NSAIDs: Veterinary Medicine

• The lecture is about Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Learning Objectives

• The mechanism of action of NSAIDs will be explained.
• The location in the body where NSAIDs have their effect will be identified.
• The clinical uses of NSAIDs will be summarized, including any contraindications.
• Specific NSAIDs clinically available for use in veterinary medicine will be compared
  • Including COX-1 vs COX-2 effects
  • Distinguishing features of particular drugs
  • Species-specific considerations
• Potential side effects of NSAIDs on body systems will be explained
  • Including ways to minimize these effects
  • Including treatment options for a patient experiencing NSAID toxicity

NSAIDs Overview

• One of the most commonly used drug classes in veterinary medicine.
• Provides analgesia, anti-inflammatory, and antipyretic effects
  • Treats the source of pain instead of masking pain.
• There is a need to exercise caution when prescribing, even though the safety profile of NSAIDs improved
• Treatment of pain, both acute and chronic, is becoming more understood, as clients are demanding that concerns are addressed.

Mechanism of Action (MOA)

• Blocks cellular expression of COX enzymes in the cell membrane.
• Trauma and/or toxins cause disruptions of tissue
• Disrupted tissue causes the release of phospholipids
• Phospholipase acts on phospholipids, forming arachidonic acid
• Lipoxygenase acts of arachidonic acid for the creation of inflammation, hyperalgesia, bronchoconstriction, vasoconstriction and plasma leakage
• Cyclooxygenase acts of arachidonic acid for the creation of PGE2, hyperalgesia and inflammation
• Inflammation is a response to tissue damage
• First step: release of arachidonic acid (AA), mediated by phospholipase A2, from injured cell membrane
• AA is a substrate for generation of various eicosanoids
  • Including Prostaglandins (PGs), leukotrienes and thromboxane A2
• The production of PGs and TXA2 is mediated by COX
• This leads to increased vascular permeability, heat, and decreased nociceptor threshold

COX Enzyme Isoforms

• COX-1
  • Primary constitutive isoform of COX
  • Responsible for basal prostaglandin (PG) production which has homeostasis in tissues, called the “Housekeeping function”
  • It is present in the stomach, kidneys, platelets, and reproductive tract
  • Responsible for gastroprotection, kidney & platelet function, and gestation & parturition
  • Expressed at sites of inflammation
• COX-2
  • An induced isoform, but is expressed in many tissues such as neural, reproductive, and renal and has homeostatic function
• There is also a COX-3 variant, but less is known about it
• COX has a bifunctional role depending on the isoform and target tissue

NSAIDs Site of Action

• Works in both the central nervous system (CNS) and peripheral tissue injury site
• Inhibition of the COX-2 enzyme peripherally blocks the formation of PGs
  • This would normally dilate arterioles and sensitize peripheral nociceptors to inflammatory mediators
  • This causes localized pain and hypersensitivity as a result
• COX-2 is expressed in the brain and spinal cord and becomes upregulated in response to traumatic injury and peripheral inflammation
  • This causes neuronal plasticity
  • This causes central sensitization
  • These are all due to the lowering of the threshold for neuronal depolarization

Prostaglandins and Pain

• PGE2 contributes to inflammatory response by causing vasodilation and enhancing inflammatory mediators and other cytokines
• Production of PGE2 is mediated primarily by COX-2
• Drug therapy has tried to target inhibition of COX-2 to decrease unwanted side effects
• COX-2 inhibition is detrimental to many normal physiologic functions such as gastric ulcer healing
• COX-1:COX-2 selectivity varies between species

Coxibs

• A subset pf NSAIDs introduced in recent years designed to have anti-inflammatory effects with reduced toxicity
• These agents are COX-2 selective and COX-1 sparing
• Structurally different from other NSAIDs, which limits their ability to bind the COX-1 site
• There are currently 4 coxibs approved for use in animals, including:
  • Deracoxib
  • Firocoxib
  • Mavacoxib
  • Robenacoxib

Pharmokinetics (PK) of NSAIDs

• In general, NSAIDs are lipid-soluble, weak organic acids that are well absorbed following oral administration.
  • These drugs have a rapid onset of action, typically 30-60 minutes
  • The duration of effect can be up to 24 hours
• There are relatively small volumes of distribution attributable to a high degree of plasma protein binding
  • This results in high protein binding as it enables consistent delivery to target tissue
• The drugs undergo an extensive hepatic metabolism to inactive metabolites
• Elimination half-life can be variable

