Transcript Tobacco Smoking “ A Pharmacological Over-view

Tobacco Smoking
“ A Pharmacological Over-view
Haider A. Ghaleb
Kasr El-Aini Faculty of Medicine
Cairo University
Nov. 7th 2007
1
2
Tobacco smoking

Cigarette smoking has been the most
popular method of taking nicotine since
the beginning of the 20th century.

Nicotine is highly addictive. It is both a
stimulant and a sedative to the central
nervous system.
3
Prevalence







1.2 billion people worldwide are known to smoke
tobacco daily.
5.6 trillion cigarettes are smoked per year.
4.2 million people die annually from tobacco
related disease.
Tobacco-related diseases will be about 10 million
in 2020. 1.2 billion people worldwide are known to
smoke tobacco daily.
5.6 trillion cigarettes are smoked per year.
4.2 million people die annually from tobacco
related disease.
Tobacco-related diseases will be about 10 million
in 2020.
4
EGYPT
5
Tobacco smoking and
 Nicotine is absorbed readily from tobacco smoke in
the lungs within 30 minutes, and it does not matter
whether the tobacco smoke is from cigarettes, cigars,
pipes or water pipes.
 Nicotine results in an almost immediate "kick"
because it causes a discharge of epinephrine from the
adrenal cortex.
 This stimulates the central nervous system, and other
endocrine glands,which causes a sudden release of
glucose.
6
Tobacco smoking and
Stimulation is then followed by depression and
fatigue, leading the abuser to seek more nicotine.
 Carving for nicotine increases as levels of
emotional and stress increases.
 When chronic smokers stops suddenly smoking,
withdrawal symptoms occurs which include
- Short temper
- Anger
- Aggression
- Negative feelings
7
Tobacco smoking and
Dependence
The increase of tolerance to nicotine leads
to increased dependence.
In animals it has been shown that stress can
directly cause relapse to nicotine selfadministration after a period of abstinence.
Animals cannot discriminate between the
effects of nicotine and the effects of cocaine
and also nicotine self-administration
sensitizes animals to self-administer cocaine
more readily.
8
Tobacco smoking and
Dependence
 Persons suffering from withdrawal also take
longer to regain emotional equilibrium following
stress.
 During periods of abstinence and/or craving,
smokers showes impairment across a wide range
of psychomotor and cognitive functions.
 Research has shown that teens are generally
resistant to many kinds of anti-smoking
messages.
9
Mechanism of rewarding



Nicotine, like cocaine, heroin, and marijuana,
increases the level of the neurotransmitter
dopamine, which affects the brain pathways that
control reward and pleasure.
Nicotinic receptor beta 2 as a critical component
in nicotine addiction.
Mice that lack this molecule fail to self-administer
nicotine, implying that without the b2 molecule,
the mice do not experience the positive
reinforcing properties of nicotine.
10
Major components of Lymbic System
11
Nicotine metabolism


Nicotine is metabolized in
the liver to cotinine by the
CYP group of enzymes.
Candidate gene studies
have investigated the
association between
smoking and
polymorphisms of genes
coding for these enzymes,
particularly
CYP2A6 and CYP2D6.
12
Role of enzyme CYP 2A6
 Individuals have greater resistance to nicotine addiction if
they have a genetic variant that decreases the function of the
enzyme CYP2A6. Individuals with an ineffective (or 'null')
form of CYP2A6, are less likely to be dependent smokers.
 The decrease in CYP2A6 slows the breakdown of nicotine
and protects individuals against nicotine addiction.
 Understanding the role of this enzyme in nicotine
addiction gives a new target for developing more
effective medications to help people stop smoking.
 Inhibiting the function of CYP2A6, could provide a new
approach to preventing and treating nicotine addiction.
13
Role of enzyme CYP 2A6



CYP2A6 enzyme does not tell the whole story. There is
unexplained gender differences in the frequency of the
null enzyme and the frequency of dependence –
perhaps indicating that there are alternative pathways
for metabolizing nicotine.
Adding weight to this idea, there are other differences
between the smoking habits of males and females.
In general, women are less nicotine-dependent and
more dependent on "factors such as the sight and smell
of tobacco, or the social aspects involved in smoking",
according to the researchers. As a result, nicotine
replacement treatment is less successful in women. 14
The Brain's Pleasure Pathway
“Reward”
Dramatic changes in the brain's pleasure
circuits during withdrawal from chronic
nicotine use.
These changes are comparable in
magnitude and duration to similar
changes observed during the withdrawal
from other abused drugs such as cocaine,
opiates, amphetamines, and alcohol.
15
The Brain's Pleasure Pathway
“Reward”

All drugs with a potential for abuse appear
to (directly or indirectly) increase Dopamine
(DA) activity in this pathway.

