NSAIDS Flashcards
Transduction
conversion of noxious stimulus into an AP at level of specialized R or nerve endings.
Transmission
propagation of APs by primary afferent neurons to spinal cord
Modulation
process by which nociceptive information is augmented or inhibited.
Projection
conveyance of nociceptive information through spinal cord to brain
o Brainstem, thalamus, then cortex
Perception
integration of nociceptive information by brain (overall conscious, emotional experience of pain).
Peripheral Sensitization
Major peripheral effect of PGE2 = sensitize afferent neurons to noxious chemical, thermal, mechanical stimuli
* Tissue injury –> inflammation at site of injury
o COX-2 enzymes upregulated
o Increased production of PGE2.
* PGE2 binds to EP receptors on peripheral nociceptor fibers –> activate phosphokinases, increases Na channel permeability, decrease firing threshold.
* When injured area touched, nociceptor already sensitized so AP induced more easily, causing exaggerated reaction to stimuli (primary hyperalgesia)
Central Sensitization
Peripheral inflammation –> production of PGs in spinal cord
o Inflammation similar to a repetitive stimulus - it does not resolve immediately
2 mechanisms for development of central sensitization related to COX-2 production
Repeated neural input from afferent neurons to dorsal horn (DH) stimulates
COX-2 production in DH neuron.
Cytokines released during tissue injury initiate a cascade –> increased IL-1β in spinal cord –> increases COX-2 production, PGE2 in DH neurons.
Role of PGE2 in Development of Central Sensitization
acts on EP4 R on pre-synaptic terminals to increase transmitter release.
o Also acts on EP2 DH R to potentiate AMPA/NMDA R, activate nonselective cation channels, block inhibitory glycinergic transmission.
o Leads to secondary hyperalgesia, allodynia
Function of NSAIDS
Relieve mild to moderately severe pain: Anti-inflammatory and anti-nociceptive
Anti-pyretic
Anti-endotoxemic
Anti-neoplastic
Formulations
o Oral tablets, caplets, liquids, chewable tablets, paste (horses)
o Oral transmucosal
o Transdermal
o Injectable: IV or SC
OG NSAID: Willowbark
17th century BCE - Willow bark (salicylate) used by ancient Egyptians
5th century BCE – Hippocrates wrote about medicinal uses of willow bark, leaves for pain, fever
1763 – Reverend Edward Stone “rediscovered” benefits of using powdered willow bark when treating fevers, wrote report on it
Synthesis of Salicylic Acid
o 1829-1838 - Salicylic acid first isolated by Henri Leroux, Raffaele Piria
Acetylsalicylic acid
Aspirin, synthesized by Felix Hoffman in 1897 while working for Bayer
1971
Sir John Vane described ability of aspirin-like drugs to inhibit production of prostaglandins
NSAID Classification
- Chemical structure
- Similar physio-chemical properties
- almost all are weak acids (pKa 3.5-6.0)
- moderate to high lipid solubility
- highly protein bound
Carboxylic Acids (R-COOH)
Salicylates (aspirin)
Indoleactic acids (etodolac)
2-arylpropionic acids (carprofen/ketoprofen)
Anthranilic acids (flunixin, Tolfenamic acid)
Salicylates
Aspirin
Carboxylic Acids (R-COOH)
Indoleacetic acids
Etodolac
Carboxylic Acids (R-COOH)
Anthranilic acids
Flunixin, tolfenamic acid
Carboxylic Acids (R-COOH)
Enolic Acids (R-COH)
-Oxicams - meloxicam, piroxicam
-Pyrazolones: phenylbutazone, dipyrone
Oxicams
Enolic acids
Meloxicam, piroxicam
Dual COX-5-LOX Inhibitors
- Tepoxalin (approved for use in US for treatment of pain, inflammation related to OA
- No longer available
COX 2 Inhibitors
- Most: sulphonamides or sulphones (robenacoxib = carboxylic acid)
- Bulky structure limit COX-1 inhibition
- Preferential/selective inhibitors of COX-2
- Firocoxib, cimicoxib, deracoxib,mavacoxib, robenacoxib, celecoxib
CINODS
- COX- inhibiting nitric oxide donors
- Nitroesters of older nonselective COX inhibitors (aspirin, phenylbutazone)
- Hydrolyzation of ester linkage yields NSAID, NO –> may enhance potency, increase gastric tolerance
- No veterinary drugs
Arachidonic Acid
Tissue damage or release of inflammatory mediators –> activation of phospholipase A2 (PLA2)
o Hydrolyzes bond btw 2nd fatty acid tail, glycerol molecule of membrane phospholipids, forming arachidonic acid (AA)
Structure of AA
- 20 carbon polyunsaturated omega-6 FA
Downstream Effect of AA
Oxidized by cyclooxygenase (COX), lipoxygenase (LOX) enzymes as part of various enzyme cascades to form eicosanoids and leukotrienes, respectively
Eicosanoids
20-carbon, hairpin-shaped FA with cyclopentane ring
Prostanoids, Thromboxane
Products act locally via GPCR to generate inflammatory, immunological responses
Prostanoids
specific eicosanoids (PGG2, PGH2) further metabolized into prostacyclin (PGI2) and various prostaglandins (PGD2, PGF2α, PGE2)
Thromboxane (TXA2)
mainly produced from PGH2 via thromboxane synthase on platelets
Prostacyclin (PGI2)
R: IP, Gs
Function of PGI2
*vasodilation
*inhibit platelet aggregation
*Bronchodilation
*Synergistic with NO
Prostaglandin D2
R: PTGDR (DP1) and CRTH2 (DP2), GPCR
Function of PGD2
