Nicotine and Caffeine.pdf

13 Nicotine and Caffeine (and Kratom) mildstimulants Nicotine • Background • Vaping • Nicotine • Basic Pharmacology and Mechanisms of Action • Behavioral and Physiological Effects • Pharmacotherapies for Tobacco Use Disorder (TUD) Vaping https://www.fda.gov/tobacco-products/youth-and-tobacc...

13 Nicotine and Caffeine (and Kratom) mildstimulants Nicotine • Background • Vaping • Nicotine • Basic Pharmacology and Mechanisms of Action • Behavioral and Physiological Effects • Pharmacotherapies for Tobacco Use Disorder (TUD) Vaping https://www.fda.gov/tobacco-products/youth-and-tobacco/results-annual-national-youth-tobacco-survey Vaping • originally developed to help smokers quit • Main difference between smoking and vaping>>>how the nicotine is delivered • Burning end of a cigarette reaches temps of up to 9000C (which creates tobacco smoke) • Process of combustion generates carcinogenic chemicals § Vaping does not involve combustion § heats the ingredients into an aerosol (aka vapor) § >>>>dramatically reduces the release of harmful chemicals (at least that is the thought) § The earliest forms of e-cigarettes hit the US market in 2007 § In 2009, FDA declared that the e-cigarettes were illegal drug-device combinations — like a nicotine patch — that had not been approved. • halted imports and warned they contained toxic chemicals and appealed to young people with flavors • Overturned in 2010 Invented by Hon Lik, 2003 Vaping It Forcarcinogenicsmoke Nicotine and NNK treatments enhance mutational susceptibility and cell transformation. ©2018 by National Academy of Sciences Hyun-Wook Lee et al. PNAS 2018;115:7:E1560-E1569 Vaping Urinalysis Results Vaping https://www.netflix.com/title/81444184 Vaping https://www.nytimes.com/2019/10/17/health/vaping-juul-e-cigarettes.html?searchResultPosition=4 Vaping Vaping In its heyday, Juul occupied 75 percent of the market share and employed 4,000 people.Credit...Jeenah Moon for The New York Times https://www.nytimes.com/2022/06/23/health/fda-juul-ecigarettes-ban.html?referringSource=articleShare Vaping https://www.nytimes.com/2019/10/31/business/altria-juul.html?searchResultPosition=1 Vaping https://www.latimes.com/california/story/2023-11-08/california-banned-the-sales-of-flavored-tobacco-products-but-researchers-say-online-sales-have-boomed Vaping https://www.nytimes.com/2021/10/12/health/ecigarettes-fda-vuse.html?referringSource=articleShare Nicotine Nicotine • • • • • Evidence for Mayan use of tobacco in 700 A.D. Mid 16th century, Jean Nicot de Villemain, French ambassador to Portugal, brought back tobacco plants to France King James I of England: “A custom loathsome to the eye, hateful to the nose, harmful to the brain, dangerous to the lungs, and in the black stinking fumes thereof, nearest resembling the horrible Stygian Smoke of the Pit that is bottomless” Ben, collateral for a loan from France, and the Revolutionary War Margestpreventablepublichealthcrisis Cigarette smoking: linked to Spanish troops returning from the Crimean War • Tobacco use limited to pipes, cigars, and chewing… until the invention of automatic cigarette roller • Duke family of Durham, NC perfected the machine in early 1880’s "the home of her tobacco" X Nicotine • Nicotine : • alkaloid produced in the roots and concentrated in the leaves as a potent antiherbivore used asinsecticide • typical cigarette: ~10 mg of nicotine § no more than 1 to 3 mg reaches bloodstream § CNS stimulant effects are felt w/I 7-10 seconds cognitive enancement t relaxingerect Nicotine and Cigarette Smoking • 15% of U.S. adults still smoke: • ~51.3 million are current cigarette smokers; • 29.7 million are daily cigarette smokers and • 12.2 million smoke a pack or more a day • rural residents are diagnosed with lung cancer at rates 18 to 20 percent above those of city dwellers • Among the nation’s less-educated people — those with a high-schoolequivalency diploma — the smoking rate remains more than 40 percent • Over 300 billion cigarettes sold in the US each year https://www.cdc.gov/tobacco/data_statistics/fact_sheets/adult_data/cig_smoking/index.htm Basic Pharmacology and Mechanisms of Action Basic Pharmacology and Mechanisms of Action • Most nicotine (~75%) is metabolized to cotinine by CYP2A6 § Basis for urine drug screens (biomarker for nicotine exposure) § Half-life of nicotine: ~ two hours • Cotinine half-life of ~20 hours anytests • Individual variability in CYP2A6 function § low CYP2A6 activity>>>reduced nicotine metabolism biologically protective factor • less likely to become ÉIÉqnem smokers mancontself • Slow breakdown of nicotine is min protective against smoking nicotine Basic Pharmacology and Mechanisms of Action • activates nicotinic cholinergic receptors (nAChRs) • a4b2 receptors are relatively rare>>> highly expressed on DA neurons in the VTA • KO mice lacking a4 or b2 subunit do not selfadminister nicotine release