Loop diuretic

Loop diuretics are diuretics that act on the ascending 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.

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Mechanism of action

Loop diuretics act on the Na⁺-K⁺-2Cl^- symporter (cotransporter) in the thick ascending limb of the loop of Henle to inhibit sodium and chloride reabsorption. This is achieved by competing for the Cl^- binding site. Because magnesium and calcium reabsorption in the thick ascending limb is dependent on sodium and chloride concentrations, loop diuretics also inhibit their reabsorption. By disrupting the reabsorption of these ions, loop diuretics prevent the urine from becoming concentrated and disrupt 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. This diuresis leaves less water to be reabsorbed into the blood, resulting in a decrease in blood volume.

Loop diuretics also cause vasodilation of the veins and of the kidney's blood vessels, mechanically causing a decrease in blood pressure.

The collective effects of decreased blood volume and vasodilation decrease blood pressure and ameliorate edema.

Clinical use

Loop diuretics are principally used in the following indications (Rossi, 2004):

• edema associated with heart failure, hepatic cirrhosis, renal impairment, nephrotic syndrome
• hypertension
• adjunct in cerebral/pulmonary edema where rapid diuresis is required (IV injection)

They are also sometimes used in the management of severe hypercalcemia in combination with adequate rehydration (Rossi, 2004).

Loop diuretic resistance

Renal insufficiency causes decreased bloodflow to the kidneys, which decreases the glomerular filtration rate (GFR) and reduces the ability of loop diuretics to reach their target organ, the loop of Henle. Similarly, non-steroidal anti-inflammatory drugs also decrease GFR with comparable results. In patients with reduced GFR, ceiling dosages of loop diuretics are increased proportional to the decrease in GFR. Simultaneous treatment with a thiazide diuretic such as hydrochlorothiazide (to inhibit sodium reabsorption at multiple sites in the nephron) is often successful.

Patients with congestive heart failure tend to retain sodium, also necessitating an increase in dosage. The same is true for patients with increased sodium intake.

Adverse effects

The most common adverse drug reactions (ADRs) are dose-related and relate to the effect of loop diuretics on diuresis and electrolyte balance.

Common ADRs include: hyponatremia, hypokalemia, hypomagnesemia, dehydration, hyperuricemia, gout, dizziness, postural hypotension, syncope (Rossi, 2004).

Infrequent ADRs include: dyslipidemia, increased serum creatinine concentration, hypocalcemia, rash (Rossi, 2004).

Ototoxicity (damage to the ear) is a serious, but rare ADR associated with use of loop diuretics. This may be limited to tinnitus and vertigo, but may result in deafness in serious cases.

Loop diuretics may also precipitate renal failure in patients concomitantly taking an NSAID and an ACE inhibitor -- the so-called "triple whammy" effect (Thomas, 2000).

Examples of loop diuretics

• Furosemide
• Bumetanide
• Ethacrynic acid
• Torsemide

References

• Rossi S (Ed.) (2004). Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2.
• Thomas, MC (2000). Diuretics, ACE inhibitors and NSAIDs -- the triple whammy. Med J Aust 172, 184–185. PMID 10772593