Lipid Mediators Flashcards
How is the potency of NSAIDs measured?
Potency of NSAID action paralleled by potency of inhibition of prostaglandins.
What is arachidonic acid?
- a precursor for biologically active lipids
What are PUFA?
PUFA: poly-unsaturated fatty acids
Where are PUFAs usually found?
The diet is usually dominated by omega-6 PUFAs
Where is AA stored?
Stored esterified in membrane phospholipids (plasma membrane & nuclear membrane)
How is AA released from membranes?
- Phospholipase A2 is activated by increase in intracellular calcium. - Many snake venoms contain Phopholipase A2 in large amounts.
Explain AA Metabolism.
Metabolism to Eicosanoids (which are biologically active metabolites of AA). The type of eicosanoid depends on the cell type. Metabolism occurs by two types of cyclo-oxygenase which is expressed in all cells: - constitutive (COX-1) - physiological prostaglandins (PGs) - inducible (COX-2) - gene induced by inflammatory stimuli (IL-1: pathophysiological PG overproduction) Metabolism also occurs by lipoxygenase which is expressed in inflammatory cells such as eosinophils and mast cells and whose production is associated with inflammation. Cyclic-endoperoxides are highly unstable and rapidly converted into stable prostaglandins.
How is the nomenclature of PGs dictated?
Nomenclature: letter denotes ring structure; subscript denotes # double bonds
Explain the action of: PGE2
relaxes vascular smooth muscle - vasodilator/natriuretic; decreases BP; hyperanalgesic (sensitises nerves to painful stimuli); pyrogenic (fever producing)
Explain the action of: PGF2α
bronchoconstrictor
Explain the action of: PGD2
bronchoconstrictor
PGE2, PGF2α and PGD2 do not circulate; what do they do?
These prostaglandins (PGs) do not circulate - degraded by endothelial cells of pulmonary capillaries and act locally at the site of production.
When are NSAIDs indicated?
Anti-inflammatory: acute and chronic conditions (RA, gout) Analgesia: headache, menstrual pain, musculo-skeletal pain Antipyretic: paracetamol often preferred.
What is a major side effect of NSAIDs?
One major adverse effect is gastric irritation/ulceration.
What is pain? (biochemically)
Long term interactions causes IL-1beta to induce an increase in BK1 receptors and an increase in COX-2 and PLA2 which causes increased pain.
What is fever? (biochemically)
Inflammation leads to macrophage activation which releases cytokines. This is also associated with increased PGE2 release which raises the temperature through cAMP in the hypothalamus.
What is the gastric role of PGE2?
PGE2 promotes blood flow and angiogenesis as well as increasing mucus secretion. It also reduces the gastric acid secretion which acts as a protective mechanism from gastric ulcers.
What are prostacyclin and thromboxane? Where/When are they produced?
During the AA cascade, prostacyclin and thromboxane are also produced. Prostacyclin is chemically unstable with a half life of around 3 minutes. It is produced by endothelial cells and is used to reduce platelet activation and as a vasodilator. It also protects against coronary artery disease. Thromboxane A2 is also chemically unstable with a half life of around 30 seconds. It is produced by platelets and increases platelet activation and acts as a vasoconstrictor. It promotes coronary artery disease. The actions directly oppose those of PGI2.
Explain Aspirin?
Aspirin is ‘special’ in that it causes acetylation of COX and vascualar protection as well as by triggering lipotoxins.
What is the significance of the enzyme 5-lipoxygenase?
- Active in the AA cascade to produce LTs - restricted to distribution to inflammatory cells - no known physiological role beyond inflammation - activated by increase in intracellular calcium by stimuli produced in infection, allergic response and other forms of inflammation.
List some properties of Leukotrienes.
- bronchoconstrictors - vasocactive - leaky vessels can cause tissue oedema - implicated in asthma - Leukotriene receptor antagonists (such as montelukast) block cysteinyl-leukotrienes
What is the action of LT B4?
Leukotriene B4: no direct actions on smooth muscle; promoted inflammation by attracting leukocytes
Where are some sites of action of NSAIDs in the AA cascade?
