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Principles of Pharmacology and Therapeutics > Rational Use of NSAIDs in Clinical Practice > Flashcards

Rational Use of NSAIDs in Clinical Practice Flashcards

1
Q

How do NSAIDs work?

A

Reduce inflammation by inhibiting production of prostaglandins (PGs) released by damaged tissue through inhibition of cyclo-oxygenase enzyme (COX)

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2
Q

What is the role of COX-1?

A

Production of PGs important in the physiological modulation of function such as gut mucosal barrier and intra-renal perfusion when renal blood flow is reduced

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3
Q

When is COX-2 activated?

A

Tissue damage, bacterial lipopolysaccaride, cytokines, growth factors, inflammation where PGE2 is predominant eicosanoid

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4
Q

What are the clinical benefits of suppressing COX-2?

A

Suppressed pain, inflammation and fever

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5
Q

What are some other benefits of suppressing COX-2?

A

Delayed onset of Alzheimers disease?

Some cancers reduced such as colon, pancreas, lung, transitiona cell carcinoma, melanoma

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6
Q

What are the three classes of NSAIDs?

A

Non-selective
Preferential - at least 2x greater inhibition of COX-2 but usually 10-40x
Selective - >100x selective for COX-2

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7
Q

What other mechanisms are NSAIDs thought to work by?

A 
5-LO inhibition
Prostaglandin receptor blockade
Scavenging free radicals
Anti-bradykinin properties
Inhibition of enzyme release or action
Inhibition of cytokine release
Inhibition of NFkB
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8
Q

How are the pharmacodynamics of COX-1 and COX-2 selectivity expressed?

A

As IC50 values

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9
Q

What are the different assay methods to determine COX-1 and COX-2 selectivity?

A

Cell based
Tumour cell lines
Whole blood - gold standard in species of interest

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10
Q

How is COX-1 inhibitory activity measured?

A

Inhibition of clot-induced thromboxam B2 production

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11
Q

How is COX-2 inhibitory activity measured?

A

Inhibition of LPS induced PGE2 production

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12
Q

What factors other than COX-1:COX-2 ratio may affect the safety of NSAIDs?

A

Degree of acidity of the pro-drug (direct GIT mucosal damage)
Plasma half life
Degree of enterohepatic recycling

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13
Q

What is the therapeutic aim when using and NSAID?

A

> 80% inhibition of COX-2 for part though not all of a 24 hour period
<10%

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14
Q

What are some examples of non-selective COX inhibitors?

A

Aspirin
Phenylbutazone
Ketoprofen
Tolfenamic acid

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15
Q

What are some examples of preferential COX-2 inhibitors?

A 
Meloxicam
Carprofen
Mavacoxib
Cimicoxib
Deracoxib in US
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16
Q

What are some examples of selective COX-2 inhibitors?

A

Firocoxib

Robenoxocib

17
Q

What is a dual inhibitor NSAID?

A

Drug that inhibits both COX and LOX

18
Q

What is an example of a dual inhibitor?

A

Tepoxalin - inhibits LOX for a short peroid, non-selective COX

19
Q

What are the species differences seen when using carprofen?

A 
Dogs = COX-2 preferential
Cats = COX-2 preferential with significantly longer half life with daily dosing causing a GI disaster
Horses = non-selective
Human = COX-1 preferential
20
Q

What are the pharmacokinetics of NSAIDs?

A

Well absorbed from the stomach and small intestine or after SC or IM injection
Topical treatment is possible as is oromucosal
Weak acids that readily penetrate inflamed tissue and highly protein bound so duration of effect may exceed their apparent systemic half-life

21
Q

How are NSAIDs metabolised?

A

Varying rates depending on the metabolic pathway and extent of enterohepatic circulation
Elimination half-life varies considerably between drugs and species

22
Q

What are the potential adverse effects of NSAIDs?

A

Gi
Renal
Haematological

23
Q

How does PGE and PGI2 protect the gastric mucosa?

A

Inhibit gastric acid secretion
Maintain mucosal blood flow
Being involved in secretion and composition of healthy mucous
May also act as intercellular messengers for the stimulus of mucosal cell turnover and migration

24
Q

How do adverse GI effects of NSAIDs occur?

A

COX-1 is predominant source of good PGs and inhibition of COX-1 is the main mechanism of GI ulceration, however, both COX-1 and COX-2 need to be inhibited to generate mucosal injury in the absence of pre-existing injury

25
Q

Which gut cells express COX-2?

A

Macrophages, Neutrophils, Myofibroblasts, Endothelial cells

26
Q

How can COX-2 inhibition cause adverse GI effects?

A

COX-2 is rapidly expressed in response to GI injury and contributes significantly to mucosal repair so it is prudent to avoid NSAID use in patients with confirmed, presumed or potential GI inflammation

27
Q

What factors other than COX-1/COX-2 inhibition contribute to the adverse GI effects of NSAIDs?

A

Relative gastric absorption
Systemic availability of the drug via the circulation to the mucosa
Direct damage to gastric mucosa
Degree of enterohepatic recycling

28
Q

What increases the potential ulcerogenic effects of NSAIDs?

A

Concurrent corticosteroids
Dehydration
Hypovolaemic shock
Disruption to normal gut blood flow

29
Q

How do prostaglandins affect renal function?

A

Immunohistochemistry of normal renal tissue shows COX-1 and COX-2
When renal perfusion reduced renal PGs maintain renal blood flow via their vasodilatory actions and COX-2 is involved in naturiesis

30
Q

What is the species difference in COX-2 expression in the kidney?

A

COX-2 expression markedly increased in volume-depleted rats and dogs but not monkeys so preferential or selective COX-2 may not be as renally safe as thought in dogs compared to primates

31
Q

When can significant NSAID renal toxicity occur?

A

Volume depleted
Avidly retaining sodium
Pre-existing renal insufficiency

32
Q

What are the potential haematopoietic effects of NSAIDs?

A

Thromboxane is a potent vasoconstrictor and activator of platelet aggregation
Inhibition of thromboxane can lead to increased risk of bleeding but usually only significant with older NSAIDs

33
Q

What are the potential adverse hepatic effects of NSAIDs?

A

NSAIDs undergo extensive hepatic metabolism so take care if using in an animal with hepatic disease

34
Q

With which other drugs should NSAID use be done with care?

A

ACE inhibitors if renal perfusion reduced
Alpha-2 agonists as pre-meds
Avoid high dose ACP as pre-med
Diuretics and NSAIDs as COX-2 inhibition may attenuate effect of diuretic

35
Q

When should NSAID use be avoided?

A 
Evidence or suspicion of GI inflammation
Gut blood flow is reduced
Renal blood flow is reduced
Pathological sodium retention is present
Renal dysfunction is present
36
Q

What must patients receiving NSAIDs be?

A

Well hydrated with good peripheral circulation and good renal function as well as have normal sodium and water balance and ideally not have liver disease or the GI disease

Principles of Pharmacology and Therapeutics (8 decks)

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