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Boards: Pharmacology > NSAIDS > Flashcards

NSAIDS Flashcards

1
Q

Transduction

A

conversion of noxious stimulus into an AP at level of specialized R or nerve endings.

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2
Q

Transmission

A

propagation of APs by primary afferent neurons to spinal cord

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3
Q

Modulation

A

process by which nociceptive information is augmented or inhibited.

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4
Q

Projection

A

conveyance of nociceptive information through spinal cord to brain
o Brainstem, thalamus, then cortex

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5
Q

Perception

A

integration of nociceptive information by brain (overall conscious, emotional experience of pain).

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6
Q

Peripheral Sensitization

A

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)

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7
Q

Central Sensitization

A

Peripheral inflammation –> production of PGs in spinal cord
o Inflammation similar to a repetitive stimulus - it does not resolve immediately

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8
Q

2 mechanisms for development of central sensitization related to COX-2 production

A

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.

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9
Q

Role of PGE2 in Development of Central Sensitization

A

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

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10
Q

Function of NSAIDS

A

Relieve mild to moderately severe pain: Anti-inflammatory and anti-nociceptive

Anti-pyretic

Anti-endotoxemic

Anti-neoplastic

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11
Q

Formulations

A

o Oral tablets, caplets, liquids, chewable tablets, paste (horses)
o Oral transmucosal
o Transdermal
o Injectable: IV or SC

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12
Q

OG NSAID: Willowbark

A

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

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13
Q

Synthesis of Salicylic Acid

A

o 1829-1838 - Salicylic acid first isolated by Henri Leroux, Raffaele Piria

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14
Q

Acetylsalicylic acid

A

Aspirin, synthesized by Felix Hoffman in 1897 while working for Bayer

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15
Q

1971

A

Sir John Vane described ability of aspirin-like drugs to inhibit production of prostaglandins

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16
Q

NSAID Classification

A
  • Chemical structure
  • Similar physio-chemical properties
  • almost all are weak acids (pKa 3.5-6.0)
  • moderate to high lipid solubility
  • highly protein bound
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17
Q

Carboxylic Acids (R-COOH)

A

Salicylates (aspirin)
Indoleactic acids (etodolac)
2-arylpropionic acids (carprofen/ketoprofen)
Anthranilic acids (flunixin, Tolfenamic acid)

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18
Q

Salicylates

A

Aspirin
Carboxylic Acids (R-COOH)

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19
Q

Indoleacetic acids

A

Etodolac
Carboxylic Acids (R-COOH)

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20
Q

Anthranilic acids

A

Flunixin, tolfenamic acid
Carboxylic Acids (R-COOH)

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21
Q

Enolic Acids (R-COH)

A

-Oxicams - meloxicam, piroxicam
-Pyrazolones: phenylbutazone, dipyrone

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22
Q

Oxicams

A

Enolic acids

Meloxicam, piroxicam

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23
Q

Dual COX-5-LOX Inhibitors

A
  • Tepoxalin (approved for use in US for treatment of pain, inflammation related to OA
  • No longer available
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24
Q

COX 2 Inhibitors

A
  • 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
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25
Q

CINODS

A
  • 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
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26
Q

Arachidonic Acid

A

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)

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27
Q

Structure of AA

A
  • 20 carbon polyunsaturated omega-6 FA
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28
Q

Downstream Effect of AA

A

Oxidized by cyclooxygenase (COX), lipoxygenase (LOX) enzymes as part of various enzyme cascades to form eicosanoids and leukotrienes, respectively

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29
Q

Eicosanoids

A

20-carbon, hairpin-shaped FA with cyclopentane ring

Prostanoids, Thromboxane

Products act locally via GPCR to generate inflammatory, immunological responses

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30
Q

Prostanoids

A

specific eicosanoids (PGG2, PGH2) further metabolized into prostacyclin (PGI2) and various prostaglandins (PGD2, PGF2α, PGE2)

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31
Q

Thromboxane (TXA2)

A

mainly produced from PGH2 via thromboxane synthase on platelets

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32
Q

Prostacyclin (PGI2)

A

R: IP, Gs

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33
Q

Function of PGI2

A

*vasodilation
*inhibit platelet aggregation
*Bronchodilation
*Synergistic with NO

