Transcript Smoking

‫بسم هللا الرحمن الرحيم‬
‫‪1‬‬
Presented By:
Magd Mohamed Galal
Professor Of Chest Diseases
Al Azhar University
Faculty Of Medicine For Girls
2012
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
Discussing the relevance of genetic profiling
of genes involved in mediating smoking
behavior and addiction
3

Although the risk of cigarette smoking is well
documented, tobacco smoking continues to
be the largest preventable cause of disease
and premature death throughout the world.

It is estimated that there are currently still
over 1.5 billion smokers worldwide , is
expected to reach about 1.6–1.9 billion by
2025 .
4

Inhalation of (cigarette) smoke has several
deleterious effects on the airways, leading to
and/or influencing chronic respiratory
diseases such as asthma and chronic
obstructive pulmonary disease (COPD).

According to World Health Organization
estimates (in 2007), 300 million people have
asthma and 210 million people have COPD.
5

In contrast to other common smokingrelated diseases, such as cardiovascular
disease and cancer, chronic respiratory
diseases are the only causes of death that are
still increasing.

By 2015, about 30% of the smoking-related
deaths will probably be caused by chronic
respiratory diseases .
Mathers & Loncar ,2006
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Smoke affects all people who are exposed to
it, but the degree and severity is modified by
many susceptibility determinants.(Martin et al2009)


Half the world’s children are involuntarily
exposed to smoke
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
440,000 deaths in the U.S. each year

4.8 million deaths world wide each year

10 million deaths estimated by year 2030

50,000 deaths in the U.S. due to second-hand smoke
exposure

8.6 million disabled from tobacco in the U.S. alone
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Comparative Causes of Annual
Deaths in the United States
440
450
400
350
300
250
*
200
150
81
100
50
17
41
19
14
Homicide
Drug
Induced
30
0
AIDS Alcohol
Motor
Vehicle
Source: Centers for Disease Control and Prevention
Suicide
Smoking
suffer from mental
*Also
illness and/or substance
abuse
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Prospective study of 34,439 male British doctors
Mortality was monitored for 50 years (1951–2001)


Years of life gained
15
On average, cigarette
smokers die approximately
10 years younger than do
nonsmokers.
10
5
0
30
40
50
60
Among those who continue
smoking, at least half will die
due to a tobacco-related
disease.
Age at cessation (years)
Doll et al. (2004). BMJ 328(7455):1519–1527.
Absorption is pH dependent
 In acidic media
 Ionized  poorly absorbed across membranes
 In alkaline media
 Non ionized  well absorbed across membranes
At physiologic pH (7.3–7.5),
nicotine is readily absorbed.
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
Inhaled nicotine is quickly absorbed from the large surface
area of the alveoli into the pulmonary veins

Rapidly enters the arterial system
 Time to arterial peak is less than 10 seconds

Easily crosses blood-brain barrier and begins to reach
nAchRs in ~20 seconds

Crosses the placenta freely

Appears in breast milk in concentrations ~x2 those found in
blood
Dani JA, et al (2009)
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Nicotine reaches the brain within 11 seconds
Plasma nicotine (ng/mL)
80
70
Arterial
60
50
40
30
Venous
20
10
0
0
1
2
3
4
5
6
7
8
9
10
Minutes after light-up of cigarette
Data from Henningfield et al., Drug Alcohol Depend 1993;33:23-29.
Graph reprinted with permission, Rx for Change, The Regents of the University of California,
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University of Southern California, and Western University of Health Sciences.

