Smoking -Drug interactions

Smoking Smoking - Drug- Drug InteractionsInteractions

Dr. P.Naina MohamedPharmacologist

IntroductionIntroductiono 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)

Pharmacokinetic InteractionsPharmacokinetic 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.

InsulinInsulinSmoking 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.

WarfarinWarfarinTobacco 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.

Duloxetine (Duloxetine (SNRI SNRI Antidepressant)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.

Fluvoxamine (Fluvoxamine (SSRI SSRI Antidepressant)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.

Tricyclic Tricyclic Antidepressants Antidepressants

(TCAs)(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.

BenzodiazepinesBenzodiazepinesSmoking 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.

AntipsychoticsAntipsychoticsTobacco 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.

OpioidsOpioidsSmoking 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.

NSAIDsNSAIDs• 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.

Paracetamol Paracetamol (Acetaminophen)(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.

TheophyllineTheophyllineTobacco 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.

CaffeineCaffeineTobacco 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 non-smokers.

TacrineTacrine• 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.

FlecainideFlecainide• 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.

Pharmacodynamic Pharmacodynamic InteractionsInteractions

• 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.

Beta blockers 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.

BenzodiazepinesBenzodiazepines• 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

Oral AntidiabeticsOral AntidiabeticsSmoking

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.

Inhaled corticosteroidsInhaled 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.

Combined oral Combined oral contraceptive pillcontraceptive 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.

CONCLUSIONCONCLUSION• 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.

ReferencesReferenceso Stockley’s Drug Interactions, 9th edition. Karen Baxtero http://www.micromedexsolutions.como http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON0

87705o http://www.ncbi.nlm.nih.gov/pubmed/10427467o http://www0.health.nsw.gov.au/pubs/2012/pdf/

tool_14_medication_intera.pdfo http://www.oregon.gov/oha/amh/tobacco-freedom/docs/drug-

interactions.pdfo http://www.health.gov.bc.ca/pharmacare/pdf/sc-interact.pdfo http://www.australianprescriber.com/magazine/36/3/102/4o http://www.merseycare.nhs.uk/Library/What_we_do/

Clinical_Services/Public_Health/Smoking_Interactions.pdf