Drug Test 2
Metabolism and Elimination
About 70-80% of nicotine in body in transformed into cotinine by a liver enzyme. Genetic variations in activity of CYP2A6 (important in metabolism of nicotine to cotinine). If you have less of this enzyme you tend to not be a smoker (less enzyme- higher levels of nicotine build up if you smoke and produces negative effects) about 20% of the population have this deficit of the enzyme. Methoxsalen inhibits the CYP2A6 enzyme that metabolized nicotine, nicotine stays in the body longer, higher levels of nicotine in the body make you feel sick, dizzy, nauseous, sweating. Half-life: 2hours if you're not a chronic user...half-life decreases in chronic users. Smokers metabolize it faster (so they need another hit quickly). Nicotine clearance from the body -> important reason why smokers smoke throughout the day). Blood levels of nicotine drop at night and people crave cigarette in the morning. Elimination principally in urine (but also in sweat, saliva, mother's milk).
Caffeine history
Caffeine is the world's most popular drug. Cradle to the grain (used by all age groups). Humans have used it since ancient times, but up until 15th/16th centuries Europe really only knew of alcohol. Traders/explorers found and brought back. Coffee from Arabia, Turkey, Ethiopia, Tea from China, Kola nut from West Africa, cocoa plant from North/South America. Worldwide consumption (2016) Ireland, England, and Turkey lead world consumption. US drinks only 1/8 of what they do.
Chocolate consumption
Switzerland is top consumer. Austria, Germany, Ireland, Uk, and Sweden. US is 19th in chocolate consumption.
Acute effects of nicotine
(Regular-moderate dose) Relaxing, nausea (stimulates emetic centers in medulla), sensory system function is augmented (CFF test: assesses acuity of our sensory systems, increases the threshold for click flicker fusion.) Cognitive and behavioral effects: reaction times are faster (amphetamines generally decrease reaction time), increased attention (enhances performance especially for monotonous tasks). Long and short term memory can be enhanced radial arm maze, passive-avoidance tasks. (High dose) toxic, 60 mg can kill you, one pack holds several lethal doses, but people tend to develop tolerance over time before they smoke an entire pack of cigs.
Cocaine Tolerance
- Acute tolerance: tolerance after one use, happens to the euphoric effects- you coke out. Can be dangerous: short-term cocaine user can build up tolerance to the "high" but not the health risks. Euphoric can build tolerance with only one dose. You don't develop a tolerance to the more lethal effects acutely- only the euphoric effects. -Functional tolerance (over long period of time) Pharmacodynamic tolerance. Synapses begin to change, develops to appetite suppressing effects, heart and BP effects, lethal effects, overtime you can take higher and higher doses, because you develop a functional tolerance to the lethal effects. No tolerance to motor effects or some brain stimulation effects- instead kindling effect: so dangerous (seizures).
Cocaine distribution, metabolism, and excretion
- Freely crosses membranes (fat soluble) -> Blood brain barrier and placenta. - Metabolized fast (effects last from 20-80 minutes) - Excreted fast (40 min half life) - Metabolized fast and excreted fast = recipe for abuse. -Metabolites detected for 2-3 days after administration. Cocaethylene toxicity (only evident when you use coke and alcohol together). More potent than coke itself, dose same things as cocaine, a lot of this metabolite in system even when coke is excreted. heart dangers of mixing alcohol and coke. Accounts for a significant percentage of the sudden, unexplained fatalities that sometimes occur in cocaine users.
Therapeutic Use of amphetamines
- Narcolepsy: uncontrollable sleep - Short-term weight reduction- used to be in diet pills, short-term. - Short term relief for nasal congestion (first medical use for amphetamines) - ADHD: millions of children are given stimulant drugs to treat ADHD (Ritalin- methylphenidate, amphetamines- adderall and other stimulants) -Brain dysfunction: related to dysfunction in DA and NE, drugs enhance the functioning of the reticular activating system which helps children focus attention and filter out extraneous stimuli -RAS: alertness, 13,000 neurons make connections with the 12 billion cells, makes you pay attention and focus, enhances signal to noise ratio: filtering out unnecessary stimuli. In class: signal is teacher, noise is everything else. Everything is noise for people with ADHD, more signal and less noise with amphetamines. - Brain waves: Beta- predominate all waves when awake and alert. Theta- awake, but daydreaming state, foggy, drowsy, happens before sleep stage. Alpha- awake but more relaxed. Normal kid: awake state ratio of theta to beta is small, ADHD kid- awake state there is a predominance of the of theta waves- ratio of theta to beta is high. They exist in an hyperarousal state, drugs activate RAS and re-adjust the proportions of beta/theta waves. Hyperactivity: ADHD, not focused, also trying to keep themselves alert to keep themselves awake, hyperactivity helps them stay awake/alert.
