Download Nicotine - People Server at UNCW

Chapter 7
Nicotine
History of Tobacco
• Smoking practiced
among the early Mayas,
probably in the district
of Tabasco, Mexico, as
part of their religious
ceremonies 86-161 AD
• Europeans’ first
exposure from
Columbus 1492.
Exposure was not
widespread. Tobacco
was not well thought of
at first
History of Tobacco
1560 - tobacco
introduced to
Europe
Proponents of tobacco
• Sir Francis Drake
• Sir Walter Raleigh
– Led to the
fashionability of pipe
smoking of tobacco
History of Tobacco- not completely
accepted in Europe
King James I of England
• 1604 - Pamphlet condemning tobacco
– “bewitching of tobacco”
Early 1700s Russia
– “Westernization” of people
– penalties for smoking (torture, Siberian exile,
death)
History of Tobacco- However….
By late 17th century
• Tobacco in Europe to stay
– In Western Europe, used as treatment for
migraines
– Japan & China stop enforcing prohibition of use
– Russia opens door to West
– Sultan of Turkey begins to smoke
Tobacco & Nicotine In US
• In U.S., tobacco became major commodity
in early 1600s, used as currency
• Financed Revolutionary War
– Ben Franklin promised Virginia's tobacco to
France
– Had it not been for tobacco, no French
assistance & no USA
U.S. Tobacco Use in 20th Century
Changing trends….cigarettes over other forms/usage
• New emphasis on social manners
• Public health issues of infectious disease
– decrease in chewing except in small rural towns of U.S.
• Women began smoking
– But, 1904 NYC woman arrested for smoking in public
• 1920s - “reach for a Lucky instead of a sweet”
– Promoted weight loss effects
• -cigarettes in WWI
Tobacco & Nicotine In US-Negative reactions
• 1890s - report no medicinal value for nicotine
– dropped from U.S. pharmacopia
• 1925 - 14 states banned smoking
• 1938 - study linking cigarettes & lung cancer
• 1954 - more stats relating smoking to lung cancer
& cardiovascular disease
• 1964 - first Surgeon General's report
– advised smoking shortens life expectancy
• 1988 - Surgeon General's report on smoking
– Use declined
• 2000 – Worldwide consumption on increase
Nicotine Forms
• Tobacco-Nicotiana tabacum
– (&Nicotiana rustica)
Smokeable
– Cigarette
– Pipe
– Cigar
• Leaf (Chewing)
• Leaf (Dip)
• Snuff (powdered)
– Transdermal Patch…others
Snuff
• fine tobacco powder
• European style- Pinch into nose &
exhale with sneeze (cleared head of
“superfluous humours”)
• 1700s Europe– snuff overtook smoking
as method of choice
– Started in France & spread through rest of
Europe
Snuff Tobacco
Chewing
In U.S., snuffing replaced by chewing
• Freed hands for working
• Low cost - democratic custom all could have
• “spitting” seen as nasty habit, also health
issue
– Major cause of spread of infectious disease (TB)
“Chew”
Cigar Smoking
• Tight rolls of tobacco leaves
• Flue-curing - process of heating tobacco
leaves
– changes their ph to alkaline.. increases
absorption through mucous membranes of
the mouth .
