Health disorders related to tobacco use and passive smoking

1. 9 Healthdisorders related to tobacco use and passive smoking Antigona Trofor Ph. D. M.D. Clinic of Pulmonary Diseases, University of Medicine and Pharmacy Iasi, Romania

2. Complexity of the tobacco use effect on human health • Biological effect of chemical compounds from tobacco smoke: carbon monoxide, nicotine, resin, irritants • Risks for diseases • Target organs ( respiratory, cardiovascular diseases) • Addictive nature of nicotine: social and behavioral aspects, psychological aspects

3. Scientific proofs – smoking is harmful 1) if no disease occurs: life expectancy shortens with 5-8 years! 2) if disease occurs: life expectancy shortens with 18-22 years!! 3) the adverse health effects of smoking are extensive and scientifically documented today; • There is a strong dose-response relation with heavy smoking, duration of smoking and early uptake. This reflects in higher risks of smoking related diseases and mortality. 4)Mortality related to smoking: • 1990 - 35% of deaths in men; • 2002 – 4 million deaths; • 2020 – 10 million deaths. 5) Useful for statistics: Relative Risk (RR) = risk of a smoker to develop a certain disease compared to the risk for the same disease a nonsmoker might have.

4. Biomarkers of smoking • Biochemical validation allows to estimate the systemic exposure to toxins in tobacco smoke, when studying the risks of smoking. • Evaluation: • Self – reported cigarette smoking; • Measurement of expired CO; • Determine cotinine (nicotine’s metabolite which is an objective proof of its presence in the body) in saliva, urine, blood, hair, cervical fluid; • Elevated levels of serum thyocianate. M.S. Jaakkolla, 2000

5. Smoking and health • Short-term effects: • Psychoactive: memory, energy, disposal, emotions, attention, behavior, sleep disorders; • Increasing heart rate and arterial pressure; • Peripheral vasoconstriction; • Increasing respiratory rhythm. • Long-term effects: • Respiratory diseases; • Cardiovascular diseases; • Ophthalmological, digestive, oral, urinary and osteoarticulary diseases; • Different cancers; • Reduces immunity; • Negative consequences on fertility, pregnancy and foetus.

6. Health disorders related to active smoking - classification I. Severe diseases in which smoking is a certain risk factor • Chronic obstructive respiratory disorders (chronic bronchitis, emphysema); • Cardiovascular diseases: ischaemic heart disease, strokes, arterial aneurysms, systemic arterial hypertension, peripheral arteriopaty • Cancer : lung, larynx, oesophagus, throat and mouth, etc. II. Diseases in which smoking is considered a possible risk factor or inhibits a good clinical evolution • Bronchial asthma; • Infectious respiratory diseases: pneumonia, TB, etc; • Other cancers: bladder, gastric, genito-urinary, pancreas; • Cardiovascular diseases: cardiac disrhytmias, sudden death, Alzheimer disease, leukemia, cataract, peptic ulcer, anxiety, periodontal disease,etc.

7. Chronic obstructive pulmonary disease (COPD) Smokers are at higher risk of decreased FEV (7-33ml/yr) in a dose-response relationship; • RR of COPD is 12,7 for smokers; • COPD occurs 6 times more often smokers, but only 20%of smokers develop COPD, due to genetic determinants (α1 - antitripsine gene, α2 -macroglobuline genes, vitamin D - coupling gene) and phenotypic susceptibility (sex, bronchial hypersensitivity and atopy); • Besides smoking, other causes of COPD: - Environmental risk factors in childhood + low socioeconomic status; - Prenatal smoke exposure; - Air pollution - Repeated respiratory infection - Occupation Ng.TP,Hui KP - 1993

8. Tobacco smoke COPD • Active chemical compounds (toxic and irritants) from smoke induce inflammatorychanges in the airways, in the lung parenchyma (neutrophilic infiltration, alveolitis) with damage of the strucural and cellular defense system impairment of the mucociliary clearanceof the airways.

