pharmacology of nicotine
DESCRIPTION
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 http://www.scs.leeds.ac.uk/cgi-bin/pfaf/arr_html?Nicotiana+tabacumTRANSCRIPT
Pharmacology of Nicotine
Colleen Miller
Lesley-Ann Giddings
What is nicotine?
• plant alkaloid
• derived from nicotinic acid
http://www.scs.leeds.ac.uk/cgi-bin/pfaf/arr_html?Nicotiana+tabacum
How does nicotine act on receptors?
• nicotinic acetylcholine receptors
• mimics acetylcholine (agonist)
• opens ion channel– depolarizes
Nicotine and Acetylcholine
http://www.biomedcentral.com/1472-6807/2/1
• Releases ACh, NE, DA, S, glutamate, and GABA
Effects of NicotinePositive:
Anxiolysis
Cognitive Enhancement
Cerebro-vasodilation
Neuroprotection
Analgesia
Anti-psychotic
Negative:
Gastrointestinal Distress
Hypothermia
Emesis
Hypertension
Seizures
Respiratory Distress
Nicotine Administration• Inhalation
– Cigarettes (~1.0 mg)– Inhaler
• Nasal– Nasal spray
• Oral– Gum – Lozenges – Tablets
• Transdermal– Patch
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
Pharmacokinetics• Inhalation of nicotine is the most addictive
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
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
Absorption through Inhalation• absorption through the surface of alveolar capillary
interface
• absorption into the pulmonary capillary blood flow
• circulates throughout entire blood volume
http://sln.fi.edu/biosci/systems/pulmonary.html
Buccal Absorption• Absorbed in small
intestine• Carried to blood• Undergoes pre-
systemic metabolism by liver
• 30-40% bioavailability
Elimination• First order
• Half-life averages 2 hours
• Metabolized in liver, lung and kidney
How is nicotine eliminated?• P-450 and aldehyde oxidase enzymes in liver
N
NCH3
N
NCH3
O
70%
4%
17%N
NH
17%out (renal excretion)
nicotine - N'-oxide
and nicotine isomethonium ion
cotinine - N'-oxide
trans-3'hydrocotinine
nicotine
cotinine
nornicotine
Therapeutic Opportunities• Cognitive Dysfunction/ Attention Disorders
• Neurodegenerative disorders (Alzheimers, Parkinsons)
• Pain
• Schizophrenia
• Depression
• Epilepsy
• Tourette’s Syndrome
• ADHD
• Anxiety
• Vestibular Function
• Gastric Disorders
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