neuropharmacology: nicotine

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