Rational Use of NSAIDs in Clinical Practice Flashcards
How do NSAIDs work?
Reduce inflammation by inhibiting production of prostaglandins (PGs) released by damaged tissue through inhibition of cyclo-oxygenase enzyme (COX)
What is the role of COX-1?
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
When is COX-2 activated?
Tissue damage, bacterial lipopolysaccaride, cytokines, growth factors, inflammation where PGE2 is predominant eicosanoid
What are the clinical benefits of suppressing COX-2?
Suppressed pain, inflammation and fever
What are some other benefits of suppressing COX-2?
Delayed onset of Alzheimers disease?
Some cancers reduced such as colon, pancreas, lung, transitiona cell carcinoma, melanoma
What are the three classes of NSAIDs?
Non-selective
Preferential - at least 2x greater inhibition of COX-2 but usually 10-40x
Selective - >100x selective for COX-2
What other mechanisms are NSAIDs thought to work by?
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
How are the pharmacodynamics of COX-1 and COX-2 selectivity expressed?
As IC50 values
What are the different assay methods to determine COX-1 and COX-2 selectivity?
Cell based
Tumour cell lines
Whole blood - gold standard in species of interest
How is COX-1 inhibitory activity measured?
Inhibition of clot-induced thromboxam B2 production
How is COX-2 inhibitory activity measured?
Inhibition of LPS induced PGE2 production
What factors other than COX-1:COX-2 ratio may affect the safety of NSAIDs?
Degree of acidity of the pro-drug (direct GIT mucosal damage)
Plasma half life
Degree of enterohepatic recycling
What is the therapeutic aim when using and NSAID?
> 80% inhibition of COX-2 for part though not all of a 24 hour period
<10%
What are some examples of non-selective COX inhibitors?
Aspirin
Phenylbutazone
Ketoprofen
Tolfenamic acid
What are some examples of preferential COX-2 inhibitors?
Meloxicam Carprofen Mavacoxib Cimicoxib Deracoxib in US
What are some examples of selective COX-2 inhibitors?
Firocoxib
Robenoxocib
What is a dual inhibitor NSAID?
Drug that inhibits both COX and LOX
What is an example of a dual inhibitor?
Tepoxalin - inhibits LOX for a short peroid, non-selective COX
What are the species differences seen when using carprofen?
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
What are the pharmacokinetics of NSAIDs?
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
How are NSAIDs metabolised?
Varying rates depending on the metabolic pathway and extent of enterohepatic circulation
Elimination half-life varies considerably between drugs and species
What are the potential adverse effects of NSAIDs?
Gi
Renal
Haematological
How does PGE and PGI2 protect the gastric mucosa?
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
How do adverse GI effects of NSAIDs occur?
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
