Cocaine, Amphetamines

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Cocaine, Amphetamines MDMA

• STIMULANTS

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• Stimulants

• Behaviorally
• Sympathomimetics - mimics action of sympathetic
  arousal
• Increase arousal/energy
• Ease depression (abuse potential)
• Euphoria (tolerance develops rapidly)
• Decrease appetite (tolerance develops rapidly,
  2-6 weeks)

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• Common Side Effects

• Anxiety
• Insomnia
• Irritability
• Headache
• Fatigue
• dizziness

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• Amphetamines

• 1920s dl-amphetamines synthesized
• Stimd NS
• Increased bp
• Reversed anesthesia
• Dilated bronchia
• 1940-1960s severe abuse
• 1980-1990s resurgence w/ intro of
  methamphetamine (crystal, ice)

Ephedrine
Can be smoked, injected or oral
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Different Forms of Amphetamine Molecules

• d-amphetamine, l-amphetamine, dl-amphetamine
• methamphetamine
• Lipid soluble, cross BBB rapidly
• Effects last 2-4 hours
• Metabolized via enzymes in liver, some excreted
  in urine unchanged
• Meth - 1/2 life is 11 hours

• d,l-amphetamine meth.
• most common

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Mechanism of Action

• Release newly synthesized DA NE (reverse
  transport vesicular)
• Block reuptake
• Inhibit MAO

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• Low dose
• increase BP, heart rate, relax bronchia
• increase alertness, euphoria
• Decrease fatigue appetite
• Metabolites in urine up to 48 hr later
• Moderate dose (5-50 mg)
• respiratory stimulation
• tremors, restlessness, agitation, insomnia
• suppressed appetite
• High (60-300mg)
• Purposeless, repetitive acts, sudden outbursts of
  aggression violence, paranoid delusions
• Anorexia
• Psychosis (especially w/ methamphetamine)
• Visual auditory hallucinations, behav
  disorganization, delusions of persecution
• NOTE Chronic users may gt3000 mg/day

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• Clinical Applications

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• Narcolepsy

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• ADHD

• Associated w/ 10X increased risk of drug abuse,
  25X increase risk for delinquency
• Evidence that DA dysfunction in NucAcc prefrtl
  ctx( mediate attention processes)
• 60-80 of kids improved behv learning ability
• Tolerance develops slowly, if at all
• Normalizes NE DA levels?
• Ritalin
• Dexedrine
• Cylert
• Concerta

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• Obesity

• Problems
• Tolerance rapid (2-6 wks)
• High abuse potential (may not suppress appetite
  anymore, but makes them feel better)

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Tolerance

• Anorexia, cardiovascular reinforcing effects
• Euphoric effects tolerance happens rapidly
• User keeps going for higher doses----lead to
  psychosis

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Sensitization

• Not all behaviors
• Hyper responsiveness can last a long time (gt 1yr)

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Neurotoxicity

• Terminal nerve damage especially on caudate,
  mesolmbic

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Cocaine

• leaves of Coca shrub

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One of the 1st local anesthetics

• Block Na channels
• Eye surgery
• Nerve block
• Led to synthesis of others which are still used
  today

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Pharmacology

• Low dose - 25-70mg
• High dose - 70-150
• Cocaine hydrochloride
• water soluble
• Inject, nasal mucosa
• Cannot smoke due to decomposition when heated
• Freebase (Crack)
• Water insoluble
• Can heat convert to stable vapor
• Makes popping sounds

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Absorption

• Penetrates brain rapidly
• Easily crosses placenta
• Rapid - IV, smoking
• Peaks in seconds/minutes lasts 30 min
• Slower - Oral, snort
• Peaks in 30-60 min lasts up to 6 hr

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Metabolism

• Rapid by enzymes in plasma liver
• 1/2 life - 30-70-min
• Metabs in urine 48hr-2 wks

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How Does Cocaine Act in Brain?

