Drug Interactions and Smoking

While smoking rates have declined significantly over the past few decades, smoking continues to be an important contributor to disease burden in Australia.

Smoking cessation is associated with significant health benefits, including rapid improvements in lung function and cardiovascular health. However, changes in smoking status can affect the plasma levels and efficacy of certain medications. These effects occur through pharmacokinetic and pharmacodynamic interactions and should be considered when someone starts or stops smoking, or changes how much they smoke.

Pharmacokinetic interactions

Pharmacokinetic interactions occur due to chemical compounds found in tobacco smoke, known as polycyclic aromatic hydrocarbons. These chemicals can affect cytochrome (CYP) P450 isoenzymes, key enzymes involved in the metabolism of many drugs. While various isoforms may be affected, CYP 1A2 is the most clinically relevant.

Smoking can induce CYP 1A2, resulting in increased metabolism of medications that are substrates of this enzyme. This enzyme induction can result in lower blood levels of these medicines. Therefore, people who smoke may have require higher doses to achieve therapeutic effect. When these individuals stop smoking, this effect is removed, and blood levels of affected medications may rise significantly.

Examples of medications that are substrates of CYP 1A2 include amitriptyline,

clozapine, and warfarin. Dose adjustment may be required when patients stop smoking to reduce the risk of adverse effects, particularly for drugs with a narrow therapeutic index.

While there is some variation between individuals, the median half-life of CYP 1A2 is around 39 hours. Therefore, normalisation of CYP1A2 activity can occur rapidly when patients stop smoking. If dose adjustment is required, it should be done within two to three days of smoking cessation. As many factors are involved, predicting the most appropriate dose adjustment can be challenging.

An interesting example of the potentially complex effects of smoking can be seen with clopidogrel. Clopidogrel is a prodrug that is converted to its active metabolite via oxidative metabolism involving several CYP450 enzymes. Smoking can increase this conversion, leading to a greater antiplatelet effect. Major randomised trials have found a substantial reduction in cardiovascular events in patients taking clopidogrel who smoke compared to non-smokers. This effect has been dubbed “the smoker’s paradox”. Other P2Y₁₂ antagonists, such as prasugrel and ticagrelor, have demonstrated more consistent antiplatelet effects within both smoking and non-smoking populations.

As this enzyme induction is mediated by compounds found in tobacco smoke and not the nicotine, these interactions typically do not occur with smokeless nicotine delivery methods (e.g. vapes, nicotine pouches). Patients switching from cigarettes to smokeless nicotine products may experience similar changes in drug levels as those who quit smoking entirely.

Pharmacodynamic interactions

Pharmacodynamic interactions from smoking may occur due to nicotine. Unlike the pharmacokinetic interactions, these effects can also occur from the use of smokeless nicotine products, including nicotine-replacement therapy.

These interactions are often related to the stimulant effects of nicotine. For example, smokers may require higher doses of benzodiazepines as nicotine can oppose their sedative effects. However, the clinical relevance of this is likely to be low.

Some further examples of interactions to consider when patients stop smoking are shown in Table 1.

Table 1. Drugs affected by smoking cessation

Relevance

While the benefits of smoking cessation cannot be overstated, its potential effects on an individual’s medication regime may need to be considered. This is true for patients who are intending to quit smoking for good as well as patients who may be obliged to temporarily abstain (e.g. during hospitalisation). It may also be relevant for patients who choose to transition from smoking to a smokeless form of nicotine.

Patients should be encouraged to discuss their smoking status and any intended changes to their smoking with their doctor. Dose modification may be considered for some prescribed therapies when there is a significant change in a patient’s smoking status.