Toxo- NSAIDs

wilsbach's version from 2016-03-03 19:35


Question Answer
most often, why are animals being toxed with NSAIDs?off-label use from owners!!!
top five NSAID contendorsaccording to poison control center of ASPCA. #1 is ibuprofin. #2 aspirin. naproxin #3 diracoxib #4, meloxicam #5
how do NSAIDs work?They inhibit COX which inhibits prostaglandin production (prostaglandins are lipid mediators) (prostaglands can be aka prostanoids aka iscotanoids)
who is more toxe by NSAIDs- dogs or cats?DOGS>>cats
is COX 1 or COX2 inducible?COX 1 is always around for basic body functions (constituant). COX2 has inflammatory effects so it is induced when it is needed (inducible). (however there are some vice-versas)
which NSAID is COX specific?Aspirin
which NSAIDS are COX 2 specific?Firocoxib, Robenacoxib, Deraxocib
so arachionic acid is either broken down into _________ by _________ or _________ by ___Either by COX into prostaglandins and thromboxanes, or by lipoxygenase into leukotrienes
(pathways) what happens if you block all of the COXs?it forces arachionic acid to to LOX path--> makes excessive leukotrienes, and leukotrienes can result in bronchoconstriction (hence aspirin induced asthma)
what is the COX-LOX specific NSAID?Tepoxalin (lox aka lipo oxygenase is for producing leukotrienes)
what are the COX-2 selective (but still do COX 1) nsaids?Meloxicam, Naproxen, Carprofen, Etodolac
PATH for MOA of NSAIDSmembrane phospholipids broken down into arachidonic acid. AA can either be broken down by LOX(lipoxygenases) into leukotrienes/other eicosenoids, or broken down by COX1 and COX2 (cyclooxygenase)--> first get prostaglanding G--->prostaglandin H2--> then you get thromboxane/PGI2 PGE2
what does thromboxane do?(breakdown product of AA by cox gets you this) it is prothrombotic, can lead to cardiotox
prostacyclin has receptors where?endothelium, kidney, PLATELETS, brain
thromboxane A2 has receptors where?PLEATELETS, vascular sm mm cells, macrophages, kidney
prostaglandin D2 has receptors where?mast cells, brain, airways
prostaglandin E2 has receptors where?brain kidney vascular sm mm cells, platelets
*which prostaglands are associated with eye/have glaucoma tx implications?PG F2-alpha
prostaglandin F2a has receptors where?UTERUS, airways, vascula sm mm cells, EYE
uterus has receptors for whar prostaglandin?F2a
which drugs have the hydrophilic group necessary to bind in the hydrophilic pocket of COX2 an can block the COX entrance?The "coxibs"
what are the big differences between COX 1 and COX2?min. amt of amino acids are diff, but entrance into enzyme is (IN PIC B IS COX 1 AND C IS COX 2) different. So normally AA goes into pocket of th enzyme where it is converted by enzymatic activity into PGs and then it leaves (As shown in A). So COX 1 has a relatively narrow opening for it to get into site where drugs are active. COX 2 is much wider, and it ALSO has a hydrophilic side pocket. SO. If you use aspirin. in COX 2, the aspirin binds into the side pocket and bc of how wide it is, AA can get around it, and aspirin doesnt block the site of enzymatic conversion (hence aspirin is only COX1 selective). So you need COX 2 specific inhibitors bc the hydrophilic group of the "coxibs" drugs which fit into hydrophilic side pocket abd then also binds to hydrophobic channel= 2 binding sites, and complete blocks the entrance so AA can't get in.
what are the functional effects of inhibition of COX1? (3 main areas)(1) Upper GI tract--> dec mucosal defence--> inc ulcers. (can happen outside of the stomach too, high doses or oral ones can lead to oral ulcerations/duodenum. RDC too.) (2) lung (PARTICULARLY asthmatic lung)--> inc leukotriene production (bc AA takes LOX path if COX is blockeD)--> bronchoconstriction. [note that the worse dzd resp system will react with worse bronchoconstriction with NSAIDs] (3) platelets--> dec TxA2 production--> anti-thrombotic (low dose has antithrombotic effect)
why do you nly need a low dose of NSAIDs to cause platelet inhibition?(COX 1) bc bind permanently to cox 1 in to platelets
what are the functional effects of inhibition of COX2? (3 main areas)(1) Kidney (fluid/salt depleted makes this worse)--> dec GFR and Na resorption--> edema, inc BP (2) tumor--> inc apoptosis--> dec tumor growth. (3) blood vessels--> dec PGI2 production-->pro-thrombotic?
