DIURETICS

DIURETICS Diuretics are drugs that increase the rate of urine flow by acting on the kidney & producing a net loss of Na+ and water NEPHRON • Appr. 120 ml of ultrafiltrate is formed each minute, yet only 1 ml/min of urine is produced Greater than 99% of the glomerular ultrafiltrate is reabsorbed Appr. 65% of filtered solutes are reabsorbed in the proximal tubule The descending thin limb is highly permeable to water, yet its permeability to NaCl and urea is low • • • • The ascending thin limb (ATL) is permeable to NaCl and urea but impermeable to water The thick ascending limb actively reabsorbs NaCl but is impermeable to water and urea Approximately 25% of filtered solutes are reabsorbed in the loop of Henle, mostly in the thick ascending limb, which has a large reabsorptive capacity • • • The hypertonicity of the medullary interstitium plays a vital role to concentrate urine and is therefore a key adaptation necessary for living in a terrestrial environment In the presence of ADH, the collecting duct system is permeable to water Final adjustments in electrolyte composition are made, by the adrenal steroid, aldosterone in the collecting duct system • • RENAL PHYSIOLOGY Classification of diuretics A. High efficacy/high-ceiling/Loop diuretics/ Inhibitors of Na+K+2Cl - symport Furosemide, bumetanide, ethacrynic acid, torsemide B. Medium efficacy diuretics/ Inhibitors of Na+Clsymport Thiazides : chlorothiazide, hydrochlorothiazide Thiazide – like : chlorthalidone, metalazone, xipamide C. Low efficacy/weak diuretics     Carbonic anhydrase Inhibitors K+ sparing diuretics Osmotic diuretics Xanthines : theophylline Prototype: acetazolamide  Develpoed from sulfanilamide, after it was noticed that sulfanilamide caused metabolic acidosis and alkaline urine. CARBONIC ANHYDRASE INHIBITORS Acetazolamide, Dorzolamide, Brinzolamide inhibit both the membrane – bound and cytoplasmic forms of carbonic anhydrase ↓ complete abolition of NaHCO3 reabsorption in the proximal tubule & collecting duct ↓ rapid rise in urinary HCO3- excretion Mechanism of Action Mechanism of Action Other Actions  Decreases the rate of formation of aqueous humor and consequently reduces intraocular pressure Decreases the rate of formation of CSF  Adverse effects Acidosis Hypokalemia Calculus formation due to precipitation of calcium phosphate salts in an alkaline urine Drowsiness, paresthesia Contraindications Hepatic cirrhosis Hyperchloremic acidosis or severe chronic obstructive pulmonary disease Therapeutic Uses      Glaucoma Acute mountain sickness Familial periodic paralysis - hyperkalemia Metabolic alkalosis Epilepsy – H2CO3 is split into water and co2. this CO2 decreases the threshold of seizures OSMOTIC DIURETICS      Freely filtered at the glomerulus Undergo limited reabsorption by renal tubule Relatively inert pharmacologically Non – metabolizable Increase plasma osmolarity Four currently available osmotic diuretics Mannitol, glycerin, isosorbide, urea Site of action: proximal tubule , (main)loop of Henle collecting tubule MECHANISM OF ACTION acts by an osmotic effect in the tubules As non-reabsorbable solutes ↓ limits the osmosis of water into the interstitial space → ↑s urine volume • • ↑s RBF → reduces medullary hypertonicity → reduced salt reabsorption In general, osmotic diuretics increase the urinary excretion of nearly all electrolytes including Na+, K+, Ca 2+, Mg2+, Cl-, HCO3& phosphate extracts water from intracellular compartments, and the extracellular fluid volume becomes expanded    Therapeutic Uses In impending renal failure (e.g shock ) Acute attacks of glaucoma For short - term reductions in IOP (both preoperatively and postoperatively)    To reduce cerebral edema and brain mass (before and after neurosurgery) Head injury with  d intracranial pressure To produce forced diuresis in poisoning  Barbitol poisoning  Prophylaxix of renal failure  Mechanism: Drastic reduction in GFR casues dramatically increased proximal tubular water