Pedia News

LOOP DIURETICS

LOOP DIURETICS

ACTIONS AND MECHANISM

In the thick ascending limb (TAL), Na+, K+, and Cl- are reabsorbed across the apical surface of the tubular epithelium on NKCC2 transporters. Such reabsorption is essential for the maintenance of a high medullary interstitial solute gradient, which permits urine concentration in the collecting duct (see Plate 3-15). In addition, recycling of the reabsorbed potassium back into the lumen through apical ROMK channels establishes the positive intraluminal charge required for reabsorption of Ca2+ and Mg2+ (see Plate 3-11).

Loop diuretics enter the nephron through the organic anion secretion pathway in the proximal tubule, then they bind to the apical surface of NKCC2 transporters and inhibit their function.

Because the distal nephron is unable to reabsorb the large sodium load rejected from the thick ascending limb, the diuresis associated with these drugs is pro-found. In addition, loop diuretics also have weak diuretic effects elsewhere in the nephron. In the proximal tubule, for example, some loop diuretics weakly inhibit carbonic anhydrase. Meanwhile, in the distal nephron, some loop diuretics weakly inhibit the thiazide-sensitive NCC Na+/ Cl- symporter.

LOOP DIURETICS
Plate 10-3


Loop diuretics also influence the excretion of several other ions. The reabsorption of both Ca2+ and Mg2+ is decreased because of the reduction in K+ recycling in the TAL. In addition, loop diuretics both increase uric acid reabsorption (by promoting fluid losses, which enhances proximal uric acid reabsorption) and decrease uric acid secretion (by competing with it at the organic anion secretion pathway). Finally, loop diuretics promote K+ secretion through various mechanisms. First, the increased Na+ load that reaches the cortical collecting duct creates a negative intraluminal charge as it is reabsorbed, promoting K secretion through apical ROM-K channels. Second, the increased urine flow through the cortical collecting duct upregulates flow-sensitive maxi-K channels.

Because NKCC2 transporters have an essential role in tubuloglomerular feedback and the regulation of renin secretion, loop diuretics also affect both of these processes. As shown in Plate 3-18, a reduction in NKCC2 transport is normally associated with a reduction in the glomerular filtration rate (GFR) because a slower urine flow rate allows the proximal tubule to capture a greater fraction of the filtered ions. The normal response to a reduction in NKCC2 transport is dilation of the afferent arteriole, which normalizes the glomerular filtration rate, and release of renin, which activates the renin-angiotensin-aldosterone system.

In the presence of a loop diuretic, NKCC2 transport is blocked. As a result, there is chronic dilation of the afferent arteriole despite high flow rates through the nephron, which enhances fluid losses. In addition, there is chronic secretion of renin, which leads to increased synthesis of angiotensin and aldosterone. The result is a further increase in K+ secretion, which contributes to the development of hypokalemia, and an increase in H+ secretion, which can result in metabolic alkalosis.

The efficacy of loop diuretics can become limited over repeated doses for several reasons. In part, this effect occurs because the distal nephron increases its reabsorptive capacity, blunting the efficacy of loop diuretics and markedly increasing salt retention between doses. Therefore, to maximize the response to a loop diuretic, patients should be maintained on a low-salt diet, dosed frequently enough to limit the time available for postdiuretic salt retention, and offered simultaneous treatment with drugs that target the distal nephron, such as thiazides.

 

COMMON AGENTS

The major loop diuretics are listed in the plate.

 

INDICATIONS

The major indications for loop diuretics include:

·      Peripheral or pulmonary edema

·      Hypertension

 

ADVERSE EFFECTS

The major adverse effects of thiazide diuretics include:

·      Ototoxicity, manifest as tinnitus, vertigo, or hearing loss

·      Hypokalemia

·      Hypomagnesemia

·  Hyponatremia. By inhibiting solute reabsorption in the TAL, loop diuretics prevent maximal urine dilution. In addition, significant fluid losses can trigger release of antidiuretic hormone (see Plate 3-17)

·      Hyperuricemia, which may precipitate gout attacks

·      Hypotension, if excessive extracellular fluid is lost

·   Metabolic alkalosis, resulting from aldosterone release secondary to volume losses and, if hypokalemia is present, an increase in proximal tubular ammoniagenesis

· Impaired glucose tolerance or diabetes mellitus secondary to multiple mechanisms, including catecholamine release (secondary to activation of the sympathetic nervous system resulting from volume depletion), as well as reduced insulin secretion (secondary to hypokalemia)

·      Hyperlipidemia, through mostly unknown mechanisms

·      Photosensiti

·      Paresthesia