Acute effects of cocaine (one-time use)
- Powerful burst of energy and sense of well-being, but followed by rebound depression/anxiety (especially intranasal, IV, or smoking routes. - Decreased appetite: why Spaniards let the workers chew the coca leaves so they would be high energy and wouldn't have to feed them as much. - High dose can cause delusions/paranoia (formication syndrome) - Sympathetic activation can be very dangerous (moderate to high doses) and can cause sudden death, cardiac arrest (cocaine binds to heart muscles)- most significant medical consequence of cocaine use. - Leonard Bias- 1980's basketball Celtics player, said to be better than Michael Jordan, OD on coke intranasally which interrupted the normal electrical control of his heart. - Cerebral hemorrhage ( large white area on a brain scan)
Second Era: Cocaine in 1880's/19th century
1886: Pemberton from Georgia made Coca Cola. Promoted as a "Brain Tonic"- nerve stimulant. Soda fountains became very popular (in the back of the pharmacy). 1903: cocaine eliminated from Coca Cola. Coca cigarettes (probably didn't do much) Used for toothaches. William Halstead- surgeon. Used cocaine to anesthetize nerves. Johns Hopkins- he got addicted to coke and morphine and continued to do surgery. 1900-1915: Peak cocaine use 1910: President Taft declared it Public Enemy #1 1914: Harrison Narcotic Act of 1914: tax law to regulate sales of narcotics (morphine and heroin) and cocaine. Caused physicians writing prescriptions to be costly for them- stopped prescribing as much. Some people argue that this act and the prohibition of alcohol started organized crime in the 20th century.
Third Era: 20th Century Cocaine Epidemic in US
1970's: coke became a popular recreational drug. Snorting and IV use of cocaine hydrochloride. Smokeable forms emerged. 1970's: Freebase cocaine, first inhalation of cocaine. Difficult to get to substance isolated, $$$ (only rockstars and famous athletes used), became a glamour drug, freebasing: >75% pure, a base smokeable, not super safe to make, extremely flammable. 1980's: another smokable form emerged. Crack cocaine in 1985: inexpensive, widespread use. Decline between 1987-1991 due to deaths of famous people and new laws in 1984. Use baking soda to extract the base, forms little rocks you smoke and they crackle hence the name crack. 75% pure, a base, smokeable, cheap, much more people started to use coke.
Tolerance, dependence, and withdrawal
Acute tolerance: pretreatment with nicotine attenuates later responses (like daily smokers). Short lived- next day they start anew. Physical dependence: yes because there are withdrawal symptoms. Other factors- not just nicotine- sensory aspects, taste, smell contribute to habit in dependent smokers. Lower heart rate, tremors, aggressiveness, hunger, heart palpitations, headaches, anxiety, lower blood pressure, short attention span, increased circulation, insomnia, fatigue, drowsiness, craving for nicotine. Psychological dependence: 70% of smokers say they want to quit, Sir Francis Bacon (16th century) described the addictive quality of tobacco. E. Everett Koop claimed that nicotine dependence is a powerful as heroin and cocaine dependence. Craving for nicotine, Freud smoked cigars: addicted to cigar smoking (smoked 20 cigars a day, 33 surgeries (oral cancer), repeatedly warned about cigars, kept smoking, Angina, Jaw entirely removed, artificial jaw, could not speak, or eat, kept smoking until he died at 83. Low-moderate doses, yes reinforcing (but high doses aversive effect) via VTA-NA circuit. Self-Administration studies in animals prove addictive properties. Not as reinforcing as cocaine, amphetamine, or opioids, but animals do self-administer it. Likelihood you will become addicted to nicotine younger ages vs older ages (rats). Adolescent vs adult rats (none had been previously exposed to nicotine), measured how many times they self-administered, measured amount of nicotine administered, adolescent rats inject more often, yielding a much higher level of nicotine, adult rats self-administer less, something about the adolescent brain that makes nicotine so appealing. Progressive ratio schedule (most effective). Conditioned place preference: nicotine in one side, placebo in other side, place them in middle and let them decide which side (drug) they prefer. Neuron activity in VTA: inhaled tobacco smoke instead of injection, more realistic, electrode in VTA or other (substantial nigra), rate of firing of cells in VTA or substantial nigra: lines on graph. VTA: increases firing of cells in this area, reward pathway activated. Substantia nigra: don't make much of a difference.