*produced by mast cells; recruits Th2 cells, eosinophils, and basophils
*In mammalian organs, large amounts of PGD2 found only in brain, mast cells
*Critical to development of allergic dz such as asthma
Receptors for prostaglandin E2 (PGE2
EP1 - Gq
EP2 - Gs
EP3 - Gi
EP4 - Gs
Functions of PGE2+EP1
bronchoconstriction
GI tract SmM contraction
(mediated by Gq)
Functions of PGE2+EP2
*bronchodilation
*GI tract smooth muscle relaxation
*vasodilation
(mediated by Gs)
Functions of PGE2+EP3
*↓ gastric acid secretion
*↑ gastric mucus secretion
*uterus contraction (when pregnant)
*GI tract smooth muscle contraction
*lipolysis inhibition
*↑ autonomic neurotransmitters
*↑ platelet response to their agonists and ↑
atherothrombosis in vivo
(mediated by Gi/o)
Functions of PGE2+EP4
*Maintain ductus arteriosus in the fetus
*Pro-inflammatory
*↑ Duodenal bicarb secretion
*↓ colonic inflammation
*May play a part in progression of some cancers
Prostaglandin F2a
R: FP via Gq
Function of PGF2a
*uterus contraction
*Bronchoconstriction
*vasoconstriction
(mediated by Gq)
TXA2
Binds to TP R via Gq
Promotion of platelet aggregation, VC
Cyclooxygense
AKA prostaglandin-endoperoxidase synthase
responsible for synthesis of prostaglandins
* 2 isoforms identified – COX-1, COX-2
* COX-3: splice variant of COX-1
COX 3
splice variant of COX-1
o Identified in dogs, mice, humans
o Does not appear to be active in humans
o Possible site of acetaminophen, dipyrone inhibition
COX 1 vs COX 2 - primary protein structure
Substitution of isoleucine in COX-1 for valine in COX-2 at position 523 results in a ~25% larger hydrophobic binding site
COX-2 also has a wider channel opening
COX 1
- “Constitutive”
- Expressed in wide range of tissues
- increases IRT stimulation by hormones, growth factors (small amount)
- Generates TXA2, PGE2, PGI2, PGD2
Housekeeping functions of COX 1
blood clotting
renoprotection
gastroprotection
regulation of vascular homeostasis
coordination of circulating hormones
COX 2
“Inducible” and “constitutive”
Expression increased on exposure to LPS, cytokines, immune, inflammatory stimuli
- Pro-inflammatory PGs (eg PGE2, PGI2)
- Anti-inflammatory PGs (15dPGJ2) in later phase
Where is COX 2 constitutive?
monocytes
macrophages
pyloric and duodenal mucosa
endothelial cells
brain
dorsal horn
kidney
ovary/uterus
ciliary body of eye
COX Selectivity
- NSAIDs often classified based on COX-1 versus COX- 2 suppression abilities
o Determined using whole-blood assay (gold standard)
o Measures COX-2 products (PGE2) from stimulated leukocytes, COX-1 products (TXA2) from stimulated platelets
COX Selectivity Expressed as a Ratio
o Derived from the concentration of NSAID necessary to inhibit 50% of activity of each of COX-1, COX-2 enzymes
* COX-1 selective <1
* COX-2 preferential >1-100
* COX-2 selective >100-1000
* COX-2 specific >1000
Limitations of COX Selectivity Ratio
- COX-1:COX-2 ratio does NOT predict clinical efficacy of an NSAID
- One NSAID may be more effective than another in individual patient
COX 1 selective
COX 1:COX 2 ratio <1
COX 1 Selective NSAIDS
COX 1:COX 2 ratio <1
Aspirin 0.4
Ketoprofen 0.88
COX 2 Preferential NSAIDS
COX 1:COX 2 >1-100
COX 2 Preferential NSAIDS
Etodolac 6.6
Meloxicam 7.3
Carprofen 16.8
Deracoxib 48.5
COX 1:COX 2 >1-100
COX 2 selective
COX 1:COX 2 >100-1000
COX 2 Selective NSAIDS
COX 1:COX 2 >100-1000
Robenacoxib 128.8
Firocoxib 155
COX 2 specific
COX 1:COX 2 >1000
None commercially available
Main MOA of NSAIDS
Suppression of COX - main MOA by which NSAIDs exert anti-inflammatory, analgesic effects
Some anti-inflammatory action may be DT insertion of NSAIDs into lipid bilayer of cell membranes
Aspirin MOA vs other NSAIDS
shown to have anti-inflammatory effects through inhibition of kinase Erk
o decreases neutrophil aggregation in areas of injury, decreases their inflammatory effects
Other potential MOA of NSAIDS
o Inhibition of nuclear factor kappa-B (NF-kB) –> promotes synthesis of other inflammatory mediators
o Interaction with endogenous opioid system
o Activation of serotonergic bulbospinal pathway
o Involvement of the nitric oxide pathway
o increase in cannabinoid/vanilloid tone
Lipoxygenase (5-LOX)
5LOX metabolizes AA to various leukotrienes (A4, B4, C4, D4, E4) which are pro-inflammatory
– ↑ vascular permeability
– Promote neutrophil chemotaxis, aggregation & degranulation
– Bronchoconstriction, ↑ airway mucus secretion
– Pulmonary vasoconstriction
Consequence of Overproduction of Leukotrienes
major cause of inflammation in asthma, allergic rhinitis, OA
Lipoxins
also metabolized from AA by 12-LOX and 15-LOX (in humans) and function to dampen and resolve inflammation
– Ex LXA4 is an endogenous allosteric enhancer for anandamide at the CB1 cannabinoid receptor
PK of NSAIDS: Absorption
- Lipid-soluble, weak acids (pKa 3.5-6) → generally well absorbed PO
o Rate and extent varies with species, gastric pH, GI motility, dosing IRT feeding
o Generally an NSAID administered with food to decrease irritant effects on the GI system
Which NSAID has lower bioavailability hen given with food?
