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Flashcards in NSAIDS Deck (20):

Describe the major differences in expression and function of COX1 and COX2. How do these differences influence their clinical and adverse effects of the NSAID drugs?

COX1 - constitutively expressed ubiquitously to maintain homeostasis
=> inhibition is adverse

COX2 - induced by pro-inflammatory cytokines; constitutively expressed in low levels in the kidney and endothelium
=> PG and thromboxane associated with COX2 => pain, fever, inflammation
=> inhibition is therapeutic

NSAIDS work by - inhibition of COX (cyclo-oxygenase 1 & 2) by preventing binding of arachidonic acid to active site
=> COX convert arachidonic acid => prostaglandins and thromboxane


Describe the MOA underlying the use of low dose aspirin as a prophylaxis in the prevention of platelet activation and development of atherosclerosis.

- primary prevention of stroke and MI in pts with high risk of CVD

1. acetylation of COX1 in platelets => permanent inhibition
2. platelets do NOT form TXA2 => anti-thrombosis
3. inhibition is long lasting b/c platelets cannot regenerate COX1
4. endothelial cells keep producing PGI2 => anti-thrombosis, vasodilation

at low doses, endothelial COX1 is spared
at high doses, both platelet and endothelial COX1 is permanently inhibited => decreased TXA2 and PGI2

effective b/c irreversible


Describe the following characteristics of salicylate toxicity:
- PK
- SX
- TX

- at low doses, salicylates exhibit 1st order kinetics and half life of 3.5 hours
- at high doses, they exhibit zero order kinetics and half life of >15 hours
- excreted in urine and can affect uric acid secretion

- decreases uric acid excretion => gout b/c serum uric acid concentration increases
- trigger increased respiration => initial respiratory alkalosis => compensatory metabolic acidosis
- promotes transport of salicylates into CNS

- early: N/V, abdominal pain, lethargy, tinnitus, vertigo
- late: hyperthermia, hyperventilation, respiratory alkalosis/metabolic acidosis, seizures, tremors, hypoglycemia, altered mental status, cerebral edema, coma

- mild: symptomatic, alkalinization of urine (increase pH) to enhance elimination of salicylate
- severe: gastric lavage, IV fluids, dialysis


List the MOA, indications, clinical uses, and contraindications for acetaminophen.

- selective COX1 and *COX2* in CNS
- mediated by metabolite AM404
- decreases pain and fever via cannabinoid system
- weak antagonist on peripheral COX1/COX2 due to high concentration of hydroperoixides in periphery

- well-absorbed
- liver metabolism

- analgesic for moderate pain (headaches, muscle, adjunct therapy for arthritis)
- anti-pyretic
- preferred for pts with aspirin hypersensitivity
- preferred in children to avoid Reye's
- preferred in hemophilia or PUD
- gout (with probenecid; does not affect uric acid levels)

- reduced due to lack of inhibition on peripheral COX1
- high doses cause dizziness, excitement, and disorientation
- larger large doses can cause hepatotoxicity


Describe the MOA by which acetaminophen overdose can lead to hepatic failure. What role does chronic alcohol consumption have on acetaminophen-induced hepatic toxicity? What is the therapeutic approach to limit liver damage?

1. overdose acetaminophen causes saturation of CYP phase II enzymes => can't conjugate
2. not enough glutathione in liver to create stable end-product
3. reaction pushed to make toxic metabolite NAPQ
4. reaction pushed to covalent bond with hepatic proteins => hepatic cell death

- increased CYP2E1
- increased metabolism of acetaminophen to NAPQ
- conjugates with proteins => toxic

N-acetyl-cysteine replenishes glutathione levels for proper conjugation and excretion


List the major therapeutic applications of NSAIDS.

- pain associated with inflammation
- chronic inflammatory diseases (RA, osteoarthritis, gout - except salicylates)
- localized musculoskeletal syndromes (sprain, lower back pain)
- pain for headaches, migraines, dysmenorrhea, post-op
- fever
- prophylaxis (aspirin)


Describe the MOA by which prostaglandins induce inflammation, pain, and fever.