Nicotine in a cigarette = 8 to 10 mg

Each cigarette delivers 1.2-2.9 mg of nicotine

A typical pack-a-day smoker absorbs 20-40mg
of nicotine each day

Half-life is ~ 2hours

During a typical day, nicotine accumulates over
6-8 hours (3-4 half-lives)
Dani JA, et al (2009)
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
The increment is 5-30 ng/ml after each
cigarette (depending on how the cigarette is
smoked)

More frequent smoking reduces fluctuations
in nicotine plasma concentration

The plateau (10-50 ng/ml) is usually reached
in the early afternoon
Dani JA, et al (2009)
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
Biphasic action- nicotinic
acetylcholine receptors
 Agonist – low doses
 Antagonist – high doses

Although a stimulant, it is often
used to relax

Works in CNS and PNS

One of the most toxic
dependence-producing
psychoactive compounds overall

Nicotine acts to stimulate
dopamine release in mesolimbic
dopamine pathway (reward
center).
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19

Nicotine rises the stimulation of nicotinic
receptors. The excessive and chronic activation
of these receptors is balanced by a downregulation in the number of active receptors.

The reduction of the number of active receptors
reduces the psychotropic effect of nicotine. Due
to the phenomenon of tolerance, the smoker
needs to smoke more and more cigarettes to
keep a constant effect.
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
The first cigarette of the day is the most
pleasant because the sensibility of the
dopamine receptors is maximal. Then, the
receptors are soon desensitized and the
pleasure wears off.
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Nigrostriatal pathway
Substantia Nigra to Striatum
. Motor control
. Death of neurons in
this pathway can result in
Parkinson's Disease
Mesolimbic and Mesocortical pathways
Ventral Tegmental Area to Nucleus
Accumbens, Amygdala & Hippocampus,
and Prefrontal Cortex
. Memory
. Motivation and emotional response
. Reward and desire
. Addiction
. Can cause hallucinations and schizophrenia if not
functioning properly
Tuberoinfundibular pathway
Hypothalamus to Pituitary gland
. Hormonal regulation
. Maternal behavior (nurturing)
. Pregnancy
. Sensory processes
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Dopamine Reward Pathway
Prefrontal
cortex
Dopamine release
Stimulation of
nicotine receptors
Nucleus
accumbens
Ventral tegmental
area
Nicotine enters
brain
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Dopamine Pathways
striatum
frontal
cortex
hippocampus
substantia
nigra/VTA
nucleus
accumbens
Functions
reward (motivation)
pleasure,euphoria
motor function (fine tuning)
compulsion
Serotonin Pathways
raphe
Functions
mood
memory processing
sleep
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Neuronal structure
(receiving)
(sending)
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stimulation
Vmat
vesicle
Neuronal terminal
transporter
How some drugs of abuse cause dopamine release
• opioids narcotics (activate opioid receptors)
• nicotine (activate nicotine receptors)
DA
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Human smokers have increased nicotine receptors in
the prefrontal cortex.
High
Low
Nonsmoker
Smoker
Image courtesy of George Washington University / Dr. David C. Perry
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Reprinted from Med Clin N Am 76(2), Benowitz NL, Cigarette smoking and nicotine addiction,
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pp. 415–437, Copyright 1992, with permission from Elsevier.
Hedonic Set Point is Altered with Chronic Drug Use
“Feel good”
Normal Affective Response
to Drugs/Alcohol
Initially use to
get high…
“Cravings”
“Feel bad”
(Koob, Science, 1997)
Now use to
“get normal”
Altered Dysregulated Set-Point
following chronic drug use
Slide from Pating,D.
H
N
N
70–80%
cotinine
CH3
10–20%
excreted
unchanged
in urine
~ 10% other
metabolites
Metabolized
and excreted
in urine
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Adapted and reprinted with permission. Benowitz et al. J Pharmacol Exp Ther 1994;268:296–303.

The CYP2A6 enzyme is
responsible for 90% of
nicotine metabolism

80% of nicotine
becomes cotinine,
which becomes 3
hydroxy-cotinine

Several genetic variants
for the CYP2A6 enzyme
have been identified
Hukkanen et al., 2005
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
The amine function of nicotine may react
with nitrogen monoxide or with nitrous acid
in order to form a "nitrosonium" type
molecule.

