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Low efficacy diuretics Dr. Iman - Potassium – sparing diuretics:Act on the collecting tubule. Inhibit both Na+ reabsorption and K+ excretion.. Used in combination with thiazide to Rx hypertension (major use). No exogenous K+ is needed. Monitor K+ level. A – Spironolactone :Mechanism of action:- - Synthetic steroid that antagonizes aldosterone at intracellular cytoplasmic receptor sites. - Spironolactone – receptor complex is inactive and it will prevent translocation of the receptor complex into the nucleus of the target cell, thus, it can not bind to DNA. - The result is a failure to produce proteins that are normally synthesized in response to aldosterone. - These proteins normally stimulate Na+ / K+ exchange sites of the collecting tubule. - Thus, a lack of mediator proteins prevents Na+ reabsorption and K+ and H+ secretion. - In patient of high aldosterone levels in blood vessels → ↑ Na + retention. - Spironolactone → ↑ Na+ excretion and retention of K+. - Spironolactone effects depend on renal PGs synthesis. - Eplerenone is a new aldosterone receptor antagonist with action comparable to spironolactone but may have less endocrine effects Therapeutic uses:a)Diuretic → low efficacy in mobilizing Na+. - Advantage of retention K+. - It is given in conjunction with thiazide or loop diuretics to prevent K+ excretion. - Diuretic of choice in hepatic cirrhosis. b) Secondary hyperaldosteronism, spironolactone is the only K+ sparing diuretic that used alone to induce net negative salt balance as in nephrotic syndrome & liver cirrhosis . c) Heart failure → prevents the remodeling that occurs as compensation for progressive failure particularly in those with reduced ejection fraction. . d) In states of mineralocorticoid excess due to primary hypersecretion {Conn's syndrome, ectopic ACTH production}. . e) Resistant hypertension: often responds well to aldosterone antagonists.This effect can be seen in those with or without elevated aldosterone levels. f. Ascites: Accumulation of fluid in the abdominal cavity (ascites) is a common complication of hepatic cirrhosis. g. Polycystic ovary syndrome: . It blocks androgen receptors and inhibits steroid synthesis at high doses, thereby helping to offset increased androgen levels seen in this disorder Pharmacokienetics:- Spironolactone and eplerenone Completely absorbed orally. - Strongly bound to plasma proteins. Rapidly converted to an active metabolite, Canrenone which has mineralocorticoid blocking activity . Spironolactone is a potent inhibitor P-glycoprotein Ion transport pathways across the luminal and basolateral membranes of collecting tubule and collecting duct cells. Inward diffusion of Na+ via the epithelial sodium channel (ENaC) leaves a lumen-negative potential, which drives reabsorption of Cl– and efflux of K+. (R, aldosterone receptor.) - - Adverse effects:Gastric upsets (frequent), can cause peptic ulcer. Gynecomastia in male and menstrual irregularities in female (similar to sex steroid structures) → acts at receptors in other organs. So it will not be given in large doses on a chronic basis. At low doses, can be used chronically with few side effects. Hyperkalemia, nausea, lethargy and mental confusion . In patients with Addison disease, no diuretic effects Potassium-sparing diuretics should be used with caution with other medications that can induce hyperkalemia, such as angiotensin-converting enzyme inhibitors and potassium supplements. B – Triamterene and Amiloride Block Na+ transport channels → ↓ Na+ / K+ exchange. Their action dose not depend on the presence of aldosterone. They have diuretic effect in primary adrenal insufficiency (Addison disease). Low efficacy. Used in combination with other diuretics. S.E. is leg cramps. ↑ Uric acid and K+ retention. Carbonic anhydrase inhibitors - Inhibit the enzyme carbonic anhydrase (C.A) in the proximal tubular epithelium. - They are much less efficacious than thiazides or loop diuretics. Acetazolamide:- Mechanism of action:Inhibits C.A enzyme in the cytoplasm and other apical membrane of the proximal tubular epithelium. C.A catalyzes the reaction of CO2 and H2O → H2CO3, which ionizes to H+ and HCO3-. The decreased ability to exchange Na+ for H+ in the presence of acetazolamide → mild diuresis. HCO3- is retained in the lumen, ↑ PH of urine. The loss of HCO3- → hyperchloremic metabolic acidosis. And ↓ efficacy after several days of Rx due to reduction in HCO3- stores (pool). Pharmacokinetics:- - Oral, once / day, secreted by proximal tubules. Therapeuticuses:1. Rx of glaucoma. - The common use for acetazolamide is to reduce high intraocular pressure of chronic open angle glaucoma by decreasing the production of aqueous humor, probably by blocking C.A in the ciliary body of the eye. - Pilocarpine is preferred for acute attack because of its immediate action. - Dorzolamide, Brinzolamide are topical C.A inhibitors, cause no systemic effects. 