What sorts of pain will NSAIDs be effective for?
pain due to inflammation - only works for mild to moderate pain, but there's fewer adverse effects
What biochemical pathway is affected by NSAIDs?
the arachidonic acid pathway
Describe the arachidonic acid pathway
trigger activates phospholipase, which releases an arachidonic acid from the membrane phospholipids
arachidonic acid is acted on by loposygenase or cyclooxygenase
lipoxygenase creates leukotrienes
cyclooxygenase makes prostaglandins, thromboxanes and prostacyclins
What enzyme in the arachidonic acid pathway is blocked by NSAIDs?
COX1 and COX2
How are COX1 and COX2 different?
COX1 is active under normal physiology - promotes prostaglandin production that provide gastric cytoprotection, vasodilation, and platelet aggregation
COX2 is inducible in response to inflammation
What effect do thromboxanes have on platelet? How about prostacylincs?
thomboxanes promote platelet aggregation
prostacyclins inhibit platelet aggregation
How are prostaglandins related to pain and why does blocking their production make pain better?
they modify te nociception threshold by making the threshold for activation lower - more sensitive to pain
What is special about aspirin among the NSAIDs?
It irreverisbly inhibits both COX1 and COX2, while the other NSAIDs reversibly inhibit them
What three things are all NSAIDS capable ot?
How is the antipyretic effect of NSAIDs mediated?
PGE2 is what triggers the hypothalamus to increase the body temp set point - that's why you get fever in inflammation
if you use NSAIDs to block PGE2 production, body temp normalizes
What are the adverse effects of the NSAIDS - especially aspirin?
It causes gastrointestinald istress
the prostaglandins that were made by COX1 and had protective effects in the GI system are no longer synthesized, so you get increased gastric acid secretion and decreased mucous secretion, leading to capillary damage, necrosis and bleeding - iron deficiency anemia
increased clotting time
respiratory and electrolyte disturbances
How significant is aspirin's impact on clotting time?
you get a 2x increase in clotting time for a week after a single dose of aspirin because of the irreversible inhibition of COX (thromboxane synthesis) in platelets
When should you stop NSAIDS before elective surgery? Aspirin specifically
stop NSAIDs 2 days before and aspirin 1 week before
How do the NSAIDs lead to respiratory and electrolyte disturbances?
high doses stimualte respiratory center int he medulla, leading to hyperventilatoin
this hyperventilation causes respiratory alkalosis (increase blood pH)
It can also cause metabolic acidosis because toxic doses of aspirin can uncouple oxidative phosphorylation such that lactic acid accumulates in the serum, decreasing blood pH - this is the bigger deal than above
What are the mild toxicity symptoms with aspirin OD?
sweating, thirst, hyperventilation
What are the most severe toxicity symptoms in aspirin OD?
agitation, hyperactivity, slurred speech, tremor, seizures, coma
fever (especially in children)
How do you treat an aspirin overdose?
gastric decontamination: induce vomiting, gastric lavage, activated charcoal
correct the acid base imbalance by giving sodium bicarb
maybe blood transfusion and dialysis to clear the system
full reovery IS possible if treated
What happens in an aspirin hypersensitivity?
rhinitis, profuse secretions, branchial asthma, bronchoconstruciton, hypotension, vasomotor collaspe, copa
It is NOT immune mediated though - they think it's because the arachidonic acid that can't be acted on by COX is shunted into the liposygenase pathway, yielding excess leukotrienes
What is the treatment for an acute aspirin hypersensitivity reaction?
epinephrine (same as an anaphylaxis)
avoid NSAIDs and other salicilates in the future
What is Reye's syndrome?
It's a fatal condition associated with aspirin use in the presence of viral infection - so don't give to kids with chidken pox
Why do you want to avoid concurrent aspirin use with other NSAIDS?
Because prophylactic aspirin targets thromboxanes first, so you get reduced clotting
However, if given with other NSAIDs, this can also target the proctacyclin production, so clotting actually can be increased!
Why is ibuprofen nice compared to aspirin?
it has fewer GI adverse effects and the clotting effects are reversible
What is special about indomethacin? WHy is it not used often?
It's the most potent COX inhibitor
It has significant toxicity, so it's usually only used if other NSAIDS have been ineffective
What congenital disorder is indomethacin used to treat?
patent ductus arteriosus
What ist he NSAID that can be injected and replace morphine if opioid addiciton is an issue?
What is special about celecoxib?
it is a selective COX2 inhibitor, so you get the inflammation reduction without the harmful GI effects
Why is acetaminophen NOT an NSAID?
It doesn't have anti-inflammatory effects although it is analgesic and antipyretic
What are the pros of taking acetaminophen besides the minimal effect on GI?
it also has no effec ton bleeding or on respiration
What is the major issue with tylenol toxicity though?
It's therapeutic index is much lower than other OTC meds because a toxic free radical metabolite is formed in the liver and can cause hepatic necrosis
Why should you not drink alcohol with tylenol?
ethanol will shift liver metabolism to the toxic metabolite, thus increasing risk of hepatotoxicity
What is the treatment for a tylenol overdose?
N-acetylcysteine works as a scavenger drug so that is picks up all the qhinone free radical product
(basically an exogenous equivalent of glutathione)