robenacoxib has a much lower bioavailability when given with food
Dogs – 62% fed, 84% fasted
Cats – 10% fed, 49% fasted (Jung et al. 2009; King et al. 2013)
NSAID PO Absorption, monogastrics
more drug un-ionized in acidic environment of stomach, favors absorption
NSAID PO Absorption, ruminants
biphasic absorption from stomach compartments, intestine
NSAID PO Absorption, horses
drug may bind to hay/digesta, can delay absorption
2-arylproprionic acids
Carprofen, ketoprofen
Carboxylic acids
NSAID Distribution
- Highly protein bound (>95%)
- Low Vd (0.1-0.3 L/kg or less)
Which are the exceptions to the normally low Vd of NSAIDS?
Flunixin in cattle – moderate to high Vd;
Tolfenamic acid in dogs, calves, pigs;
All sulphones, sulphonamide COXIBs in dogs (enterohepatic recirculation or high level of tissue accumulation)
Where do NSAIDS accumulate?
inflamed tissue DT leakage of albumin-containing inflammatory exudate
o Maintains effectiveness when plasma concentrations have decreased to low levels
o NSAIDs with short elimination half-lives are still effective with q24h dosing
Metabolism
Most NSAIDs undergo hepatic metabolism to less active (or inactive) phase 1 metabolites
Metabolites conjugated (usually glucuronidation) during phase 2 to more polar conjugates - can be easily excreted
Gut bacteria can cleave conjugate back to parent drug
Which NSAIDS are converted to active metabolites?
Aspirin, phenylbutazone converted to active metabolites (salicylate and oxyphenbutazone)
Species Specific Metabolism
- Species, inter- and intra-breed, inter- and intra-animal differences
o Clearance and terminal half-life vary markedly
What is an alternative method of metabolism?
Some biliary secretion may occur → enterohepatic recirculation
Excretion
- Only small fractions are excreted unchanged in urine due to high protein binding
Stereoisomerism
- 2-arylproprionate subgroup (carprofen, ketoprofen) characterized by possession of single chiral center
o R and S enantiomeric forms; S usually more active
o Sold as racemic mixtures (50:50)
o Each form has its own PK/PD differences
Stereoisomerism: differences in PK for each enantiomer arise from:
o Differing rates of hepatic metabolism
o Chiral inversion of some drugs (unidirectional R→S)
Important feature of carprofen and stereoisomerism
Enantioselectivity of distribution into exudate, synovial fluid for carprofen (Armstrong et al. 1999
Pharmacodynamics of NSAIDs
- Current evidence: 80% or higher inhibition of PGs may be required to achieve good clinical responses
o However, lowest effective dose = best - Effects lags behind plasma concentration (hysteresis)
o Tissue concentration dependent?