Such drugs include: alcohol, cocaine,
amphetamine, nicotine, morphine,
methadone, methylenedioxyamphetamine
(MDA), methylenedioxymethamphetamine
(MDMA or ecstasy.
16
The Brain's Pleasure Pathway
“Reward”

The specific areas effected by particular drug are
not always known and certainly some act on
areas other than the MFB*/DA reward system.
Therefore the behaviour and subjective feeling
elicited by drugs which act on similar areas of the
brain can differ.
*Medial forebrain bundle (MFB) which links the VTA and Acb
Ventral segmental area (VTA), nucleus accumbens (Acb)
17
Brain areas and pathways involved in
the pleasure circuit.
18
Nicotine
Alcohol
19
Nicotine



Stimulates nicotinic receptors (a subclass of
acetylcholine receptors) including the VTA
dopaminergic cells which carry such receptors.
Nicotine releases DA in the nucleus accumbens.
Although nucleus accumbens neurons carry
receptors for nicotine this region does not
appear to be directly involved in nicotine's
reinforcing effects
20
Effects of nicotine on dopaminergic neurotransmission. Nicotine
increases the release of dopamine (DA). TH mediates the conversion
of tyrosine to L-dopa, the precursor of dopamine; this is the rate-limiting
step in dopamine synthesis. Dopamine transporter (DAT) is the site for
reuptake of dopamine and regulates the amount of synaptic dopamine.
COMT and MAO are involved in the metabolism of dopamine.
Dopamine binds to postsynaptic receptors that mediate
neurotransmission.
The genes coding for the enzymes and receptors have been studied in
smoking. DR dopamine receptor.
21
Cannabinoid receptors


D 9-tetrahydrocannabinol (THC), the active
ingredient of marijuana, acts on cannabinoid
receptors - the endogenous cannabinoid is
anandamide (from the Sanskrit word "Ananda"
meaning bliss).
Cannabinoid receptors are present all through
the brain with few receptors in the brain stem or
and spinal cord.
22
Cannabinoid receptors

The receptors are particularly dense in the
hippocampus (memory processing), the cortex
(cognitive function) and the basal ganglia and
cerebellum (movement control).
23
Cannabinoid receptors


CB1 receptors are coupled to G proteins and are
normally activate by endocannabinoids, of which
anandamide and 2-arachidonylglycerol
Unlike neurotransmitters and neuropeptides,
endocannabinoids are not stored in synaptic vesicles
but are produced on demand and released from the
cell membrane Arachidonic Acid (A.A.) of the
neurons.
24
Cannabinoid receptors

CB1 receptors are found in high numbers
on axon terminals of γ-aminobutyric acid
(GABA)-ergic interneurons throughout the
central nervous system; activation of these
receptors inhibits GABA release; and
GABA-ergic interneurons strongly influence
the activity of dopaminergic projection
neurons.
25
Nicotine
26
Prefrontal area
27
Smoking prevalence and
reason for concern





Cancers
Health consequencesLung
of smoking
Oral cavity
Respiratory disease
Pharynx
Cardiovascular
Pancreas
disease
Kidney
Cerebrovascular
Urinary tract
disease
cancer
28
Genetics



Initiation of smoking, 50%
Maintenance, 70%
Number of cigarettes smoked, 80%
29
CYP2A6


Variations in the activity of the primary
enzyme involved in nicotine metabolism may
largely explain lower smoking levels and lung
cancer rates found in slow metabolizers,
Lowering the activity of the enzyme CYP2A6
in individuals with normal enzyme activity or
with multiple copies of the gene may be a
strategy that can help in quitting smoking or
in reducing overall exposure to carcinogens in
tobacco smoke
30
CYP2A6 and lung cancer


15% of all cancers
80-90%of lung
cancers
CYP2A6 can also activate
tobacco smoke
procarcinogens (e.g. NNK,
4-(methylnitrosamino)-1(3-pyridyl)-1-butanone
31
Years of Life Lost Due to Smoking

Based on data collected in the late 1990s, the

It can steal the quality of life long before

US Centers for Disease Control and
Prevention (CDC) estimated that adult
male smokers lost an average of 13.2
years of life and female smokers lost
14.5 years of life because of smoking.
death.
Smoking-related illness can limit activities
by making it harder to breathe, get around,
work, or play.
32
Current treatment for
tobacco dependence

