NURS 3325 Module 4 Discussion Medications
NURS 3325 Module 4 Discussion Medications
NURS 3325 Module 4 Discussion Medications
Another potentially detrimental health effect related to smoking that has implications for care of older adults is the potential for altering the effects of medications. Interactions can occur in people who smoke or use nicotine products (including smokeless tobacco) and in people who have recently quit smoking. Interactions can be due directly to the physiologic effects of nicotine or they may be caused by the hydrocarbons in tobacco smoke, which can affect hepatic metabolism of some medications. Additional information and examples of drug–nicotine interactions are discussed in Chapter 8.
Identify 2 medications affected by nicotine. What changes can it cause? How would you address this with your clients?
Cigarette smoking induces the activity of cytochrome P450 (CYP) 1A2 (via chemicals in cigarette smoke such as polycyclic aromatic hydrocarbons)10 and also CYP2B6.11 These enzymes metabolise several clinically important drugs (such as antidepressants and antipsychotics) (Box) and a number of procarcinogens (such as those in cigarettes).10,12
The effect of smoking on hepatic enzymes is not related to the nicotine component of tobacco. Nicotine replacement therapy does not influence CYP1A2 activity.13
Genetic polymorphisms of the CYP1A2 gene contribute to extensive inter-individual variability in drug metabolism14,15 and are associated with altered inducibility of gene expression in smokers.7,16 There are also marked ethnic differences in the distribution of CYP1A2 mutations,10,17 meaning that different ethnic groups respond differently when the patient stops smoking.
CYP1A2 activity is significantly higher in heavy smokers (more than 20 cigarettes/day) than in nonsmokers.18 This is likely to be clinically relevant for some drugs which have a narrow therapeutic index and are metabolised by CYP1A2, such as clozapine. The induction varies depending on the bioavailability of the components of cigarette smoke and the extent of inhalation.8 It is not known how the number of cigarettes smoked daily or inter-individual variation affects CYP1A2 induction,9 but heavier smokers appear to have a greater increase in the clearance of drugs.19
This enzyme induction is rapidly reversed when patients abruptly stop smoking, with a new steady state of CYP1A2 activity reached after approximately one week.20 This reduction in enzyme activity reduces clearance and increases the risk of adverse drug reactions for patients taking drugs metabolised by CYP1A2.20,21 These patients should be regularly asked about their smoking and the extent of their cigarette consumption.16
Clozapine and olanzapine
Cigarette smoking induces the metabolism of clozapine and olanzapine,22 resulting in lower plasma concentrations.7,16,21 The daily consumption of 7–12 cigarettes is probably sufficient to cause the maximum induction of clozapine and olanzapine metabolism.22 A 50% difference in the mean daily dose of clozapine needed by smokers and nonsmokers to reach a given blood concentration has been reported.23
Irrespective of smoking status, the mean oral bioavailability of clozapine is 27–47% and clozapine plasma concentrations have more than a 45-fold variability amongst individuals during chronic treatment.24 There are also large inter-patient differences in olanzapine exposure, with gender and genetic factors contributing.25
Non-smokers are at higher risk of adverse effects if treated with standard doses, suggesting that there is an interaction between smoking, olanzapine and clozapine.20,22 In one case report, a patient receiving olanzapine experienced extrapyramidal symptoms (including akathisia, akinesia and bradyphrenia) within days of significantly reducing tobacco consumption.21 Case reports on smoking discontinuation by patients taking clozapine outline effects including confusion,21 tonic–clonic seizures, stupor, coma26 or aspiration pneumonia.27
Clearance of clozapine has been shown to decrease when smoking is ceased, with a mean increase of 72% in plasma clozapine concentrations.27 It is suggested that daily dose reductions (of approximately 10% until the fourth day after smoking cessation) should be made whenever patients cease smoking during treatment with clozapine.20 Patients who resume smoking after leaving hospital may need their drugs and doses reviewed to account for this change.28 Therapeutic drug monitoring of clozapine is useful.
Antidepressants
As fluvoxamine is metabolised by CYP1A2, smokers might require higher doses than those recommended from clinical trial data.8 Smoking is not anticipated to alter the pharmacokinetics of other selective serotonin reuptake inhibitors as they are not substrates of CYP450 isoenzymes induced by smoking.8
Smokers might require higher than normal doses of the tricyclic antidepressant imipramine. They do not appear to require dose adjustments of amitriptyline, nortriptyline or clomipramine.8
Warfarin
Warfarin’s less active R isomer is eliminated to a minor extent by CYP1A2.29 Smoking may therefore potentially interact with warfarin by increasing its clearance and reducing its effect. A recent meta-analysis showed that smoking appeared to increase the warfarin dose requirement by 12%, resulting in an extra 2.26 mg per week compared with nonsmoking.30 Consequently, INR should be closely monitored when there is a change in patients’ smoking status.
Clopidogrel and prasugrel
CYP isoenzymes (including CYP2C19, 3A4/5, 1A2, 2B6 and 2C9) convert clopidogrel and prasugrel into their active metabolites, which bind irreversibly to the receptors on platelets. As smoking is known to enhance CYP1A2 activity, theoretically it could increase the antiplatelet efficacy of these thienopyridine drugs.31
An enhanced response to clopidogrel has been seen in smokers who are CYP1A2 (163CA) A-allele carriers.32 Two retrospective analyses of large randomised clinical trials of clopidogrel showed that clopidogrel might be more effective in active smokers.33,34 However, a systematic review concluded that smoking is not associated with reduced platelet reactivity in patients on clopidogrel.31 Genetic polymorphisms seem not to impact on the activity of prasugrel.31
Caffeine
Caffeine is highly dependent on CYP1A2 for its metabolism. Smokers require up to four times as much caffeine as non-smokers to achieve the same plasma caffeine concentration. Caffeine can increase the concentration of clozapine and olanzapine.35