| Loop diuretic | |
|---|---|
| Drug class | |
 Structure of the loop diuretics Furosemide, Azosemide, Bumetanide, Piretanide, Torasemide, Ethacrynic acid and Etozolin | |
| Class identifiers | |
| Synonyms | High-ceiling diuretic[3] |
| Use | congestive heart failure,nephrotic syndrome,cirrhosis,hypertension,edema[1] |
| ATC code | C03C |
| Biological target | Na-K-Cl cotransporter[2] |
| External links | |
| MeSH | D049994 |
| Legal status | |
| In Wikidata | |
Loop diuretics are pharmacological agents that primarily inhibit theNa-K-Cl cotransporter located on the luminal membrane of cells along thethick ascending limb of the loop of Henle.[4] They are often used for the treatment ofhypertension andedema secondary tocongestive heart failure,liver cirrhosis, orchronic kidney disease. Whilethiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function.[5]
Loop diuretics are 90% bonded to proteins and are secreted into theproximal convoluted tubule throughorganic anion transporter 1 (OAT-1), OAT-2, andABCC4. Loop diuretics act on theNa+-K+-2Cl− symporter (NKCC2) in the thick ascending limb of theloop of Henle to inhibit sodium, chloride and potassium reabsorption. This is achieved by competing for the Cl− binding site. Loop diuretics also inhibit NKCC2 atmacula densa, reducing sodium transported into macula densa cells. This stimulates the release ofrenin, which throughrenin–angiotensin system, increases fluid retention in the body, increases the perfusion ofglomerulus, thus increasingglomerular filtration rate (GFR). At the same time, loop diuretics inhibit thetubuloglomerular feedback mechanism so that increase in salts at the lumen near macula densa does not trigger a response that reduces the GFR.[6]
Loop diuretics also inhibitmagnesium andcalcium 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 is set up by potassium recycling throughrenal outer medullary potassium channel. By inhibiting the potassium recycling, the voltage gradient is abolished and magnesium and calcium reabsorption are inhibited.[7] By disrupting the reabsorption of these ions, loop diuretics prevent the generation of ahypertonicrenal medulla. Without such a concentrated medulla, water has less of anosmotic driving force to leave thecollecting duct system, ultimately resulting in increasedurine 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.[citation needed]
A secondary effect of loop diuretics is to increase the production ofprostaglandins, which results in vasodilation and increased blood supply to the kidney.[8][9] Prostaglandin-mediatedvasodilation of preglomerularafferent arterioles increases theglomerular filtration rate (GFR) and facilitates diuresis. The collective effects of decreased blood volume and vasodilation help decrease blood pressure and ameliorateedema.[citation needed]
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 the luminal wall of the proximal convoluted tubules to be able to exert its function.[citation needed]
Loop diuretics usually have a ceiling effect whereby doses greater than a certain maximum amount will not increase the clinical effect of the drug. Also, there is a threshold minimum concentration of loop diuretics that needs to be achieved at the thick ascending limb to enable the onset of abrupt diuresis.[10]
The availability offurosemide is highly variable, ranging from 10% to 90%. Thebiological half-life of furosemide is limited byabsorption from thegastrointestinal tract into the bloodstream. The apparent half-life of its excretion is higher than the apparent half-life of absorption via the oral route. Therefore, furosemide taken intravenously is twice as potent as an equivalent dose taken orally.[6]
However, for torsemide and bumetanide, their oral bioavailability is consistently higher than 90%. Torsemide has a longer half life in heart failure patients (6 hours) than furosemide (2.7 hours). A 40 mg dose of furosemide is clinically equivalent to a 20 mg dose of torsemide and to a 1 mg dose of bumetanide.[6]
Loop diuretics are principally used in the following indications:
The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guidelines stated that diuretics should not be used to treat acute kidney injury, except for the management of volume overload. Diuretics has not shown any benefits of preventing or treating acute kidney injury.[16]
They are also sometimes used in the management of severehypercalcemia in combination with adequate rehydration.[17]
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 havesodium-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 edema 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.[6]
Those with diuretic resistance, cardiorenal syndrome, and severe right ventricular dysfunction may have better response to continuous diuretic 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) andcarbonic 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.[6]
The most common adverse drug reactions (ADRs) are dose-related and arise from the effect of loop diuretics on diuresis andelectrolyte balance.[citation needed]
Common ADRs include:hyponatremia,hypokalemia,hypomagnesemia,dehydration,hyperuricemia,gout,dizziness,postural hypotension,syncope.[17] The loss of magnesium as a result of loop diuretics has also been suggested as a possible cause of pseudogout (chondrocalcinosis).[18]
Infrequent ADRs include:dyslipidemia, increased serumcreatinine concentration, hypocalcemia,rash.Metabolic alkalosis may also be seen with loop diuretic use.[citation needed]
Ototoxicity (damage to the inner ear) is a serious, but rare ADR associated with use of loop diuretics. This may be limited totinnitus andvertigo, but may result indeafness in serious cases.[citation needed]
Loop diuretics may also precipitate kidney failure in patients concurrently taking anNSAID and anACE inhibitor—the so-called "triple whammy" effect.[19]
Because furosemide,torsemide andbumetanide are technicallysulfa drugs, there is a theoretical risk that patients sensitive tosulfonamides 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.[20][21] 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.[22]
Ethacrynic acid is the only medication of this class that is not a sulfonamide. It carries a greater risk of reversible or permanent hearing loss (ototoxicity),[23] and has a distinct complication of being associated with gastrointestinal toxicity.[24]
| Loop Diuretic | Relative Potency[25] |
|---|---|
| Furosemide | 40 mg |
| Torasemide | 20 mg |
| Ethacrynic Acid | 50 mg |
| Bumetanide | 1 mg |