S8) NSAIDs Flashcards
What is the principal action of non-steroidal anti-inflammatory drugs?
Principle action – key enzymes in prostaglandin synthesis
What are the three primary therapeutic effects of NSAIDs?
- Analgesia
- Anti-Inflammatory
- Antipyretic
Why do NSAIDs commonly have short half lives?
Short half lives allows fine control of the signalling response
How are prostaglandins synthesised?
Prostaglandins are synthesised from arachidonic acid
Identify two types of prostaglandins
- Prostacyclins
- Thromboxanes
Describe the prostaglandin synthesis pathway
Prostaglandins are synthesised from cell membrane phospholipids and arachidonic acid and thereafter catalysed by COX-1/2 to produce specific PG enzymes
PG ‘E’ is the most important in mediating the inflammatory response.
Identify four of its functions
- Vasodilation
- Hyperalgesia
- Fever
- Immunomodulation
PG synthesis by COX -1 has major cytoprotective role in three locations.
Identify them
- Gastric mucosa
- Myocardium
- Renal parenchyma
What is the half life of PG and what is the significance of this for NSAIDs?
- PG t1/2 short (10 mins) – need constant synthesis
- Due to its constitutive expression, most ADRs caused by NSAIDs are due to COX-1 inhibition
What induces COX-2 expression and where is it expressed?
- COX-2 expression induced by inflammatory mediators such as bradykinin
- COX-2 appears to be constitutively expressed in parts of the brain and kidney
How do the main therapeutic effects of NSAIDs occur?
Main therapeutic effects of NSAIDs occur via COX-2 inhibition
Illustrate how differences in COX-1 and COX-2 tunnel for selective inhibition by different NSAIDs
Explain prostaglandin binding with receptors
- Prostaglandins bind with GPCRs
- Specific actions depend on PG receptor types
For PG E, at least four main types: EP 1-4
In four steps, describe how prostaglandins act as inflammatory response mediators
⇒ Range of autacoids and prostanoids released from local tissues/blood vessels post injury
⇒ Autacoid release also induces expression of COX-2
⇒ Synergise with other autacoids (bradykinin/histamine)
⇒ PGs act as potent vasodilators & synergise permeating effects of bradykinin/histamine
State the effect of prostaglandin release post injury at the following receptors:
- EP2 receptor Gs
- EP1 receptor Gq
- EP2 receptor Gs – ↑ vasodilation
- EP1 receptor Gq – ↑ peripheral nociception
With regards to sensitising peripheral nociception, describe the three effects of GPCR activation by EP1
- Increased neuronal sensitivity to bradykinin
- Inhibition of K+ channels
- Increased Na+ channels sensitivity
All act to increase afferent ‘C’ fibre activity (carry pain stimuli)
In four steps, expain how peripheral sensitisation occurs
⇒ EP 1 binding leads to ↑ ‘C’ fibre activity
⇒ ↑ intracellular [Ca2+]
⇒ Neurotransmitter release
⇒ Other autacoids involved to ↑ sensitivity
In terms of nociception, illustrate the relationship between allodynia and hyperalgesia
- Allodynia is pain due to a stimulus that does not usually provoke pain
- Hyperalgesia is increased pain from a stimulus that usually provokes pain