NSAIDS Flashcards
1
Q
State how prostanoids are synthesised
A
- In cell damage, arachidonic acid is cleaved from cell membrane phospholipids
- Eicosanoids are formed from arachidonic acid, which are used as signaling molecules
- Prostanoids (prostaglandins, thromboxanes, leukotrienes) are types of eicosanoids
2
Q
Describe the process of prostanoid synthesis
A
- Cell membrane phospholipids catalysed by phospholipase A2 to become arachidonic acid
- Arachidonic acid catalysed and recycled by COX1/COX2 to become prostaglandin G and then prostaglandin H
- PG ‘H’ converted to other prostaglandins, including PG ‘E’
- PG ‘E’ important in mediating inflammatory response - vasodilation, hyperalgesia (enhanced sensitivity to central stimuli), fever, immunomodulation
3
Q
Describe the mechanism of action of NSAIDS
A
- COX-1 and COX-2 have different shapes, and can be selectively inhibited by different NSAIDS through competitive inhibition
- COX-1 narrow mouthed while COX-2 is wide mouthed
- Small, shard, aspirin-like drugs fit in both COX-1 and COX-2 and thus can inhibit both
- Big, blunt drugs fit only into COX-2, and thus can be selectively inhibited
4
Q
State the receptor prostaglandins act on
A
GPCR receptors
5
Q
Describe some actions of prostaglandins as an inflammatory molecule
A
- Prostaglandins act as potent vasodilators
- Often action includes synergizing effects of other autacoids (histamine, bradykinin) - positive feedback
- Enhance pain by increasing C fibre activity or removing glycine inhibition
- Stimulation of pyrexia
6
Q
Describe the main actions of COX1 and COX2
A
- COX-1 expressed in wide range of tissue types (constitutive expression)
- PG synthesis by COX-1 has major cytoprotective role in gastric mucosa, myocardium, renal parenchyma
- Ensures optimised local perfusion - reduces ischaemia
- PG half life short - need constant synthesis
- COX-2 expression induced by inflammatory mediators such as bradykinin - released in tissue injury
7
Q
State whether main therapeutic effect of NSAIDS and ADRs are due to COX1 or COX2
A
- Due to COX-1’s constitutive expression, most ADRs caused by NSAIDS effects are due to COX-1 inhibition
- Main therapeutic effects of NSAIDS occur via COX-2 inhibition (activated by inflammatory mediators)
8
Q
State the main uses of NSAIDs
A
- Analgesia - inability to feel pain (EP1, EP2)
- Less effective than opiates but less ADRs
- Anti-inflammatories
- Very wide use in MSK disorders - rheumatoid, osteoarthritis
- Antipyretics - prevent or reduce fever (EP3)
9
Q
How are NSAIDs transported around the body
A
- Heavily bound to plasma protein
10
Q
Describe the main ADRs of NSAIDs
A
- Long term use in elderly associated with iatrogenic morbidity and mortality
- Impaired metabolism of drug - last longer in body
- GI symptoms - stomach pain, nausea, heartburn, gastric bleeding, ulcerations
- Cannot secrete mucus due to blocked mucosal blood flow
- Can be given with PPIs to reduce GI symptoms
- Renal ADRs in compromised patients - heart failure, renal disease, hepatic cirrhosis
- PGE2 normally vasodilates afferent arteriole - prevention leads to fall in GFR
- Vascular - increased bleeding time, increased bruising
- Hypersensitivity - skin rashes, bronchial asthma
- Stevens Johnson syndrome - compromised hepatic function leading to rash of skin and mucous membranes
- Reyes syndrome (pediatric) - rare serious brain/liver injury
11
Q
Describe some drug interactions with NSAIDs
A
- Opiates - extends therapeutic range for treating pain
- Can reduce amount of opiates given when taken with NSAIDs (reduce opiate ADRs)
- NSAIDs - competition between multiple NSAIDs for protein binding sites
- Low dose aspirin - compete for COX-1 binding sites - interfere with cardioprotective action of aspirin
- Highly protein bound drugs - concentrations will increase in blood
- Sulphonylurea (hypoglycaemia), warfarin (increased bleeding), methotrexate
12
Q
Describe the effect of NSAIDs on platelet function
A
- Aspirin irreversibly inhibits COX enzymes (unlike other NSAIDs)
- Reduces release of thromboxane A2 from platelets, which reduces vasoconstriction
- Reduces expression of GP IIb/IIIa - antiplatelet drug
13
Q
Explain the use of paracetamol
A
- Paracetamol has no anti-inflammatory action
- Effective for mild/moderate analgesia and fever (analgesic + antipyretic)
- Better ADR profile than other NSAIDs
- Mechanism currently unknown - possible weak COX inhibitor
- First order kinetics in healthy patient and normal doses
14
Q
Describe the mechanism of paracetamol overdose
A
- Paracetamol metabolised in the liver into NAPQI through phase I oxidation, which is very reactive and toxic
- NAPQI at normal doses is detoxified by phase II conjugation with glutathione
- If glutathione levels drop (increased free radical or excessive paracetamol level), NAPQI builds up
- At high doses, paracetamol becomes zero order and leads to saturation
- Also causes saturation of NAPQI
- NAPQI build up leads to necrotic hepatic cell death and possible renal failure
15
Q
What are the main endogenous opioids and opioid receptors
A
- 3 main endogenous opioids are: endorphins, enkephalins, dynorphins
- 3 major types of opioid receptors are µ, ∂ and K where µ is the most common type
