Chester Clinic

Perearsti võimalused parandada oma 300 suitsetaja tervist

NICOTINE AND DRUG INTERACTIONS lung physician Tartu University Lung Clinic

ABRUPT SMOKING CESSATION CAN AFFECT THE METABOLISM OF DRUGS.  When patients enter hospital they may have to stop smoking abruptly if the hospital has a ‘no smoking' policy.  Cigarette smoking induces the activity of human cytochromes P450 (CYP) 1A2 and 2B6.  Decreased CYP1A2 activity after smoking cessation increases the risk of adverse drug reactions, with reports of increased toxicity from clozapine and olanzapine.  Predicting the required dose reduction of drugs metabolised by CYP1A2 after smoking cessation is challenging. Therapeutic drug monitoring should be used when possible  Nicotine replacement therapy does not influence CYP1A2 Lucas C, Martin J. Smoking and drug interactions. Aust Prescr 2013;36:102–4

NICOTINE EFFECTS:  Nicotine increases blood pressure and heart rate.  Nicotine can also induce potentially atherogenic genes in human coronary artery endothelia  Microvascular injury can result through its action on nicotinic acetylcholine receptors (nAChRs)  Nicotine elevates serum cholesterol levels, supports clot formation, and aids in plaque formation by enhancing Sabha M, Tanus-Santos JE, Toledo JC, Cittadino M, Rocha JC, Moreno H (August 2000). "Transdermal nicotine mimics
the smoking-induced endothelial dysfunction". Clinical Pharmacology and Therapeutics 68 (2): 167–74.
Zhang S, Day I, Ye S (February 2001). "Nicotine induced changes in gene expression by human coronary artery
endothelial cells". Atherosclerosis 154 (2): 277–83.
Hawkins BT, Brown RC, Davis TP (February 2002). "Smoking and ischemic stroke: a role for nicotine?". Trends in
Pharmacological Sciences 23 (2): 78–82.
Jerry JM, Collins GB, Streem D (2015). "E-cigarettes: Safe to recommend to patients?". Cleve Clin J Med 82 (8): 521–6.

THE CHEMICALS IN SMOKE MAY INTERACT  via pharmacokinetic and pharmacodynamic (often nicotine-mediated) mechanisms with:  antipsychotics,  antidepressants,  benzodiazepines,  oral contraceptives,  inhaled corticosteroids  beta blockers

 Cytochrome P450 enzymes function to metabolize potentially toxic compounds, including and products of endogenous metabolism  CYPs are the major enzymes involved inaccounting for about 75% of the total metabolism. Most drugs undergo deactivation by CYPs, either directly or by facilitat from the body. Also, many substances are by CYPs to form their active compounds.  Many drugs may increase or decrease the activity of various CYP isozymes either by inducing the biosynthesis of an isozyme () or by directly inhibiting the activity of the ). This is a major source of adverse, since changes in CYP enzyme activity may affect the and of various drugs. 1.Guengerich FP (January 2008). "Cytochrome p450 and chemical toxicology".Chem. Res.
Toxicol. 21 (1): 70–83

ENZYMES INDUCED BY TOBACCO SMOKING  cytochrome P450 (CYP) 1A1, CYP1A2 and possibly CYP2E1:  CYP1A1 is primarily an extrahepatic enzyme found in lung and  CYP1A1 high inducibility is more common in patients with  CYP1A2 is a hepatic enzyme responsible for the metabolism of a number of drugs and activation of some procarcinogens  Caffeine demethylation  significantly enhances CYP2E1 activity - this enzyme metabolises a number of drugs as well as activating some carcinogens  as measured by the clearance of chlorzoxazone. Zevin S, Benowitz NL. Drug interactions with tobacco smoking. An update. Clin Pharmacokinet. 1999 Jun;36(6):425-38.

