Fitzy: NSAIDS Flashcards
What cleaves phospholipids to make AA?
Phospholipids A2
What turns AA into PGH2?
COX
What turns PGH2 into the different PG’s that we know and love?
Tissue specific isomerases
Which PG is also know as prostacyclin?
PGI2
Where is PGFalpha and E2?
Uterus
What is a cox Independent toxicity of salicylate a and aspirin?
- acid base disturbance
- tinnitus
- hypersensitivity
- Reyes syndrome
What do we get if we take too much (20 gym) of aspirin?
- early resp alkalosis
- later metabolic acidosis, fever, dehydration
- plus shock and coma
How do salicylate so makeour body think it’s in a hypoxic state?
- salicylate a stop coupling of mitochondrial ox phone…. Lower ATP
- body thinks it’s hypoxic….hyperventilation happens
- blows off CO2, resp alkalosis… Kidney depletes bicarb
- organic acids accumulate because ATP isn’t made in Rebs cycle anymore
Is Reye’s syndrome related to COX?
Nah
What drug do we give kids instead of aspirin?
Acetaminophen
What do NSAIDS block?
COX mediated formation of AA
What kind of inflammation do NSAIDs stop
LOCAL inflammation
Which COX has constitutive expression and has role in response to normal physiologic stimuli?
COX 1
How is COX2 different from 1?
This one gets INDUCED when it’s needed…. Usually pathological stimuli
-IL1,2, TNF
Which organ expresses both COX’s at the same time?
The kidney
What induces COX2 in inflammation?
Inflammatory cytokines
What do you not use NSAIDs for?
- asthma
- gut instinct inflammation
- infectious inflammation fever… Paradox
Which drug inhibits COX 2 more so than COX 1?
Celecoxib
Whaich NSAID has the most COX 1 selectivity and is the only one that is parenteral?
Ketorolac
What is an important side effect of celecoxib due to its sulfonamide characteristics
Stevens-Johnson syndrome
- if they have a sulfonamide allergy
- skin looks red and hyperreactive
What is more important, half life of cox or half life of aspirin?
Half life of cox trumps all
Can platelets regenerate cox?
No, because they don’t have a nucleus
What is a consequence of blocking PGE2?
- inhibit inflammation
- but also inhibit normal gastric mucosa…. ulcers
What is aspirin metabolize by?
- liver
- turns it into salicylate
- so , high dose ASA is a pro-drug for anti=inflammatory doses of salicylate
What was the big underlined thing that he had as a contraindication to salicylates and aspirin?
-Reye’s syndrome
Describe the progression of aspirin/salivylate toxicity
- they uncouple mitochondrial ox phos in CNS
- resp venter thinks that means low ATP
- hyperventilation happens so we can get more O2
- drop in CO2 causes alkalosis… kidney depletion of bicarb
- organic acids accumulate because ATP is no longer generated through the krebs cycle
- Metabolic acidosis becomes life-threatening
what is preferred over aspiring in children <19?
- acetaminophen
- don’t want to give them Reye’s syndrome
What are the traditional NSAIDs?
- ibuprofen
- naproxen
- diclofenac
- indomethacin
What is the one Coxib?
-celecoxib
What are the salicylates?
- salicylate
- diflunisal
- aspirin
What is the main step that NSAIDs and co. block?
-COX mediatd conversion of AA into PG
difference between COX1 and COX2?
- COX1 is constitutive: prominent role responding to physiological stimuli
- COX2 is the induced kind…. prominent role responding to pathological stimuli
- both of them are in the Kidney
COX1’s role in inflammation?
- inflammation stimulates AA release
- COX1 converts AA into PGE2
- PGE2 causes symptoms
What will amplify the symptoms of inflammation?
-COX2 derived PGE2
What does tNSAIDs mean?
- traditional NSAIDS
- Ibuprofen
- Naproxen
- Diclofenac
Are salicylates and NSAIDs selective?
- No!
- they inhibit both COX1 and 2
When are NSAIDs contraindicated?
- Asthma for sure
- Gut inflammation
- Infectious inflammation fever (paradox)
Risks and complications of tNSAIDs?
- Ulcer
- Bleeding
- Peripheral edema from high BP (b/c kidneys arent getting enough blood
What is so great about COXibs?
- selective inhibition of COX2 isoenzyme
- COX1 sparing
Coxibs contraindications?
- hypersensitivity to sulfonamides
- Stevens-Johnson syndrome
- toxic epidermal necrolysis
What contraindication do we still have with Coxibs?
-peripheral edema because COX2 is still supposed to be doing things in the renal artery
Is low dose aspirin anti inflammatory?
-no, but it is good for its anti thrombotic effects
What is special about the cox inhibition from ASA?
- it is irreversible!
- COX inhibition persists days after ASA is metabolized and excreted
- duration of action depends on cells’ ability/rate of COX regeneration
What is more important, the half life of COX protein or half life of aspirin?
-t1/2 of COX protein trumps t1/2 of aspirin
Why can’t platelets regenerate COX?
-because they don’t have a nucleus!
MOA for aspirin at anti-inflammatory doses?
- it’s a pro-drug… gets turned into salicylate which is a reversible COX inhibitor
- but aspirin itself is an IRREVERSIBLE inhibitor because it acetylates COX… so the only way we can get COX function back after that is to make more of it!
What does COX1 make that gives us increased risk for CV probs with coxibs?
-thromboxane!
With the exception of aspirin, what do all NSAIDs have as of 2005?
-a black box warning for CV risks
When should we avoid use of NSAIDs?
-pt’s with existing CV disease or risk factors for CV disease
