Lecture 19: NSAIDs Flashcards by Brooke Thornburg

NSAID activity

-anti-inflammatory
-analgesic
-antipyretic

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NSAID use

-treat pain, fever, inflammation
-treat early rheumatoid arthritis and osteoarthritis
-cancer prevention

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NSAID mech of action

-inhibit COX
=inhibit prostaglandin synthesis

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Classes of NSAIDs

-salicylates
-arylacetic acids
-arylpropionic acids
-non-carboxylate
-COX-2 selective

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Side effects of NSAIDs

-GI tract
-blood coagulation
-renal
-hypersensitivity
-Reye’s syndrome
-CNS

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GI effects of NSAIDs

-dyspepsia, nausea, vomiting
-blood loss, ulcer, hemorrhage

-aspirin ~ indomethacin > naproxen > sulindac

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Mech of NSAIDs on GI tract

-acidity
-inhibit protective PGEs in mucosa
-inhibit aggregation (increased tendency to bleed)

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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

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Renal side effects of NSAIDs

-renal failure in patients with CV, hepatic, and renal disease

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NSAID hypersensitivity

-skin rashes, hives, angioedema, asthma-like syndrome
-blocked by 5-lipooxygenase inhibitors
-0.3% of population 10% in asthmatics

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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

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CNS side effects of NSAIDs

-tinnitus
-dizziness
-headache

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Prevention of GI side effects

-misoprostol
-proton-pump inhibitors
-combo products

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Misoprostol

-synthetic PGE1 analog
-used to prevent gastric ulcers in high risk patients

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Proton-pump inhibitors (esomeprazole)

-reduce acid secretion
-protect against ulceration in absence of COX-1 activity

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Combo products for GI effects

-Naproxen/esomeprazole
-Naproxen/misoprostol
-NDicolfenac/misoprostol

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Drug interactions of NSAIDs

-may compete for serum albumin binding sites with other drugs
-ex: anticoagulants

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NSAID intereaction with anticoagulants

-inc plasma concentration of free anticoagulant
-and its WORSE bc salicylates promote bleeding

-must lower the dose of anticoagulant

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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

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Salicylates

-salicyclic acid
-acetylsalicylic acid (aspirin)
-salsalate
-diflunisal

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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