This compound may then be transformed by
the body, which means oxidized and opened.
This opening leads to two isomers, two
"nitrosamino" type molecules (R2N-N=O)
where one of the two R group is a methyl.
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
In acidic medium, the oxygen of the "nitrosamine"
group is protonated and the double bond moves to
the central nitrogen, which becomes positively
charged. This new molecule is a methyl source. The
"nitrosamine" group can then react with another
amine, which removes the positive charge from the
nitrogen.

If the amine that reacts is a part of the structure of the
DNA, an irreversible alkylation of the DNA occurs

This alkylation is really noxious and may help in the
development of cancer as it prevents the normal
development of the cell.
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35

Tobacco smoking is believed to be a complex,
multi factorial behavior with both genetic and
environmental determinants.

More recent studies have found significant
genetic influences on several aspects of
smoking behavior.
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
It has been demonstrated that genetic factors
account for approximately




40–75% of the variation in smoking initiation,
70–80% of the variation in smoking maintenance,
about 50% of the variance in cessation success
and 30–50% of the variance in risk of withdrawal
symptoms .
( Xian 2003- Pergadia 2006)
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
Variations in several genes have been suggested to
contribute to smoking behavior, and research has
been focused on two broad classes of candidate genes:

Genes that may influence the response to nicotine
 Nicotine metabolism,
 Nicotinic receptors

Genes that may predispose to addictive behavior
due to their effects on key neurotransmitter pathways
 Dopamine and
 Serotonin.
(MacLeod 2006-Batra 2003)
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
Individuals with a
may
experience fewer adverse reactions to their first
encounter with nicotine and, therefore, may have a
greater chance of continuing smoking and becoming
addicted.

Conversely,
may be less
prone to initiate smoking because they may
experience more adverse effects and would require
fewer cigarettes to maintain nicotine titres at an
optimal level once smoking is initiated .
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
The major genes responsible for the
metabolism of nicotine are the hepatic
enzymes
 cytochrome P450 2A6 (CYP2A6) and
 cytochrome P450 2D6 (CYP2D6).
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
CYP2A6 genetic variants predict level of
smoking and nicotine dependence, and
severity of withdrawal
Smoking Rate
Nicotine Dependence
Malaiyandi et al., 2006; Kubota et al., 2006
Withdrawal Symptoms
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
3HC/cotinine ratio represents
rate of metabolism (smaller
value = slower metabolism)

Those with genetic variants
thought to slow metabolism
have a lower 3/HC/cotinine
ratio

Proof of principle and
verification of 3HC/cotinine as
a phenotypic marker of
CYP2A6 genetic variants
Malaiyandi et al., 2006; Lerman et al., 2006
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
Polymorphisms in
do not seem to be
major determinants of nicotine metabolism
in smokers except in ultra metabolisers
(gene duplication) .( Saarikoski et al 2000)

This is probably because its catalytic activity
towards nicotine is negligible in the presence
of functional CYP2A6.
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Smokers with
dependent:
level of dependence or non-
Smoke small number of cigarettes per day
First cigarette delayed
Frequent periods off smoking – cold turkey each time
Minimal withdrawal symptoms
Majority of regular smokers have moderate-tosevere dependence and find it difficult to stop or
cut down
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Nicotine-d2 Clearance
(ml/min/kg)
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Duplication
(*1x2)
clearance
25
20
Inactive alleles
(*4)
 clearance
15
10
5
0
*1/*1x2
(N=8)
*1/*1
(N=155)
*1/*4
(N=12)
*4/*4
(N=1)
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Hukkanen et al., 2005

Ultra metabolisers were found to be more
likely to be heavy smokers
46

Asians and African Americans metabolize
nicotine on average more
than do
Caucasians or Hispanics
(Benowitz et al 2002).
47

The rate of nicotine metabolism is faster in
women than men
(Benowitz et al 2006).

Among women, nicotine metabolism is faster
in women taking estrogen-containing oral
contraceptives, and is even faster during
pregnancy, compared with other women.
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
The pharmacological effects of nicotine are mediated
by the activation of nicotinic acetylcholine receptors
(nAChRs).
mainly contain the
α4 (CHRNA4) and β2 (CHRNB2) subunits, and α4β2* (*
indicates that another subunit may be included) is the
most frequently encountered nicotinic receptor
subtype.