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34
Q

Prostaglandin D2

A

R: PTGDR (DP1) and CRTH2 (DP2), GPCR

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35
Q

Function of PGD2

A

*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

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36
Q

Receptors for prostaglandin E2 (PGE2

A

EP1 - Gq
EP2 - Gs
EP3 - Gi
EP4 - Gs

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37
Q

Functions of PGE2+EP1

A

bronchoconstriction
GI tract SmM contraction

(mediated by Gq)

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38
Q

Functions of PGE2+EP2

A

*bronchodilation
*GI tract smooth muscle relaxation
*vasodilation

(mediated by Gs)

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39
Q

Functions of PGE2+EP3

A

*↓ 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)

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40
Q

Functions of PGE2+EP4

A

*Maintain ductus arteriosus in the fetus
*Pro-inflammatory
*↑ Duodenal bicarb secretion
*↓ colonic inflammation
*May play a part in progression of some cancers

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41
Q

Prostaglandin F2a

A

R: FP via Gq

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42
Q

Function of PGF2a

A

*uterus contraction
*Bronchoconstriction
*vasoconstriction

(mediated by Gq)

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43
Q

TXA2

A

Binds to TP R via Gq

Promotion of platelet aggregation, VC

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44
Q

Cyclooxygense

A

AKA prostaglandin-endoperoxidase synthase

responsible for synthesis of prostaglandins
* 2 isoforms identified – COX-1, COX-2
* COX-3: splice variant of COX-1

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45
Q

COX 3

A

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

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46
Q

COX 1 vs COX 2 - primary protein structure

A

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

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47
Q

COX 1

A
  • “Constitutive”
  • Expressed in wide range of tissues
  • increases IRT stimulation by hormones, growth factors (small amount)
  • Generates TXA2, PGE2, PGI2, PGD2
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48
Q

Housekeeping functions of COX 1

A

blood clotting
renoprotection
gastroprotection
regulation of vascular homeostasis
coordination of circulating hormones

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49
Q

COX 2

A

“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
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50
Q

Where is COX 2 constitutive?

A

monocytes
macrophages
pyloric and duodenal mucosa
endothelial cells
brain
dorsal horn
kidney
ovary/uterus
ciliary body of eye

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51
Q

COX Selectivity

A
  • 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
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52
Q

COX Selectivity Expressed as a Ratio

A

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

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53
Q

Limitations of COX Selectivity Ratio

A
  • COX-1:COX-2 ratio does NOT predict clinical efficacy of an NSAID
  • One NSAID may be more effective than another in individual patient
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54
Q

COX 1 selective

A

COX 1:COX 2 ratio <1

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55
Q

COX 1 Selective NSAIDS

A

COX 1:COX 2 ratio <1
Aspirin 0.4
Ketoprofen 0.88

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56
Q

COX 2 Preferential NSAIDS

A

COX 1:COX 2 >1-100

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57
Q

COX 2 Preferential NSAIDS

A

Etodolac 6.6
Meloxicam 7.3
Carprofen 16.8
Deracoxib 48.5

COX 1:COX 2 >1-100

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58
Q

COX 2 selective

A

COX 1:COX 2 >100-1000

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59
Q

COX 2 Selective NSAIDS

A

COX 1:COX 2 >100-1000

Robenacoxib 128.8
Firocoxib 155

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60
Q

COX 2 specific

A

COX 1:COX 2 >1000

None commercially available

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61
Q

Main MOA of NSAIDS

A

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

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62
Q

Aspirin MOA vs other NSAIDS

A

shown to have anti-inflammatory effects through inhibition of kinase Erk
o decreases neutrophil aggregation in areas of injury, decreases their inflammatory effects

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63
Q

Other potential MOA of NSAIDS

A

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

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64
Q

Lipoxygenase (5-LOX)

A

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

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65
Q

Consequence of Overproduction of Leukotrienes

A

major cause of inflammation in asthma, allergic rhinitis, OA

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66
Q

Lipoxins

A

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

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67
Q

PK of NSAIDS: Absorption

A
  • 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
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68
Q

Which NSAID has lower bioavailability hen given with food?