1. COX2 => PG
2. production of PGE2/PGI2 in inflammatory cells
3. vascular permeability, phagocyte recruitment, vasodilation, increased blood flow => heat, redness, edema

1. COX2 => PG
2. lowers threshold of primary afferent pain neurons
3. PGs and cytokines increase pain stimulation

1. pro-inflammatory cytokines (IL-1) induce COX2 expression in endothelium in hypothalamus
2. PGE2 acts on the organum vasculosum lamina terminalis (OVLT) => thermoregulatory center => fever


Describe the role of COX in the stomach/GI. How does NSAID therapy affect this?

- inhibit gastric acid secretion
- increase bicarb production
- increase mucosal production
- vasodilation and increased gastric blood flow
==> protective

==> NSAID mediated inhibition of COX1 is adverse


Describe the role of COX in the kidney. How does NSAID therapy affect this?

COX1 => PG
- vasodilation => increased renal blood flow, prevent ischemia
- increased GFR
- increased water and salt secretion
- important in disease states since vasodilation is required to counteract increased vasoconstriction

==> NSAIDs decrease BF, GFR, and promote retention => exacerbate or compromise kidney function, especially in pts with kidney or heart failure


Describe the role of COX in the cardiovascular system. How does NSAID therapy affect this?

1. platelets only express COX1 => TXA2 (thromboxane)
=> vasoconstriction
=> platelet aggregation

2. endothelial cells => PGI2
=> vasodilation
=> inhibits platelet aggregation

NORMAl balanced b/w TXA2 and PGI2 to regulate BP and thrombogenesis

==> NSAIDs disrupt balance


Describe the role of COX in the female reproduction. How does NSAID therapy affect this?

1. dysmenorrhea and cramps
=> NSAIDS are therapeutic

2. stimulates uterine contraction
=> prenatal NSAID therapy can delay labor
=> therapeutic or adverse


Describe the following for aspirin/salicylates:
- PK

- rapid absorption
- short half life
- metabolized by serum esterases => salicylic acids + acetic acid
- all cross BBB except difunisal
- 50-90% bound (affect concentrations of other protein-bound drugs, i.e. warfarin)
- metabolized in liver, cleared by kidney
=> low dose = 1st order
=> high dose = zero order, longer half life

MOA = nonselective
- irreversible inhibition of COX1 via acetylation near active site => inhibits binding of arachidonic acid substrate
- less potent acetylation of COX2 b/c COX2 active site is larger and more flexible => still able to accomodate arachidonic acid
- salicylic acid inhibits COX via competitive antagonism of arachidonic acid binding

- mild pain
- inflammatory diseases
- fever
- prophylaxis for MI and stroke
- cancer chemoprevention (50% decrease in colon cancer risk)

- GI bleeding, irritation, N/V
- acute renal failure, interstitial nephritis, analgesic nephropathy
- HTN due to further vasoconstriction in pts with pre-existing HTN; only seen in high dose
- increased bleeding due to decreased TXA2
- Reye's Syndrome
- hypersensitivity leading to asthma, urticaria
- gout b/c low doses blocks uric acid transporters => buildup in serum (not seen in high doses)


What is the difference between aspirin and salicylates? Why would you use salicylates over aspirin?

salicylates are not acetylated
- reversible
- competitive inhibition
- preferable in pts with asthma, GI complications, and hemophiliacs
- some cannot cross BBB to relieve fever (diflunisal)


Describe the adverse effects of aspirin and traditional NSAIDs on the GI tract. How would you treat?

- GI = most common
=> N/V, GI bleeding, aggravate/promote ulcers
=> tx: misoprostol (PGE1 analog), omeprazole (proton pump blocker)


Describe the adverse effects of aspirin and traditional NSAIDs on the kidney. How would you treat?

