Opiates

Question 1

What are opiates?

Answer 1

They are endogenous substances -> Acts on receptors that are already in the body.

Question 2

Mechanism of opiates?

Answer 2

Opioid-receptors are all inhibitory (target to inhibit GPCR), just stimulate activity by inhibiting inhibitors.

• Increase pain inhibitory pathways
• Decrease transmission of sensory stimulus to brain -> Binds to GPCR to stop nerve firing

Question 3

Actions of opiates?

Answer 3

• Analgesia (pain killing)
• Euphoria (Sense of contentment)
• Impaired cough reflex
• Constipation

Question 4

Side-effects of opiates?

Answer 4

• Respiratory depression
• Nausea and vomiting
• Dependence/withdrawal
• Miosis (pupillary constriction)
• Pruritis (itching)

Question 5

List and describe opioid receptors

Answer 5

kappa-opioid receptor

• produces analgesia
• Side effects: dysphoria (unhappiness), hallucination

Delta-opioid receptor

• Produce analgesia
• Side effect: seizures

Mu-opioid receptor

• Main opioid receptor
• Produce all main opioid actions: strong analgesia, constipation, nausea, respiratory depression, reduced cough reflex
• inhibited by Naloxone

Question 6

Explain pain pathway overview:

Answer 6

1. Injury transmits signal through nociceptor
2. Nociceptor excites spinal cord neuron
3. Spinal neuron transmits signal to thalamus
4. Thalamus transmits signal to cortex
5. Cortex feels how bad it is and where it is
6. Cingulate cortex and insular cortex say how unpleasant the pain is

Question 7

Describe descending analgesic pathway

Answer 7

• Periaqueductal gray (PAG) of brain stem receives signal from nociceptors
• PAG sends signal along neuron to medulla
• Neuron releases glutamate into medulla
• Medulla release inhibitory neurotransmitters into spinal cord to block noxious stimuli from nociceptors

Question 8

Mechanism of analgesic effect of opioids on descending analgesic pathway

Answer 8

• Cell in PAG region produce GABA which inhibit neuron activity to medulla
• mu-opioid receptors are on GABA producing cells
• mu-opioid receptors inhibit release of inhibitory GAB, thus activating descending pathway

Question 9

Inhibition of nociceptors in mechanism of analgesic effect of opioids

Answer 9

• Opioid receptors on nociceptor terminals in spinal cord

- Opioid binding inhibits noxious stimulus of spinal cord

Question 10

Describe mechanism of euphoria/dysphoria of opioids:

Answer 10

mu-opioid receptors produce euphoria (release of dopamine)

• mu-opioid receptors are on GABA producing cells
• Inhibit inhibitory GABA release to dopamine releasing neurons.

kappa-opioid receptors produce dysphoria

• kappa-opioid receptors are on dopamine releasing neurons
• Inhibit release of dopamine directly

Question 11

List opioid drugs available

Answer 11

• Morphine
• Codeine
• Oxycodone
• Fentanyl
• Buprenorphine
• Methadone

Question 12

Clinical uses & relative potency of morphine

Answer 12

• Low oral bioavailability (30%)
• Short half-life
• Can be administered orally, subcutaneously or epidurally

Question 13

Clinical uses and relative potency of codeine

Answer 13

• Higher oral bioavailability
• Less potent than morphine
• Good for constipation but not analgesia
• Just a pro-drug of morphine: highly variable metabolism by body, risky to use

Question 14

Clinical uses and relative potency of oxycodone

Answer 14

• Binds directly to opiate receptors; quite potent
• Good oral bioavailability (80%)
• short half-life but can be extended

Question 15

Clinical uses and relative potency of fentanyl

Answer 15

• Synthetic opioid
• 80x as potent as morphine
• Short half-life
• High affinity to mu-agonist

Question 16

Clinical uses and relative potency of buprenorphine

Answer 16

• Strong analgesic
• Less side-effects as morphine
• Long half-life

Question 17

Clinical uses and relative potency of metadone

Answer 17

• Similar to morphine
• Little euphoria - used in addict recovery
• Very long half-life

Question 18

Describe the metabolism of opioids, indicating any enzymes involved

Answer 18

• Highly metabolized in liver

- Codeine is metabolized into morphine with enzyme CYP2D6 in liver: amount of CYP2D6 varies largely

Question 19

List the actions and side-effects of opiates

Answer 19

Actions of opiates:

• Analgesia (pain killing)
• Euphoria (sense of contentment)
• Impaired cough reflex
• Constipation

Side effects:

• Respiratory depression
• Nausea and vomiting
• Dependence/withdrawal
• Miosis (pupillary constriction)
• Pruritis (itching)

Question 20

Describe opioid antagonist roles of Naloxone

Answer 20

• used to reverse opioid overdose
• short acting
• Low oral bioavailability (very high liver metabolism) - must be injected
• Competitive antagonist

Question 21

Describe opioid antagonist roles of Naltrexone

Answer 21

• Long acting
• High oral bioavailability
• Used to reduce opioid dependency