromatic hydrocarbons in cigarette smoke induce CYP1A2 enzymes. are forced to abstain, nicotine withdrawal symptoms and changes in drug metabo- •  that are significantly metabolized lism can develop over several days.3-5 by CYP1A2 (major substrates) are more Smokers such as Mrs. C are at risk for cyto- likely to be impacted by changes in tobacco smoking compared with minor substrates. chrome (CYP) P450 drug interactions when they are admitted to or discharged from a • Induction of hepatic CYP1A2 enzymes smoke-free facility. Nine of Mrs. C’s medica- may be greater in heavy or moderate tions are substrates of CYP1A2 (acetamino- smokers compared with light smokers (eg, <10 cigarettes per day). phen, caffeine, , , duloxetine, melatonin, , ondan- • Evidence-based approaches for treating tobacco use in health care settings Ms. Fankhauser is Clinical Professor, Department of Pharmacy should address the risk of CYP1A2 drug Practice and Science, College of Pharmacy and Pharmacotherapy interactions in tobacco smokers and how Current Psychiatry Specialist, Arizona Smokers’ Helpline, Mel and Enid Zuckerman this impacts their clinical care. 12 January 2013 College of Public Health, University of Arizona, Tucson, AZ. Savvy Psychopharmacology

Table 1 Common major cytochrome P450 (CYP) 1A2 substrates Drug Class Alosetron3,5,6 : 3 antagonist Aminophylline3,5 Bronchodilator: theophylline derivative Betaxolol3,5 β-1 selective blocking agent Caffeine3-9 Clomipramine3-11 Tricyclic Clozapine3-10 Second-generation antipsychotic Cyclobenzaprine3-7 Skeletal muscle relaxant Doxepin3,7,10,11 Duloxetine3-6 Serotonin- inhibitor Clinical Point Estradiol3,5-8 Estrogen (active) Polycyclic aromatic Estrogens: conjugated and Estrogen (derivatives) estropipate3,5; estrone3,7 hydrocarbons in Fluvoxamine3,8,9 Selective serotonin tobacco smoke Guanabenz3,5-7 α-2 adrenergic induce hepatic Mirtazapine3-7 Antidepressant: α-2 antagonist, serotonin 2A, antagonist CYP1A1, 1A2, Olanzapine3-11 Second-generation antipsychotic and possibly 2E1 Pimozide3,5,7 First-generation antipsychotic isoenzymes Propranolol3-11 β-adrenergic blocker Ramelteon3,5,10 Melatonin receptor agonist Rasagiline3,5 Antiparkinson: type B inhibitor Riluzole3-7,10 Glutamate inhibitor Ropinirole3,5-7 Antiparkinson: 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, , olanzapine, , and theophylline) tabolizing and eliminating several classes zymes will revert to normal metabolism over of substrates (eg, drugs, hormones, endog- several weeks to a month.10 Besides tobacco enous compounds, and procarcinogens).6,13 smoke, other CYP1A2 inducers include char- Genetic, epigenetic, and environmental fac- broiled food, carbamazepine, omeprazole, tors such as smoking impact the expression , primidone, and rifampin.4,5 and activity of CYP1A2 and result in large Nicotine replacement products—such as interpatient variability in pharmacokinetic gum, inhalers, lozenges, patches, and nasal Discuss this article at drug interactions.6,12,13 CYP1A2 enzymes can spray—and nicotine delivery devices such www.facebook.com/ CurrentPsychiatry be induced or inhibited by drugs and sub- as electronic cigarettes do not induce hepatic stances, which can result in decreased or in- CYP1A2 enzymes or cause the same drug in- creased serum concentrations of substrates, teractions as cigarette smoking. respectively. When individuals stop smok- Table 13-11 and Table 2 (page 14)3-11 list com- ing and switch to other nicotine products or monly prescribed CYP1A2 substrates that Current Psychiatry devices, CYP1A2 induction of hepatic en- could be affected by tobacco smoke. There Vol. 12, No. 1 13 continued on page 15 Savvy Psychopharmacology

