NSAIDs (non-steroidal anti-inflammatory drugs)

Question 1

NSAIDs

Answer 1

• weak acids
• work on modulation and transduction
• main effects: prevent inflammation by inhibiting COX (cyclooxygenase) enzymes, most commonly used analgesics, potential adverse effects
• other uses: anti-pyretic, inhibit tumor growth

Question 2

mechanism of action of NSAIDs

Answer 2

• glucocorticoids work on phospholipases
• NSAIDs work on COX 1 and 2, cause prostaglandins to cause vasodilation, fever, pain
• piprants work on prostaglandins
• Dual Cox/ 5-LOX inhibitors work on 5-lipoxygenase
• leukotriene inhibitors work on leukotrienes
• do not use NSAIDs and steroids together

Question 3

COX-1

Answer 3

• production of prostaglandins, play important role in normal homeostasis
• thromboxane A2- COX mediated, promotes platelet aggregation in normal homeostasis
• prostaglandin E1- involved with GI mucosal maintenance and vasodilation in kidney in response to decreased blood flow- GI signs and gastric ulcers are important adverse effect (especially if NSAID and steroid are combined)

Question 4

COX-2

Answer 4

• inducible production of prostaglandins- produced during inflammation
• selectivity of COX-2 by NSAID is important when considering side effects, toxic effects, and dose

Question 5

selective COX-2 inhibition

Answer 5

• RX only

- carprofen, deracoxib, robencoxib, pirocoxib, meloxicam, piroxicam

Question 6

non-selective COX-1 and 2 inhibition

Answer 6

-phenylbutazone, Flunixin meglumine

Question 7

selective COX-1 inhibition

Answer 7

-aspirin (strongest acid NSAID)

Question 8

glucocorticoids

Answer 8

-prednisone/prednisolone

Question 9

lipoxygenase inhibitors

Answer 9

-montelukast (singulair)

Question 10

Anti-inflammatory effects of NSAIDs

Answer 10

• inhibit synthesis of eiconsanoids (thromboxane, prostacyclin, prostaglandins)
• not as potent anti-inflammatory agents as glucocorticoids
• do not delay wound healing or lead to immunosupression
• greater effect on acute inflammation

Question 11

analgesic effects of NSAIDs

Answer 11

• provide analgesia whether inflammation is present or not
• decrease prostaglandin sensitization of neurons
• centrally, interaction of prostaglandins with nociception

Question 12

antipyretic effects of NSAIDs

Answer 12

• decrease fever, will not reduce hyperthermia of normal body temp, endotoxins produce interleukins that cause fever
• underlying cause for fever should be diagnosed and addressed

Question 13

antiendotoxic effects of NSAIDs

Answer 13

beneficial if given before endotoxic challenge

Question 14

Pharmacokinestics of NSAIDs

Answer 14

• highly protein bound (95-99%)
• generally good absorption PO or IM - some may adsorb to feed and cause decreased GI absorption
• low Vd- inflammation or increase in vascular permeability leads to extravasation of plasma proteins carrying drugs with it, displacement may occur if used concurrently with other highly bound protein drugs
• can cross BBB into CNS
• some may distribute into milk
• note drug specific differences

Question 15

metabolism and excretion of NSAIDs

Answer 15

• hepatic metabolism (phase 1 and II in liver)
• differences between species, breeds, individuals
• ex: dogs with CYP2D15 enzyme metabolize 3x faster
• some NSAIDs are converted to active metabolites
• ASA–> salicyclic acid
• phenylbutazone–>oxyphenobutazone
• metabolites eliminated in urine- small amount unchanged via tubular secretion
• bilary excretion and enterohepatic recirculation in some NSAIDs- naproxen very toxic to dogs
• drug excretion almost complete after 5 half lives

Question 16

special use of NSAIDs

Answer 16

• antithrombotic effects- inhibit TXA2- low dose aspirin/ASA, TXA2 is platelet aggregating factor, causes PGI2 (platelet aggregating agent)= less inhibited, increased clotting time
• antineoplastic effects- COX-2 expressed in some cancer, transitional cell carcinoma and osteosarcoma, Piroxicam used for this

