Neurotransmitters

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Opiates
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Opiate Overview

• Opiates are derived from the poppy plant
  (Papaver somniferum) first cultivated in
  Mesopotamia (the joy plant)
• Opium crude resinous exudate, often dried and
  powdered, can be used unprocessed
• Used for medicinal purposes (pain relief,
  diarrhea, etc.) and for recreation
• Active ingredients include over 25 alkaloids,
  most importantly morphine (10 of opium), codeine
  (3 of opium), and thebaine

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Continued

• Opiates include opium, morphine, codeine,
  derivatives (e.g. diacetylmorphine or heroin) and
  synthetics (e.g. methadone)
• Refinement of opium
• Morphine made from opium - increased strength
  10X
• Heroin refined from morphine (more lipid
  soluble), made it even stronger (3X)
• Codeine 1/5 the strength of morphine

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Use and Abuse

• Pain medication is the second most common type
  of drug abuse in adolescents and adults behind
  marijuana.

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Use and Abuse (cont)
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Generation RX

• According to the Partnership for a Drug Free
  America, the most popular prescription drug
  abused by teens is Vicodin followed by Oxycontin.

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Common Pharmacokinetics

• Opiates administered by various routes
• Oral 20-30 min to reach brain
• Insufflated 5-8 min
• IV 15-30 seconds
• Smoked 7-10 seconds
• Metabolized into active and inactive components
  by kidneys
• Eliminated mostly in urine

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Opiate Effects

• Opiates inhibit brain centers (depress CNS
  activity) controlling
• pain, coughing, breathing, heart rate and
  intestinal motility.
• Opiates depress nerve transmission in sensory
  pathways of the spinal cord and brain that signal
  pain.
• Widening of blood vessels (vasodilation -
  produces a warm feeling, sweating, reduces bowel
  activity)
• Overall lethargy and lack of motivation
• At high doses, sedation occurs (overdose results
  in coma, unconsciousness, death)
• Combined with other depressants (e.g., alcohol)
  can be deadly (gt50 of overdose cases involve
  alcohol)

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Transmission of Pain

• Stimulus? Nocioceptors
• Nocioceptors are 80 C fibers (unmyelinated
  slow pain) and 20 A delta fibers
  (cold/pressure/fast pain).
• About 50 of sensory fibers have nocioceptive
  functions.
• C fibers are blocked in the presence of opiates.
• A delta fibers are unaffected by opiates

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Acute/Chronic Effects
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Pharmacodynamics

• Opiates bind to opioid receptors, including the
• mu, delta, epsilon, kappa receptors
• These G-protein-coupled receptors are involved in
  the transmission of pain signals.

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Neurotransmitters

• Endorphins, Dynorphins, Enkephalins,
• Called natural opiates
• Involved in glucose regulation
• natural neural peptides that bind to opioid
  receptors to produce euphoric effects
• Released by brain when exposed to opiates

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Neurotransmitters

• GABA
• Affects dopaminergic cells
• Opiates and opioid NTSs activate the presynaptic
  opioid receptors on GABA neurons
• This inhibits the release of GABA in the VTA
• Inhibiting GABA allows the dopaminergic neurons
  to fire faster

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Morphinefirst isolated in 1804 by Friedrich
Serturner

• Direct/indirect agonist
• Most often administered subcutaneously also
  smoked, taken orally, or via mucosa
• Not very lipid soluble, doesnt cross BBB easily

"Oh, jab me with your needle a hundred times And
a hundred times I will bless you, Saint
Morphine" Jules Verne (1828 - 1905)
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Codeine(methylated morphine)

• Direct/indirect agonist
• Alkaloid found naturally in opium in low
  concentrations (0.1-2) usually synthesized from
  morphine
• Usually administered orally
• 0.1 times as potent as morphine
• Converted into morphine after crossing BBB
• Used for cough suppression, diarrhea, moderate
  pain

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Heroin (diacetylmorphine)

• Direct/indirect agonist
• Synthesized from morphine
• Administered IV, SC, snorted or smoked
• IV and smoked lead to fast onset and rush
• 3 times as potent as morphine
• Not directly an efficacious mu agonist, but more
  lipid soluble than morphine
• Enters brain quickly, converted into morphine for
  action

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Methadone (methadone hydrochloride)

• Partial agonist
• Completely synthetic
• Orally administrated
• Mild/moderate effects over long time period
  (days)
• Used in treatment of opiate addiction to prevent
  withdrawal and craving
• Minimizes effects of short-term opiates taken
  under influence of methadone

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Methadone treatment

• Safer, less contaminated
• Taken orally - avoids injection
• No worries about where next hit is coming from
• Lasts longer in the body (taken once a day)
• Allows withdrawal from drug use with less
  discomfort
• Reduces criminal activity
• Cuts connection with drug scene
• Its cheaper

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Oxycodone

• Opioid Analgesic
• Synthesized from opium-derived thebaine
  structurally similar to codeine
• Ingested orally in tablet form
• Schedule II controlled substance
• Can only be legally obtained by prescription
• OxyContin is time release oral oxydodone.

