NSAIDS Flashcards
What are clinical uses of NSAIDs
Analgesic - toothache/headache, post op pain (opiate sparing), menstrual pain
Anti-pyretic - influenza
Anti-inflammatory - rheumatoid arthritis, oestoarthritis, gout, soft tissue injuries
What is the mechanism of action of NSAIDs
Inhibit prostanoid synthesis by blocking COX
What are prostanoids
They are derived from arachidonic acid and are widely distributed and not stored pre-formed. They are receptor mediated and examples include prostaglandins, TXA2 and prostacyclin
what do the coxib family do?
Selectively reversibly inhibit COX2 eg celecoxib
What receptors do prostanoids bind to? What type of receptor are these?
10 known receptors - 5 known prostanoids
DP1-2, ep1-4, FP, IP1-2, TP and named based on potency
All g protein coupled receptors - have effects independent of coupling however
What receptors do PGE2 activate?
EP1, EP2, EP3, EP4
What are unwanted actions of PGE2
- increased pain perception
- increase in body temperature
- acute inflam response
- other, immune respones, tumorigenesis, inhibition of apoptosis (so more likely necrosis)
What are the mechanisms of action of PGE2 depending on the receptor?
cAMP dependent - EP2/4
Ca2+ mobilisation - EP1/3
Both EP3
How does PGE2 prostanoid cause pain sensitisation?
stimulation of PG receptors sensitises the nociceptors which causes pain acutely and chronically. The mechanism for this is unclear but involves activation of EP1 and EP4 receptors in spine and periphery and endocannabinoid involvement
How does PGE2 prostanoid cause thermoregulation?
It is pyrogeneic and stimulates hypothalamic neurones to initiate a rise in body temperature leading to hyperpyrexia. NSAIDs have been shown to raise temperature in influenza
How does PGE2 prostanoid cause an acute inflammatory response
PGE2 leads to EP3 signalling, and the EP3 receptor signals downstream using two mechanisms - cAMP and Ca2+ mobilisation
What are the desirable actions of PGE2 prostanoid?
Gastro-protection
renal salt and water homeostasis
Bronchodilation
Vasoregulation
How does PGE2 prostanoid cause gastro protection? What is the problem with NSAIDs in the gut?
It stimulates mucus and bicarbonate secretion in the gut. NSAIDs increase the risk of ulceration leading to 1000 deaths per year, thought to be due to blocking of COX1/ fewer deaths using Celecoxib than normal NSAIDs
How does PGE2 prostanoid cause renal salt and water homeostasis?
PGE2 increases renal blood flow
How can NSAIDs cause renal toxicity?
Constriction of afferent renal arterioles
Reduction in renal artery flow
Reduced glomerular filtration rate
Why shouldn’t asthmatics take NSAIDs?
COV inhibition favours the production of leucotrines (as pathway for arachidonic acid is inhibited) which a potent bronchoconstrictors
what do NSAIDS do to vasoregulation?
They cause vasoconstriction, salt and water retention and reduced effect of antihypertensives. This leads to an increasing acknowledgement of risk of hypertension, mi and stroke - leading to increased CVS events
Why do COX 2 inhibitors pose a higher risk of CVS disease than conventional NSAIDs?
They raise BP, endothelial dysfunction, oxidative injury etc by an unclear mechanism
what risks do cox1 and cox2 inhibition increase?
COX-1 inhibition -> increased GI risk.
COX-2 inhibition -> increased CVS risk.
How can you tactically reduce GI side effects due to NSAIDs?
Topical application - less systemic access and limit the use in patietns with GI ulceration history or other risk factors eg alcoholics. You also should treat with H pylori if present and coadminister with omeprazole
What are the actions of aspirin? How does it work?
Anti-inflammatory, analgesic, antipyretic that reduces platelet aggregation by binding irreversibly to COX enzymes
Which COX is aspirin selective for?
COX1
How does aspirin reduce platelet aggregation?
Reduces TXA2 production via CX1 and no reproduction as the platelet has no nucleus and also reduces PGI2 via endothelial cells. Less TXA2 and still PGI2 so reduced platelet aggregation
How does aspirin affect endothelial cells?
Reduces PGI2 synthesis by COX1/2, reproduction possible still due to nucleus
What is the antiplatelet action of aspirin due to?
- High degree of COX1 inhibition which suppresses TXA2 synthesis in platelets
- Covalent bonding which permanently inhibits platelet COX1
- relatively low capacity to inhibit COX2
- need a low dose to enable endothelial resynthesis of COX2
What are side effects of aspirin?
Gastric ulceration, bronchospasm in sensitive asthmatics, prolonged bleeding time, nephrotoxicity
Why are side effects more likely in aspirin than NSAIDS
because permanent inhibition instead of irreversible
What are the actions of paracetamol?
Relieve mild to moderate pain, with antipyretic actions and NO anti inflam actions
What are the mechanisms of action of paracetamol
Not well understood but probably central using COX3, cannabinoid receptors and interactions with endogenous opiods, 5HT and/or adenosine receptors
What happens in paracetamol overdose?
Glutathionine depleted - saturated whilst metabolising other paracetamol molecules, the metabolite oxidises the thiol groups of key hepatic enzymes and cause apoptosis
what is the antidote for a paracetamol overdose?
add a compound with -Sh group eg IV acetylcysteine used in cases of attempted suicide or oral methionine
What happens if IV acetylcysteine is not administered early enough in a paracetamol overdose?
Liver failure may be unpreventable
What are legal issues with paracetamol?
1998 - pack size restricted to 16x500mg tablets and the 2009 guidlines state no more than 2 packets per transaction and not allowed to sell more than 100 pills per transaction which has decreased death by 43% since 2009!
Why is aspirin unique amongst the NSAIDS
It binds covalently to COX enzymes
Inhibition of which enzyme will reduce platelet aggregation with the fewest side effects?
Thomboxane A2 synthase because it causes platelet aggregation and not much else
