18 Opioids I Flashcards
Define opium
Dried latex obtained from the poppy (original source of opium)
Define Opiates
Any drug derived from opium
What is an opioid
Any drug that binds to an opioid receptor (includes opiates, as well as synthetic opioid agonists (eg fentanyl, heroin, oxycontin))
What type of receptor are opioid receptors?
Opioid receptors are inhibitory G-protein coupled receptors (GPCR)
What does activation of opioid receptors result in:
- Inhibition of calcium channels and activation of potassium channels and inhibition of adenylyl cyclase = hyperpolarization
- neuronal inactivation and reduced transmitter release
What are the four types of opioid receptors?
- mu
- kappa
- delta
- NOP (aka ORL1)
All four types of opioid receptors are _________ but produce very different effects when activated
All four types of opioid receptors are Gi GPCRs but produce very different effects when activated
Why do different opioid receptors produce different effects despite being structurally similar?
Differences are due to receptor distribution (different neurons, different brain circuits)
- Ligand specificity: drugs are selective for different opioid receptors
Mu opioid receptors are found where in the brain?
Limbic system (VTA and striatum)
Some in cortex
Recall: VTA = Ventral tegmental area (reward system)
ORL-1 is widely expressed in the ________.
How does it differ from the other three opioid receptors?
ORL-1 is widely expressed in the CNS.
How does it differ from the other three opioid receptors?
- last to be identified; based on sequence homology NOT functional similarities
- may be involved in fear processing
- Doesn’t share any fxnal similarities to the other opioid receptors
What effects do agonists have on the Mu receptors?
What are three examples of Mu receptors agonists?
- Analgesia
- Reward (leads to abuse liability)
- Antitussive (cough suppression)
- Constipation “narcotic gut”
- Respiratory depression
- eg:
- Morphine
- Codeine
- Heroin
What is the effect of a mu receptor antagonist?
Example?
- aversive effects: unpleasant
- Prevent reward
- block overdose
- eg
- naloxone
What effect does a Delta receptor agonist have?
- Not rewarding
- No analgesia (except in chronic pain, migraine)
- some are seizure-inducing (not commercially available, under investigation)
What response(s) would a Delta antagonist elicit?
No obvious effects
What response(s) would an agonist at the Kappa opioid receptor ilicit?
example?
- Aversive
- Hallucinogenic
- Anxiogenix
- eg:
- salvia
What response(s) would an antagonist at the Kappa receptor illicit?
Potential antidepressant/anxiolytic
(clinical trial)
What are four full mu-opioid receptor agonists?
- morphine
- methadone
- fentanyl
- heroin
Codeine is a _______ at the mu-opioid receptor. What effects does it have?
Codeine is a partial agonist at the mu-opioid receptor. What effects does it have?
- mild to moderate analgesic efficacy, but safer therapeutic index
Buprenorphine is a ______ at the mu-opioid receptor and ______ at the delta and kappa opioid receptor.
What is the clinical significance of buprenorphine?
Buprenorphine is a partial agonist at the mu-opioid receptor and antagonist at the delta and kappa opioid receptor
- used to alleviate withdrawal
- highly effective for addiction (mood + withdrawal)
What are beta arrestins?
Family of intracellular proteins important for regulating signal transduction at GPCRs - Biased agonists
What is the action of Beta-arrestins?
- Following receptor activation and G-protein cleavage, GPCR is phosphorylated, which signals Beta-arrestin to bind
- Beta-arrestin binding blocks further G-protein signaling, redirects signaling to alternative pathways and targets receptors for internalization
How does beta-arrestin lead to tolerance?
Beta arrestin arrests G-protein signaling that leads to tolerance following chronic opioid use
Beta-arrestin can activate its own ________ that contribute to some of the drug effects, such as:
Beta-arrestin can activate its own intracellular signaling that contributes to some of the drug effects, such as:
- respiratory depression
- constipation
Which type(s) of opioid ligands lead to Beta-arrestin recruitment, and which don’t?
- Beta-arrestin recruitment:
- Balanced agonist
- Beta-arrestin biased agonist
- No Beta-arrestin recruitment:
- G-protein biased agonist
Which type of opioid ligand is responsible for the analgesic effects of opioids?
