NSAIDs Smallies Flashcards
OUtlie 3 main arachidonic acid pathways LOOK UP
COX 1 physiological
How can COX2 selective drugs be made?
Phyiscal shape and size of molecule
When is COX2 activated and released?
- tissue damage
- bacterial LPS
- cytokines
- growth facos
- PGEs predominant eicosanoid -> inflam
- tumout s
COX2 inhibition clinical benefits?
> suppprression of - inflam - pain - fever > alzheimers > tumours - coon, pancreas, lung, TCC (bladder), melanoma
How are NSAIDs classfied?
> non-selective > preferential - >2x (usually 10-40x) greater inhibition of COX2 > selective - 100x selective
What do coritcosteroids inhibit?
- immune system
- phosphlipase a (cell membrane phosphlipid -> arachidonic acid)
Other than COX
- 5LO inhibition
- PG recepto blockade
- scavengin free adical s
- anti-bradykinin properites
- ihibition enzyme rlease or action
- inhibiton cytokine release
- inhibition NFkB
How are COX1/COX2 inhibition potency data expressed? Gold standard data??
IC50
(wide inter and intra laboratory variation in data)
- beware studies done on cell culture/rodents/tumour cell lines etc.
> GOLD STANDARD: wholeblood assay in species of interest
How are COW assays assessed?
Methods
> COX1 inhibition
- clot induced thromboxane B2 production inhibition
> COX 2 activity
- inhibition of LPS induced PGE2 production
What factors affect toxicity profiles of NSAIDs?
- paritially COX1:COX2 ratio
- degreee of acidity of pro-drug (direct gastric mucosal dmage)
- plasma t1/2
- degreee of enterohepatic recycling (^ in dogs c. humans)
Therapeutic aim of NSAIDs?
- > ## 80% inhibition of COX2 for as much of 24 hr period a sposs
Which drugs are non-selective COX1/2?
- aspirin
- phenylbutazone
- ketoprofen
- tolfenamic acid
What are preferential COX 2 inhibitiors?
- 2-40x more selective
- at higher end of dose range will affect COX1
- analgesic and anti-inflam activity thati nhibits COX2
- include “coxibs” (initially thought to be elective)
Which drugs are preferentially COX2 blockers?
- meloxicam
- carprofen
- mavacoxib
- cimicoxib (probs, data not published)
- deracoxib (US)
How may COX2 selecctivity in preferential drugs be affeected by dose?
Different shaped curves
- inhibition of COX1 when COX2 inhibited by 80% = ~25% carprofen and meloxicam
- inhibition of COX1 when COX2 inhibited by 100% = ~60% carprofen, ~70% meloxicam
What is a true specific COX2 inhibitor?
more than 100x selective for COX2 , no COX1
What drugs are COX2 selective (coxibs)?
- firocoxib
- robenocoxib
> no generic as still under patent (yet!)
Which drug is a dual inibitor (COX nd LOX)?
> tepoxalin
- inhibit LOX for short period during day
- non-selectie COx1 ad COX2
Which human NSAIDs are bad for pets?
- naproxen
- ibuprofen
- piroxicam (only for TCC)
- mefanamic acid
- diclofenac
- paracetamol (acetaminophen) only in cats (ok in dogs)
What does paracetamol cause in cats?
- face and feet oedema
- methaegloinaemia (brown blood)
How does carprofen action differ in cats adn dogs? Horses? Man?
- both COX2 selective
- much longer half life in cat, so daily doses -> GI disaster
- horse non-selective
- man COX1 preferentail
Pharmacokinetics of NSAIDs ? carprofen? Not sure which supposed to be
- well absorbed from stomach and SI
- well absorbed sc or im injection
- topical administration -> drug levels in tissues adn synovial fluids comparable to oral administration
- oromucosal delivery can acheive effective systemic levles eg. Revitacam (rotanacoxib??)
- weak acids so readily penetrae inflamed tissue
- highly protein bound (accumulation of drug in protein rich inflam exudate)
- duration of effect of NAIDs may exceed apparent systemic t1/2
How are NASIDs metabolised? how does this differ between individuals?
> excreted at varying rates
- depending on metabolic pathway and extent of enterohepatic circulation
elimnation T1/2 varies w/ drugs and species
toxicity and pharmacokinetic data on NSAIDs in one species EVER TRANSPOSED TO ANOTHER
How does cats ability to metabolise aspirin differ to dogs? clinical implications?
- prolonged t1/2 in cats
- same dose but q72hrs not BID
How does cats ability to metabolise carfprofen differ to dogs? clinical implications?
- T1/2 20hrs v 8 hrs
- only LIC for one use in cats
How does cats ability to metabolise meloxicam differ to dogs? clinical implications?
21hrs v 24hrs (don’t know which is which!?)
3 main areas of adverse effects of NSAIDs?