9. COPD • Survival was estimated to 50%, at 5-10 yrs, when diagnosis revealed • FEV < 1l survival can be 1-3 yrs; • Smoking cessation – real benefit in COPD, as if not, COPD can become the third leading cause of death in 2020! Advantages of smoking cessation in COPD • Even late cessation is benefic; • Decreasing severe exacerbation rates; • Better efficacy of bronchodilater inhaling therapy; • Lower risk of associated cardio-vasculary complications; • Decreasing COPD mortality. Realproblem! Smokers with COPD, continuing to smoke. Usually they are heavy smokers, heavily addicted, males, low in come, poor education and not willing to quit. Petty TL, 2000

10. Cardiovascular diseases (1) • Nicotine • Both nicotine and carbon monoxide contribute to development of ateromatous plaques, which lead to a decreased elasticity of the arteries and opposing a higher resistance to blood flow. Andrikopoulus G, 2003 • Consequence ATEROSCLEROSIS– basis of future cardiovascular dysfunction Discontinuing blood flow (obstruction) in the vessels Blood vessels HTA, circulatory peripheral defficiency, arterial aneurysms Brain vessels: strokes Heart vessels (coronares)ischaemic heart disease

11. Cardiovascular diseases (2) 1. Systemic arterial hypertension – vascular (capilar) spasm leading to paroxistic blood pressure risk. 2. Peripheral obliterative arteriopaties Carbon monoxide from tobacco smoke is responsive for the lack of oxygen delivered to brain and muscles. As a result of peripheral circulatory disorders, arteritis occur. 3. Ischaemic heart disease • Smoking is incriminated in 81% cases due to Nicotine– producing great amount of cathecolamines which results in increased blood hypertension and high heart rate Carbon monoxide - a negative role in oxygen intake to the brain, heart and skeletal muscles vessels: • 1/3 of deaths by cardiovascular diseases are atributed to smoking; • RR for ishcaemic coronaropathy is 1,6; • Favourable action: hyperlipidemia, hereditary factors, arterial hypertension; • The risk of heart attack is double over 60 yrs but can be five fold increased for under 50 yrs. Andrikopoulus G, 2003

12. 4.Strokes • Cerebro-vascular disturbances occur when systemic aterosclerosis (expressed also at the carotid artery) goes together with systemic arterial hypertension. • The disease is polimorphic: • transitory cerebral ischaemia; • silent brain infarctus; • strokes; • cerebral haemorrhagic accidents. 5. Aneurysms Fogari et al, 1997 • Smokers develop aortic aneurysms 5 timesmore frequently, especially when heavy smokers, deep inhalers, with diastolic hypertension over 100 mmHg.

13. Active smoking and cancers • Over 30% of deaths by different cancers are attributed to smoking. • Main forms: lung, larynx, oesophagus, trachea, oral cavity. • RR Major RR for lung cancer - 15, superior airways- 24. Partial RR for oesophagian cancer:7,5.

14. Active smoking and cancer of the larynx • Smoking is related to laryngeal cancer in 84%. Other risk factors:age (over 55), sex (4 times more frequent in men), black race, family history of head and neck cancer, occupation (exposure to nickel or asbestos, alcohol abuse). • Prevalence in USA: 10.000 cases/year. • Cancer can locate any segment of the larynx: vocal cords and glottis, supra or subglotic. Mainly, lesions begin in the glottis,then develop and invade locally the basic part of the tongue and then the lungs. • Complexity and gravity of the clinical evolution, as larynx caters many functions: swallowing, breathing, talking.

15. Lung cancer and active smoking • Evidence based causal relationship – over 39 years (early case control and prospective cohort studies. • Origin: • 2 reference studies – smoking is the main cause in LC (Wynder&Graham, JAMA- 1950; Doll&Hill- BMJ, 1952) • 40 years of follow-up of smokers in a prospective cohort study of male British doctors- showing the impact of smoking on longevity and pathology at different levels of exposure (Doll&Peto, BMJ, 1994) • Obvious dose-response relationship between tobacco exposure and development of lung cancer : in Western countries risk for LC is 90% in males smokers and 80% in females smokers. The risk is lower in poor countries Also, the risk is reduce to those smoking <5 cig/days and increasing with the amount of cigarette. • Carcinogens in tobacco smoke; • Only 10-155 of the smokers develop LC - genetic factors: glutation transpherase, polymorphism, enzymatic equipment of CRS P456, tumoral mutations of p 53, genetic –induced nicotine dependency). • Risk is higher in relatives of patients with LC (RR= 2,4) and descendents of LC patients (RR = 5)

