pharmacology of nicotine
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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
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