Cigar puffing
Pipe Smoking
Modern alternate forms/ routes of
administration
And of course Cigarettes
Cigarettes
• Rolls of shredded tobacco wrapped in paper
• 1614 – Invented by beggars in Seville, Spain
from scrap of cigars
• 1856 - Became popular with English soldiers in
Crimean War - Spread throughout Europe
U.S, not inclined to use it
– Public image
– Rumors of opium, arsenic laced paper, & camel dung,
– Also image:
cigarette - dainty & “sissy”
vs. cigars - fat, long & dark
Cigarettes
1881 - James Bonsack patented cigarettemaking machine
• Revolutionized tobacco industry
- From 300 cigarettes per hour by hand
to 3 machines producing 200 cigarettes
per minute
Cigarette Smoking
Nicotine in a cigarette – about 7 mg
Smoking – delivers about 1-3 mg
to the smoker about 0.7 ug/puff
Technique of smoker can increase
nicotine (time smoke is in lungs, rapid
puffing)
Pharmacology and Relationship to
Smoking
• Smoking is quickest and most efficient
way to get nicotine to the brain
– Reinforcing effects are strongest
– As nicotine blood levels fall, another puff is
taken
– Smokers may typically take about 20
puffs/cigg
– Delivering in total about 13ug/kg
Pharmacology Cont’d
• Half-life of nicotine is about 2 hours
– Metabolized mostly in the liver
• Mild withdrawal during overnight and
tolerance from previous day partially
dissipates
– Strong craving and best response in the
morning (1st cigarette)
Nicotine testing!
Nicotine Pharmacology
• Dose-dependent actionnicotinic acetylcholine
receptors
– Agonist – low doses
– Antagonist – high doses
• Although a stimulant, it
is often used to relax
– State-dependence?
• Works in CNS and PNS
Mechanisms of Action
• Direct Agonism of Nicotinic cholinergic
receptors
– Ionotropic type receptors
• When binds it opens a Na+ channel and
depolarizes the cell membrane
• May produce a secondary “Functional
antagonism”
Initial agonism may be followed by
desensitization of the nicotinic ACH receptor
Nicotine affects nicotinic Acetylcholine
receptors at the autonomic ganglia
and the NMJ to produce peripheral
effects
Peripheral Effects
• A sympathomimetic- Adrenal glands release
epinephrine and norepinephrine
• Increases heart rate, blood pressure, respiration
• A parasympathomimetic
– Increases smooth muscle (GI tract) activity
– Increases HCL production in stomach/nausea
– Chronic diarrhea, Colitis
• Body weight- appetite suppression,
increased metabolic rates
Nicotine Pharmacology- High
concentrations of nicotine binding in:
•
•
– cerebral cortex
– Thalamus
– locus coeruleus
– Hippocampus
– Cerebellum
Striatum
substantia nigra
Enhanced sensory and
cognitive processes
Disequilibrium, motor
incoordination, dizziness
Effects on Motor Performance
High concentrations of nicotine
binding in:
• Raphe Nucleus
• VTA
Mood/reward
Nicotine Binding in the Rat brain
Central Effects
• Arousal
• Improves vigilance & rapid information
processing
• Improves mental performance &
memory
• Improved motor steadiness
• Stress Reduction
• Reward?
Tolerance- to nausea, equilibrium
and motor coordination effects
• Develops rapidly
– Within the first exposure for some effects
– Can build up and dissipate over the course
of a day
– Chronic tolerance happens as well
• Dispositional Tolerance
– Some smokers clear nicotine faster
Is Nicotine Addictive?
• Self-administration- Corrigal, 1989
– Rats, mice, dogs and primates
– Adolescent v. adult exposure
Dependence- most people currently
think that:
• One of the most dependence-producing
drugs
– Pharmacology – Stimulates reward center
influences ANS
– Function – Weight control, coping with
negative affect/stress, cognitive
enhancement
– Social Factors – Friends, habit, context
Reinforcing Effects
• Mediated by activation of mesolimbic
dopamine system
• High-affinity nicotinic receptors located
in the VTA stimulate the firing of
dopaminergic neurons, which causes
increased DA release in the NA
Is Nicotine Addictive?
??Physical Withdrawal Symptoms
of Nicotine
•
•
•
•
•
•
•
•
•
irritability
impatience
hostility
anxiety
depressed mood
difficulty in concentrating
restlessness
decreased heart rate
increased appetite or weight gain
Is Nicotine Addictive… Revisited
Nicotine Is a Toxic Substance
• 60 mg
• Nicotine poisoning
– Accidental swallowing
– Excessive absorption
– Exposure to pure nicotine
• Symptoms
• CNS effects: headache, dizziness, insomnia, abnormal dreams,
nervousness
gastrointestinal (GI) distress: dry mouth, nausea, vomiting,
dyspepsia, diarrhoea
musculoskeletal symptoms: arthralgias ( joint pain) , myalgia
(muscle pain).
