test 7 Nonsteroidal anti-inflammatory drugs (NSAIDs) Flashcards
NSAIDs are a group of
o chemically dissimilar agents with different antipyretic (prevent or reduce fever), analgesic, and anti-inflammatory functions.
NSAIDs act primarily by
o inhibiting COX enzymes that catalyze the first step in prostanoid biosynthesis. Leads to decreased synthesis, with both beneficial and unwanted effects.
Metabolism of aspirin and acetylation of COX
o This is a rapid and irreversible reaction; an irreversible inhibitor substance inactivates an enzyme by bonding covalently to a specific group at the active site. The inhibitor-enzyme bond is strong. This reaction might interfere with synthesis of new enzyme in platelets.
- causes COX enzyme to become inactive
Metabolism of other NSAID
o The reaction is reversible; inactivates an enzyme by binding at the active site through noncovalent, reversible interactions. More easily reversed. Unlike an irreversible inhibitor, a reversible inhibitor can dissociate from the enzyme.
- don’t have an effect on COX enzyme
Commonly used NSAIDs inhibit what step in the process
- Cyclooxygenase
Aspirin (ASA –acetylsalicylic acid) dose dependence and inhibition of COX activity
o Low dose inhibits COX-1. This inhibits platelet generation of thromboxane A2, resulting in an antithrombotic effect
o Intermediate dose inhibits COX-1 and COX-2. Blocks prostaglandin production (PGE2) = analgesic and
antipyretic (fever-lowering, PGE2) effects
o High doses are anti-inflammatory in rheumatic disorders; effect may be by COX-2 inhibition. Usefulness of aspirin at these high doses is limited by toxicity, including hearing loss, and gastric intolerance
Therapeutic uses of aspirin
o Anti-inflammatory and analgesic use
o Treatment of osteoarthritis, gout, rheumatoid arthritis for analgesic effect. With opioids, controls pain relating to malignancy.
o By decreasing PGE2, sensation of pain can be reduced.
o Antipyretic effects.
o Fever can be caused by PGE2 when pyrogens are released from WBCs that are activated by infection, hypersensitivity, malignancy, or inflammation.
o Aspirin, ibuprofen, and naproxen used to reduce fever by preventing the release of this prostanoid.
o Cardiovascular applications:
o Aspirin inhibits platelet aggregation. Low-dose (below 325 mg, or commonly 81 mg) inhibits COX-1 production of TXA2-mediated vasoconstriction.
o Reduces risk of recurrent MI, unstable angina, and TIAs, stroke, and patients with diabetes.
Adverse effects of asparin
o Gastrointestinal:
o PGI2 inhibits gastric secretion and PGE2 and PGF2α stimulates protective mucous. COX-1 inhibition reduces this beneficial effect, and increases risk for GI bleeding and ulceration
o Risk of bleeding:
o TXA2 enhances platelet aggregation, while PGI2 decreases it. Aspirin irreversibly inhibits COX-1 and TXA2 formation, while other NSAIDs reversibly inhibit COX-1.
o Platelets cannot synthesize new enzyme (anucleate) when inhibited by aspirin, and the lack of TXA2 persists for the lifetime of the platelet (3-7 days). New enzyme is not produced until new platelets are synthesized. This delays thrombus formation.
o Therefore, aspirin is not given at least 1 week before surgery
o Cardiac effects: By COX-1 inhibition, aspirin affords protection by a reduction in TXA2. COX-2 inhibition is linked to increased risk of CV events, possibly by decreasing PGI2 production. Increased risk of CV events is associated with all NSAIDs, except aspirin
o Kidney: prevent synthesis of PGE2 and PGI2, which are responsible for maintaining blood flow. This can result in sodium and water retention.
Celecoxib (Celebrex)
o selective COX-2 inhibitor
o more selective for COX-2 than for COX-1. Imbibition of COX-2 is reversible
Celecoxib (Celebrex) Therapeutic uses
o Celecoxib is used for the treatment of osteoarthritis, RA, and pain.
o Has similar efficacy to NSAIDs in the treatment of pain.
Celecoxib (Celebrex) adverse effects
o Should be avoided with patients with liver and renal disease.
o Associated with less GI bleeding and dyspepsia (indigestion) than other NSAIDs
