Hyponatremia diuretic-induced

Fluid and sodium balance are important to the safe use of lithium. Both dehydration and a negative sodium balance (for example a low salt intake, diuretic-induced sodium loss) will reduce renal lithium clearance and predispose to toxicity (331). Hyponatremia (for example, secondary to polydipsia or SIADH) may also increase the risk of lithium toxicity (332). 

Thiazide diuretic-induced hyponatremia is much more common in older than in younger patients, probably due to thiazide-mediated impairment in renal diluting capacity superimposed on the already present age-related decrease in capacity to dilute urine. Older studies indicated this was an extremely common cause... 

Fichman M, Vorherr H, Kleeman G. Diuretic-induced hyponatremia. Ann Intern Med 1971 75 853-63. 

The use of fixed combination of a thiazide and a potassium-sparing drug, often Moduretic (hydrochlorothiazide 50 mg with amiloride 5 mg), has been consistently implicated in diuretic-induced hyponatremia. Treatment with chlorpropamide (200-800 mg/day) along with Moduretic has precipitated hyponatremia in several cases (96). Simultaneous use of Moduretic with trimethoprim has also been reported to increase the risk (97). The mechanism appears to be impairment of the clearance of free water, resulting in dilutional hyponatremia. Whether... 

SoimenbUck M, Friedlander Y, Rosin AJ. Diuretic-induced severe hyponatremia. Review and analysis of 129 reported patients. Chest 1993 103(2) 601-6. 

Diuretic-induced hyponatremia occurs more frequently in patients treated with thiazide diuretics than in patients who are receiving loop diuretics. In addition to causing extracellular volume depletion and nonosmotic stimulation of ADH, thiazides interfere with urinary dilution and water excretion by blocking tubular sodium and potassium reabsorption in the distal tubule. Water is then retained in excess of sodium by virtue of nonosmotic release of ADH and excretion of urine with a concentration of sodium and potassium that exceeds that of the plasma. 

Because Henle s loop is indirectly responsible for water reabsorption by the downstream collecting duct, loop diuretics can cause severe dehydration. Hyponatremia is less common than with the thiazides (see below), but patients who increase water intake in response to hypovolemia-induced thirst can become severely hyponatremic with loop agents. Loop agents are sometimes used for their calciuric effect, but hypercalcemia can occur in volume-depleted patients who have another—previously occult—cause for... 

Hyponatremia is an important adverse effect of thiazide diuretics. It is due to a combination of hypovolemia-induced elevation of ADH, reduction in the diluting capacity of the kidney, and increased thirst. It can be prevented by reducing the dose of the drug or limiting water intake. 

Before the introduction of specific vasopressin receptor antagonists, pharmacological treatments for hyponatremia centered on the use of loop diuretics and nonspecific inhibitors of vasopressin signaling, such as lithium carbonate and demeclocycline.11 The utility of such therapies has been limited by a range of sideeffects. Loop diuretic use can result in electrolyte imbalances and suffers from poor response predictability.11 Lithium carbonate suffers from a low therapeutic index and a risk of renal damage as well as limited effectiveness in many patients. Lithium carbonate has therefore been nearly completely supplanted by demeclocycline, a tetracycline antibiotic, in the treatment of chronic hyponatremia.12 Demeclocycline use is itself limited by its nephrotoxicity (particularly in cirrhotic patients), ability to cause reversible uremia, and ability to induce photosensitivity.1,11... 

SSRIs can reportedly cause hyponatremia (SEDA-18, 20 SEDA-26,13). In a case-control study of hyponatremia in 39 071 psychiatric inpatients and outpatients, the incidence of antidepressant-induced hyponatremia was 2.1% (33). SSRI users had a three times higher risk of developing hyponatremia relative to users of other antidepressant drugs (OR = 3.1 95% Cl = 1.3, 8.6). Additional risk factors included older age and concomitant treatment with diuretics. 