16. Lung cancer incidence is influenced by • Tobacco consumption • Gender – RR: m/f = 1 / 2-4 1/1 1,2 - 1,7/1 (1950-1960) ( 1970-1980) (1990-2000) - Women: lower risk: start later, inhale less deeply, smoke few. • Type of tobacco • The yield of cigarettes • filtered/ nonfiltered (RR is 2 in men and 2,5 in women) • Pipe, cigars, narguile • Light, ultralight, menthol cigarettes, long, super long. • Race • Passive smoking • CessationOutdoor associated pollution • Diet • Genetic protection

17. Oral cancer and active smoking (OC) • Incidence of (OC) varies: 2-18 times for smokers vs NS with a median fourfold increased risk • Great risk for users of smokeless alcohol consumers: ¾ of OC occur in both tobacco and alcohol consumers; • OC = 3% of all cancers with a M/F ratio of 2/1; • Most common type: squamous cell carcinoma(9 of every 10 oral malignancies) • 2/3 occur in the oral cavity and one third in the pharynx. Most frequent locations: tongue (20%), gingiva, mouth’s floor, lip (11%), salivary gland (8%). • Direct relationship with duration and intensity of tobacco exposure. • Important involvement: cigar and pipe users.

18. Smoking considered a risk factor in bronchial asthma (BA) • Negative role of tobacco smoke • Irritative compounds; • Susceptibility to respiratory infections; • Chronic inflamation and bronchial obstruction; • Reducing aerian flow. • Indirect proofs: • Intensifies symptoms and increases exacerbation rates; • Passive smoking – as trigger; • Higher incidence of (BA ) in children with passive tobacco exposure • Clinical observations • increased frequency of BA in a dose- response relationship; • Lung Health Study - improvement of Clinical state after Smoking cessation • Contradictory data: increasing BA incidence after cessation (Withdrawal symptoms and subjective factors) Jaakkola MS, 2000

19. Active smoking and respiratory tract infections structural level cellular Chemical substances in tobacco smoke damage human defense mechanisms at • Morphological changes in the great airways – reconstruction of the bronchial mucosa in 10-20years: • nonciliated metaplastic epithelial cells, enable to remove small particles, microorganisms or mucus; • alterated composition mucus; • Neutrophilic infiltration in airway mucosa; • Inflammatory reaction with other bronchial mucosa cells: monocytes, lymphocytes; • Intensive alveolar inflammatory reaction. Consequence Local inflamation • Pneumonia • Bronchitis • Infectious exacerbations of chronic respiratory disorders • Predisposal to pulmonary TB More frequently SMOKERS

20. Spectrum of respiratory tract infections in adults smokers Smoking • frequent risk factorin community acquired pneumonia (CAP) (RR –2 and 3,15 heavy smokers) • Cessation decreases risk to 50% after 5 years • CAP: • atypical pathogens: Legionella, Chlamidia; • associated with smoking related chronic diseases: Gramm negative (Pseudomonas) or Pneumococcus, high risk of bacteriemia • significant risk for severe pneumonia • strongest independent risk factor for invasive forms of respiratory infections in immunecompromised hosts

21. Chronic bronchitis: - 50% of heavy smokers (10-20% of them develop chronic airflow distruction) - reccurent infections exacerbation • COPD high rates of infections exacerbation result in worsening COPD symptoms increasing airflow obstruction, sputum production overall decline of quality of life Usual acute exacerbation: Streptococcus pn., Haemophilus infl., Moraxella catarrhalis Severe forms FEV<35% , Enteric bacteria, Pseudomonas species

22. Impact of active smoking an pulmonary TB • Higher risk to develop TB especially in heavy smokers • Comorbidity: alcohol, psychiatric disorders, diabetus • unfavourable/delayed clinical outcome

