NSAIDS Flashcards
What are the three main actions of NSAIDS
anti-inflammatory
analgesic
anti-pyretic
What is the action of NSAIDS molecularly
Inhibit the prostaglandin biosynthesis by direct action on the cyclo-oxygenase enzymes
what are the two mechanisms by which NSAIDS inhibit cyclo-oxygenase
1) irreversible, time dependent inhibition of the enzyme
2) a rapid, reversible competitive inhibition of the enzyme
action of aspirin
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
Action of ibuprofen
this ends by the second pathway, reversibly by competitive inhibition of the enzyme (competes with arachidonic acid which is the natural substrate)
what are prostaglandins
they are a family of compounds generated in tissues from the precursor arachidonic acid by cyclo-oxygenase enzymes
What are the two main cyclo-oxygenase enzymes
COX-1:
- constitutive
- important in maintain the GIT integrity
COX-2:
- inducible
involved in inflammatory response
- implicated in cancer development
what are some of the main roles of prostaglandins
stops platelet aggregation vasoconstriction vasodilation hyperalgesic bronchioconstricter
what are the roles of PGE2, PGI2 and PGD2
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
Anti-pyretic effect
– 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
Analgesic Effect
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
Salicylates (aspirin family)
– 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
Unwanted effects of salicylates
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
Propionic acids
– e.g. ibuprofen, naproxen
– not prodrugs
– well absorbed
– last for 4-6 hours.
Fenamates
– e.g. mefenamic acid
Paracetamol
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
Selective COX-2 inhibitors
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
Anti-inflammatory actions
– 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
