Opioids

Question 1

how can we modulate pain peripherally and centrally?

Answer 1

p = substantia gelatinosa
c = periaqueductal grey

Question 2

morphine - pharmacodynamics, metabolism, elimination, mechanism, side effects

Answer 2

strong agonist, gut absorption is erratic, 40% oral bioavailability, rapidly enters all tissues

morphine + glucuronic acid = M6G (analgesic) + M3G (neural euphoric effect)

eliminated renal, accumulation can be toxic

strong affinity for m receptors causing complete activation

resp depression, emesis, GI, CVS, miosis, histamine release

Question 3

fenantyl - pharmacodynamics, metabolism, elimination, compared to morphine, uses, side effects

Answer 3

strong agonist, absorbed into CSF space, 80-100% bioavailability, highly lipophilic and protein bound

metabolised through hepatic CYP3A4

elimination - renally excreted, short half life

compared to morphine it has 100x potency and increased affinity for m receptor

analgesia and anaesthetic (pre-op)

resp depression, constipation, vomiting

Question 4

codeine - metabolism, elimination, compared to morphine, uses, side effects

Answer 4

codeine to morphine via CYP2D6

elimination - glucoronidation of morphine and renal excretion

compared to morphine, 1/10th of potency

mild-mod analgesia and cough depressant

constipation and resp depression

Question 5

buprenorphine - pharmacodynamics, metabolism, elimination, compared to morphine, uses, side effects

Answer 5

mixed agonist-antagonist, very lipophilic

metabolised via CYP3A4, then glucoronidation before biliary excretion - safe in renal impairment

compared to morphine - v high affinity for m receptor, low Kd, long duration of action, not easy displaced
has a lower Emax as it is a partial agonist, lower efficacy, antagonist at k receptors

used in mod - severe pain, opioid addiction

resp depression, lower bp, nausea, dizziness

Question 6

naloxone - pharmacodynamics, metabolism, elimination, compared to morphine, uses, side effects

Answer 6

antagonist, v low oral bioavailability, rapid onset and very lipophilic so large distribution

hepatic metabolism to naloxone-3-glucoronide, renally excreted

compared to morhpine, greater affinity but less than buprenorphine, m>d>k

used in overdose

wears off quickly due to short half life, slow infusion needed allowing morphine/heroine to be excreted

Question 7

What happens in the process of opioid tolerance?

Answer 7

1) opioid binds to m-G protein causing decreased cAMP and pain
2) on repeated intake you get intracellular phosphorylation, the sensitivity is reduced and arrestin binds to the m receptor causing G proteins to uncouple
3) therefore there is no downstream process when opioid binds to m receptor as it is no longer coupled
4) in terms of cAMP production, when you remove opioid after repeated use, you get increased cAMP causing increased neuronal excitability and withdrawal symptoms

Question 8

what are some common side effects contraindications to opioid prescribing?

Answer 8

dependence, vomiting, constipation, hypotension, bradycardia, decreased sex drive, histamine release, miosis, drowsiness, resp depression

hepatic failure, head injuries, acute respiratory distress, raised ICP, comatose