Analgesics, Antiinflammatories, Antipyretics-I: NSAIDs Flashcards
Pharmacotherapy of Pain
- broad concept
Analgesia involves the interruption of pain pathways at one of several key points along the pathway originating at the nociceptor and finishing at higher CNS centers such as the cerebral cortex
- perception, transmission, modulation, transduction
do alpha2 work on perception, transmission, modulation, or transduction? what about local anesthetics?
Alpha2 - perception, transmission, modulation
LAs - transmission, modulation, transduction
NSAIDs
- how common?
- overview of effects?
NSAIDs are most popular analgesics used in veterinary medicine
- Most NSAIDs are capable of analgesic, antiinflammatory and antipyretic effects; mild-moderate to severe pain
how do NSAIDs work to stop pain? what are the general effects and how should we use them?
Block effects of COX1/2 to stop the downstream products
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- such as:
PGE2/PGI2 promote sensitization of nociceptors and are proinflammatory
* NSAIDs more effective when inflammation involved
* More effective when given prior to onset of inflammation
* NSAID analgesic effects have faster onset and shorter duration of action vs anti-inflammatory effects
NSAIDs -Pharmacodynamics
- COX-1: what does it do?
COX-1 traditionally viewed as the “constitutive” enzyme; protective – Good……High systemic levels
> Evidence supporting COX-1 derived PGs contribute to pain, inflammation and fever
NSAIDs -Pharmacodynamics
- COX-2: what does it do?
COX-2 traditionally viewed as the “inducible” enzyme;
proinflammatory—Bad….Low systemic levels
- However, COX-2 also shown to be beneficial !!
> Kidney; maintain RBF and GFR > important in renal compromised patients,
dehydration, and during anesthesia
> GI Tract; promotes healing of ulcers
> Antiinflammtory effects in resolution/healing phase of inflammation
NSAIDs -Pharmacodynamics-
COX Pharmacology
- cox inhibition ratio, what it tells us? classifications of NSAIDs?
The COX inhibition ratio ie IC50 COX-1/ IC50 COX-2 ratio offers some indication of theoretical drug safety
- The higher the ratio eg. 1000/1, the more selective the drug is for COX-2, as it takes much less drug to block (inhibit) COX-2 vs COX-1
- NSAIDs classified as non-selective; or COX-1 selective; or preferential or moderately selective, and highly to very highly selective, for COX-2
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Very importantly, whole blood assays give the most relevant info vs isolated enzymes, broken cells or intact cells
NSAIDs -Pharmacokinetics-
- pH and what that means
Almost all NSAIDs are weak acids (pKa 3.5-6.0)
- Most NSAIDs are of moderate to high lipid solubility
- Injectable solutions tend to be alkaline and can cause pain on administration via SC or IM routes
NSAID pharmacokinetics - oral absorption, considerations with feed?
Generally absorbed very well following oral dosing
- Feed can bind drug and delay rate of absorption in some species, such as horse or ruminants, but generally not delay extent of absorption (and we are not really interested in rate)
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- Administration with feed in companion animals can reduce GI irritation
> May delay rate of absorption, but not reduce the extent of absorption significantly
NSAIDs -Pharmacokinetics-
- protein binding? consequences? what changes this?
NSAIDs are highly protein bound (>95-99%)
- Small Vd (0.1-0.3 L/kg); distribution generally limited to the plasma space
- Coxibs have greater Vd, in part, due to enterohepatic recycling and tissue binding
- Inflammation can increase Vd at biophase as drug is protein bound to exudate
- hypoalbuminemia and ADRs from unbound drug not a clinical concern
- NSAID penetration into milk is generally poor unless mastitis present
NSAIDs -Pharmacokinetics-
> hepatic metabolism
Most NSAIDs undergo hepatic metabolism to inactive metabolites
- Large differences in clearance between species possible; can affect drug half life
- Some NSAIDs have a chiral center and possess enantiomers eg. carprofen,
ketoprofen…….have S and R enantiomers or isoforms
> Differences in PKs and PDs noted for enantiomers within and across species that can account for interindividual variability in effects and ADRs
NSAIDs General Indications in dogs:
- surgical pain (soft tissue/orthopedic)
- osteoarthritis associated pain and inflammation
- acute and chronic musculoskeletal pain and inflammation
NSAIDs General Indications in cats:
- surgical pain (soft tissue/orthopedic)
- musculoskeletal pain and inflammation
- treatment of upper respiratory tract disease and symptomatic mgmt of fever
NSAIDs used in dogs
- Robenacoxib
- Meloxicam
- Firocoxib
- Deracoxib
- Carprofen
NSAIDs used in cats
- Robenacoxib
- Meloxicam
NSAIDs -Large Animals-
- indications
General indications include pain and inflammation associated with…..
- Musculoskeletal conditions; lameness
- Mastitis and udder edema
- Respiratory disease
- De-budding of horn buds in young calves
- Withdrawal times relevant to animals destined for the human food chain
NSAIDs often used in large animals
- meloxicam
- ketoprofen
- phenylbutazone
- flunixin meglumine
- firocoxib
Grapiprant - what does this do? when do we use it? adverse effects?
- Prostaglandin E2 (PGE2) EP4 receptor antagonist
- Non-cyclooxygenase inhibiting NSAID
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Indicated for treatment and control of pain and inflammation in canine OA - 20, 60 mg (scored and can be broken) and 100 mg (not scored) tablets;
- AVOID use with other NSAIDS or corticosteroids concurrently; not well studied
- Observe adequate washout times when switching from NSAIDs to grapiprant
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Vomiting, diarrhea, lethargy possible; rare hemorrhagic diarrhea, elevated liver enzymes possible
Frunevetmab - what is this? what do we use it for? adverse effects?
