Lec 13 NSAIDS/Aspirin Flashcards
Aspirin: mech of action
step1
Irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) enzyme by covalent acetylation.
Platelets cannot synthesize new enzyme, so effect lasts until new platelets are produced:
decrease bleeding time, inhibit TXA2 and prostaglandins. No effect on PT [prothrombin time] or PTT [partial thromboplastin time].
How long does anti-platelet effect of aspirin last?
8-10 days —> need to be off aspirin for at least 7 days before surgery
Which prostaglandins increase body temp?
PGE2, PGF2, PGI2
Which prostaglandins are pro-inflammatory?
PGE2, PGI2
What is clinical use of aspirin?
Antipyretic, analgesic, anti-inflammatory, anti platelet aggregation.
Aspirin: toxicities?
Gastric ulceration, tinnitus (CN VIII).
Chronic use can lead to acute renal failure, interstitial nephritis, and upper GI bleeding.
Reye syndrome in children with viral infection.
Overdose causes respiratory alkalosis initially, which is then superimposed by metabolic acidos
What is reye syndrome?
childhood hepatoencephalopathy
= swelling of liver and brain
associated w/ viral infection [esp VZV and influenza B] that was treated w/ aspirin
What is mech of reyes?
aspirin metabolites decrease beta-oxidation by inhibition of mitochondrial enzyme
What are clinical findings of reyes?
- mitochondrial abnormalities
- fatty liver
- hypoglycemia
- vomitting
- hepatomegaly
- coma
What is samter’s triad sensitivity?
- aspirin sensitivity
- nasal polyps
- asthma
How is ASA distributed?
widely distributed = 75-90% protein bound
How is ASA metabolized/excreted?
metabolized in liver; excreted renally as salicyluric acid
What are signs of aspirin overdose?
headache tinnitus/ hearing impairment/ dizziness due to direct effect on cochlear hair cells decreased vision N/V bleeding fever acid base derangement
What kind of acid base derangement in aspirin overdose?
- respiratory alkalosis initially due to stimulation of medulla resp centers
- then superimposed metabolic acidosis: from salicylic acid and uncoupling of oxidative phosphorylation resulting in lactic acid
How does mech of action of aspirin differ from that of ibuprofen?
both are non-selective cox inhibitors
aspirin is irreversible; ibuprofen is reversible
Can you use dialysis to treat aspirin overdose?
no because it has a huge volume of distribution –> most is protein bound and will not go through dialysis membrane
Ibuprofen: mech
Reversibly inhibit cyclooxygenase (both COX-1 and COX-2). Block PG synthesis.
Ibuprofen: clinical use
Antipyretic, analgesic, anti-inflammatory
Ibuprofen: toxicity
Interstitial nephritis, gastric ulcer (PGs protect gastric mucosa), renal ischemia (PGs vasodilate afferent arteriole).
What are the 5 NSAIDS?
- Ibuprofen
- Naproxen
- Indomethacin
- Ketorolac
- Diclofenac
Celecoxib: mech
Reversibly inhibit specifically the cyclooxygenase (COX) isoform 2, which is found in inflammatory cells and vascular endothelium and mediates inflammation and pain; spares COX-1, which helps maintain the gastric mucosa.
Thus, should not have the corrosive effects of other NSAIDs on the GI lining. Spares platelet function as TXA2 production is dependent on COX-1.
Celcoxib: clinical use
Rheumatoid arthritis and osteoarthritis; patients with gastritis or ulcers.
Celcoxib: toxicity
increases risk of thrombosis. still have renal symtpoms
Sulfa allergy.
Acetaminophen: mech
weakly reversibly inhibits cyclooxygenase, mostly in CNS. Inactivated peripherally.
Acetaminophen: clinical use
Antipyretic, analgesic, but not anti-inflammatory.
Used instead of aspirin to avoid Reye syndrome in children with viral infection.
Acetaminophen: toxicity
Overdose produces hepatic necrosis; acetaminophen metabolite (NAPQI) depletes glutathione and forms toxic tissue adducts in liver.
What is treatment for acetaminophen toxicity
N-acetylcysteine is antidote—regenerates glutathione.
WHat is the major metabolite of acetaminophen that leads to hepatotoxicity?
NAPQI
