L11 - Anti-inflammatories - NSAIDs Flashcards
Aspirin discovery - 1828
White powder called salicin isolated and converted to salicylic acid
Aspirin discovery - 1897
Felix Hoffmann derivatized hydroxyl groups in salicylic acid with an acetyl group
- Reduced the negative effect of salicylic acid
- First patented on March 6, 1899
NSAIDs are prescribed for
Rheumatic musculoskeletal pains
Aches
Pains
Swelling
Arachidonic acid is produced by?
Produced from membrane phospholipids by Phospholipase A2
Arachidonic acid role
Acts as a second messenger and substrate for lipoxygenases and cyclooxygenase
- Leads to generation of lipid-soluble mediators
- Lipoxygenase and cyclooxygenase pathway
Lipoxygenase pathway
Production of leukotrienes
Cyclooxygenase pathway
Production of prostaglandins and thromboxanes
- E.g. prostaglandin E2
Prostaglandins
Unlike most hormones, they are created by cells and then act only in the surrounding area
Prostaglandins control
Constriction of muscle cells around blood vessels
Aggregation of platelets
Constriction of the uterus
Delivering and strengthening pain signals
Inducing inflammation
Properties of NSAIDs
Anti-inflammatory
Analgesic
Antipyretic
Effectiveness against headaches
Properties of NSAIDs - anti-inflammatory
Modify inflammatory reaction decreasing vasodilation and oedema
Ineffective against mediators that contribute to tissue damage associated with chronic inflammatory conditions
Properties of NSAIDs - analgesic
Decrease production of prostaglandins in damaged and inflamed tissue
Sensitises nociceptors to inflammatory mediators
Properties of NSAIDs - antipyretic
Lower raised temperature
Thermostat in hypothalamus activated via IL-1 induced COX2 production of prostaglandin
Properties of NSAIDs - headaches
Reduce vasodilator effect of prostaglandins on cerebral vasculature
COX1/COX2 selective NSAIDS
COX2-selective NSAIDs/inhibitors reduce effect of gastrointestinal toxicity (antiarthritic and analgesic)
- Concerns regarding cardiovascular safety
Most NSAIDs show little selectivity
Main differences are in toxicity, duration of action, and patient tolerance
NSAID effects from COX1 inhibition
Undesirable – gastrotoxicity
Desirable – antithrombotic
NSAID effects from COX2 inhibition
Undesirable – increased blood pressure, salt retention, prothrombotic
Desirable – anti-inflammatory, analgesic
COX1 and COX2 inhibitors inhibit
Cyclooxygenation reaction of Arachidonic Acid to prevent production of PGE2
COX2 structure
Wider at the bend because it has a smaller amino acid (valine)
Cox1 has an isoleucine
- This gives rise to a gap which can act as a filter for drug
Side effects of NSAIDs - gut
Prostaglandins normally inhibit acid secretion and protect mucosa
Leads to dyspepsia, diarrhoea, nausea, vomiting, gastric bleeding, ulceration
Co-administration of prostaglandin analogue may be protective
Side effects of NSAIDs - liver
Leads to liver damage
Paracetamol creates toxic, reactive intermediate
Side effects of NSAIDs - renal
Prostaglandins normally maintain renal blood flow
Leads to renal failure
Side effects of NSAIDs - lung
Bronchospasm asthma attacks
More common with aspirin
Side effects of NSAIDs - bleeding disorders
Thromboxane is involved in platelet aggregation
Too many drugs can reduce thromboxane
Side effects of NSAIDs - GI complications
34-45% users will sustain some form of GI damage
Small percentage lead to serious effects and hospitalisation
Aspirin binds to?
Aspirin binds covalently to a ser residue in COX
Prevents arachidonic acid from reaching the cyclooxygenase site
What is a suicide inhibitor?
Useful cardiovascular drug due to inhibition of platelet aggregation
Acts on both cox1 and cox2
Aspirin and warfarin increase risk of bleeding
Aspirin blocks?
The cyclooxygenase active site
Aspirin has two parts - an acetyl group attached to salicylic acid
When it attacks cyclooxygenase, it connects its acetyl group to a serine amino acid, permanently inactivating the enzyme
Aspiring overview
Anti-platelet action
Reduced risk of colonic and rectal cancer
Reduces risk of Alzheimer’s
Weak acid, rapid and efficient absorption in the ileum
Suicide inhibitor
Paracetamol overview
Analgesic-antipyretic due to CNS effects
Weak anti-inflammatory
Well absorbed and metabolised in the liver
Less side effects than aspirin with long term use
Large doses may increase kidney damage
Competitive inhibitor
Ibuprofen overview
Like aspirin except it is a competitive inhibitor
Clinical uses of NSAIDs
Antithrombotic
Analgesia
Anti-inflammatory
Antipyretic
Clinical uses of NSAIDs - antithrombotic
Aspirin for patients at high risk of arterial thrombosis
Clinical uses of NSAIDs - analgesia
Short term - aspirin, paracetamol, ibuprofen
Chronic pain - longer lasting more potent drug
Clinical uses of NSAIDs - anti-inflammatory
Ibuprofen
Naproxen
Clinical uses of NSAIDs- antipyretic
Paracetamol
COX subunits
Two identical subunits, each with two catalytic sides
A cyclooxygenase site that binds to the endoplasmic reticulum
A endoperorixase site
COX1
Found in most cells and is constitutively active, so a NSAID binding to COX1 may have many adverse side effects
COX2
Found in most cells and is active only when induced, so a NSAID binding to COX2 will have few, selective side effects
COX3
Found mostly on cells within the CNS and paracetamol binds to it
