Tobacco Smoking “ A Pharmacological Over-view

1. Tobacco Smoking “ A Pharmacological Over-view Haider A. Ghaleb Kasr El-Aini Faculty of Medicine Cairo University Nov. 7th 2007

3. Tobacco smoking • Cigarette smoking has been the most popular method of taking nicotine since the beginning of the 20th century. • Nicotine is highly addictive. It is both a stimulant and a sedative to the central nervous system.

4. Prevalence • 1.2 billion people worldwide are known to smoke tobacco daily. • 5.6 trillion cigarettes are smoked per year. • 4.2 million people die annually from tobacco related disease. • Tobacco-related diseases will be about 10 million in 2020. 1.2 billion people worldwide are known to smoke tobacco daily. • 5.6 trillion cigarettes are smoked per year. • 4.2 million people die annually from tobacco related disease. • Tobacco-related diseases will be about 10 million in 2020.

5. EGYPT

6. Tobacco smoking and • Nicotine is absorbed readily from tobacco smoke in the lungs within 30 minutes, and it does not matter whether the tobacco smoke is from cigarettes, cigars, pipes or water pipes. • Nicotine results in an almost immediate "kick" because it causes a discharge of epinephrine from the adrenal cortex. • This stimulates the central nervous system, and other endocrine glands,which causes a sudden release of glucose.

7. Tobacco smoking and • Stimulation is then followed by depression and fatigue, leading the abuser to seek more nicotine. • Carving for nicotine increases as levels of emotional and stress increases. • When chronic smokers stops suddenly smoking, withdrawal symptoms occurs which include - Short temper - Anger - Aggression - Negative feelings

8. Tobacco smoking and Dependence • The increase of tolerance to nicotine leads to increased dependence. • In animals it has been shown that stress can directly cause relapse to nicotine self-administration after a period of abstinence. • Animals cannot discriminate between the effects of nicotine and the effects of cocaine and also nicotine self-administration sensitizes animals to self-administer cocaine more readily.

9. Tobacco smoking and Dependence • Persons suffering from withdrawal also take longer to regain emotional equilibrium following stress. • During periods of abstinence and/or craving, smokers showes impairment across a wide range of psychomotor and cognitive functions. • Research has shown that teens are generally resistant to many kinds of anti-smoking messages.

10. Mechanism of rewarding • Nicotine, like cocaine, heroin, and marijuana, increases the level of the neurotransmitter dopamine, which affects the brain pathways that control reward and pleasure. • Nicotinic receptor beta 2 as a critical component in nicotine addiction. • Mice that lack this molecule fail to self-administer nicotine, implying that without the b2 molecule, the mice do not experience the positive reinforcing properties of nicotine.

11. Major components of Lymbic System

12. Nicotine metabolism • Nicotine is metabolized in the liver to cotinine by the CYP group of enzymes. • Candidate gene studies have investigated the association between smoking and polymorphisms of genes coding for these enzymes, particularlyCYP2A6 and CYP2D6.

13. Role of enzyme CYP 2A6 • Individuals have greater resistance to nicotine addiction if they have a genetic variant that decreases the function of the enzyme CYP2A6. Individuals with an ineffective (or 'null') form of CYP2A6, are less likely to be dependent smokers. • The decrease in CYP2A6 slows the breakdown of nicotine and protects individuals against nicotine addiction. • Understanding the role of this enzyme in nicotine addiction gives a new target for developing more effective medications to help people stop smoking. • Inhibiting the function of CYP2A6, could provide a new approach to preventing and treating nicotine addiction.

14. Role of enzyme CYP 2A6 • CYP2A6 enzyme does not tell the whole story. There is unexplained gender differences in the frequency of the null enzyme and the frequency of dependence – perhaps indicating that there are alternative pathways for metabolizing nicotine. • Adding weight to this idea, there are other differences between the smoking habits of males and females. • In general, women are less nicotine-dependent and more dependent on "factors such as the sight and smell of tobacco, or the social aspects involved in smoking", according to the researchers. As a result, nicotine replacement treatment is less successful in women.

15. The Brain's Pleasure Pathway “Reward” • Dramatic changes in the brain's pleasure circuits during withdrawal from chronic nicotine use. • These changes are comparable in magnitude and duration to similar changes observed during the withdrawal from other abused drugs such as cocaine, opiates, amphetamines, and alcohol.

16. The Brain's Pleasure Pathway “Reward” • All drugs with a potential for abuse appear to (directly or indirectly) increase Dopamine (DA) activity in this pathway. • Such drugs include: alcohol, cocaine, amphetamine,nicotine, morphine, methadone, methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA or ecstasy.

