Lecture 3a Stimulants Lecture 3P92 2023 PDF

THE STIMULANTS Cocaine Ephedrine Stimulants Methamphetamine Methylphenidate  CNS Stimulants I. Cocaine, Crack (free base or hydrochloride). II. Amphetamines: D-Amphetamine, Methamphetamine, methylphenidate...

THE STIMULANTS Cocaine Ephedrine Stimulants Methamphetamine Methylphenidate  CNS Stimulants I. Cocaine, Crack (free base or hydrochloride). II. Amphetamines: D-Amphetamine, Methamphetamine, methylphenidate (use to treat attention deficit disorders in children), phenmetrazine (Preludin) - used to treat obesity, (hallucinogens = MDA, MDMA, DOM; methylenedioxymethamphetamine, "ecstasy," dimethoxyamphetamine). III. Khat: Cathinone, methcathinone. IV. Methylxanthines: caffeine (coffee), theophyline (tea), theobromide (chocolate).  CNS Stimulants Sub-Categories of CNS Stimulants Synthetics - pharmaceuticals - illicit mfg Organics - cocaine Pharmaceutical Stimulants Medical Uses 1. control of narcolepsy 2. control of hyperactivity in children 3. prevention of fatigue 4. treatment of mild depression 5. control of appetite  Pharmaceutical Stimulants Medical Uses 6. prevention and treatment of surgical shock 7. treatment of Parkinson's disease 8. blood pressure maintenance during surgery 9. enhance the action of certain analgesic drugs 10. antagonize the effects of certain depressant drugs Pharmaceutical Stimulants Common Examples Methamphetamine (Desoxyn, Biphetamine) – weight control Ritalin (methylphenidate) – ADD Preludin (phenmetrazine) – weight control Cylert (pemoline) – ADD  Ritalin and ADHD Since Ritalin (methylphenidate) is a stimulant, how does it help rather than make things worse?! May selectively activate mesocortical pathway, improving working memory, attention May selectively activate mesolimbic pathway, improving motivation Hyperactivity may be indirect result of low DA, rather than high DA in nigrostriatal pathway  Cocaine Overview Alkaloid from Erythroxylon coca Indigenous to western South America Coca leaves used for religious, mystical, social, stimulant, and medicinal purposes Main stimulant uses: endurance, feeling of well-being, alleviate hunger Medical uses: local anesthetic, vasoconstrictor  HISTORY Inca culture Sigmund Freud (1884) Ernst von-Fleischl (1st European addict) R. L. Stevenson Arthur Conan Doyle  HISTORY Arthur Conan Doyle 1885 advertisement of cocaine for dental pain in children 1863----Vin Mariani Wine laced with cocaine U.S.A—French Wine of Cola Czar Nicholas Edison Pope Leo XIII Queen Victoria  Cocaine Production Coca paste extracted from soaked and mashed leaves (60-80% cocaine) Cocaine powder made by mixing paste with hydrochloric acid (cocaine HCl) Freebase/crack extracted from powder with baking soda  Cocaine Pharmacokinetics: Absorption Routes of administration – Insufflated (snorted) – IV (mainlined) – Inhaled (freebased) – Oral  Pharmacokinetics: Distribution and Metabolism Both cocaine and amphetamines penetrate BBB easily Half-lives – Cocaine: ~ 50-90 min – Amphetamine: ~ 5-10 hours – Meth: ~ 12 hours Metabolites include active and inactive compounds Cocaine is unusual in that it “autometabolizes” in the blood in addition to normal liver metabolism. – Cocaine ----> norcocaine, ecgonine methyl ester, benzoylecgonine  Cocaethylene Alcohol inhibits metabolism of cocaine Alcohol + cocaine chemically react to form cocaethylene Only known example where body forms new psychoactive compound from two others Cocaethylene – Similar effects to cocaine – Greater cardiac toxicity than cocaine – 3-5x the half-life of cocaine – associated with seizures, liver damage, compromised immune system  Cocaine Pharmacodynamics Indirect Agonist for – DA (high affinity) – NE (high affinity) – 5-HT (modest affinity) Mechanism: – Blocks monoamine reuptake  PHARMACODYNAMICS 1) No effect on monoamine release 2) Blocks reuptake of monoamines (NE, DA & 5-HT 3) Increases glutamate  TWO PRIMARY EFFECTS OF COCAINE 1. Powerful sympathomimetic effect Similar to amphetamines (more rapid than amphetamine) 2. Local anaesthetic When direct contact with peripheral neurons , prevents neural firing = numbing  ACUTE EFFECTS OF COCAINE 1. Powerful sympathomimetic effect Similar to amphetamines (more rapid than amphetamine) 2. Local anaesthetic When direct contact with peripheral neurons , prevents neural firing = numbing  DRUG EFFECTS ACUTE EFFECTS AT MODERATE DOSES… 3. Amelioration of fatigue (insomnia) and more resistance to boredom 4. Anorectic effect 5. Elevated