why does COX 2 cause edema and incBP?bc affects kidney-- dec GFR and Na resorption
if you wanna kill a tumor with apoptosis, which COX do you choose?COX2
why RDC in horse affected by NSAIDs so much?RDC becomes wider and stomach shaped-- and many oral NSAIDs bind to cellulose component of their food, then cellulose broken down in cecum, so large portions of NSAIDs then become avail there. From cecum into colon...eventually into RDC. and RDC wider than the rest of the colon, so thats where there is some stasis of content-- so bigger opportunity of NSAIDs to interact with gut all. And they have a DIRECT effect on mucosa. (in other portions of colon it moves a lot more and doesnt have this long contact time). Also RDC has diff blood flow so more drug is delivered there too. Dx RDC ulcers with US. (dont really see blood in feces or colic, just dont feel that well)
if given orally, where are NSAIDs absorbed? (what is their pH)They are ACIDIC drugs (remember how aspirin has acid in its formal name), absorb in stomach bc not ionized. so as soon as they move into your sm int, they are ionized and wont be absorbed
so NASAIDs are absorbed where again? what happens as soon as they are absorbed?acidic drugs-- so absorb in acidic stomach. But then enter gastric cells where it isnt as acidic and they will be ionized to a large extent-- ion trapped in stomach cells. Which means that is why they have effect on stomach
how can you use food/drugs to delay absorption of NSAIDs?Food and drugs that increase gastric pH will delay absorption
what is plasma protein binding like for NSAIDS?high (albumin)
cat alternative path to metabolism of NSAIDs since no glucoronidation?sulphate path.
what dz can lead to delay of elim of NSAIDs?liver dz bc metabolized in liver (mainly oxidation with CPY450, also cats sulphotransferase as alternative to glucoronidation)
what are the main metabolism paths in the liver for NSAIDs?(in pic bold arrows are main paths) MAINLY CyP450 mediated oxidation. (hydroxy-Nonsteroidals) then some are excreted with urine and others are glucuronidated with non-steroidal-glucuronide and then are excreted in kidney. Since cats cant glucuronidate they are often sulfated
whats UGT again?glucoronidation
there are species differences in the COX 1 COX 2 ratio. what safety implications does this have?diff ways to determine COX1 COX2 ratio. need to keep in mind neg effects and risk factors and know how they might react
horses tend to get what NSAID bad side effects? horses tend to get GI issues. Not many renal issues.(remember tables with giff COX ratios)
dogs and cats tend to get what NSAID bad side effects?DOGS/CATS tend to get more renal effects (remember tables with giff COX ratios)
Potential adverse effects of NSAIDS?Inappetence, Signs of depression, Gastric and gastrointestinal mucosal damage and ulceration: colic and diarrhoea, Weight loss, Protein losing enteropathy and septic shock, Renal papillary necrosis and interstitial nephritis
why do DOGS/CATS tend to get more renal effects than horses?(Renal papillary necrosis and interstitial nephritis) URINARY pH DIFFERENCES!!! carnivores have more acidic urine, means more uptake of the NSAIDS into renal tissue (in horses alkaline pH, ionized and excreted)
which COX affects renal Na balance? kidney development? Anti tumor effects? myocardial protection?COX 2, COX 2, COX 2, COX 2
which two prostaglandins deal with kdiney GFR maintainance?PG E2 and PG I2
explain the NSAID affects on the kidney (moa)PG E2 and PG I2 very important in maintaining the vasotension on renal artery (afferent areterioleS)--> determine GFR/amt of blood to kidney. DEC GFR--> probs with reabsorption of Na etc. So NSAIDS not only affect fxn of kidney, but also have that direct effect on tubules when they are reabsorbed. combo results in renal damage.
explain all the effects of NSAIDs on the renal microvasulatureDEC PGs and INC Leukotrienes, and INC TNF--> express adhesion molecules--> neutrophils adhere--> stasis--> ischemia--> free radical formation, activation of proteases
explain direct and PG mediated damage to GI epitheiumDIRECT: reabsorption of H+ ions, oxidative phosphorylation dec, reduced mucosal hydrophobia. PG MEDIATED: acid secretion inc, mucus sec dec, dec bicarb secretion, dec mucosal perfusion, dec cell prolif.
