May 8 Opiates

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May 8 - Opiates
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A. Endogenous Opiate Peptides Endorphins the
generic term for 3 families of endogenous
opiates Name comes from shortening of endogenous
morphine Discovered when trying to understand
how morphine works 3 families of
endorphins Beta-endorphins most
prevalent Enkephalins Dynorphins
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A. Endogenous Opiate Peptides The endorphins
mostly act through inhibition of release of other
neurotransmitters. Mostly found in interneurons
with short axons that make axo-axonic synaptic
contact. All 3 endorphin families play a role in
analgesia. Roles are receptor dependent.
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• B. Pain Control by Slow Pain System
• relevant to aching, burning, and lasting pain
  (not sharp, pricking type pain)
• Controlled by NE, SE, Substance P, Glutamate, and
  endorphins
• Sensory neurons throughout body send messages via
  spinal cord - release Substance P in spinal cord
  as the transmitter message then carried to the
  thalamus and on to cortex
• This triggers brain to release endorphins
• Endorphins then inhibit release of Substance P
  via axo-axonic synapses in periaqueductal gray
  and spinal cord, thus reducing pain messages
• Norepinephrine and Serotonin can also inhibit
  Substance P release via other receptors on
  Substance P releasing sensory neurons
• Opiate drugs also inhibit Substance P

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• C. Receptors for Endogenous Opiate Peptides
• Mu receptors
• - beta-endorphins are most potent here, then
  enkephalins, then dynorphins
• most clinically used opiate medications are
  relatively selective for mu receptors
• Morphine acts at mu receptors
• Affinity for morphine is what originally
  identified and named the receptor
• Most prevalent in limbic structures, thalamus,
  and brainstem areas, but also found in spinal
  cord
• Relevant to pain, pleasure, euphoria,
  reinforcement/ dependence, respiratory
  depression, reduced GI motility (constipation),
  pupillary constriction (pin-point pupils)
• Euphoria results from stimulation of mu receptors
  and secondarily to inhibition of GABA which then
  cannot inhibit DA release in reward centers
  more DA

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• 2. Kappa receptors
• mostly in spinal cord some in brainstem
• Inhibit Substance P release at spinal level
• Cause pupillary constriction
• Cause sedation
• Not related to euphoria, dependence or
  respiratory depression
• A selective kappa receptor action could reduce
  pain without addiction potential or respiratory
  depression
• Delta receptors
• found in spinal, brainstem and limbic areas
• Role in analgesia, reinforcement, temperature
  control

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• 2. Kappa receptors
• Delta receptors
• found in spinal, brainstem and limbic areas
• Role in analgesia, reinforcement, temperature
  control
• Sigma receptors
• found mostly in limbic system (Hippocampus and
  amygdala)
• Role in dysphoric responses

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D. Central Actions of Endorphins (across receptor
types) broad spectrum due to inhibition of
action of other transmitters GABA, NE, DA, SE,
Ach, Substance P Euphoria Analgesia Seizure
activity Enhanced motor activity Behavioral
arousal Muscular rigidity and immobility Sedation
Stereotyped behavior Eating and drinking Blood
pressure Body temperature
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E. Opiate Drugs Natural ones are derived from the
opium poppy From opium extracts, come morphine
and codeine slow to enter brain. From opium,
also comes oxycodone Percodan Oxycontin From
morphine, comes Meperidine (Demerol)
Hydromorphone (Dilaudid) and Fentanyl (Sublimaze
China White). From morphine, heroin is
synthesized more potent and crosses the
blood-brain barrier faster. Within brain, heroin
is converted to morphine and this allows it to
bind to receptors. Extensive study of morphine
actions because the drug, naloxone, blocks mu
receptors and allows study. Synthetic opiate
drugs Darvon, Talwin Methadone Opiate receptor
blockers naloxone naltrexone
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• Medical Uses of Opiate Drugs
• Pain control
• Cough suppression
• Control of diarrhea reduction of GI motility
• Recreational Use
• Prescription meds, illegals on street, and
  designer drugs
• All routes used.
• Street names
• Morphine morph, murphy, M, Miss Emma
• Heroin smack, junk, horse, H, Harry, Rufus,
  Tar, Perze
• Fentanyl China White
• Dilaudid Dillies Percodan Percs
• Darvon Pink Ladies Pumpkin seeds

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• F. Pharmacodynamic effects
• Most action related to mu receptor stimulation
• Mu receptor stimulation activates G proteins that
  then make it harder for cell to fire via
  prevention of K or Ca influx inhibit firing
  of neuron
• G. Pharmacologic Effects
• Analgesia pain relief at doses that do not
  cause loss of consciousness
• Alteration both in sensation and affective
  component of pain
• Some argue that opiates cause a relief from
  suffering, not pain per se
• Results from inhibition of Substance P release
  and direct Mu binding