2. Mountain sickness - Less commonly, acetazolamide used prophylactically in Rx of acute, mountain sickness among healthy unacclimatised individuals who rapidly ascend above 10,000 feet. (Mountain climbers). - Acetazolamide prevents weakness, breathlessness, dizziness, nausea, and cerebral as well as pulmonary edema characteristic of the syndrome due to hypoxia and alkalosis, and to ↑ respiratory drive and maintain arterial O2 tension. - Give Rx once daily for 5 days at night before the ascent - Dexamethasone can also be used. 3. Urinary alkalinization - To enhance the excretion of uric acid, cyctine (insoluble in acid urine) and weak acids like aspirin,& in cystinuria. - The effect is of short duration of action and need bicarbonate infusion to maintain continuing bicarbonate diuresis. 4. Reduction of total body bicarbonate stores - In cases of chronic metabolic alkalosis which resist other diuretics. - And in posthypercapnic metabolic alkalosis. . 5. In some forms of hypokalemic periodic paralysis with some antiepileptics. Therefore used as adjuvant to antiepileptic Rx(open potassium&calcium channels). S.E.:- Metabolic acidosis. - K+ depletion. - Renal stone formation due to phosphateuria, or hypercalciuria, because calcium is insoluble in alkaline urine. - Drowsiness, paresthesia, after large doses ,taste alteration and hypersensitivity reaction. Contraindication:In liver cirrhosis because, alkalinization of urine will ↓ urinary trapping of NH4+ → hepatic encephalopathy. 1. - - Agents that enhance waterexcretion Osmotic diuretics:Are small molecular weight hydrophilic substances that are filtered by the glumerulus but not reabsorbed by the renal tubules → ↑ osmolarity of urine. They prevent reabsorption of water (and by complex mechanisms, Only a small amount of additional salt may also be excreted), Act principally in the proximal convoluted tubule and probably in the descending loop of Henle. The result is that urine volume ↑ according to the load of osmotic diuretics. e.g. Mannitol. (is not absorbed when given orally and should be given intravenously). They ↑ water excretion and not preferred in cases with Na+ retention. Uses:-They are used to maintain urine flow following acute toxic ingestion of substances capable of producing acute renal failure. To ↓ intracranial pressure. Acute renal failure due to shock, drug toxicities, and trauma.. To ↓ intraocular pressure. Mannitol present in extracellular space will extract water from the cells causing hyponatremia (until diuresis occurs ),leading to expantion of extacellular water, so it is contraindicated in pulmonary odema & congestive heart failure Dehydration on the other hand can occur if water is not replaced. 2. ADH antagonists:- ADH (vasopressin) acts on: V1 receptors on vascular smooth muscle liver and other tissues, V2 receptors which is coupled to adenylyl cyclase, and regulate opening of the water channels (aquaporin) in cells of the renal collecting ducts. - In the absence of ADH, C.D is impermeable to water → diluted urine. - ADH secretion is regulated by serum osmolarity (↑ osmotic pressure of blood and by drugs like nicotine → ↑ ADH secretion, ↓ osmotic pressure, and alcohol → ↓ ADH secretion). - Some tumors like oat – cell lung cancer can make vasopressin or called ADH – like peptide → SIADH – syndrome of inappropriate ADH secretion → H2O retention. - ADH antagonists are useful to induce water diuresis e.g.:1) Li+ salts (their levels in blood must be monitored closely). 2) Tetracycline derivative – demeclocycline. They inhibit ADH effects at the collecting tubule by reducing the formation of cAMP in response to ADH and interfere with the actions of cAMP in the collecting tubule cells. Uses:1. SIADH. 2. Other cases of elevated ADH. E.g.in response to ↓ effective circulating blood volume e.g. heart failure, liver disease and as for SIADH, H2O restriction is the Rx of choice and if it has failed → demeclocycline may be considered. Toxicity:1. Nephrogenic diabetes insipidus: Check serum Na+ level closely, otherwise SIADH is replaced by nephrogenic D.I and hypernatremia → Rx by thiazides or amiloride. 2. Renal failure: By Li+ salts and demeclocycline. Li+ → chronic interstitial nephritis . 3.Others → due to Li+ therapy → cardiotoxicity, thyroid dysfunction, leukocytosis, mental obtundation and tremulousness. - Demeclocycline should be avoided in liver disease.