Tobacco & Nicotine PDF

Tobacco & Nicotine  most common Nicotine and Tobacco arrated ben has Tobacco cultivated from Nicotiana tabacum (...

Tobacco & Nicotine  most common Nicotine and Tobacco arrated ben has Tobacco cultivated from Nicotiana tabacum (6.17%) nicotine Nicotiana rustica: higher nicotine content (9%), harder to cultivate ↳ can have other substances in it Nicotine and Tobacco History First used by Mayans in Central America 1492: Tobacco smoking brought to Europe by Columbus; presented dry leaves by natives; reported as “drinking smoke” 1559: medicinal properties heralded by Jean Nicot; treats migraines of French Queen mother, name given to Genus Mexican Indians smoke tobacco in hollow canes, lead to invention of cigarettes 1938: first study linking smoking to lung cancer 1966: labels on cigarette packages (CIGARETTE SMOKING MAY BE HAZARDOUS TO YOUR HEALTH) 1994: commission of FDA argues nicotine is addictive and manufacturers manipulate delivery of nicotine in tobacco products 2009: Family Smoking Prevention and Tobacco Control Act brings tobacco products under control of FDA; regulate marketing and protect public health  basic-faster into body Pharmacokinetics Routes of Administration Oral administration big influence - quicker E Chewing tobacco / moist snuff - nicotine (weak into base, pKa = 8) absorbed through mucous blook membranes in cheek or under tongue stream slower , first ↳ If swallowed, not readily absorbed in acidic environment; extensively metabolized in liver pass meta decrease When absorbed, induces vomiting to expel tobacco concen from stomach (highly toxic poison) the nicotine is toxic , not nec. The tabacco (still notgood  dependsone Pharmacokinetics Moist snuff creates saliva pH 5.0 to 8.6 ↑ Dip-chew 8-10 times a day = same nicotine as 30- 40 cigarettes ↳mone than a pack a day Inhalation Most common route Cigarette ↳deceasa Flue cured; acidic smoke lowers saliva pH to 5.3; ionizes nicotine (> 90%), prevents absorption in mouth; must inhale Nicotine dissolves in mucous lining of lung surface; carried directly to the heart, then brain; 5 s (faster than iv) Average cigarette contains 10-15 mg of nicotine; 1.5-2.6 mg absorbed per 10-15 puffs; amount absorbed varies with how a cigarette is smoked  pH = absorption ↑ in more ↓ in pH =less absorption Inhalation Pipe & Cigar Air-cured; alkaline smoke; raises saliva pH to 8.5, < 50% of nicotine is ionized, nicotine rapidly absorbed from mouth (buccal absorbtion); no need to inhale Inhalation Vaping whole lot &be E-cigarette: cartridge with nicotine, propylene gycol, flavor – aerosolizes nicotine 15 puffs delivers 0.026 to 0.77 mg of nicotine – less than a cigarette [ ] of nicotine varies from 5-25 mg in disposable, 18-24 mg in refillable cartridges So we Peak levels of nicotine in blood range from ~6 to 19 ng/ml in 5 min or 15 puffs; rapid rise suggests absorption from lungs  withdrawal differ will Other forms of administration Patch: slow build up of nicotine and constant levels Gum: rise and falls in nicotine levels mimics pattern observed in smoking, but much lower levels Nasal spray: cigarette-like changes in blood levels; 3 mg spray in 10 min produces ~ 4.7 ng/ml nicotine in blood Pharmacokinetics Distribution Depends on route of administration With single puff, nicotine enters brain in 5 s, max [ ] within 1 min Leaves brain after 15 min; redistributed to liver, kidneys, salivary glands, and stomach Crosses blood-brain and placental barriers ↳ so babies can be exposed  Pharmacokinetics Metabolism as mainy E Liver metabolizes nicotine into 2 inactive in metabolites (cotenine, nicotine-l’-N- oxide) Enzyme induction: smokers metabolize nicotine faster than non-smokers Half-life ~ 90- 150 min (~ 2 h) Menthol slows metabolism 16-25% of population, genetic defect in nicotine metabolism, higher levels and lasts longer, less likely to become smokers  more excretion of nic. Pharmacokinetics Excretion dica Excretion depends on urine pH (> excretion if acidic); 30-40% excreted unchanged - unmetabolized If urine is alkaline, less excreted; elimination depends on metabolism by liver Neurophysiological Effects Stimulates cholinergic receptor sites (nicotinic) Ionotropic receptors when activated open Na+ channels (EPSP), also increase permeability to Ca+ presynaptically, á NT release High [ ] of nicotine (chronic use) causes paradoxical upregulation of number and sensitivity of receptors; when level of nicotine â , leaves high