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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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Asam s 2008 review course in addiction medicine

ASAM’s 2008 Review Course in Addiction Medicine

ACCME required disclosure of

relevant commercial relationships:

Dr. Drexler has nothing to disclose.


Objectives
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


Overview
Overview

  • Background

  • Stimulant- structure and pharmacology

  • Neurobiology of stimulant addiction

  • Management of acute intoxication and withdrawal

  • Relapse Prevention


Background
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.


History of stimulant use
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


  • Epidemiology
    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



    Epidemiology1
    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.






    Club drugs epidemiology dawn july 2001
    Club Drugs Epidemiology DAWN, July 2001


    Overview1
    Overview

    • Background

    • Stimulant- structure and pharmacology

    • Neurobiology of stimulant addiction

    • Management of acute intoxication and withdrawal


    Structure and pharmacology
    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


    Stimulant drugs

    Plant-derived

    Caffeine

    Cocaine

    Ephedra

    Khat

    Synthetic

    Amphetamine

    Methamphetamine

    Methylphenidate

    Mazindol

    Phenylpropanolamine

    Ephedrine

    Pseudoephedrine

    Phenylephrine

    MDA / MDMA*

    Stimulant Drugs



    Cocaine chemical properties

    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


    Stimulant chemical properties
    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


    Mdma properties
    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


    Clinical uses of stimulants1

    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


    Methamphetamine
    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


    Pharmacokinetics

    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


    Pharmacokinetics1
    Pharmacokinetics

    Smoked

    Oral


    Metabolism and elimination

    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


    Drug interactions
    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


  • Stimulant effects
    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


    Acute stimulant effects

    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


    Acute stimulant effects cont

    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)


    Mechanisms of action
    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


    Mesocorticolimbic pathway
    Mesocorticolimbic Pathway

    Anterior cingulate

    Prefrontal cortex

    Nucleus accumbens

    Ventral tegmental area


    Dopamine da
    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


    Cocaine microdialysis in awake squirrel monkeys
    CocaineMicrodialysis in Awake Squirrel Monkeys


    Norepinephrine ne
    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


    Serotonin 5 ht
    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


    Other neurotransmitters
    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)


    Overview2
    Overview

    • Background

    • Stimulant- structure and pharmacology

    • Neurobiology of stimulant addiction

    • Management of acute intoxication and withdrawal


    Dsm iv substance dependence
    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


    Neurobiology of dependence
    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


    Mesocorticolimbic pathway1
    Mesocorticolimbic Pathway

    Anterior cingulate

    Prefrontal cortex

    Nucleus accumbens

    Ventral tegmental area


    Amygdala limbic connections
    Amygdala – Limbic Connections

    Nucleus accumbens

    Amygdala


    Prefrontal limbic inhibition
    Prefrontal - Limbic Inhibition

    Orbitofrontal cortex

    Nucleus accumbens


    Cocaine craving-related neural activations: Men

    drug use - neutral

    Left

    Right

    insula

    -34 mm

    +34 mm

    anterior

    cingulate

    amygdala

    -19 mm

    +19 mm

    -9 mm

    +9 mm

    subcallosal

    cortex

    nucleus

    accumbens

    area


    Overview3
    Overview

    • Background

    • Stimulant- structure and pharmacology

    • Neurobiology of stimulant addiction

    • Management of acute intoxication and withdrawal


    Initial evaluation of stimulant intoxication
    Initial Evaluation of Stimulant Intoxication

    • Drug history

    • Physical examination

    • Laboratory examination

    • Manage basic life support functions

      • T> 102°F – Cooling blanket

      • T> 106°F – Cool saline hydration, ice water lavage

    • Remove drug from GI tract

      • Activated charcoal or gastric lavage

      • If within one hour of ingestion


    Management of severe agitation
    Management of Severe Agitation

    • Benzodiazepines- first line

      • Protect against CNS and cardiovascular toxicity

      • Lorazepam 2 – 4 mg PO or IV q 15 min until sedate

      • Repeat every 1 – 3 hours

    • Antipsychotics- second line

      • May prevent heat dissipation, lower seizure threshold, prolong QTc, increase dyskinesias

      • Haloperidol 2 to 10 mg PO, IM or IV q 6 – 24 hours

    • Avoid physical restraints


    Cardiovascular effects of stimulants
    Cardiovascular Effects of Stimulants

    • Myocardial ischemia is common.

      • Vasoconstriction

      • Increased myocardial workload

      • Increased platelet aggregation

        • Differential - AMI, aortic dissection, pneumothorax, endocarditis, or pneumonia

    • Arrhythmias

      • Due to ischemia, catecholamines, or sodium channel blockade


    Management of chest pain
    Management of Chest Pain

    • Observe for 12 – 24 hours

    • ECG-

      • Low sensitivity (36%)

      • Low predictive value (18%)

    • Cardiac enzymes:

      • Serial CPK- MB or troponin

    • ~ 15% of patients with stimulant-induced chest pain will have AMI.


    Management of arrhythmias
    Management of Arrhythmias

    • Treat underlying conditions

      • AMI

      • Electrolyte and acid-base abnormalities

      • Hypoxia

    • Many will resolve without treatment

    • Avoid Class I antiarrhythic drugs

    • Follow ACLS guidelines


    Management of seizures
    Management of Seizures

    • Benzodiazepines

      • Lorazepam 2 to 10 mg IV over 2 minutes

      • Diazepam 5 to 10 mg IV over 2 minutes

      • Repeat as needed

      • Monitor respirations, intubation available


    Management of rhabdomyolysis
    Management of Rhabdomyolysis

    • Diagnosis requires high suspicion

      • Muscle swelling and myalgia often absent

      • Plasma CK > 5 times normal

      • Urinalysis positive for heme without RBCs

    • IV hydration – urine output 2 ml/kg/hour

    • Urine pH > 5.6 – sodium bicarbonate


    Management of hypertension
    Management of Hypertension

    • Benzodiazepines first line

      • Lower myocardial oxygen demand

      • Lower seizure risk*

    • If severe hypertension persists

      • Alpha-adrenergic blocker

        • Phentolamine 2 to 20 mg IV over 10 min

      • No beta-adrenergic blockers

        • Unopposed alpha stimulation s vasoconstriction


    Dsm iv cocaine withdrawal
    DSM-IV Cocaine Withdrawal

    • A. Cessation of (or reduction in) cocaine use that has been heavy and prolonged.

    • B. Dysphoric mood and two (or more) :

      • Fatigue

      • Vivid, unpleasant dreams

      • Insomnia or hypersomnia

      • Increased appetite

      • Psychomotor retardation or agitation


    Management of withdrawal
    Management of Withdrawal

    • Most symptoms resolve within 2 weeks without treatment

    • Hospitalization for suicidality or psychosis

    • Pharmacologic treatment not necessary


    Relapse prevention

    Psychosocial treatment

    Cognitive behavioral therapy (CBT)

    Contingency management (MIEDAR)

    12-step facilitation- ?

    Motivation Enhancement Therapy- ?

    MATRIX model

    Treat comorbidities

    Pharmacotherapy

    No FDA approved medications

    Antidepressants

    Dopaminergic agents

    Disulfiram

    Anticonvulsants (GVG, topiramate)

    Relapse Prevention




    Summary
    Summary

    • Stimulants are common causes of drug-related morbidity and mortality.

    • Chemical structure of stimulants relates to the pharmacologic properties.

    • Neurobiology of stimulant addiction is related to blockade of monoamine transporters.

    • Management of acute intoxication and withdrawal is symptom driven.

    • Relapse prevention is based on comprehensive biopsychosocial treatment.


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