Prostaglandins

Prostaglandind; synthesis, functions, inhibitors

1. Dr Joyce Mwatonoka MMED PCH Prostaglandins

2. Introduction Eicosanoids are metabolites of arachidonic acid or other unsaturated fatty acids derived from the action of the cyclooxygenase or lypoxygenase enzymatic pathway Cyclooxygenase – prostanoids Lypoxygenase - leukotrienes Eicosanoids are classified into 2 main groups;

3. Cont… Leukotrienes and lipoxins Prostanoids Prostaglandins (PGs) Prostacyclins (PGI2) Thromboxanes (TXs)

4. Cont… The key precursor fatty acid is arachidonic acid, which is an essential fatty acid as it cannot be synthesized  de novo  in animals The primary precursor is obtained from the diet in the form of linoleic acid (polyunsaturated omega-6 fatty acid). It typically occurs in nature as a triglyceride ester

5. Prostaglandins PGs are extremely potent, biologically active lipid mediators that are synthesized throughout the body PGs have diverse hormone-like effects in animals They are derived enzymatically from the fatty acid arachidonic acid

6. Biosynthesis of PGs Involves the action of multiple enzymes, some of which are rate limiting The first step is production of free arachidonic acid from membrane phospholipids upon stimulation of the enzyme phospholipase A 2 The COX pathway, accomplished by catalytic activity of two distinct cyclooxygenase (COX-1 and COX-2) isozymes encoded by separate genes - produces PGG 2  and then PGH 2

7. Cont… 3. PGH 2 is then converted into -PGI 2  by prostacyclin synthase -TXA 2  by thromboxane synthase , and -PGE 2 , PGD 2  and PGF 2 α   by their respective synthase enzymes PGs are produced in the endoplasmic reticulum, exit the cell and signal through G protein-linked receptors at the cell surface

8. COX-1 COX-2 Constitutive Present in most tissues Synthesizes PGs that regulate physiologic processes Especially important in -gastric mucosa -kidneys -platelets -vascular endothelium Inducible Induced mainly at sites of inflammation by cytokines Synthesizes PGs that mediate inflammation, pain, and fever Constitutive expression primarily in -brain -kidneys Differences between COX-1 and COX-2

9. Cont… Both COX iso -enzymes are inhibited by NSAIDs, such as acetylsalicylic acid and ibuprofen This prevents synthesis of endogenous PGs Because of differences in the structures of the binding sites, COX-1 is completely inhibited by aspirin, whereas COX-2 is only partially inhibited Synthesis of COX-2 is inhibited by steroidal anti-inflammatory drugs at the level of transcription

10. PG Receptors PGs function close to the site of synthesis and are deactivated to inactive metabolites before moving into the circulation They act locally in very low concentrations to produce profound physiological changes through receptor-mediated G-protein linked signaling pathways The immediate effect of the appearance of PGs is a change in the rate of production of second messengers such as cAMP or Ca 2+  and a change in the activation of a specific protein kinase

11. Biological Functions of PGs Maintenance of IOP (Intraocular Pressure) Vasodilation /vasoconstriction Cause aggregation or disaggregation of  platelets Regulate inflammation I nduce labor Acts on parietal cells in the stomach wall to inhibit acid secretion Increase   glomerular filtration rate Sensitize spinal neurons to pain

12. Inhibitors of PGs NSAIDs (inhibit  cyclooxygenase ) Corticosteroids (inhibit  phospholipase A2 production ); used in allergic reaction and to relive inflammation COX-2 selective inhibitors or coxibs eg ; Celecoxib , used to treat arthritis pain and RA

13. Clinical use of synthetic PG analogs To induce  labour   or abortion   PGE 1 analogue - misoprostol PGE 2 analogue - dinoprostol   PGF 2 analogue – dinoprost To prevent closure of patent ductus arteriosus in newborns with particular CHD (PGE 1 ) As a vasodilator in severe  Raynaud's phenomenon or ischemia of a limb

14. Cont… In treatment of  IOP and glaucoma, PGF 2α analogs eg ; travoprost , latanoprost and bimatoprost In pulmonary hypertension To prevent and treat peptic ulcers (PGE) To treat erectile dysfunction or in penile rehabilitation following surgery (PGE1 as  alprostadil )

15. How PGs are different from true hormones Are formed in almost all tissues rather than in specialized glands Act locally rather than to distance sites Act on their parent cells Are not transported via blood Are synthesized as per needed Are not stored