23. Active smoking and other cancers • Gastric cancer (72%) in smokers– other risk factors: alcohol, diet; • Bladder cancer • Pancreas – 3 times more frequent in smokers • Genito-urinary renal urinary bladder col uterin double risk for smokers Current Science, vol 81, no 5, september 2001

24. Active smoking and other cardio-vascular disorders • Cardiac Disrhytmia (especially in association with coronaropathya) • Sudden death – 3 times more frequent in heavy smokers • Obliterative trombosis, obliterant trombangeitis (Buerger) • Carotidian stenosis (especially when also hipercholesterolemia and arterial hypertension present)

25. Ocular effects of active smoking • Cataract • Especially in young people (cadmium) • Macular degeneration of the aged • Decrease in visual capacity Surgeon General’s Report 2004

26. Bones and active smoking • Osteoporosis • Risk of fractures: hip Endocrine and metabolic disorders and smoking • Diabetus mellitus • Hypothyroidism Surgeon General’s Report 2004

27. Other health disorders attributable to active smoking • Alzheimer disease: smoking + family history + genetic predisposal to develop dementia • Leukemia: carcinogens- benzen, toluen, 1-3 butadien achroleyne Gastric: • ulcer peptic • infections with Helicobacter pilori • Hepatic – increasing pressure in the portal veine • Neuropsychiatric: • anxiety- direct relationship to smoking • schizophrenia, dysphoria, personality, memory or executory functions disability Trofor A., Radu-Loghin C., 2004

28. Tobacco effects in the mouth • Leukoplakia • Smoker’s palate (nicotine stomatitis) • Smoker’s melanosis: • Tooth loss (67%) in S vs NS • Tooth abrasian: Pindborg J.J et al, 1980

29. Periodontal disease ( all conditions including supporting structures of the tooth) • destructive periodontitis (pocketing, bone loss and dental calculus) • acute necrotizing ulcerative gingivitis (ANUG) • focal gingival recession with periodontal attachment loss • Other tobacco-associated oral conditions • gingival bleeding; • dental calculus; • leukoedema: • hialitosis; • chronic hyperplastic candidiasis (some studies suggest increased frequency of oral Candida albicans in smokers hairy tongue (in heavy smokers) • Possible tobacco-associated conditions • dental caries • dental plaque • salivary changes • reduced taste and smell acuity

30. Aesthetic conditions related to active smoking • Yellow nails • Yellow teeth • Wrinkles • Tooth stains • Hypersalivation

31. Active smoking and sexual life decrease of sexual potency • Men: over 45, heavy smokers: • Women: Secondary amenorheea Early climacterium (2-5 years) Infertility; Interactions to contraceptives Pregnancy difficulties: spontaneous abortion, premature delivery, Low birth weight newborns, etc Reduced fertility (number and motricity of spermatosoides)

32. Abnormal conditions which incriminate active smoking as a potential risk factor • 1) Decreased serum bilirubine (known as an endogenous antioxidant) especially in men, heavy smokers, no filtered cigarettes; • 2) Intensive eosinophilic inflammatory reaction in heavy smokers revealed by increasing eosinophils in BAL bronchial hiperresponsiveness • 3) EEG – modifications: nicotine in cigarettes amplifies electroenceplalogram’s frequency and produces a decrease in waves (denicotined cigarettes, releasing tar and very low levels of nicotine decreases spectral frequency of EEG) Conclusions: Nicotine uptake in cigarette is influencing normal rhythm on EEG, directly related to precocious registration of the brain’s activity during smoking • 4) Visual activity Nicotine is believed to improve space visual accuracy in smokers Smoking cessation determines loss of this capacity. Pascale GA et al; Pickworth WB, Hatakeyama Y. et al