Caffeine metabolism/excretion
After 3-7 hours, 1/2 caffeine still in blood. Metabolization of caffeine: primarily in the liver. Depends of infants, elderly, pregnant, or oral contraceptives = slower metabolism. Excretion of caffeine: almost entirely in the urine. Smokers = faster elimination (50% faster). Caffeine taken on an empty stomach releases stomach acids and digestive enzymes causing an upset stomach. Caffeine mechanism of action seems to be blocking of adenosine receptor sits: antagonist. Adenosine receptors: behavioral sedation (makes you tired), causes headaches (dilates cerebral arteries), makes it hard to breathe (constricts bronchial passages).
Nicotine drug therapy
Antianxiety/depression drugs (Wellbutrin or Bupropion) now called Zyban reduces the desire for nicotine, side effects include convulsions and delirium. Chantix: very popular now, binds to nicotine-receptors to give them a feeling of nicotine, keeps nicotine from binding- partial agonist, will not feel the same if they smoke while on the drug compared to off the drug. Three vaccines are being developed to prevent nicotine addictions.
Soft drink consumption
Argentina: #1 USA: #2 Chilli, Mexico, Uruguay. Caffeinated colas have most of the caffeine content added to the beverage during production. Levels of caffeine in these beverages are approx 34-55mg per 12 ounces.
Chronic effects of tobacco and nicotine
Cardiovascular diseases: coronary heart disease (30% of all CHD deaths due to smoking, arteriosclerosis- hardening arteries, ischemic stroke). Respiratory diseases of Chronic Obstructive Pulmonary Disorder: 80-90% of COPD causes linked to smoking, chronic bronchitis or emphysema. Nicotine itself contributes to the disorders. Nicotine: constricts blood vessel so it increases work of the heart muscle, bp, platelet adhesiveness (clots easier), serum cholesterol levels, CO decreases amount of oxygen available to organs, oxygen not delivered to organs- age faster, heart has to work harder. Cancer: mostly due to tar and other chemicals in tobacco (not nicotine that we know of). 80% of new lung cancer cases in 2012 were smoke related. More African American males die than white males. Men's and women's rates both on rise. World Health Organization claims tobacco use is the leading cause of preventable death in the world. Males vs. females: Males develop lung cancer peaked in 1985, started to decline. Prostate cancer went up, went down, same pattern as lung cancer for men. For women: lung cancer didn't peak, numbers are rising (through 2009), breast cancer has higher prevalence rate than lung cancer for females. More cases of lung cancer than breast cancer, most people think women suffer from breast cancer the most...not true anymore! Approx 443,000 deaths from tobacco Women's concerns: tobacco smoke and birth control pills, smoking while pregnant, babies weigh less and are more likely to be premature, higher incidence of spontaneous abortions, higher rate of stillbirths, higher rate of sudden infant death syndrome (SIDS), higher rates of psychological problems, significantly reduces fertility in women, exposure to in-utero cocaine vs nicotine: cocaine is actually better long term...issues with crack babies at first is prenatal and postnatal care (environmental influences. Nicotine effects a broader segment of the population, same things happening in all classes of families, less likely the environment is causing these consequences. Nicotine baby brains have less cells than cocaine baby brains Smokeless tobacco: gum disease, damage to tooth enamel, loss of teeth, oral cancer, cancer of the jaw, pharynx, and neck
Pharmacodynamics for amphetamines: Nervous systems
Central Nervous System: block reuptake of NE and DA, enhances release from axon terminals (NE and DA), makes the terminal kinda leaky so it leaks to synaptic cleft. At high doses- it inhibits MAO (inhibits the enzyme that breaks down neurotransmitters- enzyme degradation) Peripheral Nervous System: sympathomimetic- due to increase in NE release, heart rate goes up, pupils dilate, not a great feeling, nervous. Meth: less of sympathomimetic effects, more CNS effects rather than PNS effects, not as much jitteriness.
Forms of cocaine
Coca leaf: Oral Coca Paste (basuco): cocaine sulfate: smokable but not freebase or crack. Street cocaine: cocaine hydrochloride: intranasal, injection, put in wine and Coca Cola, water soluble IV, very expensive. Crack: freebase and crack cocaine, cheap.
Treatment Programs
Cocaine abusers can receive treatment through inpatient programs, outpatient programs, combination of the two. - Relapse is a continual concern for recovering cocaine abusers- conditioned cues in the environment. Don't go back to the environment in which you normally take the drug in. Needle freak: just looking at the needle sometimes can cause people to have those compensatory physical responses and crave the drug. - Cocaine anonymous - Cognitive behavioral therapies - Pharmacological approaches (anti-depressants to lessen depression, vigabatrin (prevents sudden surge of DA)).
