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Nicotine moddasi va uning farmakologik ta'siri.ppt
- 1. history andnumbers ◦ probably 2nd most widely used psychoactive drug in our society ◦ just another plant waiting to be discovered ◦ used long before Columbus arrived in the “new world”
- 2. History: Nosociety that has adopted tobacco has ever given it up. Only drug of abuse that is native to the Americas. ◦ Is widely speculated that tobacco has been cultivated in the Americas since 6,000 B.C. Given to Columbus when he landed at San Salvador on Oct. 12,1492. ◦ Christopher Columbus and his crewman on their voyage to the "New World" were the first Europeans to see tobacco smoking.
- 3. formally introducedto Europe as a medicinal herb over 60 species of nicotiana but only 2 major ones;
- 4. nicotine – ◦potent poison and bitter flavor! most bugs, etc will keep away from it! ◦ tobacco leaves contain up to 10% nicotine
- 5. cigarettes –predominant form of tobacco used in US ◦ cigars, pipes, smokeless tobacco
- 6. Nationwide –estimates of 51,000,000 smokers with a large proportion considered dependent on nicotine Nationwide- estimates of 25,000,000 have tried cocaine but less than 1,000,000 daily users
- 7. Cigarette smokingis the leading cause of preventable death in the United States, accounting for approximately 443,000 deaths or 1 of every 5 deaths in the United States each year. Estimated 46 million people or 20.6% of all adults (aged 18 years and older) in the United States currently* smoke cigarettes. ◦ more common among men (23.1%) than women (18.3%).
- 8. Age 21.4% of adultsaged 18–24 years 23.7% of adults aged 25–44 years 22.6% of adults aged 45–64 years 9.3% of adults aged 65 years and older Race/Ethnicity 21.3% of Blacks (non-Hispanic) 32.4% of American Indians/Alaska Natives 9.9% of Asians** 15.8% of Hispanics 22.0% of Whites (non-Hispanic) By Education 41.3% of adults with a GED diploma 35.7% of adults with 9–11 years of education 10.6% of adults with an undergraduate college degree 5.7% of adults with a graduate college degree
- 9. State Estimates* Current smokingprevalence was highest in the following states:5 Adults West Virginia 26.6% Indiana 26.1% Kentucky 25.3% Men Indiana 28.5% Missouri 27.3% Tennessee 26.7% Women West Virginia 27.1% Kentucky 24.3% Indiana 23.9%
- 10. Data fromthe WHO
- 14. Nicotine dependence– ◦ stereotypic and compulsive patterns of behavior, ◦ positively and negatively reinforcing ◦ physical dependence smoking or smokeless tobacco responsible for 400,000 deaths/year (contrast with 6000 for heroin and cocaine combined)
- 18. classified byEPA as a known cause of lung cancer in humans irritant to eyes, nose throat, estimated ~ 3000 deaths/year to nonsmokers infants and children at greatest risk for respiratory infections, ear infections, asthma ◦ (est that 200,000 to 1m asthmatic kids have condition made worse by 2nd hand smoke – may increase risk of asthma as well)
- 19. absorption- ◦ inhalation– 90% inhaled nicotine is absorbed ◦ n average cigarette yields about 1 mg of absorbed nicotine ◦ one of the most toxic drugs known – 60 mg is lethal and death follows intake within a few minutes Symptoms: Abdominal pain, nausea, vomiting, diarrhea, headaches, decrease in blood pressure, death from suppression of breathing. Absorbed from every site on, or in, the body
- 20. absorption- ◦ onestudy found an average increase of 1.6% per year between the years of 1998 and 2005. ◦ one of the most toxic drugs known – 60 mg is lethal and death follows intake within a few minutes ◦ cigars – contains enough nicotine for two lethal doses (burning destroys much of the nicotine)
- 21. smoke oftobacco in most cigarettes is ionized (?) mouth absorption is very limited – need to inhale deeply to the highly vascularized lungs
- 22. smoke ofmost pipes, cigars (and some European cigarettes) is alkaline (and nicotine is nonionized) gum and snuff are also buffered so they are at a more alkaline pH
- 23. differences inhow nicotine is absorbed contributes to the dependence potential ◦ inhalation – very rapid ◦ oral – more slowly but longer lasting
- 24. nicotine isdistributed very quickly readily crosses the blood brain barrier ~ 7 secs ½ life is around 2 hours
- 25. Nicotine isquickly and thoroughly distributed in the body, to brain, placenta, all body fluids (including breast milk). Liver metabolizes 80–90 percent before excretion by kidneys. Elimination half-life is ~2 hours. The major metabolite of nicotine is cotinine, which is basis for tests.
