Presenter: Dr. Priyanka KumawatPharmacology deptt.PGIMS, Rohtak

Introduction

• Quitting smoking- Process of discontinuing tobacco smoking

• Tobacco contains nicotine (addictive) can lead to dependence

• Nicotine addiction has historically been one of the hardest addiction to break

• Addiction- Most severe forms of dependence where compulsive craving dominates the subject's daily life.

• Quitting reduces risk of smoking related diseases

Epidemiology • There are around 1.3 billion smokers in the world

• 10 million deaths estimated by year 2030

• Smoking/Tobacco use is known to cause up to 90% of all lung cancers

• Approximately 40 percent of smokers attempt to quit annually, yet less than 5 percent actually do so.

• Smoking cessation treatments have greater cost effectiveness and clinical efficacy

Substance Abuse: Research and Treatment 2013:7 85–105

Rationale for treating smoking / tobacco dependence

5

Health Consequences of Smoking

U.S. Department of Health and Human Services. The Health Consequences of Smoking: Surgeon General, 2004.

• Cancers– Acute myeloid leukemia – Bladder and kidney– Cervical– Esophageal– Gastric– Laryngeal– Lung– Oral cavity and pharyngeal– Pancreatic

• Pulmonary diseases– Acute (e.g., pneumonia)– Chronic (e.g., COPD)

• Cardiovascular diseases– Abdominal aortic aneurysm– Coronary heart disease– Cerebrovascular disease– Peripheral arterial disease– Type 2 diabetes mellitus

• Reproductive effects– Reduced fertility in women– Poor pregnancy outcomes (e.g., low

birth weight, preterm delivery)– Infant mortality– Early menopause and osteoporosis

in females• Other effects: cataract, periodontitis, poor

surgical outcomes, cognitive decline, Erectile dysfunction

Compounds in Tobacco Smoke

– Carbon monoxideCarbon monoxide– Hydrogen cyanideHydrogen cyanide– AmmoniaAmmonia– BenzeneBenzene– FormaldehydeFormaldehyde

– NicotineNicotine– NitrosaminesNitrosamines– LeadLead– CadmiumCadmium– Polonium-210Polonium-210

An estimated 4,800 compounds in tobacco smoke

Gases Particles

11 proven human carcinogens6

Nicotine

NIH Publication No. 02-5074, October 2001

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Quitting: health benefits

Lung cilia regain normal function

Ability to clear lungs of mucus increases

Coughing, fatigue, shortness of breath decrease

Risk of stroke is reduced to that of people who have never smoked

Lung cancer death rate drops to half that of a continuing smoker

Risk of cancer of mouth, throat, esophagus, bladder, kidney, pancreas decrease

Risk of CHD is similar to that of people who have never smoked

2 weeks to

3 months

1 to 9 months

1year

5years

10years

after15 years

Time Since Quit Date

Circulation improves, walking becomes easier

Lung function increases up to 30%

Excess risk of CHD decreases to half that of a continuing smoker

Pathophysiology of smoking• Nicotine parasympathomimetic alkaloid- act on nicotinic

receptors(ganglionic) and CNS nicotinic receptor

• Helps to release epinephrine and norepinephrine (stimulant effect)- increase HR, BP, CO

lipolysis thus demand of oxygen, workload of heart, symptoms of ischaemia and other cardiovascular problems

• Release of harmful gases & oxygen free radicals in smoke leads to increase inflammatory mediators and endothelial damage

• Prothrombotic and atherogenic changes

bone resorption and reduce Ca+2 absorptionLeshner, 1997

Nicotine dependence• Rapid delivery (within seconds) of nicotine in brain from smoked cigarette

contributes to its high abuse potential.

• Nicotine stimulate the release of the neurotransmitter dopamine in the midbrain.

• Dopamine induces feelings of euphoria and pleasure and is responsible for activating the dopamine reward pathway (mesolimbic)

• Stimulation of the reward pathway reinforces the behavior so that it repeats.

• Other things which play a crucial role in reinforcement effects of nicotine are

• Upregulation of α4β2 nAChR in cerebellum & brainstem

• Reduced brain monoamine oxidase A and B activity

Pharmacological basis for treatment

• Replacement / substitution therapy for prevention and relief of withdrawal syndrome

• Drugs acting as agonists on nicotinic acetylcholine receptor

• Drugs which prevent dopamine/norepinephrine/ serotonin reuptake

• Drugs acting as antagonists on nACh receptors, which decrease the reward associated with smoking

• Others include those acting on GABA, opioid and cannabinoid receptors

Pharmacologic Methods:

First-line Drugs

Second line dugs

Need for newer drugs

• Drug dependence

• Under 18 some drugs are not to be given

• Development of tolerance

• Withdrawal effects

• Post cessation weight gain and depression

• Side effects of existing drugs

Emerging medications

Other novel approaches

SART 2013:7.85-105

Cytochrome p450 (CYP) 2A6 inhibitors

• Methoxsalen and Tranylcypromine

• Inhibit enzyme CYP2A6 which converts nicotine (orally) into cotinine

• Can be used with NRT to increase the nicotine bioavailability in the body without increasing the dose of nicotine through smoking

• This is ‘Harm reduction strategy’ to decrease the number of cigarettes consumed

• Status- Currently no CYP2A6-inhibitors approved for the treatment of tobacco (serious side effects)

GABAergic drugs

GABAergic input causes inhibition of dopaminergic tone, decreases the reinforcing properties of nicotine

BACLOFENSelective GABAB Agonist

Some clinical and preclinical evidence of its efficacy in treatment of tobacco dependence available but more to be studied

TIGABINEBlocks GABA uptake into presynaptic neurons Studies show significant decrease in craving for cigarettes and

enhancement of cognitive performance in abstinent smokers

Rimonabant

• Cannabinoid R antagonist- selectively blocking cannabinoid- 1receptor

• Activation of central cannabinoid system may participate in the motivational and reward function- play a role in dependence and habituation.