33. Is cigar a better option? • Almost the same spectrum of disease with certain particularities • RR is 2 for COPD; 1,5 for cardiovascular disease; 2,14 for lung cancer and 4 for superior aero-digestive neoplasms. • Dependency • Dimensions of the cigar can influence amounts of toxic compounds in cigar smoke,especially amonium and nitrates, also cadmium. Great concentrations of nitrates depends on the maturation processes tobacco leaves cigars are made of. Undergo. • Specific risk: • Oral, oesophagus, pharynx, larynx cancers • Pancreatic cancers; • Stomatitis (due to iritative action of the heat burning cigar produces, as it persist longer in the mouth • Dental cavities; • Tooth trauma • Lung cancer risk: compared to non smokers - LC risk is 1,9 times bigger in pipe smokers, 3 times bigger in cigar smokers and 16 times higher in cigarette smokers (Higgris and col. ,1988) • Advantages: • Occasional smokers • Rarely deeply inhaling smoke in lower airways

34. What about pipe? • Risk of lung, oral, tongue cancers • Decreased mortality: SUA: 1991 1995 deaths – pipe/year, 400000 deaths- cigarettes/ year • Advantages: • less dependent to nicotine; • Special relation – aesthetic factors (pipe, tobacco taste and flavour; • Costs; • Complexity and significance of the smoking behavior; • Easy to quit; less withdrawal symptoms

35. Narguile - a new trend? • Advantages: • washing tobacco process removes a lot of toxic compounds, as acroleine, aldehides, tar-fraction constitutes, phenols; • Less nicotine lower dependency; • More pleasure to smoke, flavoured, less toxic (recreative smoking); • Disadvantages: • Dangerous concentration of carbon monoxide (better to smoke outside) • Risk of “ mouth to mouth” contamination.

36. Passive smoking (involuntary smoking, second-hand smoking) History • 1970: first data- children and spouse’s exposure to tobacco smoke; • 1980: - contradictory data - heterogenic methodology of studies and lack of commonly accepted criteria of scientific quality in order to include data in such pooled analysis; Definitions: • Passive smoking: exposure of a person to tobacco combustion products from smoking by others. Also • Exposure of a foetus to tobacco combustion products from active and passive smoking by the mother.

37. Passive smoking ETS (85%) • Exhaled mainstream smoke: tobacco smoke generated during puff (15% inhaled from the burning tobacco product. This goes in to the smoker’s lungs and then goes aut exhaled in the environment; • Sidestream smoke (85%) is composed of Smoke compounds which diffuse through the paper covering tobacco products Smoke released in the air directly during burning tobacco product • ETS can be inhaled at work, at home, different closed public spaces. • Sidestream’s toxicity is due to great concentration of noxious chemicals (10-40 times more > mainstream) • Why? • Lower temperature of combustion • Poor oxygen distribution for burning • Greater duration of the break s between puffs

38. Constituents of ETS according to us environmentalProtection agency (US – EPA) Eur Respir Mon, 2002, 15, 323.European Respiratory Monograph

39. Assessment of ETS exposure • Questionnaires; • Measurements of cotinine in body fluids; • Risk of exposure, ventilation of the room, volume of air in the room; • Toxic compounds are nearly the same in mainstream and sides team smoke, but in different amounts, as the burning conditions are not equal. Most of those substances (including carcinogens) are found in side stream smoke at high levels, but we must be aware that side stream smoke is also diluted in a larger volume of air.

40. Lung cancer and passive smoking • 1981 – first association between exposure to tobacco smoke and lung cancer (wives of smokers: Japan and Greece) • 1986 – 3 similar studies coming from US Surgeon General - 18 published undoubtable results about capacity of ETS to induce lung cancer. • Thus, ETS became one of the KNOWN HUMAN CARCINOGENS. • 1999 – about 40 studies debated the issue. Conclusions were influenced by the including criteria, as passive exposure was assessed depending on: • Exposure at work, at home in social circumstances; • Exposure from different origins in adulthood; • Exposure from childhood; • Cumulative exposure. Martinet Y, 2003