- Feline anti-nerve growth factor monoclonal antibody
- Indicated for treatment of feline OA; monthly injection; 1 mL vials
- Vomiting, diarrhea, anti-drug antibodies possible
NSAIDs
- What’s Best?
- duration?
Generally, all NSAIDs are equally efficacious !!
- No clinical trials showing one NSAID more efficacious than another
- Duration of action usually 12-24 hrs; greater than opioids
- Individual patients may experience greater analgesia and/or less adverse effects with a particular NSAID that is based on PK or PD differences
> May require altering dosing regimen or switching drugs
> COX inhibition assays show species difference in drug selectivity for COX NZs
> Fluctuations or progression of disease and PGs involved
does blood concentration of NSAID matter for efficacy?
- how do concentrations look in exudates? relevance?
Efficacy often doesn’t correlate with plasma [NSAID] !!
- Exudate drug concentration usually greater than plasma due to protein bound drug accumulating at target site of inflammation
> Especially notable when plasma drug clearance is high and drug elimination
half-life is short
> Provides explanation for continued efficacy when plasma [NSAID] low !!
> Can explain efficacy from once daily dosing for NSAIDs with low plasma levels
NSAIDs most common adverse effects?
- can we avoid? considerations?
- can we manage?
- Most common adverse effects are GI tract events
> anorexia, diarrhea (melena), vomiting, mucosal erosions, ulcers and perforation
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**COX-1 sparing NSAIDs appear more safe WRT GI ADRs in healthy GI tracts - Not true for diseased GI tracts eg. ulcerated**
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COX-2 important in mucosal repair and angiogenesis in ulcer healing - Antiinflammatory effects in latter stages of inflammation; resolution phase
- May involve PGE2 and 15dPGJ2
<> - Direct chemical irritation of mucosa possible eg. Aspirin
- Re-direction of arachiodonic acid to the lipoxygenase pathway and LT production
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Adverse GI effects can be managed by the use of antiulcer or gastroprotectant agents
antiulcer or gastroprotectant agents that can be used to manage adverse GI effects of NSAIDs
- Proton pump inhibitors
- Prostaglandin E1 analogs
- H2 antagonists
- Sucralfate
possible adverse effects aside from GI with NSAIDs
- Adverse renal events are not uncommon
> Careful with patients predisposed to renal risks - Hepatotoxicity possible
- Bleeding tendencies most concerning with aspirin
- Myositis from flunixin meglumine in horses
- Fracture healing slowed by NSAIDs ?
NSAIDs adverse renal effects?
- when are they a problem?
- mechanism?
- is COX 1 vs 2 inhibition more safe?
- most careful with what patients?
Adverse renal events are not uncommon
- Generally, not a problem in healthy animals with free access to water
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- PGs maintain……
> RBF/GFR and tubular function during volume depletion
> Increase salt and water excretion in volume overload preventing edema
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- Adverse events involve both COX-1 and COX-2 inhibition……cannot assume COX-2 selective agents more renal safe
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Careful with patients predisposed to renal risks
- neonates, geriatrics
- anesthesia, dehydrated, working dogs?
- chronic renal failure, congestive heart failure, hepatic disease
when is hepatotoxicity from NSAIDs mostly seen?
- Most common in dogs; carprofen (idosyncratic)
- PBZ in horses
- Reduced glucuronidation in cats suggest agents using
other pathways may be preferred eg. meloxicam and robenacoxib
NSAIDs associated with bleeding disorders?
- avoid what patients? selectivity?
Bleeding tendencies most concerning with aspirin
- Ketoprofen, tolfenamic acid
- Avoid in patients with hematological disorders
- COX-2 selective agents may promote thrombosis ?
Myositis - can be an issue in horses due to which NSAID
flunixin meglumine
does fracture healing slow with NSAIDs?
- No strong clinical data showing impairment
- NSAIDs are licensed for use in vet orthopedics
when do we see most issues with NSAID use? how can we avoid this?
- Inappropriate veterinary administration along with uninformed owners accounts for most the safety issues with NSAID use in veterinary patients
<><> - Use products with a history of extensive clinical experience and good safety….veterinary-approved
- Brand name versus generics versus compounded NSAIDs
what should we check on long-term NSAID candidates?
Long-term NSAID candidates should have liver and kidney profiles checked before and during therapy
NSAID use: What if there is break-thru pain in chronic pain eg. OA?
- Oral tramadol, opioid? other adjunctive agents?; synergism with NSAIDs possible
- Acetaminophen for short periods as an option in dog if liver function is normal
if we use a certain NSAID for a dog or cat in hospital, should we send them home with the same one or a different one?
For dogs/cats, probably best to send patient home on same NSAID used in the hospital……manufacturer support is assured if ADR
when should we give NSAIDs for surgery? admin route?
- WRT surgery, give NSAIDs preemptively ideally, if patient is a good candidate; if post-op, then have other analgesic on board
> If post-op, recommend injectable over oral for first dose
what do we do if evidence for NSAID ADR?
- ideally stop NSAID, allow for adequate elimination of drug, and clinical resolution
> On-going pain managed judiciously with other analgesics eg opioids, tramadol
Switching NSAIDS for lack of efficacy - what is elimination half life to keep in mind?
5-10 elimination half-lives equating to 3-5 days for most NSAIDs
> No washout period ??
