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Tobacco Smoking “ A Pharmacological Over-view

Haider A. Ghaleb

Kasr El-Aini Faculty of MedicineCairo University

Nov. 7th 2007

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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.

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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 millionin 2020. 1.2 billion people worldwide are known tosmoke tobacco daily.5.6 trillion cigarettes are smoked per year.4.2 million people die annually from tobaccorelated disease.Tobacco-related diseases will be about 10 millionin 2020.

Prevalence

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EGYPT

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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.

Tobacco smoking and

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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

Tobacco smoking and

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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 self-administration 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.

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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.

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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.

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Major components of Lymbic System

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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, particularlyCYP2A6 and CYP2D6.

Nicotine metabolismNicotine metabolism

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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.

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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.

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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.

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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.

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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)

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Brain areas and pathways involved in the pleasure circuit.

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Nicotine Alcohol

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 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

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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.

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Cannabinoid receptors

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.

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Cannabinoid receptors

The receptors are particularly dense in the hippocampus (memory processing), the cortex (cognitive function) and the basal ganglia and cerebellum (movement control).

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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.

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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.

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Nicotine

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Prefrontal area

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Smoking prevalence and reason for concern

Health consequences of smoking

Respiratory disease Cardiovascular

disease Cerebrovascular

disease

Cancers Lung Oral cavity Pharynx Pancreas Kidney Urinary tract

15% of all cancers

15% of all cancers

80-90%of lung

80-90%of lung

cancers

cancers

cancercancer

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Genetics

Initiation of smoking, 50% Maintenance, 70% Number of cigarettes smoked,

80%

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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

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CYP2A6 and lung cancer

15% of all cancers15% of all cancers

80-90%of lung80-90%of lung

cancerscancers

CYP2A6 can also activate tobacco smoke procarcinogens (e.g. NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

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Years of Life Lost Due to Smoking

Based on data collected in the late 1990s, the 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.

It can steal the quality of life long before death.

Smoking-related illness can limit activities by making it harder to breathe, get around, work, or play.

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Current treatment for tobacco dependence

NRT NRT ((nnicotine icotine rreplacement eplacement ttherapy)herapy)

Nicotine gumsNicotine gums Transdermal Transdermal

patchespatches InhalersInhalers LozengesLozenges SpraysSprays

Bupropion Bupropion (non-nicotinic (non-nicotinic pharmacologicapharmacological agent)l agent)

Antidepressant Used in more than

50 countries as treatment of tobacco dependency.

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Minutes

Incr

ease

in

nic

oti

ne

con

cen

trat

ion

( n

g/m

l )

CigaretteGum 4 mg

Gum 2 mg

InhalerNasal sprayPatch

5 10 15 20 25 30 0

2

4

6

8

10

12

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Plasma nicotine concentrations for smoking and NRT

Source: Balfour DJ & Fagerström KO. Pharmacol Ther 1996 72:51-81.

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Decreasing “smoking behavior and

risk” through CYP2A6 inhibition

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Novel treatment strategies Novel treatment strategies based on genetic based on genetic manipulationmanipulation

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.

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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)

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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

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Slow “SMs” and Fast Slow “SMs” and Fast “FMs” Metabolizers“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.

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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. …..

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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.

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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.

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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.

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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-to-average 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.

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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.

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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

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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.

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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.

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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.

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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).

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Varenicline (Chantix®)

Partial agonist selective for α4 β2 nicotinic acetylcholine receptor subtypes.

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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

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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.

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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:

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-term abstinence

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

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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.

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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.

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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

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