A

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)

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69
Q

NSAID PO Absorption, monogastrics

A

more drug un-ionized in acidic environment of stomach, favors absorption

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70
Q

NSAID PO Absorption, ruminants

A

biphasic absorption from stomach compartments, intestine

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71
Q

NSAID PO Absorption, horses

A

drug may bind to hay/digesta, can delay absorption

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72
Q

2-arylproprionic acids

A

Carprofen, ketoprofen
Carboxylic acids

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73
Q

NSAID Distribution

A
  • Highly protein bound (>95%)
  • Low Vd (0.1-0.3 L/kg or less)
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74
Q

Which are the exceptions to the normally low Vd of NSAIDS?

A

 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)

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75
Q

Where do NSAIDS accumulate?

A

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

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76
Q

Metabolism

A

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

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77
Q

Which NSAIDS are converted to active metabolites?

A

Aspirin, phenylbutazone converted to active metabolites (salicylate and oxyphenbutazone)

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78
Q

Species Specific Metabolism

A
  • Species, inter- and intra-breed, inter- and intra-animal differences
    o Clearance and terminal half-life vary markedly
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79
Q

What is an alternative method of metabolism?

A

Some biliary secretion may occur → enterohepatic recirculation

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80
Q

Excretion

A
  • Only small fractions are excreted unchanged in urine due to high protein binding
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81
Q

Stereoisomerism

A
  • 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
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82
Q

Stereoisomerism: differences in PK for each enantiomer arise from:

A

o Differing rates of hepatic metabolism
o Chiral inversion of some drugs (unidirectional R→S)

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83
Q

Important feature of carprofen and stereoisomerism

A

Enantioselectivity of distribution into exudate, synovial fluid for carprofen (Armstrong et al. 1999

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84
Q

Pharmacodynamics of NSAIDs

A
  • 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?
85
Q

PD of NSAIDS with chiral center

A

differing potency ratios for each enantiomer for COX-1 and COX-2

86
Q

Species Differences with PD

A
  • 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
87
Q

PK-PD modeling to determine optimal and safe dosing is complicated

A

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)

88
Q

Wash Out Times

A

Typically recommend 5-7 days “wash-out” period when switching from one NSAID to another

89
Q

Single dose of perioperative parenteral NSAID followed by different oral NSAID next day

A

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

90
Q

NSAID: most have elimination half lives of what

A

-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

91
Q

Robenacoxib HL

A

very short elimination half-life of 0.6-1.1h in dogs, 0.8-1.9h in cats

92
Q

Wash Out Period if Poor Clinical Response/No AEs noted

A

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

93
Q

Actual NSAID Toxicity

A

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

94
Q

If dog on COX-1 sparing product (COX 2 selective) and then changed to aspirin…

A

7d washout recommended DT gastric adaptation, production of aspirin-triggered lipoxins (ATLs)

95
Q

ATLs

A

Aspirin-triggered lipoxins

ATLs produced, shown to exert protective effects in stomach by diminishing gastric injury

MOA: release of nitric oxide from vascular endothelium

96
Q

Problem with concurrent administration of COX-1 sparing drugs with aspirin:

A

complete inhibition of ATLs, can potentially cause significant assertation of gastric mucosal injuries

Formation of ATL yet to be proven in dog

97
Q

General Adverse Effects of NSAIDS

A

–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

98
Q

GI Effects: direct

A

Direct irritation of gastric mucosa from lipophylic NSAIDs diffusing directly into mucosal cells (PO only)

99
Q

GI Effects: indirect

A

PG inhibition (PO, parenteral)

100
Q

GI Effects of NSAIDS - MOA

A

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

101
Q

GI Effects of NSAIDS - consequences

A

Mild inflammation to catastrophic ulceration, death

102
Q

Common GI Lesion Localization: Dogs

A

pyloric antrum, proximal duodenum

103
Q

Common GI Lesion Localization: horses

A

anywhere along GI tract; right dorsal colon

104
Q

Common GI Lesion Localization: ruminants

A

abomasum

105
Q

Common GI Lesion Localizations: camelids

A

Third Compartment

106
Q

Clinical Signs of GI Issues with NSAIDS

A

anorexia, depression, lethargy, diarrhea, vomiting, hematochezia, melena, abdominal pain, anemia, hypoproteinemia, leukocytosis or leukopenia, elevated BUN (no increase in creatinine)

107
Q

Treatment Options - GI NSAIDS

A
  1. PGE1 analogs - misoprostol
  2. PPIs
  3. H2 R antagonists
  4. Sucralfate
108
Q

PGE1 analogs

A

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).

