1
3 13. Be familiar with the pharmacokinetics and pharmacology of nicotine and with current approaches to the treatment of smoking. KEY WORDS AND PHRASES: cocaine, norcocaine, d-amphetamine, dl-amphetamine, methamphetamine, phentermine, diethylpropion, methylphenidate, nicotine LECTURE OUTLINE: A. Cocaine 1. Introduction Cocaine is schedule C-II. Crack is free base cocaine, a form of cocaine that can be smoked. To make crack, cocaine is processed with ammonia or sodium bicarbonate and water, then heated to remove the hydrochloride. "Crack" refers to the crackling sound heard when the mixture is smoked (heated), presumably from the sodium bicarbonate. 2. Epidemiology Pharmacokinetics Absorption oral ingestion slow absorption (30-60 min) low bioavailability (30-40%; first pass effect) snorting bioavailability limited due to constriction of nasal mucosal vessels smoking or IV rush occurs within 1-2 minutes Distribution most tissue, including fetus t = 1-1.5 hours 0 15 30 45 60 time Cocaine "high" smoking/IV snorting oral 1975 1980 1985 1990 1995 2000 0 5 10 15 20 NIDA, Monitoring the Future Study, 2000 Percentage of High School Seniors who ever used cocaine or crack Cocaine Crack Percentage 4 oral cocaine is as effective as intranasal; peak plasma concentrations are similar; peak highs (in laboratory setting) after both routes maintained for 60 minutes (contradicts "street" reports of 15- 20 minutes); cardiovascular and subjective effects are highly correlated with rapid increase in plasma levels; effects decline faster than plasma concentrations 3. Metabolism Cocaine is metabolized to: ecgonine methyl ester by liver and plasma cholinesterases norcocaine by N-demethylation; this is an active metabolite which may in part determine cocaine's toxicity (e.g., paranoia, convulsions, respiratory arrest); it is more potent than cocaine as a local anesthetic; it is as potent as cocaine in inhibiting norepinephrine uptake benzoylecgonine by nonenzymatic hydrolysis; it can persist in brain for up to 10 days after cocaine injection; it constricts arteries in brain (may lead to delayed seizures and strokes) Cocaine + ethanol lead to the formation of: cocaethylene by liver and plasma cholinesterases; it is as potent as cocaine on dopamine uptake but much less potent on 5HT reuptake; in mice (and probably in humans) cocaethylene is 50% more potent than cocaine in causing lethality Ethanol may also increase plasma concentration of cocaine CONCURRENT USE OF ETHANOL INCREASES THE RISK OF COCAINE-RELATED SUDDEN DEATH 18-FOLD 4. Neurochemical effects Without the presence of cocaine dopamine is released in the synapse it interacts with its receptors it is cleared by reuptake In presence of cocaine cocaine blocks dopamine re-uptake dopamine levels increase in the synapse cocaine blocks also norepinephrine and serotonin reuptake 5. Acute effects of cocaine euphoria increased sense of energy, enhanced mental acuity, increased self-confidence anxiety decreased appetite decreased need for sleep activation of the sympathetic system: mydriasis tachycardia hypertension peripheral vasoconstriction 6. Signs of cocaine abuse nasal perforation madarosis (loss of eyebrows or eye lashes) cocaine tracks (injection sites) 7. Medical complications of cocaine abuse neurologic/psychiatric complications cerebral infarction and hemorrhage seizures depression 5 psychosis (paranoia-like) cardiovascular complications myocardial ischemia arrythmias infectious complications (due to IV administration) HIV hepatitis B, C endocarditis 8. Stimulant abstinence syndrome Crash extreme exhaustion craving for sleep (increased REM) hyperphagia dysphoria (anxiety and depression) lasts 3-4 days Withdrawal decreased energy (fatigue) anhedonia fluctuating drug craving (leading to binges) symptoms increase 12-96 hours after crash lasts 6-18 weeks Extinction episodic drug craving lasts months to years 9. Cocaine overdose Symptoms usually manifested by seizures and cardiopulmonary arrest death usually due to respiratory failure immediate death from heart failure may be due to: direct toxic effect on heart muscle spasms and constriction of coronary arteries platelet activation Treatment diazepam may control seizures chlorpromazine may be used for psychotic symptoms (e.g., paranoia) the use of propanolol for cardiovascular symptoms is controversial B. Amphetamines 1. Structure-activity relationships of phenylethylamines Amphetamine -CH3 is important for anorexia blocks MAO activity methamphetamine N-CH3 Increases stimulant potency 5 Symptoms usually manifested by seizures and cardiopulmonary arrest death usually due to respiratory failure immediate death from heart failure may be due to: direct toxic effect on heart muscle spasms and constriction of coronary arteries platelet activation Treatment diazepam may control seizures chlorpromazine may be used for psychotic symptoms (e.g., paranoia) the use of propanolol for cardiovascular symptoms is controversial B. Amphetamines 1. Structure-activity relationships of phenylethylamines Amphetamine -CH3 is important for anorexia blocks MAO activity methamphetamine N-CH3 Increases stimulant potency 6 2. Epidemiology 3. Neurochemical effects With increasing doses: reverses vesicular and membrane uptake transporters-- releases cytoplasmic catecholamines inhibits re-uptake of catecholamines inhibits MAO releases serotonin and inhibits serotonin re-uptake 4. Methamphetamine Street names "speed", "meth", "chalk", "ice", "crystal", "crank", "glass". Route of administration oral smoking snorting IV injection Methamphetamine versus cocaine Methamphetamine Man-made Smoking produces a high that lasts 8-24 hours 50% of the drug is removed from the body in 12 hours Cocaine Plant-derived Smoking produces a high that lasts 20-30 minutes 50% of the drug is removed from the body in 1 hour 5. Acute effects of amphetamines extreme elation wakefulness alertness enhanced self-confidence aggression talkativeness loss of appetite increased initiative increased physical activity increased respiration 1992 1994 1996 1998 2000 4,000 6,000 8,000 10,000 12,000 14,000 16,000 18,000 drug-related emergency department episodes methamphetamine amphetamine hyperthermia increased heart rate and blood pressure 6. Medical complications of amphetamine abuse neurologic/psychiatric complications episodes of violent behavior, paranoia, anxiety, confusion, and insomnia repetitive behavior patterns, and delusions of parasites or insects under the skin acute lead poisoning (illegal methamphetamine production uses lead acetate as a reagent) hyperthermia and convulsions cardiovascular complications arrythmias stroke infectious complications (due to IV administration) HIV hepatitis B, C endocardis liver, kiney, brain damage? 