Health Effects of Nicotine Addiction
• Statistically higher Probability in
smokers:
• Cardiovascular Disease
– Most likely killer
• Cancer; esp lung cancer
• Chronic Obstructive Pulmonary Disease
Health Effects of Tobacco useCompounds in Tobacco
• Tar - sticky substance
– Amount varies from 12 - 16mg to 6mg
– Last 3rd of cigarette contains 50% of
tar (final puffs more hazardous)
– Prevents cilia from working, decreases
cilia escalator
– Increases carcinogens compounds to
settle on tissue rather than being
expelled
Health Effects of Tobacco use- Other
Compounds in Tobacco
Carbon Monoxide
• Odorless & tasteless, but extremely toxic
• Attaches to hemoglobin
– Hemoglobin has greater affinity for CO than
oxygen
• Accumulation of CO occurs
• Leads to asphyxiation of body
Nicotine and other agents in tobacco smoke
Positive effects of Smoking?
Stress reduction?
Positive Health effects of Smoking?
• Protection against Parkinsons disease?!
Positive effects of Smoking?
•
January 24 - Warding off disease - The authors found that both
current smokers and past smokers were less likely to develop
Parkinson's disease than people who had never
smoked. The association was stronger in men than in women and the
risk of Parkinson's decreased as the number of cigarettes
smoked per week increased, the authors note in the Annals of
Neurology.
•
Annals of Neurology, January 2005.
Conspiracy on health effects?
Smoking-related statistics may be
confounded by many factors
Coincidence of mental disease
Poly drug use- Is Tobacco the health
culprit or other illicit substances
Smoking Propaganda?
Approaches to Treatment
• Self-help
• Behavioral intervention
• Pharmacotherapy
• Combined strategies
Pharmacotherapy
• Nicotine replacement
• Clonidine
• SSRIs
• Zyban (bupropion)
At the cutting Edge! The answer?
Varenicline- Antagonist therapy
Quitting: everything works!
•
•
•
•
Nicotine gum; patch
Hypnosis
Behavior therapy
Chantix (varenicline)
• But, 6-mo follow-up: 80%
relapse; 90% with placebo…
• Mark Twain was right! Quitting is
easy….
Abstinence and genetics?
• Dr. Jed Rose, director Duke Center for
Nicotine and Smoking Cessation.
• Says by looking at specific gene
markers, scientists can reveal how well
smokers will respond to two specific
treatments -- nicotine replacement
therapy and the prescription
medication, Zyban.
Quitting
• Switch brands
• Set quit date
• Quit
Nicotine Replacement- why isn’t it
more effective?
• Nicotine gum
• Transdermal nicotine
• Nicotine aerosols
• PHARMAKOKINETICS?
Marginal
Effectiveness!
Route of Administration may be
critical…pharmakokinetics!
Or….nicotine replacement is only
marginally effective because:
• Nicotine is not the agent of addiction in
and of itself!
– Sensory qualities associated with smoking
– Social influences
– Habit formation
– And effects of nicotine
Quitting Overall
• Combination of strategies works best
• Behavioral + replacement +
pharmacotherapy
At the cutting Edge-varenicline
• cytisine, a plant alkaloid from the
plant Cytisus laburnumor golden rain
tree, used in Eastern Europe since the
1960s by smokers wanting to quit.
Following a chemical logic the scientists
simplified the molecule to make it more
workable while maintaining its binding
to nicotinic receptors.1
May 2nd, 2008 at 12:18 pm
Study Finds No Link Between
Cancer and Smoking Marijuana
Withdrawal and gender?