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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 transc