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history and numbers
◦ probably 2nd most widely used psychoactive drug in
our society
◦ just another plant waiting to be discovered
◦ used long before Columbus arrived in the “new
world”
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History: No society that has adopted tobacco
has ever given it up.
Only drug of abuse that is native to the
Americas.
◦ Is widely speculated that tobacco has been
cultivated in the Americas since 6,000 B.C.
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Given to Columbus when he landed at San
Salvador on Oct. 12,1492.
◦ Christopher Columbus and his crewman on their
voyage to the "New World" were the first Europeans
to see tobacco smoking.
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formally introduced to Europe as a
medicinal herb
over 60 species of nicotiana but only 2
major ones;
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nicotine –
◦ potent poison and bitter flavor!
 most bugs, etc will keep away from it!
◦ tobacco leaves contain up to 10% nicotine
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cigarettes – predominant form of tobacco
used in US
◦ cigars, pipes, smokeless tobacco
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Nationwide – estimates of 51,000,000
smokers with a large proportion considered
dependent on nicotine
Nationwide- estimates of 25,000,000 have
tried cocaine but less than 1,000,000 daily
users
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Cigarette smoking is the leading cause of
preventable death in the United
States, accounting for approximately 443,000
deaths or 1 of every 5 deaths in the United
States each year.
Estimated 46 million people or 20.6% of all
adults (aged 18 years and older) in the United
States currently* smoke cigarettes.
◦ more common among men (23.1%) than women
(18.3%).
Age
21.4% of adults aged 18–24 years
23.7% of adults aged 25–44 years
22.6% of adults aged 45–64 years
9.3% of adults aged 65 years and older
Race/Ethnicity
21.3% of Blacks (non-Hispanic)
32.4% of American Indians/Alaska Natives
9.9% of Asians**
15.8% of Hispanics
By Education
22.0% of Whites (non-Hispanic)
41.3% of adults with a GED diploma
35.7% of adults with 9–11 years of
education
10.6% of adults with an undergraduate
college degree
5.7% of adults with a graduate college
degree
State Estimates*
Current smoking prevalence was highest in the following states:5
Adults
West Virginia
26.6%
Indiana
26.1%
Kentucky
25.3%
Men
Indiana
28.5%
Missouri
27.3%
Tennessee
26.7%
Women
West Virginia
27.1%
Kentucky
24.3%
Indiana
23.9%
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Data from the WHO
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Nicotine dependence –
◦ stereotypic and compulsive patterns of behavior,
◦ positively and negatively reinforcing
◦ physical dependence
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smoking or smokeless tobacco responsible
for 400,000 deaths/year (contrast with
6000 for heroin and cocaine combined)
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classified by EPA as a known cause of lung
cancer in humans
irritant to eyes, nose throat,
estimated ~ 3000 deaths/year to
nonsmokers
infants and children at greatest risk for
respiratory infections, ear infections,
asthma
◦ (est that 200,000 to 1m asthmatic kids have
condition made worse by 2nd hand smoke – may
increase risk of asthma as well)
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absorption-
◦ inhalation – 90% inhaled nicotine is absorbed
◦ n average cigarette yields about 1 mg of absorbed
nicotine
◦ one of the most toxic drugs known – 60 mg is lethal and
death follows intake within a few minutes
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Symptoms: Abdominal pain, nausea, vomiting,
diarrhea, headaches, decrease in blood pressure,
death from suppression of breathing.
Absorbed from every site on, or in, the body
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absorption-
◦ one study found an average increase of 1.6% per
year between the years of 1998 and 2005.
◦ one of the most toxic drugs known – 60 mg is
lethal and death follows intake within a few minutes
◦ cigars – contains enough nicotine for two lethal
doses (burning destroys much of the nicotine)
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smoke of tobacco in most cigarettes is
ionized (?)
mouth absorption is very limited – need to
inhale deeply to the highly vascularized lungs
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smoke of most pipes, cigars (and some
European cigarettes) is alkaline (and nicotine
is nonionized)
gum and snuff are also buffered so they are
at a more alkaline pH
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differences in how nicotine is absorbed
contributes to the dependence potential
◦ inhalation – very rapid
◦ oral – more slowly but longer lasting
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nicotine is distributed very quickly
readily crosses the blood brain barrier
~ 7 secs
½ life is around 2 hours
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Nicotine is quickly and thoroughly distributed in the body, to
brain, placenta, all body fluids (including breast milk).
