what cascade are NSAIDs active on?
the arachadonic acid cascade
what are the 2 enzymes active in the arachadonic acid cascade?
lipoxygenases, (arachidonic acid->leukotrienes) and cyclooxygenases,(arachidonic acid->thromboxanes, prostaglandind)
what is the target of NSAID inhibition? why?
cyclooxygenase, (COX). these can cut down inflammation as well as pain, (analgesic property)
what things can cause pain in the body?
potassium, serotonin (anti-pain NT in CNS/pro-pain NT in PNS ), bradykinin, histamin, *prostaglandins, leukotrienes, and substance P (NT)
what prostaglandins are responsible for inflammation?
PGE2 and PGI2 are responsible for erythema, edema and increased blood flow
what prostaglandin is associated with the production of fever?
increased PGE2 synthesis in the hypothalamus is associated with fever
how do prostaglandins affect renal function? is this good for the kidneys?
in the kidneys, prostaglandins promote increased renal flow, increased glomerular filtration rate, renal vasodilation, and increased excretion of Na+, K+ and H20 -> these are all beneficial for good kidney function
how do prostaglandins affect the GI? are the effects generally positive?
prostaglandins promote secretion of mucus and inhibit the secretion of acid, (both good for the GI)
how do prostaglandins affect the blood? do all prostaglandins have the same effect?
different prostaglandins have opposing effects on the blood: PGI2 inhibits aggregation, (antithrombogenic effects), and TXA2 induces platelet aggregation, (thrombogenic effects)
what effect do NSAIDS have in low doses?
antithrombotic effects, through more selective inhibition of thromboxane synthesis in platelets
what effect do NSAIDs have in high doses?
thrombotic effects through broad inhibition of prostacyclin
what are characteristics of most NSAIDs? in terms of effects, absorption, protein binding, site of metabolism/excretion
COX inhibition, analgesic/antiinflammatory/antipyretic/antiplatelet, absorbed from stomach/small intestines, highly bound to plasma proteins, and metabolized by the liver/excreted by the kidney
what are contraindications for most NSAIDs?
asa hypersensitivity, liver/renal dysfunction, alcoholism/smoking (lead to ulcers), caution during pregnancy/breast feeding (RA etc are exceptions)
what are3 ex of salicylates?
salicylic acid, aspirin, diflunisal
what is the generic name of aspirin?
aceytlsalicylic acid, (aspirin is an old brand name).
where did salicylic acid come from originally? why did bayer acetlyate it?
a tea made from tea bark that helped with inflammation but caused GI tract pain. bayer found that acetylating salicylic acid cut down absorbtion-associated stomach pain, (hydrolysis in digestion de-acytelates it and it becomes salicylic acid again in the bloodstream)
why can aspirin be considered a pro-drug?
it has to be biotransformed to be active
can people w/asa allergry still have a rxn to aspercreme?
what are the 4 A’s of aspirin action? does it affect respiration? how?
Analgesic, Antiinflammatory, Antipyretic, Antiplatelet. asa stimulates respiration by uncoupling oxidative phosphorylation and stimulating the medullary respiratory center. it also alters the acid-base equilibrium, b/c of action on heart/kidneys/respiration
what is asa used for?
pain, inflammation, fever, (pyrogen-induced and CNS response), cardiac conditions to reduce blood clotting
is asa’s inhibition of COX reversible? what are the implications of this?
no, asa irreversibly inhibits COX. therefore effects of the drug will last until new COX is made – this is why asa is recommended after MIs
does asa have high binding to plasma proteins? what does it compete with/what are the implication of that?
yes 80-90% asa competes with thyroxine, PCN, phenytoin, naproxen, sulfinpyrazone, and bilirubin, (it could displace them from that carrier protein – can be problematic w/phenytoin and thyroxine (T4 thyroid hormone), displaced over time can lead to hyperthyroidism
what happens to acetylsalicylic acid in the plasma?
it is hydrolyzed to salicylate
what are asa side effects on the CNS? GI? liver?
