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NicotineNicotineBrian J. Piper, Ph.D.
Goals• Pharmacokinetics
• Pharmacodynamics
• Public health/epidemiology– High school– Pregnancy
• Smoking cessation
Pharmacokinetics
• Nicotine: active ingredient of tobacco leaves– half-life: 2 hours – 1 cigarette = 9 mg
• Cotinine: inactive metabolite of nicotine– half-life: 20 hours
Nicotiana
1530-1600
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 30 minutes Hukkanen et al. (2005) Pharmacology Reviews, 57, 79-115.
Nicotine over 24 hours
• Cotinine > Nicotine• Steady state during
day
Benowitz et al. (1983). Circadian blood concentrations of nicotine and cotinine during unrestricted smoking. Clin Pharmacol Ther , 34, 604-611.
Acetylcholine
• Vagusstoff: Otto Loewi• Function: movement• Nicotinic ACh receptor• Curare = nACh
antagonist
CH3 O | ||CH3 – N - CH2 - CH2 – O – C - CH3
| CH3
For more details, see: http://faculty.washington.edu/chudler/chnt1.html
Nicotine & Cognition
Nicotine was administered either 20 minutes before sample (A), just after sample (B), or 20 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?
Fowler et al. (2003) Proceedings of the National Academy of Sciences, 100, 11600-11605.
Red = high MAO
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
Lung-Cancer999,990 999,900
Total 100,000 100,000
Absolute 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
Lung-Cancer999,990 999,900
Total 100,000 100,000
Absolute 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!
Doll, R. et al. BMJ 2004;328:1519
Fig 1 Survival from age 60 for continuing cigarette smokers and lifelong non-smokers among UK male doctors born 1851-1899 (median 1889) and 1900-1930 (median 1915), with percentages alive
at each decade of age
1912-2005
Sir Richard Doll
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?
MtF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
Epidemiology: NSDUH
MtF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
Epidemiology: NSDUH
Changing Epidemiology
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When does smoking start?
Nicotine by Region
MtF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
0.5
Nicotine by Ethnicity0.6
WhiteLatinoBlack
Nicotine x Parental Education
Nicotine by College Plans0.6
Nicotine by Population
Density
Chewing Tobacco x Sex0.3
No Sex Differences
Monitoring the Future
National HouseholdSurvey on Drug UseAnd 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, quitters
Piper et al. (2012). Drug & Alcohol Dependence, 121, 62-67.
Child Endangerment
• Toddler Smoking: 2 min
• http://www.youtube.com/watch?v=x4c_wI6kQyE
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
• 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
versus
PfizerGSK
OR = 56.9 / 43.2 = 1.70!
Aubin, Bobak, Britton, et al. (i2008). Thorax, 63, 717-724.
But there’s more …
Dysgeusia: an impairment in the sense of taste
>
>
Rates of Not quitting:Varenicline = 73.9%NRT = 79.7%
Aubin, Bobak, Britton, et al. (in press 2008). Thorax.
Neurotransmitter Cross-Talk
Acetylcholine-Dopamine Interaction
Smoking
Not Smoking
Stahl (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
• 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
versus
PfizerGSK
OR = 56.9 / 43.2 = 1.70!
Aubin, Bobak, Britton, et al. (in press 2008). Thorax.
But there’s more …
Dysgeusia: an impairment in the sense of taste
>
>
Rates of Not quitting:Varenicline = 73.9%NRT = 79.7%
Aubin, Bobak, Britton, et al. (in press 2008). Thorax.
4.4
Summary
• Epidemiology: college plans
• PK: nicotine + cotinine
• PD: nACh + dopamine
• Cessation: multimodal + keep trying