Clinical Use of NSAIDs

• Only use one NSAID at a time
  • Do not concurrently administer systemic steroids
• Check baseline renal and hepatic function prior to use
• Need to pay attention to dosages, frequency, and to offer it with food
• Use the lowest effective dose for the shortest duration possible, with frequent monitoring of patient response
• There needs to be a 5-7 day "wash out” period if switching NSAIDS

Contraindications

• Renal or hepatic insufficiency/impairment
• Active gastrointestinal (GI) disease
• Coagulopathies
• Pregnancy, or trying to become pregnant
• Decreased circulating volume
  • Such as with congestive heart failure, shock, dehydration, hypotension, ascites, or other cause of hypovolemia
• Active hemorrhage or suspected blood loss
• Significant pulmonary disease
• Known sensitivity to NSAIDs
• Currently receiving systemic steroids or another NSAID

Ways to Minimize Risks

• There are 9 ways to minimize the risks including:
  • Obtain complete medical history
  • Perform careful patient selection
  • Provide verbal and written instructions
  • Recognize adverse events and discontinue immediately
  • Monitor lab work
  • Use a balanced approach to analgesia
  • Consider washout periods
  • Consider gastroprotectants
  • Use dose optimization based on lean body weight
• Pet owners need to be told what the possible side effects are and their clinical signs.

Carprofen

• COX-1 sparing and COX-2 selective
• Approved to treat the inflammation and pain stemming from osteoarthritis, and orthopedic & soft tissue surgery in dogs.
• Can be given PO as a scored caplet or chewable tablet in a variety of dose sizes
• Can be given SQ as an injectable formulation

Other NSAIDs

• Deracoxib
  • COX-1 sparing and COX-2 selective
  • Approved oral formulation for dogs for treatment of pain and inflammation associated with OA and postop pain due to orthopedic surgery.
  • Also effective for dental or soft tissue procedures.
  • Major side effect: GI complications, perforation of an ulcer usually related to higher doses
• Firocoxib
  • COX-1 sparing and COX-2 selective
  • Approved for use in dogs as an oral formulation for treatment of pain and inflammation associated with OA.
  • Also effective for postoperative pain control
  • Injectable and oral paste formulations approved for treatment of equine OA for SID use
  • Side effects: minimal, mostly limited to GI upset
• Meloxicam
  • COX-1 sparing and COX-2 selective
  • Approved for use in dogs for treatment of pain and inflammation associated with OA
  • Approved for a single dose in cats to control pain and inflammation tied to orthopedic surgery, OHE, and castration in the USA.
  • Black box warning label issued by FDA in 2010 saying acute renal failure and death can occur after repeated used of the drug in cats
  • Available in oral, transmucosal oral mist, and parenteral formulations
  • Side effects: mostly causes GI upset
• Robenacoxib
  • COX-1 sparing and COX-2 selective
  • Approved for use in dogs and cats for treatment of pain and inflammation associated with OA, orthopedic and soft tissue surgery
  • Approved treatment time in cats 4 months is 3 days
  • Has a good safety profile in healthy young cats
  • The SQ injectable dose differs from the oral dose
• Grapiprant
  • A Non-COX-inhibiting prostaglandin receptor antagonist (PRA)
  • Approved for treatment of pain and inflammation in dogs with OA
  • Does not inhibit the production of many housekeeping prostanoids
  • Blocks the EP4 receptor, the primary mediator of canine OA pain and inflammation

Acetaminophen

• NOT an NSAID!
• Used in humans for antipyretic and analgesic properties, with reduced risk of GI ulceration
• Lacks anti-inflammatory properties
• Cats are more sensitive since they are deficient in glucuronyl transferase, and therefore have limited capacity to glucuronidate this drug
• In cats, toxicity occurs at 10-40 mg/kg while in dogs toxicity occurs at > 100 mg/kg
• Cats primarily develop methemoglobinemia within a few hours, followed by Heinz body formation
• Methemoglobinemia makes mucous membranes brown or muddy in color
  • Usually accompanied by tachycardia, hyperpnea, weakness, and lethargy
• Other clinical signs of acetaminophen toxicity include depression, weakness, hyperventilation, icterus, vomiting, hypothermia, facial or paw edema, cyanosis, dyspnea, hepatic necrosis, and death