PD of NSAIDS with chiral center
differing potency ratios for each enantiomer for COX-1 and COX-2
Species Differences with PD
- Species differences in COX-1:COX-2 ratios will alter their selectivity
o Carprofen = COX-1 selective in humans, nonselective in horses; COX-2 preferential in dogs, cats
PK-PD modeling to determine optimal and safe dosing is complicated
o In vitro model using whole blood assay to measure COX inhibition, but using IC80 for COX-2 and IC20 for COX-1 to minimize AEs
o In vivo models more likely to reflect physiologic/pathologic conditions, predict clinical outcomes (eg tissue cages, induced inflammation in a joint, etc)
Wash Out Times
Typically recommend 5-7 days “wash-out” period when switching from one NSAID to another
Single dose of perioperative parenteral NSAID followed by different oral NSAID next day
one study in normal healthy dogs given subcutaneous carprofen followed by Deracoxib PO 24 hours later x 4 days
o No differences in clinical findings or gastric lesions
o Safe to switch from single injection of 1 drug to oral formulation of another and said next day in healthy dogs
NSAID: most have elimination half lives of what
-short elimination half-life (<12 hours in dogs)
-Mavacoxib: 1x/mo NSAID for dogs available in UK with a long elimination half-life (mean of 17 days)
–Meloxicam in dogs ~24h, cats 24-36h
Robenacoxib HL
very short elimination half-life of 0.6-1.1h in dogs, 0.8-1.9h in cats
Wash Out Period if Poor Clinical Response/No AEs noted
24-48 hours
o Chp 56: many authors suggest waiting five half lives of first drug before initiating second drug to reduce plasma concentrations of first drug near 0
o One report of switching to firocoxib from another NSAID: no increase in documented side effects whether firocoxib started the next day or up to seven days after dc original drug
Actual NSAID Toxicity
If suspected or actual toxicity is noted, 5 to 7 half-lives should be appropriate to allow for ~97% elimination of the drug, healing of damaged tissue
If dog on COX-1 sparing product (COX 2 selective) and then changed to aspirin…
7d washout recommended DT gastric adaptation, production of aspirin-triggered lipoxins (ATLs)
ATLs
Aspirin-triggered lipoxins
ATLs produced, shown to exert protective effects in stomach by diminishing gastric injury
MOA: release of nitric oxide from vascular endothelium
Problem with concurrent administration of COX-1 sparing drugs with aspirin:
complete inhibition of ATLs, can potentially cause significant assertation of gastric mucosal injuries
Formation of ATL yet to be proven in dog
General Adverse Effects of NSAIDS
–Inhibition of PG synthesis by NSAIDs = basis for therapeutic effects, can also result in toxicity
–Most frequent, clinically significant AEs on GIT
–Close patient monitoring including regular bloodwork (CBC, renal, hepatic) recommended
–Majority of animals receiving recommended doses of NSAIDs do not experience clinical toxicity
–OTCs NSAIDs pose biggest risk to domestic animals, owners extrapolate human dosing to their pets
GI Effects: direct
Direct irritation of gastric mucosa from lipophylic NSAIDs diffusing directly into mucosal cells (PO only)
GI Effects: indirect
PG inhibition (PO, parenteral)
GI Effects of NSAIDS - MOA
Both COX-1, COX-2 necessary for function, maintenance, repair of mucosa
o COX-2 expression increased w/ GI inflammation
o ↓ PGE2 → ↑ gastric acid, ↓ gastric mucus, ↓ blood flow
o Selective COX-2 inhibitors less likely to cause GI SE, but may also delay healing of pre-existing inflammation
GI Effects of NSAIDS - consequences
Mild inflammation to catastrophic ulceration, death
Common GI Lesion Localization: Dogs
pyloric antrum, proximal duodenum
Common GI Lesion Localization: horses
anywhere along GI tract; right dorsal colon
Common GI Lesion Localization: ruminants
abomasum
Common GI Lesion Localizations: camelids
Third Compartment
Clinical Signs of GI Issues with NSAIDS
anorexia, depression, lethargy, diarrhea, vomiting, hematochezia, melena, abdominal pain, anemia, hypoproteinemia, leukocytosis or leukopenia, elevated BUN (no increase in creatinine)
Treatment Options - GI NSAIDS
- PGE1 analogs - misoprostol
- PPIs
- H2 R antagonists
- Sucralfate
PGE1 analogs
Eg misoprostol
prevent duodenal hemorrhage and ulceration associated with aspirin in dogs (Ward et al. 2003; Johnston et al. 1995) but have not been tested with other NSAIDs.
Shown to decrease stomach acidity in horses (Sangiah et al. 1989).
PPIs
(omeprazole, pantoprazole) decrease acid secretion by inactivating parietal cell H+K+-ATPase pumps.
Limited studies in small animals, none in combination with NSAIDs
Humans, horses (Birkman et al. 2014): shown efficacy for promoting ulcer healing
H2 R Antagonists
famotidine, etc) less effective than PPIs in animals at decreasing gastric acidity, still commonly used.
Sucralfate
to help treat but not prevent GI ulceration
Renal SE NSAIDS
NSAIDs suppress renal PGs, resulting in decreased GFR, sodium/fluid retention, decreased tubular function, azotemia
o Renal ischemia, renal papillary necrosis
* Both COX-1, COX-2 involved
Role of prostaglandins in normal renal homeostasis
regulate renal blood flow (RBF) and GFR, especially during periods of hypotension
o Autoregulation of RBF occurs when MAP 60-150 mmHg
NSAIDS and decreased renal perfusion
If decreased renal perfusion caused by dehydration, anesthesia, shock, or pre-existing renal dz at greater risk
Autoregulation
Macula densa senses Cl levels
If Cl high, constriction of afferent arterioles, ↓ GFR
If Cl low, secretes PGE2, PGI2, and NO –> Signal juxtaglomerular apparatus to secrete renin –> angiotensin I then II synthesis –> constriction of efferent arteriole thus ↑ GFR.
Role of AgtII
aldosterone secretion from adrenal cortex, promoting Na+ retention, K+ secretion.
Water Deprivation
COX-2 upregulated in renal medulla
o If NSAIDs administered, interstitial cells undergo apoptosis
Na Excess
COX-2 upregulated in medullary portion of thick ascending limb of Loop of Henle
o LoH: where sodium filtered
o NSAIDs blunt this response, edema formation can occur.
Black Box Warning - Meloxicam and Cats
FDA: “Repeated use of meloxicam in cats has been associated with acute renal failure and death. Do not administer additional injectable or oral meloxicam to cats.”
o Licensed for chronic use in several countries!
o Europe, New Zealand and Australia (long term); Canada (5 days)
Gunew et al 2008 (J Fel Meg Surg)
Long-term safety, efficacy and palatability of oral meloxicam at 0.01–0.03 mg/kg for treatment of osteoarthritic pain in cats.
