Smoking and Tobacco
Part 1
Health Risks
Epidemiology
Pharmacology of nicotine dependence
© 2010 University of Sydney
Learning objectives
To be able to:
• Recognise population impact of tobacco
use
• Understand pharmacology of nicotine
• Describe factors contributing to
dependence on tobacco smoking
• Describe benefits of smoking cessation
What is a cigarette?
• Cigarettes have long since been simple dried
tobacco
• ‘Tobacco’ in a cigarette is remanufactured leaf
– Fillers and expanders are added – bits of plant stem
and scraps and solidified tobacco dust
– The leaf is designed with the cigarette paper to burn in
a predictable and consistent fashion
– This reduces cigarette-to-cigarette variations
• There is an uncertain number of additives that
have a variety of putative roles
– Ease the otherwise irritating effect of smoke
– Increase the speed of nicotine delivery
• Highly addictive modern cigarette was
developed and extensively taste/effect tested in
the 1950s-1970s.
Smoking in Australia
Tobacco Smoking: Harms
• Major preventable cause of premature morbidity and
mortality in Australia and throughout the world
• Major risk factor for a number of diseases and
conditions, including:
–
–
–
–
coronary heart disease
stroke
peripheral vascular disease
and cancer1
• Types of cancer:
– of the mouth, larynx, oesophagus, lung, stomach,
pancreas, kidney, urinary bladder, uterine cervix and
leukemia2
1AIHW
(2008). Australia’s health 2008.
JA, et al (2009) “The Pharmacology of Nicotine and Tobacco” in Principles of
Addiction Medicine. 4th edition
2Dani
Tobacco Smoking: Harms (cont)
• Increases risk of developing:
– Respiratory tract infections
• Influenza, pneumococcal pneumonia, TB
– Peptic ulcers
– Cataracts, macular degeneration1
• Gender specific risks
– In women:
• Low levels of oestrogen, early menopause, osteoporosis
• In pregnancy – risk of spontaneous abortion and perinatal
mortality. Morbidity increased by one third and the risk of
having a low birth weight infant is doubled.
– In men:
• Erectile dysfunction, primarily in people with underlying
vascular disease and with coronary artery disease and
hypertension.1
1Dani
J et al (2009)
Smoking: any health benefits?
•
Possibly reduces symptom severity in schizophrenia
(self-medication hypothesis)
– There is deficient endogenous central nicotinic neurotransmission
in schizophrenia, which causes a disruption of sensory gating (a
possible mechanism for delusions).
– Exogenous nicotine partly compensates for this deficiency.
– Schizophrenic patients smoke larger amounts of cigarettes per
day and extract more nicotine from them – significant health risk.
– Therapeutic use of safe forms of nicotine in schizophrenia has
been proposed.1
•
Reduces risk of Parkinson’s disease
– Benefit correlates with the intensity and duration of smoking.
– Does not appear to be due to publication bias. 2
•
Does it reduce prevalence of Alzheimer’s disease?
– After controlling for tobacco industry affiliation, smoking has been
found to increase the risk of Alzheimer’s disease, RR -1.72.3
1Conway
JL. (2009) Med Hypotheses. 73(2):259-62.
M, et al (2009) Biochem Pharmacol. Oct 1;78(7):677-85.
3Cataldo et al (2009) J Alzheimers Dis. Oct 8. [Epub].
2Quik
Tobacco Smoking: Costs
• In Australia, tobacco smoking was
responsible for 7.8% of the total burden of
disease in 2003
– Lung cancer, chronic obstructive pulmonary
disease and ischemic heart disease account for
more than 3/4 of this burden1
• Estimated tangible costs of tobacco use in
2004–05 were $10.8 billion (about 1.3% of
gross domestic product)2
1Begg
S, et al (2007). The burden of disease and injury in Australia 2003.
DJ and Lapsley HM (2008). The costs of tobacco, alcohol and illicit drug abuse to
Australian Society in 2004/05.
2Collins
Annual death and burden due
to tobacco
Note: DALY = ‘Disability-adjusted life year’
• Key measure of total burden of disease and injury.