bipecitically mat important ionotropic reward VTA or Basic Pharmacology and Mechanisms of Action • Tobacco-dependent cigarette smokers were subjected to PET imaging using a radiolabeled drug that binds selectively to high-affinity a4b2 subunit–containing nAChRs in the brain • even low levels of nicotine cause significant occupancy of high-affinity nAChRs in multiple brain areas Reducedsignal nicotinebound signalradio labeled tracer is bound Dose-dependent occupancy a4β2 nAChRs hEinaEi ithlevelmic displace Basic Pharmacology and Mechanisms of Action • High doses of nicotine>>>persistent activation of nicotinic receptors § continuous depolarization of the postsynaptic cell—depolarization block • cell cannot fire again until the nicotine is removed § biphasic effect: begins with stimulation>>>turns to blockade • A mechanism of toxicity at high levels of nicotine Why is cotinine used as the basis for drug screens for nicotine usage? drugremoved from systemafter 5halflives A) Cotinine has a longer half-life than nicotine, so it will be present in the urine for a longer time period than nicotine B) Cotinine is an active metabolite of nicotine and will activate nicotinic acetylcholine receptors C) The presence of cotinine in the blood is an accurate biomarker for nicotine exposure, whereas the presence of nicotine in the blood is not always an accurate biomarker for nicotine exposure D) Nicotine is an active metabolite of cotinine and has a longer half-life than cotinine Behavioral and Physiological Effects nicotinecognitive enhancement Behavioral and Physiological Effects • Effects on smokers § produces a calm or relaxed state • partly as relief from nicotine withdrawal negative symptoms he'FfYemen § Nicotine withdrawal: psychological features • Restlessness, irritability, increased appetite, insomnia, difficulty concentrating • Effects on nonsmokers: § heightened tension or arousal, light-headedness, dizziness, and nausea § Tolerance develops with repeated use • Receptor desensitization? Behavioral and Physiological Effects Animal studies: § Nicotine enhances working memory and attention § Rats given nicotine show improvement on the 5-CSRTT of attention • improved performance with acute or chronic nicotine administration • poorer performance during withdrawal from chronic nicotine •Non-smokers given nicotine show enhanced performance on many kinds of cognitive and motor tasks Behavioral and Physiological Effects Do nAChRs have a role in attentional performance? •α7-subunit antagonist (MLA) dose-dependently blocks the influence of nicotine on omission errors § α7-containing nicotinic receptors mediate the ability of nicotine to enhance attentional function § a7 agonists to improve cognitive performance? 5-CSRTT task with MLA nonicotine contragroup Indigent the xaxis suggests aredependent responn mgngmnemmY8nF ifeng.gg seeninpatients alzheimer's sunitophnniat post mortemdecreased level ht w t does cognitive enhancement at manage Behavioral and Physiological Effects • Mesolimbic DA pathway>>>key role in reinforcement amrhein • 6-OHDA lesions in NAcc block nicotine self-admin • nAChR antagonists in VTA block self-admin • DA receptor antagonists in NAcc block self-admin Behavioral and Physiological Effects • Nicotine>>>doubling of firing rate of VTA DA neurons and enhanced DA release in NAcc Rats inhaling tobacco smoke (TS): VTA neuron • TS stimulates DA neurons • Mecamylamine (nAChR antagonist) blocks effects of tobacco smoke SN neuron Behavioral and Physiological Effects • Tobacco smoke: contains other Acarcinogenic compounds that inhibit MAO-A and MAO-B in brain and other organs PET scan of MAO-B Activity • Does MAO inhibition might contribute to reinforcing effects of smoking? oMor MAO brown • inhibition in several organs Behavioral and Physiological Effects • Nicotinic receptors: abundant in ANS (on autonomic ganglia) and adrenal medulla • Smoking activates both sympathetic and parasympathetic systems and adrenal medulla § Parasympathetic activation: • most pronounced effects in stomach>>> increases HCL secretion and increased bowel contractility § Sympathetic activation: • Tachycardia, elevated blood pressure • Adrenal medulla § Catecholamine secretion autonomic ganglia remanniakanth autonomic ganglia d I just garb http://www.ric.edu/faculty/jmontvilo/335graphics/sympathetic.gif Behavioral and Physiological Effects • Accidental nicotine poisoning: • swallowing (involving children and packs of cigarettes) • farmworkers in contact with tobacco in the field • insecticides that contain nicotine Symptoms: nausea, excessive salivation, vomiting, diarrhea, mental confusion, cold sweat § Untreated fatal dose: respiratory failure due to depolarization block of diaphragm Self Administration Studies Behavioral and Physiological Effects Difficulties with nicotine self-administration—not resolved until 1981!: • Nicotine on its own is reinforcing at the