7. Amphethamine withdrawal deep depression craving, fatigue etc. (stimulant abstinence syndrome) 8. Amphetamine overdose Symptoms restlessness tremor confusion paranoia psychosis hallucinations panic aggressiveness hypertension tachycardia, arrythmias seizures fever Treatment safe, quiet environment ice baths anticonvulsant drugs benzodiazepines neuroleptics 9. Therapeutic uses of amphetamines Weight loss Therapeutic targets for obesity Food intake central control monoamines (norepinephrine, 5HT, dopamine, histamine) neuropeptides (neuropeptide Y, proopiomelanocortin, cocaine- and amphetamine- regulated transcript, corticotropin-releasing hormone, insulin, agouti-related protein) Food intake peripheral control leptin GI peptides (cholecystokinine, ApoA-IV) pancreatic peptides (glucagon-like peptide-1, enterostatin, amylin) nutrients Fat absorption lipase inhibitors fatty acid transporters Fat metabolism diacylglycerol transferase adipocyte differentiation angiogenesis apoptosis Thermogenesis thyroid hormones 3 adrenergic agonists uncoupling proteins Central regulation of food intake Brain regions ventromedial hypothalami nucleus (VMN) = “satiety center” lateral hypothalamic nucleus (LHA) = “hunger center” arcuate nucleus (ARC) paraventricular nucleus (PVN) perifornical area (PFA) dorsomedial nucleus (DMN) Neurotransmitters that suppress food intake Norepinephine 1 receptor agonists 2 receptor agonists NE releasers NE uptake blockers 5HT 5HT2c receptor agonists 5HT releasers 5HT uptake blockers Dopamine D1 receptor agonists Abbreviations: AM, amygdala; CC, corpus callosum; CCX, cerebral cortex; HI, hippocampus; ME, median eminence; OC, optic chiasm; SE, septum; TH, thalamus; FX, fornix; 3V, third ventricle. peptides Increased adiposity leads to increased leptin production in fat tissue. Leptin stimulates neurons in the arcuate nucleus of the hypothalamus that coexpress the anorexigenic hormones -melanocyte- stimulating hormone ( -MSH, a cleavage product of proopiomelanocortin [POMC]) and cocaine- and amphetamine-regulated transcript (CART). Leptin also inhibits neurons in the arcuate nucleus that coexpress the orexigenic hormones agouti-related protein and neuropeptide Y. The neurons in the arcuate nucleus project to other regions of the hypothalamus (including the paraventricular nucleus and the lateral hypothalamic area–parafornical area), where -MSH binds to its receptor, MC4R, resulting in an up-regulation of anorexigenic effectors such as corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) and a down-regulation of orexigenic effectors such as melanin- concentrating hormone (MCH) and orexin. Agouti-related protein acts as an antagonist of MC4R. Other anorexic agents phentermine (Ionamin ® ) releaser and uptake blocker of dopamine and NE schedule C-IV short-term treatment of obesity (8-12 weeks) diethylpropion (Tenuate ® ) schedule C-IV oral, indirect acting, nonamphetamine, sympathomimetic amine direct stimulation of the “satiety” center monotherapy for short-term treatment of obesity (8-12 weeks) phendimetrazine (Plegine ® ) schedule C-III oral, indirect acting, nonamphetamine, sympathomimetic amine direct stimulation of the “satiety” center monotherapy for short-term treatment of obesity (8-12 weeks) 10 fenfluramine, dexflenfluramine, phenylpropanolamine and sibutramine have been discontinued in the US Narcolepsy Modafinil (Provigil ® ) Attention deficit hyperactivity disorder What is ADHD? ADHD is a childhood psychiatric disorder characterized by inattention impulsivity overactivity neurobiology MRI studies found right prefrontal cortex, caudate nucleus and globus pallidus were smaller than normal in boys with ADHD Genetic studies suggest that people with ADHD might have alterations in genes encoding either the D4 dopamine receptor or the dopamine transporter In people with ADHD, the brain areas that control attention used less glucose, indicating that they were less active (PET) ADHD treatment methyphenidate (Ritalin ® ) schedule CII short half-life needs to be taken 3-4 times a day catecholamine releaser extended release tablets (Concerta ® ) d-amphetamine (Dexedrine ® ) schedule CII half-life 8-10 hours d-amphetamine + dl-amphetamine (Adderall ® ) schedule CII half-life 8-10 hours lisdexamfetamine (Vyvanse ® )-- prodrug metabolized to d-amphetamine guanfacine (Intuniv ® ) not scheduled half-life 4-6 hours norepinephrine alpha 2 agonist non-stimulant atomoxetine (Strattera ® ) half-life 4-6 hours norepinephrine uptake blocker non-stimulant increased risk of suicide? C. Nicotine 1. Epidemiology In 1996 (National Household Survey on Drug Abuse) 62 million Americans were current smokers. 6.8 million used smokeless tobacco. 3,000 people under the age of 18 will start smoking. 2. Pharmacokinetics Absorption 0.5 M 8:00 pm 0.1 to 0.2 M 8:00 am 8:00 am Brain concentration half-life 8-10 hours lisdexamfetamine (Vyvanse ® )-- prodrug metabolized to d-amphetamine guanfacine (Intuniv ® ) not scheduled half-life 4-6 hours norepinephrine alpha 2 agonist non-stimulant atomoxetine (Strattera ® ) half-life 4-6 hours norepinephrine uptake blocker non-stimulant increased risk of suicide? C. Nicotine 1. Epidemiology In 1996 (National Household Survey on Drug Abuse) 62 million Americans were current smokers. 6.8 million used smokeless tobacco. 3,000 people under the age of 18 will start smoking. 2. Pharmacokinetics Absorption 0.5 M 8:00 pm 0.1 to 0.2 M 8:00 am 8:00 am Brain concentration Lung: very rapid. The drug reaches the brain within 8 sec. GI tract: slow absorption via buccal mucosa, more efficient via intestines, but high first-pass metabolism. smokers maintain a serum concentration of about 0.1-0.2 M during the night. Distribution In most tissue, including embryo and fetus if pregnant woman (spontaneous abortion, preterm birth, low birth weights). Excretion Kidney. 