NSAIDS Flashcards
How do NSAIDs work?
Inhibit prostanoid synthesis by inhibiting COX1 and 2 enzymes
Example of prostanoids? (2)
prostaglandin and thromboxane
What are all prostanoids derived from?
Arachidonic acid
What is the rate limiting step in prostanoid synthesis
COX
How’re different prostanoids produced
Different prostanoids are produced by different specific synthases downstream of the COX enzymes
How many known prostanoid receptors are there?
10 known receptors
How many known prostanoids are there
5
What receptors can PGE2 activate?
EP1, 3, 2 and 4
Which prostaglandin receptors increase Ca mobilisation?
EP1 and 3
Which prostaglandin receptors increase cAMP?
EP2 and 4
Which prostaglandin receptors downregulates cAMP?
EP3
What does PG receptor EP3 do?
Increase Ca mobilisation and downregulates cAMP
What does PG receptor EP4 do?
increase cAMP
What does PG receptor EP2 do?
increase cAMP
What does PG receptor EP1 do?
Increase Ca mobilisation
Unwanted effects of PGE2? (6)
- Increased pain perception
- Increased body temp.
- Acute inflammatory response
- Immune responses
- Tumorigenesis
- Inhibition of apoptosis
How do prostanoids lower the pain threshold? (receptors, location, other modulators, NT increased?)
EP1 receptors
EP4 receptors (in periphery and spine)
Endocannabinoids (neuromodulators in the thalamus, spine ad periphery)
Increasing beta-endorphin in the spine
What is stimulated by external irritants to produce PGE2
Keratinocytes
What are stimulated to give calcium release through EP3 receptors
Mast cells
PGE2 role in inflammation through EP3 receptors?
Keratinocytes are stimulated by external irritants to produce PGE2
EP3 receptors on mast cells are, in turn, stimulated to give calcium release and degranulation of histamine granules (histamine release)
What PG is pyrogenic?
PGE2
How does PGE2 cause a rise in body temp.?
PGE2 stimulates hypothalamic neurones initiating a rise in body temperature
Re. body temp, what do NSAIDs do?
NSAIDs reduce raised temperature
What do PGE2 analogues do re. pain threshold?
Lower it by sensitising nociceptors in the periphery
Desirable actions of PGE2? (4)
- Bronchodilation
- Renal salt and water homeostasis
- Gastroprotection
- Vaso-regulation (dilation/constriction)
Effect of NSAIDs on the respiratory system? Why?
Cause asthma attacks etc as COX products cause bronchodilation
COX inhibition favours what product that causes vasoconstriction?
Leukotrienes
What group of people should never be put on NSAIDs
Asthmatics
Regarding kidneys, what can NSAIDs induce?
Renal toxicity
How do NSAIDs induce renal toxicity (3)
- Constriction of afferent renal arteriole
- Reduction in renal artery flow
- Reduced GFR
Which COX enzymes are involved in salt and water homeostasis?
Both COX1 and 2
Role of PGE2 in gastric cytoprotection
- Parietal cell normally produces HCl and secretes it into the stomach- therefore the stomach needs protection
- This protection comes in the form of a mucus layer and bicarbonate secretion
- PGE2 normally downregulates HCl secretion, and also stimulates mucus and bicarbonate secretion THESE ARE COX-1 DEPENDENT
Which COX is involved in gastric cytoprotection
COX1
Which isoforms of COX do most NSAIDs inhibit
- Most NSAIDs reversibly inhibit both isoforms
What family of drugs Selectively and reversibly inhibit COX-2
Coxib
Example of a Coxib?
Celecoxib
Celecoxib is an example of what drugs
COX2 selective inhibitor
- NSAIDs can have serious unwanted cardiovascular effects such as: (3)
Vasoconstriction
Salt and water retention
Reduced effectiveness of anti-hypertensives
Bronchoconstriction
Which COX inhibition poses a higher risk of CVD
COX2
Which COX inhibition poses a higher risk of GI bleed
COX1
COX1 inhibition poses a higher risk of what
GI Bleeds
COX2 inhibition poses a higher risk of what
CVD
Dosage of NSAID for analgesic effect
Low
Dosage of NSAID for anti-inflammatory effect
High
Which carries less side effects, analgesic or anti-inflammatory uses of NSAIDs and why
Analgesic use (as its mainly only occasional)
Anti-inflammatory use (sustained):
- Higher doses
- Relatively high risk of side effects
STRATEGIES OTHER THAN COX-2 SELECTIVE NSAIDs FOR LIMITING GI SIDE EFFECTS: (5)
- Topical application – reducing dose and reducing amount in systemic circulation
- Minimise NSAID use in patients with history of GI ulceration
- Treat H pylori if present
- If NSAID essential, administer with omeprazole or other PPI (proton pump inhibitors to reduce acid production and provide a gastroprotective effect)
- Minimise NSAID use in patients with other risk factors and reduce risk factors where possible:
Alcohol consumption
Anti-coagulant or glucocorticoid steroid use
Aspirin is selective for?
COX1
Aspirin effects? (4)
- Has anti-inflammatory, analgesic and anti-pyretic actions
- Reduces platelet aggregation in low doses
How does aspirin interact with COX
- Binds IRREVERSIBLY to COX enzymes – to overcome it you must synthesise new enzymes
Which prostaglandin is anti-inflammatory/platelet aggregation
- PGI2 (prostacyclin from endothelial cells)
Aspirin effects on platelet aggregation (think TXA2 and PGI2)
- Aspirin inhibits thromboxane production because that requires COX-1
- PGI2 can use both COX-1 and COX-2 so it is only partially inhibited
- OVERALL: Endothelial cell recovers and continues to produce prostacyclin, but the platelet has no nucleus so it can’t do this- you get no re-synthesis of COX-1 The overall effect of this is reduced platelet aggregation
why can’t platelets resynthesise COX1 after aspirin irreversibly binds to it
Platelet has no nucleus
Difference between effect on platelet aggregation of High dose of aspirin vs low dose
High dose of aspirin has no action on platelet aggregation because you also block endothelial cell re-synthesis of COX
Aspirin side effects (4):
- Gastric irritation and ulceration
- Bronchospasm in sensitive asthmatics
- Prolonged bleeding times
- Nephrotoxicity
Why is paracetamol technically not an NSAID
- Does NOT have anti-inflammatory effect
Effects of paracetamol? (2+1 thing it doesn’t do)
- A good analgesic for mild-to-moderate pain
- Has anti-pyretic action
- Does NOT have anti-inflammatory effect Therefore TECHNICALLY it’s not an NSAID
What do we theorise aspirin interacts with?
- Via cannabinoid receptors (?)
- Interactions with endogenous opioids (?)
- Interaction with 5HT (serotonin) and adenosine receptors (?)
What metabolises aspirin
CYP450
What is the metabolite of aspirin involved in overdose
NAPQI
What converts the toxic metabolite of aspirin NAPQI into an inactive form
Glutathione
How does paracetamol OD work?
- NAPQI is the metabolite involved in overdose
- Glutathione usually converts this into an inactive form
If glutathione is depleted (O.D.), NAPQI oxidises thiol groups of key hepatic enzymes and causes cell death
What group is the antidote for paracetamol poisoning?
-SH
What is given for paracacetamol poisoning
Acetylcysteine
What is acetylcysteine used for
Paracetamol OD
Why is methionine no longer added to paracetamol to prevent overdose
issa expensive drug
What used to be added to paracetamol to prevent OD
Methionine
Legislation of paracetamol? pack size and pack number
No more than 2 packs per transaction
Illegal to sell more than 100 paracetamol in one transaction
