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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 renal insufficiency. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function.
Mechanism of actionEdit
Loop diuretics are 90% bounded to proteins and is 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 NKCC1 at macula densa, reducing the re-absorption of sodium, potassium, and chloride. The low electrolyte reabsorption level 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.
The collective effects of decreased blood volume and vasodilation decrease blood pressure and ameliorate oedema.
Loop diuretics is highly protein bound, therefore, its volume of distribution is limited. 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.
Loop diuretics are principally used in the following indications:
- Heart failure - Giving 2.5 times of previous oral dose twice daily for those with acute decompensated heart failure is a reasonable strategy. However, daily assessment of clinical response is needed to adjust the subsequent doses.
- oedema associated with liver cirrhosis, kidney impairment, nephrotic syndrome
- adjunct in cerebral/pulmonary oedema where rapid diuresis is required (IV injection)
On the other hand, in critically ill patients with acute renal failure, loop diuretics do not appear to reduce mortality, reduce length of intensive care unit or hospital stay, or hasten any recovery of renal function.
A systematic review by the Cochrane Hypertension group assessing the anti-hypertensive effects of loop diuretics found only a modest reduction in blood pressure compared to placebo; the review highlights the need for more randomized control trials to be made available in order to construct a furnished assessment.
Diuretic resistance is defined as failure of diuretics to reduce fluid retention (can be measured by low urinary sodium) despite using the maximal dose of drugs. There are various causes for the resistance towards loop diuretics. After initial period of diuresis, there will be a period of "post-diuretic sodium retention" where the rate of sodium excretion does not reach as much as the initial diuresis period. Increase intake of sodium during this period will offset the amount of excreted sodium, and thus causing diuretic resistance. Prolonged usage of loop diuretics will also contributes to resistance through "braking phenomenon". This is the body physiological response to reduced extracellular fluid volume, where renin-angiotensin-aldosterone system will be activated which results in nephron remodelling. Nephron remodeling increases the number of distal convoluted cells, principle cells, and intercalated cells. These cells have sodium-chloride symporter at distal convoluted tubule, epithelial sodium channels, and chloride-bicarbonate exchanger pendrin. This will promote sodium reabsorption and fluid retention, causing diuretic resistance. Other factors includes gut oedema which slows down the absorption of oral loop diuretics. Chronic kidney disease (CKD) reduces renal flow rate, reducing the delivery of diuretic molecules into the nephron, limiting sodium excretion and increasing sodium retention, causing diuretic resistance. Non-steroidal anti-inflammatory drug (NSAID) can compete with loop diuretics for organic ion transporters, thus preventing the diuretic molecules from being secreted into the proximal convoluted tubules.
Those with diuretic resistance, cardiorenal syndrome, and severe right ventricular dysfunction may have better response to continuous duretic infusion. Diuretic dosages is adjusted to produce 3 to 5 litres of urine per day. Thiazide (blockade of sodium-chloride symporter), amiloride (blockade of epithelial sodium channels) and carbonic anhydrase inhibitors (blockade of chloride-bicarbonate exchanger pendrin) has been suggested to complement the action of loop diuretics in resistance cases but limited evidence are available to support their use.
The most common adverse drug reactions (ADRs) are dose-related and arise from the effect of loop diuretics on diuresis and electrolyte balance.
Common ADRs include: hyponatremia, hypokalemia, hypomagnesemia, dehydration, hyperuricemia, gout, dizziness, postural hypotension, syncope. The loss of magnesium as a result of loop diuretics has also been suggested as a possible cause of pseudogout (chondrocalcinosis)
Because furosemide, torsemide and bumetanide are technically sulfa drugs, there is a theoretical risk that patients sensitive to sulfonamides may be sensitive to these loop diuretics. This risk is stated on drug packaging inserts. However, the actual risk of crossreactivity is largely unknown and there are some sources that dispute the existence of such cross reactivity. In one study it was found that only 10% of patients with allergy to antibiotic sulfonamides were also allergic to diuretic sulfonamides, but it is unclear if this represents true cross reactivity or the nature of being prone to allergy.
Examples of loop diureticsEdit
|Loop Diuretic||Relative Potency|
|Ethacrynic Acid||50 mg|
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