3. Metabolism C-oxidation by cytochrome P450 (CYP2A6 genetic polymorphisms). T1/2 is about 2 hours. Metabolites: cotinine, nornicotine. Males metabolize faster than females. Eating increases nicotine metabolism ( hepatic blood flow). 4. Neurochemical Effects nicotine receptors are ion channels they are localized in the VTA nicotine binds to its receptors dopamine neurons are activated dopamine is released in the nucleus accumbens 5. Acute effects of nicotine Relaxation Reduced stress Increased vigilance Improved cognition Reduced body weight Dizziness, nausea Tachycardia, peripheral vasoconstriction 6. Medical complications of nicotine abuse Cancers lung cancer cancers of the mouth, pharynx, larynx, esophagus, stomach, pancreas, cervix, kidney, ureter, and bladder Lung diseases chronic bronchitis emphysema exacerbation asthma symptoms Heart diseases stroke heart attack vascular disease aneurysm Accidents residential fire fatalities Role of environmental tobacco smoke “secondhand smoke” major source of indoor air contaminants linked to lung cancers, cardiovascular diseases, increased severity of asthma for children. Nicotine poisoning 12 accidental ingestion by children death from respiratory failure caused by paralysis. The adverse effects of smoking during pregnancy: increased premature delivery rate decreased birth weights 7. Nicotine abstinence syndrome Irritability, impatience, hostility Anxiety Dysphoric or depressed mood Difficulty concentrating Restlessness Decreased heart rate Increased appetite or weight gain 8. Treatment of nicotine abuse More than 90 percent of the people who try to quit smoking relapse or return to smoking within 1 year, with the majority relapsing within a week. An estimated 2.5 to 5 percent succeed on their own. Pharmacological treatments can double the odds of success. Combination of pharmacological and behavioral treatments further improves the rate of success Nicotine replacement treatments approved for use in the United States: nicotine gum (1984, OTC ‘96), the transdermal patch (1991, OTC ‘96), nasal spray (1996), and inhaler (1998) used to relieve withdrawal symptoms provide users with lower overall nicotine levels than they receive with tobacco have little abuse potential since they do not produce the pleasurable effects of tobacco products do not contain the carcinogens and gases associated with tobacco smoke. produce less severe physiological alterations than tobacco-based systems Non-Nicotine Therapies bupropion: approved for use in the United States in 1997, an antidepressant marketed as Zyban; contains no nicotine; exact mechanism unknown, although it blocks nicotinic receptors and weakly inhibits dopamine uptake varenicline: approved for use in the United States in 2006; marketed as Chantix; contains no nicotine; partial agonist (agonist/antagonist) at nicotinic receptors Behavioral Treatments discover high-risk relapse situations develop self-monitoring of smoking behavior establish coping responses Cocaine Amphetamines Nicotine cocaine, amphetamines (d, racemic, L amphetamine, methamphetamine (d-methamphetamine) Crack is freebased cocaine, mixed cocaine~HCl + H2O + na2Hco3 = crack bicarbonate + co2 + H2o cocaine is usually cocaina HCl epidemic in the 80s, newer in the 90s, more steady in the 2000 (high school students) 3-4% of high school seniors have used it is absorbed orally, nasally, smoking, IV smoking is quickest way (same as IV) oral is slowest rout of administration dictates the how addictive it is the faster = more addictive the shorter acting drugs are federally higher rated (lower scedule level) t.5 = 1- 1.5 hours not active is active, but not that contribuatory is not thought to be bioactive may be responsible for strokes and seizures eect are cumulative coke + etoh has been described as being the most addictve drug of all time: more DA > 5HT serotining regulates DA is a highly addictive drug concrrent use increases sudden death by 18 ethanol ---x metabolism of coke = raising plasma levels Mechanism normally: prsynaptic DA ---> diusion cocaine ----x DA reuptake = more DA same thing happenes @ NE and 5HT sites but the DA mechanism is thought to be the most important as far as CNS, toxic, and dangerous eects of DA Coke raises the EC [DA] in critical areas of the brain (like other addictive drugs) mainly the Nuc. AAcumbens responsible for reward (reward center) all addictive drugs have been found to raise DA in the nucleus accumbens coke: blocks reuptake amphetamine: releaser nicotine and etoh: activate cell bodies in vent teg like opiates: inhibit inhibitory interneurons neurons in vent teg cocaine: euphorias, energy, arousal, sleep, dialation mydriasis, vasoconstriciton local anesthetic, no one uses it, but is still approved ER: bloody nose, wont stop, hole in nasal septum = coke snort coke: extensive vasoconstriction = ischemia/necrosis = hole in nasal septum missing eyebrows and eyelasches: smoking crack, singe eyebrows or eyelashes IV coke: tracts bc vasoconstriction (but any IV drug) complications: seizures, stokes, MI, paranoia (schizophrenia type) hallucination (more visual > audotory) = df IV: HIV, hepatitis, endocarditis (not specic to cocaine) -contamination, poor hygene, reuse needles cocain withdrawl: used to be argued that cocaine was not addicitve or withdrawl not as bad as opiate or depressants early = crash (for days): symptoms is opposite to acute pharmacological actions of drug (rebound) -general withdrawl for all drugs is opposite, if you know what drug does, you know the rebound cocaine withdrawl syndrome is almost identical to amphetamine withdrawl = stimulant withdrawl syndrome are identical but time course dieres -amphetamine: longer duration so withdrawl is more spread out later = anhedonia (sex, food, fun) cravings = extremely dicult to extinguish, happen with all drugs of abuse overdose: ER, paranoid schizohenia, cardiopulmonary arrest = medical emergence -supportive care -benzodiazapenes for seizures -antipsychotics Sudden death phenominon: all of a sudden drops dead -coke may have toxic idiosyncratic eect on heart -ask about CPR -speculation about