Nicotine

Chapter 7

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 EuropeU.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 cigarette-making 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

action- nicotinic 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

Effects on Motor Performance

Disequilibrium, motor incoordination, dizziness

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 Symptomsof 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, nervousnessgastrointestinal (GI) distress: dry mouth, nausea, vomiting, dyspepsia, diarrhoeamusculoskeletal 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 use-Compounds 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  

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Withdrawal and gender?