Lecture 6- Autocoids; The Eicosanoids Flashcards
Eicosanoids
*arachidonic acid= most abundant precursor for eicosanoids= derived from dietary linoleic acid/ingested directly as a dietary constituent
-not pre-formed in cells but are generated from phospholipid precursors
-implicated in the control of many physiological processes + are the most important mediators + modulators of the inflammatory reaction
Biosynthesis of eicosanoids
-in mammals the main eicosanoid precursor= arachidonic acid (AA)
-most cell types = AA is esterified in the cell membrane phospholipids
-initial + rate-limiting step in eicosanoid synthesis is the liberation from phospholipids by the enzyme phospholipase A2
-once liberated= portion of AA is metabolised rapidly to the oxygenated products by the enzymes cyclooxygenase + lipoxygenases
Prostanoids
-prostanoids are the products of the cyclooxygenase pathway of AA metabolism
*prostaglandins
*thromboxanes- Pro-aggregatory
*prostacyclin- Anti-aggregatory
Biosynthesis of prostanoids; cyclooxygenase;
COX-1
-synthesis of prostanoids accomplished during the complex steps of microsomal enzymes = cyclooxygenases; 2 forms
*cyclooxygenase-1(COX-1)
*cyclooxygenase-2 (COX-2)
-COX-1 = present in most cells as a constitutive enzyme in the production of prostanoids which have homeostatic functions (e.g. protects the gastric epithelium)
Biosynthesis of prostanoids; cyclooxygenase; COX-2
-COX-2 = not normally present, but is strongly induced by inflammatory stimuli -> more relevant to the treatment of inflammatory conditions
- major source of prostanoids formed in inflammation
Pharmacological actions of prostanoids
*PGD2= causes vasodilation, inhibition of platelet aggregation, relaxation of gastrointestinal + uterine muscle
*PGF2a= causes myometrial contraction in humans
*PGI2= causes vasodilation + inhibition of platelet aggregation
*TXA2= causes vasoconstriction, platelet aggregation + bronchoconstriction
*PGE2- following actions;
- contraction of bronchial + gastrointestinal smooth muscle
-bronchodilation, vasodilation, stimulation of intestinal fluid secretion + relaxation of gastrointestinal smooth muscle
-contraction of intestinal smooth muscle, inhibition of gastric acid secretion + increased gastric mucus secretion
Prostanoids in the inflammatory process
-inflammatory response= accompanied by the release of prostanoids
*PGE2 predominates; PGI2 is also important
- acute inflammation; PGE2 + PGI2= generated by the local tissues + blood vessels while mast cells release mainly PGD2
-chronic inflammation; monocytes + macrophages also release PGE2 + TXA2
PGE2, PGI2 + PGD2= powerful vasodilators + synergies with other inflammatory vasodilators such as histamine + bradykinin
Prostanoids in the inflammatory process
-they do not directly increase the permeability of the post capillary venules but potentiate this effect of histamine + bradykinin
-do not produce pain; but potentiate the effect of bradykinin by sensitising afferent C fibres to the effects of other noxious stimuli
-causes blood vessels to become leaky, fluid accumulates in extra vascular places= oedema = because of the increase in permeability
*PGE2= makes pain possible at a lower threshold; making enough fibres more sensitive to action of other autocoids as a result of injury/ bradykinin
Clinical pharmacology of prostanoids
Prostanoids= help in maintaining integrity in gastric mucosa
*gemeprost (synthetic prostaglandin)
*misoprostol (synthetic prostaglandin)
*dinoprostone (natural PGE2)
Clinical pharmacology of prostanoids;
Abortion + postpartum haemorrhage
*PGE2 + PGF2A= potent oxytocic actions
^terminate pregnancy at any stage by contracting uterine muscle
- used for first+second trimester abortion + for priming the cervix before abortion
Clinical pharmacology of prostanoids;
Facilitation of labour
*PGE2 + PGF2A + their analogues = stimulate labour
Clinical pharmacology of prostanoids;
Gastrointestinal system
-cytoprotection is the protective effect of the E prostaglandins against peptic ulcers
-PGE compounds+ their analgoues= protect against peptic ulcers produced by steroids/NSAIDs
*misoprostol= cytoprotective at low doses + inhibit gastric acid secretion at high doses
-side effects of misoprostol= abdominal discomfort + occasional diarrhoea
Clinical pharmacology of prostanoids;
Blood
*TXA2= promotes platelet aggregation while PGI2 is anti-platelet
*PGI2 (epoprostenol)= (synthetic form of prostacyclin)- used to inhibit platelet aggregation (during haemodialysis) especially if heparin is contraindicated
Leukotrienes
*leuko= made by white blood cells/leukocytes
*trienes= contain a conjugated triene system of double bonds
*leukotrienes= synthesised from arachidonic acid by 5-lipoxygenase-catalysed pathways
-found in lung, platelets, mast cells + white blood cells
-5-lipoxygenase enzyme= acts on arachidonic acid = leading to the production of the unstable compound leukotriene
*LTA4= converted enzymatically to LTB4 + cysteinyl-containing leukotrienes; LTC4, LTD4, LTE4 + LTF4
Pharmacological actions of leukotrienes;
The respiratory system
*cysteniyl-leukotrienes= potent spasmogens= causing dose-related contraction of human bronchiolar muscle
-cause an increase in mucous secretion in airway= blocks it
-reduce specific airway conductance + maximum expiratory flow rate in humans
