Smoking alters the effects of numerous medications. Doctors and other health care providers need to be aware of these interactions when medications are prescribed and also when patients quit smoking, as drug dosages may need to be adjusted.1
Drug interactions fall into two categories: (i) pharmacokinetic interactions, which occur when cigarette smoke alters a drug’s metabolism; or (ii) pharmacodynamic interactions, which occur when the physiological effects of cigarette smoke modify the physiological effects of the drug.2,3
3.15.2.1 Pharmacokinetic drug interactions
Pharmacokinetic drug interactions occur when one drug affects the absorption (how much is taken up into the body), distribution (when a drug moves around the body and reaches its site of action), metabolism (drugs being broken down into other chemicals), or excretion (removal from the body, such as into the urine). By interfering with these four processes, smoking can change the concentration of a drug in the body, or how much gets to the active site, or how long it is present before excretion. These modifications can change the effectiveness of medications and change their toxicity. Most of the known pharmacokinetic interactions of smoking are reductions in the effectiveness of other drugs.
Pharmacokinetic drug interactions of cigarette smoke include increased metabolism of drugs such as caffeine, treatments of heart disease such as heparin, warfarin and beta-blockers (such as propranolol), drugs for respiratory disease such as theophylline, and a number of antipsychotic drugs (such as clozapine, chlorpromazine and olanzapine) and drugs to treat anxiety such as benzodiazepines.4-7 A meta-analysis of the interaction between smoking and warfarin, for example, found that smoking increased warfarin dosage requirements by about 12%.8 People with lung cancer who smoke had increased clearance of erlotinib (a non-chemotherapy) and irinotecan (a chemotherapy), which may reduce their effectiveness in treating the lung cancer.9 People with chronic obstructive pulmonary disease who smoke gained less benefit from inhaled corticosteroids than did non-smokers; they had poorer lung function and increased exacerbations of disease.10
Although it is difficult to know which of the estimated 7,000 compounds in cigarette smoke cause these interactions,11 the polycyclic aromatic hydrocarbons are suspected. These hydrocarbons may increase the amounts of liver enzymes (see Section 3.15.1.1) and thereby hasten the clearance of any drug whose metabolism requires these enzymes.2,3 Conversely, upon smoking cessation, dosages of these medications may need adjustment, as clearance may slow. For example, upon stopping smoking, caffeine consumption may need to be reduced.4 Some of the effects of smoking on the human liver result in decreasing the levels of enzymes, such as FMO3, FMO4 and FMO5, which break down a variety of biological molecules in the liver.12 Therefore smoking can feasibly increase or decrease the metabolism of many different medications.
The pharmacokinetic interaction between tobacco smoke and the antiplatelet medication clopidogrel has been described as a ‘smoking paradox’ as there is some evidence to suggest that people who smoke have higher clinical responsiveness to clopidogrel than non-smokers.4 A meta-analysis of over 70,000 patients with established cardiovascular disease found that people who smoke and take clopidogrel had a 25% lower risk of cardiovascular events compared to an 8% reduced risk in non-smokers.13 Another study suggested that doubling the dose of clopidogrel in patients who smoke was effective in reducing the risk of cardiovascular events, without an increase in the risk of bleeding.14 Dosages of clopidogrel and other antiplatelet medications (such as prasugrel) may need to be adjusted upon stopping smoking.13
A meta-analysis showed that people who smoke had significantly lower blood levels of the antipsychotic drug clozapine. The authors recommended a 30% reductions of clozapine dose for those who quit smoking15 (see also Section 9A.3).
3.15.2.2 Pharmacodynamic drug interactions
Pharmacodynamic drug interactions occur when one drug modifies the direct effect of another at its site of action, such as having the same biological target. Pharmacodynamic interactions can lead to either enhanced or diminished responses to the drug. Pharmacodynamic interactions related to nicotine include: reduced response to corticosteroids in people who smoke who are asthmatic,16,17 decreased effectiveness of benzodiazepines a common sleeping medication (possibly due to the stimulant effects of nicotine), slowed absorption of sub-cutaneous insulin among diabetics (possibly due to reduced blood flow to the skin, mediated by nicotine), and an increased risk of cardiovascular adverse events in women taking oral contraceptives.2,3 Exposure to tobacco smoke also limits the benefits of combined therapy with elexacaftor/tezacaftor/ivacaftor for people with cystic fibrosis.18,19
In the above examples, smoking modifies the effects of particular drugs. It has also been speculated that bronchodilator drugs (mainly beta-2-agonists), prescribed for people with chronic obstructive pulmonary disease, may worsen the effects of cigarette smoke. The proposed mechanism is that bronchodilation improves smoke inhalation, and may increase the deposition of cigarette smoke on the lungs, thereby increasing cardiovascular disease morbidity and mortality.20
Smoking also reduces the effectiveness of drug treatments of rheumatoid arthritis. See Section 3.17.1 for more information.
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References
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14. Bossard M, Granger CB, Tanguay JF, Montalescot G, Faxon DP, et al. Double-dose versus standard-dose clopidogrel according to smoking status among patients with acute coronary syndromes undergoing percutaneous coronary intervention. Journal of the American Heart Association, 2017; 6(11):pii:e006577. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29101117
15. Wagner E, McMahon L, Falkai P, Hasan A, and Siskind D. Impact of smoking behavior on clozapine blood levels - a systematic review and meta-analysis. Acta Psychiatrica Scandinavica, 2020; 142(6):456-66. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32869278
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18. Harris WT, Baker EH, Guimbellot JS, Collaco JM, Schechter MS, et al. Tobacco smoke exposure is associated with diminished longitudinal benefit of elexacaftor/tezacaftor/ivacaftor in cystic fibrosis. Journal of Cystic Fibrosis, 2025; 24(5):957-62. Available from: https://www.ncbi.nlm.nih.gov/pubmed/40506287
19. Baker E, Harris WT, Rowe SM, Rutland SB, and Oates GR. Tobacco smoke exposure limits the therapeutic benefit of tezacaftor/ivacaftor in pediatric patients with cystic fibrosis. Journal of Cystic Fibrosis, 2021; 20(4):612-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/33023836
20. van Dijk WD, Heijdra Y, Scheepers PT, Lenders JW, van Weel C, et al. Interaction in COPD experiment (ICE): a hazardous combination of cigarette smoking and bronchodilation in chronic obstructive pulmonary disease. Medical Hypotheses, 2010; 74(2):277-80. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19800175