Current use/trends of cocaine
Cocaine usage has been on the incline in the past few years, since 2012 in young adults. Rates are not as high as the 80's, but deaths related to cocaine is right under the synthetic opioids death rate (increase in deaths since 2013). -14,556 deaths per year from coke -combining coke and opioids together is "speedball" -Emergency department visits due to cocaine: 40% of all visits involving an illicit drug, average visits per day is 339 for patients 18-25.
Coffee history
Coffee arabica originated in Ethiopia. Discovery of coffee: sheep ingested berries off a tree from the coffea plant, then 11th-15th centuries it spread to Arabia "the wine of Islam". Leading coffee producing countries: Brazil, Vietnam, Indonesia (Island of Java). 17th/18th century England: coffee houses first opened in 1650 (Oxford) helped with gin epidemic (1720-1750). Penny universities: penny for a cup of coffee and get an education due to the highs levels of intelligent conversation. Turned into a tea drinking country. 1820: caffeine was identified by German and French scientists 18th-21st century America: tea first but then revolutionary war and coffee houses took over. By 1860, 3/4 of the world's coffee was consumed by Americans now we are about 18th in the world, some decline in coffee consumption since 1960's when colas became popular. World Coffee Consumptions (2017): US 18th per capita consumption, Finland is #1 per capita consumptions, Netherlands, Sweden, Denmark, Norway, Austria all drink a lot. Caffeine: world's most frequently consumed stimulant. Current World Trade Coffee Consumption: 1.3 kilograms per person per year. Cradle to the grave drug- consumption increases with age up to 65 years when it begins to decline.
Caffeine sources
Coffee: coffea arabica (native to Brazil, Columbia, East Africa) smooth taste, expensive. Coffea robusta (native to Indonesian island of Java hence a cup of java) more caffeine, decaf caffeine. Methylxanthine in coffee beans- caffeine only. 5oz 100mg average (but depends on how brewed, 57-145 mg), decaffeinated coffee -> robusta beans. 5mg to 32mg per 10-12 ounces (compared to 100 mg) never completely caffeine free. Tea leaves (camellia sinensis) caffeine: 5 oz cup has 60 mg. Theophylline (bronchodilator, opens up air passages) small amounts. Polyphenols- in green tea, health benefits? Cocoa beans 1 oz has 6-8 mg of caffeine. Glass of chocolate milk- 6 mg of caffeine. Theobromine 1 oz piece has 44mg, about as strong as 4mg caffeine. Soft drinks/energy drinks: West African Kola nut (not that much caffeine in the kola notes) 12 oz soda has 34-55mg of caffeine, only 5% of the caffeine comes from kola nut. 95% of caffeine is added, leftover caffeine from decaffeinated coffee is sold to soda companies to add to their drinks.
Cocaine use history and abuse: First Era
First Era: 3000 BCE - Andean regions of Bolivia, Educator, Peru, and Argentina (Andes Mountains). Chewed coca leaves to relieve fatigue, for spiritual reasons, or to enhance well-being (weak base so it's ionized in the mouth). - Inca Civilization (13th century-16th century) , Spanish conquistadores- at first they said no you can't chew these leaves, ended up letting the Incas chew the leaves so they weren't fatigued working for Spanish settlers (also cause them to eat less), before that only high priests chewed the leaves, - Today 90% of Andean highlands region males chew coca leaves. Unpurified form (2% cocaine in leaves), chewed coca leaves = slow absorption. No high, just increase in activity and suppresses appetite. Mixed with lime or ash for better absorption (ash neutralizes the coca leaves so it's absorbed easier (before adding it, it's a weak base in the mouth and becomes ionized and therefore cannot pass through the membranes, ash and lime prevent this. Cocaine addiction and abuse is not a reported problem in the Andean region
Distribution, metabolism, and excretion of amphetamines
Freely crosses membrane of blood brain barrier and placenta. Metabolized by liver at a slow rate. The half-life is 10-12 hours and they are not totally eliminated from the body for about two days. Longer lasting high than cocaine (40 min half-life of cocaine).