CAs or platelets amphetamines phenyl ethyl amine, put an alpha methyl group on it you get amphetamine (alpha methyl for anorexia, and MAOi) N-methyl group get meth-amphetamine which increases potency (still correct) -this is a myth, nmethyl is not more potent -it turns out N-methamphetamine and D-amphetamine are equally as potent (not true for boards) epidemiology dependent on access an availability methamphetamine is easier to synthesize 2010 er visits were >150000k 5 fold increase in last 10 years meth is a dicult drug to treat mechanism primary mechanism: reverse vesicular transporters -cocaine blocks reuptaker -amphetamines reverse it rst, then block it -amphetamines raise a shit ton of DA in the brain -people stop seeking pleasure in other things meth is slightly more serotonergic meth can be thought of as an extremely long acting cocaine experiment: at rst 30mins amphetamine, methamphetamine, and cocaine are indistinguishable after 2-3 hours they can tell a diernce like coke, you can take amphetamines in all routs, IV is common acute eects: hyper arousal, hyperthermia is more of ann eect of amphetamine acute eects are the same as coke, but hyperthermia is more pronounced medical complications: similar ot coke, seizures and stoke -garage: lead containing agents = lead poisoning = street drug problems IV drugs: endocarditis, HIV, hepatitis high doses of amphetamines may be able to destro DA neurons eventually we will see an increase in PD withdrawl: stimulant abstence syndrome crash > withdrawl > extinction phase shorter acting: quicker in, quicker out, more intense OD: paraoid schizophenic state, seizure, neuroleptic, benzos maybe Ice baths Amphetamines medicinal uses most prevalent: weight loss, remarkable innefective, only lose 10-15lbs, gain toleracne, gain the weight back before amphetamines were as tightly regulate there were a group of physicians in long island “diet doctors” go get your drug each week (malpractice) late 70s secratary was typing the report possibly use for very obese motivator 2) ADHD: is eective if used properly 3) Narcolepsy: is eective but now we use “medanil” Food an appetite about 30 years ago we thought we knew body weight mechanism it is actually extraordinally complex there are central mechanisms: most attention peripheral mechanisms fat as an organ, metabolism, and absorbtion metabolism and thermogenesis NE, DA, 5HT ordinary Hypothalamus: VM, lateral, arcuate, perifornical -everyone agrees on this, but how it works.... There are many substances (peptides) most potent stimulant for eating is NPY -no NPY antagonist??? Melanocyte stimulating hormone MSH CART: cocaine amphetamine regulating transcript Leptin: secreted from FAT, satiety, discovery by jefreedmant from AMC Gherlin: = hunger hormone, from stomach, opposite of leptin unsuccessful drugs ouramine dexouramine: just as toxic sebutramine: increases HTN phenylpropenalamine: fen fen cardiotoxic now we are left with very old drugs phentermine phendimetrozine diethyproprion all 3 are very amphetamine like portential toxic and abuse level 2 new agents qucimia = phenermine (stimulant) + topiramate (anticonvulsant) with some annorexic properties Newest: leurcoserin = 5HT2C agonist, cam to market, is going to be available ADD: contraversy incidence = 2-20% problem is overdiagnosis some genetic, some MRI scans very treatable and treatment is successful mainstaye: methylphenolate = ridalin only 4 hour length concerta is long acting ridalin amphetamine = d-amphetamine lis-amphetamine: prodrug vyvanse = longer acting d amphetamine most peculuare mix of 4 amphetamine salts adderall: 2di amphetamine 2 drugs: not stimulant adimoxitine: NET blocker guanfasitine: II drugs, or adjunct Stimulant: long term addiction conclusion: is no higher incidence of substance abuse later in life there drugs are frequently diverted, kids can pretent to have the disorder the abuse is not from the intendent population Nicotine “the hardest addication to break” 1 pack a day = 73000 pus a year, the chronic nature of smoking 73000 self administating behaviors, physcial actions are reinforced 440000 people die a year bc of smoking this is the single most preventable cause of death 20% of adults smoke 3 government agencys and their numbers dier 45million - 70 million from another prevalance high school are a favorite teenagers 7-8% of 12 grader smoke decrease in adults 20 years ago it was 30% teenagers are the most resistant group to change if they start young very few people that start smoking after 21 brands: marlbarro is the prefered pharmacokinetcs gets into brain in 8 seconds increases dopamine maintain nicotine levels in the brain, never fall to 0 even at night chain smokers smoke in the morning Nicotine metabolites no-nicotine: small contributions cotineine: probably inactive at low concentration but may be a sedative schizophenics (80% smoke, self medication??? not proven) Nicotine acts via nicotine receptors normal agonists area ACh many subtypes pentamers, most important is Nicotinic a4b2 AB in the brain, Gamma in muscle other importants a3b4 a6b2, a7 in hippocampus a7 in hippocampus improves memory, pharm industry ionotropic receptors act on nicotine receptors in the ventral tegmental in midbrain activate cholinergic neurons, release DA in Nuc Accumbens = responsible for addictive eects of nicotine physical eects of nicotine health eects lung cancer, other cancers addiction is a disease: no matter how aweful diseases are they are not enough to stop smoking everyday she smokes despite an email everyday many other hazards: accidents and res poisonings: if a child eats a cigarette it will kill them Prenatal: small birth wieght, increased prematurity, more miscarrages nothing good about drug nicotine abstinence syndromes -does not look distressing, but is, tend to gain weight -excuse to gain weight Rx: treatment, not as good as we hope 100 motivate people, 90% fail in a year with Rx 75% fail in a year Gum, inhaler, electronic, patch methodone approach to smoking substitute long actinge for short acting buproprion: = antidepressant that works (25% works) bupropion + patch 40% success veronicoline or shantalex, a4b2 partial agonist nicotinic is eective, success rate is 44% (@ 6 months) not a year