Dipyrone

• An atypical NSAID
• Has a weak COX-1 and COX-2 inhibition
• May inhibit COX-3
• It has been FDA approved for use in horses, but use has been described in several veterinary species
• Use caution in patients with co-morbidities

Flunixin Meglumine

• A non-selective NSAID that cannot be used in Dairy Cattle entering milk production line
• It is FDA approved for treatment of inflammation and fever in food animals
• Most commonly used NSAID for treatment of colic and associated endotoxemia (horse) which is visceral paint
• Available in oral paste and injectable formulations
  • Do not administer IM if giving as an injection because it is very irritating and could lead to clostridial yositis

Phenylbutazone

• Non-selective NSAID, used vs banamine for visceral pain
• Used to treat musculoskeletal pain and inflammation in horses
• Prohibited from use in dairy cattle, especially females > 20 months of age
• Side effects include gastric ulceration, renal necrosis, and anemia

GI Side Effects

• Most common problem associated with use of NSAIDs
  • Caused by inhibition of endogenous PGs which results in inhibition of intestinal healing mechanisms and/or gastric ulceration
• Signs may include depression, lethargy, inappetence, nausea, vomiting and/or diarrhea that may include blood, and an ulcer that could lead to perforation of the GI tract
• Lab results: decreased Hct and T.P., increased BUN due to GI hemorrhage, elevated leukocyte count
• Right dorsal colitis from PBZ admin in horses
• Consider concurrent administration of gastroprotectants when NSAIDs are prescribed for chronic use
• Signs to Watch For
  • Behavior Changes
  • Decreased Appetite
  • Skin Redness, Scabs
  • Tarry Stool/Diarrhea/Vomiting

Renal Side Effects

• Renal dysfunction may occur with NSAID administration due to PG inhibition
• During normovolemia, there is little need for production of PG
• Hypovolemia → PG production is increased and important for maintaining renal perfusion
• Avoid if possible in patients with chronic kidney disease, since kidney damage could be further exacerbated.
• Controversy surrounds the timing of perioperative NSAID administration
• Effects decision on when to administer an NSAID perioperatively
• Is a study with 60 cats, RBP healthy cats without NSAIDs in past 7/3 days.
• routine flank OVH performed by an experience surgeon+student
• the time of an Admin of NSAID treatment was either before induction, shortly after indication, or at end of surgery
• The meeting anesthesia duration among treatment groups was 55 to 70 minutes, 37 cats experienced hypotension lasting an average of 15 minutes
• No effect of drug or timing on markers of renal function with blood and urine testing conducted
• If patient is dehydrated or hypovolemic, hold off on giving NSAID until underlying problem is corrected
• If you are concerned that patient may become hypotensive during anesthesia, don't give the NSAID until stable in recovery period
• Institute corrective treatment for hypotension promptly

Hepatic Side Effects

• Carprofen associated with idiosyncratic hepatocellular necrosis
• In one study, a higher number of Labs were represented
• Very rare – 1.4 cases/10,000 dogs
• Onset of signs seen by 21 days of use in affected dogs
• Anorexia, vomiting, icterus and an increase in hepatic enzymes
• Most dogs recover if the medication is stopped and supportive care is given
• Liver function should be monitored with the use of all NSAIDs
• still do bloodwork monitor

Bone and Cartilage Effects

• PGs play an important role in bone repair and normal bone homeostasis
• Small mammal models indicate that NSAIDs potentially alter bone healing, but after discontinuation of the drug the rate of healing in a fracture returns to normal. So it is still okay to use postoperative NSAIDs to manage orthopedic pain, do not administer continuously for a few weeks.
• Experimental data suggests NSAIDs can slow the progression of OA

Effect on Coagulation

• Available published studies suggest that the NSAIDs approved in the United States that have been evaluated do not have a significant clinical effect on bleeding time following perioperative administration.
• Aspirin is the only drug of concern due to its irreversible effect on platelet function persists until the platelets are replaced
• Discontinue use 7-10 days prior to surgery
  • Often suggest 2 weeks

Treatment for NSAID Toxicity