Distribution
Inhalation: first nicotine reaches brain in 7 seconds. IV route: first nicotine reaches brain in 14 seconds
Administration
Inhalation: through lungs, most rapid and efficient method of administration. 90% of inhaled nicotine is absorbed into the blood (gets to the brain fast), average cig = .5-2mg of nicotine, 20% gets inhaled and into the bloodstream. (2-8 mg of nicotine a day if you're a one pack a day smoker). Effect of added ammonia = fast absorption of nicotine. Enters lungs on tar particles. Smoke: particle phase and gaseous phase...tar are little clusters and nicotine gets in on those clusters. Volume of smoke inhaled affects absorption (not how long you hold it in your lungs). Typical smoker takes 10 puffs and 30-60 intervals, 30 cigs per day = 300 separate hits of nicotine each day. Self-administration like lever pressing for reward. Orally: (really via crossing membranes): chewing tobacco or holding the smoke in your mouth-cigars. Transmembrane really. Slower onset than inhalation but effects last longer. If eat it: gets ionized in digestive tract and not absorbed well there. Cigars have higher level of nicotine than cigarettes, higher rates of certain cancers. Intranasal: snuff- the nicotine in one dip of snuff = four cigarettes Other methods: chewing gum, the patch, nasal spray, no one snorts or injects pure nicotine: because it's toxic in its pure form
Acute effects of amphetamines
Low-Moderate dose 1) General arousing agent: keeps people awake for long periods of time (insomnia), increases locomotor activity (stereotyped behavior, especially high doses), increases motor performance on many motor tasks (endurance), increases attention/vigilance (clock test, 2 steps instead of 1). In non-drug state: performance drops from 95% to 80% in 2 hours. 10mg amphetamines = no deterioration at all (increases resistance to fatigue/boredom). Increases perceptual abilities (CFF threshold- critical flicker fusion.) CFF: two edges of light flickering, as speed of flicker increases, humans perceive them fused together and cannot tell the flicks apart any longer. More acute your vision, faster the lights can go. Stimulants increase that threshold, not fused for a longer amount of time. 2) An "antidepressant": mood elevation. Elation/well being (A RUSH) -> lasts longer than cocaine high. (POMS: profile of moods scale). 3) An anorectic: suppressing appetite. 4) PNS: increased BP, sweating, heart rate, vasodilation -> blood flow to muscles, bronchodilator, tremors. Methamphetamines especially increase body temperature. High doses: Pyschotic reactions: amphetamine psychosis (like that found with cocaine, paranoid-schizophrenia-like), formication syndrome, give them antipsychotic meds to help. Methamphetamine: flashbacks (recurrence of psychotic behavior while abstinent from drug). Violent behavior too. Not with regular amphetamines or cocaine. Due to what the meth has done to the neural circuitry. Neurotoxicity (methamphetamine). In animals: long lasting reductions in DA and DATs. In humans: reduced DATs in striatum of meth user (even following abstinence) possibly leads to early Parkinson's disease. Risk of overdose: seizures, respiratory depression/collapse, stroke, heart attack, death. Acute tolerance develops to euphoric effects but NOT to bp and heart rate- so it's VERY dangerous
Amphetamine history
Ma Juang > 5000 years. Chinese medicinal herb, used for thousands of years as a bronchodilator. Shen Nung (emperor). Medicinal properties: hay fever, cough, cold. Ephredrine- 19th century. In Germany isolated active ingredient...ephedrine. Afraid the original plant would be depleted...now we can synthesize it Synthetic ephedra- amphetamine- 20th century. 1920's it was synthesized (caught on because of the restrictions of cocaine, heroin, morphine, and alcohol). Gordon Alles tested amphetamine is a good substance for ephedrine and as an anti-asthmatic. Medical purposes: 1932: Smith, Kline, and French produced/marketed the first "inhaler" contained 250 mg of benzedrine in a cotton plug (could be up to 400 mg). Used to relieve nasal or bronchial congestion. Began to overuse them and abuse them...some would inject and snort after destroying the inhalant contraption. Very effective, iatropic of or related to medicine, epidemic that emerged in 20's is that the doctors are the ones who started the epidemic. 1935: first tablet form marketed as treatment for narcolepsy 1937: AMAAmerican Medical Association ok'd amphetamine for treatment of narcolepsy and as a pick me up for depression and 37 other disorders (losing weight, etc). Charles Bradley: amphetamines help hyperactive kids, ADHD, college students started to use to help them stay awake. 1940's variety of uses: especially weight loss in housewives, during WW2 to ward off fatigue (oral administration = easy). By the late 1940's: world's first major amphetamines (like today's caffeine). Lots in Japan (methamphetamine)- 5% of all Japanese 16-25 yr olds were dependent on the meth. After WW2: 1950's: students, truck drivers consumed it to stay awake. Homemakers took it to stay thin. Surge in street use of amphetamine (like today's caffeine). 1960's: began injecting it. Hippies mixed it with LSD and heroin addicts used it (via injection not oral administration) to keep them alert and awake. Typical: injection every 2 hours for 3-6 days leads to exhaustion and sleep for 3 days, returned to normal for 3 days (ate a lot, very hungry) and then repeat. 1967: PEAK use and into the 1970's. 10 billion tablets produced each year- for legal uses (8% of all prescription drugs). 1970's: TIGHT regulations on distribution. So decline of amphetamines in the 70's and then cocaine became attractive once again (freebase coke in 70's- era 3). Due to hippie usage and regular home usage. 1980's With the emphasis on cocaine abuse during the 1980's, amphetamine abuse was less prominent in the public mind. Started to stray from amphetamines and back to crack cocaine (80's). 1990's abuse of methamphetamine (crank): started in 1960's, methamphetamine became the number one drug problem in rural areas and working class, motorcycle gangs in California hid it in the crank of the motorcycle and then distributed it. West to East movement of methamphetamine in the 90's- smokeable form of methamphetamine is crystal meth (ephedrine mixed with all types of chemicals, they then used pseudoephedrine to make methamphetamine)...physical harm from explosions, fires, chemical burns, toxic fumes. Environmental hazards, child engagement, child endangerment, club drug (rave, increases body temperature too much) Abuse of ephedra/ephedrine (diet pills) 1999: 2 billion doses were consumed by Americans each year. 2003: Steve Bechler (Orioles pitcher). Took diet pills containing ephedrine before a spring training workout- body temperature shot up to 108 degrees, resulting in a heatstroke. 2004: banned sale of ephedrine alkaloids in dietary supplements because of possibility of hypothermia...still debated.