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 Clinical Point Diazepam4,7,9,10 Diclofenac5,7 Nonsteroidal anti-inflammatory drug Nicotine products do Diphenhydramine6 not induce hepatic Febuxostat5 Xanthine oxidase inhibitor CYP1A2 enzymes Fluphenazine3,9 First-generation antipsychotic or cause the same Frovatriptan3 Antimigraine: serotonin 1 agonist Haloperidol3,4,6,8,9 First-generation antipsychotic drug interactions as Imipramine3,4,6-11 Tricyclic antidepressant cigarette smoking Maprotiline6 Tetracyclic antidepressant Melatonin3,4,6,7 Sleep-regulating hormone Metoclopramide3 : 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 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 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 Current Psychiatry caffeine, clozapine, olanzapine, propranolol, and theophylline) 14 January 2013 Savvy Psychopharmacology

continued from page 13 are no specific guidelines for how to as- sess, monitor, or manage pharmacokinetic Related Resources drug interactions with tobacco smoke.6-13 • Rx for Change. Drug interactions with smoking. http:// smokingcessationleadership.ucsf.edu/interactions.pdf. Induction of hepatic CYP1A2 enzymes by • Fiore MC, Baker TB. Treating smokers in the health care set- cigarette smoke may require increased dos- ting. N Engl J Med. 2011;365(13):1222-1231. ages of some psychotropics—such as tricy- Drug Brand Names clic , duloxetine, mirtazap- Albuterol/ipratropium • • Remeron ine, and some first- and second-generation Combivent Nabumetone • Relafen antipsychotics (SGAs)—to achieve serum • Axert • Amerge Alosetron • Lotronex Nicardipine • Cardene concentrations adequate for clinical effi- Aminophylline • Nifedipine • Adalat, Procardia cacy. Serum concentrations may increase Phyllocontin, Truphylline • Aventyl, • Elavil Pamelor to toxic levels and result in adverse effects Amlodipine • Norvasc Olanzapine • Zyprexa when a person quits smoking cigarettes or • Saphris Omeprazole • Prilosec • Kerlone • Zofran if a CYP1A2 inhibitor, such as amlodipine, Carbamazepine • Carbatrol, • Aloxi Clinical Point cimetidine, ciprofloxacin, diclofenac, fluox- Tegretol • Trilafon • Coreg • Orap When a patient stops etine, , or nifedipine, is added.5 • Thorazine Primidone • Mysoline smoking, clozapine SGA such as clozapine and olanzapine Chlorzoxazone • Parafon Progesterone • Prometrium are major substrates of CYP1A2 and dosag- Forte Propofol • Diprivan and olanzapine Cimetidine • Tagamet Propranolol • Inderal es may need to be adjusted when smoking Ciprofloxacin • Cipro Ramelteon • Rozerem dosages may need to status changes, depending on clinical ef- • Anafranil Ranitidine • Zantac Clopidogrel • Plavix Rasagiline • Azilect be reduced by 30% ficacy and adverse effects.10,14,15 Maximum Clozapine • Clozaril Rifampin • Rifadin, to 40% induction of clozapine and olanzapine Cyclobenzaprine • Flexeril Rimactane • Norpramin Riluzole • Rilutek metabolism may occur with 7 to 12 ciga- Diazepam • Valium Rivastigmine • Exelon rettes per day and smokers may have 40% Diclofenac • Voltaren Ropinirole • Requip • Benadryl Selegiline • Eldepryl, EMSAM, to 50% lower serum concentrations com- • Silenor, Sinequan others pared with nonsmokers.14 When a patient Duloxetine • Cymbalta Theophylline • Elixophyllin stops smoking, clozapine and olanzapine Estradiol • Estrace • Mellaril Estrogens (conjugated) • Thiothixene • Navane dosages may need to be reduced by 30% Cenestin, Premarin • Zanaflex to 40% (eg, a stepwise 10% reduction in Estropipate • Ogen • Desyrel, Oleptro Febuxostat • Uloric Triamterene • Dyrenium daily dose until day 4) to avoid elevated • Prozac • Stelazine serum concentrations and risk of toxicity • Prolixin Verapamil • Calan, Verelan Fluvoxamine • Luvox Warfarin • Coumadin, 15 symptoms. • Frova Jantoven Tobacco smokers can tolerate high daily • Wytensin Zileuton • Zyflo • Haldol • Geodon intake of caffeinated beverages because • Tofranil • Zomig of increased metabolism and clearance of • Ludiomil Zolpidem • Ambien, Edluar caffeine, a major substrate of CYP1A2.11 • Reglan When patients stop smoking, increased Disclosure caffeine serum concentrations may cause Ms. Fankhauser reports no financial relationships with any com- pany whose products are mentioned in this article or with manu- anxiety, irritability, restlessness, insomnia, facturers of competing products. tremors, palpitations, and tachycardia. Caffeine toxicity also can mimic symptoms of nicotine withdrawal; therefore, smok- ers should be advised to reduce their caf- ping smoking, exposure to secondhand feine intake by half to avoid adverse effects smoke, and other concomitant drugs con- when they stop smoking.10,11 tribute to variability in pharmacokinetic drug interactions. Heavy smokers (≥30 Adjusting dosing cigarettes per day) should be closely moni- Factors such as the amount and frequency tored because variations in drug serum of tobacco smoking, how quickly CYP1A2 concentrations may be affected signifi- Current Psychiatry enzymes change when starting and stop- cantly by changes in smoking status.4,9,11 Vol. 12, No. 1 15 continued Savvy Psychopharmacology

