18 Opioids I Flashcards by Echo Quinton

Define opium

Dried latex obtained from the poppy (original source of opium)

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Define Opiates

Any drug derived from opium

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What is an opioid

Any drug that binds to an opioid receptor (includes opiates, as well as synthetic opioid agonists (eg fentanyl, heroin, oxycontin))

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What type of receptor are opioid receptors?

Opioid receptors are inhibitory G-protein coupled receptors (GPCR)

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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

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What are the four types of opioid receptors?

mu
kappa
delta
NOP (aka ORL1)

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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

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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

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Mu opioid receptors are found where in the brain?

Limbic system (VTA and striatum)

Some in cortex

Recall: VTA = Ventral tegmental area (reward system)

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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

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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

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What is the effect of a mu receptor antagonist?

Example?

aversive effects: unpleasant
Prevent reward
block overdose
eg
- naloxone

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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)

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What response(s) would a Delta antagonist elicit?

No obvious effects

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What response(s) would an agonist at the Kappa opioid receptor ilicit?

example?

Aversive
Hallucinogenic
Anxiogenix
eg:
- salvia

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What response(s) would an antagonist at the Kappa receptor illicit?

Potential antidepressant/anxiolytic

(clinical trial)

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What are four full mu-opioid receptor agonists?

morphine
methadone
fentanyl
heroin

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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?

1. Beta endorphins 2. enkephalins 3. 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: ## Footnote **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: ## Footnote **Pro-opioimelanocortin**

* **Pro-opioimelanocortin** * ****Beta-endorphin "endorphins" * mu=delta\>\>\>kappa

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