• Describes years of life lost due to premature death plus years of
‘healthy’ life lost due to disability.
Begg S, et al (2007). The burden of disease and injury in Australia 2003. AIHW.
Lung cancer mortality,
Australia 1910–2004
• Age-standardised rates per 100,000 persons (World Standard
Population)
Source: Scollo, M and Winstanley, M [eds]. (2008) Tobacco in Australia: Facts and Issues.
Third Edition. Cancer Council Victoria.
Deaths due to smoking
• Incidence is falling in men but remain relatively constant in women
Source: NSW Health, Population Health Division. The health of the people of New South
Wales - Report of the Chief Health Officer. © - Copyright - New South Wales Health
Department for and on behalf of the Crown in right of the State of New South Wales
Tobacco Control
• The falls in COPD and lung cancer
deaths in Australia are largely
attributed to tobacco control.
• Australia ranks with Sweden, Canada
and the USA as having achieved the
largest falls in daily smoking
prevalence of any nation.
Scollo, M and Winstanley, M (2008) Tobacco in Australia: Facts and Issues. 3rd Ed.
Public Health Approaches to
Tobacco Control
• Restricting access by regulation of
supply
• Prohibition (selective or total)
• Taxation to increase price
• Demand reduction
• e.g. reducing acceptability of smoking
• Warning labels
• Harm reduction
• ?Snuff tobacco
Some Australian achievements
in Tobacco Control
• Restrictions on advertising and promotion
– TV/radio
– Print
– Elimination of sports and ‘cultural’ sponsorship
• Public places and workplace legislation
– Workplaces
– Sporting stadiums
– Pubs/clubs
– Outdoor places (beaches and parks)
Some Australian achievements
in Tobacco Control (cont)
• Innovative mass media and counter-advertising
– e.g. successful bubblewrap/COPD campaign
• Increased private smoke-free places
– Smoke-free homes
– Smoke-free cars
• Graphic pack warnings
• (Some) point-of-sale initiatives
Tobacco Control in Australia:
Major events and tobacco sales
Major events in tobacco control and tobacco products dutied for sale per person 15
years and over, Australia, 1906 -2006, (grams)
Source: Scollo, M and Winstanley, M (2008). Tobacco in Australia: Facts and Issues. 3rd Edition.
Cancer Council Victoria.
Current patterns
• Overall smoking rate has been declining.
• In the 1950s an estimated 70% of males
and 30% of females smoked.
• Currently 1 in 6 Australians aged 14 years
and over smokes (16.6%).
– Daily smoking rate is 18% in males and
15% in females
AIHW (2008). 2007 NDS Household Survey
Daily smoking rate
Source: AIHW (2008). ‘Australia’s health 2008’, cat. no. AUS 99
Daily smoking 2007
by State/Territory
30
Males
25
Females
20
15
10
5
0
WA
SA
NSW
ACT
VIC
Aust
QLD
TAS
NT
Data Source: AIHW (2008). 2007 NDS Household Survey: State and territory supplement.
Youth Daily Smoking
2007 (ages 14-19)
25
Males
20
Females
15
10
5
0
SA
WA
VIC
Aust NSW
QLD
ACT
TAS
NT
Data Source: AIHW (2008). 2007 NDS Household Survey: State and territory supplement.
Total community smoking
burden
• Daily smokers
– Male
– Female
1.54M
1.33M
• Less than daily smokers
– Male
– Female
0.26M
0.21M
– Ex-smokers
– Never smokers
4.33M
9.55M
AIHW (2008). 2007 NDS Household Survey: detailed findings.
Specific populations
• Smoking is more common in the following
groups:
– People from lower economic background
• 26% with the lowest status reported regular smoking
versus 14% with the highest status.
– Living in remote areas
• 25% of people living in remote areas compared with 18%
for people in major cities.
– Unemployed
• 38% compared to 22% (employed) or 9% (students)
– People from the Aboriginal and Torres Strait
Islander background
• 34% versus 19% (other Australians)
AIHW (2008). 2007 NDS Household Survey: detailed findings.