number of sensitized receptors Responsible for withdrawal and á response to nicotine upon waking the 3 states : Wittenberg, R. E., Wolfman, S. L., De Biasi, M., & Dani, J. A. (2020). Nicotinic acetylcholine receptors and nicotine addiction: A brief introduction. Neuropharmacology, 177, 108256. Peripheral NS Effects Stimulates neuromuscular receptors; tremors in heavy smokers á heart rate (10-20 beats/min) and blood pressure; harmful in patients with hypertension á blood flow to skeletal muscles, â to the skin (â temperature in skin; “cold touch”; wrinkles and ages faster), can not blush readily, cigarettes accused of “deadening the sense of shame” á gastrointestinal muscle contractions; cause diarrhea, cigarette can act as a laxative Central NS Effects á arousal; EEG pattern similar to a person who is working and concentrating hard , stimulates RAS á respiration (overdose produces respiratory paralysis) Induces vomiting & nausea in inexperienced smokers (“green around the gills”) á NE and DA in higher cortical centers á DA in NAc by direct stimulation of DA neurons, also activate nicotinic receptors in VTA Toxic Effects LD50 = 60 mg Several fatal doses in a pack of cigarettes; however, absorption not quick enough and elimination is efficient Overdose: convulsions followed by respiratory failure due to depolarization block of muscles of breathing Subjective Effects Acute effects Max ratings of “high” reported after 4 min (8 puffs) as plasma nicotine levels rapidly rise At 6 min (12 puffs); level exceeds 14 ng/ml; ratings of “high” â Pleasure results from rapid absorption more than maintaining constant level Performance Effects Methodological problems with studies 40% of studies (1994-2008) used smokers deprived of nicotine for 4 hours as participants, improvements may not be valid - just a reversal of performance degraded by withdrawal No placebo control, not double blind – can not rule out expectancy effect Performance Effects á fine motor abilities (finger tapping, pegboard) á speed and accuracy of alerting attention (detect target in Continuous Performance Test) á speed and accuracy of orienting attention (detect target in array of distractors) á short term episodic memory (recall list of words within 3 min after presentation)  Neurophysiological Effects Stimulates nicotinic cholinergic (ACh) receptors (nAChR) Nicotinic acetylcholine receptors are ligand-gated cation channels Pentameric structures with a central pore Widely expressed throughout the nervous system and body Post and presynaptic expression Wittenberg, R. E., Wolfman, S. L., De Biasi, M., & Dani, J. A. (2020). Nicotinic acetylcholine receptors and nicotine addiction: A brief introduction. Neuropharmacology, 177, 108256. Wittenberg, R. E., Wolfman, S. L., De Biasi, M., & Dani, J. A. (2020). Nicotinic acetylcholine receptors and nicotine addiction: A brief introduction. Neuropharmacology, 177, 108256.  Neurophysiological Effects ACh is rapidly removed from the synapse by acetylcholinesterase, nicotine persists in the synapse, leading to desensitization of the receptors nAChR levels are upregulated to maintain homeostasis following chronic nicotine Different nAChR subtypes have different sensitivities to nicotine, and desensitization time courses When level of nicotine â , leaves high number of receptors Responsible for withdrawal and á response to nicotine upon waking Nicotine and Animal Behaviour In rats, iv nicotine can substitute for cocaine, due to similar increases in dopamine release. SMA initially decreased by nicotine, increases after 7 days; tolerance of Ach system develops, increases in epinephrin remain; similar effect as amphetamine Learning Discrimination Motivation Timing Response inhibition Popke, E. J., Mayorga, A. J., Fogle, C. M., & Paule, M. G. (2000). Effects of Acute Nicotine on Several Operant Behaviors in Rats. Pharmacology Biochemistry and Behavior, 65(2), 247–254. Self Administration Nonhumans Narrow range of doses that are effective as reinforcers Monkeys respond more for light preceding infusion of nicotine than for nicotine infusion without a predictive stimulus; also respond for light paired with nicotine Humans Self administer nicotine infusions on FR10 Sensitive to changes in [ ] and adjust doses Peripheral NS Effects Stimulates neuromuscular receptors; tremors in heavy smokers á heart rate (10-20 beats/min) and blood pressure; harmful in patients with hypertension á blood flow to skeletal muscles, â