NSAIDS Flashcards
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
MOA
- acetylation of COX1 in platelets => permanent inhibition
- platelets do NOT form TXA2 => anti-thrombosis
- inhibition is long lasting b/c platelets cannot regenerate COX1
- 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
- MOA
- SX
- TX
PK
- 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
MOA
- 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
SX:
- early: N/V, abdominal pain, lethargy, tinnitus, vertigo
- late: hyperthermia, hyperventilation, respiratory alkalosis/metabolic acidosis, seizures, tremors, hypoglycemia, altered mental status, cerebral edema, coma
TX
- 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.
MOA
- 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
PK
- well-absorbed
- liver metabolism
INDICATIONS
- 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)
- NO ANTI-INFLAMMATORY
ADVERSE EFFECTS
- 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?
- overdose acetaminophen causes saturation of CYP phase II enzymes => can’t conjugate
- not enough glutathione in liver to create stable end-product
- reaction pushed to make toxic metabolite NAPQ
- reaction pushed to covalent bond with hepatic proteins => hepatic cell death
ALCOHOL
- increased CYP2E1
- increased metabolism of acetaminophen to NAPQ
- conjugates with proteins => toxic
TX
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.
INFLAMMATION
- COX2 => PG
- production of PGE2/PGI2 in inflammatory cells
- vascular permeability, phagocyte recruitment, vasodilation, increased blood flow => heat, redness, edema
PAIN
- COX2 => PG
- lowers threshold of primary afferent pain neurons
- PGs and cytokines increase pain stimulation
FEVER
- pro-inflammatory cytokines (IL-1) induce COX2 expression in endothelium in hypothalamus
- 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?
COX1 => PGE2/PGI2 - 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?
- platelets only express COX1 => TXA2 (thromboxane)
=> vasoconstriction
=> platelet aggregation - 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?
COX1 => PGE2/PGF2
1. dysmenorrhea and cramps
=> NSAIDS are therapeutic
- stimulates uterine contraction
=> prenatal NSAID therapy can delay labor
=> therapeutic or adverse
Describe the following for aspirin/salicylates:
- PK
- MOA
- INDICATIONS
- SIDE EFFECTS
- CONTRAINDICATIONS
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
INDICATIONS
- mild pain
- inflammatory diseases
- fever
- prophylaxis for MI and stroke
- cancer chemoprevention (50% decrease in colon cancer risk)
ADVERSE EFFECTS
- 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?
ACUTE RENAL FAILURE
=> 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
ACUTE NEPHRITIS/NEPHROTIC SYNDROME
- kidney failure associated with inflammatory infiltrate
- seen after several months of exposure
- SX: N/V, malaise, WBC in urine
- drug discontinuation
ANALGESIC NEPHROPATHY
- progressive renal failure => end stage renal disease
- seen in pts with NSAID combination therapy
