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Diuretics & anti diuretics

Diuretics & Anti-Diuretics drugs

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Diuretics & anti diuretics

  1. 1. DIURETICS & ANTI-DIURETICS AGENT By:- Dr. Manish Pal Singh, Associate Professor 1 AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA
  2. 2. General Physiology of Urine Formation ❑ The main function of kidneys to maintain a homeostasis balance of electrolytes and water. ❑ Urine formation starts from glomerular filtration (g.f.). ❑ Normally 180 L of fluid everyday filtered; but more than 99% of the g.f. is reabsorbed in the tubules , only about 1.5L urine is produced in 24 hr. ❑ The diuretics mainly inhibit the reabsorption at tubular side. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 2 Source*-http%3A%2F%2Fpathwaymedicine.org%2Furine-formation-mechanisms
  3. 3. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 3 ➢Each kidney contains approximately one million nephrons and is capable of forming urine independently. The nephrons are composed of glomerulus, proximal tubule, loop of henle, distal tubule. Loop of Henle Source*-https%3A%2F%2Fwww.unmc.edu%2Felearning%2Fegallery%2Fthe-main-processes-of-the-nephron
  4. 4. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 4
  5. 5. Mechanism of Tubular Reabsorption ➢ It’s an energy dependent transmembrane pumps as well as channels in between the loose fitting cells of proximal tubule (PT). ➢ All Na+ that enters through cells via Na+K+ATPase-energised Na+-K+ antiporter. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 5Source*- l=https%3A%2F%2Fcourses.lumenlearning.com%2Fsuny- ap2%2Fchapter%2Ftubular-reabsorption-
  6. 6. Stages of Tubular Reabsorption AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 6 Site-4 (Distal Tubule {DT}) Site-3 (Cortical diluting segment of loop) Site-2 (Loop of Henle) Site-1 (PT)
  7. 7. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 7 Heart • Pumping action of heart control renal blood flow. • Relative dimensions of glomerular vessels. RAS • Distal Tubular reabsorption of Na+ & Secretion of K+/H+ • AT-II- effect on intracellular beds & Na+/H2O reabsorption. Prostaglandins & Atrial natriuretic factors (ANP) • PG’s- direct renin release & inhibits the action of anti- diuretic hormone (ADH) • Atrial natriuretic peptide produced by atrium & inducing ‘Natriuresis’ in response to salt & water overload. Regulation of Renal Function (GFR)
  8. 8. DIURETICS ❑ These are drugs which cause a net loss of Na+ & water in urine. ❑ They are popularly used in the management of hypertension as their used in edema. “Diuretics (“water pills”) are the drugs which increase the urine out put (or) urine volume” . Natriuresis- “Any drug when introduce into the body increases the out put of sodium ie., loss of sodium in urine”. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 8 The first oral diuretics ‘Chlorthiazide’ (1957)- Thiazide diuretics
  9. 9. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 9Source*- https%3A%2F%2Fwww.ctdt.co.in
  10. 10. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 10 Source*- https%3A%2F%2Fslideplayer.com
  11. 11. High Ceiling (Loop) Diuretics:- {Frusemide} ➢ These agents produce a peak diuresis much greater than observed with other commonly used diuretics. ➢ They act by inhibiting the luminal Na/K/2Cl symporter. ➢ It has broader dose response curve. ➢ It is more convenient for i.v. use. ➢ Its maximal natriuretic effect is much greater than that of other classes. ➢ The onset of action- i.v. (2-5 min); oral (20-40 min) & i.m (10-20 min). AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 11
  12. 12. Mechanism Of Action ✓ Loop diuretics (ferusemide) primarily target on ‘Site-II’ (thick AscLH). ✓ Where it is inhibit Na+-K+-2Cl- co transport. ✓ Its minor action component of action on PT. ✓ K+- excretion increase due to- high Na+ load reaching DT. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 12 Source*- https%3A%2F%2Fwww.youtube.com%2Fwatch%3Fv%3D5k5btYZTKhQ&psig
  13. 13. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 13 ➢It causes changes in renal & systemic hemodynamics. ➢It can causes increases Ca++ excretion as well as Mg++ excretion ➢Molecular action of it can bind with Cl- binding site of cotransporter pump protein to inhibit its transport function. Source*- http%3A%2F%2Ftmedweb.tulane.edu%2Fpharmwiki%2Fdoku.php%2Floop_diuretics
  14. 14. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 14 Indications:- ➢Edema- in cardiac; hepatic or renal. ➢Highly preferred in CHF ➢Acute pulmonary edema (LVF); following MI ➢Cerebral edema ➢Hypertension ➢Hypercalcaemia Source*- https://encrypted-tbn0.gstatic.com/images?
