Psychostimulants

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Psychostimulants

• Cocaine and amphetamines
• Caffeine and nicotine

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Cocaine

• History
• Coca leaves used indigenously in South America
• Erythroxylon coca introduced to Europe
• Cocaine isolated from coca in 1859 by Niemann
• Freud shared cocaine with his fiancee, Martha
  Bernays, and composed a Song of praise to
  cocaine. Addicted in 1884, he renamed cocaine
  the third scourge of humanity.

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More cocaine history

• 1888 Asa Candler, a devout Christian, bought the
  rights to CocaCola, a temperance beverage
  supported by the WCTU. It contained cocaine
  until 1903.
• Mariani wine, a cocaine preparation, was lauded
  by U.S. Grant, Pope Leo XIII, and French actress
  Sara Bernhardt

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Have you consideredCocarettes?

• Ten reasons why Cocarettes should be used by all
  smokers
• 1stThey are not injurious.
• 3rdThey are made of the finest Sun-cured
  Virginia Tobacco
• 4thThey have the exact proportion of genuine
  Bolivian Coca leaf combined with the finest
  flavored Tobacco, to produce the most delicious
  flavor
• 5thThe Coca neutralizes the depressing effects
  of the Nicotine in the tobacco.

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Cocaine preparations

• Coca leaves (1 cocaine)

sulfuric acid
Coca paste (60-80 cocaine)
hydrochloric acid
Cocaine HCl (80 cocaine, but less potent)
Boil with water and either baking soda or ammonia
Boil with ether
Cocaine free base (No HCl)
Crack cocaine
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Pharmacokinetics of cocaine

• Administration
• Coca leaves Oral, by chewing the leaves
• Cocaine powder (crystal or snow) Oral,
  intranasal (Snorting), or intravenous
• In South America, mixed with tobacco and smoked
• Base and free basing Smoking
• Smokable crack cocaine

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Pharmacokinetics...

• Absorption
• Intranasal 20-30, plasma peaks in 30-60 min.
• Smoke 6-32, plasma peaks at 5 min.
• Intravenous 100, immediate, 60 sec to brain
• Distribution
• Easy access to brain
• Concentration in brain exceeds plasma level
• Crosses placental barrier freely Crack babies

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Pharmacokinetics...

• Metabolized in plasma and liver
• Half-life 30-90 minutes urinalysis to 12 hrs
• Metabolite benzoylecgonine 48 hrs-2 weeks
• Metabolite cocaethylene results when cocaine and
  alcohol are in the body at the same time.
  Cocaethylene acts like cocaine, and is more
  toxic.

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Pharmacodynamics

• Local anaesthetic and vasoconstrictor
• Blocks reuptake of monoamine NTs
• Blocking reuptake of DA produces stimulation and
  behavioral reinforcement.
• Ventral tegmental area (VTA) DA neurons project
  to medial prefrontal cortex, nucleus accumbens,
  amygdala, and hippocampus.
• Cocaine blocks DA transporter proteins.

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Long-term pharmacodynamics

• Presynaptic DA transporter levels in nucleus
  accumbens and VTA rise with abstinence, then fall
  for several months.
• These phenomena produce a prolonged abstinence
  syndrome in the reward systems.
• Result? Feeling miserable and craving.
• Tolerance develops through decreased numbers of
  postsynaptic receptors.

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Side effects

• Increased alertness, high activity levels,
  tachycardia, elevated blood pressure and
  temperature, and other sympathomimetic effects
  from low dose experimentation
• Euphoria, giddiness, boastfulness for 30 minutes,
  then 60-90 minutes of mild euphoria and anxiety
• Anxiety persists for hours depression rebound
• Appetite and sleep rebound

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Reinforcement potential of cocaine

• Low doses are reinforcing
• Cocaine craving follows
• Self-administration of cocaine persists in the
  face of punishment
• Withdrawal increases craving
• May heighten sexual interest, but does not
  improve potential or performance

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High dose effects

• Toxic paranoid psychosis, like methamphetamine
• Cocaine bugs
• Strokes and myocardial infarction
• Len Bias
• Any psychiatric disorder

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Fetal effects

• Vasoconstriction of uterus and placenta
• Preterm labor and precipitous labor
• Aberrant brain and heart development
• Educational difficulties, easily frustrated
• Difficulty dealing with stimulation
• Attachment disorder, AD/HD
• But is it all due to cocaine?