Smoking in Indigenous
population
• Rates are more than double those in general
population1
– Males
51%
– Females
47%
– No change since 1994
• Causes 12% of the burden of injury and disease
due to smoking in males and 7% in females1
– Population comparisons 9.5% & 6% respectively
• Smoking during pregnancy is very common – up
to 72%2
1Trewin
D (2006) National Aboriginal and Torres Strait Islander Health Survey: Australia,
2004–05. 2Ivers R. (2001) Indigenous Australians and Tobacco: a literature review.
• Higher prevalence of smoking in remote Indigenous communities
AIHW (2008). Indicators for chronic diseases and their determinants.
Smoking and Mental Health
• People with psychiatric disorders and
substance use disorders have 2-4 times
higher rates of smoking (range 41% and 67%
respectively) than the general population.
• 40-88% of patients with schizophrenia
smoke.
Kalman D et al(2005). American Journal on Addictions,14:106-123.
Smoking and Mental Health
(cont)
• Among current smokers in general population:
– ~ 41% report having a mental health diagnosis in the last
month.2
– 60% report a past or current history (ever history) of a mental
health diagnosis sometime in their lifetime.1
– the most common mental health diagnoses include:2
•
•
•
•
Alcohol abuse
Major Depressive Disorder
Anxiety disorders: simple phobias and social phobias
Substance Abuse
• Among those seeking help to stop smoking3:
– 30% are likely to have a history of depression
– 20% are likely to be using alcohol or other drugs
1Kalman D et al(2005). American Journal on Addictions,14:106-123.
2 Lasser K, et al. (2000) JAMA, 284:2606-2610.
3Zwar N, et al (2004). Smoking Cessation Guidelines for Australian General Practice.
Pharmacology of nicotine and
neurobiology of nicotine
dependence
Nicotine
• Naturally occurring alkaloid
– Serves as insecticide in many plants
• Major CNS active compound in tobacco
smoke
• Nicotinic cholinergic receptor agonist
• In humans acts mainly as a psychostimulant
and mood modulator.
Nicotinic Acetylcholine
Receptors (nAChRs)
• Ligand-gated ion channels (mostly Na+/K+ )
• Widespread in the CNS
• Acetylcholine (Ach) is the endogenous
ligand
• The major role in mammalian CNS is to
influence neurotransmitter release.
Dani et al (2009) Principles of Addiction Medicine. 4th Ed.
nAChR structure
• Pentamer
– 5 polypeptide subunits
– 9 subtypes
– Potential for 59 = 2 million different assemblies
• Nicotine is a potent agonist at the
nicotinic 42 receptor
β2
α4
β2
α4
β2
• Nicotine dependence is modulated primarily
through 42 nACh receptors
– In 2-subunit knock-out mice nicotine does not produce
reinforcing effect (less dopamine is released and mice do not
self-administer nicotine).1
– Alterations in 4 structure change the receptor sensitivity to
nicotine2
1Mineur
2Tapper
YS and Picciotto MR (2008) Biochem Pharmacol, 75:323-333.
AR, et al. (2004) Science, 306:1029-1032.
nAChRs: functional states
• Three states of the nAChR ion
channels:
– closed (at rest)
– open (cations flow into the cell)
– desensitised (closed and not
responsive to agonists)
Dani JA, et al (2009)
Receptor activation
• Ach (or nicotine) binds to the receptor and stabilises
the open state of the ion channel for several
milliseconds.
• Cations (Na+ and K+) enter and depolarise the cell
initiating cellular response
• A variety of neurotransmitters are released in the CNS
as presynaptic nAChRs are present on various types
of neurons.
• ACh is rapidly broken down by acetylcholine-esterase
• Nicotine has much longer duration of effect than ACh
• Receptor becomes de-sensitised and unresponsive for
a period of time
Dani JA, et al (2009)
nAChRs with repeated
smoking
• Between cigarettes nAChRs are mainly desensitised
(acute tolerance).
• Next cigarette activates a small pool of receptors that
are still responsive, producing pleasurable effects.