  15. 15. Thiazide Diuretics ❑ These drugs compete for the chloride binding site of the sodium/chloride symporter and inhibit the re-absorption of sodium &chloride. ❑ These are medium efficacy diuretics with primary ‘Site-III’ (in the cortical diluting segment or the early DT). ❑ As a result these drugs increase the concentration of Na and Cl in the tubular fluid and increase its excretion. ❑ Reduce blood volume decrease G.F.R ❑ Decrease B.P. in hypertensives. ❑ Thiazide reduce urine volume in both pituitary origin as well as renal DI (diabetic insipidus) by an unknown mechanism. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 15
  16. 16. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 16 ➢They bind to specific receptors located on the luminal membrane. ➢It can cause increased amount of Na+ is presented to distal nephron; urinary K+- excretion is increased in parallel to the natriuretic response. Source*- https%3A%2F%2Fwww.memorangapp.com
  17. 17. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 17 ADR’s:- •Potassium depletion •Hyperuricemia •Hypercalcemia and hypomagnesemia •Nausea, vomiting ,diarrhea •Ortho static hypotension •Inhibition of insulin secretion Indications:- ✓DI- they reduce urine volume ✓Hypercalciuria ✓Edema ✓Reduces the intra ocular pressure- used in treatment of Glaucoma. Source*- https%3A%2F%2Fwww.indiamart.com%2Fproddetail%2Fhydrochlorothiazide-ip-25mg-21465357162.html
  18. 18. Comparison Between Loop Diuretics ➢ They inhibit Na/K/2Cl symporter. ➢ Acts at thick ascending loop of henle. ➢ These are Ca+ wasting drugs. ➢ They cause heavy diuresis. ➢ Para thyroid hormone independent Ca absorption. ➢ It can reabsorb 25% to 30% of Na. Thiazide Diuretics ➢ They act by inhibiting Na/Cl symporter. ➢ Acts at distal convoluted tubule. ➢ These are Ca+ retaining drugs. ➢ They cause mild diuresis. ➢ Para thyroid hormone dependent Ca absorption. ➢ It can reabsorb 8% of Na. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 18
  19. 19. Carbonic Anhydrase (CAse) Inhibitors (Acetazolamide): ➢ CAse- is an enzyme which catalyses the reversible reaction H2O + CO2------- H2CO3. ➢ Transport in H+- ion secretion from tubule side, help to Na+ Reabsorption in tubular cells. ➢ Acetazolamide is a sulfonamide derivative which is a non competitive reversible inhibitor of “carbonic anhydrase enzyme”. ➢ Resulting slowing of hydration of CO2 - decreased availability of H+ to exchange with luminal Na+ through the Na+-H+ antiporter. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 19
  20. 20. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 20 CAs - enzyme is responsible for catalytic reversible hydration of carbon dioxide and dehydration of carbonic acid. The net effect is inhibition of HCO3- (with Na+) reabsoprtion in PT--- prompt but mild alkaline diuresis ensues. Source*- https%3A%2F%2Fwww.youtube.com
  21. 21. ➢ ADR’s:- ➢ Hypokalemia ➢ Acidosis ➢ Drowsiness ➢ Renal calculi. ➢ Nausea, loss of hearing, loss of appetite. ➢ Uses:- (Self limiting used as diuretics) ➢ Glaucoma ➢ To alkaline urine- for urinary tract infection or to promote excretion of certain acidic drugs. ➢ Epilepsy- in absence seizures ➢ Acute mountain sickness ➢ DIAMOX; IOPAR; SYNOMAX- (Brands) AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 21