=> primarily in pts with kidney disorders, heart failure, and cirrhosis, elderly
=> leads to renal ischemia b/c blocks PG synthesis
=> reversible if discontinue the drug

- kidney failure associated with inflammatory infiltrate
- seen after several months of exposure
- SX: N/V, malaise, WBC in urine
- drug discontinuation

- progressive renal failure => end stage renal disease
- seen in pts with NSAID combination therapy


Define Reye's Syndrome.

- unique aspirin side effect
- rare, often fatal liver degenerative disease
- associated encephalitis
- ONLY seen with aspirin
- associated with administration of aspirin during febrile viral infection in young childhood


Describe the following for traditional NSAIDs:
- general properties
- PK
- indications
- features of selected NSAIDs
- adverse effects

- drugs in this category have the same MOA and similar efficacy

- reversible competitive inhibitors of COX
- block production of PGs
- non-selective

- anti-inflammatory
- anti-pyretic
- analgesic

- well absorbed
- highly protein bound => drug interactions
- accumulate in synovial fluid (suited for arthritis)
- liver metabolism, kidney clearance

1. ibuprofen - decreased risk of GI bleeding
2. Naproxen - more potent than aspirin; rapid onset ideal for anti-pyretic
3. indomethacin (indocin) - more potent than aspirin, most effective anti-pyretic, not well tolerated, preferred for ductus arteriosus closure
4. keterolac - IV analgesic post-op, replacement for opioid analgesic

- GI: N, dyspepsia, ulcers, bleeding diarrhea
- kidney:
=> vasoconstriction (renal ischemia)
=> acute nephritis
=> chronic analgesic nephropathy
- increased risk for MI and stroke; worsening of underlying HTN
- liver: elevated liver enzyme
- increased bleeding (all NSAIDs except celecoxib)
- hypersensitivity (rhinitis, fever, rash, angioedema, asthma)
- CNS: tinnitus, aseptic meningitis, psychosis, cognitive dysfunction
- skin reactions - rare; mucosal blistering
- photosensitivity - blistering; b/c NSAIDs absorb UV
- pregnancy: associated risk for miscarriage, promotes premature closure of ductus arteriosus, delays labor, hemorrhage


Describe the following properties for celecoxib:
- general properties
- PK
- indications
- side effects

- 3 on the market = celecoxib (celebrex), rofecoxib (withdrawn), valdecoxib (withdrawn)

- selective inhibition of COX2

- anti-inflammatory
- anti-pyretic
- analgesic
- RA and osteoarthritis
(no evidence of being more efficacious)
- better for pts with GI complications
- colon cancer

- GI: reduced side effects
- no effect on platelet aggregation
- similar renal toxicities as aspirin and NSAIDs b/c COX2 is constitutively expressed in kidney
- increased CV risks
=> significant increase of MI and stroke
=> due to inhibition of PGI2 on endothelial cells tipping the balance to the thrombotic, vasoconstriction state (since TXA2 production is uninhibited)


List all contraindications for NSAIDs

- GI ulcers (except for celecoxib)
- bleeding disorders, anti-coagulant rx (not celecoxib)
- gout (for aspirin and salicylic acid)
- renal disorders
=> decreased blood flow => ischemia, water/salt retention
=> HTN
- increased risk for CVD
=> especially celecoxib
=> esp. high doses of NSAIDs
=> naproxen is safest
- hypersensitivity to aspirin
- pregnant patients (delay of labor, premature DA closing)
- elderly (toxicities)


Describe the following drug interactions (which drug, NSAID, and effect):
- low dose aspirin + NSAIDS (except celecoxib)
- anti-coagulants + NSAIDS (except celecoxib).
- anti-HTN + NSAIDS
- diuretics + NSAIDS
- oral hypoglycemics + salicylates

1. antagonize beneficial effects by preventing binding of aspirin to COX1
2. increased risk for bleeding since platelet COX1 is inhibited and blood is in an anti-thrombotic state
3. decreased anti-HTN effects b/c renal vasoconstriction
4. increased risk of HTN due to salt/water retention
5. potentiate hypoglycemia since salicylates are highly protein bound