1 NSAIDs Flashcards
Why do we use NSAIDs (3)
Vasodilation cytokines
Increased microvascular permeability
Stimulation of afferent nerves
What are the three phases of the immune response time course
Immediate - myeloid cell and clotting phase
Secondary - adaptive lymphocyte and tissue restoration phase
Resolution - of acute inflamamtion phase
What do COX-1 and COX-2 catalyse
Conversion of arachidonic acid into the intermediate metabolite PGH2
Where is COX-2 constitutively expressed in compared to COX-1
Brain and kidney
What prostanoids do COX-1 produce
Mediate homeostatic functions: gastric, small intestine, bowl mucosa
Kidney
Platelets
Vascular endothelium
What do COX-2 produce
Prostanoids that mediate inflammation, pain and fever
Where are COX-2 induced
Inflammatory sites by NK-KB mediated cytokine signalling pathways
What are NSAIDs first-line therapy for
Acute and chronic pain, particularly inflammatory pain
What is a non-selective COX inhibitor
Aspirin
What do NSAIDs differ mainly in (3)
Aspects affecting pharmacokinetics:
Route of administration - oral, topical and parenteral
Bioavailability
Cl and Half-life
How the effects of NSAIDs mediated
Anti-inflammatory (COX-2)
Analgesic (COX-2)
Anti-pyretic (COX-2)
Anti-thrombotic (COX-1)
Paracetamol is a weak COX-1 and COX-2 inhibitor true or false
True
What else does paracetamol also inhibit outside of COX-1 and COX-2
EP3
Where is COX-1 found
ER
What two catalytic sites do COX-1 have
Peroxidase active site
Cyclooxygenase active site
How does aspirin interact with COX-1 protein
Carboxylic acid group forms salt bridge with Arg 120 which is in close proximity to acetylate Ser530, blocks active site
What is larger in COX-2
Hydrophobic channel can accomodate for aromatic ring structure
What is different about COX-2 binding
COX-2 binding site is more accomodating and is characterised by a ‘side pocket’ which can accomodate bulky groups
What are three amino acid changes between COX-1 and COX-2
1) Leu in COX-2 less bulky than Phe and allows for larger groups
2) Val is less bulky than Ile and allows for larger sulphonamide
3) Arg provides hydrogen bonding stabilisation
What are propionic acid derivatives (3)
Naproxen
Ibuprofen
Ketoprofen
What are acetic acid derivatives (4)
Indomethacin
Sundilac
Ketorolac
Diclofenac
What are enolic derivatives (2)
Meloxicam
Piroxicam
Which COX activity is linear
COX-2
When does COX-2 inhibition occur
> 80%
