NSAIDs Flashcards
What are NSAIDs used for?
Relief of mild-to-moderate pain (analgesic)
Reduction of fever (antipyretic)
Anti-inflammatory
How do NSAIDs work?
Inhibition of prostanoid synthesis.
Inhibition of prostaglandin and thromboxane production.
Inhibit COX-1 and COX-2.
What are prostanoids?
Lipid mediators derived from arachidonic acid.
How many prostanoid receptors are there?
10 (known)
What are the 5 prostanoids?
Thromboxane A2 Prostaglandin I2 (prostacyclin) Prostaglandin E2 Prostaglandin D2 Prostaglandin F2 alpha
What are the unwanted actions of prostaglandin E2?
Increased pain perception Increased body temperature Acute inflammatory response Immune responses Tumorigenesis Inhibition of apoptosis
How do PGE2 analogues lower the pain threshold?
Stimulation of PG receptors in the periphery sensitises the nociceptors (lowers threshold) which cause pain both acutely and chronically.
Peripheral and central actions are involved.
Why is PGE2 pyrogenic?
PGE2 stimulates hypothalamic neurons, initiating a rise in body temperature.
What are the desirable physiological actions of PGE2 (and other prostanoids)?
Bronchodilation
Renal salt and water homeostasis
Gastroprotection
Vasoregulation (dilation and constriction depending on receptor activated)
Why should NSAIDs not be taken by asthmatic patients?
COX inhibition favours leukotriene production (bronchoconstrictors)
10% of asthma patients experience worsening symptoms with NSAIDs
PGE2 may be protective against asthma
How can NSAIDs cause renal toxicity?
PGE2 increases renal blood flow.
Constriction of afferent renal arteriole
Reduction in renal artery flow
Reduced glomerular filtration rate
What is the role of PGE2 in gastric cytoprotection?
PGE2 down regulates HCl secretion.
PGE2 stimulates mucus and bicarbonate secretion (protective layer).
NSAIDs increase the risk of ulceration.
How many deaths are caused by NSAIDs in the UK every year?
Around 2000.
What unwanted cardiovascular effects can NSAIDs have?
Vasoconstriction
Salt and water retention
Reduced effect of antihypertensives
Increased risk of hypertension, MI and stroke.
What are the risk and benefits of NSAID use?
For analgesic use, usually occasional with relatively low risk of side effects.
For anti-inflammatory use, often sustained and at higher doses, with relatively high risk of side effects.
What are the strategies for limiting GI side effects of NSAIDs?
Topical application
Minimise NSAID use in patients with history of GI ulceration
Treat H. pylori if present
If NSAID essential, administer with omeprazole or another proton pump inhibitor
Minimise NSAID use in patients with other risk factors and reduce risk factor where possible, e.g. alcohol consumption or anticoagulant or glucocorticoid steroid use.
Why is aspirin unique among NSAIDs?
Selective for COX-1
Binds irreversibly to COX enzymes
Anti-inflammatory, analgesic and antipyretic and reduces platelet aggregation
What are the anti-platelet actions of aspirin due to?
Very high degree of COX-1 inhibition which effectively suppresses thromboxane A2 production by platelets.
Covalent binding which permanently inhibits platelet COX-1.
Relatively low capacity to inhibit COX-2.
Use low dose to allow endothelial re-synthesis of COX-2.
What are the major side effects of aspirin at therapeutic doses?
Gastric irritation and ulceration Bronchospasm in sensitive asthmatics Prolonged bleeding times Nephrotoxicity Side effects likely with aspirin because it inhibits COX covalently, not because it is selective for COX-1.
What is paracetamol and why is it not classed as an NSAID?
Good analgesic for mild-to-moderate pain.
Anti-pyretic.
Does not have any anti-inflammatory effect, therefore not NSAID.
What happens in paracetamol overdose?
Can cause irreversible liver failure.
If glutathione is depleted, the metabolite oxidises thiol groups of key hepatic enzymes and causes cell death.
What is the antidote for paracetamol poisoning?
Add compound with -SH groups.
Usually i.v. acetylcysteine, occasionally oral methionine.
Acetylcysteine used in cases of attempted suicide and accidental poisoning. f not administered early enough, liver failure may be unpreventable.
