LEC 26 Inflammation and NSAIDs Flashcards
What characterizes an inflammatory response?
- Transient local vasodilation
- Increased capillary permeability
- Infiltration of leukocytes and phagocytes
- Resolution with or without tissue degeneration and fibrosis
What are the prostanoids involved in an inflammatory response?
- Prostaglandin E2 (PGE2)
- Prostacyclin I2 (PGI2)
- Thromboxane A2 (TxA2)
Which two prostanoids are important for leukocyte attraction and adhesion to endothelial cells at a site of injury?
- PGE2
- TxA2
What effect to prostaglandins have on nocireceptors?
Prostaglandins increase the sensitivity of nocireceptors causing peripheral sensitization
Reveral of this is thought to be MOA of NSAIDs
Which prostanoid contributes to central sensitization?
PGE2
What part of the brain regulates body temperature?
Hypothalamus
How are fevers mediated?
- COX-2 generation of PGE2
- PGE2 crosses blood-brain barrier resulting in elevated body temp
NSAIDs inhibit COX-2 dependent PGE2 synthesis
How do NSAIDs work?
Inhibition of cyclooxygenase
Inhibition of COX-1 results in what?
- decreased platelet fxn
- removes gastric protection
Inhibition of COX-2 results in what?
- antipyretic
- analgesic and anti-inflammatory actions
Most NSAIDs are what kind of inhibitors of COX?
competitive, noncompetitive, or mixed REVERSIBLE
Aspirin is what kind of inhibitor of COX?
non-competitive, irreversible
Acetylates the isozyme in the AA-binding channel
What are the negative effects of COX-1 selective blockers?
GI toxicity
Ulcers, GI bleeds, stomach upset
What are the negative effects of COX-2 selective blockers?
Cardiovascular side effects
What is the common suffix for COX-2 selective inhibitors?
-coxib
What is the function of COX-1 normally?
- cytoprotective for gastric epithelial cells
- forms TXA2 in platelets and cause platelet activation and constriction of injured vessels
Largely accounts for gastric side effects via PGE2
What is the function of COX-2 normally?
- BP regulation and inhibitors of hemostasis
- Inhibition of COX-2 alone can cause HTN and an increase in thrombotic events
What is aspirin’s MOA?
- Acetylates serine 529 subunits of both COX 1 & 2 blocking AA
- inhibition occurs in the endothelial cells and platelets
- Endothelial cells can make new COX enzymes but platelets cannot (permenant inactivity for lifetime of platelet, 8-12 days)
How long after taking aspirin is enough for a partial platelet pool recovery for a simple surgery?
3 Days
Why is it important that synovial concentrations of NSAIDs are about half of the plasma concentration?
Makes NSAIDs effective for arthritis pain
Where are NSAIDs metabolized?
Liver then renal exretion
In the plasma, 95-99% of NSAIDs are found bound to what?
Plasma proteins like albumin
Why are NSAIDs not removed by hemodialysis?
d/t high protein binding in the plasma
What is the dose of a baby aspirin?
81 mg
What are PGE2’s GI functions?
- Inhibit acid secretion
- Enhance mucosal blood flow
- Promote secretion of cytoprotective mucus in the intestine
What are the adverse effects of selective COX-2 inhibitors?
- Inhibit fxn of PGI2
- PGI2 inibits platelet aggregation & the prothrombotic effects of TXA2
- They do not inhibit TXA2 prodxn (COX-1)
- TXA2 is unopposed (by PGI2) and results in prodxn of new platelets and increased platelet aggregation
- INCREASED MIs AND STROKES
What effect do PGE2 and PGI2 have on the kidney?
- They are vasodilators of the afferent arteriole on each glomeruli
- This dilation is needed to maintain normal kidney perfusion especially in: Dehydration, Hypovolemia, CHF, Liver cirrhosis, and CKD
Unopposed constriction results in decreased perfussion and GFR
Why do you not give aspirin to pts under 20 y/o?
They can get Reye syndrome
acute encephalopathy, hepatomegaly, liver dysfunction, fatty liver
What is the half-life of aspirin?
2-3 hours
What is the half-life of diflunisal?
8-12 hours
How are the effects of diflunisal different from aspirin?
- 4-5x more potent analgesic/anti-inflammatory
- weaker antipyretic
- fewer platelet and GI side effects
Which salicylate is not effective orally?
Mesalamine
given as an enema or suppository for ulcerative colitis
What is the use of Indomethacin?
used to treat patent ductus arteriosis - successful closure in >70% of neonates
Has many adverse effects and is not a 1st line NSAID
What adverse effects are associated with ketorolac?
- high risk of renal dysfunction - max use of 5 days
- Steven Johnson syndrome
- gastric ulceration
PO & IM use; Potent analgesic but mod anti-inflam
What do you combine with Diclofenac to prevent ulcers?
Misoprostol
What is the advantage of naproxen over ibuprofen?
Naproxen has a longer half life allowing for BID dosing
What is the only selective COX-2 inhibitor still on the market in the US?
Celecoxib
What is the dosage limit for acetaminophen?
4 grams in 24 hours
What is the dosage limit for elderly people for acetaminophen?
2 grams in 24 hours
How many grams of acetaminophen to cause hepatotoxicity? to cause death?
Hepatotoxicity: 10-15 g
Death: >25 g
How do you treat acetaminophen overdose?
- Activated charcoal if it is still in the stomach
- N-acetylcystine IV for glutathione repletion
