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Similar to recent advances in smoking cessation
recent advances in smoking cessation
- 1. Presenter: Dr. Priyanka Kumawat Pharmacologydeptt. PGIMS, Rohtak
- 2. 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
- 3. Epidemiology • There arearound 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
- 4. Rationale for treatingsmoking / tobacco dependence
- 5. 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
- 6. 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 carcinogens 6 Nicotine NIH Publication No. 02- 5074, October 2001
- 7. 7 Quitting: health benefits Lungcilia 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 1 year 5 years 10 years after 15 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
- 8. 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 absorption Leshner, 1997
- 9. Nicotine dependence • Rapiddelivery (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
- 10. 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
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- 13. Need for newerdrugs • 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
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- 15. Other novel approaches SART2013:7.85-105
- 16. 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)
- 17. GABAergic drugs GABAergic inputcauses inhibition of dopaminergic tone, decreases the reinforcing properties of nicotine BACLOFEN Selective GABAB Agonist Some clinical and preclinical evidence of its efficacy in treatment of tobacco dependence available but more to be studied TIGABINE Blocks GABA uptake into presynaptic neurons Studies show significant decrease in craving for cigarettes and enhancement of cognitive performance in abstinent smokers
- 18. Rimonabant • Cannabinoid Rantagonist- 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
- 19. Nicobrevin • Contain 4active 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.
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- 21. Vaccines • Nicotine chemicallylinked 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-NicQb Virus like particle formed by the recombinant coat protein of the bacteriophage Qb Slightly higher abstinence rates than controls
- 22. NicVAX • Nicotine recombinantPseudomonas Aeruginosa exprotein A conjugate vaccine • Good absteinence rates TA-Nic • Immunotherapeutic vaccine • Yet to be studied further
- 23. Adjuncts Glucose tablets Hunger painsassociated with craving for cigarettes because nicotine relieves hunger in smokers Useful adjunct to smoking cessation Tryptophan and high carbohydrate diet Reduction in negative effect which is a classic symptom of withdrawal D3 receptor ligands Dopamine receptors have role in the stimulus controlled drug seeking behaviour Decrease rewarding or reinforcing effects of nicotine
- 24. Novel medications evaluatedpreviously Lobeline An alkaloid, obtained from Indian tobacco plant lobelia inflate Partial nicotine agonist Dosage form- tablets, parental injection, buffered tablets, flavoured pastilles Long term trials failed to show any benefit Mecamylamine Non competitive nicotinic Ach receptor antagonist Thought to block the physiological and reinforcing effects of smoking May be combined with nicotine transdermal medication
- 25. Silver acetate •Act asan 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
- 26. Conclusion • Newer formsof 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.
- 27. References • Pharmacotherapies forsmoking 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.
- 29. • All smokerstrying 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
- 30. • The higher-dosepreparations 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
- 31. OPIOID ANTAGONISTS Opioid systemmay be involved in the reinforcing properties of several drugs of abuse Opioid antagonists may attenuate the reinforcing value of cigarette smoking and thus decrease the number of cigarettes consumed. NALMEFENE Studies suggest that it may have efficacy as a tobacco dependence treatment NALTREXONE Used for alcohol dependence but data supporting its efficacy in tobacco withdrawl is lacking
- 32. Potential Health Benefitsof Smoking Cessation Time After Smoking 20 min BP, HR, peripheral circulation improve 24 hrs CO levels drop 48 hrs Nicotine eliminated; taste and smell improve 2-12 wks Lung function can improve 30% 3-9 mo SOB and coughing decrease 1 yr Risk of MI reduced 50% 10 yrs Risk of lung cancer reduced 50% 15 yrs Risk of MI and stroke reduce to level of nonsmoker US Department of Health and Human
Editor's Notes
- #3 obacco contains a substance - nicotine - which keeps the smoker smoking. Experts say it may be as addictive as some recreational drugs, such as cocaine. Nicotine increases the release of neurotransmitters which regulate behavior and mood. Nicotine triggers the release of dopamine, a neurotransmitter which give people a pleasant feeling. Obtaining that dopamine rush is said to be a major part of the addiction process - smokers crave that neurotransmitter (especially dopamine) rush
- #4 smoking cessation treatments have greater cost effectiveness and clinical efficacy in comparison to other preventative health measures such as treatment of hypertension and hypercholesterolemia,8–10 and research has shown that the cost per life year saved by smoking cessation interventions makes it one of the most cost-effective health care interventions.
