Kinins and Prostaglandins PDF

Kinins and prostaglandins ALI H. Saud University of Basrah Department of pharmacology December 1, 2024 General concept A variety of polypeptides effects somewhat similar to that of histamine on vascular smooth muscle ,ca...

Kinins and prostaglandins ALI H. Saud University of Basrah Department of pharmacology December 1, 2024 General concept A variety of polypeptides effects somewhat similar to that of histamine on vascular smooth muscle ,capillary permeability and bronchial smooth muscle. Bradykinin is a biologically active nonapeptide a product of the enzyme kallikrein it is a potent agent to which many function have been attributed such as :  Kinins (cont.) 1.Regulation of the microcirculation of exocrine glands 2. Mediation of inflammation. 3. The most potent vasodilators 4. Constrict the bronchial, uterine and most gastrointestinal smooth muscles. Bradykinin split by enzyme known as kininase which appears to be identical with the angiotensin converting enzyme (ACE) Kinins (cont.) Bradykinin act on its receptors known as B- receptor Lisinopril orally active ACE inhibitor is being tested at present both in treatment of hypertension and for their effect on destruction of bradykinin. Dry cough and angioedema considered as main side effects of this family and such effects related to bradykinin  Kinins (cont.) Hereditary angioedema (HAE) is a disorder characterized by recurrent episodes of sever swelling of limbs, face, intestinal tract and airway. Its begin in childhood and worsen during puberty.B2-receptor antagonist icatibant widely used in treat acute episodes of swelling and inflammation associated with hereditary angioedema prostaglandins Biosynthesis of PGs Phospholipids that found in the cell membrane of all the tissue, under effects of specific enzyme known as phospholipaseA2 can convert the phospholipids in the cell membrane into 20 carbon atoms compound known as arachidonic acid, which considered as a main source for eicosanoids synthesis  prostaglandins (cont.) Thus, arachidonic acid under effects of either cyclo-oxygenase (COX) or lipo-oxygenase (LOX), convert into prostaglandins (PGs), thromboxane (TXA2) and leukotriens (LTs) respectively. prostaglandins (cont.) Prostaglandins (PGs) acts as local hormone i.e. produce its effect at sites where they are synthesized with no or very minute serum level , which is differ from the true hormone which is migrate to the places faraway from the site of its synthesis and produce effects  prostaglandins (cont.) ❖ Cyclo-oxygenase I ( PGH synthase I) which is widely distributed in body tissues and generates prostanoids for house keeping such as gastro cytoprotection. ❖ Cyclo-oxygenase II (PGH synthase II) which is inducible by inflammatory reactions and major source of prostanoids in inflammation and cancer ❖ Non-steroidal anti-inflammatory drugs (NSAIDs) exert their therapeutic effects through inhibition of COX I and II.  Nomenclature of prostaglandins and their types 1. PGH2 2. PGD2 3. PGE1 (Misoprestol) ,Alprostadil 4. PGE2 (Dinoprostone ) 5. PGF1alpha 6. PGF2alpha (Dinoprost) 7. PGI2 (Prostacyclin) Mode of action They bind to G-protein coupled receptor which is involved in the action of PGs, after binding of PGs with its receptors, adenylcyclase will activated which cause increase in the cAMP concentration and then activated certain protein kinase with calcium utilization by various cells.  Pharmacological actions of PGs 1.Blood vessels : Smooth muscle of blood vessel will be relaxed by PGE1,PGE2 and PGI2,while PGF2α and TXA2 constrict it. 2.Bronchail smooth muscles: Smooth muscles of bronchi will be dilated by PGE1,PGE2 and PG I2, while PGF2α and TXA2 cause bronchoconstriction. Pharmacological actions of PGs 3. Reproductive system: ❑ Non pregnant women : PGE1,PGE2 cause relaxation of uterus smooth muscles, while ❑ Pregnant women : PGE1,PGE2 cause contraction of uterus smooth muscles. ❑ PGF2α and TXA2 cause uterine contraction ❑ Administration of PGF2α in the amniotic fluid can terminate pregnancy completely.  Pharmacological actions of PGs 4.Renal system: PGE1, PGE2 and PGI2 but not PGF increase GFR and increase the Na excretion , also enhance the release of rennin. TXA2 reduces renal function and GFR Pharmacological actions of PGs 5. Effect on platelets: PGI2 inhibit palateles aggregation. TXA2 strongly induced platelets aggregation.  Pharmacological actions of PGs 6.Effect on GIT: PGE2 and PGF2α cause contraction of the longitudinal muscle of the gut and cause diarrhea. PGI2 and PGF2α cause contraction of the circular muscle of the gut. PGE2 inhibits gastric secretion PGs are cyto-protective, some times combined with NSAIDs in order to reduced its ulcerogenic effects of NSAIDs Pharmacological actions of PGs 7.Effect on bone PGD2 increases bone turnover. PG is involved in bone loss in post-menopausal women  Pharmacological actions of PGs 8.Effect on eyes: PGF2α decreases intra-ocular pressure (IOP),so some ophthalmic preparations that contain PGs use in treatment of glaucoma. Pharmacological actions of PGs 9.Effect on CNS Neurotransmission: PGs inhibit the release of Nor-adrenalin from post-ganglionic sympathetic nerve endings. Neuro-endocrine: PGs promote the secretion of prolactin , GH, TSH, ACTH, and gonadotropin hormones..  Pharmacological actions of PGs 10.Fever : PGE1 and PGE2 when are injected into cerebral ventricles , they increase the body temperature. PGD2 when infused into cerebral ventricles produces sleepiness Pharmacological actions of PGs 11.Cancer There has been significant interest in the role of prostaglandins in particular the COX-2 pathway, in the development of malignancies. Pharmacologic inhibition of COX-2 restrains tumor formation in models of colon cancer. Aspirin as an example  Clinical uses of PGs preparations A. Indications of cardiovascular system 1. Pulmonary hypertension 2. Raynaud disease 3. Preventing platelets aggregation 4. Maintain patency of ductus arteriosus. B. Indications of Respiratory system 1. Relieve of bronchiospasm. C. Indications of gastrointestinal tract 1. Gastric ulcer. 2. NSAIDs induce gastric ulcer  Clinical uses of PGs preparations D. Indications of immune system 1.Reduce organ transplantation rejection. E.Ophthalmic indications 1. Treatment of glaucoma F. Indications of female reproductive system 1. Facilitates labor if given near full term. 2. Terminate pregnancy at any stage G. Indications of male reproductive system 1. Erectile dysfunction  Side effects of PGs 1. GIT upset 2. headache , dizziness 3. bronchiospasm , allergic reactions 4. hypo or hypertension 5. uterine laceration  Synthetic Analogues of PGs 1.Alprostadil (PGE1) used in treatment of impotence and maintain the ductus arteriosus patent in some neonates awaiting cardiac surgery 2.Epoprostenol,Prostacyclin (PGI2) used in treatment of pulmonary hypertension 3.Misoprostol (PGE1) used in preventing peptic ulcer, and can be used in combination with mifepristone for terminating early pregnancies 4.Latanoprost (PGF2α), Travoprost and bimatoprost used in treatment of open-angle glaucoma. 5.Iloprost (PGI2) used in treatment of PAH. 6.Treprostinil(PGI2) used in treatment of PAH