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    13. Be familiar with the pharmacokinetics and pharmacology of nicotine and with current approaches

    to the treatment of smoking. KEY WORDS AND PHRASES: cocaine, norcocaine, d-amphetamine, dl-amphetamine, methamphetamine, phentermine, diethylpropion, methylphenidate, nicotine LECTURE OUTLINE: A. Cocaine 1. Introduction

    Cocaine is schedule C-II. Crack is free base cocaine, a form of cocaine that can be smoked. To make crack, cocaine is

    processed with ammonia or sodium bicarbonate and water, then heated to remove the hydrochloride. "Crack" refers to the crackling sound heard when the mixture is smoked (heated), presumably from the sodium bicarbonate.

    2. Epidemiology

    Pharmacokinetics Absorption

    oral ingestion slow absorption (30-60 min) low bioavailability (30-40%; first pass effect)

    snorting bioavailability limited due to constriction of

    nasal mucosal vessels smoking or IV

    rush occurs within 1-2 minutes Distribution

    most tissue, including fetus

    t = 1-1.5 hours

    0 15 30 45 60time

    Coc

    aine

    "hi

    gh"

    smoking/IVsnortingoral

    1975 1980 1985 1990 1995 20000

    5

    10

    15

    20

    NIDA, Monitoring the Future Study, 2000

    Percentage of High School Seniorswho ever used cocaine or crack

    Cocaine Crack

    Perc

    enta

    ge

    4

    oral cocaine is as effective as intranasal; peak plasma concentrations are similar; peak highs (in laboratory setting) after both routes maintained for 60 minutes (contradicts "street" reports of 15-20 minutes); cardiovascular and subjective effects are highly correlated with rapid increase in plasma levels; effects decline faster than plasma concentrations

    3. Metabolism

    Cocaine is metabolized to: ecgonine methyl ester by liver and plasma cholinesterases norcocaine by N-demethylation; this is an active metabolite which may in part determine

    cocaine's toxicity (e.g., paranoia, convulsions, respiratory arrest); it is more potent than cocaine as a local anesthetic; it is as potent as cocaine in inhibiting norepinephrine uptake

    benzoylecgonine by nonenzymatic hydrolysis; it can persist in brain for up to 10 days after cocaine injection; it constricts arteries in brain (may lead to delayed seizures and strokes)

    Cocaine + ethanol lead to the formation of: cocaethylene by liver and plasma cholinesterases; it is as potent as cocaine on dopamine

    uptake but much less potent on 5HT reuptake; in mice (and probably in humans) cocaethylene is 50% more potent than cocaine in causing lethality

    Ethanol may also increase plasma concentration of cocaine CONCURRENT USE OF ETHANOL INCREASES THE RISK OF COCAINE-RELATED SUDDEN DEATH 18-FOLD

    4. Neurochemical effects Without the presence of cocaine

    dopamine is released in the synapse it interacts with its receptors it is cleared by reuptake

    In presence of cocaine cocaine blocks dopamine re-uptake dopamine levels increase in the synapse cocaine blocks also norepinephrine and serotonin reuptake

    5. Acute effects of cocaine euphoria increased sense of energy, enhanced mental acuity, increased self-confidence anxiety decreased appetite decreased need for sleep activation of the sympathetic system:

    mydriasis tachycardia hypertension peripheral vasoconstriction

    6. Signs of cocaine abuse nasal perforation madarosis (loss of eyebrows or eye lashes) cocaine tracks (injection sites)

    7. Medical complications of cocaine abuse neurologic/psychiatric complications

    cerebral infarction and hemorrhage seizures depression

    5

    psychosis (paranoia-like) cardiovascular complications

    myocardial ischemia arrythmias

    infectious complications (due to IV administration) HIV hepatitis B, C endocarditis

    8. Stimulant abstinence syndrome Crash

    extreme exhaustion craving for sleep (increased REM) hyperphagia dysphoria (anxiety and depression) lasts 3-4 days

    Withdrawal decreased energy (fatigue) anhedonia fluctuating drug craving (leading to binges) symptoms increase 12-96 hours after crash lasts 6-18 weeks

    Extinction episodic drug craving lasts months to years

    9. Cocaine overdose Symptoms

    usually manifested by seizures and cardiopulmonary arrest death usually due to respiratory failure immediate death from heart failure may be due to:

    direct toxic effect on heart muscle spasms and constriction of coronary arteries platelet activation

    Treatment diazepam may control seizures chlorpromazine may be used for psychotic symptoms (e.g., paranoia) the use of propanolol for cardiovascular symptoms is controversial

    B. Amphetamines 1. Structure-activity relationships of phenylethylamines

    Amphetamine -CH3 is important for anorexia blocks MAO activity

    methamphetamine N-CH3 Increases stimulant potency

    5

    Symptoms usually manifested by seizures and cardiopulmonary arrest death usually due to respiratory failure immediate death from heart failure may be due to:

    direct toxic effect on heart muscle spasms and constriction of coronary arteries platelet activation

    Treatment diazepam may control seizures chlorpromazine may be used for psychotic symptoms (e.g., paranoia) the use of propanolol for cardiovascular symptoms is controversial

    B. Amphetamines 1. Structure-activity relationships of phenylethylamines

    Amphetamine -CH3 is important for anorexia blocks MAO activity

    methamphetamine N-CH3 Increases stimulant potency

    6

    2. Epidemiology

    3. Neurochemical effects With increasing doses:

    reverses vesicular and membrane uptake transporters-- releases cytoplasmic catecholamines inhibits re-uptake of catecholamines inhibits MAO releases serotonin and inhibits serotonin re-uptake

    4. Methamphetamine Street names

    "speed", "meth", "chalk", "ice", "crystal", "crank", "glass". Route of administration

    oral smoking snorting IV injection

    Methamphetamine versus cocaine Methamphetamine

    Man-made Smoking produces a high that lasts 8-24 hours 50% of the drug is removed from the body in 12 hours

    Cocaine Plant-derived Smoking produces a high that lasts 20-30 minutes 50% of the drug is removed from the body in 1 hour

    5. Acute effects of amphetamines extreme elation wakefulness alertness enhanced self-confidence aggression talkativeness loss of appetite increased initiative increased physical activity increased respiration

    1992 1994 1996 1998 2000

    4,000

    6,000

    8,000

    10,000

    12,000

    14,000

    16,000

    18,000

    drug

    -rela

    ted

    emer

    genc

    y de

    partm

    ent e

    piso

    des

    methamphetamine amphetamine

    hyperthermia increased heart rate and blood pressure

    6. Medical complications of amphetamine abuse neurologic/psychiatric complications

    episodes of violent behavior, paranoia, anxiety, confusion, and insomnia repetitive behavior patterns, and delusions of parasites or insects under the skin acute lead poisoning (illegal methamphetamine production uses lead acetate as a reagent) hyperthermia and convulsions

    cardiovascular complications arrythmias stroke

    infectious complications (due to IV administration) HIV hepatitis B, C endocardis

    liver, kiney, brain damage? 7. Amphethamine withdrawal

    deep depression craving, fatigue etc. (stimulant abstinence syndrome)