- #6 goals of smoking cessation are both to reduce health risks and to improve the quality of life The 2004 Surgeon General’s Report on the health consequences of smoking describes a long list of diseases with sufficient evidence to infer a causal relationship with smoking. ♪ Note to instructor(s): For more detailed information and literature citations regarding risks for these tobacco-related illnesses, refer to the Pathophysiology of Tobacco-Related Disease module or the Surgeon General’s Report at http://www.surgeongeneral.gov/library/smokingconsequences. U.S. Department of Health and Human Services. The Health Consequences of Smoking: A Report of the Surgeon General. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2004. Available at http://www.surgeongeneral.gov/library/smokingconsequences. Accessed May 29, 2004. Slide is used with permission, Rx for Change: Clinician-Assisted Tobacco Cessation. Copyright © 1999-2009 The Regents of the University of California. All rights reserved.
- #7 Tobacco smoke, which is inhaled either directly or as second-hand smoke, contains an estimated 4,800 compounds. The majority of the compounds are present in the particulate phase, suspended in tobacco smoke. Based on a classification system by the International Agency for Research on Cancer, there currently are 11 known human carcinogens (Group I), 7 probable human carcinogens (Group 2A), and 49 animal carcinogens that possibly also are carcinogens in humans (Group 2B) (NCI, 2001). Examples of detrimental compounds (some of which are carcinogens) in tobacco smoke include the following: Carbon monoxide: automobile exhaust; binds to hemoglobin, inhibits respiration Hydrogen cyanide: gas chamber poison; highly ciliotoxic, inhibits lung clearance Ammonia: floor/toilet cleaning agent; irritation of respiratory tract Nicotine : addictive substance; toxic alkaloid Benzene: solvent, banned substance in organic chemistry labs; Group I carcinogen Nitrosamines: carcinogenic in animals and probably in humans; Group 2A and 2B carcinogens Lead: heavy metal, toxic to central nervous system; Group 2B carcinogen Cadmium: heavy metal found in rechargeable batteries; Group I carcinogen Hexavalent chromium: highlighted in the movie Erin Brockovich; Group I carcinogen Arsenic: pesticide; Group I carcinogen Polonium-210: radioactive agent; Group I carcinogen Formaldehyde: embalming fluid; Group 2B carcinogen Other substances in tobacco smoke (not listed above) that have sufficient evidence to be classified as Group I carcinogens in humans include 2-naphthylamine, 4-aminobiphenyl, vinyl chloride, ethylene oxide, beryllium, nickel, and cadmium. National Cancer Institute. Risks Associated with Low Machine-Measured Yields of Tar and Nicotine. Smoking and Tobacco Control Monograph No. 13. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, NIH Publication No. 02-5074, October 2001.
- #8 The 1990 Surgeon General’s Report on the health benefits of smoking cessation outlines the numerous and substantial health benefits incurred when patients quit smoking (USDHHS, 1990): Health benefits realized 2 weeks to 3 months after quitting include the following: circulation improves, walking becomes easier, and lung function increases up to 30%. One to nine months later, lung ciliary function is restored. This improved mucociliary clearance greatly decreases the chance of infection because the lung environment is no longer as conducive to bacterial growth. Consequently, coughing, sinus congestion, fatigue, and shortness of breath decrease. In some patients, coughing might actually increase shortly after quitting. This is because the cilia in pulmonary epithelial cells are functioning “normally” and are more effectively clearing the residual tars and other accumulated components of tobacco smoke. One year later, excess risk of coronary heart disease (CHD) is decreased to half that of a smoker. After 5 to 15 years, stroke risk is reduced to a rate similar to that of people who have never smoked. Ten years after quitting, an individual’s chance of dying of lung cancer is approximately half that of continuing smokers. Additionally, the chance of getting mouth, throat, esophagus, bladder, kidney, or pancreatic cancer is decreased. Finally, 15 years after quitting, an individual’s risk of CHD is reduced to a rate similar to that of people who have never smoked. Thus the benefits of quitting are significant. It is never too late to quit to incur many of the benefits of quitting. The next two slides depict some advantages of quitting earlier in life, as opposed to later. U.S. Department of Health and Human Services (USDHHS). (1990). The Health Benefits of Smoking Cessation. A Report of the Surgeon General (DHHS Publication No. CDC 90-8416). U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention and Health Promotion, Office on Smoking and Health. Slide is used with permission, Rx for Change: Clinician-Assisted Tobacco Cessation. Copyright © 1999-2009 The Regents of the University of California. All rights reserved.
- #9 Experts say that when nicotine is inhaled the brain is affected within seconds. After an inhalation the smoker's heart rate increases, levels of the hormones noradrelanine also increase, as well as dopamine - the whole experience is said to enhance mood, as well as the ability to concentrate. First, nicotine via cigarettes is absorbed via the lung, directly into the arterial system, without dilution of the venous system, and reaches the brain within 10 seconds [1]. This is faster than intravenous use. I know of few rewards that occur quicker. Second, if one smokes 20 cigarettes a day and takes 10 puffs per cigarette, this means 200 rewards per day.