PO meloxicam safe for long-term treatment (mean 6 months) of DJD in cats at 0.01-0.03 mg/kg/d
Gowan et al 2012 (J Fel Med Surg)
A retrospective analysis of the effects of meloxicam on the longevity of aged cats with and without overt chronic kidney disease.
Cats with CKD receiving 0.02 mg/kg daily for 6 months+ did not show any significant progression of renal disease
Gowan et al 2017 (J Fel Med Surg)
Retrospective Case—Control Study of the Effects of Long-Term Dosing with Meloxicam on Renal Fxn in Aged Cats with DJD.
Cats with CKD receiving 0.02 mg/kg daily for 1 year+ did not reduce lifespan
may even slow progression of CKD in some cats
Hepatic SE of NSAIDS
- All NSAIDs have potential DT their extensive hepatic metabolism
- Idiosyncratic or intrinsic
- Common to see elevations in bilirubin, ALT, ALKP, AST
o Resolution with discontinuation if caught early
MacPail et al. Hepatocellular toxicosis associated with administration of carprofen in 21 dogs. J Am Vet Med Assoc 1998; 212(12):1895-901
o Labradors at increased risk for acute hepatic necrosis with carprofen
o Labs over-represented in the population
Raekaillo et al. Evaluation of adverse effects of long-term orally administered carprofen in dogs. J Am Vet Med Assoc 2006; 228(6):876-80.
No evidence of renal or hepatic toxicity after 2 months of daily administration
Hematologic Effects of NSAIDS
- NSAIDs that inhibit COX-1 will decrease platelet function, clot formation
o Non-acetylated NSAIDs inhibit platelets only when concentrations maintained at inhibitory levels - Aspirin inhibits COX-1 on platelets irreversibly even at low doses
- Specific COX-2 inhibitors have little clinical effect on platelets
Hematologic Effects of Phenylbutazone
aplastic anemia in humans; blood dyscrasias in dogs
Other NSAID Effects on Platelets
Brainard et al. Changes in platelet function, hemostasis, and PG expression after treatment with NSAIDs with various COX selectivities in dogs. Am J Vet Res 2007; 68(3):251-257.
o Meloxicam had minimal effect on platelets
o Carprofen decrease clot strength, platelet aggregation – clinical significance?
Bone, Tendon, Ligament Healing
- Rodent studies: decreased but reversible fracture healing IRT nonselective, COX-2 selective inhibitors
- COX-2 up-regulated in early stages of bone healing
- Studies that show delayed bone, ligament and tendon healing in animal models did so only in early stages of healing –> did not impact the long-term outcome (Radi and Khan 2005)
- Another study: NSAIDs improved mechanical strength in later phase of healing (Riley et al. 2001)
Soft Tissue Healing and Repair
Data Lacking
- Zhao-Fleming et al. Effect of nonsteroidal anti-inflammatory drugs on post-surgical complications against the backdrop of the opioid crisis. Burns and Trauma 2018; https://doi.org/10.1186/s41038-018-0128-x
o Review of the literature in relation to the advantages and disadvantages of using NSAIDs for post-op pain management
o “There is strong evidence in animal studies that non-selective NSAIDs generally inhibit wound healing while either COX-1 or COX-2 selective NSAIDs tend to show no effect on
o wound healing. On the other hand, clinical studies show much more mixed results, with strong evidence of NSAIDs inhibiting only in bone fractures.”
CV Effects of NSAIDS
Humans, COX-2 specific inhibitors may risk of myocardial infarction, thrombosis, stroke, sudden death due to COX-1 promotion of platelet aggregation, vasoconstriction
Relevance in vet med?
Respiratory
- Some humans with asthma respiratory distress when administered aspirin, sometimes other NSAIDs
o Likely DT diversion of AA towards 5-LOX synthesis of leukotrienes that cause BC - Concern for asthmatic cats? Horses with heaves?
Pregnancy/Lactation
- Potential fertility issues
- Complete inhibition of COX-2 may be associated with abortion, fetal abnormalities
- Risk of premature closure of PDA with COXIBs
NSAIDS in Neonates
o Earliest labelled dosing: 6 weeks for carprofen in puppies
o Metacam 6 months dogs, 4 months cats; Canadian label = 6wks for dogs, 6mo for cats
NSAIDS in Milk
- Poor penetration of NSAIDs into milk (in absence of mammary gland infection)
o DT high plasma protein binding, lower pH of milk - Avoid in pregnant and lactating females, however
o Single dose postpartum unlikely to cause much harm (Therio 2019 paper)
(Theriogenology 2019)
ADD KEY FINDINGS!
