NSAIDS

Question 1

What are the three main actions of NSAIDS

Answer 1

anti-inflammatory
analgesic
anti-pyretic

Question 2

What is the action of NSAIDS molecularly

Answer 2

Inhibit the prostaglandin biosynthesis by direct action on the cyclo-oxygenase enzymes

Question 3

what are the two mechanisms by which NSAIDS inhibit cyclo-oxygenase

Answer 3

1) irreversible, time dependent inhibition of the enzyme

2) a rapid, reversible competitive inhibition of the enzyme

Question 4

action of aspirin

Answer 4

this acts by the first pathway and causes an irreversible action but then acts by the second pathway. It causes acetylation of the enzyme site where arachidonic acid normally binds therefore it is not ALLOSTERIC

Question 5

Action of ibuprofen

Answer 5

this ends by the second pathway, reversibly by competitive inhibition of the enzyme (competes with arachidonic acid which is the natural substrate)

Question 6

what are prostaglandins

Answer 6

they are a family of compounds generated in tissues from the precursor arachidonic acid by cyclo-oxygenase enzymes

Question 7

What are the two main cyclo-oxygenase enzymes

Answer 7

COX-1:

• constitutive
• important in maintain the GIT integrity

COX-2:
- inducible
involved in inflammatory response
- implicated in cancer development

Question 8

what are some of the main roles of prostaglandins

Answer 8

stops platelet aggregation 
vasoconstriction
vasodilation 
hyperalgesic 
bronchioconstricter

Question 9

what are the roles of PGE2, PGI2 and PGD2

Answer 9

these act as potent vasodilators
syngerise with other inflammatory mediators such as bradykinin and histamine
– Potentiate histamine and bradykinin actions on postcapillary venule permeability and pain sensory nerves

Question 10

Anti-pyretic effect

Answer 10

– Fever occurs when the hypothalamic thermostat “set point”
is raised
– Bacterial endotoxins cause release of factors (e.g.
interleukin 1) from macrophages
– Interleukin 1 causes generation of prostaglandins in the
hypothalamus (PGEs)
– Prostaglandins ↑ the thermostat “set point”
THEREFORE
NSAIDs act by preventing the formation of prostaglandins and prevent the rise in temperature

Question 11

Analgesic Effect

Answer 11

Inflamed regions painful due to histamine and bradykinin release
– activate nocioceptive afferent nerve terminals – register a painful stimulus
Prostaglandins sensitise nocioceptive nerves to these compounds

Question 12

Salicylates (aspirin family)

Answer 12

– pro-drug (acetylsalicylic acid)
• can directly acetylate COX enzyme
– also metabolised to active compound (salicylic acid) by plasma and tissue esterases
– salicylates found in plasma within 30 mins
– peak plasma concentrations within 1-2 hr

Question 13

Unwanted effects of salicylates

Answer 13

Stomach
– bleeding, ulcers Systemic
– tinnitus, dizziness, impaired hearing, nausea, vomiting, hypersensitivity Metabolic changes
– acid/basebalanceaffected
Haemostasis
– blood coagulation affected through and action on platelets CNS effects
– stimulation initially, ultimately coma and respiratory depression
Renal
– insufficiency insusceptible patients and with chronic use and overdose

Question 14

Propionic acids

Answer 14

– e.g. ibuprofen, naproxen
– not prodrugs
– well absorbed
– last for 4-6 hours.

Question 15

Fenamates

Answer 15

– e.g. mefenamic acid

Question 16

Paracetamol

Answer 16

Fewer side effects than other NSAIDs (perhaps due to its selectivity for COX enzymes)

Major issue is hepatotoxicity due to overdose
– Normally inactivated in the liver by glucoronate
and sulphate conjugation
– When these enzymes saturated, toxic metabolites are formed
– Result can be hepatic necrosis

Question 17

Selective COX-2 inhibitors

Answer 17

Coxibs
– e.g. celecoxib
– used for osteoarthritis and rheumatoid arthritis
– restricted for when traditional NSAIDs produce too severe GIT side effects
– cardiovascular risk needs to be assessed

Question 18

Anti-inflammatory actions

Answer 18

– Both chronic or acute inflammatory conditions
– Dosage for chronic inflammatory disorders is high
–  low incidence of side effects is important • e.g.ibuprofen
– Coxibs sometimes used for osteoarthritis and rheumatoid arthritis
Anti-pyretic
– To lower temperature
– Paracetamol preferred because it lacks GIT side effects