Download Cocaine, Stimulants, and MDMA

Cocaine, Stimulants, and
MDMA
ASAM’s 2008 Review Course
in Addiction Medicine
ACCME required disclosure of
relevant commercial relationships:
Dr. Drexler has nothing to disclose.
Objectives
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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
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Background
Stimulant- structure and pharmacology
Neurobiology of stimulant addiction
Management of acute intoxication and
withdrawal
Relapse Prevention
Background
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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
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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
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Cocaine
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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
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Cocaine Abuse/Addiction Liability
Epidemiology
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Synthetic Stimulants
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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.
Methamphetamine Lab Seizures
Trends in Illicit Drug Use
Trends in Methamphetamine Use
Trends in Drug Use Disorders
Club Drugs Epidemiology
DAWN, July 2001
Overview
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Background
Stimulant- structure and pharmacology
Neurobiology of stimulant addiction
Management of acute intoxication and
withdrawal
Structure and Pharmacology
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All stimulant drugs share a common basic
phenylalkylamine structure.
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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
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Plant-derived
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Caffeine
Cocaine
Ephedra
Khat
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Synthetic
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Amphetamine
Methamphetamine
Methylphenidate
Mazindol
Phenylpropanolamine
Ephedrine
Pseudoephedrine
Phenylephrine
MDA / MDMA*
Clinical Uses of Stimulants
Drug
Trade name Street name
CSA Indications
Amphetamine
Adderal
Dexedrine
Amp, Dex
Bennies
II
ADHD, Wt control
Narcolepsy
Coke, Crack
Flake, Snow
II
Local anesthetic
IV
Wt control
Cocaine
Mazindol
Sanorex
Methamphetamine
Adipex
Desoxyn
Ice, crystal
II
Meth, Speed
ADHD
Wt control
Methylphenidate
Ritalin
Rits, Vit R
ADHD
Narcolepsy
II
Cocaine Chemical Properties
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Cocaine HCl
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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
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Crack or Freebase
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Low melting point
(98°C)
Easy to smoke
Insoluble in water
(EtOH:H2O = 100:1)
Difficult to dissolve for
injection
Stimulant Chemical Properties
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Most variations on phenylethylamine
Phenylisopropylamine stimulants have
stereoisomers
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D-isomers - 3 – 5 times more CNS activity
D-methamphetamine – potent stimulant
 L-methamphetamine- OTC decongestant
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N
OH
OH
MDMA Properties
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3,4- Methylenedioxymethamphetamine
Stimulant, hallucinogenic, empathogenic
Taken orally as a pill
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50 mg to 250 mg
“Stacking” with other drugs (LSD, DM, ephedra)
Non-linear kinetics
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Saturation of high-affinity enzymes
Large increase in response to small dose increase
Clinical Uses of Stimulants
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Prescription cocaine
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Local anesthetic
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Prescription
stimulants
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ADHD
Narcolepsy
Weight loss
Bronchdilation
Depression, pain*
Parenteral
phenylephrine
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OTC stimulants
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Spinal anesthesia
Antihypotensive
Terminate SVT
Decongestion
Bronchodilation
None for MDMA
Methamphetamine
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Brand name: Desoxyn
ADHD: 20 – 25 mg / day
Obesity: 15 mg / day
Binge: 125 mg – 1000
mg/dose
Toxic doses*:
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4- 6 mg/kg q2h (>3 gm/day)
37% loss of dopamine
*Segal et al: 2003; Neuropsychopharmacology
Pharmacokinetics
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Smoking and IV
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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
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Intranasal and oral
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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
Smoked
Oral
Metabolism and Elimination
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Cocaine
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Hydrolysis of ester
bonds
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Amphetamines
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To metabolites
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Ecgonine methylester
Benzoylecgonine
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Cytochrome P450
Eliminated in urine
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Benzoylecgonine
detectable for ~3 days
Acidifying s excretion
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Deamination- inactive
Oxidation- active
Parahydroxylationactive
Eliminated in urine
Increased by lower pH
Drug Interactions
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Other stimulants-  sympathetic activity
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Cardiac arrhythmia
Hypertension
Seizure
Death
MAOIs- inhibit metabolism of stimulants
Tricyclics- may block presynaptic uptake
Cocaine + EtOH = cocaethylene
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 cardiac toxicity due to longer half-life
Stimulant Effects
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Range of effects vary depending on
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Structure
Dose
Route of administration
Duration and intensity of use
Typical initial doses for desired effects:
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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
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CNS
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Euphoria (low dose)
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 energy, alertness
 sociability
 appetite
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Dysphoria (high dose)
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Anxiety, panic attacks
Irritability, agitation
Suspciousness
Psychosis
Movement disorders
Seizures
Cardiovascular
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 HR, BP, vascular
resistance, temperature
Acute myocardial infarction
(AMI), ischemia, arrhythmia
Stroke
Pulmonary
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Shortness of breath
Bronchospasm
Pulmonary edema
Acute Stimulant Effects (cont)
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Musculoskeletal
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Rhabdomyolysis
Acute renal failure
secondary to
myoglobinuria
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Ketoacidosis in
diabetics
Activation of HPA
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Increased arousal
Prolonged erections
Head and neck
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Endocrine