• Interacts with reuptake transporters on monoamine
  neurons

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Action on Mesolimbic vital role in Reinforcing
Mood Altering Effects

• Increased DA in NAcc
• Block DA receptors in humans attenuate high
  by IV cocaine
• Block DA lab animals will increase
  self-administration
• Lesion VTA or NAcc stops self administration

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Tolerance Sensitization
Tolerance to locomotor activity

• Develops rapidly
• Intermittent use increased stimulation
  reinforcing effects
• Involves NAcc

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DA Depletion Hypothesis

• CRAVING

• Cocaine increases DA levels euphoria
• Drug termination decreases DA to ABNORMAL Level
  dysphoria craving

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Medical Risks
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Long-term High Dose

• Sleep deprivation
• Anxiety, hypervigilance
• Paranoia
• Distortion of reality
• Aggression/homicidal
• Cocaine Psychosis
• Transient paranoid psychosis
• Episodes increase over time

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Methylenedioxy-N-methylamphetamine (MDMA)

• M M

• E

Has stimulatory hallucinogenic effects in humans

• XTC

• Ecstasy

• Adam

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• History

• 1913 - German Co. developed as appetite
  suppressant, but too many side effects
• 1960s - rediscovered
• 1970s - small group psychiatrists used as
  therapeutic aid
• 1980s 90s -Increased illegal production of
  MDMA, abuse among young people evidence of
  brain damage led to schedule 1 classification (no
  medical use high abuse potential)

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• Escalating Use

• 2 million tablets smuggled into USA each week

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• Chemistry

• Analog of amphetamine methamphetamine
• Monoaminergic agonist

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How Does Ecstasy Work?

• 5-HT pathways regulate
• Mood, emotions, aggression, sleep, appetite,
  anxiety, memory perceptions, muscle activity
• 5-HT - transporters are one of primary targets of
  MDMA

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Administration

• Usually oral (70-150 mg)
• Supplementary doses tend to worsen side effects
  w/o increasing subjective effects
• Overdosing possible can be fatal (usually
  gt100mg)
• LD50 in monkeys 22 mg/kg
• Numbness/tingling, luminescence around objects,
  vomiting, apparent movement of floor, crying,
  hallucinations, racing heartbeat, high temp,
  increased muscle tone, hypertension progressing
  to hypotension, kidney failure, liver damage

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Weak base so ionizes in stomach passes to
Intestine where rapidly absorbed after
becomes nonpolar again. Crosses BBB easily.
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• Short-Term Effects

• Elevated mood -feelings of empathy (limbic
  structures)
• Mild stimulation - (basal ganglia (DA))
• Heightened perceptions - neocortex
• Appetite - hypothalamus

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Short-term Adverse Effects continued

• Clouded thinking, agitation, amphetamine-like
  psychosis (200 mg)
• Muscle spasms (spinal cord)
• Sweating, nausea, dry mouth, increased,
  irregular heart rate, hypertension hyperthermia
  --can be lethal-- (hypothalamic)

RAVE Party
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Stacking - dont get subjective Effects back
because there is No more 5-HT left!
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• 5-HT depleted
• The more MDMA used, the greater the deficits
• Anxiety
• Depression
• Memory (visual/verbal) cognitive (reasoning
  attention) impairments which are correlated to
  decreased 5-HT
• Jaw clenching/stiffness

• After Metabolism

These effects can be apparent 2-3 weeks after
last drug exposure
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Neurotoxic Effects (humans)
Person on right used MDMA for 1.5 years (70
times), but no Use in 3 weeks. 5-HT transporters
significantly decreased
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Monkey Experiment

• MDMA 2X/day for 4 days
• Brains looked at 2 weeks or 7 years later
• Damage appears permanent
• Similar changes in hippocampus, amygdala

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How Does MDMA Destroy 5-HT Terminals?
Involves production of oxygen radicals which are
highly reactive and destructive