Antidiuretics.pptx based on goodman and gilmans book

Antidiuretics slide based on goodman &Gilmans

1. ANTIDIURETICS Dr.Swati Rai Assistant Professor ASMC,SULTANPUR,UP.

2. ANTIDIURETICS Antidiuretics are drugs that reduce urine volume, particularly in diabetes insipidus Also called ‘Anti- aquaretics ’ because they inhibit water excretion

3. CLASSIFICATION OF ANTIDIURETIC 1. Antidiuretic hormone : Vasopressin (ADH), Desmopressin, Lypressin , Terlipressin 2. Natriuretics : Thiazide, Amiloride 3. Miscellaneous : Carbamazepine, Chlorpropamide, Indomethacin

4. ANTIDIURETIC HORMONE ( Argenine Vasopressin-AVP) It is a nonapeptide secreted by posterior pituitary (neurohypophysis) along with oxytocin Synthesized in the hypothalamic (supraoptic and paraventricular) nerve cell bodies They are transported down the axons to the nerve endings in the median eminence and pars nervosa

5. ANTIDIURETIC HORMONE Osmoreceptors are present in : - Hypothalamus - Hepatic portal system sense ingested salt and release ADH Volume receptors are present in : - Left atrium - Ventricles - Pulmonary veins regulate the rate of ADH release

6. ADH ( Contd …) Impulses from baroreceptors and higher centers on nuclei reduce ADH synthesis and affect its release The two main physiological stimuli for ADH release are 1) Rise in plasma osmolarity 2) Contraction of e.c.f . volume

7. ADH ( Contd …) Several neurotransmitters, hormones modify ADH secretion :- 1) Angiotensin II, Prostaglandin, neuropeptide Y, Ach increase ADH release 2) GABA, Atrial natriuretic peptide (ANP) decrease ADH release

8. ADH ( Contd …) The human ADH is 8-arginine-vasopressin (AVP) 8-lysine-vasopressin ( lypressin ) is found in swine and has been synthetically prepared

9. ADH receptors ( Contd …) 1) These are G- protein coupled cell membrane receptors 2) Two subtypes i ) V 1 receptors - V 1a receptor - V 1b receptor ii) V 2 receptors

10. ADH receptors ( Contd …) I) V 1 receptors :- - V 1a receptors are present on :- 1) Vascular smooth muscle (including that of vasa recta in renal medulla) 2) Uterine and other visceral smooth muscles

11. ADH receptors ( Contd …) 3) Interstitial cells in renal medulla 4) Cortical CD cells, adipose tissue, brain, platelets, liver - V 1b receptors ( Now known as V 3 receptor) are present on : 1) Anterior pituitary 2) Certain areas in brain 3) Pancreas

12. ADH receptors ( Contd …) V1 receptors function mainly through i ) Phospholipase C–IP3/DAG pathway release Ca 2+ from intracellular stores Vasoconstriction, visceral smooth muscle contraction, glycogenolysis, platelet aggregation, ACTH release

13. ADH receptors ( Contd …) ii) A ctivate phospholipase A2 Release arachidonic acid generation of PGs and eicosanoids

14. ADH receptors ( Contd …) V 2 Receptors: located on 1) Principal cells of collecting duct (CD) in kidney - regulate water permeability through cAMP production 2) AscLH cells which activate Na + K + 2Cl¯cotransporter 3) Endothelium of blood vessels causes vasodilation

15. ACTIONS OF VASOPRESSIN Kidney a) AVP acts on the collecting duct (CD) principal cells to increase their water permeability— water from the duct lumen diffuses to the Interstitium b) When AVP is absent, CD cell remain impermeable to water – dilute urine is passed

16. c) MOA :- V 2 type ADH receptor present on collecting ducts activation of these receptor increases cAMP activation of cAMP dependent protein kinase A Phosphorylation of protein which promote exocytosis of ‘aquaporin 2’ water channel containing vesicle More aqueous channel get inserted into apical membrane