Aspirin
- Not labeled for use in any animal in US
o Canada: labelled for horses, beef/dairy cattle - Mainly a COX-1 inhibitor, irreversibly inactivates COX enzymes via acetylation
o Duration of effect related to turnover rate of the COX enzymes
Aspirin in Dogs
Mainly used as an antiplatelet drug in hypercoagulable states
o 5 mg/kg PO q24h; 10-20 mg/kg q12h PO for analgesia (better alternatives)
Aspirin in Cats
Cats: long elimination half-life (22-45h) DT inability to rapidly metabolize, excrete salicylates
o 5-10 mg/kg q72h PO
Aspirin in Horses
used for antiplatelet effects in the treatment of laminitis, DIC, venous thrombosis
o 5-10 mg/kg q24-48h PO; 25-50 mg/kg q8h PO for analgesia
Aspirin in Ruminants
used an as antipyretic, for inflammation assoc with lower respiratory disease
o Strongly discouraged by FARAD
Carprofen
- Arylpropionic acid class
- COX-2 preferential, less so in cats/horses vs dogs
Carprofen Labeled Use
US labeling: for relief of pain, inflammation assoc with OA and for control of postoperative pain associated with soft tissue and orthopedic surgeries in dogs 6 weeks of age and older
o Labeled for single injection in cats, horses, and young cattle in other countries
o PO
o Off-label in multiple other species: birds, rabbits, reptiles, ferrets, mice
Carprofen in Dogs
- Dogs: 4.4 mg/kg SC or PO q24h or 2.2 mg/kg q12h
- Approximately 90% orally bioavailable
- Low volume of distribution (0.12 – 0.22 L/kg)
Carprofen Metabolism
Extensively metabolized in liver primarily via glucuronidation, oxidative processes.
Carprofen Elimination
o ~ 70-80% eliminated in feces; 10-20% eliminated in urine. Some enterohepatic recycling
* EL HL ~ 8hrs with the S(+) form having a longer half-life than the R(-) form
Other Features of Carprofen
- 0.05% or less incidence of hepatopathy with Labradors supposedly but unlikely at increased risk
- Showed lowest frequency of GI AE vs meloxicam, ketoprofen, etodolac, flunixin (Luna et al 2007)
- Three long-term studies in dogs: well-tolerated, patients improved over tx period
- Repeated dosing in cats not recommended
Deracoxib
- (COX-2 preferential) approved for post-op and OA pain in dogs; oral only
o Associated with high incidence of GI perforation
o Minimal literature but maybe some recent interest in use for canine mammary cancer
o Effective pain relief in clinical trials involving dogs with OA
Firocoxib
COX-2 selective): most COX-1 sparing NSAID available in US for dogs
o Only available as PO formulation, labeled for OA and post-op pain at 5 mg/kg q24h.
o May also be useful as an adjunct treatment for certain neoplasias
o EXPENSIVE
Effects of Firocoxib
o May have superiority in regard to lameness reduction based on subjective evaluations by owners, veterinarians vs carprofen, etodolac in dogs with OA
o Long-lasting dosing resulted in continued improvements in resolution of signs over 1yr of tx
Firocoxib in Horses
injectable, PO paste, tablets. 0.09 mg/kg IV q24h up to 5 days
o Can continue with 0.1 mg/kg PO q24h for another 9 days (do not exceed 14 days total)
Diclofenac
- 1% liposomal cream for topical application in horses
- Efficacious for treatment of OA, areas of inflammation
- Some evidence of systemic absorption
- Voltaren = common human topical
What species is diclofenac contraindicated?
BIRDS
Implicated in deaths in vultures
Etodolac
- Pyranocarboxylic acid class
- COX-1 sparing
- Narrow margin for adverse GI effects
- May have less impact on clotting times vs NSAIDs
Etodolac Labeled Use
- Labeled for use in dogs in US for treatment of pain, inflammation related to OA
o Oral formulation
o Improved rear limb function in dogs with chronic OA - Dogs: 10-15 mg/kg SC or PO q24h
Flunixin
- Non-selective COX inhibitor
- Approved for horses, cattle, swine in US; dogs in other countries.
- SLOW IV due to possible but rare anaphylaxis
Flunixin in Horses
alleviation of inflammation, pain assoc with MSK disorders; alleviation of visceral pain assoc with colic
o 1.1 mg/kg IV q24h up to 5 days, more frequent dosing off-label
Flunixin in Swine
approved for use to control pyrexia associated with swine respiratory disease
o 2.2 mg/kg IM in neck, max 10mL per site; 12d meat withdrawal
Flunixin in Dogs
Dogs more likely to have GI issues
Flunixin in Birds
Dose-related, significant renal ischemia and nephrotoxicity in birds
Flunixin: Pour On
only FDA approved NSAID for control of pain associated with foot rot and pyrexia associated with respiratory disease in beef cattle, dairy heifers <20 months of age in the US (also in Canada).
o Not for use in calves or dairy cows >20 months of age
o 3.3 mg/kg 1x topically in narrow strip along dorsal midline from withers to tail head;
o 8d meat withdrawal
Injectable form of Flunixin in Cattle
approved for control of fever assoc with respiratory disease or mastitis, fever, inflammation associated with endotoxemia in cattle. Not for use in veal calves or dairy cows.
o 1.1-2.2 mg/kg IV q24h (or split dose for q12h) up to 3 days; extra-label q6-8h
o 4d meat, 36-72h milk withdrawal
(10d meat, 96hr milk per FARAD - up to 60d meat withdrawal with repeat doses)
Ketoprofen
- Arylproprionic acid
- COX-1 selective
o Originally also thought to inhibit LOX (but doesn’t)
Use of ketoprofen
- Licensed for inj in horses in US for MSK inflammation, pain; labelled elsewhere for other species
- No evidence based judgement on effect for tx chronic pain, dysfunction in OA/ DJD in dogs, cats
PK/PD Effects of Ketoprofen
- Chirality – S(+) enantiomer associated with toxicity compared to the R(-) enantiomer
- Eliminated by kidneys as conjugated metabolite, unchanged drug
o Cats may eliminate via thioesterification - No benefit over other labelled NSAIDs in US possibly in renally compromised horses?
