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POS 2 > NSAIDs Smallies > Flashcards

NSAIDs Smallies Flashcards

1
Q

OUtlie 3 main arachidonic acid pathways LOOK UP

A

COX 1 physiological

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2
Q

How can COX2 selective drugs be made?

A

Phyiscal shape and size of molecule

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3
Q

When is COX2 activated and released?

A
  • tissue damage
  • bacterial LPS
  • cytokines
  • growth facos
  • PGEs predominant eicosanoid -> inflam
  • tumout s
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4
Q

COX2 inhibition clinical benefits?

A 
> suppprression of 
- inflam 
- pain 
- fever
> alzheimers 
> tumours
- coon, pancreas, lung, TCC (bladder), melanoma
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5
Q

How are NSAIDs classfied?

A 
> non-selective
> preferential 
- >2x (usually 10-40x) greater inhibition of COX2 
> selective
- 100x selective
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6
Q

What do coritcosteroids inhibit?

A
  • immune system

- phosphlipase a (cell membrane phosphlipid -> arachidonic acid)

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7
Q

Other than COX

A
  • 5LO inhibition
  • PG recepto blockade
  • scavengin free adical s
  • anti-bradykinin properites
  • ihibition enzyme rlease or action
  • inhibiton cytokine release
  • inhibition NFkB
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8
Q

How are COX1/COX2 inhibition potency data expressed? Gold standard data??

A

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

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9
Q

How are COW assays assessed?

A

Methods
> COX1 inhibition
- clot induced thromboxane B2 production inhibition
> COX 2 activity
- inhibition of LPS induced PGE2 production

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10
Q

What factors affect toxicity profiles of NSAIDs?

A
  • 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)
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11
Q

Therapeutic aim of NSAIDs?

A
  • > ## 80% inhibition of COX2 for as much of 24 hr period a sposs
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12
Q

Which drugs are non-selective COX1/2?

A
  • aspirin
  • phenylbutazone
  • ketoprofen
  • tolfenamic acid
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13
Q

What are preferential COX 2 inhibitiors?

A
  • 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)
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14
Q

Which drugs are preferentially COX2 blockers?

A
  • meloxicam
  • carprofen
  • mavacoxib
  • cimicoxib (probs, data not published)
  • deracoxib (US)
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15
Q

How may COX2 selecctivity in preferential drugs be affeected by dose?

A

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
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16
Q

What is a true specific COX2 inhibitor?

A

more than 100x selective for COX2 , no COX1

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17
Q

What drugs are COX2 selective (coxibs)?

A
  • firocoxib
  • robenocoxib
    > no generic as still under patent (yet!)
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18
Q

Which drug is a dual inibitor (COX nd LOX)?

A

> tepoxalin

  • inhibit LOX for short period during day
  • non-selectie COx1 ad COX2
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19
Q

Which human NSAIDs are bad for pets?

A
  • naproxen
  • ibuprofen
  • piroxicam (only for TCC)
  • mefanamic acid
  • diclofenac
  • paracetamol (acetaminophen) only in cats (ok in dogs)
20
Q

What does paracetamol cause in cats?

A
  • face and feet oedema

- methaegloinaemia (brown blood)

21
Q

How does carprofen action differ in cats adn dogs? Horses? Man?

A
  • both COX2 selective
  • much longer half life in cat, so daily doses -> GI disaster
  • horse non-selective
  • man COX1 preferentail
22
Q

Pharmacokinetics of NSAIDs ? carprofen? Not sure which supposed to be

A
  • 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
23
Q

How are NASIDs metabolised? how does this differ between individuals?

A

> 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

24
Q

How does cats ability to metabolise aspirin differ to dogs? clinical implications?

A
  • prolonged t1/2 in cats

- same dose but q72hrs not BID

25
Q

How does cats ability to metabolise carfprofen differ to dogs? clinical implications?

A
  • T1/2 20hrs v 8 hrs

- only LIC for one use in cats

26
Q

How does cats ability to metabolise meloxicam differ to dogs? clinical implications?

A

21hrs v 24hrs (don’t know which is which!?)

27
Q

3 main areas of adverse effects of NSAIDs?

A
  • GI
  • renal
  • haematological
28
Q

How do PGs ct in the gut? LOOK UP

A
  • 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
29
Q

Actions of COX1 specifically in gut

A
  • 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)
30
Q

Role of COX2 in the gut?

A 
> many gut cells express COX2
- macrophages
- neurtrophils
- myofibroblasts
- endothelial cells  
> some studies suggest COX2 inhibition may be able to retard ulcer healing!
31
Q

When should NSAIDs NOT be used?

A
  • confrmed, presumed and potential GI inflammation

- including pacreatitis

32
Q

Which NSAIDs have v GIT tox?

A
  • preferential/highly selective COX2 inhibiitors

- but GI ulceration reported occasionally

33
Q

How is ulcerogenic potential increased when giving NSAIDs?

A
  • concurrent corticosteroids
  • dehydration
  • hypovolaemic shock (v GIT blood flow)
  • disruption of normal GIT blood flow
34
Q

How are PGs involved in renal function?

A

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

35
Q

How are COX2 speces differences seen in kidneys?

A
  • 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)
36
Q

When can renal toxicity occour with NSAIDS?

A
  • volue dpeleted
  • avidly retaining sodium (eg. heart failure/hepative cirrhosis)
  • has pre-existing renal insufficiency
37
Q

What controversial findings about renal ctions of NSAIDs was recently found?

A

^ life span of CKD cats on meloxicam for DJD

???

38
Q

Which NSADIs have a lower risk of renal toxicity?

A

> 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!!!

39
Q

Wha haematopoetic effects can NSAIDs have?

A

> 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
40
Q

How does the liver affect NSAID use?

A
  • extensive hepatic metabolism of NSAIDs
  • care with hepatic dz!
  • no clear rules
  • ideally avoid
  • if you haev to, ^ dosing interval, not v dose
41
Q

How do ACE inhibitors affect NSAID use?

A
  • echo
    > use with care in conjunction with NSAIDs if risk of renal perfusion v
  • if renal perfusion reduced, there is absoltely NO protective mechanism!
42
Q

Whcih other drugs may cause issues with NSAID use? Why?

A
  • ACE inhibitors
  • a2 ags (v BP)
  • ACP high dose (v BP)
  • diuretics attenuated by COX2 inhibition
43
Q

How may diruetcs affect/be affected by NSAIDs?

A
  • COX2 inhibition may attenuate effect of diuretic
44
Q

Clinical indications for NSAIDs?

A

> 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

45
Q

Clinically, when should NSAIDs (selective or not) be avoided?

A
  • 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
46
Q

How can dosing be altered if worried about liver or kidney problems?

A
  • eg. in old cats with CKD and DJD (consider cost:benefit analysis)
  • extend dose interval, don’t lower dose
47
Q

What type of analgesia is safer to give if you are unclear of the pathology going on?

A

Opioids!! if you are not sure of renal, hepatic and GIT function

POS 2 (28 decks)

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