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87

respectively. V2 receptors are located in the renal collecting

tubules and mediate the antidiuretic effects of AVP. Antagonism of the V2 receptors

results in aquaresis, which is a unique solute-free and electrolyte-sparing (sodium

and potassium) water excretion process in the kidneys. Because circulating levels of

AVP are elevated in SIADH, cirrhosis, and HF, VRA can be beneficial in the

management of hyponatremia associated with these conditions.

Conivaptan, a mixed V1A and V2 receptor antagonist, was the first VRA approved

by the US Food and Drug Administration (FDA) for the treatment of euvolemic and

hypervolemic hyponatremia in hospitalized patients.

88 Randomized, double-blind,

placebo-controlled trials demonstrated its efficacy in increasing serum sodium

concentrations in patients with euvolemic and hypervolemic hyponatremia associated

with SIADH and HF, respectively.

88,89

It is administered as an IV infusion and its use

is restricted to a short-term (4 days) inpatient use only. Close monitoring of serum

sodium concentration is necessary to prevent overly rapid correction of hyponatremia

and central pontine myelinolysis that may ensue. Because conivaptan is a potent

inhibitor of the cytochrome P-450 3A4 (CYP3A4) enzyme, drug interactions with

medications that undergo CYP3A4-mediated metabolism are possible.

82

In addition,

patients may experience infusion-site reactions with conivaptan caused by the

organic solvent, polypropylene glycol.

Tolvaptan, a selective oral VRA, was approved by the FDA in 2009 for the

treatment of hypervolemic and euvolemic hyponatremia in patients with HF,

cirrhosis, and SIADH. Because of its selectivity for the V2 receptor, tolvaptan

increases urinary excretion of free water (aquaresis) and has less of a blood

pressure–lowering effect. As such, it may be more suitable for use in patients with

low to normal blood pressure, such as those with HF or cirrhosis. Tolvaptan has

been shown to increase serum sodium concentration significantly and correct

hyponatremia in patients with SIADH, chronic HF, or cirrhosis.

90

It has also been

studied extensively in chronic HF where improvement in signs and symptoms such as

reduction of edema and weight, as well as normalization of serum sodium

concentrations, were shown.

91,92 However, the use of tolvaptan in HF had no effect on

long-term cardiovascular mortality or hospitalization for HF.

93 More recent studies

have shown the potential benefits of tolvaptan in patients with autosomal dominant

polycystic kidney disease.

94,95 However, hepatic injury was noted in some patients,

thus resulting in the release of a safety announcement by FDA to limit tolvaptan’s use

to no more than 30 days and the removal of the indication for use in patients with

cirrhosis.

96

It should not be used also in patients with underlying hepatic disease.

Lixivaptan is another VRAs that is selective for the V2 receptor. Like tolvaptan,

they are orally active and thus useful in patients who require chronic therapy or when

oral therapy is preferred. Lixivaptan has been studied in patients with hyponatremia

from HF, cirrhosis, and SIADH; the results showed significant increases

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in aquaresis and serum sodium concentrations in both in- and outpatients.

97–101

However, it has yet to receive FDA approval.

Common adverse effects of VRAs include thirst, dry mouth, polyuria, and blood

pressure reduction. Aquaretics increase thirst by increasing blood tonicity and urine

volume; orthostatic hypotension has been reported.

83,102 These agents are thus

contraindicated in hypovolemic hyponatremia. The risk of excessive correction of

hyponatremia and the resultant neurologic complications from osmotic demyelination

exists with VRA, especially when used in combination with fluid restriction. These

agents should therefore be initiated in the inpatient setting at the lowest possible dose

and titrated slowly, with close monitoring of serum sodium concentrations and

volume status. Additionally, the VRAs are substrates and inhibitors of the CYP3A4

enzyme. As a result, there is a potential for clinically significant drug interactions,

particularly with concomitant administration of moderate or strong CYP3A4 inducers

or inhibitors.

The VRAs should be used in hyponatremic patients with mild-to-moderate severe

neurologic symptoms. Not only have they been shown to maintain normal serum

sodium concentrations both short- and long-term but their aquaretic effect could also

reduce or eliminate the need for fluid restriction normally required of patients.

90,103

The effectiveness of VRA to correct serum sodium concentration in euvolemic and

hypervolemic hyponatremia has been shown. However, their long-term safety with

chronic use and their potential benefits on morbidity and mortality still need to be

assessed. The high cost of using these agents is also a major barrier to routine

clinical use.

Hypernatremia

Hypernatremia can occur under the following conditions: (a) normal total body

sodium with pure water loss, (b) low total body sodium with hypotonic fluid loss,

and (c) high total body sodium as a result of pure salt gain.

104 Therefore, as in

hyponatremia, it is important to assess the volume status of the ECF when evaluating

hypernatremia.

Pure water loss can result from the inability of the kidney to conserve water

(diabetes insipidus) or from extrarenal water loss through the respiratory tract or the

skin.

105 Usually, pure water loss does not cause hypernatremia unless the thirst center

is damaged or access to free water is limited.

104

Hypotonic fluid loss can occur renally as a result of osmotic diuresis, use of loop

diuretics, postobstruction diuresis, or intrinsic renal disease. Extrarenally, hypotonic

fluid loss can result from diarrhea, vomiting, burns, and excessive sweating.

