Opioids

Question 1

What is the important structural group in Opiates, and what function does it provide?

Answer 1

Tertiary nitrogen

Permits Receptor anchoring which allows it to have an analgesic effect

Question 2

How does extending the side chain of Morphine to 3+ carbons change its effects?

Answer 2

Generates an antagonist

Question 3

Why is Codine considered a Prodrug?

Answer 3

Opiates require a Hydroxyl group at 3’ to allow them to bind.

Codine does not have this and needs to be converted to morphine before it has any effects

Question 4

Why is Heroin much stronger than Morphine?

Answer 4

Substituting the -OH groups at 3’ and 6’ with Acetyl groups made it much more lipid soluble allowing it to enter and have a more profound effect on the brain

Question 5

What is the pH of Opioids?

How does this affect their absorption?

Answer 5

Weak Bases

Ionised in the stomach - poor absorption

Unionised in the small intestine - more readily absorbed

Question 6

Compare the lipid solubilities of different opioids:

How does this relate to their potency?

Answer 6

Methadone/Fentanyl > Heroin > Morphine

More to less lipid-soluble

More lipid soluble = more potent

Question 7

How is the metabolism of Morphine different from other Opioids?

Answer 7

It is metabolised to other active metabolites - Morphine-6 Glucuronide (10% of metabolites)

This is secreted into bile and then undergoes enterohepatic cycling having more of an effect

Question 8

Where are most Opioids metabolised by?

Answer 8

CYPs

Morphine by Uridine-5-diphosphate glucuronosyltransferase

Question 9

Why do some patients not respond well to Codine?

Answer 9

It is metabolised by CYP2D6

Question 10

What is Methadone used for?

Question 11

Why does the metabolism of Codeine make it not very potent?

Answer 11

CYP2D6 - performs O-dealkylation and ACTIVATES codeine (this is quite SLOW)
CYP3A4 - DEACTIVATES codeine (works quite FAST)

Vast majority is deavtivated

Question 12

What are the main endogenous Opioid agonists?

Answer 12

Endorphins

Enkephalins

Dynorphins/Neoendorphins

Question 13

What are the three main Opiate receptors?

Which endogenous opioids agonise them?

Answer 13

Mu & Delta - Endorphins

Delta - Enkephalins

Kappa - Dynorphins

Question 14

What are the four main areas of the brain where Mu opioid receptors are expressed in abundance?

Answer 14

Thalamus

Amygdala

Nucleus Accumbens

Periaqueductal grey matter

Question 15

How do Opioid receptors work?

Answer 15

Depressants - slow down cellular activity

Three main mechanisms:

Hyperpolarisation (increased potassium efflux)

Reduce Ca2+ influx (Reduces neurotransmitter exocytosis)

Reduced Adenylate cyclase activity (general reduction in cellular activity)

Question 16

What are the three main effects of Opioids?

Answer 16

Analgesia

Euphoria

Anti-tussive (Depression of cough centre)

Question 17

What are four side effects of Opioids?

Answer 17

Depression of respiration (medulla) - Most dangerous side-effect

Stimulation of Chemoreceptor trigger zone (nausea/vomiting)

Pupillary constriction

GI effects

Question 18

What are the two main methods of analgesia?

Answer 18

Decrease pain perception

Increase pain tolerance

Question 19

Describe how pain is sensed - what pathway does it take?

Answer 19

Stimulus @ sensory neurones in the periphery

Conducted via dorsal horn to spinothalamic tract

Thalamus receives the painful information and distributes it to different sites

It activates the PAG (Periaqueductal grey matter) which is the central pain coordinating region of the brain

Question 20

How is Pain tolerance increased?

Answer 20

Signals from the thalamus and cortices converge on the PAG - causes it to active the nucleus raphe magnus (NRM)

This projects down the spinal cord sends inhibitory neurones to the dorsal horn which dampen further pain perception