reabsorption and a large drop in urinary excretion  Osmotic diuretiics are still filtered under these conditions and retain an equivalent amount of water, maintaining urine flow  Adverse Effects   Headache, nausea, vomiting Loss of water in excess of electrolytes can cause hypernatremia and dehydration Contraindicated in  Anuria due to severe renal disease/ATN  Heart failure / acute LVF  Active cranial bleeding LOOP DIURETICS   High-ceiling diuretics Furosemide, bumetanide, ethacrynic acid, torsemide Mechanism of action: Blocks the Na+ - K+ - 2Cl - symporter in the thick ascending limb of the loop of Henle MECHANISM OF ACTION MECHANISM OF ACTION  Abolition of the transepithelial potential difference results in marked increase in the excretion of Ca2+ and Mg2+ Increases systemic venous capacitance and thereby decrease left ventricular filling pressure (before diuresis ensues) NSAIDs attenuate the diuretic response to loop diuretics, by preventing PG mediated increases in RBF   Adverse Effects  Hyponatremia,hypokalemia,hypomagnesemia hypocalcemia Ototoxicity (esp. ethacrynic acid) Hyperuricemia,hyperglycemia,hyperlipedemia Skin rashes, photosensitivity, paresthesias, bone marrow depression & g. i disturbances Dilutional hyponatremia     Contraindications    Severe Na+ and volume depletion Hypersensitivity to sulfonamides Anuria Drug interactions     Aminoglycosides Digitalis glycosides NSAIDs, cisplatin, lithium Propranolol, Probenecid Therapeutic Uses     Acute pulmonary edema Chronic congestive heart failure Hypertension To induce a forced diuresis in drug overdose Hypercalcemia   Edema associated with chronic renal insufficiency     ARF Cerebral edema Blood transfusion Edema and ascites of liver cirrhosis THIAZIDES      Sulfonamides, benzothiadiazine derivatives Primary site of action : early part of DCT Inhibit the Na+ Cl - symporter Moderately efficacious Decrease Ca2+ excretion  Prototype drug : hydrochlorothiazide MECHANISM OF ACTION MECHANISM OF ACTION Adverse Effects      Extracellular volume depletion, hypotension Hypokalemia,hyponatremia,hypomagnesemia Hypercalcemia,hyperuricemia,hyperlipedemia Metabolic alkalosis Decreased glucose tolerance Therapeutic Uses Edema associated with  Heart (congestive heart failure)  Liver (hepatic cirrhosis)  Renal (nephrotic syndrome chronic renal failure, acute glomerulonephritis) Hypertension  Calcium nephrolithiasis   Nephrogenic diabetes insipidus ! K+ SPARING DIURETICS o Triamterene, Amiloride, Spironolactone o Site of action: principal cells in the late distal tubule and collecting duct Blocks renal epithelial Na+ channels Decreases cation secretion o o MECHANISM OF ACTION MECHANISM OF ACTION Adverse Effects o Hyperkalemia o Nausea, vomiting, diarrhea, headache, leg cramps, and dizziness Contraindicated in patients with / on o Renal failure o ACE inhibitors Therapeutic Uses Major utility is in combination with other diuretics to o Prevent hypokalemia & o To augment the diuretic & antihypertensive response Amiloride – Li+ - induced nephrogenic diabetes Insipidus Improves mucociliary clearance in cystic fibrosis Spironolactone : Aldosterone antagonist Site of action : epithelial cells in the late distal tubule and collecting duct Mechanism of Action competitively inhibit the binding of aldosterone to the mineralocorticoid receptor ↓ Inactivaton of the Na+ channels Adverse Effects o o Life - threatening hyperkalemia gynecomastia, impotence, decreased libido, hirsutism, deepening of the voice & menstrual irregularities GI effects - diarrhea, gastritis, gastric bleeding, peptic ulcers o o CNS - drowsiness,lethargy,ataxia,confusion, headache Therapeutic Uses o Edema and hypertension (with thiazide / loop diuretics) o Refractory edema associated with secondary aldosteronism (cardiac failure, hepatic cirrhosis, nephrotic syndrome, severe ascites) (diuretic of choice in patients with hepatic cirrhosis) Primary hyperaldosteronism (adrenal adenomas or bilateral adrenal hyperplasia) o