___ function as vasodilatory agents to regulate renal blood flow. Explain the effects of their inhibition.PGE 2 and PGI 2, Decreased renal perfusion: afferent arteriolar dilation. Effects more prominent during hemodynamic compromise! NSAID-use will result in ischemic injury - acute renal failure
what factors can make renal damage from NSAIDs even worse?Concurrent use of other nephrotoxic drugs, Shock - dehydration - post-surgical (hemodynamic compromise)
explain the effects of NSAIDs on the stomachplay large role in epithelial cells and parietal cells. Normally, prostaglandins stim prosta receptors--> in parietal cell, leads to dec in H+ and K+ atpase pump (proton pump) if dec activity of pump, less H into stomach, so stomach less acidic. at same time, superficial epi cells-- prostaglandins stim prost receptor-- inc mucus production and inc elim of bicarb. (mucus cytoprotection and bicarb results in buffer between gastric lumen and mucus cell lauer where pH about 7. so use NSAIDs, the break on elim of acid is gone (the poroton pump signsal is gone, so pumps out more hydrogen)--> more acidi stomach, and then stop mucus production ,and stop cystoprotective bicarb. produce more aci and take away defense mechanisms of cells in the stomach. ALSO inhibit of COX (esp2) inhibits angiogenesis-- so if any damage to parietal cells, then nees to be repaired by inc bloodflow to that area...[SO, PRODUCE MORE ACID AN TAKE AWAY DEFENSE BARRIERS]
_________ play a role in the formation of the production of the bicarbonate rich mucous gel layerEndogenous PGs
COX _________ inhibition particularly inhibits angiogenesis2 (inplications of blood supply to stomach with damage)
what are the local vs systemic effects of NSAIDs on the stomachLocal effects: concentrated in the stomach wall due to ion-trapping - physical properties of NSAIDs. Systemic effects: result of effects of NSAIDs on endogenous PG production
flowchart of all the factors contributing to ulcers in the stomach
horse GI effects of NSAIDS ulceration, also many infltrates of WBCs (inc leukocyte adherence proteins)
explain effects of NSAIDs on CV system?debate over if it is caused by COX 1 or 2. (COX2 inhibitors showed inc in cardiac failures in humans) failure/arrest/stroke. but dont really see it in animals that much. inc production of thromboxane and vasoconstruction. (remmeber thromboxane made with PGs) can lead to enhanced clot formation
platelets only have what COX?only COX 1
explain COX inhibition and affect on coagCOX-1 effect (only COX-1 in platelets) Inhibition of TxB 2 (thromboxane) synthesis: decreasing the ability to adhere, Acetylsalisylic acid binds irreversibly to COX-1: effect only reversed with production of new platelets. Low concentration does this!! like a tenth of a dose of a headache dose.
need to consider NSAID paththrough body- how are they recycled? implications?enerohaptic circulation. so need to go aggressive contamination for several days in a row.
ways to tx GI issues from NSAID tox?Directly give PG: (misoprostol - synthetic PG analogue)<--bind to EP3 receptors to restore their fxn.. H2-blockers (cimetidine, ranitidine, famotidine), Proton-pump inhibitors (omeprazole, esomeprazol, pantoprazole), Sucralfate
how can you try to help kidney from NSAID tox?Symptomatic treatment: intravenous fluids - increase renal perfusion
if you see liver damage (inc liver enzymes) with nsaid tox wat can you give to tx? why liver damage happening?SAMe in animals with signs of increased liver enzymes. if NSAIDS start having effect on liver, result of lipidpperxoidase formation, reactive o2 spec formation...particular antioxidant drugs can be helpful there.