Nicotine Pharmacology and Principles of Addiction

1
Copyright 1999-2006 The Regents of the University of California, University of Southern

California, and Western University of Health Sciences. All rights reserved.
NICOTINE PHARMACOLOGY and
PRINCIPLES of ADDICTION
NICOTINE ADDICTION
U.S. Surgeon Generals Report (1988)
Cigarettes and other forms of tobacco are
addicting.
Nicotine is the drug in tobacco that causes
addiction.
The pharmacologic and behavioral processes
that determine tobacco addiction are similar to
those that determine addiction to drugs such as
heroin and cocaine.
U.S. Department of Health and Human Services. (1988). The Health Consequences
of Smoking: Nicotine Addiction. A Report of the Surgeon General.
Nicotiana tabacum
Natural liquid alkaloid
Colorless, volatile base pK
a
= 8.0
N
CH
3 N
H
Pyridine ring
Pyrrolidine ring
CHEMISTRY of NICOTINE
PHARMACOLOGY
Effects of the body on the drug
Absorption
Distribution
Metabolism
Excretion
Effects of the drug on the body
Pharmacokinetics
Pharmacodynamics
NICOTINE ABSORPTION
Absorption is pH dependent
In acidic media
Ionized poorly absorbed across membranes
In alkaline media
Nonionized well absorbed across membranes
At physiologic pH (7.37.5), ~31% of nicotine is
unionized
At physiologic pH,
nicotine is readily absorbed.
NICOTINE ABSORPTION:
BUCCAL (ORAL) MUCOSA
The pH inside the mouth is 7.0.
Acidic media
(limited absorption)
Cigarettes
Alkaline media
(significant absorption)
Pipes, cigars,
spit tobacco,
oral nicotine products
Beverages can alter pH, affect absorption.
2
NICOTINE ABSORPTION: SKIN
and GASTROINTESTINAL TRACT
Nicotine is readily absorbed through intact skin.
Nicotine is well absorbed in the small intestine
but has low bioavailability (30%) due to first-
pass hepatic metabolism.
NICOTINE ABSORPTION: LUNG
Nicotine is distilled from burning tobacco and
carried in tar droplets.
Nicotine is rapidly absorbed across respiratory
epithelium.
Lung pH = 7.4
Large alveolar surface area
Extensive capillary system in lung
NICOTINE DISTRIBUTION
Henningfield et al. (1993). Drug Alcohol Depend 33:2329.
0
10
20
30
40
50
60
70
80
0 1 2 3 4 5 6 7 8 9 10
Minutes after light-up of cigarette
P
l
a
s
m
a

