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Year 2 LCRS Pharmacology > 17: NSAIDs > Flashcards

17: NSAIDs Flashcards

1
Q

What is the overall MOA by which NSAIDs work?

A

By inhibiting the synthesis of Prostanoids via inhibiting of Cyclooxygenase 1/2 (COX) enzymes

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2
Q

Explain the synthesis of Prostanoids

A
  1. Essential phospholipids –> Phospholipase A2–
  2. Arachidonic acid –> COX1/2
  3. Prostaglandin H2 (PGH2)
  4. Prostanoids
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3
Q

What is PGE2?

A

A Prostaglandine –> in these notes: used as an example for the (complex) effects of prostanoids on the body

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4
Q

What are the unwanted actions of PGE2 on the body?

A
  • Increased pain perception
  • Increased body temperature
  • Acute inflammatory response
  • Immune responses
  • Tumorigenesis
  • Inhibition of apoptosis
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5
Q

Explain the analgesic effect of NSAIDs

A

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
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6
Q

What is the role of PGE2 in pain perception?

How is this likes to inflammation?

A
  1. PGE2 binds to EP receptors
    1. increase in cAMP
  2. –> Activates P2X3 nocioceptors
  3. If only PGE2 –> only PKA increases expression of nocioceptors

But in Inflammation:

  1. •PGE2 + inflammation Epac pathway activated and additionally, more PGE2 produced
  2. Greater activation of P2X3 receptors –> more pain
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7
Q

Explain the role of PGE2 in body temperature regulation

A

PGE2 Stimulates hypothalamic neurones initiating a rise in body temperature

–> pyrogenic

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8
Q

Explain the anti-pyrogenic effects of NSAIDs

A

They inhibit the PGE2-mediated hypothalamic stimmulation of neurons that result in body temperature rise

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9
Q

How do prostanoids cause an effect in the cell?

A

Binding causes

  • G-protein mediated (cAMP) as well as cAMP independant downstream mechanisms
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10
Q

What are the desirable effects of Prostanoids?

A
  • Bronchodilation (although there is evidence that PGE2 can desensitise β2adrenoceptors)
  • Gastroprotection
  • Renal salt and water homeostasis
  • Vasoregulation (dilation and constriction depending on receptor activated)
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11
Q

What is the role of Prostanoids in bronchial tone?

How does this influence the use of NSAIDs?

A

Normally: Prostanoids (PGE2) are brochiodilatory + protective

  • NSAIDs might cause worsening of Astmah in Astmathics
  • •NSAIDS should not be taken by asthmatic patients
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12
Q

Explain the role of PGE2 in the GI tract

A

In the stomach: Activated by COX 1

  • decrease HCL production
  • increase production of gastic mucus and Bicarbonate
  • –> protective!
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13
Q

Explain the effects of NSAIDs on the stomach

A

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
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14
Q

What is the MOA of Asperin?

A

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
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15
Q

Explaint the role of PGE2 in the kidney

A
  • Dilation of afferent renal arteriole
  • –> increase in renal artery flow
  • increase in glomerular filtration rate
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16
Q

What are the effects of NSAID on the kidney?

A

•NSAIDs can cause renal toxicity

  • •Constriction of afferent renal arteriole
  • •Reduction in renal artery flow
  • •Reduced glomerular filtration rate
  • –> •Salt and water retention
17
Q

What are the vascular side-effects of NSAIDs?

A
  • Vasoconstriction
  • Salt and water retention
  • Reduced effect of antihypertensives

Might cause:

  1. Hypertension
  2. Myocardial infarction
  3. Stroke
18
Q

Explain the difference in side-effects in selective COX1 and COX2 inhibitors

A

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
19
Q

What are the cardiovascular side-effects of COX2 inhibitors?

A
  1. On endothelium
    • no limitation of platelet activation on plaques
      • increase of coronary aterothrombosis
    • decrease in NO
  2. Loss of protective function of Prostanoids on cardiac myocytes protection against arrythmias
  3. Kidney–> more salt+ water retention, deccreased GFR
    • hypertension
    • heart failure
20
Q

Explain the risks and benefits of NSAIDs in analgesic and anti-inflammatory use

A

Analgesic use

  • Usually occasional
  • Relatively low risk of side effects

Anti-inflammatory use

  • Often sustained
  • Higher doses
  • Relatively high risk of side effects
21
Q

Which strategies could you use to minimise the side-effects of NSAIDs?

A
  • 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
22
Q

Summarise the side-effects of NSAIDs

A
  • 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
23
Q

What are the main side-effects of Asperin?

Why?

A
  • 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
24
Q

What is Ryes syndrome?

A

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
25
Q

What kind of drug is Paracetamol?

A

Not clear

  • cannot be counted as NSAIDs due to its very low anti-inflammatory effects
26
Q

Explain the problem with Paracetamol overdose

A

Paracetamole is metabolised into NAPQI (intermediate product) that is very toxic

  • Normally 2nd step metabolism by Glutathione
  • But with overdose: accumulation of NAPQI that will bind to any SH group (present in many endogenous liver enzymes) and destroy the molecule
  • Cell death and liver failure
27
Q

Explain the effect and MOA of paracetamol

A

The MOA is Not understood, probably central and peripheral but it causes

  • low-moderate analgesic effect
  • anti-pyretic
28
Q

Why has the number of deaths fromparacetamol overdose fallen steadily in England and Wales?

A

Legal restriction of over the counter dosage of paracetamol

29
Q

Whay is Asperin an effective treatment in Rheumatoid Arthritis?

A

Asperin decreases PGE2 producion

PGE2 would

  • bind to EP4 receptors
    • dendritic cells and
    • naive T-cells to
      • increases production + proliferation of Th17
      • produce IL-17 which is known to have destructive effects on bone and cartilage

Year 2 LCRS Pharmacology (38 decks)

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