• In chronic smokers (e.g. with daily smoking for 6
months or longer):
–
–
–
–
Tolerance
Withdrawal syndrome on cessation of smoking
Long-term desensitisation of nAChRs
Increase in receptor density (upregulation of nAChRs)
as a compensatory response to desensitisation of the
large proportion the total number of nAChRs receptors.
Nicotine effects
• Releases multiple neurotransmitters in the CNS,
including:
– ACh, dopamine, noradrenaline, GABA, serotonin and
glutamate
• Produces CNS stimulatory effects:
– Increased arousal, decreased fatigue, decreased appetite
– Improved attention, concentration and cognitive function
– Euphoria and increased sense of wellbeing
• Decreases anxiety (particularly in stressful
situations) and reduces muscle tension
– important effects that are perceived as beneficial by
smokers
Reinforcement
• Reinforcing effect is mediated mostly
via activation of the dopaminergic
neurones and release of dopamine in
the mesolimbic reward pathway
– Ventral Tegmental Area - Nucleus
Accumbens - Prefrontal Cortex
• These areas have high concentrations
of nAChRs, both presynaptic and
postsynaptic.
Other effects
• Sympathetic stimulation
– Increased heart rate and blood pressure
• Some unpleasant effects occur at
initiation of smoking, but tolerance to
these effects quickly develops if
smoking is continued
– nausea, headache, dizziness
Nicotine pharmacokinetics:
Absorption
• 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)
Nicotine metabolism
• Extensively metabolised in the liver
• CYP2A6 is the major enzyme involved
• Major metabolite: cotinine
– ~ 80% of nicotine converted to cotinine
– long half-life: 20 hours
– appears in urine
• Induction of CYP2A6 enzyme may enhance clearance and
contribute to metabolic tolerance
• Metabolism of nicotine is faster during pregnancy and in
women on estrogen containing contraceptive pill or
hormone replacement therapy (estrogen is the CYP2A6
inducer).
Dani JA, et al (2009)
Nicotine plasma concentration
• Each cigarette delivers 1.2-2.9mg 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)
• The increment is 5-30ng/ml after each cigarette
(depending on how the cigarette is smoked)
• More frequent smoking reduces fluctuations in
nicotine plasma concentration
• The plateau (10-50ng/ml) is usually reached in the
early afternoon
Dani JA, et al (2009)
Nicotine plasma concentrations
Smoking 3 cigs/hour
Russel MA and Feyerabend C (1978) Cigarette smoking: a dependence on high-nicotine boli.
Drug Metabolism Review. 8(1):29-57. © 1978. Reprinted by permission of Taylor & Francis.
How smokers titrate their dose
of nicotine
• Smokers control nicotine intake to achieve desired
effect by altering:
– the puff volume
– the number of puffs they take from a cigarette
– the depth of inhalation
• Initial puffs are rapid and deep to achieve rapid
nicotine delivery
• Smokers tend to take smaller puffs towards the
end of a cigarette (when desired nicotine has been
delivered) to titrate the dose
Nicotine withdrawal
• Nicotine plasma concentration significantly drops
overnight, which leads to withdrawal symptoms in
the morning in chronic smokers.
• Withdrawal onset is usually within a few hours after
last cigarette
• Nicotine withdrawal syndrome includes:
– Mood changes
• dysphoria, depressive mood
–
–
–
–
–
Irritability, frustration or anger
Anxiety, restlessness
Difficulty concentrating, impaired attention
Hunger, increased appetite or weight gain
Craving
Nicotine withdrawal (cont)
• First morning cigarette produces the most pleasurable
effect
– After an overnight abstinence more receptors become
available for activation
– It also relieves withdrawal symptoms
• The earlier the smoker begins to smoke after waking
in the morning the more severe the dependence
• If abstinence continues, withdrawal symptoms peak at
24-48 hours and gradually subside over several
weeks.
