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
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
- MOA
- indications
- features of selected NSAIDs
- adverse effects
GENERAL
- drugs in this category have the same MOA and similar efficacy
MOA
- reversible competitive inhibitors of COX
- block production of PGs
- non-selective
INDICATIONS
- anti-inflammatory
- anti-pyretic
- analgesic
PK
- well absorbed
- highly protein bound => drug interactions
- accumulate in synovial fluid (suited for arthritis)
- liver metabolism, kidney clearance
KEY FEATURES
- ibuprofen - decreased risk of GI bleeding
- Naproxen - more potent than aspirin; rapid onset ideal for anti-pyretic
- indomethacin (indocin) - more potent than aspirin, most effective anti-pyretic, not well tolerated, preferred for ductus arteriosus closure
- keterolac - IV analgesic post-op, replacement for opioid analgesic
ADVERSE
- 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
- MOA
- PK
- indications
- side effects
GENERAL
- 3 on the market = celecoxib (celebrex), rofecoxib (withdrawn), valdecoxib (withdrawn)
MOA
- selective inhibition of COX2
INDICATIONS - anti-inflammatory - anti-pyretic - analgesic - RA and osteoarthritis (no evidence of being more efficacious) - better for pts with GI complications - colon cancer
ADVERSE EFFECTS
- 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
- antagonize beneficial effects by preventing binding of aspirin to COX1
- increased risk for bleeding since platelet COX1 is inhibited and blood is in an anti-thrombotic state
- decreased anti-HTN effects b/c renal vasoconstriction
- increased risk of HTN due to salt/water retention
- potentiate hypoglycemia since salicylates are highly protein bound
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Principles of Pharmacology7
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Drug Absorption & Distribution28
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Drug Elimination & Multiple Dosing18
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Clinical Pharmacokinetics17
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Drug Metabolism23
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Drug Transporters24
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Pharmacogenomics12
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Pharmacodynamics I22
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Pharmacodynamics II13
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Drug Toxicity13
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Drug Discovery and Clinical Trials17
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Drug Actions in Synaptic Transmission20
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Adrenergic Agonists31
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Adrenergic Antagonists14
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Cholinergic Agonists & Antagonists31
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Neuromuscular Relaxants25
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Serotonin and Dopamine22
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General Anesthetics16
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Local Anesthetics9
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Opioids13
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NSAIDS20
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Acupuncture5
