Lecture 18: Opioids

Question 1

What is Opium?

Answer 1

Dried latex obtained from the poppy

Question 2

What are Opiates?

Answer 2

Any drug derived from opium

Question 3

What is an Opioid?

Answer 3

Any drug that binds to an opiod receptor

Question 4

What is Narcotic?

Answer 4

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

Question 5

What are Synthetic Opioid Agonists?

Answer 5

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

Question 6

What are examples of Synthetic Opioid Agonists?

Answer 6

Fentanyl, Heroin, Oxycontin

Question 7

What kind of receptors are Opioid receptors?

Answer 7

The are inhibitory G-protein coupled receptors

Question 8

What does activation of Opioid receptors do?

Answer 8

They inhibit calcium channels, activate K+ channels and inhibit adenylyl cyclase

Question 9

What are the four types of opioid receptors?

Answer 9

Mu, Kappa, Delta, ORL1

Question 10

Why do the different opioid receptors produce such diverse effects in the brain?

Answer 10

They are found in different parts of the brain.

Different drugs are selective to different receptors

Question 11

Where is the ORL-1 receptor widely expressed?

Answer 11

In the the CNS

Question 12

What is the most widely expressed opioid receptor in the brain?

Answer 12

The ORL-1 receptor

Question 13

What are the extracellular loops of opioid receptors important for?

Answer 13

Controlling which ligands bind

Question 14

What are the intracellular loops of opioid receptors important for?

Answer 14

The control which type of G proteins bind

Question 15

What does activation of the mu opioid receptor cause?

Answer 15

• Analgesia
• Reward/euphoria
• Respiratory depression
• Antitussive
• Constipation

Question 16

Why do Mu opioid agonists cause constipation?

Answer 16

Because they inhibit gut motility

Question 17

What is Narcotic gut?

Answer 17

When people on narcotics long term to manage pain have constipation because mu agonist inhibit gut motility

Question 18

What drugs are Mu opioid agonists?

Answer 18

• Morphine
• Codeine
• Heroin

Question 19

What are Mu receptor antagonists used for?

Answer 19

Opioid addiction or to prevent overdose

Question 20

What is an example of a Mu antagonist?

Answer 20

Naloxone

Question 21

What effects do Mu antagonists have?

Answer 21

• Aversive
• Prevent reward
• Block overdose

Question 22

What is an example of a Mu antagonist?

Answer 22

Naloxone

Question 23

What are the effects of agonists at the Delta receptors?

Answer 23

• Not rewarding
• No analgesia (except in chronic pain)
• Seizure inducing

Question 24

What are the effects of antagonists at the Delta receptors?

Answer 24

There are no obvious effects

Question 25

What are the effects of agonists at the Kappa receptors?

Answer 25

* Aversive * Hallucinogenic * Anxiogenic (anxiety)

Question 26

What is an example of a Kappa receptor agonist?

Answer 26

Salvia

Question 27

What are the effects of antagonists at the Kappa receptors?

Answer 27

Potential antidepressant/anxiolytic (reduce anxiety)

Question 28

What are the full mu opioid receptor agonists?

Answer 28

Morphine Methadone Fentanyl Heroin

Question 29

What is the partial mu opioid receptor agonists?

Answer 29

Buprenorphine

Question 30

What are the consequences of Buprenorphine being only a partial agonist at the mu opioid receptor?

Answer 30

It has less analgesic effect and less respiratory depression

Question 31

Which one is more potent: Fentanyl or Morphine?

Answer 31

Fentanyl

Question 32

Is there a strong connection between efficacy and potency with opiates?

Answer 32

No you can have a partial agonist that is very potent and you can have a full agonist that is weekly potent

Question 33

What is an example of an opioid ligand that is not specific to one receptor?

Answer 33

Buprenorphine

Question 34

What receptors can Buprenorphine target and what does it do at the receptor?

Answer 34

* Partial agonist at the mu opioid receptor | * Antagonist at the delta and kappa opioid receptor

Question 35

What is Buprenorphine important in managing?

Answer 35

Pain and opioid addiction

Question 36

What drug is used in Opioid agonist therapy?

Answer 36

Buprenorphine

Question 37

What are Biased Agonists?

