22 NSAIDs and Arachidonic Acid Pathway

• NSAIDs are oral analgesics, consistently effective in dogs, cats, horses, and cattle, for mild to moderate pain.
• NSAIDs are associated with the greatest number of adverse effects reported to the FDA.
• The primary goal when using NSAIDs is careful patient selection to minimize adverse effects by considering patient demographics and potential drug interactions.
• A secondary goal is to use drugs that decrease adverse effects.
• Adverse effects from NSAIDs are most likely to occur early in treatment (first 4 weeks) or during chronic treatment.

Arachidonic Acid Pathway

• Phospholipids convert to Arachidonic Acid via Phospholipase A2.
• Arachidonic Acid is metabolized through three different pathways:
  • 5-LOX creates LT A4, which then forms LT B4, LT C4, LT D4, and LT E4 (Leukotrienes).
  • COX-1 creates PGD2, PGE2, PGF2, and TXA2 (Prostaglandins).
  • COX-2 creates PGE2 and PGI2, which then form Lipoxins.
• LOX stands for Lipoxygenase.
• COX stands for Cyclooxygenase.
• PG stands for Prostaglandin.
• LT stands for Leukotriene.

Cyclooxygenase / PGs

• The "Good" effects of Cyclooxygenase/Prostaglandins:
  • Gastroprotection via COX1 & COX2
  • Renal blood flow via COX1 & COX2; COX2, particularly during hypoperfusion
  • Anti-inflammatory effects via COX2 (lipoxin)
  • Platelet activation via COX1
  • Platelet inhibition via COX2
• The "Bad" effects of Cyclooxygenase/Prostaglandins:
  • Pain via COX2 (some COX1) in acute and chronic conditions, as well as central sensitization such as ""Wind up"".
  • Pro-inflammatory effects via COX1 & COX2
  • Platelet activation via COX1
  • Platelet inhibition via COX2
• The "Ugly" effect of Cyclooxygenase is COX inhibition by NSAIDs.

GI Adverse Effects

• Most common adverse effects reported to the FDA for NSAIDs are in dogs and horses.
• Adverse effects can range from vomiting/diarrhea without apparent GI damage, to gastritis/enteritis (right dorsal colitis in horses), gastric/intestinal ulcers, perforating ulcers, and death.
• All analgesic NSAID doses inhibit COX-2.
• COX-2 preferential NSAIDs tend to have less GIT adverse effects than nonselective COX inhibitors.
• Some COX-1 activity remains, maintaining some gastroprotective effects.
• 3-10% of dogs may experience GI adverse effects, resulting in NSAID discontinuation.
• Animals with GI lesions up-regulate COX-2 for healing, therefore all NSAIDs should be used cautiously in underlying GI lesions, erosions, or after surgery.

GI Protectants

• Acid suppression therapy is used to decrease NSAID GI adverse effects.
• Omeprazole is a proton pump inhibitor (high efficacy in humans and animals).
• Famotidine is an H2 antagonist with moderate efficacy in humans and animals.
• Sucralfate is a gastroprotective coating and antacid with moderate efficacy in humans and animals.
• Misoprostol is a synthetic PGE with high efficacy in humans and animals, but can cause abortion in humans from handling tablets.

Potential Adverse Drug Interactions (GI)

• Aspirin combined with another NSAID enhances the potential for GI adverse effects.
• Multiple NSAIDs administered concurrently show no evidence of additive or synergistic analgesic effects.
• There is no extensive data available on sequential or switching NSAIDs.
• Most recommendations are anecdotal for withdrawal times.
• If concerned, omeprazole or misoprostol could be used.
• Drug interactions increase GI risks if using glucocorticoids (prednisone, prednisolone, dexamethasone).
• Avoid if possible.
• Numerous studies have confirmed a high adverse effect rate of Glucocorticoids in dogs.
• No studies have evaluated a withdrawal/washout period.
• The adverse effects are probably related to the dose and duration of glucocorticoid therapy and the presence of GI lesions/adverse effects.
• Dexamethasone likely lasts longer than prednisone.
• If concerned and GC is needed, omeprazole or misoprostol could be used.
• Serotonin drugs in humans:
• Selective Serotonin Reuptake Inhibitors (Fluoxetine, et al).
• Not tricyclic antidepressants (Amitriptyline, clomipramine).
• Serotonin enhances gastric acid secretion.
• Platelets can be affected if there is serotonin depletion due to serotonin reuptake inhibition, causing increased bleeding. _ Co-administration of famotidine or omeprazole appears to mitigate adverse effects in humans.
• Tramadol:
• Case series shows that dogs receiving deracoxib and tramadol had higher than expected GI adverse effects.
• Tramadol is a serotonin/norepinephrine reuptake inhibitor.
• There are no reported tramadol/NSAID interactions in humans.
• Low intrinsic activity of tramadol likely limits adverse effects in dogs.
• May be best to administer with famotidine or omeprazole.
• Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake, and a less potent inhibitor of dopamine reuptake.
• Serotonin release by platelets plays an important role in hemostasis, so concurrent use of an NSAID or aspirin may potentiate the risk of bleeding.
• Bismuth subsalicylate contains the active ingredient bismuth subsalicylate, which is chemically related to aspirin and may cause serious adverse effects such as bleeding.
• Should not be taken by kids recovering from a viral infection, or people taking oral antidiabetic drugs (OADs), anticoagulants, warfarin (Coumadin), or clopidogrel (Plavix).

Renal Adverse Effects

• All analgesic NSAID doses inhibit COX-2.
• Renal adverse effects are primarily due to the inhibition of COX-2.
• Adverse effects are similar regardless of COX selectivity.
• Predisposing physiologic factors:
• Hypotension
• Dehydration
• Sodium depletion (hyponatremia)
• Pre-existing renal disease
• Potential drug interactions increasing the risk of renal adverse effects (human data):
  • Aminoglycosides (nephrotoxicity & impaired aminoglycoside excretion) such as Gentamicin or amikacin.
  • Diuretics (fluid & sodium depletion) such as Furosemide.
  • ACE inhibitors (renal hypotension) such as Enalapril or benazepril.

Minimizing Potential Renal Adverse Effects During Anesthesia

• Monitor cardiovascular status via non-invasive blood pressure (NIBP) and heart rate.
• Administer IV fluids during anesthesia to patients receiving NSAIDs.
• Administer NSAIDs after anesthesia is complete.
• There is no evidence that NSAID administration before anesthesia is more beneficial than post-op administration.
• Normalize sodium prior to NSAID administration.

Hepatic Adverse Effects

• Overall, rare.
• Less frequent than GI or renal.
• Typically idiosyncratic.
• Normal dosage.
• Reported for all veterinary approved NSAIDs.
• Onset is from days to months.
• Many within 3 weeks.
• There is no breed predisposition.
• Often incorrectly stated that Labradors are more susceptible.
• Clinical signs: lethargy, anorexia, depression
• Clinical Pathology may include:
• Elevated bilirubin.
• Elevated AST, ALT, or ALP over twice the upper end normal range.
• Elevated bile acids.
• It may be better to check hepatic parameters early in the treatment (1-2 weeks) compared to later.
• NSAIDs are the drug class with the most reported adverse drug events, but are also commonly administered.

Drug Interaction Summary

• Glucocorticoids: GI
• Other NSAIDs concurrently (including aspirin): GI and renal
• Serotonin reuptake inhibitors (e.g., fluoxetine): GI
• Tramadol: GI?
• Bismuth subsalicylate: GI
• Aminoglycosides: Renal
• Diuretics: Renal
• ACE inhibitors: Renal