Lecture 19: NSAIDs Flashcards
NSAID activity
-anti-inflammatory
-analgesic
-antipyretic
NSAID use
-treat pain, fever, inflammation
-treat early rheumatoid arthritis and osteoarthritis
-cancer prevention
NSAID mech of action
-inhibit COX
=inhibit prostaglandin synthesis
Classes of NSAIDs
-salicylates
-arylacetic acids
-arylpropionic acids
-non-carboxylate
-COX-2 selective
Side effects of NSAIDs
-GI tract
-blood coagulation
-renal
-hypersensitivity
-Reye’s syndrome
-CNS
GI effects of NSAIDs
-dyspepsia, nausea, vomiting
-blood loss, ulcer, hemorrhage
-aspirin ~ indomethacin > naproxen > sulindac
Mech of NSAIDs on GI tract
-acidity
-inhibit protective PGEs in mucosa
-inhibit aggregation (increased tendency to bleed)
Side effects of NSAIDs on blood coagulation (ASPIRIN)
-Aspririn prolongs bleeding time by IRREVERSIBLE inhibition og COX-1 and reduced formation of TXA2
-don’t use before surgery
-can prevent coagulation in CV disease
Renal side effects of NSAIDs
-renal failure in patients with CV, hepatic, and renal disease
NSAID hypersensitivity
-skin rashes, hives, angioedema, asthma-like syndrome
-blocked by 5-lipooxygenase inhibitors
-0.3% of population 10% in asthmatics
Reye’s Syndrome (NSAID effects)
-only from salicylates
-rare life threatening
-vomiting, delirium, coma
-brain damage
-occurs in children who have had flu or pox
-do NOT give to anyone under 12 w a fever
CNS side effects of NSAIDs
-tinnitus
-dizziness
-headache
Prevention of GI side effects
-misoprostol
-proton-pump inhibitors
-combo products
Misoprostol
-synthetic PGE1 analog
-used to prevent gastric ulcers in high risk patients
Proton-pump inhibitors (esomeprazole)
-reduce acid secretion
-protect against ulceration in absence of COX-1 activity
Combo products for GI effects
-Naproxen/esomeprazole
-Naproxen/misoprostol
-NDicolfenac/misoprostol
Drug interactions of NSAIDs
-may compete for serum albumin binding sites with other drugs
-ex: anticoagulants
NSAID intereaction with anticoagulants
-inc plasma concentration of free anticoagulant
-and its WORSE bc salicylates promote bleeding
-must lower the dose of anticoagulant
SAR of NSAIDs
-acidic group off the ring
-add a methyl group to that C to increase activity (ibuprofen)
-another area of lipophilicity (another ring or alkyl) inc activity
Salicylates
-salicyclic acid
-acetylsalicylic acid (aspirin)
-salsalate
-diflunisal
Salicylic Acid
-from willow tree
-slightly acidic
-absorbed as ionic form in small intestine
-absorbed as acid form in stomach
-REVERSIBLE COX1/2 inhibiton
-may suppress COX-2 induction
Aspirin (acetylsalicylic acid)
-IRREVERSIBLY inhibits COX
-acetylates serine in active site
-absorbed intact but hydrolyzed to salicylate by esterase
-2-fold more potent than salicylic acid ad analgesic/antipyretic
-blocks TXA2
-inc risk of bleeding
-reduces risk of MI
-not stable in solutions
Salsalate
-dimer of salicylic acid
-hydrolyzed in SI
-does NOT cause GI bleeding
Diflunisal
-better analgesic than aspirin
-fewer side effects
-less antipyretic activity
-longer half life
-F
Arylacetic Acids
-indomethacin
-sulindac
-etodolac
-diclofenac
Indomethacin
-v potent
-lots side effects
-do NOT use long term
-not atble in solution (hydrolysis of amide bond)
Sulindac
-prodrug (sulfoxide reduced to active sulfide intermediate in circulatory system
-less side effects
-ok for long term use
Etodolac
-pyranocarboxylic acid
-almost as potent as indomethacin
-a lil selective for COX2
-less GI bleeding
-long term use for osteoarthritis
Diclofenac
-most widely used NSAID in the world
-as potent as indomethacin
-lil selective for COX-2
-inhibits COX and lipoxygenase pathways
Arylpropionic Acids
-ibuprofen
-naproxen
-ketorolac
Ibuprofen
-OTC analgesic
-more potent than aspirin
-less potent than indomethacin
-some GI irritation
Ibuprofen SAR
-a-methyl group enhances activity and reduced side effects
-racemic mix
-R is converted to S in vivo
Naproxen
-S enantiomer
-more potent than ibuprofen
-GI irritation
-treat rheumatoid arthritis and osteoarthritis
Ketorolac
-cyclized heteroarylpropionic acid derivative
-short-term
-analgesic activity similar to centrally acting analgesics
-alt to narcotics
Non-carboxylates
-nabumetone
-meloxicam
Nabumetone
-nonacidic prodrug
-metabolized to 6-MNA which is effective inhibitor of COX
-minimum effects
potent anti-inflammatory
-weak analgesic
Meloxicam
-belongs to oxicam class
-resembles peroxy radical intermediate in COX
-enolic acid
-long acting, qd dose
-as potent as indomethacin
-a lil selective for COX-2
Doses
slide 33
Effects of COX-1 Inhibition
-stomach irritation
-ulceration
-block aggregation
-block uterine motility
-blovk prostaglandin-mediated renal function
-hypersensitivity
Preferential inhibition of COX-2 gives
anti-inflammatory effects with lower incidence of gastric ulceration
Selective COX-2 Inhibitor drugs
-Celecoxib
-rofecoxib (disc)
-valdecoxib (disc)
Selective COX-2 inhibitors
-valine in NSAID binding site of COX-2 is swapped for isoluecine in COX-2
-exploit larger binding sire in COX-2 with big substituents
Side effects of selective COX-2 inhibtion
-inc BP
-atherogenesis
-no PGI2 production
-does NOT affect TXA2 production by COX-2
-BUT TXA2 inc in response to plaque
-inc risk of heart attack/strokeq
Celecoxib
-first COX-2 inhibitor NSAID
-use for osteoarthritis and rheumatoid arthritis
-fights pain, inflammation, and fever
-as potent as naproxen
-less GI side effects
-NO antiplatelet activity
Acetaminophen activity
-analgesic and antipyretic effects like aspririn
-weaker as an anti-inflammatory
Acetaminophen mech of action
-does NOT inhibit arachidonic acid binding to PGHS
-Scavenges peroxynitrite required for PGHS activity
Peroxynitrite
-major oxidant for PGHS in the CNS
-concentration is high in inflammation and acetaminophen scavenging is overwhelmed
Acetaminophen effects
-less GI
-tolerated in blood coagulation diseases
-no reye’s syndrome
-maybe a rash but not rlly hypersensitivity
-does not cross-react w aspirin
Acetaminophen hepatotoxicity
-CYP450 hydroxylation forms N-acetylimidoquinone
-reacts w glutathione
-high doses overload glutathione and cell damage occurs in liver
