Pharmacology of Nicotine

S. Mahalakshmi
II- UG Biotech
 What is nicotine?
• plant alkaloid
• derived from tobacco leaves.
• A hygroscopic, oily liquid.
• Easily penetrates the skin.
• Forms salts with acid.
• Optically active. Naturally
occurring form- L form.
• D form- physiologically
less active.

Nicotiana tobacum
 Nicotine Administration
• Inhalation
– Cigarettes (~1.0 mg)
– Inhaler

• Nasal
– Nasal spray

• Oral
– Gum
– Tablets

• Transdermal
– Patch
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
 Pharmacokinetics
• cigarettes have additives that cause addiction.
• Inhalation causes nicotine to cross blood brain
barrier more rapidly.
• It takes about 7 sec to reach the brain when
inhaled.
• Nicotine - metabolized in liver by cytochrome P450.
• The metabolites are cotinine, nicotine N1 oxidase,
nornicotine & nicotine glucuronide.
• Gluconuration & oxidative metabolism of nicotine –
inhibited by menthol, which increases the half life of
nicotine.
 METABOLISM
• P-450 and aldehyde oxidase enzymes in liver
O
CH3 cotinine - N'-oxide
N
70%
17%
N
out (renal excretion)
cotinine
CH3
N
4% trans-3'hydrocotinine
N
nicotine nicotine - N'-oxide

NH

17%
N and nicotine isomethonium ion
nornicotine
 Pharmacokinetics

A graph showing the action of nicotine inside the body

when administrated through different modes.
 Pharmacodynamics
• Nicotine acts on the nicotinic acetylcholine
receptors (ganglion type nicotinic receptors &
CNS nicotinic receptors) and increases the
activity of these receptors.

• It also has effects on other neurotransmitters

also.
 How does nicotine act on
receptors?
• nicotinic acetylcholine
receptors

• mimics acetylcholine
(agonist)

• opens ion channel

– depolarizes
Nicotine and Acetylcholine
 In CNS
• By binding to nicotinic acetylcholine
receptors, it increases the levels of several
neurotransmitters- acting as a volume
control.
• The increased level of Dopamine in brain is
responsible for the euphoria, relaxation and
eventual addiction of nicotine.
 In PNS
• It also activates the sympathetic nervous
system.
• Acting via the nerves in the adrenal
medulla, stimulates the release of
epinephrine.
• Acetylcholine released by preganglionic
sympathetic fibres of these nerves acts on
nicotinic acetylcholine receptors, causing
the release of epinephrine & nor-
epinephrine into the blood stream.
 In Adrenal Medulla
• By binding to ganglion type nicotinic receptors in the
adrenal medulla, nicotine increases the flow of
adrenaline, a stimulating hormone.
• By binding to the receptors, it causes cell
depolarization and an influx of calcium through
voltage-gated calcium channels.
• Calcium triggers the exocytosis of chromaffin
granules and thus releases the epinephrine into the
blood stream.
• The release of epinephrine causes an increase in
heart-rate, blood pressure & respiration as well as
higher glucose levels.
 Toxicology
• Nicotine has a high toxicity in comparison
with many other alkaloids such as cocaine.
• It is very sensitive to skin & hence when
high concentration of the drug is spilled on
the skin, it can result in intoxication or even
death.
• It is detoxified by cytochrome P450.
 Elimination
• First order

• Half-life averages
2 hours

• Metabolized in
liver, lung and
kidney
• Broken down by lung and liver
– >90% in liver

• Excreted through kidneys (urine)

• Lungs do some excretion

• Renal excretion depends on pH and flow

(accounts for 5-10%)
 Psychoactive effects
• Nicotine is both a stimulant and a relaxant.
• It causes the release of glucose from liver
and epinephrine from the adrenal medulla
causing stimulation which leads to the
feeling of relaxation, sharpness, calmness
and alertness.
• It reduces apetite and increases the rate of
metabolism.
 Effects of Nicotine
Positive:
Anxiolysis • Anxiolysis: reduced anxiety;
• Cerebro-vasodilation: increased
Cognitive Cerebral blood flow
Enhancement • Neuroprotection: regulation of
neuronal responses to
neurotransmitters.
Cerebro-vasodilation
• Analgesia: Pain-relief,
Neuroprotection • Anti-psychotic- treatment for
schizophrenia.
Analgesia
Anti-psychotic
 Negative:
Gastrointestinal Distress
Hypothermia
Emesis
Hypertension
Seizures
Respiratory Distress
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
Symptoms are rapid breathing, unusual breathing movement, shortness of breath,
cessation of breathing