In contrast, published case reports and case series have provided more insight into the potential nephrotoxicity associated with COX-2-selective inhibitors. Taken together, these case reports suggest that COX-2 inhibitors, like non-selective NSAIDs, produce similar and consistent renal adverse effects in patients with one or more risk factors that induce prostaglandin-dependent renal function (that is patients with renal and cardiovascular disease and taking a number of culprit medications, such as diuretics and ACE inhibitors). Acute renal insufficiency, disturbances in volume status (edema, heart failure), metabolic acidosis, hyperkalemia, and hyponatremia have been commonly described. The duration of treatment with COX-2 inhibitors before the development of chnically recognized renal impairment ranged from a few days to 3-4 weeks. Withdrawal of COX-2 inhibitors and supportive therapy most often resulted in resolution of renal dysfunction, but in some patients hemodialysis was required (102,108-112). 

Cyclophosphamide, a nitrogen mustard alkylating agent, is a widely used cancer chemotherapeutic drug to treat lymphomas, leukemias, multiple myeloma and a numerous solid tumors. Cyclophosphamide can induce nephrotoxicity characterized as decreased water excretion and an inappropriate concentration of urine. These effects are due to a direct effect of one or more alkylating cyclophosphamide metabolites at distal tubules and collecting ducts. Special caution is warranted to avoid water-induced diuresis or diuretic therapy in these patients as hyponatremia can become a problem. 

Diuretic drugs often cause a mild reduction of the plasma potassium concentration hyponatremia may be observed. Hypercalcemia may occur with hemoconcentration, but occasionally the free-ionized and the protein-bound fraction is increased. Thiazides cause hyperglycemia and reduce glucose tolerance, especially in diabetics. Thiazides may cause prerenal azotemia with hyperuricemia as a result of decreased renal blood flow and GFR as a result of reduced blood volume. Thiazides, like other diuretics, by causing hemoconcentration increase the plasma concentration of lipids. Many thiazides induce microsomal enzymes and thus affect lipoprotein concentrations. 

Like other diuretics, thiazides can induce hypokalemia, hyponatremia, hypochloiemia. hypomagnesemia. hypercalcemia, hyperuricemia, glucose intolerance, dehydration, and changes in the lipid profile. Thiazides may also cause photosensitivity reactions. 

Diuretics are used widely for the treatment of hypertension see Chapter 32), and loop diuretics appear to lower blood pressure as effectively as Na+-CL symporter inhibitors e.g., thiazides and thiazide-hke diuretics) while causing smaller perturbations in the Upid profile. However, the short elimination half-lives of loop diuretics render them less useful for hypertension than thiazide-type diuretics. The edema of nephrotic syndrome often is refractory to other classes of diuretics, and loop diuretics often are the only drugs capable of reducing the massive edema associated with this disease. Loop diuretics also are employed in the treatment of edema and ascites of hepatic cirrhosis however, care must be taken not to induce encephalopathy or hepatorenal syndrome. In patients with a drug overdose, loop diuretics can be used to induce a forced diuresis to facilitate more rapid renal elimination of the offending drug. Loop diuretics, combined with isotonic saline administration to prevent volume depletion, are used to treat hypercalcemia. Loop diuretics interfere with the kidney s capacity to produce a concentrated urine. Consequently, loop diuretics combined with hypertonic saline are useful for the treatment of hfe-threatening hyponatremia. Loop diuretics also are used to treat edema associated with chronic renal insufficiency. Most patients with ARE receive... 

ADVERSE EFFECTS AND PRECAUTIONS Adverse effects of diuretics see Chapter 28) determine tolerance and adherence. Erectile dysfunction is a troublesome adverse effect of thiazide diuretics physicians should inquire specifically regarding its occurrence. Albeit uncommon, gout may be a consequence of the hyperuricemia induced by these diuretics. Either of these adverse effects is reason to consider alternative therapies. Hydrochlorothiazide may cause rapidly developing, severe hyponatremia in some patients. Thiazides inhibit renal Ca " excretion, occasionally leading to hypercalcemia although generally mUd, this can be more severe in patients subject to hypercalcemia, such as those with primary hyperparathyroidism. The thiazide-induced decreased Ca excretion may be used therapeutically in patients with osteoporosis or hypercalciuiia. 

Carbamazepine and lithium can elevate each other s serum levels (the mechanism is unknown). Toxicity is possible while blood levels are within the normal range, and is partially associated with pre-existing brain abnormalities. The diuretic effect of lithium outweighs the antidiuretic effect of carbamazepine. Carbamazepine does not protect against lithium-induced diabetes insipidus. Lithium can enhance carbamazepine-induced hyponatremia. 

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