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