NSAIDs Flashcards by Serinna Singh

Define eicosanoid and list four major classes

Inflammatory mediators

Classes:
\+Prostaglandins
\+Prostacyclin
\+Thromboxanes
\+Leukotrienes

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Describe the synthesis of eicosanoids via the COX and LOX pathways

With stimulus (injury or inflammation),

Phospholipids are metabolized by PLA2 into arachidonic acid

COX will turn this into PGs, prostacyclin, and thromboxanes

LOX will turn into leukotrienes

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What receptor does prostacyclin (PGI2) act on?

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What receptor does PGE2 act on?

EP 1-4

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What receptor does thromboxane act on?

TP alpha

TP beta

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Compare and contrast the functions of COX1 and COX2

COX1
+constitutively expressed
+dominant source of prostanoids for housekeeping functions (gastric cytoprotection, maintenance of kidney function)

COX2
+induced by cytokines, tumor promoters
+important source of eicosanoids in inflammation and cancer

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How do PGE2 and PGI2 affect vascular smooth muscle?

Gs pathway
= inc. cAMP
= vasodilation (+ more blood flow)
= more vascular permeability

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What effect does TXA2 have on vascular smooth muscle?

Activate Gq
= inc. Ca
= vasoconstriction

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What factors can stimulate free nerve endings to be interpreted as pain?

PH changes

Heat

Inflammation

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Differentiate between Adelta and C fibers

A-delta = myelinated
= faster transduction
= sharp pain

C fibers = no myelin
= slow travel
= throbbing pain

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How is it that PGE2 and PGI2 sensitize afferent nerves to pain?

PGs are pain modulators - they can reduce threshold of pain

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How do PGI2 and TXA2 compare in their influence toward platelet aggregation?

TXA2 promotes platelet aggregation

PGI2 inhibits platelet aggregation

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What are the effects of PGE2 and PGI2 on kidneys?

Vasodilation
=maintain RBF + GFR

PG induced inhibition of NaCl reabsorption

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What is the effect of eicosanoids on the lungs?

Bronchoconstriction

Leukotrienes

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What are the effects of eicosanoids on pregnancy?

Increase during labor

Maintain ductus arteriosus

Inc. uterine tone

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Describe the MOA of NSAIDs

Inhibit production of PGs by competing with arachidonic acid for binding in COX catalytic site

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What is the mechanism behind

Anti-inflammatory

Action of NSAIDs?

Prostanoids (PGE/PGI) significantly increase in inflamed tissue
= blood flow to these sites will worsen inflammation
=vascular permeability inc.
=more leukocyte infiltrate

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What are AEs associated with NSAIDs?

Renal

Pulmonary

Hypersensitivity

Pregnancy precaution

Describe GI NSAID AEs

Inhibition of COX1 = dec. mucosal cytoprotective PGs

Sx: abdominal pain, N/V, ulcers or bleeding

Describe renal AEs associated with NSAIDs

Renal insufficiency, renal failure

Salt and water retention (inc. BP)

Hyperkalemia
(Less blood flow = less K secretion)

Describe hypersensitivity AE associated with NSAIDs

Sx: vasomotor rhinitis, generalized urticaria, bronchoconstriction, flushing, hypotension, shock

Describe pregnancy precaution associated with NSAIDs

Inc. risk of postpartum hemorrhage

May prolong gestation

Premature closing of ductus arteriosus

What drugs interact with NSAIDs? How?

ACEIs

dec. anti-HPT response
hyperkalemia

Diuretics
-reduce response to diuretics because they inc. salt retention

Highly protein bound drugs
-NSAIDs are highly protein bound and can displace other drugs from their binding sites (ex: Warfarin, MTX)

List contraindications/ precautions for NSAIDs

Hypersensitivity to NSAID

Renal disease
GI bleeding/disease

Hypovolemia
Bleeding disorders

Labor
Surgery

What effect does aspirin have on platelets?

Low dose is more selective for COX1 (dominant version in platelets) Blocking COX1 = dec. TXA (Why it's anti-thrombotic) More for COX2 to use to make PGI

What are AEs of aspirin?

Inc. bleeding time Reye's syndrome Tinnitus Hypersensitivity

How should aspirin and additional NSAID be separated?

Aspirin 2 hours BEFORE Or 8 hours AFTER

Why would NSAIDs interact with aspirin?

Aspirin would block COX1 (low dose for cardioprotective effect)... But addition of more non-specific NSAID means it would go and block COX2.. thus messing with helpfulness of cardioprotective effect by dec. PGI2 (useful for vasodilation)

List contraindications/precautions associated with aspirin

Hemophilia Children/teenagers w/ flu Sx's = risk of Reye's syndrome Hypersensitivity Surgery (stop 1 week before)

Describe MOA of indomethacin

Nonselective inhibitor of COX More potent than aspirin Intolerance limits dose **

What are AEs associated with indomethacin?

CNS = hallucinations, depression, seizures, headaches, dizziness (Pts who take for long periods)

What are clinical uses for indomethacin?

NSAIDs general use *** only drug approved for: Patent ductus arteriosus in neonates

Describe MOA of ketorolac

Nonselective inhibitor of COX Very potent analgesic but only moderate effective anti-inflammatory

What is the therapeutic use of ketorolac?

Severe pain (use limited to less than 5 days)

What are AEs associated with ketorolac?

CNS | Somnolence, dizziness, headache

What is MOA of APAP?

Weak COX inhibitor in CNS but NO COX inhibition in peripheral tissues

What are major differences between NSAIDs and APAP?

No anti-inflammatory effects Well tolerated + low incidence of GI effects Acute overdosage = severe hepatic damage

Acetaminophen is the preferred drug for which patients?

Allergic to aspirin Hemophilia H/o peptic ulcers Bronchospasms from aspirin Children Pregnant women

Describe AEs of APAP

Intoxcication >7.5 g | Most serious = fatal hepatic necrosis

What is the MOA of diclofenac?

Selective COX2 inhibitor

What are benefits of selective COX2 inhibitors vs. traditional NSAIDs

target inflammatory reactions: inflammation, pain and fever

What are clinical uses and AEs associated with celecoxib?

Use: anti-inflammatory, analgesic AEs: - fewer GI unwanted effects - MI and stroke: suppression of PGI2 opposes effects of PGI and TXA = more TXA = more platelet aggregation

What are contraindications for celecoxib?

MI and stroke Coronary artery bypass graft surgery Hypersensitivity to NSAIDs