Exam 2: Opioids Flashcards
What are opioid antagonists?
Naloxone (narcan) - reverses agnoists, precipitates withdrawal
Naltrexone (trexan)- long acting form
What is the difference between natural opioids, semi-synthetics, and fully synthetic?
??
What criteria must a compound meet to be an opioid agonist?
1) Exerts effects similar to morphine
2) Acts at opioid receptors
3) Effects blocked by antagonist, naloxone
What are the effects of an opioid agonist?
Active Gi
Low cAMP
Decrease Ca2+ influx
Increase K+ efflux
What are the pharacokinetic properties of opioids: administration?
1) Synthetics (m/c) oral
2) Syntehtics (M)- parenteral
3) Fentanyl - transdermal
non-therapeutic:
4) Heroin/morphine- parenteral
5) heroin- intranasla
6) opium/heroin- inhalation
Kinetics of opioids: distribution?
???
Kinetics of Opioids: Biotransformation?
Phase 2 conjugation by liver.
Glucuronide (6 active, 3 inactive)
Kinetics of Opioids: Elimination?
???
How were opioid receptors discovered?
Smooth muscle bioassay: opioids inhibit contraction caused by electical stimulation, but naloxone brings it back
[3H] Naloxone
What are the types of opioid receptors?
1) Mu- reward, cough, emesis, miosis, respiratory, CV, GI suppression
2) Delta - reward, congition, motor, respiratory/GI suppress
3) Kappa- Dysphoria, anxiety
4)Orphan- feed, learn, motor
All analgesia
What is the relevance of opioid receptor affinity to opioid potency?
Lower Ki= high affinity = high potency = low ED50
How has smooth muscle been used to study the biological effects of opioids? How did this bioassay lead to the discovery of endogenous opioids?
Brain extract blocks contraction of smooth muscle (must be something in brain doing it)
Add naloxone back, inhibits
What are the specific synaptic mechanisms by which all opioids affect cellular activity?
A) IPSP (K+ efflux, hyperolarize)
B) Pre inhibition (low transmitter release, reduce Ca2+ influx)
C) autoreceptor activated (decrease transmitter release, reduce Ca2+ influx)
What are the acute effects of opioids
sedation, drowsiness, relax, euphoria, constrict pupil (miosis), nausea/vmoit, no cough/respiration, hypothermia, reduced sex drive, analgesia, constipation
How do opioids exert analgesic effects to reduce pain?
Spinal/Brain Analgesia = inhibits pain sensation
Limbic/Thalamic/Cortical= inhibit pain perception
In all forms of opioids on the table, receptor affinity is…
High or in case of fentanyl and carfentanil, insane
What is the only opioid with partial intrinisic efficacy
Buprenorphine
What are the symptoms of opioid OD?
Dizzy/confused, tiny pupil, gruggle, snore/choke, blue lips/nails, can’t wake up, slow/no breathing, cold clammy skin, no movement
What mechanisms account for opioid OD?
Suppression of medullary center of respiration
What interventions can treat opioid OD?
Naloxone vapor
What common therapeutic uses of exogenous opioids?
Analgesia Fentanyl- anesthesia Cough Suppression Substance abuse treatment reduce intestinal motility
How are symptoms of opioid withdrawal related to the acute effects of opioid admin?
They are the opposite.
Acute: constipation, hypothermia, flushing,
Withdrawal: chills, bp, dilation, respiration, pain, depression
What cellular mechanism is proposed to underlie tolerance and physical dependence associated with chronic opioid use?
Dynamic tolerance- decrease receptors and increase adenylyl cyclase
cAMP levels adapt to exposure, increase dramatically
Context tolerance too: rat experiment shows more likely to OD
What cellular mechanism is proposed to underlie physical dependence associated with chronic opioid use?
Dependence: opposite acute effects, 1-2 weeks, not life threatening
Positive reinforcement: CRAVING, INCREASE RELEASE OF DOPAMINE IN NA
How do dopaminergic and GABAergic neurons contribute to positive reinforcement of opioid use?
Koob.
Opioids inhibit GABA in VTA
Disinhibit DA neurons in VTA
Increase DA release in NA
By what mechanisms can each drug
contribute to recovery from opioid addiction?
METHADONE
Fully agonist
Oral
Typical opioid, but mild. Reduce withdrawal symptoms/OD risk
By what mechanisms can each drug
contribute to recovery from opioid addiction?
BUPRENORPHINE
Partial agonist
Sublingual/Buccal
Typical opioid but mild, reduces risk of OD/withdrawal intensity
By what mechanisms can each drug
contribute to recovery from opioid addiction?
CLONIDINE
Noradrenergic alpha autoreceptor agonist
Suppresses physical withdrawal symptoms during week of withdrawal
Reduces release of NE in vesicles, fewer Ca2+ channels open, low cAMP
By what mechanisms can each drug
contribute to recovery from opioid addiction?
NALTREXONE
Full antagonist
blocks effects of opioids, precipitates withdrawal in users, blocks life-threatening effects
What factors are proposed to account for current epidemic of opioids?
???
Suboxone
Buprenorphine and naloxone.
Sublingual
No effect if drug extracted and injected because naloxone blocks effects
Morphine becomes heroin by
acetic anhydride, put 2x acetyl groups on it
