Neuropharmacology: Nicotine

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Lecture 12 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Focus is on pharmacokinetics, pharmacodynamics, epidemiology, and health risks

Text of Neuropharmacology: Nicotine

  • 1. NicotineBrian J. Piper, Ph.D.

2. Goals Pharmacokinetics Pharmacodynamics Public health/epidemiology High school Pregnancy Smoking cessation 3. Pharmacokinetics Nicotine: active ingredient of 1530-1600tobacco leaves half-life: 2 hours Nicotiana 1 cigarette = 9 mg Cotinine: inactive metabolite ofnicotine half-life: 20 hours 4. Metabolism Julien et al. (2011). p. 25 5. Nicotine by Route of Administration Blood nicotine after smoking 1.33 cigarettes for 9 minutes (upper left) or 2.5 g oral snuff(upper right), 7.9 g chewing tobacco (lower left), two-2 mg pieces of nicotine gum for 30minutes Hukkanen et al. (2005) Pharmacology Reviews, 57, 79-115. 6. Nicotine over 24 hours Cotinine > Nicotine Steady state during dayBenowitz et al. (1983). Circadian blood concentrations of nicotine and cotinineduring unrestricted smoking. Clin Pharmacol Ther , 34, 604-611. 7. CH3 O | || CH3 N - CH2 - CH2 O C - CH3Acetylcholine| CH3 Vagusstoff: Otto Loewi Function: movement Nicotinic ACh receptor Curare = nAChantagonistFor more details, see: http://faculty.washington.edu/chudler/chnt1.html 8. Nicotine & CognitionNicotine was administered either 20 minutes before sample (A), just after sample (B), or20 minutes before choice (C).Picture from Ennaceur, Figure adapted from Puma et al. (1999) Eur J Neuropsychopharm, 9, 323-327. 9. Smoking increases nACh Smoking increases receptorlevels in human post-mortemtissue in hippocampus (top)and thalamus (bottom).Breese et al. (1997). JPET, 282, 7-13. Non-Sm Smoker Ex-smoker 10. Smoking & MAO Monoamine oxidase is anenzyme that breaks down 5-HT and NE. Whole body PET scan ofhumans with [11C]deprenyl insmokers and non-smokersreveals differences. Self-medication? Red = high MAO Fowler et al. (2003) Proceedings of the National Academy of Sciences, 100, 11600-11605. 11. Statistics There are three types of lies: lies, damn lies,and statistics (Leonard Courtney) Absolute Risk: Rate of condition/totalpopulation studied Relative Risk: Rate of condition amongexposed divided by rate of condition amongunexposed (aka Odds Ratio)see Statistics_Primer.ppt for additional information 12. Example: Smoking & Lung-CancerNon-SmokersSmokers Death from Lung-Cancer 10 100 Non-Death from 999,990999,900 Lung-Cancer Total100,000100,000Absolute Risk of Non-Death: Smokers: 99.990% Non-Smokes: 99.999%Relative Risk: Smokers Odds of Lung Cancer Death 100/100,000 or .001Non-Smokers Odds of Lung Cancer Death of 10/100,000 or .0001 13. Example: Smoking & Lung-CancerNon-SmokersSmokers Death from Lung-Cancer 10 100 Non-Death from 999,990999,900 Lung-Cancer Total100,000100,000Absolute Risk of Non-Death: Smokers: 99.990% Non-Smokes: 99.999%Relative Risk: Smokers Odds of Lung Cancer Death 100/100,000 or .001Non-Smokers Odds of Lung Cancer Death of 10/100,000 or .0001 .001/.0001 = 10 Fold! 14. Fig 1 Survival from age 60 for continuing cigarette smokers and lifelong non-smokers among UKmale doctors born 1851-1899 (median 1889) and 1900-1930 (median 1915), with percentages aliveat each decade of age Sir Richard Doll Doll, R. et al. BMJ 2004;328:15191912-2005 15. But theres good news!Doll, R. et al. (2004) BMJ, 328:1519 16. Epidemiology: Who will smoke more? 1) 1970s versus today? 2) Region of country? 3) Parental SES? 4) College plans? 5) Urban versus rural? 6) Males or Females? 