17. The Brain's Pleasure Pathway “Reward” • The specific areas effected by particular drug are not always known and certainly some act on areas other than the MFB*/DA reward system. Therefore the behaviour and subjective feeling elicited by drugs which act on similar areas of the brain can differ. *Medial forebrain bundle (MFB) which links the VTA and Acb Ventral segmental area (VTA), nucleus accumbens (Acb)

18. Brain areas and pathways involved in the pleasure circuit.

19. Nicotine Alcohol

20.  Nicotine • Stimulates nicotinic receptors (a subclass of acetylcholine receptors) including the VTA dopaminergic cells which carry such receptors. • Nicotine releases DA in the nucleus accumbens. • Although nucleus accumbens neurons carry receptors for nicotine this region does not appear to be directly involved in nicotine's reinforcing effects

21. Effects of nicotine on dopaminergic neurotransmission. Nicotine increases the release of dopamine (DA). TH mediates the conversion of tyrosine to L-dopa, the precursor of dopamine; this is the rate-limiting step in dopamine synthesis. Dopamine transporter (DAT) is the site for reuptake of dopamine and regulates the amount of synaptic dopamine. COMT and MAO are involved in the metabolism of dopamine. Dopamine binds to postsynaptic receptors that mediate neurotransmission. • The genes coding for the enzymes and receptors have been studied in smoking. DR dopamine receptor.

22. Cannabinoid receptors • D9-tetrahydrocannabinol (THC), the active ingredient of marijuana, acts oncannabinoid receptors - the endogenous cannabinoid isanandamide (from the Sanskrit word "Ananda" meaning bliss). • Cannabinoid receptors are present all through the brain with few receptors in the brain stem or and spinal cord.

23. Cannabinoid receptors • The receptors are particularly dense in the hippocampus (memory processing), the cortex (cognitive function) and the basal ganglia and cerebellum (movement control).

24. Cannabinoid receptors • CB1 receptors are coupled to G proteins and are normally activate by endocannabinoids, of which anandamide and 2-arachidonylglycerol • Unlike neurotransmitters and neuropeptides, endocannabinoids are not stored in synaptic vesicles but are produced on demand and released from the cell membrane Arachidonic Acid (A.A.) of the neurons.

25. Cannabinoid receptors • CB1 receptors are found in high numbers on axon terminals of γ-aminobutyric acid (GABA)-ergic interneurons throughout the central nervous system; activation of these receptors inhibits GABA release; and GABA-ergic interneurons strongly influence the activity of dopaminergic projection neurons.

26. Nicotine

27. Prefrontal area

28. Health consequences of smoking Respiratory disease Cardiovascular disease Cerebrovascular disease Cancers Lung Oral cavity Pharynx Pancreas Kidney Urinary tract Smoking prevalence and reason for concern 15% of all cancers 80-90%of lung cancers cancer

29. Genetics • Initiation of smoking,50% • Maintenance,70% • Number of cigarettes smoked,80%

30. CYP2A6 • Variations in the activity of the primary enzyme involved in nicotine metabolism may largely explain lower smoking levels and lung cancer rates found in slow metabolizers, • Lowering the activity of the enzyme CYP2A6 in individuals with normal enzyme activity or with multiple copies of the gene may be a strategy that can help in quitting smoking or in reducing overall exposure to carcinogens in tobacco smoke

31. CYP2A6 and lung cancer • 15% of all cancers 80-90%of lung cancers • CYP2A6 can also activate tobacco smokeprocarcinogens (e.g. NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

32. Years of Life Lost Due to Smoking • Based on data collected in the late 1990s, the US Centers for Disease Control and Prevention (CDC) estimated that adult male smokers lost an average of 13.2 years of life and female smokers lost 14.5 years of life because of smoking. • It can steal the quality of life long before death. • Smoking-related illness can limit activities by making it harder to breathe, get around, work, or play.

33. NRT (nicotine replacement therapy) Nicotine gums Transdermal patches Inhalers Lozenges Sprays Bupropion (non-nicotinic pharmacological agent) Antidepressant Used in more than 50 countries as treatment of tobacco dependency. Current treatment for tobacco dependence

34. Plasma nicotine concentrations for smoking and NRT 14 12 10 8 Increase in nicotine concentration ( ng/ml ) Cigarette Gum 4 mg Gum 2 mg Inhaler Nasal spray Patch 6 4 2 0 5 10 15 20 25 30 Minutes Source: Balfour DJ & Fagerström KO. Pharmacol Ther 1996 72:51-81.

35. Decreasing “smoking behavior and risk” through CYP2A6 inhibition

36. Novel treatment strategies based on genetic manipulation • CYP2A6 • Hepatic enzyme • 90% of inactivation of nicotine to cotinine • 17 allelic variants • The allelic variants vary in the ability to metabolize CYP2A6 substances • The metabolic ratio of cotinine to nicotine is also greater in Korean than Japanese population.