Question 17

adverse effects NSAIDs

Answer 17

• GI irritation/ulceration- due to inhibition of prostaglandins
• all NSAIDs can cause vomiting, diarrhea, anorexia, with steroids increased chance of ulcers
• renal damage, decreased blood flow- PGs control vasodilation of renal vascular beds, risk increases with overdose or other risk factors present, risk increases in cats
• don’t use NSAIDs post op until anesthesia is cleared
• hepatotoxicity- acetiminophen can produce toxic intermediates by phase 1 metabolism, greater production in cats, may occur idiosyncratically/dose dependent
• less common adverse effects- bleeding, bone marrow suppresion/agranulocytis

Question 18

Flunixin Meglumine (Banamine)

Answer 18

• large animal NSAID- don’t use in small animals
• main clinical use- analgesic for colic and endotoxemia in horses, visceral pain in cattle, also for acute pulmonary emphysema
• route of administration- PO- horses, IV cattle, IM swine, rarely seen anyphylaxis after IV administration
• do not use IM in horses- muscle necrosis
• intracorotid can cause seizures/CNS stimulation
• caution with GI, renal, hepatic, hematological dz
• avoid in birds, renal toxicity

Question 19

Phenylbutazone (Bute)

Answer 19

• common in horses, banned in dairy cattle
• main clincal uses: musculoskeletal pain
• route of administration- PO, IV, can cause sloughing and necrosis in IM/SC
• intracorotid injection= seizures/CNS
• can mask lameness- withdrawal time for racing animals

Question 20

COX-2 preferentials

Answer 20

-Carprofen
-Meloxicam
Deracoxib
-small animal med- analgesics and antiinflammatory
-oral: tablets, liquids, transmucosal for meloxicam
-carprofen and meloxicam- injectable SQ
-meloxicam is single injection in cats

Question 21

COX-2 selectives

Answer 21

• Firocoxib- oral paste in horses, chewable tablets in dogs
• Robenacoxib- first NSAID approved for multiple doses in cats, appears effective with similar safety profile in dogs when compared to Meloxicam for post-op anesthesia

Question 22

Washout periods

Answer 22

• NSAID–> sterood 1-2 wks
• Steroid–> NSAID- wean steriod, minimum 1 wk washout
• 2 different NSAIDs washout based on half life ~1 wk

Question 23

Acetaminophen “non-NSAID”

Answer 23

• non-anti-inflammatory, antipyretic analgesic
• no significant anti-platelet effect
• MOA and metabolism: does not inhibit COX, interferes with conversion of endoperoxidases to other PGs and TXs, may be more effective with PG synthesis inhibition in CNS, hepatic metabolism
• clinical use: dogs only
• toxicity: methemoglobinemia, hepatic necrosis, cats extremely sensitive, hemolysis, icterus, anemia, Heinz bodies, facial swelling, edema

Question 24

other analgesics- Gapiprant

Answer 24

• piprant
• non-COX inhibiting, non-NSAID
• MOA: antagonist at PGE2 E4 receptor which subdues pain and inflammation, some GI and renal effects

Question 25

Gabapentin

Answer 25

• neural steroid- dogs, cats, horses
• anti-hyperalgesic- wide therapeutic margin, minimal side effects
• main clinical uses: control of neuropathic pain–> can prevent allodynia, laminitis, pre-emptively for acute pain, augments analgesic effect of other drugs, adjunct therapy for refractory complex seizures
• MOA- not well known, alter Ca+ influx in neuronal cells
• precautions: may cause sedation/ataxia- dose dependent effects, renal excretion, beware renal insufficiency

Question 26

Amantadine

Answer 26

• antiviral drug with NMDA receptor agonist properties- narrow therapeutic window in small animals
• MOA of analgesic effects: NMDA receptor agonist, dorsal horn of spinal cord “wind up pain”
• main clinical uses: less common adjunctive analgesic in small animals- chronic pain , neuropathic pain “dorsal horn wind up”, oral

Question 27

omega-3 FA

Answer 27

• produced by COX, LOX, cytochrome P450 pathways

- help reduce and clear up inflammation