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Cocaine, Stimulants, and MDMA

Cocaine, Stimulants, and MDMA. dr shabeel pn. ASAM’s 2008 Review Course in Addiction Medicine. ACCME required disclosure of relevant commercial relationships : Dr. Drexler has nothing to disclose. Objectives. The participant will be able to understand:

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Cocaine, Stimulants, and MDMA

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  1. Cocaine, Stimulants, and MDMA dr shabeel pn

  2. ASAM’s 2008 Review Course in Addiction Medicine ACCME required disclosure of relevant commercial relationships: Dr. Drexler has nothing to disclose.

  3. Objectives • The participant will be able to understand: • How chemical structure of stimulants influences pharmacology • Basic neurobiology of stimulant dependence • How to recognize and manage acute stimulant intoxication and withdrawal

  4. Overview • Background • Stimulant- structure and pharmacology • Neurobiology of stimulant addiction • Management of acute intoxication and withdrawal • Relapse Prevention

  5. Background • Stimulants have been used by humans for thousands of years to increase energy. • Plant-derived stimulants have been refined and new drugs developed to increase potency and duration. • As potency increases negative effects become apparent.

  6. History of Stimulant Use • 3000 B.C. – Ma-Huang • 0 A.D. – Coca leaf chewing and coca tea • 1860 – Cocaine isolated • 1887 – Amphetamine synthesized • 1914 – Harrison Narcotic Act • MDMA • 1919 – Methamphetamine • 1930s – Benzedrine inhaler • 1959 – Benzedrine banned • 1980s – Crack

  7. Epidemiology • Cocaine • 2nd most widely used illicit drug in U.S. • Most frequent illicit drug in ED visits • In 2004 (NHSDA and DAWN) • 11.2% lifetime use; 1.5% past year; 0.8% past month • 2.7% lifetime prevalence of dependence • 19% of drug-related ER visits • 39% of drug-related deaths

  8. Cocaine Abuse/Addiction Liability

  9. Epidemiology • Synthetic Stimulants • Non-prescription use peaked at 1.3% in 1985 • In 2004 (NHSDA) • 6.6% lifetime non-prescription use • 1.7% lifetime prevalence of dependence • Methamphetamine • Most commonly used synthetic stimulant • In 2004, 59% of users had a use disorder • Up from 27.5 % in 2002.

  10. Methamphetamine Lab Seizures

  11. Trends in Illicit Drug Use

  12. Trends in Methamphetamine Use

  13. Trends in Drug Use Disorders

  14. Club Drugs Epidemiology DAWN, July 2001

  15. Overview • Background • Stimulant- structure and pharmacology • Neurobiology of stimulant addiction • Management of acute intoxication and withdrawal

  16. Structure and Pharmacology • All stimulant drugs share a common basic phenylalkylamine structure. • Additions to the phenyl group tend to increase hallucinogenic properties. • Additions of a methyl group to the nitrogen atom tend to increase the stimulant properties. N OH OH

  17. Plant-derived Caffeine Cocaine Ephedra Khat Synthetic Amphetamine Methamphetamine Methylphenidate Mazindol Phenylpropanolamine Ephedrine Pseudoephedrine Phenylephrine MDA / MDMA* Stimulant Drugs

  18. Clinical Uses of Stimulants

  19. Cocaine HCl High melting point (195°C) Pyrolysis destroys most of the drug Soluble in water (EtOH:H2O = 1:8) Easily dissolved for injection or absorption across mucous membranes Crack or Freebase Low melting point (98°C) Easy to smoke Insoluble in water (EtOH:H2O = 100:1) Difficult to dissolve for injection Cocaine Chemical Properties

  20. Stimulant Chemical Properties • Most variations on phenylethylamine • Phenylisopropylamine stimulants have stereoisomers • D-isomers - 3 – 5 times more CNS activity • D-methamphetamine – potent stimulant • L-methamphetamine- OTC decongestant N OH OH

  21. MDMA Properties • 3,4- Methylenedioxymethamphetamine • Stimulant, hallucinogenic, empathogenic • Taken orally as a pill • 50 mg to 250 mg • “Stacking” with other drugs (LSD, DM, ephedra) • Non-linear kinetics • Saturation of high-affinity enzymes • Large increase in response to small dose increase

  22. Prescription cocaine Local anesthetic Prescription stimulants ADHD Narcolepsy Weight loss Bronchdilation Depression, pain* Parenteral phenylephrine Spinal anesthesia Antihypotensive Terminate SVT OTC stimulants Decongestion Bronchodilation None for MDMA Clinical Uses of Stimulants

  23. Methamphetamine • Brand name: Desoxyn • ADHD: 20 – 25 mg / day • Obesity: 15 mg / day • Binge: 125 mg – 1000 mg/dose • Toxic doses*: • 4- 6 mg/kg q2h (>3 gm/day) • 37% loss of dopamine *Segal et al: 2003; Neuropsychopharmacology