Pure salt gain can result from the use of hypertonic saline during abortion, sodium

bicarbonate administration during cardiopulmonary resuscitation, hypertonic feedings

in infants, and, rarely, mineralocorticoid excess.

The management of hypernatremia includes correcting the underlying cause of the

hypertonic state, replacing the water deficits, and administering adequate water to

match ongoing losses.

104 The pure water deficit can be estimated as follows:

where desired serum sodium is usually 140 mEq/L.

The rate at which hypernatremia should be corrected depends on the severity of

symptoms and degree of hypertonicity. Too-rapid correction can precipitate cerebral

edema, seizures, and irreversible neurologic damage, and can be fatal. For

asymptomatic patients, the rate of correction probably should not exceed changes of

0.5 mEq/L/hour in plasma sodium. A rule of thumb is to replace half the calculated

deficit with hypotonic solutions over the course of 12 to 24 hours. Any ongoing water

loss, including insensible loss, should also be replenished while carefully monitoring

the patient’s neurologic status. The remaining deficit can then be replaced during the

ensuing 24 to 48 hours. Concomitant solute deficits and ongoing solute losses should

also be replaced as appropriate. If hypernatremia is caused only by pure water loss,

free water can be administered as 5% dextrose in water. Half-normal saline or

quarter-normal saline is used if a sodium deficit is also present. In patients with

hypotension or shock, the effective arterial blood volume should be restored with

normal saline or colloids before the plasma tonicity is corrected.

CLINICAL USE OF DIURETICS

Diuretics reduce sodium and chloride reabsorption in the renal tubules, thereby

increasing urine volume. Enhanced solute and fluid excretion can be initiated through

osmotic diuresis or inhibition of transport in the kidney tubules. Diuretics are

categorized according to the sites within the kidney tubules where they inhibit sodium

reabsorption (see Chapter 9, Essential Hypertension, and Chapter 28, Chronic

Kidney Diseases).

Loop Diuretics

The loop diuretics—furosemide, bumetanide, torsemide, and ethacrynic acid—are

the most potent diuretics available. They are also known as high-ceiling diuretics

because they can inhibit the reabsorption of up to 20% to 25% of the filtered sodium

load. The loop diuretics act in the medullary and cortical portion of the thick

ascending limb of Henle’s loop. Sodium and chloride transport through the

Na

+

/K+

/2Cl

− carrier in the luminal membrane is inhibited. Reabsorption of calcium

and magnesium is reduced secondary to the reduction in sodium chloride transport.

The loop diuretics also possess a vasodilatory effect that can contribute to their

diuretic activity.

Thiazide Diuretics

The thiazide diuretics are a group of structurally similar compounds that share a

common mechanism of action. Several other sulfonamide diuretics that differ

chemically, such as chlorthalidone, indapamide, and metolazone, also have diuretic

effects similar to the thiazides. The primary site of action of these diuretics is at the

proximal portion of the distal tubule. Sodium reabsorption via the Na

+

/Cl

−

cotransporter is blocked through competition with the chloride site of the transporter.

Some of these agents, such as chlorothiazide, may also reduce sodium transport in the

proximal tubule. The contribution of this effect toward net diuresis is negligible,

however, because the sodium ions that are not reabsorbed in the proximal tubule will

subsequently be reabsorbed in Henle’s loop. Thiazide diuretics can enhance the

reabsorption of calcium ion through a direct action on the early distal tubule.

Therefore, these agents are useful to reduce calciuria in patients with kidney stones.

In contrast, magnesium excretion is increased by the thiazides, which may result in

hypomagnesemia.

Potassium-Sparing Diuretics

SPIRONOLACTONE, TRIAMTERENE, AND AMILORIDE

Spironolactone, triamterene, and amiloride are potassium-sparing diuretics that

inhibit sodium reabsorption in the cortical collecting tubules through different

mechanisms. Spironolactone is a competitive receptor-site antagonist of aldosterone

in the distal

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segment of the renal tubule and is indicated especially for patients with

hyperaldosteronism secondary to decreased renal perfusion. Patients with

hyperaldosteronism can be identified by urinary electrolyte screening, which shows

high urine potassium excretion with concomitant diminished or absent urine sodium

excretion. By serving as an aldosterone antagonist, spironolactone inhibits sodium

reabsorption and decreases the excretion of potassium and hydrogen ions. Dosages as

high as 200 to 400 mg/day may be needed to induce natriuresis in patients with

hyperaldosteronism.

In contrast to spironolactone, triamterene and amiloride reduce the passage of

sodium ions through the luminal membrane, independent of aldosterone activity, by

directly acting on sodium and potassium transport processes in the distal renal

tubular cells. Triamterene and amiloride offer the advantage of a more rapid onset of

action than spironolactone.

The initial effects of spironolactone are usually delayed for 2 or 3 days, and

several additional days are needed to attain maximal diuretic effect. This delay is

caused partly by the formation of an active metabolite, canrenone, which accounts for

approximately 70% of the antimineralocorticoid activity of spironolactone. The

elimination half-life of canrenone is 13.5 to 24 hours in normal subjects and is

prolonged in patients with chronic liver disease (59 hours [range, 32–105 hours]) or

HF (37 hours [range, 19–48 hours]).

106 Although the elimination half-life of

canrenone is prolonged in these patients, plasma canrenone concentrations do not

differ significantly from those in normal subjects because assay methods for

canrenone are nonspecific and include measurement of both active and inactive

metabolites.