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 Characterized based on CNS Effects:  Increased energy, mental alertness  Positive hedonic effects, euphoria  Reduced fatigue, decreased sleepiness.

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Presentation on theme: " Characterized based on CNS Effects:  Increased energy, mental alertness  Positive hedonic effects, euphoria  Reduced fatigue, decreased sleepiness."— Presentation transcript:


2  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  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  Snuff  Chewing tobacco  Cigars  Cigarettes  Nicotine Replacement Treatments  Chewing gum, lozenge, inhaler, patch

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

6  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  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  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  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  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  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  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  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  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  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 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., McGraw Hill)

17  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  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  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

20  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 Caffeine, Theophylline, Theobromine

22  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 BeverageCaffeine Content (mg)/cupAmount Brewed coffee oz. Instant coffee oz. Decaffeinated coffee oz. Tea oz. Cocoa oz. Coca-Cola 4512 oz. Pepsi-Cola 3812 oz. Mountain Dew 5412 oz. Chocolate bar oz.

24  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  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  Caffeine main methylxanthine in tea  Amount varies, ~ mg per 5 oz cup  Theophylline in small amounts  Theophylline is a potent respiratory stimulant, widely used to treat asthma

27  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  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  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  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  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  Unconditioned Behavior  Caffeine increases spontaneous motor activity in mice at mg/kg. 80 mg/kg decreases activity.  LD 50 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  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  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  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  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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