17: NSAIDs Flashcards
What is the overall MOA by which NSAIDs work?
By inhibiting the synthesis of Prostanoids via inhibiting of Cyclooxygenase 1/2 (COX) enzymes
Explain the synthesis of Prostanoids
- Essential phospholipids –> Phospholipase A2–
- Arachidonic acid –> COX1/2
- Prostaglandin H2 (PGH2)
- Prostanoids
What is PGE2?
A Prostaglandine –> in these notes: used as an example for the (complex) effects of prostanoids on the body
What are the unwanted actions of PGE2 on the body?
- Increased pain perception
- Increased body temperature
- Acute inflammatory response
- Immune responses
- Tumorigenesis
- Inhibition of apoptosis
Explain the analgesic effect of NSAIDs
Ihibit the PGE2-mediated lowering of pain threshold–> higher pain threshold via
- inhibition of cAMP mediated upregulation of P2X3 nocioceptors on cells
Might also
- increase the release of endocannabinoids
- beta-endorphin in spine
What is the role of PGE2 in pain perception?
How is this likes to inflammation?
- PGE2 binds to EP receptors
- increase in cAMP
- –> Activates P2X3 nocioceptors
- If only PGE2 –> only PKA increases expression of nocioceptors
But in Inflammation:
- •PGE2 + inflammation Epac pathway activated and additionally, more PGE2 produced
- Greater activation of P2X3 receptors –> more pain
Explain the role of PGE2 in body temperature regulation
PGE2 Stimulates hypothalamic neurones initiating a rise in body temperature
–> pyrogenic
Explain the anti-pyrogenic effects of NSAIDs
They inhibit the PGE2-mediated hypothalamic stimmulation of neurons that result in body temperature rise
How do prostanoids cause an effect in the cell?
Binding causes
- G-protein mediated (cAMP) as well as cAMP independant downstream mechanisms
What are the desirable effects of Prostanoids?
- Bronchodilation (although there is evidence that PGE2 can desensitise β2adrenoceptors)
- Gastroprotection
- Renal salt and water homeostasis
- Vasoregulation (dilation and constriction depending on receptor activated)
What is the role of Prostanoids in bronchial tone?
How does this influence the use of NSAIDs?
Normally: Prostanoids (PGE2) are brochiodilatory + protective
- NSAIDs might cause worsening of Astmah in Astmathics
- •NSAIDS should not be taken by asthmatic patients
Explain the role of PGE2 in the GI tract
In the stomach: Activated by COX 1
- decrease HCL production
- increase production of gastic mucus and Bicarbonate
- –> protective!
Explain the effects of NSAIDs on the stomach
COX1 inhibitors cause stomach ulcerations and many side effects due to
- inhibition of PGE2 mediated reduction of HCL and inhibition of production of mucus and bicarbonate
What is the MOA of Asperin?
It is a selevtive, irreversible COX1 inhibitor
- reduces prostanoid levels –> analgesic effect, anti-pytetic, etc.
- but also: reduced platelet aggregation in low dose–> becuase COX1 selective
- –> inhibtion of production of TXA2 but still production of Prostacyclin
Explaint the role of PGE2 in the kidney
- Dilation of afferent renal arteriole
- –> increase in renal artery flow
- increase in glomerular filtration rate
What are the effects of NSAID on the kidney?
•NSAIDs can cause renal toxicity
- •Constriction of afferent renal arteriole
- •Reduction in renal artery flow
- •Reduced glomerular filtration rate
- –> •Salt and water retention
What are the vascular side-effects of NSAIDs?
- Vasoconstriction
- Salt and water retention
- Reduced effect of antihypertensives
Might cause:
- Hypertension
- Myocardial infarction
- Stroke
Explain the difference in side-effects in selective COX1 and COX2 inhibitors
Though all NSAIDs increase risk of GI bleeds, ulcers and CVS events, it is far more likely for
- COX1 inhibitors to cause GI symptoms
- COX2 inhibitors cause CVS effects
What are the cardiovascular side-effects of COX2 inhibitors?
- On endothelium
- no limitation of platelet activation on plaques
- increase of coronary aterothrombosis
- decrease in NO
- no limitation of platelet activation on plaques
- Loss of protective function of Prostanoids on cardiac myocytes protection against arrythmias
- Kidney–> more salt+ water retention, deccreased GFR
- hypertension
- heart failure
Explain the risks and benefits of NSAIDs in analgesic and anti-inflammatory use
Analgesic use
- Usually occasional
- Relatively low risk of side effects
Anti-inflammatory use
- Often sustained
- Higher doses
- Relatively high risk of side effects
Which strategies could you use to minimise the side-effects of NSAIDs?
- Topical application
- In GI
- Minimise NSAID use in patients with history of GI ulceration
- Treat H pylori if present
- If NSAID essential, administer with omeprazole or other proton pump inhibitor
- Minimise NSAID use in patients with other risk factors and reduce risk factors where possible e.g.
- Alcohol consumption
- Anticoagulant or glucocorticoid steroid use
Summarise the side-effects of NSAIDs
- GI side effects
- risk of stomach ulcerations and bleed
- due to COX1 inhibition
- Kidney side effects
- salt and water retention
- HTN
- Haemodynamic AKI
- CVS
- stroke
- MI
What are the main side-effects of Asperin?
Why?
- 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 Ryes syndrome?
Syndrome occuring in viral infections and aspirin:
- Patients under 20
- Damage to mitochondria leading to ammonia production resulting in damage to astrocytes – oedema in brain –> severe outcomes