17. Epidemiology: NSDUHMtF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf 18. Epidemiology: NSDUHMtF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf 19. Changing Epidemiology---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 20. When does smoking start? 21. 0.5Nicotine by Region MtF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf 22. 0.6Nicotine by EthnicityWhiteLatinoBlack 23. Nicotine x Parental Education 24. 0.6Nicotine by College Plans 25. Nicotine byPopulation Density 26. 0.3Chewing Tobacco x Sex 27. No Sex Differences Monitoring the FutureNational HouseholdSurvey on Drug UseAnd Health 28. Smoking &Pregnancy Risks of smoking: Spontaneous abortion: 26 weeks Small size: SGA SIDS: 1 month to 1 year Behavioral issues: ADHD Smoking Cessation: NRT PK?NHSDUH, 2011 29. Dose Related? Online study with Craigslist volunteers Behavioral Rating of Executive Function Piper & Corbett (2012) Nicotine & Tobacco Research, 14, 191-199. 30. Benefits of Quitting Smoking Hypothesis:Smoking duringpregnancy, but notquitting, hasnegative outcomes Online study ofnon-smokers,smokers, quittersPiper et al. (2012). Drug & Alcohol Dependence, 121, 62-67. 31. Child Endangerment Toddler Smoking: 2 min http://www.youtube.com/watch?v=x4c_wI6kQyE 32. Smoking cessation Psychological: behavioral modification hypnosis stress-management Pharmacological: nicotine replacement therapy (NRT) Wellbutrin (Zyban): nACh antagonist, dopamineuptake inhibition Chantix: targets subtype of nACh,mixed agonist/antagonist 33. The nicotinic cholinergic receptor Chantix: Alpha4 Beta2 agonist 34. versus PfizerGSK Smokers were assigned toeither nicotine replacement(N=376) for 10 weeks (21,14,7 mg) or Chantix (N=370) for11 weeks. Most participants in bothgroups (60%+) in both groupscomplete the 1 year study Dependent measures = self-reported abstinence(confirmed by CO), weightgain, adverse effects OR = 56.9 / 43.2 = 1.70!Aubin, Bobak, Britton, et al. (i2008). Thorax, 63, 717-724. 35. But theres more > > Rates of Not quitting:Varenicline = 73.9%NRT = 79.7%Dysgeusia: an impairment in the sense of tasteAubin, Bobak, Britton, et al. (in press 2008). Thorax. 36. Neurotransmitter Cross-Talk 37. Acetylcholine-Dopamine InteractionSmokingNot SmokingStahl (2001) p. 525 38. Insula 39. Lesions of Insula Smoking following braindamage was examined inpatients with insuladamage.Naqvi et al. (2007). Science, 315, 531-534. 40. Lesions of Insula Smoking following brain damage was examined in patients with insula damage. He quit because his body forgot the urge to smokeNaqvi et al. (2007). Science, 315, 531-534. 41. Smoking cessation Psychological: behavioral modification hypnosis stress-management Pharmacological: nicotine replacement therapy (NRT) Wellbutrin (Zyban): nACh antagonist, dopamineuptake inhibition Chantix: targets subtype of nACh,mixed agonist/antagonist 42. versusPfizerGSK Smokers were assigned to either nicotine replacement (N=376) for 10 weeks (21,14, 7 mg) or Chantix (N=370) for 11 weeks. Most participants in both groups (60%+) in both groups complete the 1 year study Dependent measures = self- reported abstinence (confirmed by CO), weight gain, adverse effects OR = 56.9 / 43.2 = 1.70! Aubin, Bobak, Britton, et al. (in press 2008). Thorax. 43. 4.4 But theres more > > Rates of Not quitting:Varenicline = 73.9%NRT = 79.7%Dysgeusia: an impairment in the sense of tasteAubin, Bobak, Britton, et al. (in press 2008). Thorax. 44. Summary Epidemiology: college plans PK: nicotine + cotinine PD: nACh + dopamine Cessation: multimodal + keep trying