  22. 22. Potassium Sparing Diuretics (Spironolactone):{Aldosterone Antagonist} ➢ These are either aldosterone antagonist or directly inhibit Na+ channels in DT & CD cells to indirectly converse K+. ➢ They act by inhibiting sodium reabsoprtion in the late distal tubule and thus indirectly spare potassium excretion. ➢ Spironolactone is a steroid ,chemically related to the mineralocorticoid aldosterone. ➢ Aldosterone, by binding to its receptor- {Aldosterone induced proteins- (AIPs)} in the cytoplasm increases expression &function of Na channel and sodium pump {K+ secretion}. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 22
  23. 23. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 23 ➢Competitive and reversible inhibition of the aldeosterone present in the cytoplasm of principal cells(located in late DCT and cortical CT). ➢Formation of inactive spironoloactone- receptor complex which cannot get traslocated into the nucleus to bind to DNA. ➢Failure to produce “aldosterone- induced proteins” which normally promote Na+ reabsoprtion via ENac and as a result of which K+ secretion via K+ channel is facillated. ➢Decreased Na+ reabsorption and decreased K+ secretion. Source*- https%3A%2F%2Fhealthjade.net%2Fpotassium-sparing- diuretics
  24. 24. ADR’s:- ▪ Gynaecomastia and impotence in male; hirsutism ▪ breast discomfort and menstrual irregularities in female. ▪ GI upset –can cause peptic ulcer. ▪ Hyperkalemia. Uses:- ▪ Fluid retention of hyperaldosteronism ▪ Resistant HTN (used only as adjuvant to thiazide to prevent hypokalemia). ▪ To counteract K+ loss due to thiazide and loop diuretics ▪ Hypokalemia and hypomagnesemia ▪ Heart failure AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 24
  25. 25. Osmotic Diuretics (Mannitol): ➢ Osmotic diuretics act on proximal tubule and also at loop of henle .where they prevent water reabsoprtion by increasing osmolality of tubular fluid. ➢ Mannitol is a nonelectrolyte of low molecular weight; freely filtered at the glomerulus & undergoes limited reabsorption ; therefore excellently suited to be used as osmotic diuretic. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 25 increase urine volume flow rate Decrease contact time between fluid and tubular epithelium Decrease Na+ reabsorption
  26. 26. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 26 Uses:- ▪Increased intracranial or intraocular tension(acute congestive ▪glaucoma,head injury,storke,etc.) ▪To maintain g.f.r. and urine flow in impending acute renal Failure ▪To counteract low osmolarity of plasma/e.c.f.due to rapid Haemodialysis. ADR’s:- ▪ It is contraindicated in acute tubular necrosis ▪ Anuria ▪ Pulmonary edema ▪ Acute LVF ▪ CHF ▪ Cerebral haemorrhage Source*- htpp/:OsmoseIt%2Fposts%2Fwhat-are-some-side-effects-of-osmotic-diuretics- share-your-answers-in-the-commen
  27. 27. Anti-Diuretics ➢ Antidiuretics ( inhibit the water excretion without affecting salt excretion) are drugs that reduce urine volume, particularly in diabetes insipidus(DI). AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 27 Anti-Diuretics Miscellaneous:- Indomethacin; Chlorpropamide ADH (Vasopressin) Thiazide diuretics
  28. 28. ADH {Anti-diuretics hormone}: ➢ ANTIDIURETIC HORMONE (ADH) is secreted by the posterior pituitary gland. ➢ It’s a nonpeptide secreted along with ‘Oxytocin’. ➢ The rate of ADH release governed by body hydration. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 28 ADH- release Contraction of e.c.f. volume Rise in plasma osmolarity
