Name 4 adverse effects of NSAIDs?
- gastrointestinal: anorexia, diarrhoea, vomiting, lethargy
- renal toxicity
- hepatic toxicity
- decreases platelet aggregation
Name 8 relative contraindications for NSAIDs?
- History of GI disease
- NSAID intolerance
- uncontrolled renal or hepatic disease
- Anaemia
- Coagulopathy
- Hypovolemia or dehydration
- Hypotension
- Hypoproteinemia or Hypoalbuminemia
Name 7 common reasons for development of serious adverse effects?
- concurrent corticosteroid administration
- concurrent or recent administration of other NSAIDs
- Higher than recommended dose
- Higher than recommended frequency of administration
- Continued administration in the presence of GI signs
- Lack of close patient monitoring
- Owner’s inability to report or identify clinical signs
How long should the wash-out period after aspirin be and why?
9-11 days due to platelet lifespan
How long should the wash-out period be between 2 different NSAIDs or glucocorticoids and NSAIDs according to clinical experience?
48-72hr
What is the general mechanism of action of NSAIDs?
act in cell membranes by inhibiting the expression of cyclo- oxygenase (COX) enzymes that are essential in the biosynthesis of prostaglandins
Name 2 types of prostaglandins and their associated COX enzyme?
Constitutive prostaglandins = COX-1
- gastroprotection: gastric mucus + bicarbonate production
- maintainance of renal perfusion via renal afferent vasodilation under hypotensive conditions
- vascular homeostasis via TXA2 + PGI2 production
- expression also during inflammation
Inducable prostaglandins = COX-2
- overexpressed after tissue injury
- production of inflammatory mediators (e.g. endotoxins, cytokines, growth factors responsible for sensitizing peripheral nociceptors)
- ulcer healing
Why may selective COX2 inhibitors (coxibs) induce adverse effects in small animals when dosage regimens are not appropriate?
prostaglandins via COX2 activity may have physiological functions in several tissues and in ulcer healing
Where can COX-3 be found and what is it?
- canine and human cerebral cortex
- COX3 is a subform of COX1 –> central analgesic effect via decreased PGE2 synthesis
- acetaminophen, metamizole
How are NSAIDs metabolised and excreted?
hepatic cytochrome P450 enzymes via glucuronidation (e.g., phenolic compounds) or oxidation (e.g., oxicam group) into inactive or less active metabolites
excretion: biliary (fecal), urine
Why may cats be more susceptible to some NSAID toxicity?
- Cats have deficient glucuronidation which is important for metabolisation of some NSAIDs
- e.g. acetaminophen (paracetamol), carprofen (slow elimination and longer half-life than in dogs)
What is the most common predisposing factor for GI ulceration and perforation in dogs? What is the difference to cats?
NSAID therapy
NSAID related GI ulceration in cats is uncommon.
Hunt JR reported the frequency of reported adverse events associated with NSAID administration in dogs and cats in the United Kingdom in Vet J 2015. What were the findings?
- no differences in terms of frequency of NSAID induced adverse effects between dogs and cats
- reported frequency of adverse effects higher after coxibs than noncoxibs (could reflect their increased usage in comparison with noncoxibs + increased reporting in general)
What clinical consequence does COX1-inhibition have on the GI tract?
- decreased local gastric blood flow
- suppression of bicarbonate secretion
- decreased mucus production
- ion trapping: acidic environment of the stomach + weak acid nature of NSAIDs causes cellular accumulation + damage:
–> disrupt mitochondrial function –> uncoupling of oxidative phosphorylation –> reduced ATP production –> cell injury + apoptosis
–> damage to gastric mucosal barrier –> increases susceptibility to acid + digestive enzyme injury
What clinical consequence does COX2-inhibition have on the GI tract?
- impaired tissue healing
- ion trapping
Discuss the mechanism of NSAID inducsed lower GI toxicity?
enterohepatic recycling causes prolonged + repeated exposure of the intestinal mucosa to the drug and its compounds
Discuss co-administration of NSAIDs and PPIs in people and dogs/cats? What recommendations are made by ACVIM consensus statement?
People:
- PPI induced alterations of the intestinal microbiome –> - coadministration lead to decreased upper GI adverse events but increased lower GI adverse events
dogs/cats: no clear evidence of increased NSAID toxicity with the coadministration of PPIs
ACVIM consensus:
- intestinal dysbiosis is a possible sequela and may further contribute to complications from NSAID therapy.
- PPIs should NOT be indiscriminately administered to dogs receiving NSAID therapy
- PPIs should be restricted to patients with increased risk of GI toxicity
Name COX enzymes expressed in the kidney?
COX1 + COX2
Discuss the role of prostaglandines on the level of the kidneys?
PGE2 + PGI2:
- renal vasodilation
- increases natriuresis (prevents FO):
–> inhibits NK2Cl cotransporter in LOH via EP1 receptor
–> decreases ENAC channels in CD
Thromboxane A2:
- renal vasoconstriction (TP receptor, CD38/cADP-ribose signaling, ROS) –> decreased RBF–> stimulates renin release
Discuss how administration of NSAIDs that inhibit prostaglandin production produces adverse renal effects in sick animals?
- interfering with the autoregulation of renal perfusion pressure
- supression of PGE2 + PGI2 mediated vasodilation
- supression of PGE2 + PGI2 mediated inhibition of Na+ reabsorption with a protective function of the kidneys
Discuss the effect of COX1 activity on coagulation?
produces thromboxane A2:
- platelet aggregation
- vasoconstriction
Discuss the effect of COX2 activity on coagulation?
produces prostacyclin:
- anticoagulant effects
- vasodilation
Discuss the effects of NSAIDs on hemostasis and aspirin on hemostasis? What recommendations can be made?
- Studies in dogs (ketoprofen, meloxicam): decreases PLT aggregation + increases aPTT - but still within RR; BMBT did not change
Aspirin (nonpreferential COX inhibitor) irreversibly binds to the COX complex, potentially irreversibly impairing PLT aggregation
SACCM recommendation:
Patients that are thrombocytopenic, coagulopathic, or at high risk of bleeding should not be administered NSAIDs.
Discuss hepatic side effects and their mechanism of action in NSAIDs? What breed may be predisposed to this side effect?
- idiosyncratic reaction (hepatotoxicity)
- increases in liver enzymes + acute liver toxicosis in patients with preexisting liver disease
Labrador Retrievers –> hepatocellular toxicosis after carprofen therapy
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Alpha2-agonists43
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Benzodiazepines17
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Gabapentin/Pregabalin8
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Trazodone8
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NSAIDs40
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Opioids46
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Immunosuppressive drugs31
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Gastrointestinal drugs67
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diuretics17
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anithypertensives9
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Catecholamines26
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Vasopressin22
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pharmacology33
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cardiac drugs17
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coagulation drugs27
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Local anesthetics8
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NMBA16
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Cannabinoids9
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Induction agents12