Liver metabolizes 80–90 percent before excretion by
kidneys.
Elimination half-life is ~2 hours. The major metabolite of
nicotine is cotinine, which is basis for tests.
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Enzymes in the CYP 450 family
◦ (mostly CYP2A6, also CYP 2B6
◦ A major metabolite is cotinine.
All psychoactive effects are most likely due to
nicotine – some of the more carcinogenic
effects are due to how we get nicotine into
our body.
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rewarding, pleasurable effects
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paradoxical effects on arousal
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decreased hunger and resulting weight
reduction
◦ how?
◦ biphasic effect with increased attention at lower
doses but decreased anxiety/arousal at higher
doses
◦ nt release and increased metabolism because of
sympathetic NS activation
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nACh receptors – nicotinic subtype of ACh
receptors
at least 17 subtypes now recognized
4 families of nicotinic receptors
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nACh receptors – nicotinic subtype of ACh
receptors
where are these receptors found?
◦ PNS
 autonomic ns
 neuromuscular junction
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nACh receptors – nicotinic subtype of ACh
receptors
◦ fast onset; short duration; excitatory
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where are these receptors found?
◦ PNS
 autonomic ns
 neuromuscular junction
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biphasic effect
◦ low dose – stimulation; high dose – brief
stimulation followed by blockade of transmission
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found in hippocampus
some nAChR are presynaptic and when bound
may enhance excitatory input to DA neurons
in reward areas
Nicotine
Pharmacological effects
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Initially causes nausea and vomiting by stimulating
vomiting center in brain stem and sensory endings in
stomach. This becomes tolerant.
Stimulates hypothalamus to produce antidiuretic
hormone, causing fluid retention.
Reduces activity coming in from muscles, producing
relaxation.
Increases heart rate, blood pressure and contractility;
but carbon monoxide in smoke combines with oxygen
better than hemoglobin, so it decreases oxygen
carrying capacity (suffocates cells).
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stimulates release of catecholamines, stress
hormones, adrenaline, epinephrine, etc..
Nicotine
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Constricts blood vessels in skin, producing
cold, thin, wrinkles (faster aging).
Inhibits stomach secretions, stimulates bowel
(laxative in nontolerant person).
May increase metabolism of fat; dull taste
buds.
Slows stomach contractions; increases blood
sugar.
May improve attention/memory; although high
doses may increase nervousness, tremors,
seizures, panic attack.
May have an antidepressant effect (i.e., are
smokers self-medicating?).
Nicotine
Nesbitt’s paradox: Nicotine causes arousal
and a release of epinephrine, yet most
people say it relaxes them. This may be
relevant to the reason people smoke.
Is it simply relief from withdrawal? Does it
depend on the stress of the situation?
(Relaxation with high stress, stimulation with
low?)
Smokers report positive subjective effects if
nicotine is given by smoking or
intravenously, but nonsmokers do not like it.
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first smoking experience
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overnight abstinence
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low nicotine cigarettes and behavior
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smoking (almost certainly due to nicotine)
◦ reduces risk of Parkinson’s disease
◦ reduces risk of Alzheimers
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schizophrenics on neuroleptics smoke in
very large numbers – why?
nicotine also can
◦ be neuroprotective (against ETOH WD
neurotoxicity for example)
◦ suppress certain autoimmune diseases
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nicotine self-administration
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smoking chambers
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primates
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most surveys show that the majority of
smokers want to quit…….
behavioral therapies may be important
pharmacotherapy may be important
neither of these (alone or together) is enough
for most!
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psychological dependence vs physical
dependence
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physical withdrawal signs
◦ lower heart rate, tremors, headaches, anxiety,
shorter attention span, insomnia, increased
appetite, etc….
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Psychological dependence
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substitution and weaning
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substitution and weaning
◦ nicotine patch,
◦ nicotine gum
◦ nicotine inhaler – approved in 1996
Figure 14.8 Plasma
nicotine levels
Julien: A Primer of Drug
Action, Eleventh Edition
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other drugs
◦ Zyban (buproprion) – approved in 1997 for smoking
cessation
 originally an antidepressant (Wellbutrin)
 mechanism of action not well understood
 weak inhibitor of dopamine and noradrenaline
reuptake, and has also been shown to antagonize
nicotinic acetylcholine receptor function.
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partial agonist/antagonist
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alpha4/beta2