CIGARETTE SMOKING…  induces metabolism of several drugs:  theophylline,  haloperidol,  pentazocine,  propranolol,  flecainide and  results in faster clearance of heparin, (activates thrombosis with enhanced heparin binding to antithrombin III)  Slows the rate of insulin absorption (via cutaneous vasoconstriction by nicotine) Zevin S, Benowitz NL. Drug interactions with tobacco smoking. An update. Clin Pharmacokinet. 1999 Jun;36(6):425-38

CIGARETTE SMOKING …  Due to pharmacodynamic interactions, most likely reflecting the effects of the stimulant actions of nicotine:  cigarette smoking is associated with:  a lesser magnitude of blood pressure and heart rate lowering during treatment with beta-blockers,  less sedation from benzodiazepines and  less analgesia from some opioids. Zevin S, Benowitz NL. Drug interactions with tobacco smoking. An update. Clin Pharmacokinet. 1999 Jun;36(6):425-38 CIGARETTE SMOKING CAN AFFECT THE PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES OF MANY PSYCHOTROPIC DRUGS  increase the metabolism and decrease the plasma concentrations of imipramine, clomipramine, fluvoxamine and trazodone.  The effect on the plasma concentrations of amitriptyline and nortriptyline is  Amfebutamone (bupropion) does not appear to be affected by smoking.  increased clearance of tiotixene, fluphenazine, haloperidol and olanzapine.  Plasma concentrations of chlorpromazine and clozapine are reduced  Clinically, reduced drowsiness in smokers receiving chlorpromazine, and benzodiazepines, compared with nonsmokers has been reported.  Increased clearance of the benzodiazepines alprazolam, lorazepam, oxazepam, diazepam and demethyl-diazepam is found in cigarette smokers,  chlordiazepoxide does not appear to be affected by smoking.  Carbamazepine appears to be minimally affected by cigarette smoke. Desai HD, Seabolt J, Jann MW. Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. CNS Drugs 2001;15(6):469-94.  Nicotine activates the central nervous system and this may explain the attenuated sedation observed in smokers compared to non-smokers taking benzodiazepines.  Prescribers should be aware that when patients taking benzodiazepines stop smoking, there is a risk of central nervous system depression.  attenuates nicotine withdrawal. Reducing methadone doses when the patient is trying to stop smoking could be detrimental. WARFARIN ("MAREVAN")  Smoking may increase warfarin's clearance and reduce its effect.  smoking appeared to increase the warfarin dose requirement by 12%, resulting in an extra 2.26 mg per week compared with nonsmoking.  Consequently, INR should be closely monitored when there is a change in patients' smoking status.  is highly dependent on CYP1A2 for its  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. COMBINED ORAL CONTRACEPTIVES  Smoking increases the adverse effects:  thromboembolism,  ischaemic stroke and myocardial infarction).  The combined oral contraceptive pill:  is contraindicated in women aged 35 years or older who smoke 15 or more cigarettes a day.  For smokers who use combined low-dose oral contraceptives, the attributable risk of death from cardiovascular disease is:  19.4 per 100 000 women aged 35–44 years  (vs 3.03 per 100 000 for non-smoking women of the same age). This risk is also presumed to be associated with other contraceptives containing oestrogen.  Limited data suggest no convincing association between cardiovascular disease and progestogen-only pill use. If smoking cessation is unsuccessful, non-hormonal or progestogen-only contraceptives are preferred from a cardiovascular perspective. . Schwingl PJ, Ory HW, Visness CM. Estimates of the risk of cardiovascular death attributable to low-dose oral contraceptives in the United States. Am J Obstet Gynecol 1999;180:241-9. INHALED CORTICOSTEROIDS  The efficacy of inhaled corticosteroids may be reduced in asthmatic patients who smoke, so these patients might require higher doses of inhaled corticosteroids to attain asthma control.  