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Sexual function
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Renal
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Chronic rhinitis, nasal
septal perforation
Xerostomia
Bruxism
Fetal effects
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Most Category C
Mechanisms of Action
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All stimulants enhance monoamine activity
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Inhibition of presynaptic monoamine
transporters
Dopamine – reward, psychosis
 Norephinephrine – physiological arousal
 Sertonin – mood elevation, psychosis
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OTC stimulants bind to and activate
norepinephrine receptors
Mesocorticolimbic Pathway
Anterior cingulate
Prefrontal cortex
Nucleus
accumbens
Ventral
tegmental
area
Dopamine (DA)
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Stimulants acutely enhance dopamine activity
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Cocaine, methylphenidate- transporter blockers
Amphetamines- false substrates
Stimulants chronically deplete dopamine
DA activity key in mediating addictive potential
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Fluctuations in mesolimbic DA parallel cocaine selfadministration
Stimulant potency correlates with potency for binding
at DA transporter
Cocaine
Microdialysis in Awake Squirrel Monkeys
Norepinephrine (NE)
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Stimulants acutely block NE transporter
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 plasma NE and epinephine
NE release correlates with subjective and
physiological stimulant effects
Ephedrine related compounds stimulate
alpha-adrenergic NE receptors
Serotonin (5-HT)
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All stimulants acutely enhance 5-HT
activity by blocking serotonin transporter
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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
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Endogenous opioid activity
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Mesolimbic glutamate
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Cocaine s
Amphetamine s
Acetylcholine
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No direct stimulant effect
Cocaine indirectly s
Cocaine s
Sodium channel blockade (cocaine only)
Overview
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Background
Stimulant- structure and pharmacology
Neurobiology of stimulant addiction
Management of acute intoxication and
withdrawal
DSM-IV Substance Dependence
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>/= 3 of the following over a 12-month period:
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Tolerance
Characteristic withdrawal
Larger amounts than intended
Persistent efforts to cut down or control use
A great deal of time spent getting the substance,
taking it, or recovering
Important activities given up or reduced
Continued use despite psychological or physical
problem caused by or exacerbated by use
Neurobiology of Dependence
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Sensitization of incentive salience
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Drug
Conditioned cues
Impairment of inhibition of urges to use
Chronic effects of drug
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Signal transduction
Gene transcription
Mesocorticolimbic Pathway
Anterior cingulate
Prefrontal cortex
Nucleus
accumbens
Ventral
tegmental
area
Amygdala – Limbic Connections
Nucleus
accumbens
Amygdala
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
Overview
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Background
Stimulant- structure and pharmacology
Neurobiology of stimulant addiction
Management of acute intoxication and
withdrawal
Initial Evaluation of Stimulant
Intoxication
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Drug history
Physical examination
Laboratory examination
Manage basic life support functions
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T> 102°F – Cooling blanket
T> 106°F – Cool saline hydration, ice water lavage
Remove drug from GI tract
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Activated charcoal or gastric lavage
If within one hour of ingestion
Management of Severe Agitation
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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
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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
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Avoid physical restraints
Cardiovascular Effects of
Stimulants
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Myocardial ischemia is common.
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Vasoconstriction
Increased myocardial workload
Increased platelet aggregation
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Differential - AMI, aortic dissection, pneumothorax,
endocarditis, or pneumonia
Arrhythmias
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Due to ischemia, catecholamines, or sodium
channel blockade
Management of Chest Pain
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Observe for 12 – 24 hours
ECG
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Cardiac enzymes:
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Low sensitivity (36%)
Low predictive value (18%)
Serial CPK- MB or troponin
~ 15% of patients with stimulant-induced
chest pain will have AMI.
Management of Arrhythmias
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Treat underlying conditions
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AMI
Electrolyte and acid-base abnormalities
Hypoxia
Many will resolve without treatment
Avoid Class I antiarrhythic drugs
Follow ACLS guidelines
Management of Seizures
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Benzodiazepines
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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
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Diagnosis requires high suspicion
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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
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Benzodiazepines first line
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Lower myocardial oxygen demand
Lower seizure risk*
If severe hypertension persists
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Alpha-adrenergic blocker
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Phentolamine 2 to 20 mg IV over 10 min
No beta-adrenergic blockers
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Unopposed alpha stimulation s vasoconstriction
DSM-IV Cocaine Withdrawal
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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
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Management of Withdrawal
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Most symptoms resolve within 2 weeks
without treatment
Hospitalization for suicidality or psychosis
Pharmacologic treatment not necessary
Relapse Prevention
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Psychosocial treatment
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Cognitive behavioral
therapy (CBT)
Contingency management
(MIEDAR)
12-step facilitation- ?
Motivation Enhancement
Therapy- ?
MATRIX model
Treat comorbidities
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Pharmacotherapy
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No FDA approved
medications
Antidepressants
Dopaminergic agents
Disulfiram
Anticonvulsants (GVG,
topiramate)
Disulfiram Patients Have Less
Cocaine Use
Carroll et al, 2004
Modafinil Decreases Cocaine Use
Dackis 2005
Summary
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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.