NSAIDs Flashcards
Name the 3 properties of NSAID?
- antiinflammatory
- antipyretic
- analgesic
Name 4 adverse effects of NSAIDs?
- gastrointestinal: anorexia, diarrhoea, vomiting, lethargy
- renal toxicity
- hepatic toxicity
- decreases platelet aggregation
veterinary approved, NSAID induced GI adverse effects are usually mild and selflimited –> ulceration/perforation when label recommendations are not followed or CI ignored
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 according to clinical experience?
2-3 days
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 two types of prostaglandins and their associated COX enzyme?
Constitutive prostaglandins = COX-1
- gastroprotection via secretion of gastric mucus and production of bicarbonate
- renal perfusion under hypotensive conditions
- vascular homeostasis via thromboxane and prostacyclin 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 func tions in several tissues and in ulcer healing
Do preferential and selective COX2 inhibitors have a superior safety profile when compared with nonselective COX-inhibitors?
yes
Where can COX-3 be found and what is it?
- canine and human cerebral cortex
- COX3 is a subform of COX1
How do COX3 inhibitors mediate their analgesic effect?
- decrease PGE2 synthesis
- suggesting central mechanisms of analgesia
- e.g. acetaminophen (paracetamol), metamizole
How are NSAIDs metabolised?
primarily via cytochrome P450 enzymes either via glucuronidation (e.g., phenolic compounds) or oxidation (e.g., oxicam group) into inactive or less active metabolites
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)
Why is acetaminophen contraindicated in cats?
Cats have deficient glucuronidation which is important for metabolisation of acetaminophen
How are NSAIDs exrected?
predominantly biliary (fecal) and urine
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.
What is the reported mortalitiy rate in dogs with GI perforation?
37% to 69%
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
some NSAIDs (e.g., aspirin) might cause direct damage to the GI mucosa
What clinical consequence does COX2-inhibition have on the GI tract?
- impaired tissue healing
some NSAIDs (e.g., aspirin) might cause direct damage to the GI mucosa
Discuss the mechanism of NSAID inducsed lower GI toxicity?
- enterohepatic recycling and consequent prolonged and 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:
- promote vasodilation
- promote inhibition of Na+ reabsorption with a protective function of the kidneys
Thromboxane A2:
- modulates renin production + vasoconstriction
What effect does Thromboxane A2 mediate on the level of the kidneys?
modulates renin production + vasoconstriction
What effect does PGE2 mediate on the level of the kidneys?
- promote vasodilation
- promote inhibition of Na+ reabsorption with a protective function of the kidneys