Answer 37

Agonists that bind to the receptor and stimulate unique intracellular signalling pathways

Question 38

What are Beta-arrestins?

Answer 38

A family of intracellular proteins important for regulating signal transduction at GPCRs

Question 39

What is binding of Beta-arrestin intracellularly thought to do?

Answer 39

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

Question 40

What signals Beta-arrestin to bind to a receptor?

Answer 40

Phosphorylation of a GPCR after the G-protein is cleaved

Question 40

What signals Beta-arrestin to bind to a receptor?

Answer 40

Phosphorylation of a GPCR after the G-protein is cleaved

Question 41

How does Beta-arrestin work in chronic opioid use?

Answer 41

IT arrests G-protein signalling which leads to higher tolerance of the drug

Question 42

How does Beta arrestin contribute to some drug effects?

Answer 42

By activativating its own intracellular signaling

Question 43

With opioids what does the GPCR elicit?

Answer 43

Analgesia

Question 44

With opioids what does the beta-arrestin pathway elicit?

Answer 44

Depression and constipation

Question 45

What signalling pathways can Biased Agonists activate?

Answer 45

Some are better at activating the GPCR pathway and some are better at activating the beta arrestin pathway

Question 46

What is Functional Selectivity?

Answer 46

When different drugs activate the different signalling pathways depending on how it stimulates the receptor

Question 47

Why are biased agonists so important?

Answer 47

Because the different signalling pathways they target can drive different aspects of the drug

Question 48

How would a biased morphine mu agonist be beneficial?

Answer 48

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

Question 49

What happens when Morphine is taken orally?

Answer 49

IT undergoes extensive first pass metabolism

Question 50

How is Codeine affected by first pass metabolism?

Answer 50

Codeine effect is not reduced by first pass metabolism so it is more effective orally

Question 51

Where are the highest concentrations of opioid agonists usually?

Answer 51

In highly perfused tissues such as the brain, lungs, liver, kidneys and spleen

Question 52

What is Morphine metabolized by and into what?

Answer 52

Phase II glucuronidation into morphine-3-glucuronide and morphine-6-glucuronide

Question 53

What enzyme metabolizes morphine?

Answer 53

UGT2B7

Question 54

What kind of metabolite is morphine-6-glucuronide?

Answer 54

An active metabolite

Question 55

What is Glucuronidation?

Answer 55

The addition of large polar bodies that make them more likely to be excreted

Question 56

What is codeine metabolized into?

Answer 56

Morphine

Question 57

What kind of drug is Codeine?

Answer 57

A prodrug

Question 58

What is codeine metabolized into morphine by?

Answer 58

CYP2D6

Question 59

What do genetic polymorphisms of CYP2D6 do?

Answer 59

Cause variation in analgesic and adverse responses among patients particularly for codeine

Question 60

How are poor metabolizers affected?

Answer 60

They need much higher doses of Codeine to feel an effect

Question 61

How are fast metabolizers affected by codeine?

Answer 61

They have heightened responses to codeine and find it more analgesic and need lower doses

Question 62

Where are polar metabolites mainly excreted?

Answer 62

In the urine

Question 63

How are patients with renal impairment affected by active polar metabolites (M6G)?

Answer 63

The effects of the active polar metabolite are amplified because the individual cannot excrete the actual metabolites quickly

Question 64

What are the three types of endogenous opioid peptides?

Answer 64

* Beta endorphins * Enkephalins * Dynorphins

Question 65

What do the Endogenous peptides mediate?

Answer 65

* Pain * Reward * Learning * Memory * Cognition

Question 66

What are endogenous opioid peptides generated from?

Answer 66

Protein precursors that are cleaved by proteases •Proenkephalin •Proopiomelanocortin •Prodynorphin

Question 67

What do all endogenous opioid peptides share?

Answer 67

The common amino acid sequence Tyr - Gly - Gly - Phe

Question 68

Which receptor do beta endorphins have the highest affinity for?

Answer 68

Mu but also delta

Question 69

Which receptor is enkephalin selective for?

Answer 69

Delta>Mu>Kappa

Question 70

What is the Dynorphin peptide more selective for?

Answer 70

Kappa>mu=delta