  29. 29. ADH-Receptors: AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 29 • Located on vascular & other smooth muscles, platelets etc. • Follow IP3/DAG- Ca+ release- ACTH release, vasoconstriction etc.V1 • Located primarily on the CD cells in the kidney • Regulate their water permeability- CAMP production • Its more sensitive to ADH than V1-receptors.V2 ADH-receptors- ‘G-protein coupled’- receptors
  30. 30. MAO- ADH (Kidney cells): ➢ ADH enhances water reabsorption by acting on the collecting duct. ➢ ADH activates the V2 receptors present on the cell membrane of the collecting duct and increases the water permeability of these cells. ➢ ADH causes vasoconstriction and raises BP mediated by V1receptors. ➢ Vasopressin is given parentally as injection of SC,IM,IV. ➢ When ADH is absent, CD cells remain impermeable to water--- dilute urine (produced by the diluting segments) is passed as such. ➢ Activation of V2- receptor by ADH– increased CAMP dependent protien kinase A- which promote “aquaporin-2” water channel containing vesicles. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 30
  31. 31. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 31 ➢The water permeability of CD cells is increased in proportion to the population of aquaporin-2 channels in the apical membrane at any given time. ➢While V1- receptors activation constricts vasa recta to diminish blood flow to inner medulla which will help in maintaining high osmolarity in this region and thus contributing to antidiuresis . Source*- https%3A%2F%2Fwww.qsstudy.com
  32. 32. Vasopressin Analogues:- ❑ Lypressin:- {20 IU, 10 IU-IM or SC or 20 IU diluted in 100-200 ml of dextrose solution and infused IV in 10-20 min}. ❑ Terlipressin:- {2mg, repeat 1-2 mg every 4-6hr} ❑ Desmopressin:- {IV or SC; 2-4Ug/day} AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 32 Uses:- ✓Diabetes insipidus of pituitary origin desmopressin is the preparation used. ✓It should be used lifelong. ✓Bleeding esophageal varices-ADH constricts mesenteric blood vessels (v1receptors ) and may help. ✓Before abdomonal radiography-expels gases from the bowel. ✓Hemophilia and von willebrand’s disease- ADH may release factor VIII and prevent bleeding. Source*- https%3A%2F%2F1.bp.blogspot.com
  33. 33. ADR’s& Contraindication of ADH- Analogues ▪ When used intranasally ADH can cause nasal irritation, allergy, rhinitis and atrophy of nasal mucosa's. ▪ Other effects include nausea, abdominal cramps and backache (due to constriction of the uterus). ▪ Patient suffering from vascular disease, especially disease of coronary arteries. ▪ V2- selectively desmopressin produces fewer adverse effects than vasopressin, lypressin or terlipressin. ▪ Its contraindicated in patients with ischemic heart disease. AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 33
  34. 34. Miscellaneous Anti-Diuretics: Chlorpropamide--- has a long duration of action oral hypoglycemic, found to reduce urine volume in DI of pituitary origin ➢ But not in renal DI is sensitize the kidney to ADH action its efficacy depends on small amount of the circulating home one. ➢ It is not active when ADH is totally absent. ➢ It also directly prone salt reabsorption in the ascending limb C-may contribute to its antidiuretic action. Carbamazepine--- is an antiepileptic anticonvulsant, drug which, reduces urine volume in DI of pituitary origin. ➢ It has been shown to stimulate ADH secretion. However it is not valuable in the treatment of DI. ➢ Contraindications- Abnormalities in liver function AGRA PUBLIC PHARMACY COLLEGE, ARTONI, AGRA, UP, INDIA 34

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