17. MECHANISM OF ACTION OF VASOPRESSIN Source: K.D. Tripathi (8 th edition)

18. ACTIONS ( Contd …) 2) Blood vessels AVP constricts blood vessels through V1 receptors and can raise BP (hence name vasopressin), but much higher concentration is needed than for maximal antidiuresis Source: K.D. Tripathi (8 th edition)

19. ACTIONS ( Contd …) c) Other actions: 1) UTERUS : is contracted by AVP acting on oxytocin receptors 2) CNS : i ) Exogenously administered AVP does not penetrate blood brain barrier ii) it is now recognized as a neurotransmitter and regulate body temperature

20. ACTIONS ( Contd …) 3) CVS : AVP induces i ) Platelet aggregation ii) Release coagulation factor VIII and von Willebrand’s factor from vascular endothelium through V 2 receptors

21. PHARMACOKINETICS OF VASOPRESSIN AVP is inactive orally because it is destroyed by trypsin It can be administered by any parenteral route or by intranasal application The peptide chain of AVP is rapidly cleaved enzymatically in many organs, especially in liver and kidney Plasma t½ is short ~25 min

22. VASOPRESSIN ANALOGUES 1) Lypressin : It is 8-lysine vasopressin Acts on both V 1 and V 2 receptors and has longer duration of action (4–6 hours) It is being used in place of AVP—mostly for V 1 receptor mediated actions Doses :- 10 IU i.m. , 20 IU in 100-200 ml dextrose solution and infused i.v. over 10- 20 min

23. ANALOGUES ( Contd …) 2) Terlipressin Synthetic prodrug of vasopressin is specifically used for bleeding esophageal Varices Produce less severe adverse effects than lypressin Doses :- 2 mg i.v. , repeat 1-2 mg every 4-6 hours

24. ANALOGUES ( Contd …) 3) Desmopressin ( dDAVP ) This synthetic peptide is a selective V 2 agonist More potent antidiuretic than AVP (12 times) Desmopressin is the preparation of choice for all V 2 receptor related indications Dose : Intranasal :- - Adult :10 – 40 µg/day in 2- 3 divided dose,

25. ANALOGUES ( Contd …) - Children : 5 – 10 µg at bed time ( for bed wetting) Parenteral ( s.c or i.v. ) :- 2-4 µg/day in 2- 3 divided dose

26. USES OF VASOPRESSIN A) Based on V 2 actions 1) Diabetes insipidus 2) Bedwetting in children and nocturia in adults 3) Hemophilia, von willebrand’s disease

27. USES ( Contd …) B) Based on V1 actions 1) Bleeding esophageal varices :- Vasopressin/ terlipressin stop bleeding by constricting mesenteric blood vessels and reducing blood flow through the liver to the varices, allowing clot formation 2) Before abdominal radiography :- AVP/ lypressin has been occasionally used to drive out gases from bowel

28. ADVERSE EFFECT OF VASOPRESSIN Adverse effect are mainly V 2 receptor mediated On local application : Nasal irritation, congestion, rhinitis, epistaxis Systemic side effect : nausea, abdominal cramps, urge to defecate, backache in female Precipitate angina by constricting coronary vessels

29. CONTRAINDICATION OF VASOPRESSIN Ischemic heart disease Hypertension Chronic nephritis

30. VASOPRESSIN ANTAGONISTS I) Tolvaptan: 1) Orally active nonpeptide selective V 2 receptor antagonist 2) Used for treatment of hyponatraemia due to CHF, liver Cirrhosis or SIADH 3) Side effect : - Thirst - Dry mouth 4) T 1/2 : 6- 8 hours

31. ANTAGONISTS ( Contd …) II) Mozavaptan : (V 2 selective antagonist) III) Conivaptan (V 1a +V 2 antagonist)

32. THANK YOU