CT/MSK: Anti-Inflammatory Drugs Flashcards
Comment on the differences between ACUTE and CHRONIC inflammation in terms of:
histology (content of cellular infiltrate)
onset
vascular dilation permeability
drug treatments
Acute
- Neutrophils
- faster onset
- more vascular dilation + permeability
- Rx: NSAIDs, COX2, acetaminophen
Chronic
- Mixed inflammatory cell infiltrate (macrophage, lymphocytes, plasma cells)
- Slower onset and more protracted course
- less vascular dilation + permeability
- Rx: DMARDs, steroids, anti-biologics
What is the key step to initiating chronic inflammation?
leukotriene-mediated chemotaxis of cells to site of inflammation
T/F Acute inflammation always precedes chronic inflammation.
FALSE.
chronic inflammation CAN occur w/o acute inflammation (ie reactivation of dz, autoimmune disease)
Why wouldn’t use use NSAIDs to treat a chronic inflammation?
NSAIDs can provide some relief but will not resolve chronic inflammation (they block COX enzymes, but remember, the key step in initiation of chronic inflammation is leukotriene-mediated chemotaxis of cells to site of inflammation, which involves lipoxygenases)
Diagram the production of prostaglandins (generally) and indicate where these drugs will affect the pathway:
glucocorticoids
NSAIDs
COX2 inhibitors
Rapid Associations:
Role of COX in GI protection
PGE2/PGI2 -> decrease proton pump activity & increase mucus secretion
Rapid Associations:
Role of COX in platelets
COX1 -> increase thromboxane A2 (TXA2) -> pro-thrombotic
Rapid Associations:
Role of COX in endothelial cells
COX2 –> increase prostacyclin -> anti-thrombosis + vasodilation
Rapid Associations:
Role of COX in the kidney
- COX1 functions in control of renal hemodynamics and GFR (produces prostglandins for vasodilation of afferent arteriole)
- COX2 functions effect salt and water excretion (NSAID decreases PGI2 -> hyperkalemia and acute renal failure)
Rapid Associations:
Role of COX in the brain
COX3 -> does not actually exist!!! Ha..ha…ha
What is the role of COX1? COX2?
- *COX1** = homeostatic regulation: maintenance of normal renal function, gastric mucosal integrity, and hemostasis
- expressed constitutively and synthesizes PGE2
- *COX2** = induced in response to stress, infections, cytokines and inflammatory mediators (IL1, TNF, LPS, mitogens, ROS).
- expression increases during inflammation/stress, and causes an increased PGE2; results in
- vasodilation (redness, warmth, swelling)
- pain transmission
- fever (via signaling at the hypothalamus, which subsequently leads to the production of IL2, IL6, which drives fever and temperature)
What are NSAIDs?
What organ systems do they affect and what is the mechanism by which it occurs? (4)
What are the toxicities? (6)
What are the contraindications? (2)
- weak organic acids; **non-selective COX inhibitor **
**GI effects **- COX1 production of PGE2/PGI2 -> increased proton pump activity and decreased mucus production -> increased acid + decreased protective layer (managed with PPIs)
Platelet effects - COX1 inhibition - decreased thromboxane A2 -> limited thrombotic reaction
- *Renal effects**
- COX1 inhibition -> decreased PGE2 -> Na retention (low FENA due to afferent arteriole vasoconstriction), increased BP/weight (H2O retention) and CHF (rare)
- COX2 inhibition -> decreased PGI2 -> hyperkalemia and acute renal failure
- *Pathophysiology effects**
- COX inhibition -> decreased inflammation, pain, fever)
- *Toxicities**
- GI Toxicity
- Bleeding
- CNS toxicity (at very high doses)
- Salicylism (tinnitus, nausea, vomiting)
- Anaphylactic shock
- Fluid retention and renal distress/failure
Contraindications
- 3rd trimester of pregnancy (PGE2 maintains patency of ductus arteriosus): NSAIDs can cause premature PDA closure in utero
- children with viral fever: NSAIDs can cause Reyes Syndrome
Do NSAIDs affect the leukotriene pathways?
most do not inhibit leukotriene synthesis, therefore if COX activity is inhibited, then there is an accumulation of arachadonic acid that can get shunted into the leukotriene pathways.
Reason why you can get NSAID-induced asthma.
Which one is reversible and which one is irreversible?
NSAIDs
Aspirin
NSAIDS - REVERSIBLE
Aspirin - IRREVERISBLE)
Why are COX2 selective inhibitors taken off the market at one point?
Endothelial cells – COX2 inhibition - decreased prostacyclin production -> vasoconstricton + increased thrombotic event (since platelets are still capable of initiating thrombosis)
increased risk of cardiac events and stroke
(but do not cause bleeding problems, renal complications)
What is the mechanism by which Acetaminophen acts?
What is the main toxicity?
mechanism is unknown, but it is still widely prescribed.
hepatotoxicity/liver failure
