Opioids

Question 1

Name 6 pure agonist of opioid receptor

Answer 1

1. codeine
2. methadone
3. etorphine
4. morphine
5. fentanyl
6. pethidine
   -> all high affinity for mu receptors
   -> varying affinity for delta and kappa receptors

Question 2

Name 3 partial agonist/ mixed agonist-antagonist

Answer 2

1. buprenorphine - high mu affinity but partial agonist
2. nalorphine - mu antagonist
3. pentazocine - mu antagonist
   -> diminish analgesia by full agonist
   -> k agonist: dysphoria
   -> reduce side effects
   -> can be used to control mild pain as k agonist (latter two)

Question 3

Name 2 opioid antagonist and their effects

Answer 3

1. naloxone
2. naltrexone
   -> block effect of opioids
   -> precipitate severe abstinence syndrome in addicts

Question 4

Overall MOA of opioids

Answer 4

1. reduce presynaptic release
2. hyperpolarization of postsynaptic neurons

Question 5

MOA in spinal cord dorsal horn

Answer 5

1. presynaptic neuron terminal: mu, delta, kappa receptors -> lower Ca2+ influx -> less presynaptic neurotransmitter release
2. postsynaptic neuron: mu receptor -> K+ efflux -> hyperpolarizaton

Question 6

MOA in brainstem

Answer 6

1. GABA inhibitory interneuron/ terminal:
   - bind mu receptor on it -> removes its inhibition on the downstream pain inhibitory neuron -> activation of the pain inhibitory neuron

• the pain inhibitory neuron goes from PAG to nucleus raphe magnus -> release 5-HT and enkephalin at dorsal horn

Question 7

Functional effect of opioids receptor with elaboration

Answer 7

1. euphoria
2. dysphoria
3. sedation and drowsiness
4. respiratory depression
5. cough supression
6. nauseant and emetic effect
7. miosis
8. tolerance, addiction, dependence
9. GI effects: increase resting tone but decrease motility
10. histamine release
11. CV effects: vasodilation & bradycardia

Question 8

State 11 functional effects of opioid receptors

Answer 8

1. euphoria
2. dysphoria
3. sedation and drowsiness
4. respiratory depression
   -> direct effect on brainstem resp centre
   => usual cause of death from morphine
5. cough suppression
   -> direct effect on cough centre in medulla
6. nauseant and emetic
   -> direct stimulation of chemoreceptor trigger zone in area postrema of medulla
7. miosis
   -> pinpoint pupil - characteristic of opioid use
   -> removal of cortical inhibitory action on Cn3 -> increased parasym. tone
8. tolerance, dependance, addiction
9. GI effects: increase m. resting tone but decrease motility -> delay gastric emptying -> constipation
   -> biliary colic (increase intraluminal pressure)
10. histamine release
11. cardiovascular effects:
    - vasodilation
    - impair sym. vascular reflex: veno and arteriolar dilation
    - stimulate vagal center: bradycardia

Question 9

State morphine metabolism and hence contraindicated use in what person

Answer 9

1. glucuronic conjugation in liver (p450) -> urinary excretion
   -> morphine 6 glucuronide - more active analgesia
2. neonates: low level of conjugating enzyme
   -> avoid morphine cogeners in neonates and childbirth

Question 10

State acute and chronic adverse effects

Answer 10

acute:
1. resp depression
2. nausea and vomitting
3. constipation
4. sedation and mental clouding
5. itching

chronic:
1. tolerance
2. dependance

Question 11

Pharmacological effects with minimal tolerance

Answer 11

• miosis
• constipation

Question 12

Mechanism of tolerance

Answer 12

• prolonged agonist stimulation
• endocytosis of receptors (GPCR internalization)
  -> loss of receptors on cell surface
  -> desensitization and dev of tolerance

Question 13

Physical symptoms of abstinence syndrome due to dependence

Answer 13

1. sweating, fever
2. piloerection
3. yawning
4. pupillary dilation
5. nausea/ diarrhoea
6. insomnia

Question 14

Symptoms of acute opioid poisoning and treatment

Answer 14

Symptoms:
1. unconsciousness
2. pupillary constriction
3. resp depression

Treatment:
- intravenous naloxone injection
-> acute withdrawal syndrome in addicts

Question 15

Heroin/ diamorphine

Answer 15

• rapidly convert to morphine and 6 monoacetylmorphine
• strong agonist
• more lipid soluble than morphine -> enter CNS rapidly

Question 16

Etorphine

Answer 16

• very strong agonist (x100 than morphine)
• immobilize wild animals
• injectable naloxone must be avavilable (in case potential human exposure)

Question 17

codeine

Answer 17

• weak agonist for mild pain
• marked antitussive action
• often pair with paracetamol
• metabolize to morphine in liver by 2D6

Question 18

pethidine / meperidine

Answer 18

• strong agonist
• anti muscarinic: confusion
• useful in labour: rapid clearance, not delay labour
• n-demethylation -> norpethidine => hallucinogenic and convulsant
• block neuronal uptake of serotonin

Question 19

fentanyl

Answer 19

• strong agonist
• short duration of action
• transdermal patch: high abuse potential and risk of overdose

Question 20

methadone

Answer 20

• strong agonist
• longer duration of action: extensive plasma protein binding
• clinically used to treat opioid addiction
  -> due to more prolonged & smooth effect but slower onset
  -> less severe physical abstinence syndrome

Question 21

tramadol

Answer 21

• opioid substitute
• weak mu receptor agonist and potency
• inhibitor of 5HT and NA reuptake -> the main mechanism for its analgesia
• weakly antagonised by naloxone

Question 22

buprenorphine

Answer 22

• partial mu receptor agonist
• strong binding to receptor
  -> more resistant to naloxone reversal
  -> displace morphine/ stronger opioids fro receptors
  => withdrawal syndrome in opioid addicts
• very lipid soluble (sublingual and transdermal)

Question 23

pentazocine

Answer 23

• mixed agonist antagonist (mu receptor antagonist)
  -> reduce analgesia if concurrent with morphine
  -> withdrawal syndrome in heroin addict

Question 24

Drug interaction

Answer 24

1. sedative-hypnotics: increase CNS and resp depression
2. antipsychotics tranquilizers: compete for conjugating enzyme -> increased CNS depression
3. monoamine oxidase inhibitor
   -> contraindication to all opioids analgesics
   -> intensity toxicity due to CYP450 inhibition by MAOI

-> serotonin syndrome when pethidine used with MAOI

Question 25

Contraindication in what people

Answer 25

1. pulmonary failure and asthma 2. severe hepatic and renal disease 3. cranial trauma, increased intracranial pressure

Question 26

Name 6 non-opioid drugs for pain relief

Answer 26

1. paracetamol NSAIDs: 2. aspirin 3. ibuprofen 4. indomethacin -> most likely to cause adverse GI effect 5. diclofenac

Question 26

Name 6 non-opioid drugs for pain relief

Answer 26

1. paracetamol NSAIDs: 2. aspirin 3. ibuprofen 4. indomethacin -> most likely to cause adverse GI effect 5. diclofenac