Walsh Flashcards
Kinin Cascade
Responsible for the pain involved in inflammation. Also Causes vasodilation, increased permeability of blood vessels, and most importantly it stimulates pain receptors.
- Bradykinin
- – PGs potentiate the action of bradykinin
Prostaglandins
Derived from arachidonic acid
- belongs to the eicosanoid family, which includes PGs, Thromboxanes, and Leukotrienes
- exert their effects locally and they will have different effects in different parts of the body
Prostanoids
PGs and Thromboxanes
PGE2 and PGF2alpha
Promotes gastric mucus secretion and inhibits gastric acid secretion
- protects stomach lining
Mnemonic - eliminating farts, not really applicable but it’s a good way to remember that it has too do with the stomach.
PGE2 is also the main Prostanoid Involved In inflammation
- vasodilation, vascular permeability, increased sensitivity to bradykinin, pain neuromodulation in spinal cord, fever
- So, PGE2 is good in the stomach but will cause ill effects elsewhere
PGI2
Otherwise known as Prostocyclin
- Inhibits platelet aggregation in the clotting process, vasodilation
TXA2 - Thromboxane A2
Promotes platelet aggregation
- the name has thrombus in it so it makes sense
How does PGE2 get to the site of the injury?
Macrophages and monocytes will secrete PGE2 at the site of injury.
What enzyme is responsible for making PGE2?
COX2
What does COX-1 do?
Housekeeping functions
How do NSAIDs work
Reduce the production of PGE2 and therefore reduce swelling, pain, fever, and platelet aggregation
- they inhibit COX-II
Side effects of NSAIDs? Why?
Stomach discomfort because COX-1 and COX-2 are isozymes and NSAIDs are not specific to one of the COX enzymes. Therefore, COX-1 is being inhibited as well. COX-1 is responsible for eh other action of PGE2 - gastric mucus and minimizing gastric acid.
Why might people taking NSAIDs cause allergies and asthma?
Because while you are Blocking COX, you are forcing the other pathway, through 5-lipoxyganse,, and. Make leukotrienes.
5-lipoxygenase
Enzyme in the other half of the arachidonic acid pathway that makes leukotrienes
Why does aspirin Works longer than other NSAIDs
It binds covalently (irreversibly) to COX-1 and COX-2 in platelets
Effect of eating a lot of Omega-3 fatty acids
Reduces platelet aggregation and reduces inflammatory diseases
Rofecoxib
VIOXX
- selective COX-2 inhibitor so tat it only deals with inflammation and platelets but not stomach stuff.
Celecoxib
CELEBREX
- selective COX-2 inhibitor
WHy is there a cardiovascular risk for VIOXX and some of the other COX-2 inhibitors?
Because it causes an increase in the amount of TXA2 relative to PGI2, which will cause clots to form and MI. This is because TXA2 is more made my COX-1 and PGI2 is more made by COX-2.
Why is a baby aspirin good for your heart?
It actually decreases MI risk because it causes you to have more PGI2 than TXA2. This is because TXA2 is made in the RBCs which don’t have a nucleus whereas PGI2 is made in the endothelial cells. If you destroy COX-1 , the TXA2 won’t be made because the lack of nucleus doesn’t allow more to be made. You have to wait for a whole new batch to be made.
Acetaminophen
Tylenol
- reduces pain but not swelling so not technically an NSAID
- reduces PGs in the hypothalamus
- narrow therapeutic window and an overdose can kill the patient.
- heptotoxicitiy can occur in 2-3 times the normal dose. The toxic metabolite is called N-acetyl-p-benzoquinone Imine (NAPQI).
- Antidote for acetaminophen toxicity is N-Acetylcysteine (NAC)
NAPQI
Toxic metabolite in liver during acetaminophen toxicity.
- it is a reducing agent that depletes the glutathione stores
NAC
Antidote for acetaminophen overdose. It increases glutathione stores in the liver
Why might alcoholics get liver injury more easily than regular people from Acetaminophen
They have upregulated CYP450 enzymes, which will make more of the NAPQI.
- they also already have bad livers.
What are corticosteroids used for?
Anti-inflammatory effects - inhibits COX-2
- immunosuppressive effects also
Side effects of corticosteroids
Most are the immunosuppressive effects
- suppression of injury response, wound healing
- suppression of response to infection
- osteoporosis, muscle wasting
- Moon Face (Cushingoid facies)
- can increase blood sugar, increased fatty acid distribution
Neutrophils
First WBCs to arrive on scene and remove debris by phagocytosis
