A Brief Review of Drug-Induced Syndrome of Inappropriate Secretion of Antidiuretic Hormone

January 24, 2002

Abstract and Introduction


Drugs are a common cause of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in the elderly. The mechanism of action by which a drug interferes with the normal secretion and action of the antidiuretic hormone (ADH) depends on the drug. It is important to diagnose and treat the hyponatremia associated with SIADH because, if left untreated, the hyponatremia can lead to serious neurologic consequences. Diagnosis of SIADH is a diagnosis of exclusion because many disorders, including head trauma, can impair the patient's ability to excrete water. Also, it is important to consider the possibility of pseudohyponatremia. Usually, discontinuation of the suspected drug is effective in reversing the drug-induced SIADH. Pharmacists can play an active role in identifying patients with drug-induced SIADH by being familiar with the clinical signs and symptoms and the biochemical changes associated with drug-induced SIADH.


Water constitutes 55% to 80% of the body's weight, depending on the patient's age and sex.[1] Since water provides a milieu vital for survival, any excess increase in the body's water can cause death. The antidiuretic hormone (ADH), arginine vasopressin (AVP), plays an important role in regulating water balance and osmolality by increasing renal reabsorption of water.

Drug-induced hyponatremia is a common electrolyte abnormality.[2] One form of hyponatremia is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).[3] The syndrome results from sustained or inappropriate secretion of the ADH although the patient's serum osmolality is low and extracellular fluid volume is increased.[1,2] The severity of the condition depends on the speed of onset and the degree of fluid and electrolyte imbalance (eg, hyponatremia).[4]


Serum osmolality can be defined as the concentration of electrolytes and other osmotically active particles.[5] Sodium, the dominant extracellular cation, is the primary determinant of serum osmolality.[6]Hyponatremia, a serum sodium concentration of < 136 mEq/L (137 mmol/L), is usually associated with hypotonicity. For example, if the concentration of the total-body water changes without an accompanying change in total-body solute (eg, sodium), changes in the serum sodium concentration (eg, hyponatremia) reflect pathologic alterations in water homeostasis.[6]

Physiology of ADH

The ADH is produced by specialized cells in the hypothalamus and is stored in the posterior pituitary gland.[7] The hormone is secreted by the posterior pituitary gland in response to changes in the patient's blood osmolality and blood volume. When ADH is released into the circulation, the hormone attaches to receptor sites in the kidney's distal tubule and collecting duct, which results in enhanced permeability to water at these sites. The increased renal reabsorption of solute-free water into the circulation causes a decrease in urinary output.[7]

Two physiologic mechanisms control the release of ADH from the posterior pituitary gland.[5] First, an increase in serum osmolality stimulates osmoreceptors in the hypothalamus, which causes the release of ADH from the posterior pituitary gland.

In the kidneys, reabsorption of water results in diluting the serum and lowering the osmolality. Conversely, a decrease in serum osmolality inhibits the release of ADH. The kidneys respond by increasing urinary output.

Second, stretch receptors within the left atrium and baroreceptors in the carotid sinus and aortic arch respond to changes in blood volume.[1] When the blood pressure increases, the receptors respond by inhibiting impulses from the hypothalamus to the posterior pituitary gland to decrease the rate of release of ADH. A decrease in circulating ADH increases urinary output and a drop in blood volume to normal levels.[5]

Conversely, a decrease in blood volume increases the rate of release of ADH. The kidneys respond by decreasing urinary output.


In 1957, SIADH was recognized in patients with bronchogenic carcinoma.[8] Since that time, associations between SIADH and many commonly prescribed drugs[9] have been reported, and correlations have been found between SIADH and certain disorders, including pancreatic malignancies and insults to the central nervous system (CNS), such as vascular injury (eg, thrombosis) and trauma (eg, intracranial hemorrhage).[10] In the elderly, small oat cell carcinoma is the most common malignancy associated with SIADH.[10]

SIADH occurs because the physiologic mechanisms that regulate ADH malfunction -- ie, there is a continual release of ADH into circulation that is unrelated to plasma osmolality.[11] In other words, the kidneys "inappropriately" concentrate the urine when the body is attempting to correct a state of hypotonicity.[6] Since these patients are unable to excrete a dilute urine, ingested fluids are retained; this results in expansion of the extracellular fluid volume and the development of dilutional hyponatremia.[11] The syndrome is characterized by hyponatremia and impaired excretion of water in the absence of hypovolemia, hypotension, or abnormal functioning of the cardiac, renal, and thyroid or adrenal systems.[12]

The clinical features of SIADH are attributed to water retention, hyponatremia, and hypo-osmolality of the serum.[7] Usually, the patient with hyponatremia does not experience symptoms until the serum sodium concentration falls below 125 mmol/L.[6] Initially, the symptoms include lethargy, muscle cramps, anorexia, nausea, and vomiting.[13] When hyponatremia develops more rapidly or more profoundly, coma, convulsions, and death may occur.