Proposed mechanisms of corticosteroid insensitivity include suppression of histone deacetylase expression and activity by cigarette smoking, causing inflammatory gene expression and a reduction in glucocorticoid  Clearance of corticosteroids from the lungs may be altered by increased mucus secretion or airway  Smokers may require higher doses of beta blockers. Although propranolol is a CYP1A2 substrate (), nicotine-mediated central nervous system activation may diminish the effect of beta blockers on blood pressure and heart rate.  Sub/cutaneous: Any factors that alter the rate of blood flow through the skin and fat will change insulin absorption. Smoking decreases blood flow.  Inhaled insulin (in clinical trials): The amount of insulin absorbed during the first 6 h after dosing was significantly greater in smokers; peak concentration was both higher and earlier in the smokers (time to maximal serum concentration of insulin [t(max)]31.5 vs. 53.9 min, P = 0.0003). Himmelmann A, Jendle J, Mellén A, Petersen AH, Dahl UL, Wollmer P. The impact of smoking on inhaled insulin. Diabetes Care. 2003;26(3):677.  the risk of a poor tuberculosis treatment outcome was 70% greater in current smokers compared to never smokers. Patients being treated for MDR tuberculosis had a 3-fold greater risk of a poor outcome compared to patients being treated for other forms of tuberculosis. We also found that patients who had recently stopped smoking had a lower risk of a poor tuberculosis outcome than current Medea Gegia, et al. Tobacco smoking and tuberculosis treatment outcomes: a prospective cohort study in
Georgia. Bulletin of the World Health Organization 2015;93:390-399
 Imipramine (Tofranil)  Oxazepam (Serax)  Propranolol (Inderal)  Labetalol (Normodyne, Trandate)  Prazosin (Minipress)  Theophylline (Theo-Dur, Theochron, Theolair)  Pentazocine (Talwin) Nicotine (Nicorette) Side Effects SUITSETAMISE LÕPETAMINE VÕIB PÕHJUSTADA  metabolismi aeglustumist, mille tulemusena võib vajalikuks osutuda samaaegselt kasutatavate ravimite annuse korrigeerimine. Seda peab silmas pidama ravimite juures, mida katalüüsib CYP1A2 (võimalik, et ka CYP1A1). Nendeks ravimiteks on näiteks kofeiin, teofülliin, flekainiid, takriin, klosapiin ja ropinool. Osaliselt CYP1A2 kaudu metaboliseeruvad ravimid on näiteks imipramiin, olansapiin, klomipramiin ja fluvoksamiin.  Piiratud andmed on olemas selle kohta, et flekainiidi ja pentasosiini ainevahetus võib samuti olla indutseeritud suitsetamisest.  Kliiniliselt olulisi koostoimeid nikotiini ja teiste ravimite vahel ei ole täheldatud, kuid nikotiin võib tugevdada adenosiini toimet hemodünaamikale NICOTINE IS POWERFULLY ADDICTIVE • Nicotine is as addictive as heroin or • Nicotine addiction has a neurobiological basis • 97% smokers fail to give up using THE POWER OF ADDICTION want to stop1
succeed in
stopping
each year3
try each year2
1. Bridgwood et al, General Household Survey 1998. 2. West, Getting serious about stopping smoking 1997. 3. Arnsten, Prim Psychiatry 1996.
 Smoking is a disease, classified as mental and behavioural disorder due to use of tobacco F17.25  International Statistical Classification of Diseases and Related Health Problems, WHO 1992 The addiction pathways ‘Reward' pathway
(mesolimbic dopamine system)
‘Withdrawal' pathway
(locus coeruleus)
MECHANISMS OF ADDICTION Nicotine
Nicotine
abstinence
Acute effect
Pleasure
Altered DA, NA
Tolerance
Withdrawal
Normal DA, NA
symptoms
and cravings
function