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• G. Pharmacologic Effects
• Analgesia pain relief at doses that do not
  cause loss of consciousness
• Motor System Effects thought to result from
  inhibition of GABA, DA, and Ach in the
  nigrastriatal system (basal ganglia)
• Mixed effects relaxation and rigidity
• Muscular relaxation, eyelids droop, speech
  slurred, heaviness in limbs, walking is slow
• High doses catatonia muscular rigidity
• If beta-endorphin is injected directly into the
  brain get muscular rigidity, then relaxation

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• Pharmacologic Effects
• Analgesia pain relief at doses that do not
  cause loss of consciousness
• Motor System Effects thought to result from
  inhibition of GABA, DA, and Ach in the
  nigrastriatal system (basal ganglia)
• Euphoria/Tranquility mood alteration attributed
  to mu receptor activation in ventral tegmental
  area plus secondary activation of DA neurons
  that project to the nucleus accumbens
• Mu receptor activation inhibits GABA releasing
  neurons in reward circuit ? GABA cannot then
  inhibit DA release ? DA release is enhanced
• Not exclusively a DA effect give DA receptor
  blockers and still get some effects mu
  receptors themselves do some

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• Analgesia pain relief at doses that do not
  cause loss of consciousness
• Motor System Effects thought to result from
  inhibition of GABA, DA, and Ach in the
  nigrastriatal system (basal ganglia)
• Euphoria/Tranquility mood alteration attributed
  to mu receptor activation in ventral tegmental
  area plus secondary activation of DA neurons
• Body temperature drops due to action on
  hypothalamic heat regulating centers (But high
  dose to chronic users may cause temp. elevation)
• Hormonal effects inhibition of release of
  certain reproductive hormones (LH FSH
  testosterone), also beta-endorphins. Female
  addicts have irregular cycles males have reduced
  sex drive.
• 6. Antidiuretic effects cannot relax muscles
  and decreased fluid volume cant go.

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• Analgesia
• Motor System Effects
• Euphoria/Tranquility
• Body temperature drops due to action on
  hypothalamic heat regulating centers
• 5. Hormonal effects inhibition of release of
  certain reproductive hormones (LH FSH
  testosterone), also beta-endorphins
• Antidiuretic effects cannot relax muscles and
  decreased fluid volume
• Pupillary constriction excitatory action on
  oculomotor nerve pinpoint pupils
• Respiration depressed caused by mu receptor
  activation in medulla (brainstem resp. center)
• Death from overdose due to respiratory depression.

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• Analgesia
• Motor System Effects
• Euphoria/Tranquility
• Body temperature drops
• Hormonal effects
• Antidiuretic effects
• Pupillary constriction
• Respiration depressed caused by mu receptor
  activation in medulla (brainstem resp. center)
• Cough suppression depression of cough center in
  medulla (hence use of codeine for cough
  suppression)
• Nausea/vomiting direct stimulation of
  chemoreceptor trigger zone in medulla
• During opiate analgesia use, 40 experience
  vomiting.

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• 8. Respiration depressed caused by mu
  receptor activation in medulla (brainstem resp.
  center)
• 9. Cough suppression depression of cough
  center in medulla (hence use of codeine for cough
  suppression)
• 10. Nausea/vomiting direct stimulation of
  chemoreceptor trigger zone in medulla
• During opiate analgesia use, 40 experience
  vomiting.
• Reduced blood pressure - Opiates facilitate the
  release of histamine hypotension
• Flushing of skin dilation of blood vessels in
  skin and redness from histamine release
• GI tract decreased acid and fluid release (dry
  internally and dry eyes) decreased muscle tone
  and motility (codeine for diarrhea)
• Addicts have chronic constipation.

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• GI tract decreased acid and fluid release
  decreased muscle tone and motility (codeine for
  diarrhea)
• Weakened immune function enhanced growth of
  tumors reduced cell-killing activity of bodys
  cells that kill foreign invaders
• But endogenous opiates are important regulators
  of immune functions. Beta-endorphins enhance
  killer cell activity.
• Endogenous opiates are important in recovery
  from illness.
• Chronic drug use apparently interferes with
  these actions.
• 15. Increased possibility of seizures opiate
  drugs inhibit GABA and then neurons are more
  excitable

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H. Heroin Important Circuits for Heroins Actions

• Limbic system and reward centers euphoria
• Medulla respiratory depression
• Spinal cord pain relief

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• Short Term Effects of Heroin Use (acute effects)
• "Rush"
• Depressed respiration
• Clouded mental functioning
• Nausea and vomiting
• Suppression of pain
• Heaviness in extremities
• Delayed nodding out
• Overdose effects sedation respiratory
  depression
• Treatment of overdose use opiate antagonists
• Naloxone (Narcan) - injected

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• Heroin Use Patterns
• until 90s, had been stable since late 70s
• during 90s, use escalated. Now 3X higher than
  91, and moving to younger ages
• now purer heroin on street
• new forms allow snorting and smoking
• Addiction pattern among the young, snort ?
  inject.
• Smoking is least common route.
• Route of use patterns vary across country.

