13 – NSAIDs Flashcards
Leaves and bark of willow tree
- Anti-inflammatory properties
- *contains SALICYCLIC ACID: pre-cursor to aspirin
5 cardinal signs of inflammation
- Redness
- Heat
- Swelling
- Pain
- Loss of function
- **caused by vasodilation, edema, nociceptive stimulation
If wanting to prevent peripheral inflammation, NSAIDs or steroids?
- Can use either or
NSAID uses
- Prevent or reduce inflammation
- Reduce fever (anti-pyretic)
- *Analgesic (central and/or peripheral effects)
NSAID: prevent or reduce inflammation
- Block formation of inflammatory EICOSANOIDS
o Ex. prostaglandins, thromboxane, leukotrienes
NSAID: reduce fever (anti-pyretic)
- PGE2 (prostaglandin) is an endogenous pyrogen
o Increase body T by re-setting the ‘set-point’ in hypothalamus - *if more prostaglandin expressed=increase T
- *if decrease prostaglandin=decrease T
NSAID inflammation pathway: peripheral
- Prevent AA from going to prostaglandins
o Block COX1 and COX2 - Do NOT get PGE2 or PGF2
- *Immune-mediated products (ex. leukotrienes) are STILL PRODUCED!
NSAID analgesia
- Reducing PERIPHERAL may decrease pain sensation
o If due to swelling/pressure (same mechanism as with corticosteroids) - Prostaglandin ‘synergy’ with bradykinin and histamine
PG ‘synergy’ with bradykinin(BK) and histamine(HT)
- PG can increase afferent neurone firing due to BK&HT-mediated stimulation of peripheral nociceptors
o Hyperalgesia (increase effect of painful stimuli)
o Allodynia (normally non-painful stimuli become painful)
What about Tylenol (ex. acetaminophen)?
- Has lots of CENTRAL analgesia effect
o Still lots of PGs being produced in CNS - Poor PERIPHERAL analgesia effect
- Not much anti-inflammatory activity
‘central’ analgesia
- Both cyclo-oxygenase isoforms (COX-1 and COX-2) are present in brain and spinal tissue
o Produce PGs in neural tissues
What is the result of ‘central’ PGE formation?
- Sensitizes central nociceptors (‘wind-up”)
- Lowers spinal depolarization threshold
NSAIDs is one of most commonly classes of vet drugs
- Efficacious
- Relatively safe
- Potential for profit (giving multiple times a day)
NSAIDs and reported adverse effects (‘pharmovigilance’)
- Typically 10% of total adverse effects
- Used a lot, so will see more adverse effects
- Tend to use them in animals that are less healthy
o Geriatric, perioperative, etc.
NSAIDs: GI adverse drug events
*60%
- Vomiting
- Diarrhea
- Ulcers
- Melena
- *PG usually protect
- *direct GI irritation (aspirin, meloxicam tablets)
NSAIDS: renal adverse events
*20%
- PG help maintain GFR
o NSAIDs: decrease GFR
- Renal papillary necrosis
NSAIDs GI and renal adverse events
- *DOSE-DEPENDENT in most cases
o Use lowest dose that is still effective
NSAIDs hepatic adverse events
15%
- Idiosyncratic hepatic necrosis/toxicity
- Increase liver enzymes: change in bile acids?
- *cats most susceptible, but can’t predict individual toxicity
- **probably dose-dependent, but dose-independent is (‘less) common’
o If see independent=liver
NSAIDS hematologic adverse events
1%
- Prolonged bleeding time with aspirin and ketoprofen
COX1
- Constitutive (produced constantly)
- Present under normal conditions in many cells
- Produce ‘cytoprotective’ PGs (vasodilation, mucous)
o *positive
COX1 present under normal conditions in many cells
- Platelets and endothelium
- Mucosal cells (GI)
- Renal tubule cells
- Neural tissues
COX2
- Inducible (expressed in response to inflammatory mediators)
- Often formed at sites of inflammation
o *what we want to target - Constitutive in some tissues
COX2 selective
- Drugs that inhibit COX2 (but not COX1) at label dose
COX2 preferential
- Drugs that inhibit COX2 at lower drug concentrations than COX1
o Some COX1 inhibition at label dose
COX nonspecific
- Both COX1 and COX2 are inhibited at label doses
How to determine which category of NSAID? (‘older’ concept)
- COX inhibition
- IC50: drug concentration at which 50% of enzyme activity is inhibited
- *lower IC means increased drug potency
Wanted to get an NSAID where IC50 for COX1 was really high (older concept)
- High number means LESS inhibition
- COX1 is ‘spared’
IC ratios problems
- In vitro data does not pan out when given to animals
- Species differences in IC values
- Chirality
*HARD TO COMPARE IC BETWEEN NSAIDs or SPECIES
Overly-simplistic (and wrong) theory
- COX1 is good, COX2 is bad
- Higher COX1 : COX2 IC50 ration =better NSAID
*past this point!
COX2 is not all bad
- Constitutive in some tissues (kidney, brain, SC)
- Expressed near gastric ulcers=accelerates healing
COX3
- Derivative of COX1
- Found in brain
- Unknow function, but inhibited by older NSAIDs that ‘seem to work’
PK/PD data and NSAID comparison of safety and efficacy
- Cannot make decisions solely on PK/PD data
o Need clinical trials! (not in vitro data)
NSAID general PK properties
- Generally good oral bioavailability
- Primarily eliminated by HEPATIC metabolism
- Highly protein bound (lead to low Vd)
o Present at sites of peripheral inflammation - Usually weak acids (can be ion-trapped in cells)
- *kinetics highly variable between species
o Cats=poor glucuronidation (low clearance, long half-life)
COXIB-specific drug properties
- Varying degrees of COX2 selectivity
- Generally, very LIPOPHILIC
- Hepatic metabolism: CYP450
o When use with other drugs, if both substrates for same enzyme=induction/inhibition
VIOXX (first COXIB in human med)
- Recalled
- Increased risk of CV events (heart ailments, strokes)
o Not an issue in dogs or cats
Intravenous lipid emulsion (ILE) therapy
- May be helpful in cases of lipophilic NSAID toxicosis
- Concept: lipophilic drug distributes from CNS into lipid emulsion in vasculature=facilitates clearance (DRUG DISTRIBUTION)
- BUT: limited efficacy (case reports, are NOT clinical trials)
o One case of respiratory distress reported after ILE
Washout periods
- Time period when switching between 2 drugs
- *allows 1st drug to be eliminated, increasing margin of safety when 2nd drug is administered
- *very important for anti-inflammatory drugs
o Even though different enzyme targets, it is the same pathway
Is it a good idea to use a ‘washout period’ when switching between NSAIDs?
- Yup!
How do you know how long a washout period to use when switching NSAIDs?
- *BE CAREFUL
- Use some length (whatever is feasible for patient/owner)
- Warn owner of risks!