right dose • high doses are aversive because of side effects • Self-admin is not as strong as opioids or psychomotor stimulants • Reinforcement by smoking is more than just the delivery of nicotine Behavioral and Physiological Effects •Aversive effects of nicotine— mediated by a5nAChR subunit? •KO mice administer successively greater amounts of nicotine as the dose per infusion increases •WT mice plateau at a relatively low level of intake because of the aversive effects of nicotine at higher doses (a5 subunit) Which of the following mouse lines will show a reduction in nicotine self-administration when compared with wild-type mice? A. Mice with a hypoactive form of CYP2A6 B. alpha-4 nicotinic receptor subunit KO mice C. beta-2 nicotinic receptor subunit KO mice D. alpha-5 nicotinic receptor subunit KO mice E. All of the above F. A, B, and C metabolitedoing IFEFEY Tolerance Behavioral and Physiological Effects Acute tolerance to nicotine: •Cigarette smokers undergo acute tolerance over the course of the day •related to desensitization of nicotinic receptors VTA Neurons in nicotine “bath” reference nicotine De-sensitization baseline • • Re-sensitization in giliigitigitigated ripply receptorligand ache Spikes induced by ACh application (arrowheads) Desensitization of DA neurons to continuous nicotine exposure Behavioral and Physiological Effects • 24-hour period: a regular smoker undergoes repeated elevations and drops in plasma nicotine levels • Early in the day, mood may be elevated above baseline level • later peaks in nicotine may be only enough to maintain neutral mood (avoid withdrawal symptoms) • nAChRs re-sensitize significantly overnight>>>allows cycle to repeat everyday one giantten Yearor Behavioral and Physiological Effects Tolerance and dependence in animals: •Withdrawal symptoms occur when the pump runs out of nicotine or if a nicotinic receptor antagonist (mecamylamine) is given binge III5Yah •Brain reward function is reduced during withdrawal from chronic nicotine §increased threshold for ICSS §Withdrawal symptoms are mediated by reduced DA activity in NAcc and increased CRF in amygdala continuous exposure via an osmotic minipump under the skin a Smokers claim that the first cigarette of the day is paan often the best. This is due to the phenomenon of (acute/metabolic/behavioral/pharmacodynamic) nicotine tolerance, which in turn is caused by the (desensitization/sensitization/upregulation) of (muscarinic/nicotinic) acetylcholine receptors over the course of a day. Cigarette Smoking Cigarette Smoking Mark Twain Photo from the Dave Thomson collection Cigarette Smoking “Why otherwise reasonable, sentient individuals continue to abuse their bodies by acquiring and persisting in the use of tobacco products for their nicotine addiction” Neuropsychopharmacology, 9th Ed. • For people dependent on nicotine, brief abstinence of a few hours leads to craving and a growing urge to smoke § correlates with a drop in blood nicotine levels • Withdrawal is relatively short § most symptoms are gone by four weeks § It is more than nicotine abstinence syndrome that makes it hard to quit Cigarette Smoking https://www.cdc.gov/tobacco/data_statistics/fact_sheets/cessation/smoking-cessation-fast-facts/index.html Cigarette Smoking Cigarette Smoking and Secondary Reinforcers: §Sensory stimuli associated with the act of smoking become conditioned to the reinforcing effects of nicotine Regular Smokers Ikon n'noticing nine't sighsgenic all sensory exp but I Yest Cigarette Smoking • most common pharmacological intervention: nicotine replacement therapy (NRT) § relieves withdrawal symptoms § delivered in safer ways than smoking withdraw symptoms workto limit Cigarette Smoking • Pharmacological interventions: § Bupropion (Wellbutrin, Zyban): initially developed as an antidepressant • a dopamine and NE reuptake inhibitor (NDRI) • similar in structure to stimulants • Reduces cravings and withdrawal symptoms Cigarette Smoking Pharmacological interventions: better than does • Varenicline (Chantix) • partial agonist of α4β2 nicotinic receptors • produces a moderate amount of receptor activation • reduces nicotine cravings and adverse withdrawal symptoms • More effective than buproprion You are a psychiatrist treating a patient for Major Depressive Disorder. The patient returns to you after a 6-week course of the drug and tells you that not only does she have a reduction in her depressive symptoms but also has not smoked a cigarette in over three weeks. What did you prescribe her? A. Buproprion B. Mecamylamine C. Nicotine replacement therapy (NRT) D. Varenicline E. an SSRI Caffeine • Background • Behavioral and Physiological Effects • Mechanisms of Action Caffeine: Background • Major source of caffeine is coffee beans>>>seeds of the plant Coffea arabica • normally consumed orally in beverages § completely absorbed from the GI tract in 30 to 60 minutes not subiente