Dosage reductions of potentially toxic References 1. Centers for Disease Control and Prevention (CDC). Vital signs: drugs should be done immediately when current cigarette smoking among adults aged ≥18 years— a heavy tobacco user stops smoking.10 For United States, 2005-2010. MMWR Morb Mortal Wkly Rep. 2011;60(35):1207-1212. CYP1A2 substrates with a narrow thera- 2. Ziedonis D, Hitsman B, Beckham JC, et al. Tobacco use and peutic range, a conservative approach is to cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res. 2008;10(12):1691-1715. reduce the daily dose by 10% per day for 3. Choe JY. Drug actions and interactions. New York, NY: several days after smoking cessation.11,16 McGraw-Hill Medical; 2011. 4. Tatro DS. Drug interaction facts. St. Louis, MO: Wolters Kluwer The impact on may con- Health; 2011. tinue for weeks to a month after the per- 5. Lacy CF, Armstrong LL, Goldman MP, et al, eds. Drug son stops smoking; therefore, there may information handbook, 20th ed. Hudson, OH: Lexicomp; 2011. 6. Zhou SF, Yang LP, Zhou ZW, et al. Insights into the substrate be a delay until CYP1A2 enzymes return specificity, inhibitors, regulation, and polymorphisms and 4,8,9,15 the clinical impact of human cytochrome P450 1A2. AAPS J. to normal hepatic metabolism. In most 2009;11(3):481-494. Clinical Point situations, smoking cessation reverses in- 7. Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002;34(1- Those exposed to duction of hepatic CYP1A2 enzymes back 2):83-448. secondhand smoke, to normal metabolism and causes serum 8. Zevin S, Benowitz NL. Drug interactions with tobacco smoking. drug concentrations to increase.10 Because An update. Clin Pharmacokinet. 1999:36(6):425-438. 9. Desai HD, Seabolt J, Jann MW. Smoking in patients receiving which induces secondhand smoke induces hepatic CYP1A2 psychotropic medications: a pharmacokinetic perspective. CNS hepatic CYP1A2 enzymes, those exposed to smoke may have Drugs. 2001;15(6):469-494. 10. Schaffer SD, Yoon S, Zadezensky I. A review of smoking enzymes, may changes in drug metabolism due to environ- cessation: potentially risky effects on prescribed medications. mental smoke exposure.11 J Clin Nurs. 2009;18(11):1533-1540. experience changes 11. Kroon LA. Drug interactions with smoking. Am J Health Syst Tobacco smokers who take medica- Pharm. 2007;64(18):1917-1921. in drug metabolism tions and hormones that are metabolized 12. Plowchalk DR, Yeo KR. Prediction of drug clearance in a smoking population: modeling the impact of variable cigarette by CYP1A2 enzymes should be closely consumption on the induction of CYP1A2. Eur J Pharmacol. monitored because dosage adjustments 2012;68(6):951-960. 13. Faber MS, Jetter A, Fuhr U. Assessment of CYP1A2 activity in may be necessary when they start or stop clinical practice: why, how, and when? Basic Clin Pharmacol smoking cigarettes. An assessment of CYP Toxicol. 2005;97(3):125-134. 14. Haslemo T, Eikeseth PH, Tanum L, et al. The effect of variable drug interactions and routine monitoring cigarette consumption on the interaction with clozapine and of efficacy and/or toxicity should be done olanzapine. Eur J Clin Pharmacol. 2006;62(12):1049-1053. 15. Lowe EJ, Ackman ML. Impact of tobacco smoking cessation on to avoid potential adverse effects from stable clozapine or olanzapine treatment. Ann Pharmacother. medications and to determine if changes 2010;44(4):727-732. 16. Faber MS, Fuhr U. Time response of cytochrome P4501A2 in dosages and disease state management activity on cessation of heavy smoking. Clin Pharmacol Ther. are required. 2004;76(2):178-184.

Current Psychiatry 16 January 2013