1. Pharmacology of Nicotine
Colleen Miller
Lesley-Ann Giddings

2. What is nicotine? plant alkaloid derived from nicotinic acid
Nicotine is an alkaloid. Alkaloids are a group of compounds that are typically produced by plants to discourage animals from eating them.
Nicotine commonly comes from the tobacco plant
There are 66 other plants from which nicotine can be obtained.
These plants are apart of the nightshade family (include eggplant, tomato, potato, green pepper)
Free-base nicotine is used as an insecticide since it is highly poisonous and reactive with oxygen and other chemicals, destroying cells and tissues.
1) Nicotinic acid+SOCl2, heat  C6H4ONCl
(nicotinoyl chloride) 
2) Nicotinoyl Chloride +C2H5OCH2CH2CH2CdCl  C11H15O2N 
3) C11H15O2N+NH3, H2, catalyst  C11H18ON2
4) C11H18ON2+HBr+strong heat  C9H12N2+ethyl bromide 
5) C9H12N2+CH3I, NaOH  C10H14N2
((+)-nicotine)
6) ( + )-nicotine + (+)tartaric acid  2C14H20O6N2
7) C14H20O6N2+NaOH  (-)-nicotine+sodium tartrate

3. How does nicotine act on receptors?
nicotinic acetylcholine
receptors
mimics acetylcholine
(agonist)
opens ion channel
depolarizes
There are 2 types of neuronal nicotinic receptors, cns and pns (alpha-bungarotoxin). These are ligand gated ion channels.
Nicotine binds to these receptors that are located on nerve terminals or on axons on cell bodies
alpha-bungarotoxin, polypeptide that binds irreversibly to nicotinic receptors with a high binding affinity
Nicotinic acetylcholine receptors are made up of alpha and beta subunits that form a pentameric motif
Different combinations of these subunits have different effects in the body.
interferes with the binding of acetylcholine, binds to the receptor which then opens the ion channel releasing sodium into the cell.
Depolarization causing an action potential
Nicotine’s most important effect is the activation of the reward pathway which is caused by dopamine release.
two binding sites :
high affinity site,42
low affinity 7

4. Nicotine and Acetylcholine

5. Releases ACh, NE, DA, S, glutamate, and GABA
nAChR is an integral membrane glycoprotein
Pentomeric structure of receptor
binding site is on the alpha subunit
Found in the Central and peripheral nervous system
The combination of subunits is specific to the location
Releases ACh, NE, DA, S, glutamate, and GABA

6. Effects of Nicotine Positive: Anxiolysis Cognitive Enhancement
Cerebro-vasodilation
Neuroprotection
Analgesia
Anti-psychotic
Negative:
Gastrointestinal Distress
Hypothermia
Emesis
Hypertension
Seizures
Respiratory Distress
Anxiolysis: reduced anxiety; anxiety results in aggression
Cerebro-vasodilation:increased Cerebral bloodflow
Neuroprotection: regulation of neuronal responses to neurotransmitters. It has been shown that smokers who quit smoking have a reduced chance of developing neurodegenerative diseases. Acute administration if nicotine to patients who suffer from Alzheimer’s disease has led to an improvement in their recall abilities. However when a transdermal patch was used for 6 months Alzheimer’s patients did not show any improvements.
Analgesia: Pain-relief, this was first documented in the 1930s. Another alkaloid, Epibatidine and other derivatives have been found to selectively bind to nicotinic acetylcholine receptors rather than to opioid receptors. However since it doesn’t bind selectively to nicotinic acetylcholine receptors it is too toxic to complete clinical trials.
Anti-psychotic- treatment for schizophrenia. People who suffer from schizophrenia usually tend to be heavy smokers. People have found that if you withdraw them from smoking, schizophrenia is exacerbated. Nicotine administration restores the P50 potential wave. This is somehow related to schizophrenia but is not understood.
Negative Effects:
Gastrointestinal distress: Diarrhea, nausea, and vomiting.
Hypothermia: Occurs due to the constriction of blood vessels preventing blood from reaching the extremities of the body.
Emesis: Nausea and vomiting
Hypertension: Increased blood pressure from vasoconstriction.
Seizures: A result of group of neurons firing action potentials all at once.
Respiratory Distress: The air sacs collapse due to lack of pulmonary surfactant (nothing to keep them open).
Symptoms are rapid breathing, unusual breathing movement, shortness of breath, cessation of breathing
Take home message: The nicotinic acetylcholine receptors are not localized in the brain and pns; hence, nicotine’s wide range of positive and negative effects.