What is tobacco
Nicotine: primary psychoactive ingredient (3 disease-causing culprits: tar, nicotine, and carbon monoxide. Nicotine: acute pharmacological effects of smoking, dependence of cigarettes, it is toxic, 60 mg on tongue could kill you, insecticide. Chief long term effects are principally related to the other compounds Tar: gives tobacco its taste and smell and so contributes to the reinforcing effects of smoking. Carcinogens (affects ciliary escalator), contain most of the cancer-causing substances. In the leaf- other added carcinogens when they make cigarettes and stuff. Carbon monoxide: impedes the oxygen carrying capacity of the blood (200X greater affinity for hemoglobin than oxygen). Carbon monoxide molecules bind from hemoglobin and cannot led oxygen through, impairs circulation, increases cholesterol and deposits and atherosclerosis, so cardiovascular problems: much harder on your heart. Wrinkle more than people who don't smoke because of lack of oxygen to those face areas, other chemicals in cigarettes make it burn more steadily (more than 100 chemicals).
Caffeine administration/absorption
Oral Absorption: very lipid soluble rapidly -> absorbed from the GI tract and distributed throughout the body. Peak levels of caffeine 15-45 minutes after ingestion. Peak effects occur 2 hours after consumption. Immediate buzz likely related to the sugar or a learned response.
Cocaine administration and absorption
Oral Administration: (chew leaves), efficacy reduced taken in this way, takes 10-15 min for drug action to begin, cocaine is a weak base so ionization occurs in the stomach, slowest Intranasal: (snorting- hydrochloride salt). Good absorption through mucous membranes of nose. Big CNS stimulation for 15-30 min then you crash. Snorting is 20-30mg per line. Relatively slow compared to other routes of administration (but coke effects are felt very fast) IV injection: (hydrochloride salt), LARGE doses introduced very quickly, within seconds-> incredible state of euphoria, but short lived (5-10 min), BIG crash, so to prevent this you re-administer every 10-30 min. Speedball is coke and heroin injected simultaneously. Inhalation: Smoking freebase or crack cocaine. Effects of smoking as intense and fast than IV route! Fast into the blood, but not that much at a time (can only inhale so much at a time), can get to your brain very quickly (probably faster than an IV injection), very quick, very brief high
Administration and absorption of amphetamines
Oral administration: pill typical doses, 5-15mg, weak base so ionized in belly- not absorbed well there (but better than cocaine). IV route: large doses introduced very quickly, within seconds -> get rush, IV binges or runs (injections every 2 hours for 3-6 days) so take with a barbiturate or with heroin (speedball) to take the edge off. Methamphetamines: oral, intranasal, IV, or inhalation (Ice, crystal meth)
Cocaine Dependence and Withdrawal
Physical Dependence/withdrawal - no severe life threatening abstinence syndrome is observed- when drug use is discontinued. - Withdrawal symptoms include depression, lack of energy, poor appetite, restlessness, and agitation - Can't really say people are physically dependent on cocaine because they don't have severe withdrawal effects...but they def feel depressed, lethargic, etc - Debate is whether this withdrawal effect is a true withdrawal effect. Psychological Dependence: (mesolimbic dopamine system- ventral segmental area to the nucleus accumbens). - Drug self-administration studies - Pickens and Thompson (1986) Rats in a Skinner box, given a lever that administers coke through IV. First demonstration of self-administration of a drug other than morphine. Established that a drug with no apparent withdrawal symptoms could be a positive reinforcer (because it feels good) that one injection produced a euphoria and they continued to present the lever to get the same effects. Positive reinforcement model -Likely the MOST reinforcing model - Progressive ratio schedule: one monkey 6400 times, how addictive might a drug be? Progressive ratio schedule, train animal to press lever and get drug, then you change rules, they have to hit the lever 10 times before they get one injection...then 100 times hitting the lever. Interval ratio schedules: based on number of times the animal has to hit the lever. - 6 Monkeys: 4/6 cocaine was the most powerful reinforcer worked harder to get the cocaine...5th monkey was a tie between coke and amphetamines. 6400- how many times the monkey would hit the lever to get that one injection of coke. - Pattern of administration like human pattern. The way animals use cocaine is not very different from how humans use it. They'll use it until they crash and then take it again. CPP studies- "conditioned place preference" Put them in dark and light areas (light with drug, but dark with nothing, rats usually really like the dark, but choose light with drug. - Immediately want to take it again - "I need it"