Later on, hyponatremia can cause neurologic signs and symptoms such as altered levels of consciousness, headache, impaired memory, and confusion.[7] If the serum sodium concentration drops below 110-115 mmol/L, seizures and irreversible brain damage can occur.[1] The neurologic manifestations occur because the osmotic movement of water into the brain cells causes cerebral edema.[7] However, the brain has unique protective mechanisms to minimize cellular swelling in patients with chronic development of hyponatremia.[14,15]

Diagnosis of drug-induced SIADH is based on exclusion of underlying diseases such as congestive heart failure, renal failure, cirrhosis with ascites, and adrenal insufficiency, all of which are associated with impaired ability to excrete water.[16] Hyponatremia may also occur in a state of normal or elevated plasma osmolality.[17]

This situation is known as pseudohyponatremia. Diagnosis of pseudohyponatremia is important because any attempt to increase the plasma sodium concentration is contraindicated.

Severe hyperlipidemia or hyperproteinemia may cause reduction of the fractional volume of the plasma that is composed of water.[17] As a result, the decrease in sodium content of whole plasma (mmol/L) falls in parallel with the decrease in the aqueous content of the plasma. In this situation, the plasma osmolality remains normal.[17]

Hypertonic hyponatremia can occur as a result of hyperglycemia or after the administration of mannitol or glycerol.[17] The osmotically active non-electrolytes in the extracellular fluid (ECF) create an osmotic gradient that draws water out of the cells and into the extracellular space. This results in a dilutional hyponatremia.

It is important to consider factitious SIADH in patients when the cause of hyponatremia cannot be explained.[18] For example, the synthetic ADH analog desmopressin in the form of a nasal spray is prescribed to treat urinary incontinence or nocturnal enuresis that is associated with antipsychotic drug therapy.[18] However, the drug can cause factitious SIADH in patients who inadvertently or surreptitiously use the nasal spray.

The Elderly and SIADH

Disease- or drug-induced SIADH are the most common causes of hyponatremia in older persons who reside in the community.[10] The elderly are at greater risk for disease-induced SIADH than younger patients,[19] partly because of age-related physiologic changes in fluid and electrolyte balance and also because they receive treatment with many common drugs that can cause SIADH.[9]

The results of a clinical study support the hypothesis that age itself may be a risk factor for SIADH-like hyponatremia.[20] The researchers concluded that elderly patients may develop idiopathic SIADH-like hyponatremia, which appears to be a result of the normal aging process that affects fluid balance.

Drug-Induced SIADH

Initially, pharmacologic agents that had antidiuretic action were prescribed to treat patients with diabetes insipidus (DI).[21] Later on, numerous reports documented serious adverse effects, such as water retention and dilutional hyponatremia, associated with these drugs.

The proposed mechanism by which a drug interferes with the normal secretion and action of ADH depends on the drug.[14] Drugs that stimulate the release of ADH from the posterior pituitary gland include nicotine, phenothiazines, and tricyclics. Some drugs increase or potentiate the renal action of ADH. They include desmopressin, oxytocin, and prostaglandin synthesis inhibitors. Drugs that cause SIADH by means of mixed or uncertain mechanism of action include chlorpropamide, carbamazepine, cyclophosphamide, and vincristine.[14]

In 1994, researchers reported the first case suggesting a cause-effect relationship between omeprazole and SIADH.[22] However, the mechanism of omeprazole-induced SIADH needs to be established.

Ecstasy, or 3,4 methylene dioxymethamphetamine (MDMA), a powerful derivative of amphetamine that is popular among adolescents, can cause SIADH.[23] However, the mechanism of MDMA-induced SIADH is not well understood.

SIADH induced by angiotensin-converting enzyme (ACE) inhibitors (eg, lisinopril) is a rare but possible adverse effect of this category of drugs.[24] The SIADH-type of dilutional hyponatremia induced by ACE inhibitors may be mediated by the potentiation of the action of plasma renin, which results in increased levels of brain angiotensin.[10] This, in turn, results in the release of AVP from the hypothalamus and an increase in thirst.[10]

A review article in Drugs & Aging provides an in-depth discussion of the mechanisms of action by which drugs may induce SIADH.[9]

It is estimated that psychotropic drugs are administered to approximately 50% of institutionalized older patients.[10] Some of the older antipsychotic drugs, such as fluphenazine, thiothixene, and phenothiazine, and the tricyclic antidepressants (eg, amitriptyline) can cause hyponatremia with characteristics of SIADH.[10]