to the skin (â temperature in skin; “cold touch”; wrinkles and ages faster), can not blush readily, cigarettes accused of “deadening the sense of shame” á gastrointestinal muscle contractions; cause diarrhea, cigarette can act as a laxative Central NS Effects á arousal; EEG pattern similar to a person who is working and concentrating hard, stimulates RAS á respiration (overdose produces respiratory paralysis) Induces vomiting & nausea in inexperienced smokers (“green around the gills”) á NE and DA in higher cortical centers á DA in NAc by direct stimulation of DA neurons, also activate nicotinic receptors in VTA Toxic Effects LD50 ~6.5-13 mg/kg As little as 6 mg can be fatal in children Several fatal doses in a pack of cigarettes; however, absorption not quick enough and elimination is efficient E-liquid refills can contain 1500 mg of nicotine; ingestion can be fatal in adults Toxic Effects Low doses cause stimulation (hypertension, tachycardia, seizures, etc.); high / sustained doses cause depression (hypotension, bradycardia; paralysis) Overdose: convulsions followed by respiratory failure due to neuromuscular blockade of the muscles of breathing Subjective Effects Acute effects Max ratings of “high” reported after 4 min (8 puffs) as plasma nicotine levels rapidly rise At 6 min (12 puffs); level exceeds 14 ng/ml; ratings of “high” â Pleasure results from rapid absorption more than maintaining constant level  Mello, N. K., Peltier, M. R., & Duncanson, H. (2013). Nicotine Levels After IV Nicotine and Cigarette Smoking in Men. Experimental and Clinical Psychopharmacology, 21(3), 188. Nicotine (ng/ml) VAS (mm) Time (min) Performance Effects Methodological problems with studies 40% of studies (1994-2008) used smokers deprived of nicotine for 4 hours as participants, improvements may not be valid - just a reversal of performance degraded by withdrawal No placebo control, not double blind – can not rule out expectancy effect Performance Effects á fine motor abilities (finger tapping, pegboard) á speed and accuracy of alerting attention (detect target in Continuous Performance Test) á speed and accuracy of orienting attention (detect target in array of distractors) á short term episodic memory (recall list of words within 3 min after presentation)  Harmful Effects 480,000 smoking-related deaths/year in US Heart Disease reduces E Nicotine á workload of heart; CO reduces oxygen hearts ability carrying capacity of blood; â oxygen to heart also works - harder to absorb ye keep Other constituents in smoke â ability of lungs to upoxy to oxygen absorb oxygen; á need to pump blood through a lungs to maintain oxygen levels Harmful Effects Lung Disease (COPD) “Paving” the lungs with ash and tar overwhelms cilia that clear pollutants and reduce actions of phagocytes that attack foreign matter Smoker is more susceptible to toxins and infections Inflammation reduces airflow to and from lungs Harmful Effects Cancer Smoking responsible for 30% of all cancer deaths Smoking increases the risk of cancer (23 X higher in male smokers, 13 X in females) Risk of lung cancer â by quitting smoking Harmful Effects Reproduction â fertility in males and females âsemen volume, sperm count, motility, and viability in males Females that smoke > 20 cigarettes/day 1.7 - 3.2 times more likely to be infertile á risk of birth defects, LBW (infants born to smoking mothers 150-200 g lighter)  Environmental tobacco smoke (ETS) (Second Hand Smoke) MS mainstream smoke exhaled by smoker; SS sidestream smoke comes from cigarette between puffs Flame that creates MS is 300 degrees hotter than thesmon flame that produces SS smoke [ ] of carcinogens is higher in SS smoke -  Living with smoker á risk of lung cancer 20- 30%, á risk of heart disease by 25–30% ETS responsible for 46,000 heart disease deaths/year, 3000 lung cancer deaths/year Third hand smoke smoking in house /apartment deposits toxins that give off toxic compounds for months after smoking increase also risk Why do people smoke? Constant blood level theory Try to maintain constant level of nicotine in blood Predictions: Changing nicotine content of cigarettes should change smoking behavior to compensate (Dose compensation) Compensate not by smoking more cigarettes; instead take deeper, more frequent puffs First few puffs on a cigarette will be rapid and deep as smoker attempts to rapidly raise blood levels and then puff rate decreases Individuals should be highly motivated to smoke