Key: DA = dopamine NA = noradrenaline Adapted from: Benowitz et al, CNS Drugs 2000. NEUROBIOLOGIC STIMULUS BY NICOTINE IN CENTRAL NERVOUS SYSTEM nicotin activates N-acetylcholine receptors Presynaptic release of dopamin ( ) Dopaminergic stimulation in mesolimbilic system COUNSELLING INCLUDES THE KNOWLEDGE OF NEUROBIOLOGIC ADDICTION  Many smokers are thinking about smoking as a way of living and believe that it is only a habit  A smoker feels euphoric directly after smoking a cigarette due to the neurobiologic stimulus of nicotine ("pipe of peace") DESIRABLE LEVEL OF NICOTINE FOR A HIGHLY DEPENDANT SMOKER Habitual concentration on nicotine PHARMACOLOGICAL INTERVENTION • Duration: 4-12 weeks (depends on severety of nicotine dependence) • Nicotine replacement therapy (NRT) • Bupropion (on prescription) • Varenicline (on prescription) NICOTINE REPLACEMENT THERAPY • Based on nicotine weaning • Increases chance of stopping by 1.6– • Smokers try different formulations • Different formulations have similar 1. Silagy et al, The Cochrane Library 1999.
FAGERSTRÖM TEST FOR NICOTINE DEPENDENCE  How soon after you wake up do you smoke your  within 5 minutes (3 points) first cigarette? 5 to 30 minutes (2 points) 31 to 60 minutes (1 point) after 60 minutes (0 points) Do you find it difficult not to smoke in places where you shouldn t (in church, school, movie,  Yes (1 point) at library, on bus, in court, hospital)? Which cigarette would you most hate to give up;  The first one in the morning (1 which cigarette do you treasure the most? Any other (0 points) How many cigarettes do You smoke each day? 10 or fewer (0 points) 11 to 20 (1 point) 21 to 30 (2 points) Do you smoke more during the first few hours 31 or more (3 points) after waking up than during the rest of the day? Do you still smoke if you are so sick that you are in bed most of the day, or if you have a cold or the flue and have trouble breathing? NICOTINE REPLACEMENT THERAPY 3-4 weeks
3-4 weeks
3-4 weekst
• mild (3…0) THE EMOTIONAL STATE QUESTIONNAIRE (EST-Q-2)  To select the quitters with major depressive episode or anxiety indicate how often each problem has bothered during the past month Contains subscales of Depression, Agoraphobia-Panic, Fatigue and Subscale of depression (cut-point >12) Not at all
Feelings of sadness Feeling no interest in Self-accusations Recurrent thoughts of death or suicide Hopelessness about the Impossible to enjoy Subscale of anxiety (cut-point >12) Not at all
Feeling easily irritated Feeling anxious or Tension or inability to Excessive worry about several different things Feeling so restless that it is hard to sit still BUPROPION SR (ZYBAN/ELONTRIL/WELLBUTRIN) • Noradrenergic and dopaminergic • inhibit the neuronal transports for dopamine and noradrenaline • potentiates their effects in the brain • an effective aid to smoking cessation Ascher et al. Clin Psychiatry1995 Martin et al. Psychopharmacology 1990 Goldstein. J Clin Psychiatry 1998 Hurt et al. N Engl J Med 1997 Bupropion HCl SR acts
s involved in
nicotine ad
a diction
BUPROPIOONI TOIME KESKNÄRVISÜSTEEMIS Bupropioon pärsib Nikotiini vajadus puudub Nikotiini vajadus Dopami nergiline stimulatsioon mesolimbilises süsteemis VARENICLINE (CHAMPIX)  Varenicline binds with high affinity and selectivity at the α4β2 neuronal nicotinic acetylcholine receptor, where it acts as a partial agonist. Its binding both alleviates symptoms of craving and withdrawal, and reduces the rewarding and reinforcing effects of smoking by preventing nicotine binding to α4β2 receptors. VARENIKLIINI TOIME KESKNÄRVISÜSTEEMIS Varenikliin aktiveerib N-atsetüülkoli ni retseptorid, samas blokeerib retseptori Dopami nergiline stimulatsioon mesolimbilises süsteemis BUPROPION OR VARENICLINE • first 3 days 1 tab. x 1 + smoking • next 4 days 1 tab. x 2 + smoking • from the 8th day 1 tab. x 2 and quit • treatment will last for 7…8 weeks (12 weeks if needed) DSM-IV DIAGNOSTIC CRITERIA FOR NICOTINE WITHDRAWAL – Dysphoric or depressed mood – irritability, frustration or anger – difficulty concentrating – restlessness – decreased heart rate – increased appetite or weight gain NIKOTIINSÕLTUVUSE JA RAVI HINNAD (EUR) 2 näd. 6 näd. Kokku (8näd) Näts "Nicorette" 20x/päevas 60 16 t plaaster "Nicorette" 24 t plaaster "Niquitin" Varenikliin "Champix" (F17) 40 Sigaretid 2.10/pakk (20sigarettti/päevas) jätkub –>
766/aastas
PROCESS OF QUITTING Primary (short term) Permanent effect

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