A systematic review of reported cases was conducted to evaluate the relationship between hyponatremia and SIADH with the use of selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, fluvoxamine, paroxetine, and sertraline.[25] According to the study, fluoxetine is the SSRI most commonly reported to cause hyponatremia and SIADH. However, the mechanism of action responsible for SSRI-induced SIADH is not known.[25]

According to the 30 published reports of hyponatremia and SIADH associated with SSRIs, age ≥ 65 years may be a risk factor for hyponatremia and SIADH associated with SSRIs.[25] More than 50% of these patients developed hyponatremia within 13 days. The hyponatremia was reversible within 2-28 days after the SSRI was discontinued.[25]

Patients with hyponatremia can experience symptoms that mimic psychosis or depression.[26] Therefore, monitoring of serum sodium levels is very important in patients who are being treated with psychotropic drugs. Also, any change in the course of the psychiatric disease may suggest the possibility of drug-induced SIADH.[27]

An excellent review article in Drug Safety[27] the role of psychotropic drugs inducing hyponatremia and SIADH.

Treatment of Drug-Induced SIADH

Management of SIADH involves reversing excessive intakes of fluid, restoring sodium balance, and inhibiting the antidiuretic actions of ADH.[13] Treatment of drug-induced SIADH by discontinuing the suspected drug is usually effective.[9] However, patients with symptomatic hyponatremia require additional treatment, which includes fluid restriction and intravenous sodium chloride and/or furosemide.[9]

In some situations, it may be necessary to continue treatment with the drug that is causing the SIADH.[27] In such cases, treatment such as fluid restriction, sodium chloride and diuretics, or demeclocycline may be required to reduce the tendency of hyponatremia.[27]

Both demeclocycline and lithium carbonate can cause a state of nephrogenic DI by interfering with the renal action of ADH.[28] Both drugs interfere with the cellular action of ADH by preventing the formation of cyclic 3',5' adenosine monophosphate (cAMP) and the subsequent action of cAMP on the renal tubules.

In 1975, lithium carbonate was the only drug available to treat SIADH.[29] Although lithium carbonate was effective in reversing hyponatremia within 2 days, there was a gradual return of the hyponatremic state when the drug was discontinued.[30] A few months later, researchers reported the first study of the effect of prolonged treatment with demeclocycline (900 mg/day) in a patient with SIADH.[29] The results of this study suggested that the antibiotic may be of value in treating patients with chronic SIADH.

In 1978, researchers compared the effectiveness of demeclocycline vs lithium carbonate in treating 10 patients with chronic SIADH.[31] Initially, 3 of the patients who were treated with lithium carbonate (600-900 mg/day) for 3-5 days did not respond to treatment. Two of the 3 patients experienced adverse CNS symptoms (eg, confusion, disorientation, and paresthesia). When all of the patients were treated with demeclocycline (600-1200 mg/day), the drug was effective in restoring serum sodium concentration within 5-14 days without restricting water. In this study, serious adverse effects of demeclocycline were not noted. The researchers concluded that the antibiotic was superior to lithium carbonate in treating SIADH.[31]

Demeclocycline is not recommended for treatment of acute SIADH because its onset of action requires several days.[7] However, it is considered the drug of choice if pharmacologic management of SIADH is necessary.[14] The drug is administered in divided doses ranging from 600-1200 mg/day.[32] Since it takes several days to achieve maximal diuretic effects, the dose should not be increased for 3-4 days.

Renal function should be monitored if the patient is treated with demeclocycline on a regular basis.[32] Demeclocycline can cause reversible azotemia (uremia), but the drug should be stopped if there is an increase in the amount of urea and other nitrogenous wastes in the blood. Nephrotoxicity is a possible side effect, particularly in patients with cirrhosis.

Patients should be advised to avoid exposure to ultraviolet (UV) light because demeclocycline, a tetracycline, can induce photosensitivity. The drug should be administered 1 hour before or 2 hours after meals. Also, they should be advised that products containing aluminum, magnesium, iron, or calcium impair the absorption of demeclocycline.

In the future, AVP antidiuretic receptor antagonists that target specific AVP receptors in the kidney will hopefully make it easier and more effective to treat patients with chronic hyponatremia.[32]


Pharmacists need to be aware that many commonly prescribed drugs cause SIADH. Concomitant treatment with several drugs that can each cause SIADH when administered alone is not recommended.[9] Pharmacists can play an active role in identifying patients with drug-induced SIADH by obtaining a history of the patient's pharmacologic treatment, including initiation and discontinuation of each drug.[33] Pharmacists need to be familiar with the clinical signs and symptoms and the biochemical changes associated with drug-induced SIADH. And finally, they need to understand the importance of ensuring proper monitoring of the patient's daily fluid intake, changes in weight, and serum sodium concentrations.[33]


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