Nicotine and Tobacco

1. Nicotine and
Tobacco Subramani Parasuraman
Faculty of Pharmacy
AIMST University
Malaysia

2. Loarning outcome
• Upon successful completion of this topic, students
should be able to
• describe the pharmacological properties of nicotine.
• discuss the adverse health effects related with nicotine
use.

3. Tobacco
• Tobacco is the common name of several plants in the
genus Nicotiana of the family Solanaceae. More than
70 species of tobacco are known, but the chief
commercial crop is Nicotiana tabacum.
• Dried tobacco leaves are mainly
used for smoking in cigarettes and
cigars, as well as pipes and shishas.
• They can also be consumed as snuff,
chewing tobacco, dipping tobacco,
and snus.
• Tobacco contains the highly
addictive stimulant alkaloid
nicotine as well as harmala
alkaloids such as harmine,
harmaline, and harmalol.

4. Nicotine
• Nicotine is a stimulatory alkaloid found in tobacco
products that is often used for the relief of nicotine
withdrawal symptoms and as an aid to smoking
cessation.
• Nicotine is highly toxic alkaloid. It is the agonist at
nicotinic cholinergic receptors.

5. Mechanism of action for nicotine
• Nicotine acts as an agonist on both NN and NM
subtypes of nicotinic cholinergic receptors.
Sympathetic as well as parasympathetic ganglia are
stimulated, but larger doses cause persistent
depolarization and ganglionic blockade.

6. Pathways associated with nicotine addiction
• Cholinergic system: Nicotine easily enters BBB stimulating
nicotinic ACh receptors. Cholinergic receptors are located
in several brain segments particularly located in the
midbrain tegmentum, the striatum, nucleus accumbens
and the ventral tegmentum.
• Dopaminergic System: Stimulation of central nicotinic
acetylcholine receptors by nicotine results in the release
of a variety of neurotransmitters in the brain, most
importantly dopamine. Nicotine causes the release of
dopamine in the mesolimbic area, the corpus striatum,
and the frontal cortex. The release of dopamine in the
shell of the nucleus accumbens, as this pathway appears
to be critical in drug-induced reward.
Ref: Benowitz NL. Annu Rev Pharmacol Toxicol. 2009;49:57-71.

7. Psychoactive Effects of Nicotine and Nicotine
Withdrawal
• In humans, nicotine from tobacco induces stimulation and
pleasure, and reduces stress and anxiety.
• Smokers come to use nicotine to modulate their level of
arousal and for mood control in daily life. Smoking may
improve concentration, reaction time, and performance
of certain tasks.
• When a person stops smoking, nicotine withdrawal
symptoms emerge. These include irritability, depressed
mood, restlessness, anxiety, problems getting along with
friends and family, difficulty concentrating, increased
hunger and eating, insomnia, and craving for tobacco.
Nicotine withdrawal in untreated smokers produces mood
disturbances comparable in intensity to those seen in
psychiatric outpatients.
Ref: Benowitz NL. Annu Rev Pharmacol Toxicol. 2009;49:57-71.

8. Nicotine pharmacokinetics and metabolism
• Absorption: Nicotine is a weak base (pKa = 8.0).
Absorption through mucous membranes depends on pH.
Smoking is a highly efficient form of drug administration,
as the drug enters the circulation rapidly through the
lungs and moves into the brain within seconds. Inhaled
drugs escape first-pass intestinal and hepatic
metabolism. The more rapid the rate of absorption and
entry of a drug into the brain, the greater the rush, and
the more reinforcing the drug. Smoking produces high
concentrations of a drug in the brain that are
comparable to those seen after intravenous
administration.
Ref: Benowitz NL. Annu Rev Pharmacol Toxicol. 2009;49:57-71.
https://www.healthline.com/health/how-much-nicotine-is-in-a-cigarette
The average amount of nicotine in a single cigarette is around 10 to 12 mg.

9. Nicotine pharmacokinetics and metabolism
• Distribution: After absorption, nicotine enters the
bloodstream where, at pH 7.4, it is about 69% ionized
and 31% unionized. The peak plasma nicotine
concentration during smoking is 10 to 50 ng/mL with
about 5 percent being protein-bound. The half-life
averages two hours.
• The highest affinity for nicotine is in the liver, kidney,
spleen, and lung and lowest in adipose tissue. In skeletal
muscle, concentrations of nicotine and cotinine are
close to that of whole blood. Nicotine binds to brain
tissues with high affinity, and the receptor binding
capacity is increased in smokers compared with
nonsmokers.
Ref: Benowitz NL. Annu Rev Pharmacol Toxicol. 2009;49:57-71.;
Benowitz NL et al., Handb Exp Pharmacol. 2009;(192):29-60.

10. Nicotine pharmacokinetics and metabolism
• metabolism: Nicotine is rapidly and extensively
metabolized by the liver, primarily by the liver enzyme
CYP2A6. Although glucuronidation is usually a minor
pathway of nicotine metabolism, in people who have low
CYP2A6 activity, glucuronidation can be a major
determinant of nicotine clearance. Approx. 80 to 90
percent of nicotine is metabolized by lung, liver, and
kidney; the principal metabolite is cotinine, which has a
plasma concentration that is 10-fold higher than
nicotine. Cotinine has a half-life of 15 to 20 hours and is
used as a biomarker of nicotine exposure. The rate of
nicotine metabolism is faster in women than men.
Ref: Benowitz NL. Annu Rev Pharmacol Toxicol. 2009;49:57-71.

