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CNS Stimulants Tobacco & Nicotine Caffeine and Other Methylxanthines

CNS Stimulants Tobacco & Nicotine Caffeine and Other Methylxanthines. Introduction to CNS Stimulants. Characterized based on CNS Effects: Increased energy, mental alertness Positive hedonic effects, euphoria Reduced fatigue, decreased sleepiness Casually referred to as “uppers”

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CNS Stimulants Tobacco & Nicotine Caffeine and Other Methylxanthines

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  1. CNS StimulantsTobacco & NicotineCaffeine and Other Methylxanthines

  2. Introduction to CNS Stimulants • Characterized based on CNS Effects: • Increased energy, mental alertness • Positive hedonic effects, euphoria • Reduced fatigue, decreased sleepiness • Casually referred to as “uppers” • Toxicities associated with excessive CNS stimulation: e.g., seizures, cardiac and respiratory failure • Over-the-Counter Stimulants • Nicotine, Caffeine, Theophylline, Theobromine, Ephedrine • Legally Restricted Stimulants • Cocaine, Amphetamine, Methamphetamine

  3. History of Tobacco Use • Early Medicinal Uses • Europe • New World • The spread of tobacco use • Tobacco production • Nicotiana tobacum • Spanish monopoly on sales to Europe • Tobacco colony in Virginia • Popularity of snuff in England

  4. Forms of Tobacco/Nicotine Use • Snuff • Chewing tobacco • Cigars • Cigarettes • Nicotine Replacement Treatments • Chewing gum, lozenge, inhaler, patch

  5. Trends in Cigarette Sales Trends in cigarette sales since 1945 (Ksir et al., 2006. McGraw Hill)

  6. Statistics on Smokers • Males more likely than females • Recent downward trends in use among high school seniors • 36% in 1997; 22% (F), 26% (M) in 2003 • Among 18- to 25-year olds • 44% of males, 36% of females (2002 survey data) • College students less likely to smoke than non-students in this age range. • Current smokers are more likely to also be heavy drinkers and/or illicit drug users. • Higher smoking prevalence among people with psychiatric diagnosis (consume 70% of cigarettes in U.S.) • Smoking more common among lower socioeconomic classes • e.g., Smoking prevalence among Medicaid recipients 40% greater than that in overall U.S. adult population.

  7. Nicotine Pharmacokinetics • Colorless, highly volatile liquid alkaloid • Highly toxic in pure form • Diluted concentrations when administered through tobacco use • Nicotine is only one of ~4000 compounds in tobacco smoke • cardiovascular, pulmonary, & carcinogenic effects related to multiple chemicals in tobacco • Absorption • Weak base, pKa ~ 8, poorly absorbed in digestive system • Smoked: rapid absorption into the bloodstream • 90% of inhaled nicotine is absorbed • Chewed or dipped: absorbed through the mucus lining of the mouth • Pipe/Cigar tobacco • air-cured, more alkaline smoke (pH 8.5), absorption in mouth, inhalation not required

  8. Nicotine Pharmacokinetics • Distribution • Depends on route and time since administration • High concentration achieved in brain • Crosses most barriers, including placenta • Metabolism/Elimination • Liver metabolizes 80-90% before excretion • Two metabolic pathways • Metabolites: cotinine, nicotine-l’-N-oxide • Excretion by kidneys depends on urine pH • Reduced ionization in alkaline pH increases reabsorption • Half-life ~ 30 minutes • Rapid elimination, no day-to-day accumulation • Individual Differences in Elimination • Smokers metabolize faster • Gender differences in nicotine metabolism • Genetic differences • 16-25% of population with genetic “defect” in ability to metabolize nicotine. • May protect against becoming a smoker

  9. Nicotine Pharmacodynamics • Physiological Effects • Low-level nicotine poisoning causes nausea, dizziness, and a general weakness • Low doses stimulate respiration, high doses paralyze respiratory muscles (acute toxicity) • Mechanisms of Action • Mimics and Blocks ACh • Facilitates Adrenalin Release

  10. Behavioral/Cognitive Effects • Subjective Effects • Acute Effects vs. Chronic Effects • Nesbitt’s Paradox (Arousal or Calming Effect?) • influenced by smoker’s history • Effects on Performance • Inconsistent findings • Dependent on Smoking history • Enhanced Concentration and Attention • Sustains performance on monotonous tasks, improves speed and accuracy • Memory Enhancement • Improved cognitive functioning in Alzheimer’s patients

  11. Behavioral Effects in Nonhuman Studies • Unconditioned Behavior • Spontaneous motor activity initially depressed by 0.8 mg/kg, probably due to initial effects on ACh transmission in brain. • With repeated testing, tolerance develops and SMA is increased, likely due to effects on epinephrine. • Conditioned Behavior • Effects of nicotine on operant behavior (positively and aversively motivated) are similar to those of amphetamine • Similarities likely related to nicotine’s indirect actions on catecholamine release • Effects blocked by nicotinic antagonist, mecamylamine

  12. Behavioral Effects in Nonhuman Studies • Drug Discrimination Studies • Nicotine is discriminated by rodents at 0.2 mg/kg • NO generalization to caffeine or to any CNS depressants, hallucinogens, or opioids • Some evidence for partial generalization between nicotine and amphetamine or cocaine. • Nicotine discrimination blocked by nicotinic antagonists.