Mavacoxib
COX 2 Selective
long acting PO NSAID for dogs, half-life of up to 38 days.
First 2 doses administered 14d apart, 1mo intervals thereafter
Effects of Mavacoxib
o Approved in EU as oral formulation for pain, inflammation assoc with OA
o No clinical data beyond that available from approval process, one abstract – difficult to provide any evaluation of efficacy
Cimicoxib
2mg/kg PO q24h in dogs for OA, surgical pain; not much different than other coxibs
o Coxib family
o PO formulation in EU for tx of pain, IFM assoc with OA, postop pain in dogs
o Non-inferiority vs carprofen in managing postop pain for dogs undergoing either orthopedic or STSx
o Lack of peer reviewed data
Meloxicam
- Oxicam
- COX-2 preferential; long half-life compared to other NSAIDs (24h dog)
Meloxicam - US label
inj labeled dose for dogs 0.2mg/kg IV/SC, cats 0.3mg/kg SC 1x; PO dogs 0.1mg/kg PO q24h
o Labeled elsewhere for cats with different dosing
o Oral, OTM mist, parenteral formulations
* “Adverse Effects Renal – CATS” for literature on safety and long term use in cats
Horses and Meloxicam
Used off-label in horses, found to be effective for inflammatory pain, +/- less compromise to gastric mucosa vs phenylbutazone
o Safe for extended use 0.6mg/kg q24h
o One study: safe in foals 0.6mg/kg q12h (faster clearance).
Meloxicam in Other Countries in Livestock
- 20 mg/mL solution is labeled for use in cattle (SC/IV), swine (IM), and sheep (IM) in Canada.
o Meat withdrawal 20d cattle, 5d swine, 11d sheep. Milk withdrawal 4d.
o Calves: 0.5-1mg/kg single dose 21d, up to 1mg/kg multiple days 30d
o Goats, sheep: 1mg/kg single dose 15d meat
o Literature: efficacy, safety in beef, dairy cattle, calves for treating pain, inflammation
o Less literature for sheep and swine, but is all positive
In what species is meloxicam used off label in the US?
- Also used off label in goats, llamas, alpacas, and multiple exotic animal species.
- Labeled for guinea pigs in the UK
- May be the safest NSAID for use in birds – 0.5 mg/kg IM, 1.0 mg/kg IV
SE of Meloxicam
- Second only to carprofen in lowest frequency of adverse GI effects in dogs (Luna et al. 2007)
- PO bioavailability poor in many species
- Possibility of injection site myositis
Meloxicam in Reptiles
- Has been used in reptiles but minimal literature
o No effect in Ball pythons at 0.3 mg/kg
o Some PK studies in turtles – 0.2 mg/kg IM shown to be safe but unknown efficacy
Phenylbutazone
- Non-selective COX inhibitor
- Labeled for horses for treatment of musculoskeletal pain, inflammation - not for use in food!
Can you use phenylbutazone in livestock?
NO!!!!
Banned in female dairy cattle >20mo, minimum 55d withdrawal in beef cattle
Phenylbutazone in dogs
o Licensed for use in dogs in US, safer alternatives are available
o 2.2-4.4mg/kg IV, PO q12h
o do not admin IV > 5 days in a row; decrease to lowest effective dose after 48-96 h
Problems with Phenylbutazone
- Perivascular irritant causing tissue necrosis and sloughing (do not administer IM/SC!)
- Associated with blood dyscrasias in humans - wear gloves
Piroxicam
- Not approved for use in veterinary patients
- Adjunctive tx for several types of neoplasia that contain genes for expression of COX enzymes
o TCC, mammary carcinoma, STS, oral SCC in dogs
SE Piroxicam
- Gastric ulceration common, GI protectants recommended
- Possible data that shows more selective COX-2 inhibitors improved efficacy over piroxicam?
Robenacoxib
- Coxib, COX-2 selective
- Licensed for use in cats, dogs >4 mos of age
- For: control of postop pain, inflammation assoc with orthopedic surgery, OVH, and castration in cats; control of postop pain, inflammation assoc with STSx in dogs
o Labeled for long term use for OA management in other countries (incl Canada)
Robenacoxib Formulations
- Injectable solution, oral tablet
- Very short EL HL in both species, persists at higher concentrations at sites of inflammation
- Bioavailability poor in cats when administered with food
Robenacoxib Dosing
Cats: 2 mg/kg SC q24h up to 3 days; 1 mg/kg PO q24h up to 3 days
Dogs: 2 mg/kg SC or PO q24h up to 3 days
Robenacoxib
- US label: avoid in cats with cardiac disease due to prolongation of QT interval
o No data to support, two studies in dogs showed no ECG changes
Cats and Robenacoxib
Well tolerated when administered daily for 1 month in cats with osteoarthritis, including cats with evidence of concurrent CKD
No clinical indication of damage to gastrointestinal tract, kidney or liver.