11. Nicotine pharmacokinetics and metabolism
• Excretion: Nicotine is excreted by glomerular filtration
and tubular secretion, with variable reabsorption
depending on urinary pH. Approximately 17 percent of
nicotine is excreted unchanged in the urine. The rate of
urinary excretion is pH-dependent, decreasing in an
alkaline urine. Nicotine is found in the milk of lactating
women with concentrations that parallel those of plasma.
• GENETIC CONSIDERATIONS: Nicotine is metabolized
primarily by the liver enzyme cytochrome P450 2A6
(CYP2A6). Genetically slow metabolizers tend to smoke
fewer cigarettes per day and are able to quit smoking
more easily than fast metabolizers.
Ref: Elsa-Grace Giardina. Cardiovascular effects of nicotine. © 2023 UpToDate, Inc.
Benowitz NL et al., Handb Exp Pharmacol. 2009;(192):29-60.

12. Adverse health effects of nicotine use
• Immediate Effects: Nicotine on direct application in
humans causes irritation and burning sensation in the
mouth and throat, increased salivation, nausea,
abdominal pain, vomiting and diarrhea.
Gastrointestinal effects are less severe but can occur
even after cutaneous and respiratory exposure.
Nicotine also causes an increase in plasma free fatty
acids, hyperglycemia, and an increase in the level of
catecholamines in the blood. LD50 in adults of around
30-60 mg of nicotine. In children the LD50 is around 10
mg.
Ref: Mishra et al., Indian J Med Paediatr Oncol. 2015 Jan-Mar;36(1):24-31.

13. Adverse health effects of nicotine use
• Green Tobacco Sickness: This is an acute form of
nicotine toxicity that is known to occur due to
handling of green tobacco leaves, with symptoms
lasting from 12 to 24 h. The acute symptoms include
headache, nausea, vomiting, giddiness, loss of
appetite, fatigue and tachyarrythmias.
• Nicotine Addiction: Nicotine interacts with the
nicotinic acetyl choline receptors and stimulates the
dopaminergic transmission. This in turn stimulates
the reward centre and is responsible for the mood
elevation and apparent improvement in cognitive
function.
Ref: Mishra et al., Indian J Med Paediatr Oncol. 2015 Jan-Mar;36(1):24-31.

14. Adverse health effects of nicotine use
• Effects on Metabolism: Nicotine causes
catecholamine release and stimulates the autonomic
system. Nicotine increases glycogen synthesis,
reduces fasting blood glucose levels, decreasing body
weight and affects insulin resistance.
Ref: Mishra et al., Indian J Med Paediatr Oncol. 2015 Jan-Mar;36(1):24-31.

15. Adverse health effects of nicotine use
• Nicotine And Cancer: The stimulation of nicotinic
acetylcholine receptor by nicotine has biologic effects
on cells and initiates progression of cancer. It activates
signal transduction pathways directly through
receptor-mediated events, allowing the survival of
damaged epithelial cells.
• Nicotine forms arachidonic acid metabolites which
cause increased cell division. Binding to Bcl-2 and
action on vascular endothelial growth factor and
cyclooxygenase-2 (COX-2) causes increased cancer
proliferation.
• Nicotine increase the risk of cancer in lungs,
gastrointestinal tract, pancreas, breast, Kidney and
reproductive system organs.
Ref: Mishra et al., Indian J Med Paediatr Oncol. 2015 Jan-Mar;36(1):24-31.

16. Nicotine dependence (tobacco addiction)
• Nicotine addiction occurs when smokers come to
depend on smoking to modulate mood and arousal,
relieve withdrawal symptoms, or both.
• Symptoms
• Can’t stop smoking
• Have withdrawal symptoms when try to stop
• Keep smoking despite health problems
• Give up social activities

17. Management of Nicotine dependence
• Nicotine replacement therapy (NRT): In NRT, nicotine
is given in the form of gum, patches, sprays, inhalers,
or lozenges – but not the other harmful chemicals in
tobacco. NRT can help relieve some of the physical
withdrawal symptoms so that you can focus on the
psychological (emotional) aspects of quitting.
• Varenicline (Drug therapy): It is used for smoking
cessation. Is a partial agonist of the alpha4/beta2
subtype of the nicotinic acetylcholine receptor, that
leads to the release of the dopamine in the nucleus
accumbens (reward center of the brain) and has the
capacity to reduce the feelings of craving and
withdrawal caused by smoking cessation.
Ref: American Cancer Society

18. Management of Nicotine dependence
• Bupropion (Drug therapy): It is a weak inhibitor of
dopamine and noradrenaline reuptake and
antagonise nicotinic acetylcholine receptor function.
Bupropion can decrease nicotine withdrawal
symptoms (such as irritability, anxiety, restlessness)
and urge to smoke.
• E-cigarettes: An e-cigarette is an electronic device
that delivers nicotine in a vapour. This allows to inhale
nicotine without most of the harmful effects of
smoking, as the vapour contains no tar or carbon
monoxide.
Ref: American Cancer Society

19. Management of Nicotine dependence
• Behavioral Treatments
• Cognitive Behavioral Therapy (CBT)
• Motivational Interviewing
• Mindfulness
• Telephone support and quitlines
• Text messaging, web-based services, and social media support
• Transcranial magnetic stimulation (TMS): TMS is a relatively
new approach being tested to treat addiction. It is a physiological
intervention that noninvasively stimulates neural activity in targeted
areas of the brain using magnetic fields.
• Other therapies:
• Hypnotherapy
• Acupuncture
• Aversion therapy
• Yoga
Ref: NIDA.NIH.GOV | National Institute on Drug Abuse (NIDA)
UCSF Health