Pharmacokinetic interactions of Smoking with drugs such as Duloxetine (SNRI Antidepressant), Fluvoxamine (SSRI Antidepressant), Tricyclic Antidepressants ( Amitriptyline, Clomipramine, Imipramine, Nortriptyline, etc.), Benzodiazepines (Alprazolam, Chlordiazepoxide, Clonazepam, Diazepam, Loprazolam, Lorazepam, Lormetazepam, Nitrazepam, Oxazepam, Temazepam), Antipsychotics (Olanzapine, Clozapine, Haloperidol, Thioridazine, Chlorpromazine and Fluphenazine), Opioids (Methadone, Dextropropoxyphene, Fentanyl, Hydrocodone, Oxycodone, Morphine, Nalbuphine and Pethidine (Meperidine)), NSAIDs (Diflunisal, Phenazone and Phenylbutazone), Paracetamol (Acetaminophen), Theophylline, Caffeine, Tacrine, Insulin and Warfarin are discussed in this presentation. Pharmacodynamic interactions of Smoking with drugs like Beta blockers, Benzodiazepines, Oral antidiabetics, Inhaled corticosteroids and Oral contraceptive pills are also dealt in this presentation.

1. Smoking - Drug
Interactions
Dr. P.Naina Mohamed
Pharmacologist

2. Introduction
o Many drug interactions have been
reported with cigarette smoking.
o Tobacco smoke contains the chemicals like
Polycyclic aromatic hydrocarbons (PAHs)
and Nicotine which interact with drugs
either by• Pharmacokinetic mechanisms (mostly
PAHs mediated) or
• Pharmacodynamic mechanisms (mostly
Nicotine mediated)

3. Pharmacokinetic Interactions
 Pharmacokinetic interactions of smoking may affect the absorption,
distribution, metabolism, or elimination of other drugs, which leads to altered
pharmacologic response.
 Polycyclic aromatic hydrocarbons in tobacco smoke are believed to be
responsible for the induction of cytochrome P450 (CYP) 1A1, CYP1A2 and
possibly CYP2E1.
 CYP1A1 is primarily an extrahepatic enzyme found in lung and placenta. The
patients with lung cancer have high inducibility of CYP1A1.
 CYP1A2 is a hepatic enzyme responsible for the metabolism of a number of
drugs and activation of some procarcinogens.
 CYP2E1 metabolises a number of drugs as well as activating some
carcinogens.
 The mechanism involved in most interactions between cigarette smoking and
drugs involves the induction of metabolism. Enzyme induction results in faster
clearance of medication from the body reducing serum drug levels and
decreasing efficacy.
 Such interactions may cause smokers to require larger doses of certain drugs
through an increase in plasma clearance, a decrease in absorption, enzyme
induction or a combination of these factors.

4. Insulin
Smoking interacts with insulin by both pharmacokinetic and
pharmacodynamic mechanisms to reduce its efficacy.
Smoking
Peripheral vasoconstriction which reduces absorption of Insulin from s.c
tissue &
Increase the levels of hormones opposing Insulin actions
Decreased efficacy of Insulins
•
•
•
•
Caution is advised with concurrent insulin treatment and cigarette
smoking.
Increased insulin dosages may be required in patients who smoke
cigarettes.
Conversely, a decrease in the insulin regimen may be necessary in
patients who achieve smoking cessation.
Close monitoring may be warranted.

5. Warfarin
Tobacco smoke
Induce or inhibit warfarin metabolism
Increased or decreased international normalized ratio (INR) or
prothrombin time
•
•
The effect of smoking tobacco on warfarin metabolism may
vary from one patient to the next.
The INR or prothrombin time should be monitored carefully if
the patient begins or stops tobacco use while taking warfarin.

6. Duloxetine (SNRI
Antidepressant)
Tobacco smoke
Release of polycyclic aromatic hydrocarbons
Stimulation of CYP1A2 enzymes
Increased metabolism of Duloxetine
Reduced Plasma levels
•
•
•
Smokers may have plasma levels 50% lower than nonsmokers due to
enzyme induction and increased metabolism.
Advise patients to stop smoking during treatment with Duloxetine due
to the potential reduction in efficacy.
If Duloxetine therapy is required in patients who smoke, consider
monitoring for reduced efficacy and adjusting the Duloxetine
dosage if needed.

7. Fluvoxamine (SSRI
Antidepressant)
Tobacco smoke
Release of polycyclic aromatic hydrocarbons
Stimulation of CYP1A2 enzymes
Increased metabolism of Fluvoxamine
Altered drug clearance of Fluvoxamine
•
•
•
Serum levels of Fluvoxamine is significantly lower in smokers than
nonsmokers.
Advise patients to stop smoking during treatment with Fluvoxamine
due to the potential reduction in efficacy.
If Fluvoxamine therapy is required in patients who smoke, consider
monitoring for reduced efficacy and adjusting the Fluvoxamine
dosage if needed.