Dependence on amphetamines
Physical dependence: no severe/medically serious withdrawal syndrome is observed when drug use is discontinued. Depression due to long term effects of drug (depletion and monoamines) and anhedonia. Amphetamine withdrawal: psychiatric depression. Withdrawal from meth is difficult: highest relapse of all drugs. Psychological dependence: taps into the reward circuit (VTA to NA), very reinforcing in humans and other animals, conditioned place preference, drug discrimination studies: can you discriminate against this drug and a placebo? The drug and another drug? Train them to press different levers for amphetamines and placebo. Animals will not be able to discriminate between amphetamines and cocaine. Humans describe not much of a difference between amphetamines and cocaine, they know it but it's not that different, they're similar. Pursuit Motor Test: circle needle test, psychomotor test
Pharmacodynamics: Nervous systems
Somatic Nervous System: acts as a local anesthetic (by blocking sodium channels), only accepted medical use for cocaine (ergo schedule 2 drug). Procaine, novocaine, preferred for longer anesthetic effects and less potential for side effects. Numbs muscles of the eyeballs for eye surgery- why they use this and not other anesthetics. Autonomic Nervous System: acts as a sympathomimetic (increases sympathetic activation) Central Nervous System: cocaine increased DA and NE in brain, main effect of coke is blocking reuptake especially of Dopamine. Key areas coke targets: mesolimbic dopamine system (nucleus accumbent, ventral segmental area- pleasure, want it feeling). And Nigrostriatal pathway: motor system stimulant, pathway that is important in regulating motor control, when this is messed up it results in Parkinson's disease.
Second Era: 1880's/19th century European Cocaine Epidemic
Spaniards brought coca leaves to Europe (16th century), but in 1860 Alfred Neimann isolated purified coke and named it cocaine. (good thing: water soluble in someway, control over the substance, bad thing: abuse increases). 1863: Angelo Mariani: purified coke in wine (Mariani wine, the Pope loved it). Alcohol and cocaine consumed together created cocaethylene which makes the half life much longer. 1884: Sigmund Freud: wrote his book "Uber Coca" used it frequently, toying around with coke when he was a neurologist med student. He was drinking purified form. Reported it creates a warm cooling feeling, increases capacity of body for short period of time, far less dangerous than alcohol according to Freud. Though it would cure anything. Gives Von Fleischl-Marxow cocaine to ween him off of morphine addiction- he kept taking more. Developed formication syndrome (feeling of bug under your skin, form of psychosis, first cocaine-induced form of psychosis. Freud then began to see negative effects and took back a lot of what he said. Treasure Island and Sherlock Holmes authors believed to be under influence of cocaine while writing. 1885: Karl Koller: figured out anesthetic properties of coke. Has numbing effects- new local anesthetic for eye surgery. Good for dentists, they didn't have novacane at the time.
Acute effects of caffeine
Stimulates CNS activity and other parts of body. Diuresis, heart stimulation, relaxation of smooth muscles, dilates bronchial passages (theophylline is more potent), gastric acid stimulation, increases blood sugar levels so decreases appetite, delay sleep onset, increases body temperature. Profile of moods scale: measuring mood. CNS stimulation action of caffeine elevated mood and focuses attention. Feelings associated with moderate doses of caffeine: energized creative, efficient, confident, alert. Performance effects: range of caffeine effects is wide, increases vigilance, decreases fatigue, decreases the response times to simple visual and auditory signals...but tends to impair the decision making part of choice tasks. It increases sensory system sensitivity, caffeine use by well-conditioned athletes has been found to improve endurance on a short-term basis- but mixed findings. Side effects can include nervousness, anxiety, insomnia, heart burn Toxic effects of caffeine: caffeinism: acute caffeine intoxication. Occurs at doses of 600 mg or higher, caffeine overdose, above 1000mg of caffeine daily: muscle twitching, rambling flow of thought and speech, cardiac arrhythmia, psychomotor agitation.