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Treatment models

• Needs analysis
• Begin abstinence
• Diagnose comorbid disorders
• Relate cocaine use to disorders
• Maintain abstinence while treating disorders
• Prevent relapse

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Treatment models, continued

• Abstinence pattern analysis
• Crash 9 hours to 4 days, out of it
• Withdrawal 1 to 10 weeks, craving and relapse
• Extinction Indefinite, cued craving
• Pharmacotherapy
• Antagonize cocaine Not yet
• A cocaine version of Antabuse Not yet
• Treat comorbid problems Antidepressants
• Reduce cocaine craving Dopamine agonists

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Amphetamines

• History
• Pharmacokinetics
• Oral administration Bennies
• IV administration Speed
• Smoke Shabu or Ice, aka crank, crystal or
  crystal meth, speed.

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Pharmacodynamics of amphetamines

• PNS effects Sympathomimetic
• Constrict blood vessels Elevate blood pressure
• Increase heart rate
• CNS effects Psychostimulant
• Increases in motor activity
• Insomnia
• Loss of appetite

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Neurotransmitter effects

• Increase release of catecholamines
• Dopamine and norepinephrine on mesolimbic system,
  nucleus accumbens Activation
• Dopamine on basal ganglia High dose stereotypy
  and aggression
• Counterintuitive calming effects in AD/HD

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Dose-dependent effects
Outbursts Stereotypy Paranoia Insomnia Agitation
Increase BP Lower appetite Improve mood Alertness
Low Medium High

• Dosage/Method

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Amphetamine-like compounds

• Methylphenidate (Ritalin) and pemoline (Cylert)
  for AD/HD
• Amphetamine (Adderall) for AD/HD (1997)
• Concerta , Metadate and time-release Ritalin
• Attenade and Focalin D-isomer of Ritalin
• Bupropion (Wellbutrin) DSRI
• Atomoxetine (Strattera, 2003) NESRI
• First drug treatment for AD/HD in adults

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Stimulant treatment of AD/HD

• 1.29 million children currently taking stimulants
  to treat AD/HD
• About half of cases persist into adulthood
• AD/HD increases antisocial personality disorder
  risk 10X, and perhaps in connection, quintuples
  incidence of drug abuse
• Stimulants slow growth of children, but this also
  rebounds with abstinence the drug holiday
• See http//www.fmsnutrition.com/adhd_self_testing_
  or_test.htm for an AD/HD self-test.
• How do stimulants treat AD/HD?

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The Yerkes-Dodson Law
Complex task Simple task
Performance
Low Medium
High
Arousal
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More amphetamine-like compounds

• Fenfluramine, phentermine, phenmetrazine for
  obesity treatment
• Fen-phen withdrawn from market, September, 1997
• Sibutramine (Meridia) announced November, 1997
  for market in 1998 contributes to weight loss of
  5 to 10 in one year elevates pulse and blood
  pressure in some initial FDA rejection
• Ephedrine, pseudephedrine, and phenylephrine for
  nasal decongestion
• Herbal weight loss or energy-boosting products
  often contain ephedrine (ma huang), now known to
  be dangerous.

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Enzyme metabolism of cocaine

• Butyrylcholinesterase (BChE)
• Found in plasma and in red blood cells
• Metabolizes cocaine, aspirin, amitriptylene
  activates heroin
• Red blood cell activity more effective
  metabolizing cocaine
• Women have more red blood cell BChE
• Women are less susceptible to cocaine effects
• Women even more immune in luteal phase Mucous
  secretion decreases absorption of snorted cocaine
• BChE also protects against cocaine toxicity and
  nerve agent toxicity