Pharmacology of inflammation Flashcards
What type of drug is aspirin?
What is it derived from?
What are the clinical effects of aspirin ?
NSAID - Non steroidal anti inflammatory drug Derived from salicylic acid - Anti inflammatory - Anti pyretic - Analgesic - Anti thrombotic : Only aspirin
What are ecosanoids?
What are some examples of molecules with are ecosanoids?
Type of lipid Inflammatory mediators - Prostaglandins - Leukotrienes - Thromboxanes - Lipoxins
Describe the structure of a phospholipid
Phosphate group
Glycerol
2 fatty acids
1 fatty acid may be arachidonic acid
Describe arachidonic acid metabolism
Which enzymes are responsible
2 stages
Arachidonic acid -> Prostaglandin G2 = COX
Prostaglandin G2-> prostaglandin H2 = COX
What is another name for COX1/COX2?
PGH2 synthase
What do NSAIDS do? ( activity)
Competitive reversible inhibitors at COX enzymes
Inhibit the formation of Prostaglandin G2 + prostaglandin H2
What activity does aspirin have?
Irreversible inhibitors at COX enzymes
Why is blocking prostaglandin G2 + prostaglandin H2 bad?
Many prostaglandins are derived from Prostaglandin H2
E.g PGD2, PGE2, PGI2, thromboxane
What type class are prostanoid receptors?
GPCRS
What type of drugs are
- OST
- Iprant
Agonists
Anatagonists
What are the desired effects of NSAIDS and why do these occur?
Anti inflammatory : Blockage of PGE2,PGD2 + PGI2
Anti pyretic: Blockage of PGE2
Analgesic : Blockage of PGE2
Anti thrombotic: Blocks synthesis of TxA2 which activates platelets
What are the roles of PGE2?
What converts PGH2 -> PGE2?
- Vasodilation + inflammation
- Sensitise nerve endings
- Fever
- Protects gastric mucosa
PGE2 synthase
What are the undesired effects of NSAIDS?
GI bleeding + ulceration: PGE2 contribues to defense layer of the gastric mucosa by decreasing gastric acid/ increases bicarb
Altered renal blood flow: PGE2 + PGI2 regulate renal blood flow
Where are exogenous steroids derived from?
Cholesterol
Precursor to vitamin D, contributes to bile acids and steroid hormones
What are the main corticosteroids and where are they produced?
Glucocorticoids - zona fasiculata
mineralocorticoids - zona glomerulosa
sex steroids - zona reticularis
How do steroids pass into the nucleus?
Steroids are lipid soluble so can pass into any cell
They enter cell and bind to cytoplasmic receptors (GR/MR/Sex steroid receptors)
Receptors coupled with heat shock proteins which dissociate upon binding
Steroid receptor complex dimerises
Translocates to the nucleus
Binds to response elements of DNA
Transactivation or transrepression
Why does cortisol have a higher affinity for MR but does not activate them?
What is the inactive form of cortisol?
Pre receptor metabolism
Cortisone = inactive at GR + MR
Cortisol = active at both
Enzymes:
11 beta HSD type 1 : Converts cortisone -> cortisol
11 beta HSD type 2: Converts cortisol -> cortisone
Where is 11 beta HSD type 1 normally found?
Where is 11 beta HSD type 2 normally found?
Abundant + with gluco-corticoid receptors so cortisone -> cortisol and receptor activation
Restricted distribution e.g in renal tubules. + with mineralocorticoid receptors. So cortisol -> cortisone to prevent MR activation
What do steroids upregulate ( transactivation)?
- Annexin A1 which inhibits PLA2 so decreases eicosanoids, prostaglandins and leukotrienes
- Upregulate anti inflammatory cytokines e.g IL-10
What is Annexin 1?
Lipocortin
Inhibits PLA2
Decreases eicosanoids, prostaglandins + leukotrienes
What do steroids down regulate ( transrepression)?
Pro inflammatory
- COX-2
- PLA2
- NOS
- Pro inflammatory cytokines
Compare NSAIDS vs Steroids
NSAIDS: Real adverse affects, targeted action COX
Steroids: Severe and predictable adverse effects, potent, non selective action
What is the final end product of purine metabolism in humans ?
Uric acid
Purines -> xanthine
Xanthine -> uric acid by xanthine oxidase
What does increased uric acid lead to?
Urate crystal production -> inflammation
