Lecture 7 - Anti-inflammatory and immunosuppressant drugs Flashcards
What are the 3 groups of anti-inflammatory and immunosuppressants drugs?
NSAIDs, Coxibs & Paracetamol
Describe the formation of Aspirin
Salicin - converted to salicylic acid. Derivatized one of the hydroxyl function groups in salicylic acid with an acetyl group- forming the acetyl ester - which reduces the negative effect. This was developed into Aspirin
What are inflammatory mediators and sites of action of NSAIDs?
Arachidonic acid is produced from membrane phospholipids by the enzyme Phospholipase A2. It acts as a second messenger AND a substrate for 2 important groups of enzymes - lipozygenases & cyclooxygenase. This ultimately leads to generation of a lot of LIPID-soluble mediators.
What does the lypooxygenase pathway lead to?
Production of leukotrienes
What does the cyclooxygenase pathway lead to?
Production of prostoglandins and thromboxanes
What are prostaglandins?
Created by cells and act on surrounding areas. Also involved in delivery and strengthening of pain signals and induce inflammation. Also involved in processes such as constriction of muscle cells around blood vessels, aggregation of platelets during blood clotting and constriction of the uterus during labour.
What are the 3 types of NSAIDs?
- Anti-inflammatory
- Analgesic
- Antipyretic
What do anti-inflammatory NSAIDs do?
Modify inflammatory reaction
- decrease vasodilation, and in turn oedema
- ineffective against mediators that contribute to tissue damage associated with chronic inflammatory conditions
What do analgesic NSAIDs do?
Reduce certain sorts of pain
- decrease production of prostaglandins in damaged and inflamed tissue with sensitives, nociceptors to inflammatory mediators - e.g. bradykinin, 5-HT
What do antipyretic NSAIDs do?
Lower raised temperature
- thermostat in hypothalamus activated via IL-1 induced COX2 production of PGE
Describe the make up of COX
- made up of 2 identical subunits - each with 2 catalytic sites
- 2/3 isoforms
What is the function of COX-1?
Constitutive expression, platelets, stomach, kidney, colon, most tissues
What is the function of COX-2?
Inducible expression - most cells, but especially inflammatory cells after stimulation with cytokines, growth factors or tumour promoters. Immediate-early response gene
What is the function of COX-3?
In CNS, target for paracetamol
Describe the 2 different active sites of COX
They are collectively termed prostaglandin synthase
- 1st site - cyclooxygenase active site
- 2nd site - entirely separate perioxidase reaction (breakdown of hydrogen peroxide by peroxidase enzymes, resulting in water being produced) - needed to activate the heme groups that participate in the cyclooxygenase reaction
What is the cyclooxygenase reaction?
The cyclooxygenase (COX) enzyme catalyzes the conversion of arachidonic acid, a fatty acid, into prostaglandin H2 (PGH2)
Describe the enzyme complex created
Enzyme complex is a dimer of identical subunits - so all together, there are 2 cyclooxygenase activate sites anf 2 peroxidase active sites in close proximately
Describe what each subunit has
Each subunit has a small carbon-rich knob, pointing downwards. These knobs anchor the complex to the membrane of the endoplasmic reticulum.
What do COX1 & COX2 inhibitors inhibit?
Inhibit cyclooxygenation reaction of arachidonic acid to prevent production of PGs.
Where is the enzyme cyclooxygenase found?
Enzyme is resident in the ER membrane. COX2 has a slightly wider structure due to small bend.
What does Aspirin bind to?
Binds covalently to a Ser residue in COX preventing arachidonic acid from reaching the cyclooxygenase site
What is the composition of aspirin?
Aspirin is composed of 2 parts:
- acetyl group attached to salicylic acid. When it attacks cyclooxygenase, it connects its acetyl group to a serine amino acid, permanently inactivating the enzyme
What are the main differences in NSAIDs?
Toxicity, duration of action and patient tolerance
What level of selectivity is seen in NSAIDs?
Little selectivity