109
Q

PPIs

A

(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

110
Q

H2 R Antagonists

A

famotidine, etc) less effective than PPIs in animals at decreasing gastric acidity, still commonly used.

111
Q

Sucralfate

A

to help treat but not prevent GI ulceration

112
Q

Renal SE NSAIDS

A

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

113
Q

Role of prostaglandins in normal renal homeostasis

A

regulate renal blood flow (RBF) and GFR, especially during periods of hypotension
o Autoregulation of RBF occurs when MAP 60-150 mmHg

114
Q

NSAIDS and decreased renal perfusion

A

If decreased renal perfusion caused by dehydration, anesthesia, shock, or pre-existing renal dz at greater risk

115
Q

Autoregulation

A

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.

116
Q

Role of AgtII

A

aldosterone secretion from adrenal cortex, promoting Na+ retention, K+ secretion.

117
Q

Water Deprivation

A

COX-2 upregulated in renal medulla
o If NSAIDs administered, interstitial cells undergo apoptosis

118
Q

Na Excess

A

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.

119
Q

Black Box Warning - Meloxicam and Cats

A

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)

120
Q

Gunew et al 2008 (J Fel Meg Surg)

A

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

121
Q

Gowan et al 2012 (J Fel Med Surg)

A

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

122
Q

Gowan et al 2017 (J Fel Med Surg)

A

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

123
Q

Hepatic SE of NSAIDS

A
  • 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
124
Q

MacPail et al. Hepatocellular toxicosis associated with administration of carprofen in 21 dogs. J Am Vet Med Assoc 1998; 212(12):1895-901

A

o Labradors at increased risk for acute hepatic necrosis with carprofen
o Labs over-represented in the population

125
Q

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.

A

No evidence of renal or hepatic toxicity after 2 months of daily administration

126
Q

Hematologic Effects of NSAIDS

A
  • 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
127
Q

Hematologic Effects of Phenylbutazone

A

aplastic anemia in humans; blood dyscrasias in dogs

128
Q

Other NSAID Effects on Platelets

A

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?

129
Q

Bone, Tendon, Ligament Healing

A
  • 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)
130
Q

Soft Tissue Healing and Repair

A

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.”
131
Q

CV Effects of NSAIDS

A

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?

132
Q

Respiratory

A
  • 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?
133
Q

Pregnancy/Lactation

A
  • Potential fertility issues
  • Complete inhibition of COX-2 may be associated with abortion, fetal abnormalities
  • Risk of premature closure of PDA with COXIBs
134
Q

NSAIDS in Neonates

A

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

135
Q

NSAIDS in Milk

A
  • 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)
136
Q

(Theriogenology 2019)

A

ADD KEY FINDINGS!

137
Q

Aspirin

A
  • 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
138
Q

Aspirin in Dogs

A

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)

139
Q

Aspirin in Cats

A

Cats: long elimination half-life (22-45h) DT inability to rapidly metabolize, excrete salicylates
o 5-10 mg/kg q72h PO

140
Q

Aspirin in Horses

A

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

141
Q

Aspirin in Ruminants

A

used an as antipyretic, for inflammation assoc with lower respiratory disease
o Strongly discouraged by FARAD

142
Q

Carprofen

A
  • Arylpropionic acid class
  • COX-2 preferential, less so in cats/horses vs dogs
143
Q

Carprofen Labeled Use

A

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

144
Q

Carprofen in Dogs

A
  • 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)
145
Q

Carprofen Metabolism

A

Extensively metabolized in liver primarily via glucuronidation, oxidative processes.

146
Q

Carprofen Elimination

A

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

147
Q

Other Features of Carprofen

A
  • 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
148
Q

Deracoxib

A
  • (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
149
Q

Firocoxib

A

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

150
Q

Effects of Firocoxib

A

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

151
Q

Firocoxib in Horses

A

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)

152
Q

Diclofenac

A
  • 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
153
Q

What species is diclofenac contraindicated?

