Flashcards in Anti inflammatory drugs Deck (64)
Broad reasons for using anti inflammatory drugs
1. anaphylaxis is life threatening
2. autoimmune damage e.g. RA
3. pain, especially chronic
What's the major molecule involved in producing inflammatory mediators?
What functions are eicosanoids involved in?
platelet aggregation, uterine motility, vasoconstriction/vasodilation, bronchodilation/bronchoconstriction, inflammation, gastric function, allergic response
What are the clinical indications for use of NSAIDs?
- mild-moderate pain due to tissue injury
- fever (antipyretic)
- platelet aggregation
What drug group does aspirin belong to?
non-steroidal anti-inflammatory drugs
What is the action of NSAIDs?
What are the COX groups, found in which cells?
COX-1: house keeping (platelet aggregation, vascular flow, renal function), found in most cells
COX-2: induced in activated inflammatory cells
In terms of COX inhibition, what is the effect of aspirin at different doses?
- low dose aspirin = selective for COX-1
e.g. prevent platelet aggregation and thrombosis, prevent heart attack and stroke
- high dose aspirin = non selective, (platelets)
(most other NSAIDs are non selective)
What are the adverse effects of NSAIDs?
GIT peptic ulcers due to lack of prostaglandin inhibition of gastric acid secretion, leading to enhanced mucosal blood flow and increased secretion of mucus
Platelet aggregation inhibited = increased bleeding time, GIT blood loss
allergic = bronchospasm, rhinitis due to increased synthesis of leukotrienes
What is one way to reduce mucosal damage?
An enteric NSAID has a
What does an enteric form mean re NSAID?
Coating over the drug allows it to bypass the stomach and be released in the duodenum
How can foecal blood loss be reduced in using NSAIDs?
Reduce 3-8ml faecal blood loss by 50% by using a soluble rather than compressed formulation
What is a selective COX-2 inhibitor?
Advantage of selective COX-2 inhibitors
Lower risk of GIT effects, but at higher doses there is a higher risk of cardiovascular events
How is the structures of COX-1 and COX-2 different?
COX-2 has a side pocket, shape of COX-2 enzyme channels allows for larger molecules to bind: size and shape of the molecule depends on whether it is a COX-1 or COX-2 inhibitor
How do NSAIDs bind to COX?
NSAIDs enter hydrophobic channel forming reversible hydrogen bonds (@ arginine 120), preventing fatty acids from entering
How is aspirin/ acetyl salicylic acid metabolised?
aspirin is a prodrug that is converted to salicylic acid in the liver: 30% of the prodrug is lost to first pass metabolism
Pharmacokinetics of salicylic acid?
pKa of 3.5 (weak acid)
dose-dependent kinetics - is saturable
t 1/2 = 2-4hours in low doses
t 1/2 = 15-30 hours in high doses
How does aspirin irreversibly inhibit COX?
Enters active site with -OH, irreversibly acetylates a serine @ position 530
Doses for aspirin?
0.5-1mg/kg = low dose, e.g. anti-platelet
5-10mg/kg = moderate dose, e.g. analgesic, antipyretic
>30mg/kg = high dose, e.g. anti-inflammatory
normal tablet has 300mg
What are symptoms of salicylism/aspirin toxicity?
Tinnitus, deafness, headache, mental confusion, convulsions, coma and death
- requires CV and respiratory support, correct acid-base abnormalities and eliminate salicylate/prevent further absorption
What are the three groups of corticosteroids?
Mineralocorticoids, androgens, glucocorticoids - antiinflammation
Where are the corticosteroids synthesised and secreted?
Corticosteroids and cholesterol?
All three groups of corticosteroids are derived from cholesterol
What do mineralocorticoids do?
affect water and electrolyte balance (Na+/K+)
Example of a mineralocorticoid?
What do glucocorticoids do?
affect carbohydrate and protein metabolism
Example of a glucocorticoid?
Glucocorticoid effect as a drug?
Anti-inflammatory activity in doses above normal levels