Pharmacology - Analgesia

Question 1

What is the mechanism of action of morphine

Answer 1

-mechanism of action: full agonist mostly active at the mu receptor, but also active at kappa and delta (g protein)
reduces pre-synaptic neurotransmission (especially glutamate), inhibits postsynaptic neurons

-effect at different opioid receptors:
mu receptor (μ) = analgesia, sedation, euphoria, miosis, respiratory depression, constipation
kappa receptor (Ƙ) = analgesia, sedation, dysphoria, miosis, diuresis, constipation
delta receptor (𝛅) = analgesia

Question 2

What are the pharmacokinetics and adverse effects of morphine

Answer 2

-pharmacokinetics: high first pass metabolism, conjugated to M3G in liver (has neuroexcitatory properties)
small amount is metabolised to M6G (increased analgesic potency), renal excretion

-adverse effect: sedation, respiratory depression, nausea/vomiting, histamine release, dysphoria, seizure
nervous system: analgesia, euphoria, sedation, respiratory depression, cough suppression, miosis, nausea
peripheral: constipation, biliary smc contraction, bradycardia, stimulate release of ADH/prolactin/somatotrophin

Question 3

Why do opiates cause respiratory depression

Answer 3

due to inhibition of brainstem respiratory controls, allowing less response to hypercapnea

Question 4

What is the mechanism of action, pk and side effects of fentanyl

Answer 4

-moa: agonist at the mu receptor

-pharmacokinetics: highly lipid soluble, high first pass metabolism, duration of action 1-1.5 hours, t1/2 5 minutes
hepatic metabolism, no active metabolites, can be given iv, im, in, sc, sl, buccal, td, epidural
good in renal failure

-adverse effects: respiratory depression, nausea, vomiting, dysphoria, cough, sedation, itch, laryngeal rigidity

Question 5

• compare potency to morphine:fentanyl

- draw dose response curve comparing fentanyl and morphine

Answer 5

100 x more potent than morphine

Question 6

Compare morphine and fentanyl - receptors

Answer 6

-receptors:
morphine = mu agonist but also works on kappa and delta receptors
fentanyl = only agonist on mu receptors, more potent than morphine (100x)

Question 7

Compare morphine and fentanyl - absorption

Answer 7

morphine = well absorbed, high first pass metabolism, onset 30-60 minutes, doa 3-4 hours
fentanyl = absorbed orally, high first pass metabolism, onset 2-5 minutes, doa 1-1.5 hours

Question 8

Compare morphine and fentanyl - metabolism

Answer 8

morphine = conjugated to M3G in liver (neuroexcitatory property) and small amount of M6G (analgesic)
fentanyl = metabolised by P450CY3A4, no active metabolites

Question 9

Compare morphine and fentanyl - elimination

Answer 9

morphine = mainly in the urine, t1/2 1.7-4.5 hours, need to adjust does in renal failure
fentanyl = small amount of renal excretion, t1/2 2 hours

Question 10

How does methadone differ from morphine and fentanyl

Answer 10

• methadone also blocks nmda receptors and monoamine reuptake
• methadone also has a high oral:parenteral potency ratio (morphine and fentanyl have low)
• t1/2 of methadone is longer than morphine and fentanyl

Question 11

Describe the mechanism of action and pharmacokinetics of oxycodone

Answer 11

-moa: mu, kappa and delta agonist
-pharmacokinetics: good oral absorption, high vod, low first pass metabolism, doa 3-4 hours
metabolised by P450CYP2D6 to oxymorphone (active metabolite)
excreted in kidneys
-adverse effect: sedation, respiratory depression, nausea, vomiting, hypotension, dysphoria, biliary colic, renal
-strategy to reduce dependence: establish goals, combine with non-opioid analgesics, small dose at long intervals

Question 12

Name some drugs used to treat opiate addiction

Answer 12

-buprenorphine: partial mu agonist and partial delta and kappa antagonist
long duration of action due to slow dissociation from mu receptors
resistant to naloxone reversal
high dose results in mu antagonism
-naltrexone: long acting pure antagonist for mu receptor
-methadone: long acting mu receptor agonist and blocks nmda reuptake
tolerance and dependance develop more slowly than with morphine

Question 13

What are the advantages of using buprenorphine in treating heroin addiction over methadone

Answer 13

• buprenorphine has a lower risk over overdose fatalities because high dose has antagonism effect
• buprenorphine also has a long duration of action due to slow dissociation from mu receptors