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Vicodin

• Narcotic Analgesic
• Hydrocodone bitartrate (opioid analgesic) and
  Acetaminophen (non-opiate analgesic)
• Ingested orally in tablet form
• Schedule III controlled substance
• Can only be legally obtained by prescription

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Naloxone (Narcan)

• Synthetic direct antagonist
• Administered IV onset 2 min
• Few low-dose effects on normal persons
• Rapidly precipitates withdrawal in
  opiate-dependent persons
• Elicits tobacco craving in dependent individuals
• Used to reverse respiratory depression from
  overdoses

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Naltrexone (Trexan)

• Direct antagonist
• Administered orally
• Works like naloxone but since oral more useful
  for long-term
• Used after recovery from withdrawal period (also
  used to treat alcoholism)
• Prevents opiate agonists from having an effect

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Tolerance

• Develops to respiratory depression, analgesia,
  euphoria, sedation
• Little tolerance to pupil-constriction and
  constipation
• Profound behavioral/associative tolerance
• Cross-tolerance develops between different
  opiates and between opiates and opioids

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Mechanisms for Tolerance

• Downregulation (conversely, antagonists
  upregulate)
• Decreased receptor sensitivity
• Reduced synthesis of opioid peptides
• Also, another possible mechanism, based on
  synthesis...

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Change in Opioid Synthesis

• 1) POMC yields two major species of
  beta-endorphins, normal longer form and shorter
  form in brains of normal rats ratio between 11
  and 1.51 (normalshort)

2) Hammonds et al. (1984) showed short version
seems to be an antagonist capable of reversing
many of the effects of the normal long version
3) Bronstein et al. (1990) showed rats made
tolerant to morphine (3 days with subcutaneous
pellets) have ratio of almost 12 (in favor of
short version)
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Opiate Withdrawal (5-10 days)

• A. Either of the following
• (1) Cessation of (or reduction in) opiate use
  that has been heavy and prolonged (several weeks
  or longer)
• (2) Administration of an opioid antagonist after
  a period of opioid use (rapid vs slow abstinence)
• B. Three or more of the following, developing
  within minutes to days after Criterion A
• (1) Dysphoric mood, depression
• (2) Nausea or vomiting
• (3) Muscle aches, cramps, tremors
• (4) Watery eyes or runny nose
• (5) Dilated pupils, goosebumps, or sweating
• (6) Diarrhea
• (7) Yawning
• (8) Fever
• (9) Insomnia
• C. Symptoms in Criterion B cause clinically
  significant distress or impairment in social,
  occupational, or other important areas of
  functioning.

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Protracted Abstinence Syndrome

• Can last up to 6-7 months after withdrawal
• Vague sense of feeling abnormal
• Depression (increased propensity to sleep)
• Abnormal response to stress
• Abnormal respiration and temperature
• Decreased self-esteem
• Anxiety
• Craving
• Confounded by high comorbidity with other
  psychiatric disorders

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Additional Problems

• Neonatal Effects cross the placental barrier
  giving large doses to unborn fetus
• Overdose occurs when so much of the drug enters
  the brain the nervous system shuts down. Blood
  pressure drops, heart becomes to weak to pump
  blood, lungs labor fill with fluid
• Dirty Shared Needles Hepatitis B C, HIV,
  flesh eating bacteria, gangrene, endocarditis,
  malaria, syphilis

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Polydrug Use

• Mixing Opioid users often mix cocaine or
  amphetamine, speedball - combine heroin
  marijuana to give it more kick.
• Alcohol benzodiazepines create synergistic
  effects increase potential for overdose,
  respiratory depression death
• Cycling Addicts go on off their drug of
  choice.
• Lowers tolerance tissue dependence so the
  body can attempt to return to normal.
• Switch to alcohol, marijuana, barbiturates,
  benzodiazepines

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Treatment

• Conventional Detox Centers
• Buprenorphine, Subutex
• Opioid partial agonist
• Once abstinence begins, buprenorphine minimizes
  discomfort
• When fully detoxed, buprenorphine is phased out.
• Lasts 10-14 days.

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Treatment (cont)

• Rapid Opiate Detox
• Lasts 4-6 hours, released 24-48 hours after
• Patient is anesthetized so that the patient does
  not experience withdrawal
• Naltrexone
• opioid blocker
• Naloxone
• counteracts effects of opioid

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Treatment (cont)

• Detox is only the beginning
• Continuing programs are needed to prevent relapse
• Methadone-based programs exist
• But not as popular
• Methadone is only a replacement
• Cognitive therapy, 12-steps, meditation/hypnosis,
  etc