Lecture 7 - NSAIDs Flashcards
What does Phospholipase A2 generate?
precursor called arachidonic acid
Role of arachidonic acid
acts as secondary messenger and a substrate for groups of enzymes lipoxygenases and cyclooxygenase (COX) to produce lipid-soluble mediators.
what does lipoxygenase enzyme pathway produce?
leukotrienes
what does COX pathway lead to?
production of Prostaglandins and thromboxanes
what is COX pathway inhibited by?
NSAIDs (e.g. aspirin, paracetamol and ibuprofen) during inflammatory response
What do NSAIDs work as?
- Anti-inflammatory
- Analgesic (certain types of pain)
- Antipyretic (reducing high temperature)
Structure of COX enzymes
- made up of two identical subunits (dimeric)
- each subunit has a small carbon-rich knob to anchor into ER
what are the two active sites of COX enzymes?
- Cyclooxygenase site - buried deep and guides arachidonic acid out of membrane into enzyme.
- Peroxidase site - activate heme groups to participate in cyclooxygenase reaction
COX 1 isoform
- expressed in most tissues
- has homeostatic function
COX2 isoform
- is an inducible enzyme (not expressed in cells)
- inducible expression in inflammatory cells after cytokine stimulation, GF and tumour promoter.
- immediate response gene
COX 3 isoform
- variant of COX1
- expression is limited, found in brain and kidneys
- paracetamol acts through COX3 (for headaches)
what inhibits the cyclooxygenation reaction of arachidonic acid?
COX1 and COX2 inhibiters to prevent production of prostaglandin E2
How is COX2 structure different to COX1?
it has a smaller amino acid (valine) to make it a wider channel compared to COX1 which has isoleucine. Means COX2 can selectively filter drugs.
what is the danger of inhibiting prostaglandins?
mucous no longer produced by GI tract so no protection from acid (or aspirin) and burns stomach lining. Also maintains blood flow of kidneys.
what is the aspirin action on COX enzymes?
acetyl group part connects to serine amino acid to permanently inactivate enzyme.
what is suicide inhibition?
identifies a drug that covalently causes a permanent inactivation of the target (e.g. aspirin on COX)
- only solved by forming new enzymes and no drug
selectivity of NSAIDs
- most show little selectivity and work same way, except for paracetamol (no anti-inflammatory effect)
most desired target for NSAIDs
COX2 for its anti-inflammatory effect and COX1 has unwanted side effects (e.g. GI tract). COX2 found in CNS, kidney and tumours
Side effects of using NSAIDs
- causes GI tract issues from acid ( gastric bleeding and ulcers)
- effects renal function and could cause kidney failure
- causing liver damage as metabolite of phase 1 reaction for paracetamol is toxic.
- could cause asthma attacks and skin rashes
What NSAID has higher risk of causing gut problems?
Naproxen
Advantages of COX2 selective drugs
NSAIDs like Vioxx and Valdecoxib reduce the unwanted GI tract effects
Disadvantages of COX2 selective drugs
- may have cardiovascular effects as mechanism is unknown
- could increase blood pressure, atherogenesis and thrombotic tendency.
Disadvantages of COX1 selective drugs
- controls blood clot formation so patients with bleeding disorders would have an undesired side effect
characteristics of aspirin
- has anti-platelet action and reduces inflammation
- reduces risk of colonic and rectal cancer
- weak acid, rapid and efficient absorption in ileum
- suicide inhibitor so action is irreversible
characteristics of ibuprofen
- similar action to aspirin accept it is a competitive inhibitor
characteristics of paracetamol
- analgesic and lowers body temp (antipyretic)
- COX3/1 selective
- well absorbed and metabolised in liver
- precursor is hepatotoxic in unconjugated form
- competitive inhibitor
clinical use of aspirin
used as an antithrombotic for patients at high risk of arterial thrombosis
what NSAIDs are used as an anti-inflammatory as clinical use?
ibuprofen, naproxen (codeine)
what is used as an antipyretic?
Paracetamol