CNS: tinnitus, vertigo, confusion/delirium. GI: nausea+emesis (vomiting), local gastric irritation w/bleeding (prostaglandins increase mucus+decrease acid in the stomach/duodenum and asa decreases platelets), hepatoxicity w/prolonged high doses or viral infection
what are contraindications for asa?
asa hypersensitivity, chronic liver disease, gout, peptic ulcer, hemophilia/vit K deficiency (already have excessive bleeding), diabetes (renal complications), chickenpox or influenza in children -> high risk of developing reyes syndrome, (metal retardation)
what is salicylism?
asa overdose. when mild: headache/dizziness, tinnitus, dim vision, mental confusion, drowsiness, vomiting/diarrhea, sweating, thirst, nausea and hyperventilation
what happens at higher dose salicylism?
generalized convulsions, skin eruptions, marked alterations in acid-base balance, fever, and serious dehydration due to hyperpyrexia, sweating, vomiting and loss of water vapor (during hyperventilation)
at what plasma level are asa’s analgesisic, antiplatelet and antipyretic effects seen
0-10 mg/dL
at what plasma level are asa’s antiinflammatory effects seen?
10-50 mg/dL
at what plasma level do you start seeing asa’s mild intoxication effects? **what is an important marker for this plasma level?**
50-80 mg/dL, tinnitus will start at mild intoxication
at what plasma level do you start seeing asa’s moderate intoxication effects?
80-100 mg/dL
at what plasma level do you start seeing asa’s severe intoxication effects?
110-160 mg/dL
at what plasma level do you start seeing asa’s lethal intoxication effects?
past 160 mg/dL
what starts at mild asa intoxication?
tinnitus will start at mild intoxication, this used to be used as doctors’ way of managing individual doses, (they would prescribe up to this point)
what are treatments of asa toxicity?
induce emesis (vomiting), gastric lavage, activated charcoal, hydrate, and correct acid/bast balance. the first three procedures try to minimize asa levels, and the liver really has to do the rest.
what is DOLOBID/diflunisal? what is its potency relative to asa? does it have anti-pyretic effects? how does it affect platelet levels?
diflunisal is a difluorophenyl derivative of salicylic acid. it is a more potent antiinflammatory/analgesic effects than asa, but has no antipyretic effects due to poor CNS penetration. it has less antiplatelet activity, leading to insignificant prologation of bleeding time and less occult blood loss than asa (blood in stool – doesn’t affect platelets as much, so even if it damages the GI, clotting occurs better).
what is diflunisal used for?
pain, osteoarthritis, RA -> more severe inflammatory conditions
what is diflunisal’s mechanism of inhibition?
it is competetive COX inhibitor
how much of diflunisal binds to albumin? what does it compete with?
it binds 99% to plasma albumin and competes with oral hypoglycemics (like metformin for diabetics) and anticoagulants (coumadin/warfarin)
what are side effects associated with diflunisal? is tinnitus associated with diflunisal?
dizziness, nephritis, and gastric ulceration. diflunisal does not produce tinnitus
is diflunisal contraindicated for anything?
asthma, may have to do with issues of pushing respiration
what is acetaminophen? what are its effects?
a para-aminophenol derivative. it is an analgesic, antipyretic, and has a weak antiinflammatory effect. it is known as paracetamol in europe.
when is acetaminophen used?
when asa and other NSAIDs are contraindicated, (such as asa sensitivity or chickenpox/infuenza to avoid reyes syndrome)
can acetaminophen be used to treat gout?
yes, it is used concomitantly with probenecid for gout tx
what is the acetaminophen’s mechanism of antipyretic action? is acetaminophen’s mechanism of analgesic action known?
acetaminophen blocks COX in the hypothalamus (lowers fever) BUT elsewhere it only inhibits COX in environments w/low levels of peroxides. there are high levels of peroxides in inflammatory lesions, which is why it has weak inflammatory effects. its analgesic mechanism is unknown.
how much plasma protein does acetaminophen bind?
how does the liver metabolize acetaminophen?
90%+ of acetaminophen conjugated with glucuronic acid, sulfuric acid, or cysteine in the liver. a small portion (~10%), of acetaminophen is also metabolized in the liver by microsomal enzymes
can acetaminophen cause GI, bleeding, renal or pH problems? what side effects can it cause?
acetaminophen causes no GI, bleeding, renal or pH problems. it can cause hepatoxicity,
what is seen within 12 hrs of acute acetaminophen intoxication?
nausea, vomiting, lethargy, renal tubular necrosis, hypoglycemic coma
what is seen within 48 hrs of acute acetaminophen intoxication?
potentially fatal hepatic necrosis (dose and treatment timing dependent)
what are contraindications for acetaminophen?
acetaminophen is not used for inflammatory conditions (it is however used for analgesia adjunct w/other antiinflammatory agents). it should be used with caution in light of liver disease
who is the hepatoxicity and acetaminophen risk worse for?
children, (ironic b/c it used for fever reduction)
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