Session 8 Flashcards
- Recognise the central role of arachidonic acid in prostanoid synthesis
- Understand the general pharmacology of NSAID action on COX-1 on COX-2 inhibition
- Understand therapeutics / ADRs in terms of action on COX-1 and COX-2
- Appreciate the use of NSAID as analgesics, anti-inflammatories and antipyretics
- Recognise the differences in NSAID pharmacokinetics
- Describe the major ADRs / drug interactions associated with NSAIDs
- Understand the mode of action of NSAIDs on platelet function exemplified by aspirin
- Appreciate the special case of paracetamol as an analgesic / antipyretic
- Recognise the main features of paracetamol overdose and toxicity.
Non Steroidal Anti-Inflammatory Drugs (NSAIDs):
- Principle action - ?
- Three primary therapeutic effects:
- key enzymes in prostaglandin synthesis
- Analgesia
Anti-Inflammatory
Antipyretic
The Inflammatory Response
- Fundamental response of body to injurious stimuli - includes wide variety of noxious agents. Give examples:
- Why have it?
- Physical /Chemical Injury
- Structural Strain
- Infections Many Diseases
- Autoimmune Conditions - Normally protective response to reduce risk of further damage to organism
- Alerts body through signalling pain - reduces risk of further damage through continued use/activity
- Normally protective response to reduce risk of further damage to organism
Autacoids Signal the Inflammatory Response
- Diverse range of local molecular mediators and signalling agents employed - the Autacoids * including?
- Signalling overlap ensures robust inflammatory response
- Key feature of autacoids is?
- Bradykinins
- Histamine
- Cytokines
- Leukotrienes
- Nitric Oxide
- Neuropeptides
- Eicosanoids – Includes Prostaglandins
2.
- localised release + short half lives allows fine control of the signalling response
Recognise the central role of arachidonic acid in prostanoid synthesis LO
- What is the structure of Eicosanoids and their use?
- Variation in synthetic routes give rise to different classes of Eicosanoids: \
- All Eicosanoid classes derived from?
- 20 C phospholipid derivatives
- signalling molecules
- 20 C phospholipid derivatives
- Prostanoids: Prostaglandins (PGs) Prostacyclins Thromboxanes
- Leukotrienes
- Prostanoids: Prostaglandins (PGs) Prostacyclins Thromboxanes
- Arachidonic Acid which is cleaved from cell membrane phospholipids
Recognise the central role of arachidonic acid in prostanoid synthesis LO
Draw a diagram showing the synthesise of PGs

How is COX-1 Isoform expressed?
- COX-1 expressed in ?
- PG synthesis by COX -1 has major cytoprotective role of?
- What is the t1/2 for PG ?
- Due to its constitutive expression, most ADRs caused by NSAIDs effects are due to ?
Constitutively Expressed
- wide range of tissue types
- Gastric mucosa
+Myocardium
+ Renal parenchyma - Ensures optimised local perfusion – reduces ischemia
- short = 10 mins - need constant synthesis
- COX-1 inhibition

- How is COX-2 Isoform expressed?
- COX-2 expression induced by?
- COX-2 appears to be constitutively expressed in parts of the ?
- Main therapeutic effects of NSAIDs occur via ?
- COX-1 and 2 do not work independently and PG synthesis with both enzymes depends on tissue and organ type
- Induced by Injurious Stimuli
- inflammatory mediators such as Bradykinin
- brain and kidney
- COX-2 inhibition
5.
Differences in COX-1 and COX-2 tunnel for catalysing Arachidonic Acid
???

Understand the general pharmacology of NSAID action on COX-1 on COX-2 inhibition LO
Differences in COX-1 and COX-2 tunnel for selective inhibition by different NSAIDs
1 - first time you have sex ur tight
2 time u r baggy
aspirin is small! Can fit into both
aspirin for ALL

