NSAIDs Flashcards
What is the MOA
NSAIDS inhibit cycolooxygenase (COX) 1 and 2 stopping the release of thromboxane and PG’s
Note all have same MOA- inhibit COX, thus are equally efficacious
flow diagram:
cell damage
phospholipids
phospholipase (inhibited by corticosteroids)
arachidonic acid
COX 1 and 2 > thromboxane and PGs
Lipoxygenase (no commercial drug to inhibit) - leukotrienes
Use indications - why would we give NSAIDs
SEVERE INFLAMMATION - this is a big priority
Moderate pain relief - we may want to add a stronger analgesic but not as a replacement for an anti-inflammatory
Chronic arthritis - is both chronic and active. The damage from chronic inflammation is almost permeant but we can stop further acute inflammation and so the joint feels better
- Analgesia via anti-inflammatory
- surgeries (desexing, orthopaedics)
- trauma
Side effects/contraindications
What are the 1) GASTROINTESTINAL TRACT side effects
All have side effects. Nearly entirely related to the adverting inhibition of COX 1
Cox selectivity helps us because the majority of toxicity of NSAIDS is ulceration and bleeding
Good PGs normally:
inhibit acid secretion
increase mucosal blood flow
increase mucous production
Thus NSAID potential for: erosion, ulceration, haemorrhage
How can you attempt to alleviate GIT side effects?
a) H2 blockers - Ranitidine
b) proton-pump inhibitors - omeprazole (this decreases acid secretion and is gold standard for ulcer treatment)
c) sucralfate - binds to an ulcer, does not prevent ulcers
Side effects/contraindications
What are the 2) ALTERED PLATELET FUNCTION side effects
- abnormal bleeding
Thromboxane normally: is a pro aggregator of platelets needed for thrombus formation and haemostats
PGI2 normally: inhibitor of platelet aggregation
Thus NSAID potential for decreased thromboxane and PGI2 = a net decrease in platelet aggregation potentially resulting in abnormal bleeding
Note aspirin binds to COX irreversibly which makes a good candidate to help prevent formation of a new blood clot formation
Side effects/contraindications
What are the 3) KIDNEY side effects
- risk of renal failure (vets are nervous giving NSAIDs when needing to do an anaesthesia due to the risk of renal failure)
PGE2 normally: increased salt and water excretion
PG!2 normally: renal vasodilation which promotes blood flow to kidney
NSAID potential for:
- decreased renal blood flow -> leading to interstitial; papillary necrosis and nephritis
- water retention -> hypertension
Patients with heart disease may have decreased CO. Some of these PGS act as a back up by increasing renal perfusion. These patients are at greater risk of kidney related NSAID complicaitons
What are the 3 inflammatory phases
Acute transient phase - local vasodilation, increases capillary permeability
Delayed, subacute phase
infiltration of neutrophils and mononuclear leucocytes. Phagocytosis
Chronic proliferation phase
tissue degeneration and fibrosis
PK quirks
All have a longer DOA than T1/2 would predict
COX-2 is wider and has valine in side pocket - using a drug that fits/binds with COX2 preferentially to COX1 allows for selectivity of COX2
Representative drugs
Meloxicam
- studied in multiple species including exotic
- cat friendly preparations (lower concentration)
Firocoxib
-decreased side effects (COX-2 selectivity), especially used for chronic therapy
Carprofen
Onsior - registered for cats
Off-label for SA - aspirin - option when $ is low
Piroxicam: cost effective for large dog OA
Chrondroprotectives: pentosan polysulfate glucosamine (safe, poor PO bioavailability) chrondroitin (safe) green lipped mussel (safe) shark cartilage (controversial ethics) marine fatty acids
What are commonly used NSAIDs in production animals?
None registered for sheep - except oral meloxicam (buccalgesic)
Telfenamic acid - structural analogue of flunixin (has established WHPs)
Flunixin - old, cheap, established WHPs COX 1 selective - 100% efficacious
Phenylbutazone ‘Bute’ - old, cheap, NO established WHPs in production animals due to decreased drug clearance
What are commonly used Equine NSAIDs?
phenylbutazone 'bute' no COX1/COX2 selectivity side effects (colitis with dorsal colon ulceration) zero order kinetics --> if the horse eats the drug is is carried to the right dorsal colon
meloxicam - its use is slowly increasing
Flunixin - empirica; use for colic horses
Tell me about COX 1 (constitutive)
numerous protective roles in blood vessels, gastrointestinal mucosa and kidney
Tell me about COX2 (induced)
induced after an insult to produce the mediators of inflammation, pain and pyrexia
Why wouldn’t we want to give a NSAID?
Cat is probable dehydrated so more likely to get side effects of NSAIDs especially kidney problems
–> if severely dehydrated, should be given IV fluids, which will improve hydration and therefore blood flow to the kidneys. This should help reduce NSAUD associated kidney problems
increased coagulation time
–>probably won’t be clinically significant but ensure that there is no major bleeding somewhere
cats are poor phase 2 metabolise of NSAIDs - toxicity
–> choose an appropriate drug and dose
Pharmacokinetics of NSAIDs
- highly bound to plasma proteins (albumin)
- low Vd, suggesting minimal tissues binding
- NSAIDs are well absorbed by the GIT
- administration with food or antacids may lead to delayed absorption
- elimination is hepatic biotransformation