8. Tricyclic Antidepressants
(TCAs)
Smoking reduces the plasma levels of Tricyclic Antidepressants like Amitriptyline,
Clomipramine, Imipramine, Nortriptyline, etc.
Tobacco smoke
Release of polycyclic aromatic hydrocarbons
Stimulation of CYP1A2 enzymes
Increased metabolism of TCAs
Reduced Plasma levels
•
•
•
Although serum levels of tricyclic antidepressants fall in smokers, free drug
levels rise, minimising the clinical significance.
Advise patients to stop smoking during treatment with TCAs due to the
potential reduction in efficacy.
If TCA therapy is required in patients who smoke, consider monitoring for
reduced efficacy and adjusting the TCA dosage if needed.

9. Benzodiazepines
Smoking interacts with Benzodiazepines (Alprazolam, Chlordiazepoxide,
Clonazepam, Diazepam, Loprazolam, Lorazepam, Lormetazepam,
Nitrazepam, Oxazepam, Temazepam) and Zolpidem and decreases their
plasma levels.
Tobacco smoke
Stimulation of CYP enzymes
Increased metabolism of Benzodiazepines
Reduced Plasma levels
•
•
•
•
Plasma concentrations of Benzodiazepines may be decreased up to 50%
in smokers compared to non-smokers.
Patients should be advised not to smoke cigarettes.
An increase in the Benzodiazepines dose should be considered for those
patients who smoke concurrently with Benzodiazepines treatment.
A decrease in the Benzodiazepines dose should be considered when a
patient treated with Benzodiazepines stops smoking.

10. Antipsychotics
Tobacco smoke interacts with Antipsychotics like Olanzapine, Clozapine,
Haloperidol, Thioridazine, Chlorpromazine and Fluphenazine and reduces their
serum levels.
Tobacco smoke
Release of polycyclic aromatic hydrocarbons
Stimulation of CYP1A2 enzyme
Increased metabolism of Antipsychotics
Reduced Serum levels
•
•
•
Several studies have shown that smokers require and are prescribed higher
doses of psychotropic medication than non-smokers.
Advise patients to stop smoking during treatment with Antipsychotics due to
the potential reduction in efficacy.
If Antipsychotics therapy is required in patients who smoke, consider
monitoring for reduced efficacy and adjusting the Antipsychotics dosage if
needed.

11. Opioids
Smoking decreases the plasma levels of Opioids such as Methadone,
Dextropropoxyphene, Fentanyl, Hydrocodone, Oxycodone, Morphine,
Nalbuphine and Pethidine (Meperidine).
Tobacco smoke
Release of polycyclic aromatic hydrocarbons
Stimulation of CYP1A2 enzyme
Increased metabolism of Opioids
Reduced Plasma levels
•
•
Reduction or cessation of tobacco use may increase the risk for
methadone toxicity (increasing sedation, confusion, and labored
breathing).
Patients who use tobacco products concomitantly while on stable
opioids may require close monitoring and dose adjustments to avoid
opioid toxicity upon reduction or cessation of tobacco products.

12. •
NSAIDs
Smoking decreases the plasma levels of NSAIDs such as
Diflunisal, Phenazone and Phenylbutazone.
Tobacco smoke
Stimulation of CYP enzymes
Increased metabolism of NSAIDs
Reduced Plasma levels
May require higher doses
• The clearance of diflunisal and phenylbutazone from the
body is greater in smokers than in non-smokers.

13. Paracetamol
(Acetaminophen)
Tobacco smoke
Release of polycyclic aromatic hydrocarbons
Stimulation of CYP1A2 enzyme
Increased metabolism of Paracetamol
Increased Clearance of Paracetamol
Reduced Plasma levels
•
•
Advise patients to stop smoking during treatment with Paracetamol due to
the potential reduction in efficacy.
If Paracetamol therapy is required in patients who smoke, consider monitoring
for reduced efficacy and adjusting the Paracetamol dosage if needed.

14. Theophylline
Tobacco smoke
Release of polycyclic aromatic hydrocarbons
Stimulation of CYP1A2 enzyme
Increased metabolism of Theophylline
Reduced Plasma levels
Higher maintenance dose needed
•
•
•
•
•
In smokers, the halflife of theophylline is reduced, clearance is considerably more
rapid, due to enzyme induction.
Smokers need higher doses than nonsmokers.
For heavy smokers the dose may need to be doubled.
Advise patients to stop smoking during treatment with Theophylline due to the
potential reduction in efficacy.
If Theophylline therapy is required in patients who smoke, consider monitoring for
reduced efficacy and adjusting the Theophylline dosage if needed.

