Opioids I Flashcards
Opium
Dried latex from the opium poppy
Untransformed
Opiates
Any drug derived from opium
(Morphine and Heroin)
Opioid
Any drug that binds to an opioid receptor (Includes opiates and synthetic opioid agonists)
(Fentanyl and Heroin)
Narcotic
Used to refer to drugs with sleep inducing properties
Now is referred to illegal use of opioids with non-medical purposes
What are the 4 opioid receptors
Mu
Delta
Kappa
Orphanin receptor ligand (ORL-1) or NOP
What differs between the different opioid receptor types
Receptor distribution
Ligand specificity
Where are Mu Opioid Receptors? What are they responsible for?
Subcortical cortex, thin vertical line near centre
Emotional reactions
Where are Kappa Opioid Receptors? What are they responsible for?
Cortex region, outlines the edges of the cortex
Coordination and sensory info
Where are Delta Opioid Receptors? What are they responsible for?
Cortex region, horizontal lines spanning both cortical and subcortical cortex
Coordination and sensory info
Where are ORL-1 Opioid Receptors? What are they responsible for?
Wildly expressed in the central nervous system, basically everywhere in the brain
May be involved in fear processing
Describe homology between opioid receptors
The centres of opioid receptors are highly conserved and are identical regions between all opioid receptors
The ends of the opioid receptors differ between the different types, this difference dictates what ligand specificity and what ligand binds for different opioid receptors
What is the most common opioid receptor
Mu opioid receptors
What are the effects of a Mu agonist, give some examples
Analgesia
Reward
Cough suppressant
Respiratory depression
Constipation
Morphine, heroine, codeine
What are the effects of a Mu antagonist, give some examples
Aversive
Prevents reward
Blocks overdose
Naloxone
What are the effects of a Delta agonist
Not rewarding
No analgesia effects
Seizure inducing
What can delta agonists potentially treat, what are the side effects
Could potentially treat chronic migraines, leads to unregulated cortical activity, causes seizures
What are the effects of a Kappa agonist, give some examples
Aversive
Hallucinogenic
Anxiogenic (Causes anxiety)
What are the effects of a Kappa antagonist
Potential antidepressant and reverses anxiety (anxiolytic)
What are the best analgesics
Opioids are great at blocking acute pain
List a partial agonist at the mu opioid receptor, what are its benefits
Buprenorphine, mild to moderate analgesic efficacy, has a safer therapeutic index
Only partially inhibits breathing complex, impossible to overdose
List some full agonists at the mu opioid receptor
Morphine, methadone, fentanyl, heroine
What has a higher potency, morphine or fentanyl. What does this mean?
Fentanyl has a higher potency meaning it has higher analgesic effects and more side effects at a lower dosage
What kind of ligand is buprenorphine. What does it bind to and what are its effects
Mixed agonist-antagonist
Partial agonist at mu opioid receptor
Used to stabilize people addicted to full opioid agonists (morphine, fentanyl). and alleviates withdrawal symptoms
Antagonist at delta and kappa opioid receptors
Antidepressant through antagonist effects at kappa receptor
What are Beta-arrestins and what do they do
Intracellular proteins that regulate signal transduction in G-protein coupled receptors by binding to phosphorylated receptors
Internalizes receptors
Arrests G-protein receptors and redirect signaling to alternative pathways
What is the mechanism behind beta-arrestins
GPCR is activated by ligand binding –> G-protein is cleaved forming two subunits -> Receptor is phosphorylated –> signals beta-arrestin to bind
Beta-arrestin binds blocking further G-protein signaling –> Redirects signaling to alternative pathways –> Targets receptor for internalization
In opioids what are the effects of G-protein biased agonists
Analgesic effects
In opioids what are the effects of beta-arrestin biased agonists
Respiratory depression and Constipation
What kind of drug is codeine and what is it metabolized into
Prodrug and is metabolized into morphine by liver enzymes
What is impacted more by first pass metabolism
Codeine or Morphine
Morphine
Where are opioid agonists most widely distributed
Highly perfused tissues (Brain, lungs, liver, kidney, and spleen)
Order these administration of opioids from largest effect to smallest effect
SQ, PO, IV
Intravenous (IV) > Subcutaneous (SQ) > Mouth (PO)
What is morphine metabolized into, what is the percentage of each metabolite
Morphine-3-glucuronide (M3G)
90%
Morphine-6-glucuronide (M6G)
10%
Morphine metabolism enzyme
UGT2B7
What are the efects of M6G
Active metabolite that prolongs the effects of morphine
What metabolizes codeine into morphine
CYP2D6
Why do different people have different reactions to codeine
Genetic Polymorphisms of CYP2D6
Different people either have a slow or fast metabolizer
Variation in analgesic and adverse responses
What are polar metabolites, how are they mainly excreted
Glucuronide conjugates (M3G and M6G) of opioid analgesics are excreted mainly through urine
How are uncharged drugs excreted
Morphine, an uncharged drug is found in small amount in urine
How can renal impairment affect opioid use
If someone has impairment of renal functions they will not be able to excrete out metabolites of potent opioids.
Can cause sedation and respiratory depression due to an accumulation of active polar metabolites (M6G)
What are the three types of endogenous opioid peptides. What do endogenous opioid peptides do?
Beta endorphins
Enkephalins
Dynorphins
Neurotransmitters that mediate pain, reward, learning, memory, and cognition
How are endogenous opioid peptides formed
Proteases cleave a protein precursor
What is the protein precursor of enkephalins? Where are they found?
Proenkephalin
Brain, adrenal chromaffin cells
What is the protein precursor of dynorphins? Where are they found?
Prodynorphin
Pituitary/adrenal medulla
What is the protein precursor of beta-endorphins? Where are they found?
Proopiomelanocortin
Pituitary
What do all opioid peptides share in common
A common amino acid sequence
Tyr-Gly-Gly-Phe
Various extensions are added during post-translational modification
What are the different variations of beta-endorphins
Just beta-endorphins
What are the different variations of dynorphins
Dynorphins A
Dynorphins B
Neoendorphins
What are the different variations of Enkephalins
Met Enkephalins
Leu Enkephalins
What the opioid receptor affinity for Enkephalins
Delta > Mu > > > Kappa
What is the opioid receptor affinity for Dynorphins
Kappa > > > Mu = Delta
What is the opioid receptor affinity for Beta-endorphins
Mu = Delta > > > Kappa
What does it mean when opioid peptides have different affinities
The peptides have different preferences to different receptors, they can bind to all of them, its just they select certain ones that they prefer