A

BIRDS
Implicated in deaths in vultures

154
Q

Etodolac

A
  • Pyranocarboxylic acid class
  • COX-1 sparing
  • Narrow margin for adverse GI effects
  • May have less impact on clotting times vs NSAIDs
155
Q

Etodolac Labeled Use

A
  • 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
156
Q

Flunixin

A
  • Non-selective COX inhibitor
  • Approved for horses, cattle, swine in US; dogs in other countries.
  • SLOW IV due to possible but rare anaphylaxis
157
Q

Flunixin in Horses

A

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

158
Q

Flunixin in Swine

A

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

159
Q

Flunixin in Dogs

A

Dogs more likely to have GI issues

160
Q

Flunixin in Birds

A

Dose-related, significant renal ischemia and nephrotoxicity in birds

161
Q

Flunixin: Pour On

A

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

162
Q

Injectable form of Flunixin in Cattle

A

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)

163
Q

Ketoprofen

A
  • Arylproprionic acid
  • COX-1 selective
    o Originally also thought to inhibit LOX (but doesn’t)
164
Q

Use of ketoprofen

A
  • 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
165
Q

PK/PD Effects of Ketoprofen

A
  • 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?
166
Q

Mavacoxib

A

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

167
Q

Effects of Mavacoxib

A

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

168
Q

Cimicoxib

A

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

169
Q

Meloxicam

A
  • Oxicam
  • COX-2 preferential; long half-life compared to other NSAIDs (24h dog)
170
Q

Meloxicam - US label

A

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

171
Q

Horses and Meloxicam

A

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).

172
Q

Meloxicam in Other Countries in Livestock

A
  • 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
173
Q

In what species is meloxicam used off label in the US?

A
  • 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
174
Q

SE of Meloxicam

A
  • 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
175
Q

Meloxicam in Reptiles

A
  • 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
176
Q

Phenylbutazone

A
  • Non-selective COX inhibitor
  • Labeled for horses for treatment of musculoskeletal pain, inflammation - not for use in food!
177
Q

Can you use phenylbutazone in livestock?

A

NO!!!!

Banned in female dairy cattle >20mo, minimum 55d withdrawal in beef cattle

178
Q

Phenylbutazone in dogs

A

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

179
Q

Problems with Phenylbutazone

A
  • Perivascular irritant causing tissue necrosis and sloughing (do not administer IM/SC!)
  • Associated with blood dyscrasias in humans - wear gloves
180
Q

Piroxicam

A
  • 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
181
Q

SE Piroxicam

A
  • Gastric ulceration common, GI protectants recommended
  • Possible data that shows more selective COX-2 inhibitors improved efficacy over piroxicam?
182
Q

Robenacoxib

A
  • 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)
183
Q

Robenacoxib Formulations

A
  • 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
184
Q

Robenacoxib Dosing

A

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

185
Q

Robenacoxib

A
  • 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
186
Q

Cats and Robenacoxib

A

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.

187
Q

Robenacoxib vs Other NSAIDS

A

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

188
Q

Tepoxalin

A
  • 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
189
Q

Effects of Tepoxalin

A
  • May be more effective than carprofen or meloxicam for controlling uveitis in dogs
  • Dogs with atopic dermatitis had decreased pruritus
190
Q

Safety, Efficacy of Tepoxalin

A

No published reports available to support clinical efficacy, safety beyond data submitted as part of approval process for use in dogs

191
Q

Tolfenamic Acid

A
  • 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
192
Q

Tolfenamic Acid Use

A
  • 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
193
Q

Grapriprant

A

Prostaglandin E2 EP4-receptor antagonist

194
Q

MOA Grapriprant

A
  • 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
195
Q

Advantages of Grapiprant

A
  • 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
196
Q

Dosing of Grapiprant

A

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?

197
Q

Use of Grapiprant

A
  • 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
198
Q

Acetaminophen

A
  • Exact MOA not well understood
    o Produces analgesia, antipyresis via a weak, reversible, isoform-nonspecific inhibition of cyclooxygenase (COX-3; Cox-1-v1)
199
Q

Acetaminophen in Dogs

A
  • 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
200
Q

Acetaminophen - contraindications

A

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

201
Q

Gabapentin MOA

A

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.

202
Q

Gabapentin

A

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.

203
Q

Use of Gabapentin

A
  • 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
204
Q

PK of Gabapentin in dogs

A

Dogs PO bioavailability ~ 80% at a dose of 50 mg/kg.
o Peak plasma levels occur about 2 hours post dose.

205
Q

Elimination of Gabapentin

A

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).

206
Q

Cats and Gabapentin

A

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).

207
Q

Safety of Gabapentin

A
  • 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
208
Q

Dosing for Dogs, Cats

A
  • 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

Boards: Pharmacology (9 decks)

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