NRT

Nicotine gums




(nicotine
replacement
therapy)

Transdermal patches

Inhalers
Lozenges
Sprays

Bupropion
(non-nicotinic
pharmacological
agent)
Antidepressant
Used in more than 50
countries as
treatment of tobacco
dependency.
33
Increase in nicotine concentration
( ng/ml )
14
Plasma nicotine concentrations for
smoking and NRT
12
10
8
Cigarette
Gum 4 mg
6
Gum 2 mg
4
Inhaler
Nasal spray
Patch
2
0
5
10
15
Minutes
20
25
30
Source: Balfour DJ & Fagerström KO. Pharmacol Ther 1996 72:51-81.
34
Decreasing
“smoking behavior and
risk” through CYP2A6
inhibition
35
Novel treatment strategies based
on genetic manipulation






CYP2A6
Hepatic enzyme
90% of inactivation of nicotine to
cotinine
17 allelic variants
The allelic variants vary in the ability to
metabolize CYP2A6 substances
The metabolic ratio of cotinine to
nicotine is also greater in Korean than
Japanese population.
36
Risk of tobacco-related
cancers and mutations

Carcinogen components in
cigarette
Tobacco specific nitrosamines
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanon (NNK)
N’-nitrosonornicotine (NNN)
 Polycyclic aromatic hydrocarbons
(PAHs)
 Aromatic amines(5-200ng/cigarette)

37
Public health implications of
CYP2A6 polymorphism



Decreases risk of smoking initiation
and dependence
Decreases amount smoked tobacco
Decreases risk of tobacco-related
cancers and mutations
38
Slow “SMs” and Fast “FMs”
Metabolizers





Start smoking 3 years later.
Smoke for shorter duration.
Have an increased probability of quitting than Fast
Metabolizers “EMs”
Faster CYP2A6 metabolism has been associated
with higher levels of smoking, increased failure on
nicotine patch, and higher cancer risk.
.
39
Existing NRTs fail for several
reasons Existing NRTs fail for
several reasons





Inadequate extent of replaced nicotine
compared to the nicotine of cigarette.
NRT dos not mimic the rapid rise and
fall in plasma like cigarette nicotine.
Wide variation in nicotine metabolism
among individuals leads to variation of
nicotine concentration when an standard
dose is taken.
Dermal or gastric irritation.
…..
40
How Nicotine Replacement Works

Treats the difficult withdrawal symptoms and cravings that 70% to 90% of
smokers say is their only reason for not giving up cigarettes. Using a
nicotine substitute, reduces a smoker's withdrawal symptoms.

Most smokers do it on the first try.

In fact, smokers usually need many tries -- sometimes as many as 8 to 10 -before they are able to quit for good.

Most quitters go back to smoking within the first 3 months of quitting.


So don't be discouraged if the smoker start smoking again; stop again and
make another attempt more successful by adding another method or
technique to help you quit.
Reducing these symptoms with nicotine replacement therapy and a support
technique, gives smokers who want to quit have a better chance of quitting
and staying quit.
41
Nicotine replacement therapy



Nicotine replacement therapy only deals with
the physical addiction
Combine it with other smoking cessation
methods that help the psychological
(emotional and habitual) components of
smoking, such as a stop smoking program.
Pairing NRT with a program that helps to
change behavior -- can double your chances
of successfully quitting.
42
Nicotine Replacement Therapy



Nicotine in cigarettes leads to actual physical
dependence, which can cause unpleasant
symptoms when a person tries to quit.
Nicotine replacement therapy (NRT) gives you
nicotine -- in the form of gums, patches, sprays,
inhalers, or lozenges -- but not the other harmful
chemicals in tobacco.
It can help relieve some of these symptoms so
that you can focus on the psychological aspects
of quitting.
43
Nicotine replacement therapy (NRT) Cont.



The 24-hour patch provides a steady dose of nicotine,
avoiding peaks and valleys. It helps with early morning
withdrawal. But, there may be more side effects such as
disrupted sleep patterns and skin irritation.
Data suggests that nicotine replacement (specifically the
nicotine patch) can be used safely even in people who have
heart or blood vessel (cardiovascular) disease under a doctor's
careful monitoring.
The 16-hour patch works well if the smoker is a light-toaverage smoker. It is less likely to cause side effects like skin
irritation, racing heartbeat, sleep problems, and headache. But
it does not deliver nicotine during the night, so it is not helpful
for early morning withdrawal symptoms.
44
Nicotine replacement therapy (NRT) Cont.