15. Caffeine
Tobacco smoke
Release of polycyclic aromatic hydrocarbons
Stimulation of CYP1A2 enzyme
Increased metabolism of Caffeine
Reduced Plasma levels
Require higher doses
• Caffeine is highly dependent on CYP1A2 for its
metabolism.
• Smokers drink more often tea or coffee than nonsmokers.

16. •
Tacrine
Higher doses of Tacrine (Anticholiesterase) are needed to treat Alzheimer’s
disease in Smokers.
Tobacco smoke
Release of polycyclic aromatic hydrocarbons
Stimulation of CYP1A2 enzyme
Increased metabolism of Tacrine
Reduced Plasma levels
•
•
More dose needed
Advise patients to stop smoking during treatment with Tacrine due to the
potential reduction in efficacy.
If Tacrine therapy is required in patients who smoke, consider monitoring for
reduced efficacy and adjusting the Tacrine dosage if needed.

17. •
Flecainide
The therapeutic efficacy of Flecainide (Antiarrhythmic) is reduced
by tobacco smoke.
Tobacco smoke
Stimulation of CYP enzymes
Increased metabolism (O- dealkylation) of Flecainide
Increased Clearance from the body
Rdeuced therapeutic efficacy
•
•
•
Caution is advised with concurrent flecainide treatment and
cigarette smoking.
Smokers require higher doses to control arrythmia.
Monitor patients who smoke cigarettes for decreased efficacy of
flecainide, and consider dose increases as warranted.

18. Pharmacodynamic
Interactions
• Pharmacodynamic interactions alter the expected
response or actions of other drugs.
• Such interactions may increase the risk of adverse
events.
• The nicotine in tobacco is highly addictive and can
cause pharmacodynamic interactions.

19. Beta blockers
•
Smoking interacts with Beta blockers and reduces their
efficacy.
Smoking
Nicotine mediated Sympathetic activation
Increased HR and BP
Less effective antihypertensive and heart rate control effects of
Beta blockers
Smokers may need more dosage
•
•
Smoking can reduce the beneficial effect of beta-blockers on
blood pressure and heart rate.
Smokers may need larger doses due to increased clearance.

20. Benzodiazepines
• Tobacco smoke interacts with Benzodiazepines like
diazepam and chlordiazepoxide pharmacokinetically and
pharmacodynamically and reduces their therapeutic
efficacy.
Tobacco smoke
Nicotine mediated CNS Stimulation
Counteracts the sedation and drowsiness induced by
Benzodiazepines
Smokers may need higher dose

21. Oral Antidiabetics
Smoking
Impaired Peripheral Insulin action
Reduced peripheral glucose utilisation &
Increased hepatic glucose production
Decreased effectiveness of oral antidiabetics
 The effectiveness of oral antidiabetics is reduced by
smoking.

22. Inhaled corticosteroids
Smoking
Increased Oxidative stress
Reduced Histone deacetylase activity
Impaired glucocorticoid receptor function
Reduced response to corticosteroids
 Smokers with asthma may have less of a response to
inhaled corticosteroids such as Beclomethasone,
Budesonide and Fluticasone.

23. Combined oral contraceptive
pill
Smoking
Reduced Oxygen carrying Capacity of blood
Increased severity of ischemia
Increased cardiovascular risk of Oral contraceptives
 Smoking also increases the incidence of bleeding which
decreases the acceptibility of oral contraceptives.
 Oral contraceptive pills are contraindicated in 35 years or
more older women who smoke 15 or more cigerettes per
day.

24. CONCLUSION
• Numerous drug interactions exist with smoking.
• Cigarette smoking can affect drug metabolism via
pharmacokinetic and pharmacodynamic mechanisms.
• A change in smoking status may put the patients at risk of
serious adverse reactions.
• Smokers taking a medication that interacts with smoking
may require higher dosages than nonsmokers.
• Conversely, upon smoking cessation, smokers may require
a reduction of dose of an interacting medication.
• Patients should be regularly monitored with regard to their
smoking status and extent of cigarette consumption and
doses of relevant medications adjusted accordingly.

25. References
o
o
o
o
o
o
o
o
o
Stockley’s Drug Interactions, 9th edition.
Karen Baxter
http://www.micromedexsolutions.com
http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON087705
http://www.ncbi.nlm.nih.gov/pubmed/10427467
http://www0.health.nsw.gov.au/pubs/2012/pdf/tool_14_medication_in
tera.pdf
http://www.oregon.gov/oha/amh/tobacco-freedom/docs/druginteractions.pdf
http://www.health.gov.bc.ca/pharmacare/pdf/sc-interact.pdf
http://www.australianprescriber.com/magazine/36/3/102/4
http://www.merseycare.nhs.uk/Library/What_we_do/Clinical_Services/
Public_Health/Smoking_Interactions.pdf