  24. Smoking and IV Reaches brain in 6 – 8 seconds Onset of action and peak occur in minutes Rapid decline in effect Rapid onset of withdrawal symptoms and craving Intranasal and oral Slower absorption and peak effect (30 – 45 minutes) Longer peak effect and gradual decline Peak intensity less than smoking or IV Alkalinization enhances absorption Pharmacokinetics

  25. Pharmacokinetics Smoked Oral

  26. Cocaine Hydrolysis of ester bonds Ecgonine methylester Benzoylecgonine Cytochrome P450 Eliminated in urine Benzoylecgonine detectable for ~3 days Acidifying s excretion Amphetamines To metabolites Deamination- inactive Oxidation- active Parahydroxylation- active Eliminated in urine- Increased by lower pH Metabolism and Elimination

  27. Drug Interactions • Other stimulants-  sympathetic activity • Cardiac arrhythmia • Hypertension • Seizure • Death • MAOIs- inhibit metabolism of stimulants • Tricyclics- may block presynaptic uptake • Cocaine + EtOH = cocaethylene •  cardiac toxicity due to longer half-life

  28. Stimulant Effects • Range of effects vary depending on • Structure • Dose • Route of administration • Duration and intensity of use • Typical initial doses for desired effects: • 5 to 20 mg of oral amphetamine, methylphenidate • 100 to 200 mg of oral cocaine • 15 to 20 mg of smoked cocaine • 50 to 250 mg of MDMA

  29. CNS Euphoria (low dose)  energy, alertness  sociability  appetite Dysphoria (high dose) Anxiety, panic attacks Irritability, agitation Suspciousness Psychosis Movement disorders Seizures Cardiovascular  HR, BP, vascular resistance, temperature Acute myocardial infarction (AMI), ischemia, arrhythmia Stroke Pulmonary Shortness of breath Bronchospasm Pulmonary edema Acute Stimulant Effects

  30. Musculoskeletal Rhabdomyolysis Renal Acute renal failure secondary to myoglobinuria Endocrine Ketoacidosis in diabetics Activation of HPA Sexual function Increased arousal Prolonged erections Head and neck Chronic rhinitis, nasal septal perforation Xerostomia Bruxism Fetal effects Most Category C Acute Stimulant Effects (cont)

  31. Mechanisms of Action • All stimulants enhance monoamine activity • Inhibition of presynaptic monoamine transporters • Dopamine – reward, psychosis • Norephinephrine – physiological arousal • Sertonin – mood elevation, psychosis • OTC stimulants bind to and activate norepinephrine receptors

  32. Mesocorticolimbic Pathway Anterior cingulate Prefrontal cortex Nucleus accumbens Ventral tegmental area

  33. Dopamine (DA) • Stimulants acutely enhance dopamine activity • Cocaine, methylphenidate- transporter blockers • Amphetamines- false substrates • Stimulants chronically deplete dopamine • DA activity key in mediating addictive potential • Fluctuations in mesolimbic DA parallel cocaine self-administration • Stimulant potency correlates with potency for binding at DA transporter

  34. CocaineMicrodialysis in Awake Squirrel Monkeys

  35. Norepinephrine (NE) • Stimulants acutely block NE transporter •  plasma NE and epinephine • NE release correlates with subjective and physiological stimulant effects • Ephedrine related compounds stimulate alpha-adrenergic NE receptors

  36. Serotonin (5-HT) • All stimulants acutely enhance 5-HT activity by blocking serotonin transporter • MDMA s 5-HT by blocking transporters • Cocaine acutely s firing in mesolimbic serotonergic neurons, but s firing in dorsal raphe nucleus • Serotonin appears to play a permissive, but not obligatory role in reward

  37. Other Neurotransmitters • Endogenous opioid activity • No direct stimulant effect • Cocaine indirectly s • Mesolimbic glutamate • Cocaine s • Amphetamine s • Acetylcholine • Cocaine s • Sodium channel blockade (cocaine only)

  38. Overview • Background • Stimulant- structure and pharmacology • Neurobiology of stimulant addiction • Management of acute intoxication and withdrawal

  39. DSM-IV Substance Dependence • >/= 3of the following over a 12-month period: • Tolerance • Characteristic withdrawal • Larger amountsthan intended • Persistent efforts to cut down or control use • A great deal of time spent gettingthe substance, taking it, or recovering • Important activitiesgiven up or reduced • Continued use despite psychological or physical problem caused by or exacerbated by use

  40. Neurobiology of Dependence • Sensitization of incentive salience • Drug • Conditioned cues • Impairment of inhibition of urges to use • Chronic effects of drug • Signal transduction • Gene transcription

  41. Mesocorticolimbic Pathway Anterior cingulate Prefrontal cortex Nucleus accumbens Ventral tegmental area

  42. Amygdala – Limbic Connections Nucleus accumbens Amygdala

  43. Prefrontal - Limbic Inhibition Orbitofrontal cortex Nucleus accumbens

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