Opioids I Flashcards by Kevin Tea

Opium

Dried latex from the opium poppy
Untransformed

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Opiates

Any drug derived from opium
(Morphine and Heroin)

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Opioid

Any drug that binds to an opioid receptor (Includes opiates and synthetic opioid agonists)
(Fentanyl and Heroin)

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Narcotic

Used to refer to drugs with sleep inducing properties

Now is referred to illegal use of opioids with non-medical purposes

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What are the 4 opioid receptors

Mu
Delta
Kappa
Orphanin receptor ligand (ORL-1) or NOP

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What differs between the different opioid receptor types

Receptor distribution

Ligand specificity

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Where are Mu Opioid Receptors? What are they responsible for?

Subcortical cortex, thin vertical line near centre

Emotional reactions

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Where are Kappa Opioid Receptors? What are they responsible for?

Cortex region, outlines the edges of the cortex

Coordination and sensory info

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Where are Delta Opioid Receptors? What are they responsible for?

Cortex region, horizontal lines spanning both cortical and subcortical cortex

Coordination and sensory info

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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

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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

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What is the most common opioid receptor

Mu opioid receptors

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What are the effects of a Mu agonist, give some examples

Analgesia
Reward
Cough suppressant
Respiratory depression
Constipation

Morphine, heroine, codeine

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What are the effects of a Mu antagonist, give some examples

Aversive
Prevents reward
Blocks overdose

Naloxone

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What are the effects of a Delta agonist

Not rewarding
No analgesia effects
Seizure inducing

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What can delta agonists potentially treat, what are the side effects

Could potentially treat chronic migraines, leads to unregulated cortical activity, causes seizures

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What are the effects of a Kappa agonist, give some examples

Aversive
Hallucinogenic
Anxiogenic (Causes anxiety)

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What are the effects of a Kappa antagonist

Potential antidepressant and reverses anxiety (anxiolytic)

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What are the best analgesics

Opioids are great at blocking acute pain

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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

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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