Lecture 18: Opioids Flashcards
What is Opium?
Dried latex obtained from the poppy
What are Opiates?
Any drug derived from opium
What is an Opioid?
Any drug that binds to an opiod receptor
What is Narcotic?
Originally used to refer to any drug with sleep inducing properties but now used by law enforcement to refer to illegal use of opioids for non-medical purposes
What are Synthetic Opioid Agonists?
Drugs or compounds that have been manufactured to bind to the same receptors that opium and opiates do but do not naturally occur within the opium poppy
What are examples of Synthetic Opioid Agonists?
Fentanyl, Heroin, Oxycontin
What kind of receptors are Opioid receptors?
The are inhibitory G-protein coupled receptors
What does activation of Opioid receptors do?
They inhibit calcium channels, activate K+ channels and inhibit adenylyl cyclase
What are the four types of opioid receptors?
Mu, Kappa, Delta, ORL1
Why do the different opioid receptors produce such diverse effects in the brain?
They are found in different parts of the brain.
Different drugs are selective to different receptors
Where is the ORL-1 receptor widely expressed?
In the the CNS
What is the most widely expressed opioid receptor in the brain?
The ORL-1 receptor
What are the extracellular loops of opioid receptors important for?
Controlling which ligands bind
What are the intracellular loops of opioid receptors important for?
The control which type of G proteins bind
What does activation of the mu opioid receptor cause?
- Analgesia
- Reward/euphoria
- Respiratory depression
- Antitussive
- Constipation
Why do Mu opioid agonists cause constipation?
Because they inhibit gut motility
What is Narcotic gut?
When people on narcotics long term to manage pain have constipation because mu agonist inhibit gut motility
What drugs are Mu opioid agonists?
- Morphine
- Codeine
- Heroin
What are Mu receptor antagonists used for?
Opioid addiction or to prevent overdose
What is an example of a Mu antagonist?
Naloxone
What effects do Mu antagonists have?
- Aversive
- Prevent reward
- Block overdose
What is an example of a Mu antagonist?
Naloxone
What are the effects of agonists at the Delta receptors?
- Not rewarding
- No analgesia (except in chronic pain)
- Seizure inducing
What are the effects of antagonists at the Delta receptors?
There are no obvious effects
What are the effects of agonists at the Kappa receptors?
- Aversive
- Hallucinogenic
- Anxiogenic (anxiety)
What is an example of a Kappa receptor agonist?
Salvia
What are the effects of antagonists at the Kappa receptors?
Potential antidepressant/anxiolytic (reduce anxiety)
What are the full mu opioid receptor agonists?
Morphine
Methadone
Fentanyl
Heroin
What is the partial mu opioid receptor agonists?
Buprenorphine
What are the consequences of Buprenorphine being only a partial agonist at the mu opioid receptor?
It has less analgesic effect and less respiratory depression
Which one is more potent: Fentanyl or Morphine?
Fentanyl
Is there a strong connection between efficacy and potency with opiates?
No you can have a partial agonist that is very potent and you can have a full agonist that is weekly potent
What is an example of an opioid ligand that is not specific to one receptor?
Buprenorphine
What receptors can Buprenorphine target and what does it do at the receptor?
- Partial agonist at the mu opioid receptor
* Antagonist at the delta and kappa opioid receptor
What is Buprenorphine important in managing?
Pain and opioid addiction
What drug is used in Opioid agonist therapy?
Buprenorphine
What are Biased Agonists?
Agonists that bind to the receptor and stimulate unique intracellular signalling pathways
What are Beta-arrestins?
A family of intracellular proteins important for regulating signal transduction at GPCRs
What is binding of Beta-arrestin intracellularly thought to do?
Shut off the intracellular signalling pathway. It blocks further G-protein signaling, redirects signaling to alternative pathways (beyond Gi, Gs, and Gq) and targets receptors for internalization
What signals Beta-arrestin to bind to a receptor?
Phosphorylation of a GPCR after the G-protein is cleaved
What signals Beta-arrestin to bind to a receptor?
Phosphorylation of a GPCR after the G-protein is cleaved
How does Beta-arrestin work in chronic opioid use?
IT arrests G-protein signalling which leads to higher tolerance of the drug
How does Beta arrestin contribute to some drug effects?
By activativating its own intracellular signaling
With opioids what does the GPCR elicit?
Analgesia
With opioids what does the beta-arrestin pathway elicit?
Depression and constipation
What signalling pathways can Biased Agonists activate?
Some are better at activating the GPCR pathway and some are better at activating the beta arrestin pathway
What is Functional Selectivity?
When different drugs activate the different signalling pathways depending on how it stimulates the receptor
Why are biased agonists so important?
Because the different signalling pathways they target can drive different aspects of the drug
How would a biased morphine mu agonist be beneficial?
It would only activate the G protein signal which leads to analgesia and not the Beta arrestin pathway that leads to respiratory depression and constipation
What happens when Morphine is taken orally?
IT undergoes extensive first pass metabolism
How is Codeine affected by first pass metabolism?
Codeine effect is not reduced by first pass metabolism so it is more effective orally
Where are the highest concentrations of opioid agonists usually?
In highly perfused tissues such as the brain, lungs, liver, kidneys and spleen
What is Morphine metabolized by and into what?
Phase II glucuronidation into morphine-3-glucuronide and morphine-6-glucuronide
What enzyme metabolizes morphine?
UGT2B7
What kind of metabolite is morphine-6-glucuronide?
An active metabolite
What is Glucuronidation?
The addition of large polar bodies that make them more likely to be excreted
What is codeine metabolized into?
Morphine
What kind of drug is Codeine?
A prodrug
What is codeine metabolized into morphine by?
CYP2D6
What do genetic polymorphisms of CYP2D6 do?
Cause variation in analgesic and adverse responses among patients particularly for codeine
How are poor metabolizers affected?
They need much higher doses of Codeine to feel an effect
How are fast metabolizers affected by codeine?
They have heightened responses to codeine and find it more analgesic and need lower doses
Where are polar metabolites mainly excreted?
In the urine
How are patients with renal impairment affected by active polar metabolites (M6G)?
The effects of the active polar metabolite are amplified because the individual cannot excrete the actual metabolites quickly
What are the three types of endogenous opioid peptides?
- Beta endorphins
- Enkephalins
- Dynorphins
What do the Endogenous peptides mediate?
- Pain
- Reward
- Learning
- Memory
- Cognition
What are endogenous opioid peptides generated from?
Protein precursors that are cleaved by proteases
•Proenkephalin
•Proopiomelanocortin
•Prodynorphin
What do all endogenous opioid peptides share?
The common amino acid sequence Tyr - Gly - Gly - Phe
Which receptor do beta endorphins have the highest affinity for?
Mu but also delta
Which receptor is enkephalin selective for?
Delta>Mu>Kappa
What is the Dynorphin peptide more selective for?
Kappa>mu=delta
