Pharmacology of inflammation / Flashcards
What type of drug is aspirin?
NSAID
What is aspirin derived from?
Derived from salicylic acid
What does aspirin do clinically in common with other NSAIDs, and what is its unique effect?
In common with other NSAIDs:
- Analgesic: pain relief
- Anti-pyretic: decrease fever
- Anti-inflammatory: decrease inflammation
Unique property:
- Anti-thrombotic: reduce heart attacks
What are the cardinal signs of inflammation?
Rubor - redness
Calor - heat
Tumor - swelling
Dolor - pain
Loss of function
What are the patho-physiological localised responses of inflammation?
Increased blood flow
Increased blood vessel permeability
Increased neuronal sensitivity
What are the mediators of inflammation?
Peptides/proteins: bradykinins, neuropeptides (substance P, CGRP, nuerokinin A), Complement (C3a, C5a, Coagulation (hageman factor, thrombin)
Cytokines: interleukins, chemokines, interferons
Small molecules: histamine
Free radicals: nitric oxide
Lipids: Eicosanoids, PAF
What is the structure of arachidonic acid, and where is it found?
Poly-unsaturated fatty acid
Sometimes part of glycerol as the fatty acid chain
> Hydrophobic tail in the phospholipid bilayer
What is the process of arachidonic acid metabolism?
Membrane phospholipids > (PLA2 breaks it down) > Arachidonic acid > (COX) > Prostaglandin G2 > (COX) > Prostaglandin H2
Prostaglandin H2 - PGH2 - forms all types of PGEs via different enzymes
What is the pharmacology of aspirin?
Targets cyclo-oxygenase - COX - COX1 & 2
Irreversible inhibitor
What effects does aspirin have physiologically?
Inhibits COX2 enzymes which produce PGEs which normally mediate sensitising nerve endings, potentiate action of vasodilators, and mediates thermoregulatory centre response to infection
What do PGEs bind to?
Prostanoid receptors which are GPCRs
Cells and tissues express different receptors for PGEs
What are the desired effects of aspirin?
Anti-inflammatory: prevents PGE2 mediated vasodilation - increase blood supply & fluid extravasation
Anti-pyretic: prevents PGE2 mediated thermoregulation in hypothalamus
Analgesic: prevents PGE2 mediated sensitisation of nerve endings
Anti-thrombotic (unique to aspirin): reduces TxA2 production in platelets
What are the undesired effects of aspirin?
GIT ulceration, bleeding: PGE2 protects gastric lining - decreases gastric acid secretin, increases mucus/HCO3- secretion
Adverse renal effects: PGE2 and PGI2 regulate renal BF
Anti-haemostatic: decrease in TxA2 production in platelets
What are the two subtypes of COX enzymes, and what do they do?
COX-1: PGH2 synthase, constitutive: platelets, gut, kidney, endothelium etc., physiological function, produces the undesired effects when NSAIDs inhibit
COX-2: PGH2 synthase, inducible; macrophages, inflammatory cells, pathophysiological, inhibited by NSAIDs
What is an endogenous steroid example?
Originates from within the body
Cholesterol
- Present in lipid membranes
- Synthetic precursor for Vit D, bile acids, steroid hormones
- Can lead to atheroclerosis - statins inhibit HMG CoA reductase - enzyme in cholesterol synthesis