• Also protect quitters from significant post cessation weight gain

• S/Es – nausea and URTI

• Drug withdrawn from European market in 2008 due to increased levels of suicidal thoughts and depression

Nicobrevin

• Contain 4 active ingredients-• Quinine (15mg- reduce cravings)• Methyl valerate (100mg- sedative)• Camphor (10mg- relieves respiratory congestion)• Eucalyptus oil (10mg- relieves respiratory congestion and

gastrointestinal disturbances)

• Study in 2011 found it to be ineffective in smoking cessation

• Risks of the product outweighed the benefits

• S/E- Nausea, stomach ache, constipation, loss of appetite, vertigo, burning tongue, photosensitivity,insomnia etc..

• Withdrawn from market of UK & others in 2011.

E- cigarettes

Vaccines

• Nicotine chemically linked to carrier act as hapten

• Antibodies nicotine complex- too large to cross BBB

• It eliminate the brain rush that smokers experience & there is no point in smoking for most addicted smokers.

CYT002-NicQbVirus like particle formed by the recombinant coat protein of the

bacteriophage QbSlightly higher abstinence rates than controls

NicVAX

• Nicotine recombinant Pseudomonas Aeruginosa exprotein A conjugate vaccine

• Good absteinence rates

TA-Nic

• Immunotherapeutic vaccine • Yet to be studied further

AdjunctsGlucose tablets

Hunger pains associated with craving for cigarettes because nicotine relieves hunger in smokers

Useful adjunct to smoking cessation

Tryptophan and high carbohydrate dietReduction in negative effect which is a classic symptom of

withdrawal

D3 receptor ligandsDopamine receptors have role in the stimulus controlled drug

seeking behaviour Decrease rewarding or reinforcing effects of nicotine

Novel medications evaluated previously

Lobeline

An alkaloid, obtained from Indian tobacco plant lobelia inflatePartial nicotine agonistDosage form- tablets, parental injection, buffered tablets,

flavoured pastillesLong term trials failed to show any benefit

Mecamylamine

Non competitive nicotinic Ach receptor antagonistThought to block the physiological and reinforcing effects of

smokingMay be combined with nicotine transdermal medication

Silver acetate

•Act as an aversive stimulus to inspire smoking cessation by producing an unpleasant metallic taste when combined with cigarettes•Less efficacious than NRT•Combination used with NRT

Atropine, scopolamine and chlorpromazine combination

•Act on muscarinic sites in cerebral cortex which are involved in mediation of nicotine withdrawal•Practically found to be of no use

Conclusion

• Newer forms of NRT like nicotine straw, pulmonary delivered nicotine and nicotine containing electronic cigarettes have yet to establish their place in therapy for smoking cessation.

• Vaccines are new and a ray of hope to improve cessation attainment.

• Behavioral therapies for smoking cessation constitute a very important part of treatment because they increase the smoker’s will to quit

• Promising new therapeutic products are emerging and they will provide smokers additional options to assist in achieving smoking cessation.

References

• Pharmacotherapies for smoking cessation. Substance Abuse: Research and Treatment 2013:7

• G Bhutani (MD), J Kaushal (MD), M C Gupta (DM)Critical Appraisal of The Existing and Emerging Therapies for Smoking CessationMed J Malaysia Vol 66 No 5 December 2011

• Raupach et al. Nicotine Vaccines to Assist with Smoking Cessation.Drugs 2012; 72 (4)

• Nicotine vaccines to treat tobacco dependence.

• All smokers trying to quit should be offered medication

• There is insufficient evidence of effectiveness for pregnant women, smokeless tobacco users, light smokers, and adolescents

• All seven of the FDA-approved medications for treating tobacco use are recommended

• There are no well-accepted guidelines for optimal selection among the first-line medications

• The higher-dose preparations of nicotine gum, patch, and lozenge have been shown to be effective in highly dependent smokers

• Consider prescribing second-line agents (clonidine and nortriptyline) for patients unable to use first-line

OPIOID ANTAGONISTSOpioid system may be involved in the reinforcing

properties of several drugs of abuseOpioid antagonists may attenuate the reinforcing

value of cigarette smoking and thus decrease the number of cigarettes consumed.

NALMEFENEStudies suggest that it may have efficacy as a tobacco

dependence treatmentNALTREXONE

Used for alcohol dependence but data supporting its efficacy in tobacco withdrawl is lacking

Potential Health Benefits of Smoking Cessation

Time After Smoking

20 minBP, HR, peripheral circulation improve

24 hrsCO levels drop

48 hrsNicotine eliminated;

taste and smell improve

2-12 wksLung function can

improve 30%

3-9 moSOB and coughing

decrease

1 yrRisk of MI reduced 50%

10 yrsRisk of lung cancer

reduced 50%

15 yrsRisk of MI and

stroke reduce to level of nonsmoker

US Department of Health and Human Services 2010.