Loop diuretic are agents that primarily inhibit the Na-K-Cl cotransporter located on the luminal membrane of cells along the thick ascending limb of the loop of Henle.
They are often used for the treatment of hypertension and edema secondary to congestive heart failure, liver cirrhosis, or chronic kidney disease.
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.
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 by competing for the Cl− binding site.
Loop diuretics also inhibit NKCC2 at macula densa, reducing sodium transported into macula densa cells.
Reduced sodium transported into macula densa cells 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).
Loop diuretics also inhibit magnesium and calcium reabsorption in the ascending limb.
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.
Prostaglandin-mediated vasodilation of preglomerular afferent arterioles increases the glomerular filtration rate (GFR) and facilitates diuresis.
The collective effects of decreased blood volume and vasodilation help decrease blood pressure and ameliorate edema.
Loop diuretics are highly protein bound and therefore have a low volume of distribution.
Loop diuretics usually have a ceiling effect whereby doses greater than a certain maximum amount will not increase the clinical effect of the drug.
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.
The availability of furosemide is highly variable (from 10% to 90%).
The biological half-life of furosemide is limited by absorption from the gastrointestinal 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.
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.
Loop diuretics are principally used in the following indications:
Heart failure
Edema
Cerebral edema
Pulmonary edema
Hypertension
They are also sometimes used in the management of severe hypercalcemia in combination with adequate rehydration.
Diuretic resistance is defined as failure of diuretics to reduce fluid retention, and can be measured by low urinary sodium) despite using the maximal dose of drugs.
Causes for the resistance towards loop diuretics: After initial diuresis, there will be a period of 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 contributes to resistance through a braking phenomenon of a 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, sodium-chloride symporter at distal convoluted tubule, epithelial sodium channels, and chloride-bicarbonate exchanger promoting sodium reabsorption and fluid retention, causing diuretic resistance.
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, 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 diuretic infusion.
Thiazide, amiloride and carbonic anhydrase inhibitors are 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: hyponatremia, hypokalemia, hypomagnesemia, dehydration, hyperuricemia, gout, dizziness, postural hypotension, syncope.
Infrequent ADRs include: dyslipidemia, increased serum creatinine concentration, hypocalcemia, rash, and metabolic alkalosis may also be seen with loop diuretic use.
Ototoxicity is a rare ADR associated with use of loop diuretics, that may be limited to tinnitus and vertigo, but may result in deafness in serious cases.
Loop diuretics may also precipitate kidney failure in patients concurrently taking an NSAID and an ACE inhibitor
Furosemide, torsemide and bumetanide are technically sulfa drugs, and have a theoretical risk that patients sensitive to sulfonamides may be sensitive to these loop diuretics.
Ethacrynic acid is the only loop diuretic class that is not a sulfonamide.
Ethacrynic acid carries a greater risk of reversible or permanent hearing loss and has a distinct complication of being associated with gastrointestinal toxicity.
Furosemide 40 mg Bumetanide 1 mg Ethacrynic Acid 50 mg Torasemide 20 mg