Opioids

Question 1

Summarise the pharmacokinetics of opioids

Answer 1

• Oral (20% bioavailability) - ionised in blood, heavily metabolised in liver
• i.v. (100%)
• Weak bases (pKa>8) - not ionised in stomach, ionised in SI
• More lipid soluble = more potent in general

Active metabolites:

• Heroin/codeine –> morphine –> morphine 3-G glucuronide/morphine 6-G glucuronide
• Less likely to cause dangerous -ve side effects

Question 2

What are the pharmacological actions of opiates/opioids?

Answer 2

• Analgesia
• Euphoria
• Antitussive (depression of cough centre)
• Respiratory depression (depression of medulla)
• N+V (stimulate CTZ)
• Reduced GI tract motility
• Pupil constriction
• Histamine release

Question 3

What are the different types of opioid receptors and their endogenous ligands?

Answer 3

Endorphins - mu, delta

Enkephalins - delta

Dynorphins - kappa

Question 4

What are the main pathways concerned with pain transmission/perception

Answer 4

• Sensory neurone from periphery to dorsal horn
• Spinothalamic neurones from dorsal horn to nucleus reticularis paragigantocellularis (NRPG) and thalamus (+)
• Neurone from NRPG to nucleus raphe magnus (NRM) (+)
• Neurone from thalamus to periaqueductal grey matter (PAG) (+)
• Neurones from cortex and hypothalamus to PAG (+/-)
• Neurone from PAG to NRM (+)
• Descending motor neurones from NRM to dorsal horn (-) - 5-HT, enkephalin
• Neruone from locus ceruleus (LC) to dorsal horn (-) - NA

Question 5

How do opioids impact the pain pathways?

Answer 5

• Stimulatory to PAG and NRPG (switch off inhibitory GABA)
• Inhibitory to dorsal horn
• Ca

Question 6

How do opioids activate the reward pathway in the brain?

Answer 6

• Switch off inhibitory GABAergic neurones to ventral tegmental area
• Increase dopamine release from nucleus accumbens

Question 7

How can opiates/opioids produce tolerance?

Answer 7

Overstimulation of opioid receptors leads to receptor internalisation via arrestin

Question 8

How can opiates/opioids produce dependence?

Answer 8

• Overactive cell activity
• Increases adenylate cyclase
• Converts ATP to increase cAMP
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Question 9

What are opiates?

Answer 9

Alkaloids derived from opium which is derived from poppy seeds (Papaver somniferum)

Question 10

What are opioids?

Answer 10

Compounds that act like morphine but which do not resemble morphine chemically, e.g. endogenous opioid peptides

Question 11

How do exogenous opioids produce their biological actions?

Answer 11

By acting on opioid receptors and mimicking the actions of endogenous opioid peptides (endorphins, enkephalins and dynorphins)

Question 12

What is the cellular mechanism of action of opioids?

Answer 12

• Depressant effect
• Hyperpolarisation (K+ efflux)
• ↓ Ca2+ inward current ↓ NT release
• ↓ adenylate cyclase activity

Question 13

Where are opioid receptors found?

Answer 13

Located mainly in the CNS but also found in the periphery

Question 14

Why are there good and poor metabolisers of codeine?

Answer 14

• Common polymorphisms in CYP2DG (O-dealkylation - activates codeine)
• CYP3A4 deactivates

Question 15

How does the clearance of fentanyl and methadone differ?

Answer 15

Methadone = 0.5 ml/kg/min - lots of enzymes tf builds up in blood + fat

Fentanyl = 15

• 1 enzyme
• Fast effect, quickly lost

Question 16

Why are fentanyl and methadone more potent than codeine and morphine?

Answer 16

More lipid soluble

Question 17

Compare codeine and morphine

Answer 17

Codeine:

• Methyl-morphine
• More lipid soluble - should cross BBB more easily
• Must be converted to -OH - e.g. prodrug

Morphine:

• Tertiary nitrogen = analgesia - permits R anchoring
• Hydroxyl groups - needed for activity

Question 18

What happens if you oxidise the hydroxyl groups at position 6 on morphine?

Answer 18

Increases lipophylicity

Question 19

What is opioid withdrawal associated with?

Answer 19

Psychological craving
Physical withdrawal
Like flu

Question 20

How can opioids cause analgesia?

Answer 20

• Decrease pain perception

- Increase pain tolerance

Question 21

How do opioids cause pupil constriction (miosis)?

Answer 21

• GABA disinhibition of occulomotor nerve fibres from Edinger-Westphal nucleus to ciliary ganglion
• Mui opioid receptor

Question 22

How do opioids cause nausea and vomiting?

Answer 22

• GABA disinhibition of nerve fibres to chemoreceptor trigger zone (mui opioid receptors)
• CTZ communicates w/medullary vomiting centre
• VC –> vomiting reflex

Question 23

How do opioids act as anti-tussives?

Answer 23

1. Reduce info relay to brain
2. Depress cough centre
3. Inhibit feedback of 5-HTRs

Question 24

How do opioids cause respiratory depression?

Answer 24

1. Inhibit central chemoreceptors that sense PaCO2

2. Decrease rhythm generation in Pre-Botzinger complex