• Some symptoms persist for months
– mild depression, dysphoria and anhedonia
Dani JA, et al (2009)
Cycles of pleasure and
withdrawal
Nicotine used for pleasure,
enhanced performance,
mood regulation
Tolerance and physical
dependence1,2
•
Initial activation causes
pleasure response but…
•
Dopamine falls quickly over
the next 2 hours
•
As levels fall the smoker feels
displeasure or withdrawal
•
The next cigarette reduces
the cravings and other
withdrawal symptoms and
produces some positive
effects
•
This reinforces the
compulsion to smoke
•
Environmental cues are also
important in producing
addiction
Nicotine used to
self-medicate
withdrawal symptoms1
Abstinence produces
withdrawal symptoms
and cravings1
1Jarvis
MJ. (2004) BMJ, 328:277-279.
VI (1997) Nature, 390:401-404.
2Pidoplichko
Standard Elements of
Dependence
• Context
• Ritual behaviours
• Sensory stimulation
• Reinforcing (nicotine) stimulus
Context
• Some places, times and situations are closely
associated with smoking and enhance craving:
– Morning coffee with breakfast
– Coffee shop
– Tea breaks
• Some places and situations are now negatively
associated and cravings can be less severe:
–
–
–
–
–
Places of worship
Sporting stadiums
In aircraft
Smoke-free homes
Around children
Ritual behaviours
• Going to a place where smoking is
possible
• Accessing the cigarette – e.g. opening
handbag
• Getting match or lighter
• Lighting cigarette
Sensory stimuli
• Touch/feel of cigarette
• Light from flame
• Smell of smoke
• Direct airway stimulation from smoke
– Anaesthetising the airway reduces reported
smoking satisfaction
• These all travel to brain at nerve speed
preceding the arrival of nicotine
Addictive qualities
• Fast absorption of nicotine and short time needed to
reach receptor targets (and hence to exert
pleasurable effects) are important factors in
development of addiction
• When linked with context/ritual/sensory stimuli they
produce a strong reinforcing effect
• In animals, random boluses of IV nicotine without the
context associations cannot establish addiction and
self-administration of nicotine does not occur.
Individual variability
• Smokers with low level of dependence or
non-dependent:
– 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-to-severe dependence and find
it difficult to stop or cut down
Genetics
• Heritability ~50% (range 28-84%)1
• Effect of gene polymorphisms
– People with defective alleles of CYP2A6 gene
have slow metabolism of nicotine and lower
rates of smoking and tobacco dependence.1
– People with CHRNA4 gene polymorphism
(gene coding for α4 subunit of the nicotinic Ach
receptor) have higher rates of tobacco
dependence.2
1Schnoll
et al. (2007) Curr Psychiatry Rep, 9:349-357.
et al. (2007) Arch Gen Psychiatry, 64(9):1078-1086.
2Hutchison
Health Benefits of
smoking cessation
If smoking continues
• Risk of further illness is greatly increased1
– Second heart attacks are more common amongst
cardiac patients if they continue to smoke.
– Increased risk of a second cancer in people with
successfully treated cancers who continue to smoke
– Diabetics who smoke increase their risk of
cardiovascular disease, peripheral vascular disease,
progression of neuropathy and nephropathy.
– There is a clear relationship between continued smoking
and progression of COPD.
1Zwar
N, et al (2004). Smoking Cessation Guidelines for Australian General
Practice.
Recent smokers - attempts
to quit/cut down1
• Most smokers regret having started smoking and have
made at least one attempt to quit.
• A third of recent smokers reported decrease in the
number of cigarettes smoked in the previous year.1
1AIHW
(2008). 2007 NDS Household Survey
Motivating Factors
• Major motivating factors – health or fitness and cost
AIHW (2008). 2007 NDS Household Survey.
Smoking reduction:
Ineffective Strategies
• 1) Smoking cigarettes with reduced tar and nicotine
delivery
• 2) Reducing number of cigarettes smoked in a day
(as a life-time strategy)
• Neither strategy significantly reduces exposure to
smoke
• Smokers compensate for reduced delivery of
nicotine:1
– By taking more frequent and deeper breaths
– Increasing smoke intake by blocking the ventilation
holes of the filter with their fingers or their lips
1Dani
JA, et al (2009)
Reduced Tar Cigarettes: Effect on
the hazard ratio for lung cancer
Source: Harris et al (2004) BMJ, 328:1-8
© BMJ. Reproduced with permission from BMJ Publishing Group.
