Lecture 7 (Anti-inflammatories) Flashcards
What do NSAIDs do?
They reduce the production of prostaglandins and thromboxane
What do anti-inflammatory NSAIDs do? (2)
(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? (2)
(reduce certain sorts of pain)
-Decrease production of PGs (prostaglandins) in damaged and inflamed tissue which sensitises nociceptors to inflammatory mediators eg. bradykinin, 5-HT
What do antipyretic NSAIDs do? (2)
(lower raised temperature)
-Thermostat in hypothalamus activated via IL-1 induced COX2 production of PGE (Prostaglandin E1)
How many subunits is COX made up from?
two identical subunits, each with two catalytic sites
Where are these expressed? (3) :
COX1
COX2
COX3
-COX1 is expressed in many tissues and has homeostatic function
-COX2 is not expressed by cells and is inducible enzyme, induced made in cells in response to injury and inflammation for protective function
-COX3 its expression is limited and found in brain and kidneys – paracetamol exerts its action through COX3 (why its for headaches)
What do COX 1 and 2 inhibitor do?
COX1 and COX2 inhibitors inhibit Cyclooxygenation reaction of Arachidonic Acid to prevent production of PGE2
What is COX3 a variant of?
COX1
How does the structure of COX1 and COX2 differ?
Pore is slightly different between COX 1 and 2
In kink there is isoleucine for COX 1 and valine for COX2 (smaller amino acid)
so allows bigger drugs to get in compared to COX1
What do prostaglandins do? (3)
Affect several bodily functions, including inflammation, pain and uterine contractions.
What does aspirin bind to covalenty?
Aspirin binds covalently to a Ser residue in COX preventing arachadonic acid from reaching the cyclooxygenase site
What are desired effect mediated by (which COX)? (2)
and which COX mediates unwanted side effects? (2)
Most Desired effects (anti-inflammatory) mediated by COX2
Unwanted side effects eg. on gastrointestinal tract, mediated by COX-1
What type of inhibitor are most NSAIDs?
Suicide inhibitors (irreversible)
What side effects are associated with NSAIDs? (5)
-Dyspepsia, diarrhoea, nausea, vomiting, gastric bleeding, ulceration
-Renal failure
-Liver Damage
-Bronchospasm asthma attacks
-Skin Rashes
What should drugs target to avoid targets of NSAIDs?
COX2 / COX3
What are the NSAID effects of COX1?
Undesirable (1)
Desirable (1)
Undesirable : Gastrotoxicity
Desirable : Antithrombotic (reduces formation of clots)
What are the NSAID effects of COX2?
Undesirable (3)
Desirable (2)
Undesirable : Increases blood pressure, salt retention, prothrombotic
Desirable : Anti-inflammatory, Analgesic
What is the clinical use of antithrombotic drugs?
e.g. Aspirin for patients at high risk of arterial thrombosis
What are the clinical uses of analgesic drugs? (3)
-Short term aspirin, paracetamol, ibuprofen
-Chronic pain longer lasting more potent drug eg. Naproxen (+codeine)
-Reduce requirement for narcotic analgesics
What is and example of an anti-inflammatory drug and an antipyretic drug? (2)
-Ibuprofen
-Paracetamol
What does Thromboxane do?
Thromboxane’s lead to blood clotting and also involve vasoconstriction
What is COX?
Cyclooxygenase (COX) is an enzyme that helps create the chemicals prostaglandin and thromboxane
What COX should you avoid targeting to avoid most side effects?
COX1
What do COX1 and COX2 do?
COX1 – has homeostatic function in maintaining body health
COX2 – induced enzyme in response to inflammation
What does Aspirin do? (3)
What does Ibuprofen do? (1)
-Anti-platelet action
-Weak acid, rapid and efficient absorption in the ileum
-Suicide inhibitor (irreversible) - Irreversibly inhibits COX1 and 2 (inhibits 1 more than 2)
Reduced risk of colonic and rectal cancer
Reduced risk of Alzheimer’s
-Same as Aspirin but competitive inhibitor
What does paracetamol do? (4)
-Analgesic-antipyretic (group of drugs) due to CNS effects
-Weak anti-inflammatory
-Cox3/1 selective
-N-acetyl-p-benzoquinone imine is hepatotoxic in unconjugated form competitive Inhibitor
Well absorbed, metabolized in liver
Less side-effects than aspirin with long term use, but large doses may increase kidney damage