Several nAChR subunit genes have been examined for
associations with smoking status (e.g. CHRNA4,
CHRNA5, CHRNA7, CHRNB1, CHRNB2 and CHRNB3),
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
People with
polymorphism
(gene coding for α4 subunit of the nicotinic Ach
receptor) have higher rates of tobacco
dependence.
1Schnoll
et al. (2007) Curr Psychiatry Rep, 9:349-357.
et al. (2007) Arch Gen Psychiatry, 64(9):1078-1086.
2Hutchison
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
Investigators have examined the association
between smoking behavior and variations in
several genes involved in the dopamine
pathway, such as
 Dopamine receptors,
 The dopamine transporter and
 Enzymes involved in dopamine synthesis and
metabolism .
(Balfour 2004)
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53

Variants in several
(e.g.
DRD1, DRD2, DRD4 and DRD5) have been detected
and studied in relation to smoking behavior.

Overall, genotypes associated with reduced dopamine
receptor expression or function seem to predict a
higher chance of becoming a smoker, a younger age
of onset, and fewer and less successful quit attempts .
( Laucht et al 2005)
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
The
moves the dopamine
released in the synapse into a neuron, glial cell or
astrocyte to terminate the dopamine signal.

A reduction in
resulting in
levels,
 less clearance and
 greater bio-availability of dopamine,
has been shown to be related to a lower chance of
becoming a smoker, a lower nicotine intake and
longer periods of smoking cessation
(Lerman et al 1999)
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
Several
, such as tyrosine hydroxylase (TH), 3,4dihydroxyphenylacetic acid decarboxylase (DDC), dopamine
β-hydroxylase (DBH), catechol-O-methyl-transferase
(COMT) and monoamine oxidase (MAO)-A and -B, are
involved in the synthesis and metabolism of dopamine.

Only limited data on the effects of variations in these
enzymes on smoking behaviour are available.

Associations between smoking and variations in genes for
MAO-A, MAO-B, DBH and DDC have been found .
(Zhang et al, 2006)
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
In addition to direct and indirect stimulation of
neurotransmitter release, chronic cigarette smoking
(but not nicotine administration) reduces brain
monoamine oxidase A and B (MAO A and MAO B)
activity, which would be expected to increase mono
aminergic neurotransmitter levels such as dopamine
and nor epinephrine in synapses, thus augmenting the
effects of nicotine and contributing to addiction .
MansvelderHD,&McGeheeDS.2002.
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
The serotonin pathway is also under
investigation in genetic studies of smoking, for
several reasons.
, nicotine has been shown to increase the
secretion of serotonin in the brain . (Mihailescu et al
1998)
, increased serotonin levels have
been associated with decreased food intake and
weight gain, and have been shown to have an
antidepressant effect . (Ribeiro et al 1993)
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, lower serotonin re-uptake
has been associated with several behavioural
traits (e.g. neuroticism, novelty seeking and
anxiety-related personality traits) that are
related to an increased incidence of smoking,
increased nicotine dependence and difficulty
in quitting smoking . (Hu et al 2000)
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
Candidate polymorphisms include those involved in
(TPH))
HTT)).

(e.g. tryptophan hydroxylase
(e.g. serotonin transporter (5-
Individuals homozygous for a variant of TPH, with an
unknown effect, have been shown to be more prone to
initiate smoking and to start smoking at an earlier age,
but no effect on progression to nicotine dependence
and smoking status has been found . (Mizunoet al 2006)
61

Smoke affects all people who are exposed to it, but the degree
and severity is modified by many susceptibility determinants

Genetic factors account for approximately,40–75% of the
variation in smoking initiation, 70–80% of the variation in
smoking maintenance, about 50% of the variance in cessation
success and 30–50% of the variance in risk of withdrawal
symptoms .
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Presented by
Prof. Magd Mohamed Galal