- 27. Enzymes inthe CYP 450 family ◦ (mostly CYP2A6, also CYP 2B6 ◦ A major metabolite is cotinine.
- 28. All psychoactive effectsare most likely due to nicotine – some of the more carcinogenic effects are due to how we get nicotine into our body.
- 29. rewarding, pleasurableeffects ◦ how? paradoxical effects on arousal ◦ biphasic effect with increased attention at lower doses but decreased anxiety/arousal at higher doses decreased hunger and resulting weight reduction ◦ nt release and increased metabolism because of sympathetic NS activation
- 30. nACh receptors– nicotinic subtype of ACh receptors at least 17 subtypes now recognized
- 31. 4 families ofnicotinic receptors
- 32. nACh receptors– nicotinic subtype of ACh receptors where are these receptors found? ◦ PNS autonomic ns neuromuscular junction
- 33. nACh receptors– nicotinic subtype of ACh receptors ◦ fast onset; short duration; excitatory where are these receptors found? ◦ PNS autonomic ns neuromuscular junction biphasic effect ◦ low dose – stimulation; high dose – brief stimulation followed by blockade of transmission
- 34. found inhippocampus some nAChR are presynaptic and when bound may enhance excitatory input to DA neurons in reward areas
- 35. Pharmacological effects Initiallycauses nausea and vomiting by stimulating vomiting center in brain stem and sensory endings in stomach. This becomes tolerant. Stimulates hypothalamus to produce antidiuretic hormone, causing fluid retention. Reduces activity coming in from muscles, producing relaxation. Increases heart rate, blood pressure and contractility; but carbon monoxide in smoke combines with oxygen better than hemoglobin, so it decreases oxygen carrying capacity (suffocates cells). Nicotine
- 36. stimulates releaseof catecholamines, stress hormones, adrenaline, epinephrine, etc..
- 37. Constricts bloodvessels in skin, producing cold, thin, wrinkles (faster aging). Inhibits stomach secretions, stimulates bowel (laxative in nontolerant person). May increase metabolism of fat; dull taste buds. Slows stomach contractions; increases blood sugar. May improve attention/memory; although high doses may increase nervousness, tremors, seizures, panic attack. May have an antidepressant effect (i.e., are smokers self-medicating?). Nicotine
- 38. Nesbitt’s paradox: Nicotinecauses arousal and a release of epinephrine, yet most people say it relaxes them. This may be relevant to the reason people smoke. Is it simply relief from withdrawal? Does it depend on the stress of the situation? (Relaxation with high stress, stimulation with low?) Smokers report positive subjective effects if nicotine is given by smoking or intravenously, but nonsmokers do not like it. Nicotine
- 39. first smokingexperience overnight abstinence low nicotine cigarettes and behavior
- 40. smoking (almostcertainly due to nicotine) ◦ reduces risk of Parkinson’s disease ◦ reduces risk of Alzheimers schizophrenics on neuroleptics smoke in very large numbers – why? nicotine also can ◦ be neuroprotective (against ETOH WD neurotoxicity for example) ◦ suppress certain autoimmune diseases
- 41. nicotine self-administration smoking chambers primates
- 42. most surveysshow that the majority of smokers want to quit……. behavioral therapies may be important pharmacotherapy may be important neither of these (alone or together) is enough for most!
- 43. psychological dependencevs physical dependence physical withdrawal signs ◦ lower heart rate, tremors, headaches, anxiety, shorter attention span, insomnia, increased appetite, etc…. Psychological dependence
- 44. substitution andweaning
- 45. substitution andweaning ◦ nicotine patch, ◦ nicotine gum ◦ nicotine inhaler – approved in 1996
- 47. Figure 14.8 Plasma nicotinelevels Julien: A Primer of Drug Action, Eleventh Edition
- 48. other drugs ◦Zyban (buproprion) – approved in 1997 for smoking cessation originally an antidepressant (Wellbutrin) mechanism of action not well understood weak inhibitor of dopamine and noradrenaline reuptake, and has also been shown to antagonize nicotinic acetylcholine receptor function.
- 50. partial agonist/antagonist alpha4/beta2