when blood levels are low (lowest levels occur after night of sleeping - 14% light up after 5 min, 50% after 30 min) stress Stress causes urine to become acidic, á excretion of nicotine, why drop in nicotine levels stimulates smoking 3 induces cravings Nicotine Bolus Theory Rapid inhalation produces a sudden high level of nicotine in the blood and brain (bolus) Bolus is reinforcing and pleasurable Explains why tobacco cravings are worse for smokers than users who administer tobacco by other routes  Dual Reinforcement Theory Role of Non-nicotine factors Sensory experiences assoc w smoking acquire reinforcing properties and play a role in maintaining smoking and relapse in withdrawal Experiment: 2 groups the act fSmokinga IV administrations of nicotine to mimic cigarette blood levels IV administrations plus puff on de-nicotinized cigarette Later allowed to smoke usual brand for 3 hours IV alone had no effect on ad-lib smoking level; IV + puffing on de-nicotinized cigarette reduced ad-lib smoking Implication: NRT therapy alone may be insufficient Dual Reinforcement Theory Nicotine is a primary reinforcer Stimuli predictive of nicotine are secondary (conditioned) reinforcers Nicotine enhances the effect of stimuli associated with nicotine administration Evidence: rats given chance to press lever for changes in visual stimuli and rats given chance to press a lever for nicotine infusion – press levers at low rates, but when both levers present and active, rats press at a higher rate for visual stimuli Stimuli maintain smoking and play a role in relapse Caggiula, A. R., Donny, E. C., Palmatier, M. I., Liu, X., Chaudhri, N., & Sved, A. F. (2009). CHAPTER 6: THE ROLE OF NICOTINE IN SMOKING: A DUAL-REINFORCEMENT MODEL. Nebraska Symposium on Motivation. Nebraska Symposium on Motivation, 55, 91. Caggiula, A. R., Donny, E. C., Palmatier, M. I., Liu, X., Chaudhri, N., & Sved, A. F. (2009). CHAPTER 6: THE ROLE OF NICOTINE IN SMOKING: A DUAL-REINFORCEMENT MODEL. Nebraska Symposium on Motivation. Nebraska Symposium on Motivation, 55, 91. Withdrawal Psychologically stressful, ex-heroin addicts claim harder to give up tobacco Symptoms: â heart rate, á food intake, inability to concentrate, á awakenings, cravings, anxiety, aggression, depression Develop over first 2 days, peak after 1 week; cravings subside 1 to 6 months, but can be initiated by social / environmental cues Alleviate symptoms with nicotine gum or patch; â by taste and smell of tobacco or act of smoking a denicotinized cigarette Withdrawal Severity of symtoms not related to dose Fast metabolizers show more severe withdrawal than slow metabolizers Severity: associated with reduced DA in NAc, suppression of reward system assoc w/ anhedonia  Treatment 2/3 of adults who smoke wish they could quit 17 million try each year, < 1 in 10 succeed Nicotine replacement therapies (NRT) Effectiveness: 10% quit with placebo after 6 months, 17% with NRT More slowly absorbed than with cigarettes, do not produce “liking” due to rapid increase and only partially eliminate withdrawal symptoms Nasal Spray / Lozenge > Patch and Gum  Treatment E-Cigarettes as NRT Randomized, placebo controlled studies do not support e-cigarettes as effective for smoking cessation Risks á likelihood of later cigarette use in adolescents á likelihood of nicotine addiction as devices become more efficient at nicotine delivery Surge in popularity, perceived lack of danger, broad acceptance will renormalize smoking / á use of vapor-emitting devices  Treatment Buproprion Inhibits reuptake of NE and DA (antidepressant, Wellbutrin) Sold as Zyban Diminishes reinforcing effect of nicotine and reduces aversive effects of withdrawal As effective as NRT, (OR [odds ratio] 1.9) taken alone, > if combined with NRT (OR 2.9) Beneficial side effect: reduces post-smoking weight gain  Treatment Varenicline Partial agonist for nicotinic receptor (produces weaker effect than nicotine and blocks nicotine) Sold as Chantix (US) / Champix (Canada) Alleviates withdrawal and blocks effect of nicotine from smoking 2006 Pfizer study – rate of continuous abstinence after one year 23% on varenicline 15% on bupropion 13% on NRT 10% on placebo  Treatment Behavioral treatments Group therapy – (OR 2.17), as effective as pharmacological treatments Vaccination Several vaccines against nicotine have been developed; based on preventing the nicotine from reaching cite of action in the brain; clinical trials have not been successful