ANTIDIURETICS.pptx FIFTH SEMESTER B.PHARM

PHARMACOLOGY II V SEM B.PHARM KUHS

1. ANTIDIURETICS NEETHU IS ASSISTANT PROFESSOR DEPARTMENT OF PHARMACOLOGY EZHUTHACHAN COLLEGE OF PHARMACEUTICAL SCIENCES

2. Antidiuretics (more precisely ‘anti- aquaretics ’, because they inhibit water excretion without affecting salt excretion) are drugs that reduce urine volume, particularly in diabetes insipidus (DI) which is their primary indication. Antidiuretics are medications that preserve the water content of the body by reducing urination. PARADOXICAL REACTION

3. ANTIDIURETIC HORMONE (Arginine Vasopressin—AVP) The human antidiuretic hormone (ADH) is 8-arginine vasopressin (AVP), which is a nonapeptide secreted by posterior pituitary (neurohypophysis) along with oxytocin ADH (Vasopressin) receptors These are G protein coupled cell membrane receptors; two subtypes V1 and V2 have been identified V1 Receptors All vasopressin receptors except those on renal collecting duct (CD) cells, thick ascending limb of loop of henle (TAL) cells and vascular endothelium are of the V1 type. These are further divided into V1a and V1b subtypes: V1a receptors are present on vascular smooth muscle (including that of vasa recta in renal medulla), uterine and other visceral smooth muscles, interstitial cells in renal medulla, cortical CD cells, adipose tissue, brain, platelets, liver, etc. The V1b receptors are localized to the anterior pituitary, certain areas in brain and in pancreas.

4. The V1 receptors function mainly through the phospholipase C–IP3/DAG pathway—release Ca2+ from intracellular stores—causing vasoconstriction ,visceral smooth muscle contraction, glycogenolysis, platelet aggregation, ACTH release, etc. These actions are augmented by enhanced influx of Ca2+ through Ca2+ channels as well as by DAG mediated protein kinase C activation which phosphorylates relevant proteins. V1 receptors, in addition, activate phospholipase A2—release arachidonic acid resulting in generation of PGs and other eicosanoids which contribute to many of the V1 mediated effects. V2 Receptors These are located primarily on the principal cells of collecting ducts (CDs) in the kidney regulate their water permeability through cAMP production. Some V2 receptors are also present on TAL cells which activate Na+K+2Cl¯ cotransporter.

5. Activation of V2 receptors increase urea permeability in CD Stimulate vasopressin regulated urea transporter Augment medullary hypertonicity Activation of v1 receptors Constrict vasarecta Diminish blood flow to inner medulla Antidiuretic effect

6. Blood vessels AVP constricts blood vessels through V1 receptors and increases peripheral resistance. Other actions Most visceral smooth muscles contract. Increased peristalsis in gut (especially large bowel), results in evacuation of bowels and expulsion of gases. Uterus is contracted by AVP acting on oxytocin receptors.. C NS Exogenously administered AVP does not penetrate blood-brain barrier. Uses A. Based on V2 actions (Desmopressin is the drug of choice) 1. Diabetes insipidus DI of pituitary origin -neurogenic) is the most important indication for vasopressin, but it is ineffective in renal (nephrogenic) DI, because kidney is unresponsive 2. Bedwetting in children and nocturia in adults 3. Haemophilia, von Willebrand’s disease

7. B. Based on V1 actions 1. Bleeding esophageal varices Vasopressin/ terlipressin often stop bleeding by constricting mesenteric blood vessels and reducing blood flow through the liver to the varices(Enlarged veins) , allowing clot formation. 2. Before abdominal radiography AVP/ lypressin has been occasionally used to drive out gases from bowel. A/E Nasal irritation,rhinitis,nausea,belching,backache,abdominal cramps

8. Vasopressin regulated urea transporter

9. This antidiuretic action results from three main effects of VP on principal cells of the collecting duct (CD) mediated by occupancy of peritubular V2 receptors. ( i ) Increase in water permeability along the entire CD (via AQP2). (ii) Increase in urea permeability in the terminal inner medullary CD (via UT-A1). (iii) Stimulation of sodium reabsorption, mainly in the cortical and outer medullary CD (via ENaC)-epithelial sodium channels. VP also acts on medullary vasculature (V1a receptors) to reduce blood flow to inner medulla without affecting blood flow to outer medulla

10. Rapid actions (1) Translocation of water channel containing vesicles (WCVs) and exocytotic insertion of aquaporin 2 water channels into the apical membrane of principal cells of collecting ducts. This is the primary action responsible for antidiuresis. (2) Inhibition of endocytotic removal of aquaporin 2 channels from the apical membrane . (3) Activation of vasopressin regulated urea transporter (VRUT) at apical membrane of collecting ducts in the inner medulla. (4) Translocation of Na+K+2Cl¯ cotransporter to the luminal membrane of cells in thick ascending limb of loop of Henle (TAL). (5) Activation of Na+K+2Cl¯ cotransporter in TAL cells. (6) V1a receptor (V1aR) mediated vasoconstriction of vasa recta Long-term actions (7) Gene mediated increased expression of aquaporin 2 channels in collecting duct cells. (8) Gene mediated increased expression of Na+K+2Cl¯ cotransporter in TAL cells. PKA—cAMP dependent protein kinase.