cox inhibitors Flashcards
explain mechanism of action of COX inhibitors
cyclooxygenase is an enzyme that converts arachidonic acid to prostanoids (prostoglandins and thromboxanes)
inhibiting the enzyme has analgesic, antipyretic and anti-inflammatory effects as prostanoids can lead to vasodilation, pain sensitization and temperature increases.
what are side effects of COX inhibitors
when used for joint diseases that require high doses there is high incidence of GI/kidney/liver/blood/bone marrow side effects
mainly due to inhibition of PGs produced by COX-1 (which have roles in normal physiology)
ex:
GI: gastric inhibition of COX-1 independent of route of administration can cause symptoms like discomfort, constipation, nausea, vomiting, bleeding and ulcers (damages mucosal layer). replacement prostoglandin analogues such as misoprostol can help reduce. COX-2 selective inhibitors also have some GI side effects
skin: mechanism unclear. hives and photosensitivity
renal: reversible renal insufficiency (inhibits synthesis of prostanoids involved in renal blood flow maintenance. fluid retention
cardiovascular: mechanism unclear. elevated BP could have relationship with the renal effects. renal cells can control blood pressure.
protective prostanoid inhibition can lead to heart attack/stroke
increased risk of clotting (not aspirin)
bronchospasm with “aspirin sensitive” asthma
give examples for the role of prostanoids on inflammation
PGE2 PGI2 and PGD2 are vasodilators (cause redness and increased blood flow to areas of inflammation)
also increase permeability of post capillary venules (connection between capillaries and larger veins)
also:
PGE2 mediates increases in temperature and contracts bronchial and GI SM
PGI2 inhibits platelet aggregation
PGD2 inhibits platelet aggregation
and:
PGF2a contracts uterus
TXA2 vasoconstrictor and platelet aggregation
differentiate between NSAIDs COX inhibitors and aspirin MOA
NSAIDs generally inhibit both COX-1 enzyme pathway and COX-2 enzyme pathway whereas COX inhibitors are more selective for the COX-2 enzyme.
the COX-1 enzyme produces prostanoids that carry out mucosal functions in the GI, effect blood flow to kidney, and have effects on platelet aggregation whereas the COX-2 produces prostanoids that have effects on inflammation and pain
Aspirin acetylates serine residues in COX to permanently inhibit its activity (irreversible inactivation) whereas the other inhibitors binds to the catalytic site and exert its effects via antagonism.
COX-2 binding sites are larger compared to COX-1. bulkier drugs can be created to promote cox-2 selectivity.
describe how COX inhibitors lead to analgesic, anti inflammatory and anti pyretic effects
anti-inflammatory: does not treat inflammation but supresses it. vasodilation facilitates the actions of mediators that increase permeability of venules which can leads to inflammation. blocks blood flow to inflammation area. inhibits vasodilator prostaglandin synthesis by blocking COX enzyme.
analgesic: perpipherally decreases prostaglandins that sensitize nocioceptors to inflammatory mediators
centrally decreases PG release in spinal cord (peripheral inflammation can increase COX-2 which causes more PG synthesis in spinal cord leading to pain transmission)
antipyretic: reduce PG production in hypothalamus (hypothalamic center dysregulation leads to fevers)
what are some clinical uses of COX inhibitors
antithrombotic ex: aspirin
other NSAIDS do not cause inhibition of TX synthesis leading to an increase in thrombotic risk
analgesic for headache backache dysmenorrhea postop
short term: aspirin paracetamol ibuprofen
chronic: naproxen (more potent and longer lasting)
to reduce narcotic analgesic dose: ketorolac (prevents tolerance)
anti-inflammatory
ex: ibuprofen and naproxen for symptom relief in arthritis, gout, strains and sprain (soft tissue problems)
antipyretic
ex: paracetamol
give information on aspirin
Irreversibly inactivates both COX
also inhibits platelet aggregation so mainly used for cardiovascular disease
given orally rapidly absorbed
75% metabolized to salicylate
unwanted effx:
theraputic: gastric bleeding
larger dose: compensated respiratory alkolosis from “salicylism” which leads to diziness deafness and tinnitus
toxic doses: metabolic acidosis
give info on paracetamol
potent analgesic and antipyretic, weaker anti inflammatory effects (inhibition is specific to CNS enzymes.)
no platelet or gastric side effects
well absorber orally
therapeutic: allergic skin rxns (uncommon)
larger dose over long period: kidney damage
toxic dose: hepatotoxicity.
what are the three cox inhibitors available
offered to patients that have high risk of GI side effects
ex:
celecoxib, etoricoxib administered orally
side effects: headache, diziness, skin rashes
parecoxib> prodrug of valdecoxib liscenced for short term post op pain
side effects: skin rxns renal effx and postop anemia
