Antidiuretics
- 1. Antidiuetics
- 2. 1. VASOPRESSSIN • Antidiuretic hormonev ( ADH) , Arginine vasopressin ( AVP) • Nonapeptide • Posterior pitiutary( source) Cystein at 1 and 6 position and the disulfide bond is essential for its Antidiuretic activity.
- 3. REGULATION OF SECRETION • STIMULUS: MAJOR • Increase in PLASMA OSMOLALITY MINOR • Severe hypovolemia/hypotension • Certain endogenous hormones / neurotransmitters • Pharmacologic agents
- 4. OSMOREGULATION Subfornical organ, organum vasculoasm, preoptic nucleus (osmoreceptors) Supraoptic N.(SON) + Paraventricular N.(PVN) (synthesis) Transported via axons to posterior pitutiary for release
- 5. Physiological effects of ADH 1.↑ BP due to vasoconstriction ( V1a) 2.↓ urine output ( water reabsorbtion) 3. ACTH from anterior pitiutary 4. ↓ sweating
- 7. VASOPRESSINRECEPTOR CHARACTERISTICS V 1a V 1b ( V 3) V2 LOCATION Vascular & smooth muscle, platelets, hepatatocytes anterior pitiutary CD cells of kidney, vascular endothelium FUNCTION Vasoconstriction , platelet aggregation , glycogenolysis ACTH release Antidiuretic action MECHANISM Release of ca+2 by PLC / IP3 – DAG pathway same as V1a ++ of adenyl cyclase
- 9. ADH receptor agoinst VASOPRESSIN: • t1/2 -20 min • V1/ V2- non selective • route : parentral/ intranasal • orally: inactivated by trypsin
- 10. Contd.... DESMOPRESSIN: • t1/2 -2 hr • Action : 10 hr • V2 selective • Route : parentral/ nasal/ oral 15 times more potent then vasopressin
- 11. THERAPEUTIC USES V1 receptor action: 1. Bleeding oesophageal varices: • Terlipressin • V1 receptor → vasoconstriction of mesentric vessel • Dose : 2 mg → 1 mg / 6 hrly i.v → bleeding stop (max 72 hr)
- 12. Contd.. 2. Contraction of intestinal smooth muscle : Postoperative ileus Intestinal gas before abdominal radiography 3. Portal HT : ↓ haemorrhage during surgery 4. Acute haemorrhagic gastritis
- 13. V2 receptor action 1. Diabetes insipidus : 2 types – CENTRAL DI – deficiency of ADH – NEPHROGENIC DI –non functional ADH receptor not responsive to ADH Symptoms:- – Polyuria – kidneys do not conserve water so large amount of dilute urine is excreted. – Polydipsia
- 14. CONTD.... Central DI : Desmopressin • Dose : oral- 100 microg TDS : nasal -10-40 microgram / day :1-4 microgram/day ( i.v , i.m, s.c) Nephrogenic DI : – Thiazides – Carbamazepine – Amiloride
- 15. CONTD... 2.Primary noctural enuresis : • Intranasal desmopressin • Fluid restriction Dose : oral -200-400 microgram at bed time : nasal 20-40 microgram 3. Post – lumbar puncture headache
- 16. Contd... 4. von Willebrand Disease:- Desmopressin increase von willebrand factor and factor VIII & ↓ the Bleeding Time. Dose : 0.3-0.4 microgm/ kg slow i.v ( 15-30 min)
- 17. Adverse effects of ADH agonist V1 receptor ( vasoconstriction ) V2 receptor Facial pallor Fluid retention & water intoxication Nausea , abdominal cramps, urge to defecate Dilutional hyponatraemia Angina Intranasl- ulceration & rhinits C/I – in HT & I HD Allergy- urticaria & pruritis Vasopressin, terlipressin desmopressin
- 18. ADH receptor antagonists Why were antagonists developed? 1. To counteract V1a receptor mediated effects when TPR ↑↑ 2.To counteract V2 receptor mediated effects when there is excessive reabsorption of water. 3. V1a / V2 combination- diseases associated with ↑ TPR & fluid retention like CHF.
- 19. VAPTANS( non –peptide ADH receptor antagonist) V1a selective Relcovaptan V2 selective Lixivaptan, Mozavaptan, Tolvaptan V1a / V2 selective Conivaptan INDICATION: 1. Euvolaemic hyponatraemia( SIADH) 2. Water retention in CCF ( excess of ADH)
- 20. Vaptans (Contd...) Side effects: • Postural hypotension • Hypokalemia • Polydipsia • Polyuria
- 21. THANK YOU