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

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Neuropharmacology: Nicotine

  1. 1. NicotineBrian J. Piper, Ph.D.
  2. 2. Goals• Pharmacokinetics• Pharmacodynamics• Public health/epidemiology – High school – Pregnancy• Smoking cessation
  3. 3. Pharmacokinetics• Nicotine: active ingredient of 1530-1600 tobacco leaves – half-life: 2 hours Nicotiana – 1 cigarette = 9 mg• Cotinine: inactive metabolite of nicotine – half-life: 20 hours
  4. 4. Metabolism Julien et al. (2011). p. 25
  5. 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. 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. 7. CH3 O | || CH3 – N - CH2 - CH2 – O – C - CH3 Acetylcholine | CH3• Vagusstoff: Otto Loewi• Function: movement• Nicotinic ACh receptor• Curare = nACh antagonistFor more details, see: http://faculty.washington.edu/chudler/chnt1.html
  8. 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. 9. Smoking increases nACh • Smoking increases receptor levels in human post-mortem tissue in hippocampus (top) and thalamus (bottom).Breese et al. (1997). JPET, 282, 7-13. Non-Sm Smoker Ex-smoker
  10. 10. Smoking & MAO• Monoamine oxidase is an enzyme that breaks down 5- HT and NE.• Whole body PET scan of humans with [11C]deprenyl in smokers and non-smokers reveals differences.• Self-medication? Red = high MAO Fowler et al. (2003) Proceedings of the National Academy of Sciences, 100, 11600-11605.
  11. 11. Statistics • There are three types of lies: lies, damn lies, and statistics (Leonard Courtney) • Absolute Risk: Rate of condition/total population studied • Relative Risk: Rate of condition among exposed divided by rate of condition among unexposed (aka Odd’s Ratio)see Statistics_Primer.ppt for additional information
  12. 12. Example: Smoking & Lung-Cancer Non-Smokers Smokers Death from Lung-Cancer 10 100 Non-Death from 999,990 999,900 Lung-Cancer Total 100,000 100,000Absolute Risk of Non-Death: Smokers: 99.990% Non-Smokes: 99.999%Relative Risk: Smokers Odds of Lung Cancer Death 100/100,000 or .001 Non-Smokers Odds of Lung Cancer Death of 10/100,000 or .0001
  13. 13. Example: Smoking & Lung-Cancer Non-Smokers Smokers Death from Lung-Cancer 10 100 Non-Death from 999,990 999,900 Lung-Cancer Total 100,000 100,000Absolute Risk of Non-Death: Smokers: 99.990% Non-Smokes: 99.999%Relative Risk: Smokers Odds of Lung Cancer Death 100/100,000 or .001 Non-Smokers Odds of Lung Cancer Death of 10/100,000 or .0001 .001/.0001 = 10 Fold!
  14. 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 alive at each decade of age Sir Richard Doll Doll, R. et al. BMJ 2004;328:1519 1912-2005
  15. 15. But there’s good news!Doll, R. et al. (2004) BMJ, 328:1519
  16. 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. 17. Epidemiology: NSDUHMtF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
  18. 18. Epidemiology: NSDUHMtF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
  19. 19. Changing Epidemiology----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  20. 20. When does smoking start?
  21. 21. 0.5 Nicotine by Region MtF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
  22. 22. 0.6 Nicotine by Ethnicity White Latino Black
  23. 23. Nicotine x Parental Education
  24. 24. 0.6 Nicotine by College Plans
  25. 25. Nicotine byPopulation Density
  26. 26. 0.3 Chewing Tobacco x Sex
  27. 27. No Sex Differences Monitoring the Future National Household Survey on Drug Use And Health
  28. 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. 29. Dose Related?• Online study with Craigslist volunteers• Behavioral Rating of Executive Function Piper & Corbett (2012) Nicotine & Tobacco Research, 14, 191-199.
  30. 30. Benefits of Quitting Smoking• Hypothesis: Smoking during pregnancy, but not quitting, has negative outcomes• Online study of non-smokers, smokers, quittersPiper et al. (2012). Drug & Alcohol Dependence, 121, 62-67.
  31. 31. Child Endangerment• Toddler Smoking: 2 min• http://www.youtube.com/watch?v=x4c_wI6 kQyE
  32. 32. Smoking cessation• Psychological: – behavioral modification – hypnosis – stress-management• Pharmacological: – nicotine replacement therapy (NRT) – Wellbutrin (Zyban): nACh antagonist, dopamine uptake inhibition – Chantix: targets subtype of nACh, mixed agonist/antagonist
  33. 33. The nicotinic cholinergic receptor Chantix: Alpha4 Beta2 agonist
  34. 34. versus Pfizer GSK • 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. (i2008). Thorax, 63, 717-724.
  35. 35. But there’s 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. 36. Neurotransmitter Cross-Talk
  37. 37. Acetylcholine-Dopamine Interaction Smoking Not SmokingStahl (2001) p. 525
  38. 38. Insula
  39. 39. Lesions of Insula• Smoking following brain damage was examined in patients with insula damage.Naqvi et al. (2007). Science, 315, 531-534.
  40. 40. Lesions of Insula • Smoking following brain damage was examined in patients with insula damage. • He quit because his “body forgot the urge to smoke”Naqvi et al. (2007). Science, 315, 531-534.
  41. 41. Smoking cessation• Psychological: – behavioral modification – hypnosis – stress-management• Pharmacological: – nicotine replacement therapy (NRT) – Wellbutrin (Zyban): nACh antagonist, dopamine uptake inhibition – Chantix: targets subtype of nACh, mixed agonist/antagonist
  42. 42. versusPfizer GSK • 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. 43. 4.4 But there’s 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. 44. Summary• Epidemiology: college plans• PK: nicotine + cotinine• PD: nACh + dopamine• Cessation: multimodal + keep trying

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