2 University Hospital Integrated Service, Verona
Tobacco smoke: what are smokers inhaling?
In the last few years, a new health and hygiene awareness has matured, leading to healthier nutrition and life-styles. Consumers of any social and cultural level are nowadays able to read the ingredients of the product they are about to purchase and can choose based on their knowledge of potential risk factors, allergies or diet recommendations. Every package displays the “product’s information” or almost every one does. Cigarettes packages, in fact, do not. This is a paradox for a society more and more alert and sensitive about correct and salutary life-styles.
Can drugs act differently on smokers?
Tobacco smoke contains more than 4,000 substances.1 Many of these are carcinogenic, have harmful acute and chronic effects and are potential risk factors for several correlated diseases. Some of these substances, such as nicotine, cause addiction, therefore increasing the probability of smoking for many years and being exposed to the other…3,999 ones. Besides potential risks for several pathologies, smokers should be aware of the possible interactions between drugs and cigarettes, since smoking can alter the therapeutic effects of medicines, modifying their effectiveness and tolerability by acting on their pharmacodynamics and pharmacokinetics.2
Interaction between drugs and tobacco smoke cannot be neglected: about one fifth of the Italian population smokes and smokers are about 1,3 billion worldwide. Besides, in some patient categories (such as subjects treated for neuropsychiatric diseases), high comorbidity with cigarettes smoke increases the probability of unexpected reaction to therapies, meaning both effectiveness and potential adverse reactions.
The issue of drug interaction
Drug interaction generally modifies intensity and duration of pharmacologic effects. Pharmacokinetic interactions among drugs are well known as the most relevant risk factors for adverse reactions, and the principal interaction between tobacco smoke and drugs is at the pharmacokinetic level. Changes in drug’s absorption, distribution, metabolism and elimination can modify product’s effectiveness and tolerability, therefore increasing the incidence of adverse events, severe ones included.
Drug interactions with tobacco smoke are numerous since the latter affects the activity of cytochrome P450 metabolic isoenzymes. The cytochrome P450 family consists of several isoenzymes (about 30 identified to date) localized at hepatic level and, to a smaller degree, in the respiratory, gastrointestinal and renal apparatus and in the central nervous system. About seven of these isoenzymes metabolize the majority of administered drugs.
Interactions between drugs and substances are ascribable to two types of enzymatic phenomena: inhibition and induction. Inhibition takes place when a bond is common with the isoenzyme itself, with consequent competition and reduced metabolism of the less similar substance/drug. From a pharmacological point of view, this generally means higher systemic bioavailability of the less similar drug and risk of overdosing and adverse events. Induction, on the other side, consists of increased isoenzyme activity, with consequent higher metabolism, reduced bioavailability and effectiveness.
Unlike inhibition, induction can take days for becoming evident.
Smoke as a mix of substances
Which ones of the 4,000 substances contained into cigarette smoke could be responsible of drug interactions? It has been demonstrated that polycyclic aromatic hydrocarbons such as benzopyrene, anthracene and phenanthrene, gases like carbon monoxide and heavy metals such as cadmium, nickel and chrome can induce enzyme inhibition and induction.3Interestingly, nicotine does not induce relevant effects of inhibition or induction on cytochrome P450. These data are important when taking decisions about smoking cessation intervention. On the other side, the effect of the complex mix of substances contained in cigarette smoke is widely characterized by clinic relevance. Obviously, the presence of hundreds of compounds prevents a systematic analytical characterization of the precise substances responsible of relevant interactions. Anyway, smokers are always exposed to them all.
Altered blood levels for antidepressants, anticoagulants and cardiovascular drugs
The most characterized effect of smoke is the induction of the isoenzyme CYP1A2. CYP1A2 activity is much higher in heavy smokers than in non-smokers. In this case, induction depends on the quantity of inhaled smoke, therefore on the quantity of inhaled substances. Quitting smoking normalizes the CYP1A2 activity quite rapidly, usually in about one week. CYP1A2 induction corresponds to increased metabolism of drugs metabolized by this isoenzyme. At this level, the most relevant case is the antipsychotic clopazine. Interaction with smoking increases the metabolism and reduces the plasma concentration of this drug. Seven to twelve cigarettes per day are enough to reach the maximum induction, therefore needing a 50% increase in the clopazine dosage in order to keep the same plasma levels. Quitting smoking suddenly and out of medical control, then, could lead to rapid induction reversals and reduced antipsychotic clearance, with possible toxicity. It has been observed a 72% increase of clopazine levels after smoking cessation, therefore clopazine and olanzapine doses should be monitored and stabilized to about 10% reduction until the fourth day after smoking cessation.
Similar monitoring precautions are recommended for antidepressants (such as fluvoxamine – higher doses might be needed for smokers), anxiolytics and warfarin. For the latter, increased metabolism caused by interaction with smoking could lead to lower anticoagulant activity. A recent meta-analysis showed that warfarin dosage should be increased of 12% for smokers. Another class of isoenzymes affected by smoking is CYP2B6. Some cardiovascular drugs like clopidogrel and the new platelet inhibitor prasugrel are converted into active metabolites in particular by CYP1A2 and CYP2B6. The potential increase in these drugs activity for smokers has been clearly demonstrated by data, which confirm reduced platelet aggregation in treated smokers.
Information and monitoring needed
The list of drug interactions caused by tobacco smoke at cytochrome P level is long and still in progress: beta-blockers, calcium antagonists, furosemide, theophylline, corticosteroids inhalers and contraceptives. Interaction takes place even with caffeine: smokers, in fact, might need up to 4 times higher doses in order to reach the same plasma levels of non-smokers, therefore increasing the number of daily coffees 4 times! Tobacco smoke diffusion and potential passive exposition since birth contribute to making it “a normal custom” phenomenon. Therefore, besides justifying definitions (“Smoking is just a bad habit”), it is important to deepen knowledge and awareness of smoking indirect consequences.
From a pharmacologic point of view, it is essential to know smoker’s status and number of daily smoked cigarettes, therefore adjusting the pharmacologic treatment to the possible modification induced by interactions. In case of smoking cessation, good practice urges dosages’ reconsideration of the administered drugs. Anyway, quitting smoking should be the priority. Effective drugs for smoking cessation are available, such as nicotine substituted and varenicline, which, by the way, do no interact with cigarette smoke.
- IARC. World Cancer Report. Lione, IARC Press, 2003. CDI #fff#
- Aust Prescr 2013, 36:102-4. CDI #fff#
- Tabaccologia 2013;1:35-47. CDI #fff#