  13. Behavioral Effects in Nonhuman Studies • Drug Self-Administration Studies • It is surprisingly difficult to establish nicotine as a positive reinforcer in nonhumans. • Monkeys have been trained to inhale cigarette smoke, following initial period of forced consumption and reinforcing smoke inhalation with water or juice access. • Some reports of intravenous nicotine self-administration in nonhumans • Response rates low and patterns of responding inconsistent • Stimuli associated with nicotine delivery contribute to its reinforcing efficacy. • Conditions that support nicotine self-administration include: • a period of forced consumption of nicotine • stimuli paired with the nicotine infusion • FI schedule or a second order schedule that imposes a period of abstinence between self-administration opportunities

  14. Nicotine Dependence • Withdrawal Syndrome • Intensity varies among individuals • Symptoms include: decreased heart rate, concentration difficulties, poor sleep, anxiety, irritability, anger and aggression, increased eating and weight gain. • For most, symptoms subside within a month, but may persist for several months, and craving may continue for several years. • Quitting Smoking • “Cold turkey” • Behavior Modification • Pharmacological Treatments for Dependence • Nicotine gum • Nicotine patches • Nicotine nasal spray • Nicotine inhalers • Wellbutrin (buproprion: DA reuptake blocker) • Chantix (varenicline: partial nicotinic agonist)

  15. Health Risks • Tobacco presents a greater public health threat than all other drugs combined, including alcohol • Adverse Health Effects • Emphysema & Bronchitis • Cardiovascular Disease • Smoking accounts for 30% of CV disease related deaths • ~150,000 premature deaths per year • Cancer • 85% of lung cancers occur in smokers • Smoking accounts for 30% of all cancers • ~150,000 premature deaths per year • Chronic Obstructive Pulmonary Disease • ~80,000 premature deaths per year

  16. Mortality Statistics on Smoking Mortality ratios (total death, mean age 55 to 64) as a function of the age at which smoking started and the number of cigarettes smoked per day. (Ksir et al., 2006. McGraw Hill)

  17. Health Risks • Smoking and Pregnancy • higher miscarriage rates • lower birth weight • Some evidence for long-lasting intellectual and physical effects in children of mother’s who smoked during pregnancy • e.g., lower IQ, increased prevalence of ADHD • Sudden Infant Death Syndrome (SIDS)

  18. Health Risks • Passive Smoke Health Risks • Exhaled Mainstream Smoke - smoke exhaled by the smoker • Side stream smoke - smoke released from burning end of a cigarette • Environmental tobacco smoke – mixture of side stream smoke and exhaled mainstream smoke • U.S. Dept of Health and Human Services Data • In 2005, exposure to second hand smoke responsible for the following deaths: • 3000 adults due to lung cancer • 46,000 adults due to coronary artery disease • 430 newborns due to SIDS

  19. Health Risks • More than 50 cancer-causing chemicals are found in secondhand smoke including: • Polynuclear aromatic hydrocarbons (PAHs) (such as Benzo[a]pyrene) • N-Nitrosamines (such as tobacco-specific nitrosamines) • Aromatic amines (such as 4-aminobiphenyl) • Aldehydes (such as formaldehyde) • Miscellaneous organic chemicals (such as benzene and vinyl chloride) and • Inorganic compounds (such as those containing metals like arsenic, beryllium, cadmium, lead, nickel and radioactive polonium-210). Source: Office of the Surgeon General http://www.surgeongeneral.gov/library/secondhandsmoke/factsheets/factsheet9.html

  20. Social & Economic Dilemmaof Smoking • Economic Impact of Tobacco Sales • Total annual sales almost $50 billion • Advertising funding for newspapers and magazines • The federal government collects $6 billion and states collect $7.5 billion annually in taxes • Health Care and Productivity Losses Related to Tobacco • $75 billion medical costs • $82 billion lost productivity

  21. Methylxanthines Caffeine, Theophylline, Theobromine

  22. Caffeine • Caffeine is the most frequently consumed stimulant in the world • Chemical classification: methylxanthine • Multiple Products Widely Available • Coffee • Tea and Chocolate (also contain other methylxanthines) • Soft drinks and Energy drinks • Over the Counter Products • Analgesics (aspirin/caffeine combinations) • Stimulants (Caffeine is the only FDA-approved OTC “stimulant”) • Diuretics (weight loss products) • In the U.S., average daily caffeine intake equivalent to 2 cups of coffee (approx. 200 mg)

  23. Beverage Caffeine Content (mg)/cup Amount Brewed coffee 90-125 5 oz. Instant coffee 35-164 5 oz. Decaffeinated coffee 1-6 5 oz. Tea 25-125 5 oz. Cocoa 5-25 5 oz. Coca-Cola 45 12 oz. Pepsi-Cola 38 12 oz. Mountain Dew 54 12 oz. Chocolate bar 1-35 1 oz. Caffeine Content of Beverages and Chocolate