41. Asthma and passive smoking Can ETS exposure contribute to asthma development? • 5 studies revealed increased risk for asthma, especially related to work tobacco smoke exposure, with on without home exposure • Greer (1993) USA - asthma diagnosis after 10 years of exposure at work OR = 1,45 (10-100% young adults + 40-60% older adults); • dose-response relationship - HU (1997) USA increased risk with number of parents smokers; NG (1993) Singapore – in relation to heavy vs, light exposure; Lenenberger (Swiss) 1994 in relation to nr. hours of exposure/ day. • 2 studies – no relevant association • Confusion – objective diagnosis of Asthma vs. self reporting diagnosed asthma. Conclusion • ETS may cause Asthma in adulthood • Role of irritants in tobacco smoke chronic inflammation; • Tobacco smoke is responsive for increased permeability of bronchial epithelium to allergens, leading to secondary allergic reactions. Barnes DE, Bero LA, 1998

42. Effect of ETS on respiratory chronic and acute symptoms, in the absence of any defined respiratory disease • Acute iritative symptoms of the nose, throat, lower airways (more evident in atopic patients). Some patient may by allergic to tobacco leaves. • Chronic symptoms: cough, sputum, dyspnoea, wheezing with an excess risk of 30-100% due to ETS exposure. • Symptoms are variable according to: nr. of hours of exposure, nr.of smokers producing ETS in a room, duration of ETS exposure (years)

43. Impact of ETS on lung function • Lebowitz (1984) USA: follow up of 2 years: 229 adults: no significant relationship between PEF and ETS even in asthmatic patients! • Studies considering both home/workplace exposure, quantified actual level of exposure and child hood ETS exposure to reveale influence of ETS on lung function. Conclusion: inconsequence of data more relevant significance of ETS role if adulthood exposure is correlated to early/childhood e exposure ( mother + spouse) Thus, late adulthood ETS exposure seems not to dangerous, but during lung maturation period. Cunningham J et al, 1994

44. Cardiovascular risk and passive smoking • 2 - 4% time folds more frequent vs. never smokers • 50% risk for myocardial infarctisationAssociated risk factors: • Arterial Hypertension • Diabetus mellitus • Hyperholesterolemia Glantz SA et al, 1991

45. ETS exposure in childhood • 1970: first alarm : effect of passive smoking on respiratory disorders in children. • 1992: US report – causal relation ETS –illness in low respiratory tract. • Overview of 38 studies: conclude: ETS exposure in infancy and first years of life by parental smoking generate lower respiratory illness • Wide spectrum: • Bronchitis, pneumonia, • Bronchiolitis (involving respiratory syncityal virus infection), • Wheezing related disorders • OR for: • lower respiratory tract infections diseases: 1,54 (if either parent smokers) • Wheezing related disease: 1,55, but 2,09, respectively 1,53 if mothers smoke. • Great susceptibility to ETS in children – especially to infants and early childhood. If low birth weight or lack of breast feeding is added – greater impact of ETS. • Parental/family exposure: more influent - mother than father (other family members): smoking, mother's smoking during pregnancy Casale R. et al., 1991

46. ETS role in causing respiratory symptoms in children • One parent smoker risk for wheezing (24%), cough (40%) • Attention: • Respiratory infections contagious from ill smoking parents! • Teenagers smoking without declaring! • Atopy Adjustment

47. ETS exposure’s role on lung function in children • Several studies suggest the importance of the “in utero” exposure to maternal smoking during pregnancy: small FEV deficits observed at school-age children. • Addictive effect: parental smoking after birth, assessed by objective follow-up of lung-function growth in children. • Poor prognosis: children with initially low values of lung function; • Male children more vulnerable than female children; • Dose-response relation. Lodrup Carlsen KC. et al, 1997, Sherrill D et al, 1998

48. Pharmacologic therapy of nicotine addiction

49. Classification • Treatment with nicotinic substituents • Bupropion • Varenicline • Mecamylamine • Glucose • Antidepressives: Nortriptyline • Clonidine • Rimonabant • Nicotinic vaccine

50. Treatment with nicotinic substituents (TSN) General landmarks: • a logical solution: the body continues to receive the NICOTINE, but from another source. • the absorption is mainly venous: more reduced blood level of NICOTINE, cerebral delayed affectation (minutes) • duration of therapy: 3-6 months • side effects: minimum