7. Nicotine Administration
Inhalation
Cigarettes (~1.0 mg)
Inhaler
Nasal
Nasal spray
Oral
Gum
Lozenges
Tablets
Transdermal
Patch
There are many other compounds/toxins present in cigarettes that contribute to nicotine dependence.

8. Chemistry of Nicotine basic compound water soluble lipophilic
environments:
no absorption in acidic environments
functions at blood pH = 7.4 (31%)
absorption occurs readily in basic environments
Properties of nicotine allow it to cross blood brain barrier
In acidic environments nicotine is ionized, preventing it from readily crossing membranes.

9. Pharmacokinetics Inhalation of nicotine is the most addictive
Nicotine's pharmacokinetic properties have been found also to enhance its abuse potential. Cigarette smoking produces a rapid distribution of nicotine to the brain, with drug levels peaking within 10 seconds of inhalation. The acute effects of nicotine dissipate in a few minutes, causing the smoker to continue dosing frequently throughout the day to maintain the drug's pleasurable effects and prevent withdrawal.
NRT is not addictive due to the dose and the speed of delivery to the brain

10. Addiction via smoking cigarettes have additives that cause addiction
sensory cues (heat, sight, and smell)
smokers have greater number of nicotinic receptors
inhalation from cigarettes causes nicotine to cross blood brain barrier more rapidly
Upregulation may be due to decrease in turnover rate and receptor desensitization
higher nicotine concentration in the brain

11. Nicotine absorption from cigarettes
Readily absorbed through oral and nasal mucous membrane
basic pipe or cigar smoke leads to rapid increases in nicotine without inhalation
flue-cured cigarettes are acidic
little buccal absorption
need to absorb nicotine through inhalation

12. Absorption through Inhalation
absorption through the surface of alveolar capillary interface
absorption into the pulmonary capillary blood flow
circulates throughout entire blood volume
Nicotine steady state volume of distribution (2.6L/kg) to tissues
Entire blood volume passes through lung every minute.

13. Buccal Absorption Absorbed in small intestine Carried to blood
Undergoes pre-systemic metabolism by liver
30-40% bioavailability
Even if we can assume that a drug is completely absorbed across the G-I tract, a proportion of the dose may be eliminated by the liver before reaching the systemic circulation because of the anatomical arrangement of the portal circulation.
Important not to swallow nicotine during therapy
FYI: for gum, the rate of chewing, buccal factors, and swallowing affects nicotine absorption

14. Elimination First order Half-life averages 2 hours
Metabolized in liver, lung and kidney
Half-life varies from person to person
Renal excretion depends on pH and flow (accounts for 5-10%)

15. How is nicotine eliminated?
P-450 and aldehyde oxidase enzymes in liver
Cotinine half-life is 16 hours, so used to test if someone has been smoking

16. Therapeutic Opportunities
Cognitive Dysfunction/ Attention Disorders
Neurodegenerative disorders (Alzheimers, Parkinsons)
Pain
Schizophrenia
Depression
Increase NE, DA, Ah which has been shown to increase cognitive performance in mice and primates
Smokers have decreased incidence; increases DA; symptom relief and fewer incidences in primates
Not thought to work until discovery of epibatidine which acts on AChR’s but is less selective than nicotine and therefore toxic.
Almost all schizo. Patients smoke and symptoms increase when they try to stop. May have to do with decreased gating of auditory evoked potential wave.
Current drugs for depression work to release NE, DA, 5-HT – all of these are increased with nicotine

17. Epilepsy Tourette’s Syndrome ADHD Anxiety Vestibular Function
Gastric Disorders
At high doses, nicotine has both convulsant and anti-convulsant properties.
Clinical trials have shown it can alleviate symptoms
Current medications act by increasing DA – nicotine has shown some improvement in trials
The research is usually done in smokers, so it might be the relief of withdrawl-induced anxiety, but animal tests show positive results.
Alpha-9 AChRs are specific to inner ear, so there may be some use.
Smoking decreases chance of ulcers. Clinical trials are positive but the effects are short-term.
Nicotine has very broad effects, so the idea is to try to find nicotine derivatives that are more selective and then we can target specific sub-units and, in doing so, generate specific effects.

18. And the take home message is…
The pharmacokinetics are important for determining addictive potential of nicotine
Inhalation of nicotine is the most addictive form of uptake
There are many therapeutic opportunities to be developed
Nicotine replacement therapy is not as successful due to a lower nicotine concentration in brain