NSAIDS Flashcards
How do NSAIDS work
Inhibition of prostaglandin and thromboxane synthesis
Lipid mediators derived from arachidonic acid
Cyclo-oxygenase enzymes
Widely distributed
Not stored pre-formed
Receptor-mediated
Describe the arachidonic acid pathway
- Membrane phospholipid converted to arachidonic acid via phospholipase A2
- Conversion to prostaglandin H2 or leukotrienes (bronchoconstrictor)
What enzyme is used to convert arachidonic acid to prostaglandin H2 and what can be produced from this
COX 1 and 2
PGE2, PGI2 (prostacyclin), Thromboxane A2
PGF2A, PGD2
What enzyme is used to convert arachidonic acid to leukrotrienes
Lipooxygenase
What are the unwanted actions of PGE2
Lowers the pain threshold Increases body temperature (fever) Causes inflammation Activates T-helper cells involved in certain hypersensitive conditions Tumorigenesis Inhibition of apoptosis
What receptors can PGE2 activate and what is the order of affinity for them
EP1-4
EP1 has the greatest affinity and EP4 has the least affinity
cAMP-depednent and independent downstream mechanisms
How does PGE2 cause fever and inflammation
PGE2 stimulates the neurones in the hypothalamus involved in temperature control leading to an increase in temperature (fever!)
PGE2 leads to mast cell degranulation leading to inflammation
How does PGE2 lower pain threshold
Increases pain sensation by sensitising the nociceptors
What are the desirable effects of PGE2
Is cytoprotective in the stomach
Causes bronchodilation a long with other prostaglandins
Increases GFR -> renal salt and water homeostasis
Vasoregulation (dilation and constriction depending on receptor activated)
Explain how PGE2 is gastroprotective
stimulates bicarbonate and mucous secretion in the stomach
Downregulates HCl secretion
Explain how PGE2 causes an increased GFR
Increases renal blood flow by acting as a vasodilator on the afferent arteriole to the glomerulus
Why may NSAIDS cause renal toxicity
Constriction of afferent renal arteriole
Reduction in renal artery flow
Reduced glomerular filtration rate
Why may NSAIDS cause worsening symptoms in asthmatics
Cyclooxygenase inhibition favours production of leukotrienes, which are bronchoconstrictors
What are the unwanted effects of NSAIDS
Vasoconstriction Salt and water retention Reduced effect of antihypertensives Hypertension Myocardial infarction Stroke
Compare COX-1 and COX-2 and their inhibitors
Different (but overlapping) cellular distributions
Most NSAIDs reversibly inhibit both isoforms (example: ibuprofen)
Coxib family: selectively reversibly inhibit COX-2 (example: celecoxib)
What class of drug is ibuprofen
Non-selective reversible COX inhibitor
Describe the pharmacodynamics of ibuprofen
Inhibits COX, which stops PGE2 production leading to analgesia, reduced inflammation and reduced fever
What are the side effects of ibuprofen
Gastric irritation and ulceration
Bronchospasm
Prolonged bleeding
Nephrotoxicity
What is the advantage of COX-1 specific inhibitors over COX-2 specific inhibitors
COX-2 inhibitors increase the risk of CVD compared to COX-1 specific inhibitors
May be due to imbalance between anti-thrombolytic prostacyclin and pro-thrombotic thromboxane A2
Compare the roles of COX-1 with COX-2
COX-1 - more involved in gastric cytoprotection and platelet haemostasis
COX-2 - Expressed in inflammatory cells, involved in pain and inflammation
What is the advantage of COX-2 specific inhibitors over COX-1 specific inhibitors
Cause fewer GI effects because there is a smaller decrease in PGE2 in the stomach.
What class of drug is Celecoxib
Selective reversible COX2 inhibitor
Describe the pharmacodynamics of celecoxib
Has similar effects to ibuprofen but you get more PGE2 formed in the stomach (because PGE2 is formed from COX1 in the stomach) so there is less risk of ulceration
What are the side effects of celecoxib
Less severe GI and nephrotic side effects compared to aspirin and ibuprofen
Greater risk of CVD
Describe paracetamol metabolism and why it is important in overdose
Produces a toxic metabolite that is usually inactivated by glutathione.
If this metabolite is produced in excess (e.g. in paracetamol overdose), then the metabolite starts binding to hepatic enzymes with –SH groups on them.
This leads to liver failure
What drug is used for a paracetamol overdose and why
Acetylcysteine
Contains an –SH group, and so mops up the toxic metabolite during paracetamol overdose
Why is aspirin the only NSAID used to manage thrombotic disease
Aspirin irreversibly binds to COX1
Platelets lack a nucleus and so cannot resynthesise COX1
Irreversibly inhibiting COX1 will permanently prevent TXA2 production from the targeted platelets, but endothelial cells will be able to replenish their COX1 and continue to produce prostacyclin, which is anti-thrombitic