    8. Amphetamine overdose Symptoms

    restlessness tremor confusion paranoia psychosis hallucinations panic aggressiveness hypertension tachycardia, arrythmias seizures fever

    Treatment safe, quiet environment ice baths anticonvulsant drugs benzodiazepines neuroleptics

    9. Therapeutic uses of amphetamines Weight loss

    Therapeutic targets for obesity Food intake central control

    monoamines (norepinephrine, 5HT, dopamine, histamine) neuropeptides (neuropeptide Y, proopiomelanocortin, cocaine- and amphetamine-

    regulated transcript, corticotropin-releasing hormone, insulin, agouti-related protein)

    Food intake peripheral control leptin GI peptides (cholecystokinine, ApoA-IV) pancreatic peptides (glucagon-like peptide-1, enterostatin, amylin) nutrients

    Fat absorption lipase inhibitors fatty acid transporters

    Fat metabolism diacylglycerol transferase adipocyte differentiation angiogenesis apoptosis

    Thermogenesis thyroid hormones 3 adrenergic agonists uncoupling proteins

    Central regulation of food intake

    Brain regions ventromedial hypothalami nucleus (VMN) = satiety center lateral hypothalamic nucleus (LHA) = hunger center arcuate nucleus (ARC) paraventricular nucleus (PVN) perifornical area (PFA) dorsomedial nucleus (DMN)

    Neurotransmitters that suppress food intake Norepinephine

    1 receptor agonists 2 receptor agonists NE releasers NE uptake blockers

    5HT 5HT2c receptor agonists 5HT releasers 5HT uptake blockers

    Dopamine D1 receptor agonists

    Abbreviations: AM, amygdala; CC, corpus callosum; CCX, cerebral cortex; HI, hippocampus; ME, median eminence; OC, optic chiasm; SE, septum; TH, thalamus; FX, fornix; 3V, third ventricle.

    peptides

    Increased adiposity leads to increased leptin production in fat tissue. Leptin stimulates neurons in the arcuate nucleus of the hypothalamus that coexpress the anorexigenic hormones -melanocyte-stimulating hormone ( -MSH, a cleavage product of proopiomelanocortin [POMC]) and cocaine- and amphetamine-regulated transcript (CART). Leptin also inhibits neurons in the arcuate nucleus that coexpress the orexigenic hormones agouti-related protein and neuropeptide Y. The neurons in the arcuate nucleus project to other regions of the hypothalamus (including the paraventricular nucleus and the lateral hypothalamic areaparafornical area), where -MSH binds to its receptor, MC4R, resulting in an up-regulation of anorexigenic effectors such as corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) and a down-regulation of orexigenic effectors such as melanin-concentrating hormone (MCH) and orexin. Agouti-related protein acts as an antagonist of MC4R.

    Other anorexic agents

    phentermine (Ionamin) releaser and uptake blocker of dopamine and NE schedule C-IV short-term treatment of obesity (8-12 weeks)

    diethylpropion (Tenuate) schedule C-IV oral, indirect acting, nonamphetamine, sympathomimetic amine direct stimulation of the satiety center monotherapy for short-term treatment of obesity (8-12 weeks)

    phendimetrazine (Plegine) schedule C-III oral, indirect acting, nonamphetamine, sympathomimetic amine direct stimulation of the satiety center monotherapy for short-term treatment of obesity (8-12 weeks)

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    fenfluramine, dexflenfluramine, phenylpropanolamine and sibutramine have been discontinued in the US

    Narcolepsy Modafinil (Provigil)

    Attention deficit hyperactivity disorder What is ADHD?

    ADHD is a childhood psychiatric disorder characterized by inattention impulsivity overactivity

    neurobiology MRI studies found right prefrontal cortex, caudate nucleus and globus pallidus were

    smaller than normal in boys with ADHD Genetic studies suggest that people with ADHD might have alterations in genes

    encoding either the D4 dopamine receptor or the dopamine transporter In people with ADHD, the brain areas that control attention used less glucose,

    indicating that they were less active (PET) ADHD treatment

    methyphenidate (Ritalin) schedule CII short half-life needs to be taken 3-4 times a day catecholamine releaser extended release tablets (Concerta)

    d-amphetamine (Dexedrine) schedule CII half-life 8-10 hours

    d-amphetamine + dl-amphetamine (Adderall) schedule CII half-life 8-10 hours lisdexamfetamine (Vyvanse )-- prodrug metabolized to d-amphetamine

    guanfacine (Intuniv) not scheduled half-life 4-6 hours norepinephrine alpha 2 agonist non-stimulant

    atomoxetine (Strattera) half-life 4-6 hours norepinephrine uptake blocker non-stimulant increased risk of suicide?

    C. Nicotine 1. Epidemiology In 1996 (National Household Survey on Drug Abuse)

    62 million Americans were current smokers. 6.8 million used smokeless tobacco. 3,000 people under the age of 18 will start

    smoking. 2. Pharmacokinetics

    Absorption 0.5 M

    8:00 pm

    0.1 to 0.2 M

    8:00 am8:00 am

    Brai

    n co

    ncen

    tratio

    n

    half-life 8-10 hours lisdexamfetamine (Vyvanse )-- prodrug metabolized to d-amphetamine

    guanfacine (Intuniv) not scheduled half-life 4-6 hours norepinephrine alpha 2 agonist non-stimulant

    atomoxetine (Strattera) half-life 4-6 hours norepinephrine uptake blocker non-stimulant increased risk of suicide?

    C. Nicotine 1. Epidemiology In 1996 (National Household Survey on Drug Abuse)

    62 million Americans were current smokers. 6.8 million used smokeless tobacco. 3,000 people under the age of 18 will start

    smoking. 2. Pharmacokinetics

    Absorption 0.5 M

    8:00 pm

    0.1 to 0.2 M

    8:00 am8:00 am

    Brai

    n co

    ncen

    tratio

    n

    Lung: very rapid. The drug reaches the brain within 8 sec. GI tract: slow absorption via buccal mucosa, more efficient via intestines, but high first-pass metabolism. smokers maintain a serum concentration of about 0.1-0.2 M during the night.