Robenacoxib vs Other NSAIDS
Superior to meloxicam in post-op pain assessment, poor agreement btw evaluators, subjective criteria used
No difference btw meloxicam, robenacoxib post-op, but also no difference btw robenacoxib and placebo from days 2-9 post-op
Tepoxalin
- Dual COX/LOX inhibitor, no longer available in US
o Inhibits both Cox isoenzymes, 5 lipoxygenase - Approved for use in dogs to control pain, inflammation associated with OA
o Was available in oral formulation
Effects of Tepoxalin
- May be more effective than carprofen or meloxicam for controlling uveitis in dogs
- Dogs with atopic dermatitis had decreased pruritus
Safety, Efficacy of Tepoxalin
No published reports available to support clinical efficacy, safety beyond data submitted as part of approval process for use in dogs
Tolfenamic Acid
- Anthranilic acid derivative, fenamates class of NSAIDS
- Non-selective COX inhibitor with direct inhibition of PG receptors
o Significant anti-TXA2 activity → not recommended to use administer pre-surgically
Tolfenamic Acid Use
- Approved in Canada and Europe for dogs and cats; Cattle and swine in Australia
- Data in dogs and cats for short term use only (3-7d), lack of long term data
Grapriprant
Prostaglandin E2 EP4-receptor antagonist
MOA Grapriprant
- New class of non-COX inhibiting NSAID (piprant) for treating osteoarthritis pain in dogs.
o Decreases PGE2’s influence on pain transmission at sensory neurons, ameliorates inflammatory effect
o EP4-receptor = sole PGE2-mediated receptor for stimulation of stomach acid secretion, mucus secretion in stomach, LI
o Also inhibits PGE2-mediated SI motility, cytokine expression in LI
Advantages of Grapiprant
- Potentially significantly fewer severe AEs in dogs than other NSAIDs
o Observed adverse effects include mainly GI effects (vomiting and loose, mucoid, watery, or bloody stools).
o Dose-dependent ↓ in albumin during safety studies using up to 15x label dose for up to 9mo
Dosing of Grapiprant
Dogs: 2 mg/kg PO q24h >9mo of age; use lowest effective dose for chronic use
o Washout period after an NSAID or glucocorticoid recommended
o Monitoring?
Use of Grapiprant
- Improvement compared to a placebo.
o Unpublished study: no difference btw grapiprant vs carprofen for acute pain in dogs
(AJVR 2023 article) - Safe when administered to cats at doses up to 15 mg/kg once daily
o PO bioavil low, further studies needed to assess minimal effective concentration in cats - Plasma concentrations achieved exceeded minimal effective concentration for dogs for 10hr
Acetaminophen
- Exact MOA not well understood
o Produces analgesia, antipyresis via a weak, reversible, isoform-nonspecific inhibition of cyclooxygenase (COX-3; Cox-1-v1)
Acetaminophen in Dogs
- Dogs: 10-15 mg/kg PO q8h, consider decreasing to q12h after 5 days. Minimal GI or renal effects.
- Dogs: not as effective at metabolizing it –> narrow safety margin, educate owners if used
- Anecdotally not very effective on own, used as an adjunct to other analgesics including NSAIDs
Acetaminophen - contraindications
DO NOT USE IN CATS OR FERRETS!!! (Maybe not in sugar gliders, or hedgehogs)
o Methemoglobinemia, Heinz-body anemia, icterus, death
o Toxic metabolites formed DT inability to effectively metabolize by glucuronidation
Gabapentin MOA
MOA not fully understood: it appears to bind to CaVa2-d (alpha2-delta subunit of VG Ca channels).
o By decreasing Ca influx, release of excitatory NTs (e.g., substance P, glutamate, NE) inhibited.
Gabapentin
Categorized as an anticonvulsant – used adjunct for refractory seizures, tx of neuropathic pain
Structurally related to GABA, but does not appear to alter GABA binding, reuptake, or degradation, or serve as a GABA agonist in vivo.
Use of Gabapentin
- Does not appear to be of significant use for treating acute pain, it may be of benefit when given pre-emptively for acute pain in dogs (e.g., before surgery) when used adjunctively with other analgesics (Crociolli et al. 2015)
- Most useful in treating chronic pain, particularly neuropathic pain in small animals
PK of Gabapentin in dogs
Dogs PO bioavailability ~ 80% at a dose of 50 mg/kg.
o Peak plasma levels occur about 2 hours post dose.
Elimination of Gabapentin
Elimination primarily via renal routes, but gabapentin is partially metabolized to N-methylgabapentin in dogs.
Elimination half-life ~2-4 hours (Vollmer et al. 1986; Kukanich & Cohen 2011).
Cats and Gabapentin
well absorbed after PO dosing with a bioavailability average of 90%
o Significant interpatient variation (50%-120%).
o Peak levels occurred about 100min after dosing.
o Volume of distribution relatively low (apparent Vdss of 0.65 L/kg.)
o Clearance ~ 3 mL/min/kg
o Mean elimination half-life of 2.8 hours (Siao et al. 2010).
Safety of Gabapentin
- Very large margin of safety - sedation and ataxia are probably the most likely adverse effects
o Humans: 100% renally excreted, used with caution in patients with renal insufficiency
o Dogs 30-40% metabolized prior to excretion, may consider decreasing dose in later stage CKD patients
Dosing for Dogs, Cats
- Dogs: 5-20 mg/kg q8-12h PO, start with low end of the dose and increase as needed
- Cats: 3-10 mg/kg q8-12h PO
- Commercial oral solution contains xylitol – do not use
