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Neuropharmacology: Nicotine
 

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, ...

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 Neuropharmacology: Nicotine Presentation Transcript

    • NicotineBrian J. Piper, Ph.D.
    • Goals• Pharmacokinetics• Pharmacodynamics• Public health/epidemiology – High school – Pregnancy• Smoking cessation
    • 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
    • Metabolism Julien et al. (2011). p. 25
    • 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.
    • 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.
    • 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
    • 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.
    • 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
    • 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.
    • 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
    • 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
    • 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!
    • 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
    • But there’s good news!Doll, R. et al. (2004) BMJ, 328:1519
    • 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?
    • Epidemiology: NSDUHMtF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
    • Epidemiology: NSDUHMtF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
    • Changing Epidemiology----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
    • When does smoking start?
    • 0.5 Nicotine by Region MtF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
    • 0.6 Nicotine by Ethnicity White Latino Black
    • Nicotine x Parental Education
    • 0.6 Nicotine by College Plans
    • Nicotine byPopulation Density
    • 0.3 Chewing Tobacco x Sex
    • No Sex Differences Monitoring the Future National Household Survey on Drug Use And Health
    • 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
    • Dose Related?• Online study with Craigslist volunteers• Behavioral Rating of Executive Function Piper & Corbett (2012) Nicotine & Tobacco Research, 14, 191-199.
    • 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.
    • Child Endangerment• Toddler Smoking: 2 min• http://www.youtube.com/watch?v=x4c_wI6 kQyE
    • 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
    • The nicotinic cholinergic receptor Chantix: Alpha4 Beta2 agonist
    • 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.
    • 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.
    • Neurotransmitter Cross-Talk
    • Acetylcholine-Dopamine Interaction Smoking Not SmokingStahl (2001) p. 525
    • Insula
    • Lesions of Insula• Smoking following brain damage was examined in patients with insula damage.Naqvi et al. (2007). Science, 315, 531-534.
    • 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.
    • 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
    • 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.
    • 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.
    • Summary• Epidemiology: college plans• PK: nicotine + cotinine• PD: nACh + dopamine• Cessation: multimodal + keep trying