Depending on body size, most smokers should
start using a full-strength patch (15-22 mg of
nicotine) daily for 4 weeks, and then use a weaker
patch (5-14 mg of nicotine) for another 4 weeks.
The patch should be put on in the morning on a
clean, dry area of the skin without much hair. It
should be placed below the neck and above the
waist -- for example, on the arm.
The FDA recommends using the patch for a total
of 3 to 5 months.
45
Some possible side effects of the nicotine
patch include:








skin irritation -- redness and itching
dizziness
tachycardia
sleep problems or unusual dreams
headache
nausea
vomiting
muscle aches and stiffness
46
Patient’s advise
What to do about side effects:





Do not smoke while you are using a patch.
Try a different brand of patch if your skin
becomes irritated.
Reduce the amount of nicotine by using a
lower dose patch.
Sleep problems may be short-term and pass
within 3 or 4 days. If not (and you're using a
24-hour patch), try switching to a 16-hour
patch.
Stop using the patch and try a different form of
nicotine replacement.
47
Nicotine gum (nicotine
polacrilex):

avoid acidic foods and drinks such as
coffee, juices, and soft drinks for at
least 15 minutes before and during gum
use.
48
Nicotine nasal spray:

Smokers usually like the nasal spray
because it is easy to use. However, the
FDA warns users that since this product
contains nicotine, it can be addictive. It
recommends that the spray be
prescribed for 3-month periods and
should not be used for longer than 6
months.
49
Bupropion (Zyban®)





Bupropion (Zyban®) is an antidepressant in an
extended-release form that reduces symptoms of
nicotine withdrawal.
It can be used alone or together with nicotine
replacement.
Bupropion works best if it is started 1 or 2 weeks
before the quit date.
The usual dosage is one or two 150 mg tablets per
day.
Contraindications : seizures, heavy alcohol use,
serious head injury, bipolar (manic-depressive)
illness, anorexia or bulimia (eating disorders).
50
Varenicline (Chantix®)

Partial agonist
selective for α4 β2
nicotinic
acetylcholine
receptor subtypes.
51
Varenicline (Chantix®) Cont.




Most of the active compound is excreted renally
(81%).
Side-effects, none common, include:
Nausea, headache, vomiting, flatulence,
insomnia, abnormal dreams, alteration in taste
Pregnancy Category C.
Nursing mothers; not adivsed unless highly
indicatesd
52
Varenicline (Chantix®) Cont.

Because varenicline is excreted substantially by the
kidney, patients with impaired renal function may be
at increased risk for toxic reactions.

Although no dosage adjustments are required for
mild to moderate impairment, patients with severe
renal impairment should receive a reduced initial
dose of 0.5 mg/day to be titrated as needed to a
maximum dose of 0.5 mg twice daily.
53
Usual Dosage for Adults







The patient has to be motivated to stop smoking
The patient should set a date to stop smoking.
Dosing should start one week before this date.
Should be taken after eating and with a full glass of water.
The recommended dose is 1 mg twice daily for a week , then
readjust the dose:
“Lower the dose temporarily or permanently” as follows:
Days 1 - 3
0.5 mg once daily
Days 4 - 7
0.5 mg twice daily
Day 8 -End of treatment
1.0 mg twice daily
Treatment has to continue for 12 weeks.
Patients who have successfully stopped smoking at the end of
12 weeks, an additional course of 12 weeks treatment is
recommended to further increase the likelihood of long-term54
abstinence
Varenicline (Chantix)


It lessens the pleasurable physical effects a
person gets from smoking, and it reduces the
symptoms of nicotine withdrawal.
Reported side effects:
headaches, nausea, vomiting, trouble sleeping,
unusual dreams, flatulence (gas), and changes
in taste.
Although these side effects may occur,
varenicline is usually well-tolerated.
55
Atropine and scopolamine
combination therapy


Atropine and scopolamine combination
therapy
Some smoking cessation clinics offer a
program using shots of the drugs
atropine and scopolamine to help
reduce nicotine withdrawal symptoms.
56
Other pharmacological treatments


Nortriptyline - There is evidence for
effectiveness of this tricyclic antidepressant but
because of the side effect profile it should be
considered only as a second line therapy after
bupropion and NRT
Clonidine has been found to be effective but its
usefulness is limited by side effects
57
58
59