Khat plant
Synthetic version put in bath salts, considered a stimulant. Synthetic cathinones became widely used stimulants in recent years primarily marketed legally over the internet as "bath salts" or "plant food". Two of these drugs (mephedrone and MDPV) were banned by the Prevention of Synthetic Drugs Act of 2012.
Tea history
Tea (camellia sinensis). China: emperor Shen Nung credited with its discovery in 2700 BC, oldest caffeine containing beverage, also used amphetamines: ma juang. Britain: Dutch traders brought tea from Asia to Western Europe, became popular in Russia and England. Tea became major element of English economy (3rd largest export to American colonies, Boston Tea Party, Tea became "unpatriotic" and America became a coffee country. Colonized India-> opium wars trading tea for opioids in China and England.
Chronic effects of amphetamine use
Tolerance develops quickly- many users increase the dosage or go on binges to maintain their high. Functional tolerance can develop: appetite suppressing effects, heart and bp effects, lethal effects (one man- 15,000 mg of administered over a 24 hr period (1000X LD50).
Nicotine natural species
Two types of tobacco plant Large leaf from nicotiana tabacum: principal source of modern tobacco, originated in South America. Small leaf from nicotiana rustica: native to Eastern N America
Prevalence of tobacco
US companies export more than $2 billion worth of tobacco products, Russia smokes a lot of cigs, 61% of male doctors in China smoke cigs. Cigs smoking is the most common way to use tobacco, smoking in the US has continued to decline since the middle of the 20th century, decreased use linked to Surgeon General's 1964 report; detailed the health hazards of cigarette smoking. 18-25 yr olds: steady decline in prevalence of smoking cigs (2002-2017), less smoking more than one pack a day, 22% 26+: relatively constant until end, 18.9% Gender differences: in our age group (18-25), males- 54.5%, females- 44.5% Ethnic differences within the US: American Indian or Alaskan Natives have highest rates, Asian typically the lowest.
Chronic effects of cocaine
Undesirable mood changes (depression, anxiety). When you stop taking it you get a sense of dysphoria. Heavy users may not just experience a high they may experience a manic episode followed by severe depression- crash following by cocaine administration. - Decreased sexual performance - Cocaine psychosis (formication syndrome) - Physical deterioration of the nasal membranes if coke is administered intranasally - Reduce dopamine receptors in brain by 20% due to receptor down regulation!! Not only in the striatum, but other places in the brain as well.
Pharmacodynamics
nicotine is a cholinergic agonist that has biphasic (stimulant and depressant) action. Acetylcholine receptors in both CNS and PNS. Subtype: nicotinic acetylcholine receptors, agonist at these receptors. Biphasic effect: stimulation of the nicotinic receptors (low doses) then stimulates and does what acetylcholine dose. Nicotinic depolarization block (high doses) especially on muscles, acts more as an antagonist, keeps cell from depolarizing, perceived as calming although it is a stimulant. PNS: Somatic Division. Striated muscles at neuromuscular junction. Nicotine at moderate doses -> more relaxed muscles. Neurotransmitters at the neuromuscular junction are acetylcholine, they are nicotinic receptors so you end up stopping your muscles from contracting (what acetylcholine controls) you produce a perception of a calm feeling. PNS: Autonomic Division. Stimulant effects reflected (mostly) in sympathetic activation increases respiration, heart rate, bp (makes heart work harder), constricts blood vessels. HR + BP + carbon monoxide you're taking in, put tremendous stress on your cardiovascular system. Constricting blood vessels = not as much blood is flowing. Smoker's have cold hands and don't blush very much. Buerger's disease: limbs, hands, fingers, begin to not receive blood and they turn purple, vascular disease brought on by smoking, leads to amputations, pretty rare. GI tract: inhibits hunger for 1 hour, laxative if you're not used to it, can cause weight loss in the beginning, increases secretion of hydrochloric acid, causes increases in blood sugar, increases bowel movements. CNS: acetylcholine receptors in CNS. Striatum and cerebellum effect movement. Hippocampus effects memory. Nucleus accumbens effects reward and pleasure systems, reward of smoking would reinforce behavior "where pleasure is located in the brain". Areas of the medulla oblongata effect respiration and circulation, life functions, nausea is the key here: something foreign to the body, medulla makes you want to throw up. Areas in cortex: effect judgment.