mood and sociability (emotional instability)  DRUG EFFECTS ACUTE EFFECTS AT HIGH DOSES… 6. Present-oriented/Stimulus Bound 7. Hyper-vigilance 8. Psychomotor stimulation  Chronic Effects Medical Effects: Cardiomyopathy Stroke Renal damage Liver damage 2. Tolerance & Withdrawal (coke bugs) 3. Intense craving 4. Stimulant psychosis  Cocaine Withdrawal A) Stop using cocaine B) CRASH Vivid or Psychomotor unpleasant retardation/ dreams agitation Depression Insomnia/ Hypersomnia Hunger Fatigue  Cocaine Withdrawal C) Symptoms cause clinically significant distress or impairment D) Symptoms not due to GMC or another mental disorder Amphetamine Overview (crystal meth, ice, glass, speed) Synthetic analog of ephedrine, active ingredient in mahuang Mahuang used in China for asthma – Chinese (Mandarin) má huáng : má, hemp + huáng, yellow Methamphetamine and Methylphenidate (Ritalin) are very similar Medical uses: obesity, ADHD, narcolepsy  How Amphetamines Work chemical structure that mimics the structure of the neurotransmitters adrenaline (epinephrine), noradrenaline (norepinephrine), and dopamine biological processes controlled by adrenaline, noradrenaline, and dopamine are enhanced amphetamine is NOT metabolized rapidly  Amphetamine Pharmacodynamics Indirect Agonist for – DA (high affinity) – NE (high affinity) – 5-HT (low affinity) Mechanisms: – Blocks monoamine reuptake – Inhibit vesicular storage – Inhibit MAO metabolism – Reverses reuptake  Short-Term Effects Amphetamines enhance the actions of adrenaline, noradrenaline, and dopamine increasing adrenaline and noradrenaline from nerve endings Increase heart rate Increase blood pressure Urinary retention Nausea, vomiting, diarrhea Loss of appetite/weight loss Euphoria Decreased sleep  Short-Term Effects Amphetamines Increased alertness Increased energy Narrowing of focus Thirst suppression “Rush”  Long-Term Effects Amphetamines Tolerance Psychosis Exhaustion Malnutrition Interpersonal problems Cognitive defects Paranoia Mood swings Trouble breathing Seizures  Long-Term Effects Amphetamines Brain hemorrhage Heart failure Hyperpyrexia Coma  Methamphetamine Derivative of amphetamine First synthesized in Japan Typically smoked Meth labs Not legal in Canada  Long-Term Effects of Methamphetamine Dental problems Undernourishment Skin infections Heart failure Psychosis Brain abnormalities  Tolerance, Withdrawal, Addiction High abuse potential (Schedule 2) Physical and psychological dependence Tolerance to euphoria, appetite suppression; sensitization to psychomotor Withdrawal – Physically mild to moderate (hunger, fatigue, anxiety, irritability, depression, panic attacks, dysphoric syndrome) Dysphoric syndrome (1-5 days after the crash): characterized by decreased activity, amotivation, intense boredom and anhedonia, intense “craving” for cocaine. May last 1-10 weeks. – Anhedonia from biogenic amine depletion? – Intense cravings Route of administration important to addiction risk  Cost of Methamphetamine use – 2008 (RAND Corporation) In 2007 about 13 million Americans (ages 12 and up) reported using meth at least once in their lifetimes Accounts for 6 - 8 percent of the total cost of drug abuse in the United States. $23.4 billion per year costs – lost lives (900 individuals died in 2005); thousands addicted – productivity, – drug treatment, – law enforcement expenses (arresting, prosecuting and incarcerating meth users ), – economic costs of crimes committed National Survey on Drug Use and Health In 2009, 4.8 million Americans age 12 and older had abused cocaine at least once in the year. Cocaine use peaked in 1985 at 5.7 million. 788K use non-cocaine prescription-like stimulants; 387K of them use methamphetamine. Use in Canada Use in Canada  Pharmacotherapies Treatment of withdrawal: Chlorpromazine: DA antagonist (also blocks alpha receptors) Haloperidol (antipsychotic – 50x more potent than chlorpromazine). Alprazolam (Xanax - benzodiazepine) for panic attacks. Antidepressants (fluoxetine or desipramine). Diazepam (Valium) for seizures - binds to benzodiazepene site of GABAa receptor.  New Treatment Approaches IMMUNOLOGICAL Antibodies made against cocaine, to break-down the molecule and stop its effects. Undergoing Phase III trials in US An inactive cholera toxin protein – attach inactivated cocaine Immune system makes antibodies against both When individual takes cocaine, antibodies bind to it and prevent it from reaching brain – high does not occur, patient loses interest