n
i
c
o
t
i
n
e

(
n
g
/
m
l
)Arterial
Venous
Nicotine reaches the brain within 11 seconds. Nicotine reaches the brain within 11 seconds.
Metabolized
and excreted
in urine
NICOTINE METABOLISM
CH
3 N
H 1020%
excreted
unchanged
in urine
Adapted and reprinted with permission. Benowitz et al. (1994). J Pharmacol Exp Ther 268:296303.
7080%
cotinine
~ 10% other
metabolites
N
NICOTINE EXCRETION
Half-life
Nicotine t
= 2 hr
Cotinine t
= 19 hr
Excretion
Occurs through kidneys (pH dependent;
with acidic pH)
Through breast milk
NICOTINE
PHARMACODYNAMICS
Nicotine binds to receptors
in the brain and other
sites in the body.
Other:
Neuromuscular junction
Sensory receptors
Other organs
Central nervous system
Exocrine glands
Adrenal medulla
Peripheral nervous system
Gastrointestinal system
Cardiovascular system
Nicotine has predominantly stimulant effects.
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NICOTINE
PHARMACODYNAMICS (contd)
Central nervous system
Pleasure
Arousal, enhanced vigilance
Improved task performance
Anxiety relief
Other
Appetite suppression
Increased metabolic rate
Skeletal muscle relaxation
Cardiovascular system
Heart rate
Cardiac output
Blood pressure
Coronary vasoconstriction
Cutaneous vasoconstriction
NEUROCHEMICAL and RELATED
EFFECTS of NICOTINE
Dopamine
Norepinephrine
Acetylcholine
Glutamate
Serotonin
-Endorphin
GABA
N
I
C
O
T
I
N
E
Benowitz. (1999). Nicotine Tob Res 1(Suppl):S159S163.
Pleasure, reward
Arousal, appetite suppression
Arousal, cognitive enhancement
Learning, memory enhancement
Mood modulation, appetite suppression
Reduction of anxiety and tension
Reduction of anxiety and tension
WHAT IS ADDICTION?
Compulsive drug use, without
medical purpose, in the face of
negative consequences
Alan I. Leshner, Ph.D.
Former Director, National Institute on Drug Abuse
National Institutes of Health
BIOLOGY of NICOTINE ADDICTION:
ROLE of DOPAMINE
Nicotine
stimulates
dopamine release
Repeat administration
Tolerance develops
Discontinuation leads to
withdrawal symptoms.
Pleasurable feelings
Nicotine addiction
is not just a bad habit.
Nicotine enters Nicotine enters
brain brain
Stimulation of Stimulation of
nicotine receptors nicotine receptors
Dopamine release Dopamine release
DOPAMI NE REWARD PATHWAY
Prefrontal
cortex
Nucleus
accumbens
Ventral
tegmental
area
CHRONIC ADMINISTRATION of
NICOTINE: EFFECTS on the BRAIN
Perryet al. (1999). J Pharmacol Exp Ther 289:15451552.
Nonsmoker Smoker
Human smokers have increased nicotine
receptors in the prefrontal cortex.
High
Low
Image courtesy of George Washington University / Dr. David C. Perry
4
Depression
Insomnia
Irritability/frustration/anger
Anxiety
Difficulty concentrating
Restlessness
Increased appetite/weight gain
Decreased heart rate
Cravings*
NICOTINE PHARMACODYNAMICS:
WITHDRAWAL EFFECTS
American Psychiatric Association. (1994). DSM-IV.
Hughes et al. (1991). Arch Gen Psychiatry 48:5259.
Hughes &Hatsukami. (1998). Tob Control 7:9293.
Most symptoms
peak 2448 hr
after quitting and
subside within
24 weeks.
* Not considereda withdrawal symptombyDSM-IV criteria.
HANDOUT
NICOTINE ADDICTION CYCLE
Reprinted with permission. Benowitz. (1992). Med Clin N Am 2:415437.
NICOTINE ADDICTION
Tobacco users maintain a minimum serum
nicotine concentration in order to
Prevent withdrawal symptoms
Maintain pleasure/arousal
Modulate mood
Users self-titrate nicotine intake by
Smoking/dipping more frequently
Smoking more intensely
Obstructing vents on low-nicotine brand cigarettes
ASSESSING
NICOTINE DEPENDENCE
Fagerstrm Test for Nicotine Dependence (FTND)
Developed in 1978 (8 items); revised in 1991 (6 items)
Most common research measure of nicotine dependence;
sometimes used in clinical practice
Responses coded such that higher scores indicate higher
levels of dependence
Scores range from 0 to 10; score of greater than 5
indicates substantial dependence
Heathertonet al. (1991). British Journal of Addiction 86:11191127.
HANDOUT
FACTORS CONTRIBUTING to
TOBACCO USE
Physiology
Genetic predisposition
Coexisting medical
conditions
Environment
Tobacco advertising
Conditioned stimuli
Social interactions
Pharmacology
Alleviation of
withdrawal symptoms
Weight control
Pleasure
Tobacco
Use
TOBACCO DEPENDENCE:
A 2-PART PROBLEM
Tobacco Dependence Tobacco Dependence
Treatment should address the physiological
and the behavioral aspects of dependence.
Physiological Physiological Behavioral Behavioral
Treatment Treatment
The addiction to nicotine
Medications for cessation
The habit of using tobacco
Behavior change program
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ADDICTION: SUMMARY
Tobacco products are effective delivery systems for
the drug nicotine.
Nicotine is a highly addictive drug that induces a
constellation of pharmacologic effects.
Nicotine activates the dopamine reward pathway in
the brain, which reinforces continued tobacco use.
Tobacco users who are dependent on nicotine self-
regulate tobacco intake to maintain pleasurable
effects and prevent withdrawal.
ADDICTION: SUMMARY (contd)
Nicotine dependence is a form of chronic brain
disease.
Tobacco use is a complex disorder involving the
interplay of the following:
Pharmacology of nicotine (pharmacokinetics and
pharmacodynamics)
Environmental factors
Physiologic factors
Treatment of tobacco use and dependence
requires a multifaceted treatment approach.

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Copyright 1999-2006 The Regents of the University of California, University of Southern

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