NSAIDS Flashcards
what type of activities do NSAIDs have
antipyretic, analgesic, anti inflammatory activities
mechanism of NSAIDs
inhibitor of COX so both inhibition of both prostaglandins and thromboxanes
difference between COX-1 and COX-2
- COX-1 is a constitutively active enzyme that is expressed in most tissues and is main source of cytoprotective prostaglandin formation
- COX-2 is inducible and is main source of prostanoids in inflammation and cancer
where in the body is COX-2 constitutively active
kidney and brain as it is the main source of vascular prostacyclin
why has there been a search for selective COX-2 inhibitors versus COX-1 inhibitors
inhibition of COX-1 causes inability to form protective prostaglandin leading to gastric damage as a side effect
What are the non selective COX inhibitors
PINK AID
Piroxicam Ibuprofen Naproxen Ketorolac Aspirin Indomethacin Diclofenac
what are the COX-2 inhibitors
Celecoxib
Meloxicam
how do NSAIDs produce their analgesic action
they decrease PGE2 synthesis hence repressing the sensation of pain
dominant source of prostaglandins that mediate the rise in temperature
COX-2 hence why both selective and non selective are consistent with antipyretic clinical efficacy of both subclasses of NSAIDs
therapeutic effects of NSAIDs
- antipyretic, anti inflammatory, analgesic
- tx for mild to moderate pain
- pain arising from inflammation (usually not visceral pain with exception to menses)
- tx of musculoskeletal disorders
- rheumatoid arthritis, gout, osteoarthritis, ankylosing spondylitis, dysmenorrhea
NSAIDs used to treat gout
- Indomethacin
- Other NSAIDs excluding AST (Aspirin, Salicylates, Tolmetin) used for acute gout
NSAIDs that decreases the risk of colon cancer
Aspirin
how do NSAIDs help with tolerating Niacin
- with increased dose or first dose, Niacin causes flushing which is mediated by release of PGD2 from the skin
- this release can be inhibited by COX inhibitor NSAIDs
NSAID used for closure of ductus arteriosus
Indomethacin
FUN FACT: Alprostadil is used to keep patent ductus arteriosus from closing
what are the GI effects caused by using NSAIDs
- inhibition of COX-1 in gastric epithelial cells depresses mucosal cytoprotective prostaglandins (PGI2 and PGE2)
- local irritation from contact of NSAIDs with gastric muxosa
what does PGI2 and PGE2 do
inhibit acid secretion by the stomach, enhance mucosal blood flow, promote secretion of cytoprotective mucus in the intestine
this is all inhibited by blocking COX-1
less side effects with selective COX-2 inhibitor
which one of the NSAIDs has the lowest risk and which has highest risk of GI adverse effects
lowest - Celecoxib
highest - Piroxicam
adverse effects of NSAIDs other than GI adverse effects
- increase cardiovascular risk
- decrease in renal blood flow
- analgesic nephropathy from long term use
- aspirin hypersensitivity
- hypersensitivity to sulfa since Celecoxib is a sulfonamide
what do COX-1 and COX-2 produce and inhibition of which one has more of a cardiovascular risk and why?
- COX-1 produces vasoconstricting, platelet aggregating thromboxane A2
- both COX-1 and COX-2 produce vasodilating, platelet inhibiting prostacyclins
-COX-2 selective inhibitors have more of a cardiovascular risk because COX-1 is left to produce vasoconstriction, platelet aggregation, and thrombosis
how do NSAIDs cause a decrease in renal blood flow
- it only affects persons with CHF, chronic kidney failure, or those with hypoperfusion to the kidney
- they rely on the vasodilative effects of COX to maintain the GFR so its inhibition leads to decreased GFR, sodium and water retention, edema, high BP, hyperkalemia, and acute renal failure
what is aspirin hypersensitivity associated with
increased synthesis of leukotrienes reflecting diversion of arachidonate to LOX metabolism due to COX inhibition
NSAIDs interaction with other drugs
- ACEIs prevent breakdown of bradykinin which stimulates PG production and NSAIDs prevent PG production. Together they decrease antihypertensive effect of ACEIs
- diuretics effects reduced
- with corticosteroids, increases severity GI ulceration
- increases bleeding with warfarin
what is triple whammy when it comes to NSAIDs
use of ACEIs (or ARBs) with NSAIDs and diuretics
NSAIDs constrict the afferent arteriole and reduce GFR. ACEIs (or ARBs) dilate the efferent arteriole and reduce GFR. Diuretics decrease plasma volume and GFR. Together, they all lead to acute renal failure.
contraindication of NSAIDs
- Pregnancy close to term
- Reye’s syndrome –> aspirin and other salicylates are contraindicated in children or those less than 20 with fever and viral illnesses (give them acetaminophen or ibuprofen)
the only COX-2 inhibitor
celecoxib since meloxicam preferentially does COX-2 over COX-1 but not selective for COX-2
what makes aspirin different from the other NSAIDs
it a salicylate that irreversibly acetylates COX thus inactivating it
how does aspirin become a salicylate
it is deacetylated in the body by esterases which makes it a salicylate
actions of aspirin on respiration and platelets
- at therapeutic level, it increases alveolar ventilation because salicylates uncouples oxidative phosphorylation leading to elevated CO2 and respiration
- higher doses, hyperventilation and resp alkalosis
- toxic doses, respiratory paralysis
- low doses, irreversibly inhibits thromboxane
- inhibits COX but action doesn’t last long because of production of new COX molecules
- low dose PGI2 not affected so vasodilation still occurring and platelet aggregation inhibition
uses of aspirin
- anti inflamm, analgesic, antipyretic
- inhibit platelet aggregation so at low doses is used prophylactically for cardiovascular applications
- decreases risk of colon cancer
dosage of salicylates
low doses are analgesic and antipyretic and high doses are anti inflammatory
how is aspirin metabolized in the body
- it is metabolized by esterases in tissue to salicylate and acetic acid then salicylate is converted by liver to conjugates with glycine and glucuronate, which is then eliminated by first order kinetics
- high doses over 1g is eliminated by zero order kinetics because conjugation enzymes are saturated, until it comes back down to 300mg then it is eliminated by first order
adverse effects of aspirin
- GI epigastric distress
- risk of hemorrhage for those with bleeding disorders since it inhibits platelet aggregation
- those with Reye’s syndrome can be fatal
- uses same transport as uric acid –> hyperuricemia
- causes hepatic injury
- pregnancy in later trimester
who is aspirin contraindicated in
Reyes Syndrome
Chronic liver disease
what happens with salicylate poisoning - mild and severe
mild - salicylism which includes headache, mental confusion, tinnitus, hyperventilation, diarrhea etc
severe - mixed respiratory alkalosis and metabolic acidosis –> respiratory depression –> respiratory failure
what is acetaminophen classified as in terms of mechanism and what are its actions
it is NOT AN NSAID though it has weak COX-1 and COX-2 inhibition
analgesic and anti pyretic action but no anti inflammatory action or anti platelet effects
who do you give acetaminophen to
- those to relieve pain and fever especially children with flu like symptoms
- safe for pregnant women
- not useful for inflamm conditions like RA
adverse effects of acetaminophen
- severe hepatic injury especially with overdose when all the glutathione stores are used and NAPQI causes hepatotoxicity
- narrow therapeutic window for alcoholics or those with liver disease
what is used to treat acetaminophen overdose
N-acetylcysteine because it replenishes glutathione stores