- GI
- renal
- haematological
How do PGs ct in the gut? LOOK UP
- PGi2 (prostacyclin) and PGE2 maintain integrity of protective barrier
- prevents gastric mucosa from damage by gastric acid
> PGE and PGI2 protect gastric muscosa by: - inhibit gastric acid secretion
- maintain mucosal bloodflow
- involved in secretion and composition of mucus
- also act as intracellular messengers for stimulus of mucosal cell turnover and migration
Actions of COX1 specifically in gut
- predominnat source of good PGs
- inihibition of COX1 -> ulceration
- but both COX1 and COX2 need to be inhibited to GENERATE mucosal injury (ie. in the absence of pre-existing injury)
Role of COX2 in the gut?
> many gut cells express COX2 - macrophages - neurtrophils - myofibroblasts - endothelial cells > some studies suggest COX2 inhibition may be able to retard ulcer healing!
When should NSAIDs NOT be used?
- confrmed, presumed and potential GI inflammation
- including pacreatitis
Which NSAIDs have v GIT tox?
- preferential/highly selective COX2 inhibiitors
- but GI ulceration reported occasionally
How is ulcerogenic potential increased when giving NSAIDs?
- concurrent corticosteroids
- dehydration
- hypovolaemic shock (v GIT blood flow)
- disruption of normal GIT blood flow
How are PGs involved in renal function?
COX1 and COX2 present in normal kidney (shown with IHC)
> so must have physiological role
- when renal eprfusion reduced, renal PGs maintain renal blood flow via vasodilation (COX 1 and COX 2)
- COX2 also invovled in naturiesis (Na excretion)
> minimal action in normally perfused kidneys
How are COX2 speces differences seen in kidneys?
- COX2 expreission markedly INCEASED in volume depleted rats and dog but not monkeys
- hence prefential or selective COX2 inhibitiors no as renally safe as thought in dogs (cf. primates)
When can renal toxicity occour with NSAIDS?
- volue dpeleted
- avidly retaining sodium (eg. heart failure/hepative cirrhosis)
- has pre-existing renal insufficiency
What controversial findings about renal ctions of NSAIDs was recently found?
^ life span of CKD cats on meloxicam for DJD
???
Which NSADIs have a lower risk of renal toxicity?
> preferential (carprofen, meloxicam)
to a greater extent selective (fibrocoxib, robenacoxib, mavocoxib, cimicoxib) COX2 inhibitiors
- have less risk of renal toxicity if renal perfusion is reduced
- cf. nonselective (aspirin, PBZ, ketoprofen, tepoxalin)
but no NSAID is completely reanlly safe if perfusion is reduced!!!
Wha haematopoetic effects can NSAIDs have?
> thromboxane potent vasoconstrictor and activator ofplatelet aggregation
- inhibition of TXA -> ^ risk of bleeding
- usually only significant with older NSAIDs
- use any NSAID with care in breeds pdf vonWillebrands
How does the liver affect NSAID use?
- extensive hepatic metabolism of NSAIDs
- care with hepatic dz!
- no clear rules
- ideally avoid
- if you haev to, ^ dosing interval, not v dose
How do ACE inhibitors affect NSAID use?
- echo
> use with care in conjunction with NSAIDs if risk of renal perfusion v - if renal perfusion reduced, there is absoltely NO protective mechanism!
Whcih other drugs may cause issues with NSAID use? Why?
- ACE inhibitors
- a2 ags (v BP)
- ACP high dose (v BP)
- diuretics attenuated by COX2 inhibition
How may diruetcs affect/be affected by NSAIDs?
- COX2 inhibition may attenuate effect of diuretic
Clinical indications for NSAIDs?
> paina nf inflam esp. noninfectious nonallergic disease
- DJD
- perioperatively
v platelet aggregation
- thromboembolus
- heartworm
opthalmology
- rx keratitis and scleritis
- do not inhibit re-epithelialisation of the cornea
- intraocular surgery (may minimise postop ^ protein content of aq humour)
managing immunological dz
- SLE, rheumatoid arthritis
- snti-inflam
- may stim T-suppressor cells in action againt T helper cell snad autoAb producing T cells
endotoxic shock
- if administered prior to or immediately at onset of endotoxaemia in soncjunction with supportive tx
Clinically, when should NSAIDs (selective or not) be avoided?
- evidence or suspicion of GIT inflammation
- gut blood flow reduced/potential to be reduced (Shock, dehydration, v CO)
- renal blood flow reduced/potential to be reduced
- pathological NA retention eg. with CHF, nephrotic syndrome or cirrhotic hepatic disease
How can dosing be altered if worried about liver or kidney problems?
- eg. in old cats with CKD and DJD (consider cost:benefit analysis)
- extend dose interval, don’t lower dose
What type of analgesia is safer to give if you are unclear of the pathology going on?
Opioids!! if you are not sure of renal, hepatic and GIT function