Prostaglandins: General Pharmacology
- Prostaglandins bind with ?
- Specific actions depends on ?
- For PG ‘E’ at least four main types: ?
- Often action includes?
- GPCRs
- PG receptor types
- EP 1-4
- synergising effects of other autacoids – eg. Bradykinin/Histamine
Prostaglandin Pharmacology - Inflammatory Response Mediators
- Range of autacoids and prostanoids released post injury esp. ?
- Released from ?
- Autacoid release also induces ?
- Synergise with other autacoids – e.g.
- Action of PGs?
- PGE2 - also PGD2
- local tissues and blood vessels
- expression of COX-2
- Bradykinin/Histamine
Prostaglandin release following injury.
- Function of EP2 receptor?
- Function of EP1 receptor?
- Gs -> vasodilation
- Gq -> peripheral nociception
2 veSSels
Prostaglandin Pharmacology- Pain 1: Sensitising Afferent Nociception - EP1
How do EP1 receptors sensitise harmful stimuli?
- Painful stimuli carried by afferent ‘C’ fibres (non myelinated)
- Following trauma/injury surrounding tissue and neurons synthesise PGs - PGE
- Other autacoids released - notably Bradykinin
- PGE2 binds with ‘C’ fibre neuronal EP1 GPCR receptor
Pain 1: Sensitising Peripheral Nociception - EP1
- GPCR activation results in:
- PGs may also activate ?
- Increased neuronal sensitivity to Bradykinin
- Inhibition of K+ channels
- Increased Na+ channels sensitivity
- In combination - these act to increase ‘C’ fibre activity
- Increased neuronal sensitivity to Bradykinin
- previously silent ‘C’ fibres
Peripheral Sensitisation (at synapse?)
- What effect does EP 1 binding have on C fibres?
- What type of receptor is EP1? What does binding to the receptor result in?
- INCRESE ‘C’ fibre activity
- Gq GPCR
INCREASE intracellular Ca2+
Increase Neurotransmitter release
Other autacoids involved INCREASE sensitivity
- Explain what this graph is showing
- What is the meaning of:
Allodynia
Hyperalgesia

Explain how we Pain Sensitise Central Nociception
- Increased sustained nociceptive signalling peripherally result in INCREASE cytokine levels in dorsal horn cell body
- This causes INCREASE COX-2 synthesis & INCREASE PGE2 synthesis
- PGE2 then acts via local GPCR EP2 receptor (Gs Type)
- This increase sensitivity + discharge rate of secondary interneurones
- One aspect is removal of glycinergic inhibition
- What are the effects of PGE2 when it binds to EP2 receptor ?
- Leading to what overall effect?
- Increase cAMP increase PKA
- Decrease Glycine Receptor Binding Affinity
- Increase Pain perception
- Increase cAMP increase PKA
- Increased pain perception
Sensitisation in dorsal horn by PGE2

How do prostaglandins result in pyrexia?
Pyr3xia – EP3
+ In infected /inflammatory states bacterial endotoxins stimulate macrophage release of IL-1
+ IL-1 within the hypothalamus (via induction of COX-2?) stimulates PGE2 synthesis
+ PGE2 via EP3 receptor - Gi type GPCR
+ Results in both INCREASE heat production & DECREASE heat loss
NSAIDs: Therapeutic Effects - General
1 Main therapeutic effects achieved via ?
- Pharmacological action for nearly all NSAIDs via ?
- Occupation of COX-1 / 2 hydrophobic channel by NSAID competes with ?
- With = 50 different NSAIDs wide variation in ?
- COX-2 inhibition
- competitive inhibition of COX-1 and COX-2
- AA site occupation
- Affinity, Efficacy and COX-1/COX-2 selectivity (see later)
NSAIDs: Therapeutic Effects General
- Main therapeutic effects achieved via?
- Nearly all have therapeutic efficacy as?
Often dominant disease state and individual patient response determine physician choice
- COX-2 inhibition
- analgesics, anti- inflammatories, and antipyretics
NSAIDs :Therapeutic Effects Pharmacokinetics
- Administration?
- Linear pharmacokinetics within therapeutic dose range (see Aspirin/Paracetamol)
- T1/2s two groups: ?
- Free or bound drug?
- Typically given orally but many topical preparations for soft tissue injury
2.
- T ½ < 6hrs
T ½ > 10 hrs
- Many heavily bound to plasma protein 90-99%
Appreciate the use of NSAID as analgesics, anti-inflammatories and antipyretics LO
NSAIDs : Main Therapeutic Uses
- When is NSAIDS used as Anti-Inflammatories?
Analgesia
- What type of pain is it used for? Why is it better than other pain relief?
- When used?
- Very wide use in Musculoskeletal Disorders – Rheumatoid/Osteoarthritis
- Mild to moderate pain though less effective than opiates - better ADR profile
- Moderate pain accompanies many disease states very common with many medical procedures.
- NSAID universal use in Hospitals / OTC
- Moderate pain accompanies many disease states very common with many medical procedures.



