Loop diuretic

Loop diuretics are diuretics that act at the ascending limb of the loop of Henle in the kidney. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or chronic kidney disease. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function. Loop diuretics are diuretics that act at the ascending limb of the loop of Henle in the kidney. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or chronic kidney disease. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function. Loop diuretics are 90% bonded to proteins and are secreted into the proximal convoluted tubule through organic anion transporter 1 (OAT-1), OAT-2, and ABCC4. Loop diuretics act on the Na+-K+-2Cl− symporter (NKCC2) in the thick ascending limb of the loop of Henle to inhibit sodium, chloride and potassium reabsorption. This is achieved by competing for the Cl− binding site. Loop diuretics also inhibits NKCC2 at macula densa, reducing sodium transported into macula densa cells. This stimulates the release of renin, which through renin–angiotensin system, increases fluid retention in the body, increases the perfusion of glomerulus, thus increasing glomerular filtration rate (GFR). At the same time, loop diuretics inhibits the tubuloglomerular feedback mechanism so that increase in salts at the lumen near macula densa does not trigger a response that reduces the GFR. Loop diuretics also inhibits magnesium and calcium reabsorption in the thick ascending limb. Absorption of magnesium and calcium are dependent upon the positive voltage at the luminal side and less positive voltage at the interstitial side with transepithelial voltage gradient of 10 mV. This causes the magnesium and calcium ions to be repelled from luminal side to interstitial side, promoting their absorption. The difference in voltage in both sides are set up by potassium recycling through renal outer medullary potassium channel. By inhibiting the potassium recycling, the voltage gradient is abolished and magnesium and calcium reabsorption are inhibited. By disrupting the reabsorption of these ions, loop diuretics prevent the generation of a hypertonic renal medulla. Without such a concentrated medulla, water has less of an osmotic driving force to leave the collecting duct system, ultimately resulting in increased urine production. Loop diuretics cause a decrease in the renal blood flow by this mechanism. This diuresis leaves less water to be reabsorbed into the blood, resulting in a decrease in blood volume. A secondary effect of loop diuretics is to increase the production of prostaglandins, which results in vasodilation and increased blood supply to the kidney. The collective effects of decreased blood volume and vasodilation decrease blood pressure and ameliorate edema. Loop diuretics are highly protein bound and therefore have a low volume of distribution. The protein bound nature of the loop diuretic molecules causes it to be secreted via several transporter molecules along luminal wall of the proximal convoluted tubules to be able to exert its function. The availability of furosemide is high variable from 10% to 90%. The biological half-life of furosemide is limited by absorption from gastrointestinal tract into the bloodstream. The apparent half-life of its excretion is higher than the apparent half-life of absorption via oral route. Therefore, intravenous dose of furosemide is twice as potent as the oral route. However, for torsemide and bumetanide, their oral bioavailability are consistently higher than 90%. Torsemide has longer half life in heart failure patients (6 hours) when compared to furosemide (2.7 hours). Loop diuretics usually has a 'ceiling' effect where there is a maximum level of dosage where further increase in dosage will not increase the clinical effect of the drug. A dose of 40 mg of furosemide is equivalent to 20 mg of torsemide and 1 mg bumetamide.