oh'ma • Converted to a variety of metabolites by the liver (CYP1A2) § 95% are eliminated through the urine • Average plasma half-life is about four hours Caffeine: Background Behavioral and Physiological Effects Behavioral and Physiological Effects r • In laboratory animals>>>biphasic effects § low doses of caffeine >>>stimulant effects § at high doses animals show reduced activity § § Low doses in humans>>positive subjective effects • feeling of well-being, increased energy, increased alertness, enhanced sociability high doses in humans>>>anxiogenic • People with panic disorder are hypersensitive to caffeine’s anxiogenic effects Behavioral and Physiological Effects • Cognitive effects • Autonomic effects: increased blood pressure and heart rate, and increased urine output § Chronic caffeine use leads to tolerance § Can produce a mild form of dependence § Caffeine Withdrawal: • sleepiness, headache, and irritability • intense craving § Relief from withdrawal>>>a major factor in chronic coffee drinking Behavioral and Physiological Effects • Acute caffeine intake leads to several physiological effects: § increased blood pressure and respiration rate § enhanced water excretion (diuresis) • Most evident in non-regular caffeine drinkers Behavioral and Physiological Effects • Greatest health risks occur with highest doses: § Caffeinism (aka: Caffeine Intoxication; 1000 mg or more/day ) • characterized by restlessness, nervousness, insomnia, tachycardia, and GI upset • difficult to distinguish from a primary anxiety disorder • Individuals experience very strong withdrawal symptoms and craving when usage is reduced Behavioral and Physiological Effects Therapeutic uses: • potentiates analgesic properties of aspirin and acetaminophen • included in some OTC pain medications (Anacin and Excedrin) • effective in treatment of apnea in premature newborns • regularizes breathing Caffeine Use Disorder—”a condition for further study” included in DSM-5 • Behavioral and Physiological Effects Mechanisms of Action Mechanisms of Action • Mechanism by which caffeine exerts its mild SHT stimulant effect is not known NE MDA § Does not directly influence catecholamine systems like other psychomotor stimulants • Caffeine’s biochemical effects: • Inhibition of PDE • Blocks GABAA receptors • Stimulates Ca2+ release within cells • Blockade of A1 and A2A adenosine receptors Brain It Mechanisms of Action • only partial blockade of A1 and A2A adenosine receptors has effects that operate at doses found in a cup of coffee erectcylus iscareas orare ine man no erects seenowmum doses by mediated take Mechanisms of Action • Adenosine § in the brain, has NT-like function § a modulator in inducing drowsiness and sleep? • stimulant properties of caffeine depend on antagonism of adenosine receptors in the brain, especially the striatum ocaffeine antYeh fine https://caffeineenlightenment.files.wordpress.com/2012/03/adenosine3.jpg Mechanisms of Action Caffeine and DA: Caffeine may remove the “brake” on DA signaling that is normally mediated by adenosine • Striatum expresses high levels of A2AR • co-expressed with postsynaptic D2 receptors (D2R)>>>form A2AR-D2R heterodimers • adenosine inhibits D2R signaling § In striatal neurons, A2AR agonists decrease D2R agonist binding • caffeine-induced increases in locomotor activity and arousal are absent in A2AR KO mice Caffeine enhances DA signaling in the striatum by antagonizing A2A receptors Although the molecular mechanism of action of caffeine is incompletely understood, we do know that A2A receptors are co-expressed with postsynaptic (dopamine/epinephrine/serotonin) receptors, and that binding of adenosine to these A2A receptors normally (inhibits/enhances) signaling from the coexpressed receptors. Kratom Kratom •Kratom (Mitragyna speciosa) is a tree in the coffee family found in Thailand and neighboring SE countries. •leaves are steeped into a tea or chewed, like coca •people use kratom’s stimulating effects to endure long hours of manual labor •More than two million Americans consume kratom every year •At low doses (chewing leaves), kratom acts as a stimulant •At higher doses (concentrated paste), has a sedative or narcotic effect •also used to manage withdrawal from prescription painkillers and heroin---a potential cure for opioid addiction? •widely available usedtodeal wopioid or disorder Kratom •early 2018, FDA commissioner Scott Gottlieb said the agency determined that kratom was an opioid 910 EMILY 18 •Classified as an opioid because its active ingredients appear to bind to some of the opioid receptors-- Nature's “atypical opioids” •chemical structures of mitragynine and all the other naturally occurring compounds in kratom, do not resemble a typical opioid such as morphine •In 2016, the DEA initiated a formal process to put kratom in on Schedule I drug but backed off affianbingithine Pain Ther. 2020 Jun; 9(1): 55–69. Kratom