    Distribution In most tissue, including embryo and fetus if pregnant woman (spontaneous abortion, preterm birth, low birth weights).

    Excretion Kidney.

    3. Metabolism C-oxidation by cytochrome P450 (CYP2A6 genetic polymorphisms). T1/2 is about 2 hours. Metabolites: cotinine, nornicotine. Males metabolize faster than females. Eating increases nicotine metabolism ( hepatic blood flow).

    4. Neurochemical Effects nicotine receptors are ion channels they are localized in the VTA nicotine binds to its receptors dopamine neurons are activated dopamine is released in the nucleus accumbens

    5. Acute effects of nicotine Relaxation Reduced stress Increased vigilance Improved cognition Reduced body weight Dizziness, nausea Tachycardia, peripheral vasoconstriction

    6. Medical complications of nicotine abuse Cancers

    lung cancer cancers of the mouth, pharynx, larynx, esophagus, stomach, pancreas, cervix, kidney, ureter, and bladder

    Lung diseases chronic bronchitis emphysema exacerbation asthma symptoms

    Heart diseases stroke heart attack vascular disease aneurysm

    Accidents residential fire fatalities

    Role of environmental tobacco smoke secondhand smoke major source of indoor air contaminants linked to lung cancers, cardiovascular diseases, increased severity of asthma for children.

    Nicotine poisoning

    12

    accidental ingestion by children death from respiratory failure caused by paralysis.

    The adverse effects of smoking during pregnancy: increased premature delivery rate decreased birth weights

    7. Nicotine abstinence syndrome Irritability, impatience, hostility Anxiety Dysphoric or depressed mood Difficulty concentrating Restlessness Decreased heart rate Increased appetite or weight gain

    8. Treatment of nicotine abuse More than 90 percent of the people who try to quit smoking relapse or return to smoking within 1 year, with the majority relapsing within a week. An estimated 2.5 to 5 percent succeed on their own. Pharmacological treatments can double the odds of success. Combination of pharmacological and behavioral treatments further improves the rate of success

    Nicotine replacement treatments approved for use in the United States: nicotine gum (1984, OTC 96), the transdermal patch (1991, OTC 96), nasal spray (1996), and inhaler (1998) used to relieve withdrawal symptoms provide users with lower overall nicotine levels than they receive with tobacco have little abuse potential since they do not produce the pleasurable effects of tobacco products do not contain the carcinogens and gases associated with tobacco smoke. produce less severe physiological alterations than tobacco-based systems

    Non-Nicotine Therapies bupropion: approved for use in the United States in 1997, an antidepressant marketed as Zyban; contains no nicotine; exact mechanism unknown, although it blocks nicotinic receptors and weakly inhibits dopamine uptake varenicline: approved for use in the United States in 2006; marketed as Chantix; contains no nicotine; partial agonist (agonist/antagonist) at nicotinic receptors

    Behavioral Treatments discover high-risk relapse situations develop self-monitoring of smoking behavior establish coping responses

    Cocaine Amphetamines Nicotinecocaine, amphetamines (d, racemic, L amphetamine, methamphetamine (d-methamphetamine)

    Crack is freebased cocaine, mixed cocaine~HCl + H2O + na2Hco3 = crack bicarbonate + co2 + H2ococaine is usually cocaina HCl

    epidemic in the 80s, newer in the 90s, more steady in the 2000 (high school students)

    3-4% of high school seniors have used

    it is absorbed orally, nasally, smoking, IVsmoking is quickest way (same as IV) oral is slowest

    rout of administration dictates the how addictive it isthe faster = more addictivethe shorter acting drugs are federally higher rated(lower scedule level)t.5 = 1- 1.5 hours

    not activeis active, but not that contribuatory

    is not thought to be bioactivemay be responsible for strokes and seizureseffect are cumulative

    coke + etoh has been described as being the most addictvedrug of all time: more DA > 5HT serotining regulates DA is a highly addictive drug concrrent use increases sudden death by 18 ethanol ---x metabolism of coke = raising plasma levels

    Mechanismnormally: prsynaptic DA ---> diffusioncocaine ----x DA reuptake = more DAsame thing happenes @ NE and 5HT sitesbut the DA mechanism is thought to be the most importantas far as CNS, toxic, and dangerous effects of DA

    Coke raises the EC [DA] in critical areas of the brain (like other addictive drugs)mainly the Nuc. AAcumbens responsible for reward (reward center)all addictive drugs have been found to raise DA in the nucleus accumbenscoke: blocks reuptakeamphetamine: releasernicotine and etoh: activate cell bodies in vent teg likeopiates: inhibit inhibitory interneurons neurons in vent teg

    cocaine: euphorias, energy, arousal, sleep, dialation mydriasis, vasoconstricitonlocal anesthetic, no one uses it, but is still approved

    ER: bloody nose, wont stop, hole in nasal septum = cokesnort coke: extensive vasoconstriction = ischemia/necrosis = hole in nasal septummissing eyebrows and eyelasches: smoking crack, singe eyebrows or eyelashes

    IV coke: tracts bc vasoconstriction (but any IV drug)

    complications: seizures, stokes, MI, paranoia (schizophrenia type) hallucination (more visual > audotory) = dfIV: HIV, hepatitis, endocarditis (not specific to cocaine) -contamination, poor hygene, reuse needles

    cocain withdrawl: used to be argued that cocaine was not addicitve or withdrawlnot as bad as opiate or depressantsearly = crash (for days): symptoms is opposite to acute pharmacological actions of drug (rebound) -general withdrawl for all drugs is opposite, if you know what drug does, you know the reboundcocaine withdrawl syndrome is almost identical to amphetamine withdrawl = stimulant withdrawl syndromeare identical but time course differes -amphetamine: longer duration so withdrawl is more spread outlater = anhedonia (sex, food, fun)cravings = extremely difficult to extinguish, happen with all drugs of abuse

    overdose: ER, paranoid schizohenia, cardiopulmonary arrest = medical emergence -supportive care -benzodiazapenes for seizures -antipsychotics

