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).
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.
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.
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
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.
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
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.
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.
loop diuretics are listed in the plate.
indications for loop diuretics include:
Peripheral or pulmonary edema
adverse effects of thiazide diuretics include:
Ototoxicity, manifest as tinnitus, vertigo, or hearing loss
· 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