Which type is responsible for the adverse effects of overdose?
- Which type of opioid ligand is responsible for the analgesic effects of opioids?
- G-protein biased agonist
- Which type is responsible for the adverse effects of overdose?
- Beta-arrestin biased agonist
For the mu-opioid receptor, G-protein signaling pathway drives ________ while Beta-arrestin signaling pathway drives _______
For the mu-opioid receptor, G-protein signaling pathway drives analgesia while Beta-arrestin signaling pathway drives respiratory depression
Opioid pharmacokinetics (ADME)
What is the absorption profile of opioids?
- Most mu-agonist opioids are well absorbed when taken orally
- morphine, however, undergoes extensive first pass metabolism
- Codeine effect is not reduced by first pass metabolism so more effective orally
Opioid pharmacokinetics (ADME)
What is the distribution profile of opioids?
- Opioid agonists are widely distributed through body tissues, with highest concentrations in highly perfused tissues such as the brain, lungs, liver, and kidney and spleen
- Depends on route of administration (IV = highest)
- Cross placental barrier and exert effects on fetus which can result in both respiratory depression and physical dependence in neonates
Morphine is metabolized by _______ into morphine-3-glucuronide and morphine-6-glucuronide
Morphine is metabolized by phase II glucuronidation into morphine-3-glucuronide and morphine-6-glucuronide
(add’n of large polar bodies = inactivates and increases likelihood of excretion)
The most important glucuronidation enzyme is _______.
Metabolizes morphine to ________
The most important glucuronidation enzyme is _UGT2B7 (_UDP-Glucuronosyltransferase-2B7)
Metabolizes morphine to M3G (morphine-3-glucuronide)
Morphine-6-glucuronide is an active metabolite. What does this mean?
Can prolong morphine effects
- quickly metabolized
Codeine is metabolized into ______ by CYP2D6
Codeine is metabolized into morphine by CYP2D6 (ie codeine is a prodrug)
Genetic polymorphisms of CYP2D6 linked to variation in ______ and _____ responses among patients, particularly for the drug _________
Genetic polymorphisms of CYP2D6 (fast or slow metabolizers) linked to variation in analgesic and adverse responses among patients, particularly for the drug codeine
How would dose change for Cyp2D6 poor metabolizers?
Lower response = need a higher dose
How are opioids excreted?
- Polar metabolites, including the glucuronide conjugates (M3Gand M6G) of opioid analgesics, are excreted mainly in the urine
- Small amounts of unchanged drug may also be found in the urine
Why would you want to be cautious before administering potent opioids (such as morphine) to patients with renal impairment?
In patients with renal impairment, the effects of active polar metabolites (M6G) should be considered before the administration of potent opioids such as morphine due to the risk of sedation and respiratory depression
What are the three types of endogenous opioid peptides?
- Beta endorphins
- enkephalins
- dynorphins
“endorphins”
endogenous opioid peptides are widely distributed _________ that mediate _____, _____, ______ and _______
endogenous opioid peptides are widely distributed neurotransmitters that mediate pain, reward, learning and memory and cognition
Endogenous opioid peptides are generated from a _______\_
Endogenous opioid peptides are generated from a protein precursor
Each protein precursor for endogenous opioid peptides is subject to ________ that results in synthesis of _________
Each protein precursor for endogenous opioid peptides is subject to post-translational modifications that result in synthesis of multiple active peptides
What is the common amino acid (aa) sequence shared by all opioid peptides?
Tyr-Gly-Gly-Phe
Given the precursor, name the endogenous peptide(s) and rank the affinity for opioid receptors:
Pro-enkephalin
- Proenkephalin
- [Met] enkephalin
- [Leu] enkephalin
- Delta>>>Mu>>>Kappa
Given the precursor, name the endogenous peptide(s) and rank the affinity for opioid receptors:
Pro-opioimelanocortin
-
Pro-opioimelanocortin
-
Beta-endorphin “endorphins”
- mu=delta>>>kappa
-
Beta-endorphin “endorphins”
Given the precursor, name the endogenous peptide(s) and rank the affinity for opioid receptors:
Pro-Dynorphin
- ProDynorphin
- Dynorphin A
- Dynorphin B
- neoendorphin
- Kappa>>>Mu=delta
