Case 1 - Inflammation, NSAIDS and Analgesics

Question 1

NSAIDs stand for

Answer 1

non-steroidal anti-inflammatory drugs

Question 2

PLA2 (phospholipase A2) generate what FA precursor (that is very widely used)?

Answer 2

Arachidonic acid

[In response to demand, fatty acids (FA) can be cleaved from PLA2, which is a membrane phospholipid]

Question 3

PGHS (prostaglandin H synthase) converts AA (arachidonic acid) + O2 into what?

Answer 3

2 initial endoperoxides (PGG2 & PGH2) which can then be modified into cell-specific prostaglandins

Question 4

PGHS (prostaglandin H synthase) consist of how many isoforms?

Answer 4

3 different isoforms: PGHS-1, PGHS-2, PGHS-3

[their expressions and activity in specific tissues determines the local effects observed.]

Question 5

what do all the isoforms of PGHS produce

Answer 5

all produce prostaglandin-H2 that can get converted to many other prostaglandins

Question 6

PG-H2 can get converted into PG-E2, which is used for?

Answer 6

PGE2 - GI mucosa & renal protection, causes uterine contraction, pain sensitizer, inflammatory mediator (causing: local vasodilation, histamine & bradykinin release, eosinophil & basophil chemotaxis)

Question 7

PG-H2 can get converted thromboxane synthase (TXA2), which is used for?

Answer 7

TXA2 - causes platelet aggregation and local vasoconstriction

Question 8

PG-H2 can get converted PGI2 synthase, which is used for?

Answer 8

PGI2 - inhibits platelet aggregation, causes local vasodilation

Question 9

prostaglandin receptors are all ________ coupled?

Answer 9

G-protein coupled

Question 10

what about prostaglandin receptors on cell/tissues?

Answer 10

the cell/tissue effect observed is a function of the type of G-protein that’s activated when the PG (prostaglandin) activates the receptor

the specific intracellular cascade then determines the (often opposing) effects observed in tissues

Question 11

NSAID mechanism

Answer 11

NSAIDs have the same “class” action - they inhibit COX (cyclo-oxygenase) domain activity in PGHS, preventing generation of the precursor endoperoxides PGG2 and PGH2

NO PG-H2 produced for subsequent conversion

NSAIDs differ individually in how they inhibit PGHS and their specificity for different PGHS isoforms

Question 12

anti-inflammatory effect of NSAIDs

Answer 12

NSAID inhibition of PGHS-2 derived prostaglandins (e.g PGE2) reduces the extent and duration of local inflammation caused by vasodilation and increased vascular permeability

[NSAIDs are not as potent/good at reducing inflammation than steroids]

Question 13

NSAIDs in pain and fever reduction

Answer 13

PGE2 normally sensitises A delta and C nociceptive neurones to serotonin, bradykinin and “substance P”. NSAIDs inhibit this process of sensitization

NSAIDs can also inhibit hypothalamic PGHS-2/3 (which normally generates PGE2 in response to circulating pyrogenes)

Question 14

ibuprofen

Answer 14

ibuprofen is produced as a racemate. the S-enantiomer is the active NSAID

Question 15

ibuprofen mechanism of action

Answer 15

ibuprofen competes with arachidonic acid for the COX (cyclo-oxygenase) domain active site of PGHS1 and PGHS2.

ibuprofen is a reversible, competitive inhibitor

Question 16

origin of ibuprofen

Answer 16

derived from propanoic acid and synthesised by chemists

Question 17

aspirin

Answer 17

acetyl salicylic acid is the only irreversible inhibitor of PGHS

Question 18

aspirin mechanism of action

Answer 18

acteylation of a serine residue in the COX domain active site

Question 19

aspirin origin

Answer 19

willow tree bark (containing salicin). Drugs company Bayer formulated a more gastrically tolerable derivative

Question 20

Paracetamol

Answer 20

Paracetamol may be chosen before NSAIDs as it can have better analgesic and anti-pyretic (reducing fever) effects. But it has very little anti-inflammatory activity

Question 21

Paracetamol MOA

Answer 21

Paracetamol’s MOA is under debate:

it MAY inhibit peroxidase domain activity in PGHS-2 or PGHS-3 in the CNS

OR

its metabolites may be having effects in the CNS

Question 22

2 significant NSAID adverse drug reactions you must be aware of:

Answer 22

potential for gastric ulceration (and gastric bleeding)
compromised renal function

Question 23

NSAIDs are contra-indicated if: [list of 4]

Answer 23

pregnant.
sensitized to salicylates/NSAID allergic.
already on and NSAID.
younger than 16 - as use of NSAID is associated with development of Reye’s syndrome.

Question 24

the WHO guidelines for pain management are like a ladder that indicates the intensity of pain: [going up the ladder - start from bottom to the top]

Answer 24

mild pain - paracetamol and NSAIDs
Co-codamol
moderate to strong pain
weaker opioids
strong pain - stronger opioids
severe/agony - diamorphine, fentanyl +/- sedation

Question 25

case A - for mild to moderate joint pain - what should you give?

Answer 25

probably paracetamol first, or ibuprofen (also acts as an anti-inflammatory - however note that NSAIDs technically slow wound healing process) for stronger pain, consider co-codamol if swelling is NOT resolving overtime, consider steroids (however note that steroids technically slow wound healing process)

Question 26

steroids and NSAIDs in wound healing process

Answer 26

steroids and NSAIDs will technically slow wound-healing process

Question 27

name 3 medications available over the counter (OTC) and through prescribing them

Answer 27

paracetamol (can be prescribed if given IV or if patient can't afford OTC) ibuprofen aspirin

Question 28

the type of analgesic you (Dr) prescribe should be based on what?

Answer 28

based on evidence for its efficacy in managing the type and intensity of pain the patient is experiencing

Question 29

PGHS enzymes generates prostaglandins by?

Answer 29

by using arachidonic acid and oxygen as substrates

Question 30

NSAIDs inhibit PGHS enzymes typically by blocking?

Answer 30

cyclo-oxygenase domain activity