    Sudden death phenominon: all of a sudden drops dead -coke may have toxic idiosyncratic effect on heart -ask about CPR -speculation about CAs or platelets

    amphetaminesphenyl ethyl amine, put an alpha methyl group on it youget amphetamine (alpha methyl for anorexia, and MAOi)N-methyl group get meth-amphetamine which increases potency (still correct) -this is a myth, nmethyl is not more potent -it turns out N-methamphetamine and D-amphetamine are equally as potent (not true for boards)

    epidemiologydependent on access an availabilitymethamphetamine is easier to synthesize2010 er visits were >150000k5 fold increase in last 10 yearsmeth is a difficult drug to treat

    mechanismprimary mechanism: reverse vesicular transporters -cocaine blocks reuptaker -amphetamines reverse it first, then block it -amphetamines raise a shit ton of DA in the brain -people stop seeking pleasure in other thingsmeth is slightly more serotonergic

    meth can be thought of as an extremely long acting cocaineexperiment: at first 30mins amphetamine, methamphetamine, and cocaine are indistinguishableafter 2-3 hours they can tell a differnce

    like coke, you can take amphetamines in all routs, IV is common

    acute effects: hyper arousal, hyperthermia is more of ann effect of amphetamineacute effects are the same as coke, but hyperthermia is more pronounced

    medical complications: similar ot coke, seizures and stoke -garage: lead containing agents = lead poisoning = street drug problems

    IV drugs: endocarditis, HIV, hepatitis

    high doses of amphetamines may be able to destro DA neuronseventually we will see an increase in PD

    withdrawl: stimulant abstence syndrome crash > withdrawl > extinction phase

    shorter acting: quicker in, quicker out, more intense

    OD: paraoid schizophenic state, seizure, neuroleptic, benzos maybe Ice baths

    Amphetamines medicinal usesmost prevalent: weight loss, remarkable innefective, only lose 10-15lbs, gain toleracne,gain the weight back

    before amphetamines were as tightly regulate there were a group of physiciansin long island diet doctors go get your drug each week (malpractice) late 70ssecratary was typing the report

    possibly use for very obese motivator

    2) ADHD: is effective if used properly

    3) Narcolepsy: is effective but now we use medafinil

    Food an appetiteabout 30 years ago we thought we knew body weight mechanismit is actually extraordinally complex

    there are central mechanisms: most attention

    peripheral mechanisms

    fat as an organ, metabolism, and absorbtion

    metabolism and thermogenesis

    NE, DA, 5HT ordinary

    Hypothalamus: VM, lateral, arcuate, perifornical -everyone agrees on this, but how it works....

    There are many substances (peptides)

    most potent stimulant for eating is NPY -no NPY antagonist???

    Melanocyte stimulating hormone MSH

    CART: cocaine amphetamine regulating transcript

    Leptin: secreted from FAT, satiety, discovery by jeff freedmant from AMC

    Gherlin: = hunger hormone, from stomach, opposite of leptin

    unsuccessful drugsflouraminedexflouramine: just as toxicsebutramine: increases HTNphenylpropenalamine: fen fen cardiotoxic

    now we are left with very old drugsphenterminephendimetrozinediethyproprion

    all 3 are very amphetamine likeportential toxic and abuse level

    2 new agentsqucimia = phenermine (stimulant) + topiramate (anticonvulsant) with some annorexic properties Newest: leurcoserin = 5HT2C agonist, cam to market, is going to be available

    ADD: contraversyincidence = 2-20% problem is overdiagnosissome genetic, some MRI scansvery treatable and treatment is successfulmainstaye: methylphenolate = ridalin only 4 hour length concerta is long acting ridalinamphetamine = d-amphetaminelis-amphetamine: prodrug vyvanse = longer acting d amphetaminemost peculuare mix of 4 amphetamine salts adderall: 2di amphetamine

    2 drugs: not stimulantadimoxitine: NET blockerguanfasitine: II drugs, or adjunct

    Stimulant: long term addictionconclusion: is no higher incidence of substance abuse later in lifethere drugs are frequently diverted, kids can pretent to have the disorder

    the abuse is not from the intendent population

    Nicotinethe hardest addication to break1 pack a day = 73000 puffs a year, the chronic nature of smoking73000 self administating behaviors, physcial actions are reinforced

    440000 people die a year bc of smokingthis is the single most preventable cause of death20% of adults smoke

    3 government agencys and their numbers differ45million - 70 million from another

    prevalancehigh school are a favoriteteenagers7-8% of 12 grader smokedecrease in adults20 years ago it was 30%

    teenagers are the most resistant group to changeif they start young

    very few people that start smoking after 21

    brands: marlbarro is the prefered

    pharmacokinetcsgets into brain in 8 secondsincreases dopaminemaintain nicotine levels in the brain,never fall to 0 even at nightchain smokers smoke in the morning

    Nicotine metabolites no-nicotine: small contributions cotineine: probably inactive at low concentration but may be a sedative schizophenics (80% smoke, self medication??? not proven)

    Nicotine acts via nicotine receptorsnormal agonists area AChmany subtypespentamers, most important is Nicotinic a4b2AB in the brain, Gamma in muscleother importants a3b4 a6b2, a7 in hippocampusa7 in hippocampus improves memory, pharm industry

    ionotropic receptorsact on nicotine receptors in the ventral tegmental in midbrainactivate cholinergic neurons, release DA in Nuc Accumbens= responsible for addictive effects of nicotine

    physical effects of nicotine

    health effectslung cancer, other cancers

    addiction is a disease: no matter how aweful diseases arethey are not enough to stop smokingeveryday she smokes despite an email everyday

    many other hazards: accidents and fires

    poisonings: if a child eats a cigarette it will kill them

    Prenatal: small birth wieght, increased prematurity, more miscarrages

    nothing good about drug

    nicotine abstinence syndromes-does not look distressing, but is, tend to gain weight-excuse to gain weight

    Rx: treatment, not as good as we hope100 motivate people, 90% fail in a yearwith Rx 75% fail in a year

    Gum, inhaler, electronic, patchmethodone approach to smokingsubstitute long actinge for short acting

    buproprion: = antidepressant that works (25% works)bupropion + patch 40% success

    veronicoline or shantalex, a4b2 partial agonist nicotinicis effective, success rate is 44% (@ 6 months) not a year