- #10 Nicotine triggers the release of dopamine, a neurotransmitter which give people a pleasant feeling. Obtaining that dopamine rush is said to be a major part of the addiction process - smokers crave that neurotransmitter (especially dopamine) rush. Experts say that when nicotine is inhaled the brain is affected within seconds. After an inhalation the smoker's heart rate increases, levels of the hormones noradrelanine also increase, as well as dopamine - the whole experience is said to enhance mood, as well as the ability to concentrate. Some time after the last cigarette, the levels of these hormones drops, leaving the smoker feeling anxious and possibly irritable, and in need of another nicotine boost. Hereditary - geneticists believe that the reason some people try cigarettes and do not become smokers, while others do so very quickly is probably linked to the type of genes we inherit from our parents. Some people can smoke once in a while, throughout their lives, and never seem to become addicted, while others are unable to stop smoking without experiencing the unpleasant withdrawal symptoms. It is most likely that the way the receptors on the surface of our brain nerve cells respond to nicotine is influenced by our genes. Dopamine regulates the sensitivity of nicotinic receptor
- #12 The type of NRT recommended or prescribed will depend on several factors, including the smokers personal choice, perception of ease of use, and how addicted he/she is. Heavy smokers may prefer the NRT nasal spray because of its fast action. Doctors recommend a total quit within six months of starting Nicotine-assisted reduction to stop treatment. Varenicline (Chantix/Champix) - this drug interferes with the brain nicotine receptors, resulting in less pleasure from smoking and eventually fewer withdrawal symptoms. Varenicline should not be taken by patients under the age of 18 years, pregnant or breastfeeding women, individuals with advanced kidney disease, and people with epilepsy Basis of nrt The principal action is believed to be the relief of craving and withdrawal symptoms when a person stops tobacco use. desensitize a subtype of nicotinic acetylcholine receptors, namely α4β2 nAChRs, which results in a reduced effect of nicotine from cigarettes antagonist at the nicotinic acetylcholine receptor,
- #13 Antidepressants - bupropion (Wellbutrin, Zyban) raise levels of dopamine and norepinephrine, as does nicotine. Some doctors may recommend a combination of bupropion and nicotine patch. This medication also reduces the risks of weight gain; a common consequence of giving up smoking. Patients with a history of seizures or serious head trauma, those under 18 years of age, pregnant or breastfeeding women, patients with anorexia or bulimia, individuals with a central nervous system tumor, and people with severe cirrhosis of the liver should not take bupropion
- #14 Development of tolerance Down regulation of CNS Ach receptors Nicotine replacement needed to maintain elated mood and thus causing dependence Withdrawl symptoms Irritability, anxiety, depression, restlessness, poor concentration, increased appetite, insomnia Weight gain after smoking cessation Depends on genetic factors Occurs mostly due to increase in sub-cutaneous body fat
- #19 potential for protecting successful quitters from significant post-cessation weight gain. Smoking cessation itself is associated with weight gain, which deters some smokers from making quit attempts; it was hoped that rimonabant would act as a cessation aid for these smokers
- #21 electronic nicotine delivery system (ENDS) a battery or USB powered device which simulates tobacco smoking. It generally uses a heating element known as an atomizer, that vaporizes a liquid solution. They may carry a risk of developing nicotine addiction, and their regulation is the subject of ongoing debate. WHO) states that as of July 2013, the efficacy in using electronic cigarettes to aid in smoking cessation has not been demonstrated scientifically. They recommend that "consumers should be strongly advised not to use" electronic cigarettes until a reputable national regulatory body has found them safe and effective. A 2013 randomized controlled trial found no difference in smoking cessation rates between e-cigarettes with nicotine, e-cigarettes without nicotine and traditional NRT patches. Liquid for producing vapor in electronic cigarettes, commonly known as e-juice or e-liquid, is a solution of propylene glycol (PG), vegetable glycerin (VG), and/or polyethylene glycol 400 (PEG400) mixed with concentrated flavors; and optionally, a variable concentration of nicotine.[43] The solution is often sold in a bottle or in pre-filled disposable cartridges. They are manufactured with various tobacco, fruit, and other flavors, as well as variable nicotine concentrations ( evidence suggests they are safer than real cigarettes, and possibly as safe as other nicotine replacement products. Electronic cigarettes are marketed as a healthier alternative to tobacco smoking by claiming that most of the harmful material produced by the combustion of tobacco in traditional cigarettes is not present in the atomised liquid of electronic cigarettes.
- #22 Nicotine is a small molecule unable to produce antibodies itself in the body. antibodies will “trap” nicotine in the plasma, thereby preventing it from penetrating into the brain and stimulating the neuronal pathways implicated in dependence.