  24. Historical Notes on Coffee • Arabian goatherd legend • “The women’s petition against coffee” • British Tax Act • Coffee consumption increased during prohibition • Commercial roasting began in 1790, NYC • First commercial blend in 1892, Maxwell House • Recent popularity of specialty coffee shops • From ~200 in 1989 to 15,000 in 2004

  25. Tea • First reliable report was in a Chinese document, dated 350 AD • First European record of Tea, 1559 • English East India Company • Popular in new colonies • Boston Tea Party

  26. Methylxanthines in Tea • Caffeine main methylxanthine in tea • Amount varies, ~ 40-60 mg per 5 oz cup • Theophylline in small amounts • Theophylline is a potent respiratory stimulant, widely used to treat asthma

  27. Chocolate • Cocoa: Aztec and Mayan origins • 17th century spread to wealthy in Europe • Drinks and Coffee Houses • First chocolate bar, 1847 • Milk chocolate invented by Swiss, 1876 (sold under Nestle label) • Theobromine main methylxanthine in chocolate (200 mg; 4 mg caffeine)

  28. Caffeine Pharmacokinetics • Methylxanthines are alkaloids • Slightly soluble in water • Absorption of Caffeine • Rapid, peak blood levels within 30 min. • Maximum CNS effects ~ 2 hours • Metabolism and Elimination • Half-life ~3 hours • < 10% excreted unchanged

  29. Caffeine Pharmacodynamics • Mechanism of Action • Adenosine Antagonism • Adenosine is a neuromodulator which inhibits release of a variety of neurotransmitters. • CNS effects of adenosine include behavioral sedation. • Caffeine exerts its actions by inhibiting these effects of adenosine.

  30. CNS Effects of Methylxanthines • Mild CNS effects with low to moderate doses • Enhance alertness, cause arousal, diminish fatigue • Potential adverse CNS effects with high doses • Insomnia, increase in tension, anxiety, and initiation of muscle twitches • Over 500 milligrams - panic sensations, chills, nausea, clumsiness • Extreme high doses (5 to 10 grams) - seizures, respiratory failure, and death

  31. Physiological Effects • Cardiovascular system • Low doses - heart activity increases, decreases, or do nothing • High doses - rate of contraction of the heart increases, minor vasodilation in most of the body, cerebral blood vessels are vasoconstricted • Respiratory system • Opens airways and facilitates breathing

  32. Behavioral Effects in Nonhuman Studies • Unconditioned Behavior • Caffeine increases spontaneous motor activity in mice at 20-40 mg/kg. 80 mg/kg decreases activity. • LD50 in rodents ~250 mg/kg (i.p.) • Automutilation has observed following chronic high dose administration. • Conditioned Behavior • Pavlov (1927) first to show caffeine can disrupt conditioned discriminations (i.e., increased responding to CS-). • Effects on operant behavior similar, but not identical to those of psychomotor stimulants, like the amphetamines. • Caffeine increases avoidance responding (indicative of anxiogenic effects).

  33. Behavioral Effects in Nonhuman Studies • Drug Discrimination Studies • Rats can be trained to discriminate 32 mg/kg caffeine. • Generalization to other methylxanthines • NO generalization to nicotine • Some evidence for partial generalization between low dose caffeine and amphetamine or cocaine • DA antagonists block discrimination of low doses caffeine, but not high doses.

  34. Behavioral Effects in Nonhuman Studies • Drug Self-Administration Studies • By itself, caffeine is a relatively weak positive reinforcer. • Caffeine maintains low and inconsistent patterns of responding, but generally higher responding compared to vehicle. • Initial forced consumption is usually required to establish caffeine as a reinforcer in nonhumans. • Caffeine has been shown to potentiate reinforcing effects of low cocaine doses. • Caffeine has been shown to prime reinstatement of previously extinguished cocaine self-administration.

  35. Health Risks • Potential Health Risks of Caffeine Use • Increased risk of pancreatic cancer ? • Original research criticized for methodological flaws • Currently no support for this putative link • Other research shows a relationship with: • cancers of the bladder, ovaries, colon, and kidneys • women - fibrous cysts in breasts • Reproductive Effects • High daily doses (> 300 mg/day) may inhibit pregnancy, promote miscarriage, and slow fetal growth • Heart Disease • Some retrospective studies report the incidence of nonfatal heart attacks in men under 55 directly related to amount of coffee consumed • A prospective study showed that men who consume 5 or more cups of coffee daily are 2.5 x more likely to suffer from coronary artery disease.

  36. Health Risks • Caffeine Intoxication • Caffeinism: restlessness, nervousness, excitement, insomnia, flushed face, diuresis, muscle twitching, rambling thoughts and speech, stomach complaints • Caffeine Dependence • Primary withdrawal symptom: headache ~18 hours after last use • Other symptoms include increased fatigue, reduced energy evident within first two days, with decreased symptoms over 5-6 days.

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