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• I. Addiction Mechanisms
• Mu agonist drugs have the highest abuse
  potential.
• Mechanism of dependence/tolerance
• Mu receptor sensitivity is reduced. No apparent
  effect on numbers of receptors, but sensitivity
  decreases via down regulation of second messenger
  systems. Withdraw the drug rebound excitation
  of receptors causes effects.
• Drug Metabolism is increased.
• Endogenous production of endorphins is decreased.

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J. Addiction Potential across opiate
drugs Potencies of mu activation 5 mg injected
dose of heroin is as potent as a 10 mg injected
dose of morphine re analgesia and euphoria. 5
mg injected dose of heroin potency of 130 mg of
oral codeine. 5 mg injected dose of heroin
potency of 250-400 mg of oral Darvon. Tolerance
develops rapidly to opiates when used
continuously, but varies across effects.
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K. Tolerance Tolerance develops rapidly to
opiates when used continuously, but varies across
effects. Generally, repeated doses lead to
shorter duration and decreased intensity
of analgesia euphoria sedation depressive
effects on respiration Less tolerance for miosis
(pinpoint pupils) and constipation. Begin at 5 mg
dose of injected heroin few months later may
shoot 500 mg.
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Rapid tolerance First dose initiates
tolerance give morphine to naïve subjects, then
6-8 hours later give naloxone causes pain.
Give naloxone to subjects without morphine
pretreatment benign. Naloxone a mu receptor
antagonist blocks action of opiate drugs Among
addicts, tolerance disappears rapidly as well.
Return to use after hiatus, may OD on dose they
were using before.
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But tolerance and drug addiction are not exactly
the same thing. 1. May establish tolerance for
morphine when used as pain killer, but when meds
(and pain) stop, no craving or compulsive drug
seeking. 2. Viet Nam vets many used heroin in
Viet Nam, but stopped on return without
difficulty. Wide individual differences in
reaction to withdrawal not well-understood.
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L. Nature of Withdrawal from Heroin when done
without medical/drug supports 8-12 hours after
last dose Lacrimation tearing Rhinorrhea nose
running Sweating 12-14 hours Tossing, restless
sleep for several hours wake up more restless
and more miserable 15-24 hours Dilated
pupils Restlessness Reduced appetite Irritability
Tremors
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L. Nature of Withdrawal from Heroin when done
without medical/drug supports 24-48 hours peak
then lessening over days Irritability Insomnia Ap
petite Suppression Tearing Severe sneezing
Violent yawning Muscle weakness Abdominal
cramps Intestinal cramps diarrhea nausea
vomiting Kicking movements (hence kicking the
habit) Chills and gooseflesh (hence going cold
turkey Increased blood pressure and heart
rate No seizures rarely life-threatening like
a bad flu 7-10 days gross symptoms over. But
6 mo or longer, hormonal disruptions (menstrual
irregularity water balance problems
thermoregulation problems)
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• M. Long Term Consequences of Heroin Abuse
  (chronic effects)
• Addiction
• Infectious diseases, for example, HIV/AIDS and
  hepatitis B and C
• Collapsed veins
• Bacterial infections
• Abscesses
• Infection of heart lining and valves
• Arthritis and other rheumatologic problems

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• N. Treatments for Heroin and Other Opiate
  Addictions get from textbook
• Methadone - oldest, since 1965
• 2. LAAM since 1993
• levo-alpha-acetylmethadol
• 3. Buprenorphine (Buprenex) since 1996
• 4. Naltrexone (ReVia) - tablets
• 5. Vaccine under development

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• O. Oxycontin
• pure oxycodone at doses up to 80 mg/pill
• other meds that contain oxycodone Percodan
  Percoset
• Percodan aspirin plus 5 mg oxycodone
• Percoset acetaminophen plus 5 mg oxycodone
• problem due to high concentration, purity, and
  absence of protective agents in the formulation
• tablets can be crushed then snorted or injected
• need to add encapsulated naltrexone to prevent
  abuse naltrexone would be released only if
  tablet was crushed