Smoking Fewer Cigarettes
Copenhagen Studies
• N=19,732 (from 3 studies)
– Examined between 1967 and 1988
– Reexaminations at 5 to 10 year intervals
– Mean follow-up of 15.5 years
• Three groups
– Continued smokers of >15 cigs/day
– Reducers of >50%
– Quitters
• Reducers vs. continuing smokers
–
–
–
–
CV disease
Resp. disease
Tobacco cancers
All-cause mortality
HR = 1.01 (0.76-1.35)
HR = 1.20 (0.70- 2.07)
HR = 0.91 (0.63-1.31)
HR = 1.02 (0.89-1.17)
Godtfredsen et al (2002) Am J Epidemiol, 156:994-1001.
Quitters
0.88
0.77
0.36
0.65
Smoking cessation
• Benefits are seen quickly
– 5 Days
• Sense of taste and smell improve
– 6 Weeks
• Safer surgery with fewer wound infections
• Improved control of asthma
– 3 Months
• Cilia begin to recover and lung function improves
– 1 year
• Risk of coronary heart disease is halved
compared to continuing smokers
Zwar N, et al (2004). Smoking Cessation Guidelines for Australian General Practice.
Benefits timeline (cont.)
• 10 years:
– Risk of lung cancer is less than half that of a continuing smoker
and continues to decline
• 10-15 years:
– Risk of coronary heart disease the same as a non-smoker
– All-causes of mortality decline to the same level as people who
have never smoked.
• In addition:
– Women who quit before or in the early months of pregnancy have
the same risk of having a low birth-weight baby as women who
have never smoked.
– Quitting slows the rate of loss of lung capacity in chronic airways
disease
– Improved appearance of skin and fitness
– Saves money - based on one $10 pack of cigarettes per day: 1
year the cost is $3,650, over 5 years: $18,250.
Zwar N, et al (2004).
Conclusions (1)
• Smoking is the leading cause of preventable illness
and premature death.
• The majority of smokers consider the health risks of
smoking.
• Nicotine is the main addictive substance in tobacco
smoke.
• Nicotine is rapidly delivered to the target receptors in
the brain.
• Nicotine activates ACh receptors in the CNS
stimulating release of an array of neurotransmitters
including dopamine.
• It produces mostly stimulant effects but also relieves
anxiety and muscle tension.
Conclusions (2)
• Cigarette smoking is highly addictive when linked
with environmental cues.
• Abstinence from smoking results in a withdrawal
syndrome in dependent smokers.
• Most smokers have tried to quit or alter their pattern
of smoking in a way that they believe is healthy.
• Benefits of smoking cessation are evident as early
as several days of stopping.
• After 10-15 years the risk of morbidity and mortality
is the same as in people who never smoked.
Case Study
• John, aged 39 presents with his third chest
infection in 12 months. He reports that despite two
attempts to quit, he is still smoking a pack a day.
He is not motivated to quit because ‘it‘s just too
hard to do it right now’. He is under stress at work
and needs his cigarettes. He now requests a
prescription for antibiotics.
• How important is it for John to stop smoking?
• What would you say to John about benefits of smoking
cessation?
• How soon after quitting could he expect to see health
risks reduce to non-smoker levels?
• What are the major motivating factors for quitting?
Case Study Answers
• If John continues smoking:
– antibiotics prescribed for current chest infection will be less
effective
– he is likely to suffer from more chest infections and may
develop COPD in future
– increased risk for lung cancer, cancer of other organs, cardiovascular disease, stroke, peripheral vascular disease, peptic
ulcer, cataracts etc
• Benefits of quitting:
–
–
seen as early as 5-6 weeks after quitting.
immune function will improve and he will be less likely to suffer from
chest infections.
– Health risks return to non-smoker levels after 10-15 years of
abstinence.
• Major motivating factors for quitting are health or
fitness and cost.
Contributors
Dr Olga Lopatko
University of Sydney
Clinical A/Professor Matthew Peters
Concord Hospital & University of Sydney
All images used with permission, where applicable