NSAIDs Flashcards
What are the major clinical uses of NSAIDs?
Relief of mild pain (analgesic): - Toothache, headache and backache -Post-op pain -Dysmenorrhoea Reduction of fever (antipyretic) Reduction of inflammation (anti-inflammatory): -Rheumatoid arthritis -Osteoarthritis -Soft tissue injuries -Gout
How do NSAIDs work?
They inhibit the production of prostanoids by COX enzymes
What are prostanoids derived from?
Arachidonic acid
Name three main prostanoids?
Prostaglandins
Thromboxane
Prostacyclin
What are prostanoid actions mediated by?
They are all receptor mediated: DP1 DP2 EP1 EP2 EP3 EP4 FP IP1 IP2 TP
What are prostanoid receptors named based on?
Their potency/highest affinity- DP1 has the greatest affinity for prostaglandin D2
What sort of receptors are all prostanoid receptors?
G protein coupled but not all their actions are G protein mediated
How many prostaglandins do we have?
5
Which receptors can PGE2 activate and how many pathways does it work through?
4 receptors: EP1, EP2, EP3 and EP4
5 pathways
What is neuroplasticity?
A desirable feature- ability of one neurone to take over the job of another neurone if it were to become damaged
What are the unwanted actions of PGE2?
Increased pain perception Thermoregulation Acute inflammatory response Immune responses Tumorigenesis Inhibition of apoptosis- more likely to get necrosis
What effect do PGE2 analogues have on pain threshold?
Lower the pain threshold and increases pain sensitivity
What is believed to be involved in the mechanism by which COX inhibitors raise the pain threshold?
EP4 receptors (in periphery and spine) Endocannabinoids (neuromodulators in thalamus, spine and periphery)- cross talk between the two so there is neuromodulation They block the production of PGE2
What effect does PGE2 have on body temperature?
It is pyrogenic- it stimulates hypothalamic neurones initiating a rise in body temperature
What mediates the effect of PGE2 on the immune system?
EP4
What inflammatory conditions are treated with NSAIDs?
Contact dermatitis
Multiple sclerosis
Rheumatoid arthritis
PGE2 is important in acute and chronic inflammation
Why are the anti-apoptic effects of prostaglandins undesirable?
You are more likely to get necrosis- will contribute to inflammation
What desirable actions do PGE2 and other prostanoids have?
Gastroprotection
Regulation of renal blood flow
Bronchodilation
Vasoregulation
How does PGE2 have a role in gastroprotection?
Downregulates HCl secretion in the stomach
Stimulates production of mucus (physical barrier) and bicarbonate (neutralises stomach acid)
What effect does NSAID use have on the gastric system?
Reduces PGE2 so causes increase in risk of ulceration
What effect do NSAIDs have on renal blood flow?
Can cause renal toxicity:
Constriction of afferent arteriole
Reduction in renal artery flow
Reduced glomerular filtration rate
In terms of the lungs what do most COX products cause?
Bronchodilation
What do asthma patients experience with use of NSAIDs?
Exacerbation of symptoms- Inhibition of COX favours production of leukotrienes which are bronchoconstrictors
What effect do NSAIDs have on cardiovascular system?
Serious unwanted effects- increase incidence in MI and stroke:
Small rise in blood pressure
Sodium retention
Vasoconstriction
What is the risk vs benefit of NSAID use like for analgesic use and anti-inflammatory use?
Analgesic: Usually occasional Low risk of side effects Anti inflammatory: Often sustained Higher doses High risk of side effects
Do NSAIDs vary in affinity for COX-1 and COX-2?
Yes
What is the selectivity for ibuprofen and indomethacin like?
Typically non-selective NSAIDs and inhibit both COX1 and 2 - irreversibly
What effects do ibuprofen and indomethacin have?
Analgesic
Anti-pyretic
Anti-inflammatory
Why are selective COX-2 inhibitors used more to avoid side effects?
It’s very difficult to make a selective COX-2 inhibitor because both COX enzymes are structurally very simiilar
What does celecoxib do?
Selectively inhibits COX2- less effect on COX-1 mediated process than conventional NSAIDs such as ibuprofen- led to decrease in ulceration
What do COX-2 selective inhibitors pose a greater risk of than conventional NSAIDs?
Cardiovascular disease even though mechanism is unclear
What is the difference between COX-1 selective NSAIDs and conventional NSAIDs?
Cardiovascular risk is unchanged but GI risk is increased- PGE2 in stomach is generated through COx-1
How are COX-2 inhibitors tolerated in asthmatics?
Well but not recommended
What happens when a patient on antihypertensives takes ibuprofen?
Blood pressure will rise
How do non-selective and COX 2 selective drugs increase cardiovascular disease?
They cause an increase in work
COX2 selective probably exert effects via interfering with balance between prostacyclin and thromboxane- increase in thromboxane will cause increased risk of thrombosis
All NSAIDs increase production of oxygen free radicals and they affect multiple different pathways that contribute to CVD
What other strategies are there to limit GI side effects of NSAIDS apart from COX2 selective?
Topical application
Minimise NSAID use in patients with history of GI ulceration
Treat H pylori if present
Administer with omeprazole or other proton pump inhibitor
Minimise NSAID use in patients with other risk factors and reduce risk factors where possible
What does aspirin do?
Selective for COX1 and binds irreversibly
Has analgesic, anti-inflammatory and anti-pyretic actions
It is unique among NSAIDs
What is the effect of aspirin on platelets?
Inhibit thromboxane (which enhances platelet action) production by platelets In high doses, reduces prostacyclin (which decreases platelet action) production by endothelial cells
Why are platelets not able to resynthesises COX after aspirin binds?
Platelets lack a nucleus so once aspirin irreversibly inhibits the COX enzymes in a platelet, it will not be able to resynthesise COX and hence will not regain its ability to produce thromboxane
(Endothelial cells can replenish so maintain prostacyclin)
What is responsible for anti platelet actions of aspirin?
Very high degree of COX-1 inhibition by covalent binding which irreversibly suppresses thromboxane A2 production
Why do you need to give a low dose of aspirin?
To allow endothelial cells to resynthesises COX otherwise you will keep inhibiting endothelial COX as fast as it’s being made so won’t get beneficial effects- the inhibition of prostacyclin is proportional to the inhibition of thromboxane
What are the major side effects seen at therapeutic doses of aspirin?
Gastric irritation and ulceration Bronchospasm in asthmatics Prolonged bleeding times Nephrotoxicity Side effects more likely with aspirin than other NSAIDs because it inhibits covalently
What does paracetamol do?
It is a good analgesic for moderate pain and has anti-pyretic action
Why is paracetamol not a NSAID?
It is not anti-inflammatory
What is thought to be involved in the mechanism of paracetamol’s action?
COX-3
Via cannabinoid receptors
Interaction with endogenous opioids
Interaction with 5HT and adenosine receptors
What can overdose of paracetamol cause?
Liver failure
What normally happens in paracetamol metabolism?
Toxic metabolite is formed (toxic= generates free radicals) and is normally mopped up by glutathione and is rendered safe
How does paracetamol overdose cause liver failure?
Too much toxic metabolite is being generated leading to depletion of glutathione which means the toxic metabolite will indiscriminately bind to any -SH group that it can find- most of which are attached to key hepatic enzymes and you get inevitable cell death