37. Risk of tobacco-related cancers and mutations • Carcinogencomponents in cigarette • Tobacco specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanon(NNK) N’-nitrosonornicotine(NNN) • Polycyclic aromatic hydrocarbons (PAHs) • Aromatic amines(5-200ng/cigarette)

38. Public health implications of CYP2A6 polymorphism • Decreases risk of smoking initiation and dependence • Decreases amount smoked tobacco • Decreases risk of tobacco-related cancers and mutations

39. Slow “SMs” and Fast “FMs” Metabolizers • Start smoking 3 years later. • Smoke for shorter duration. • Have an increased probability of quitting than Fast Metabolizers “EMs” • Faster CYP2A6 metabolism has been associated with higher levels of smoking, increased failure on nicotine patch, and higher cancer risk. • .

40. Existing NRTs fail for several reasons Existing NRTs fail for several reasons • Inadequate extent of replaced nicotine compared to the nicotine of cigarette. • NRT dos not mimic the rapid rise and fall in plasma like cigarette nicotine. • Wide variation in nicotine metabolism among individuals leads to variation of nicotine concentration when an standard dose is taken. • Dermal or gastric irritation. • …..

41. How Nicotine Replacement Works • Treats the difficult withdrawal symptoms and cravings that 70% to 90% of smokers say is their only reason for not giving up cigarettes. Using a nicotine substitute, reduces a smoker's withdrawal symptoms. • Most smokers do it on the first try. • In fact, smokers usually need many tries -- sometimes as many as 8 to 10 -- before they are able to quit for good. • Most quitters go back to smoking within the first 3 months of quitting. • So don't be discouraged if the smoker start smoking again; stop again and make another attempt more successful by adding another method or technique to help you quit. • Reducing these symptoms with nicotine replacement therapy and a support technique, gives smokers who want to quit have a better chance of quitting and staying quit.

42. Nicotine replacement therapy • Nicotine replacement therapy only deals with the physical addiction • Combine it with other smoking cessation methods that help the psychological (emotional and habitual) components of smoking, such as a stop smoking program. • Pairing NRT with a program that helps to change behavior -- can double your chances of successfully quitting.

43. Nicotine Replacement Therapy • Nicotine in cigarettes leads to actual physical dependence, which can cause unpleasant symptoms when a person tries to quit. • Nicotine replacement therapy (NRT) gives you nicotine -- in the form of gums, patches, sprays, inhalers, or lozenges -- but not the other harmful chemicals in tobacco. • It can help relieve some of these symptoms so that you can focus on the psychological aspects of quitting.

44. Nicotine replacement therapy (NRT) Cont. • The 24-hour patch provides a steady dose of nicotine, avoiding peaks and valleys. It helps with early morning withdrawal. But, there may be more side effects such as disrupted sleep patterns and skin irritation. • Data suggests that nicotine replacement (specifically the nicotine patch) can be used safely even in people who have heart or blood vessel (cardiovascular) disease under a doctor's careful monitoring. • The 16-hour patch works well if the smoker is a light-to-average smoker. It is less likely to cause side effects like skin irritation, racing heartbeat, sleep problems, and headache. But it does not deliver nicotine during the night, so it is not helpful for early morning withdrawal symptoms.

45. Nicotine replacement therapy (NRT) Cont. • Depending on body size, most smokers should start using a full-strength patch (15-22 mg of nicotine) daily for 4 weeks, and then use a weaker patch (5-14 mg of nicotine) for another 4 weeks. • The patch should be put on in the morning on a clean, dry area of the skin without much hair. It should be placed below the neck and above the waist -- for example, on the arm. • The FDA recommends using the patch for a total of 3 to 5 months.

46. Some possible side effects of the nicotine patch include: • skin irritation -- redness and itching  • dizziness  • tachycardia • sleep problems or unusual dreams  • headache  • nausea  • vomiting  • muscle aches and stiffness

47. Patient’s advise What to do about side effects: • Do not smoke while you are using a patch. • Try a different brand of patch if your skin becomes irritated. • Reduce the amount of nicotine by using a lower dose patch. • Sleep problems may be short-term and pass within 3 or 4 days. If not (and you're using a 24-hour patch), try switching to a 16-hour patch. • Stop using the patch and try a different form of nicotine replacement.

48. Nicotine gum (nicotine polacrilex): • avoid acidic foods and drinks such as coffee, juices, and soft drinks for at least 15 minutes before and during gum use.

49. Nicotine nasal spray: • Smokers usually like the nasal spray because it is easy to use. However, the FDA warns users that since this product contains nicotine, it can be addictive. It recommends that the spray be prescribed for 3-month periods and should not be used for longer than 6 months.

50. Bupropion (Zyban®) • Bupropion (Zyban®) is an antidepressant in an extended-release form that reduces symptoms of nicotine withdrawal. • It can be used alone or together with nicotine replacement. • Bupropion works best if it is started 1 or 2 weeks before the quit date. • The usual dosage is one or two 150 mg tablets per day. • Contraindications : seizures, heavy alcohol use, serious head injury, bipolar (manic-depressive) illness, anorexia or bulimia (eating disorders).