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Drug-induced syndrome of inappropriateantidiuretic hormone HYPONATREMIA, OFTEN DEFINED AS SERUM SODIUM LESS THAN 130 a low plasma osmolality, elevated urine osmolality (>100 mmol/L, is the most common electrolyte disturbance among mOsm/kg, usually >300 mOsm/kg), a urine sodium concentra- hospitalized patients.1,2 A complication of a variety of diseases, tion above 40 mEq/L, and low blood urea nitrogen and serum surgical treatments, or drugs, it may be hypertonic, hypotonic, uric acid concentration. Plasma creatinine, acid-base, and potas- sium balance, as well as adrenal and thyroid function, are all typ- Antidiuretic hormone (ADH) is also known as arginine vaso- pressin (AVP). Produced in the posterior pituitary gland in In most cases of drug-induced SIADH, patients have mild, response to an increased plasma sodium concentration, it asymptomatic hyponatremia that remains undetected. Others induces water retention. It increases cellular permeability to will fully recover once diagnosed. However, at least 6 deaths water in the distal tubule and collecting duct of the nephron, related to hyponatremia induced by ecstasy (methylene- leading to increased water resorption by the kidney.3,4 dioxymethamphetamine, or MDMA) have been reported. Mor- The syndrome of inappropriate antidiuretic hormone secre- tality has also been associated with cyclophosphamide- and car- tion (SIADH) is characterized by either the sustained release of ADH in the absence of stimuli, or by the enhanced action ofADH on the kidneys.5 Increased ADH activity impairs the kid- Drugs that can cause SIADH
ney’s ability to dilute urine, resulting in decreased excretion of While a large number of drugs may be associated with SIADH, ingested water and a highly concentrated and decreased volume most suspected cases are not drug-related. The selective serotonin of urine.3,4 If fluid intake is not sufficiently reduced in the setting reuptake inhibitors (SSRIs), various chemotherapeutic agents of increased ADH activity, serum hypotonicity and hypona- (e.g., cyclophosphamide, cisplatin, vincristine, vinblastine), tremia will occur. Patients with SIADH will present with normal chlorpropamide, carbamazepine, MDMA, tricyclic antidepres- volume status (euvolemic) because the excess water distributes sants, and antipsychotics appear to be most strongly associated evenly throughout the body’s fluid compartments.4 Causes of with SIADH.3,4,6 The incidence of drug-induced SIADH with car- SIADH include malignant diseases (e.g., carcinoma, lymphomas, sarcomas), pulmonary disorders (e.g., pneumonia, asthma), cen- Drug-induced SIADH can occur due to either an increased tral nervous system disorders (e.g., meningitis, stroke, head sensitivity to ADH in the nephron (e.g., cyclophosphamide, chlorpropamide, carbamazepine), or an increase in ADH pro-duction centrally (e.g., vinca alkaloids, cyclophosphamide, car- Signs and symptoms
bamazepine, antipsychotics, antidepressants).4 A list of drugs that Clinical manifestations of SIADH relate to the degree of hypo- may cause SIADH is provided in Table 1. Many of these associa- tonicity. Signs and symptoms of moderate hyponatremia (serum tions are based on as little as one case report.4,6-9 sodium concentration 115–120 mEq/L) include anorexia, nau- A review of spontaneous reports of hyponatremia associated sea, vomiting, muscle weakness, and cramps. Severe hypona- with SSRI use found that the median time to onset was 13 days tremia (<110 mEq/L) may be characterized by gait disturbances, after initiation of therapy, with a range of 3 to 120 days.4,10 While falls, stupor, tremors, seizures, and, in rare cases, death.4 the occurrence of hyponatremia with antidepressants appears to Headache, lethargy, disorientation, restlessness, and obtundation be highest during the first few weeks of treatment, the time to are other possible manifestations.2 Patients typically present with onset with antipsychotics seems to be considerably longer.5 Risk C P J / R P C • N O V E M B E R / D E C E M B E R 2 0 0 7 • V O L 1 4 0 , N O 6 TABLE 1 Drugs that may cause SIADH4,6-9
ADH analogues
Cardiovascular agents
Hypoglycemic agents
Antiparkinson agents
factors for SSRI-induced SIADH include advanced age, female however, the risk of nephrotoxicity and variable efficacy may gender, concomitant diuretics, hyperkalemia, baseline hypona- limit its use.1 Urea (30 g po daily) increases urine production by acting as an osmotic diuretic, but it is generally not well toler-ated.1,7 The crystals may be mixed with 10 mL of Maalox and dis- Management
solved in 100 mL of water to reduce gastrointestinal upset.7,11 The The only definitive treatment for drug-induced SIADH is unpleasant taste can be masked by using juices or carbonated removal of the offending agent. Most cases resolve promptly beverages, or by mixing the crystals with jelly or jam.11 Lithium upon drug discontinuation. Management should be guided by has also been used with some success, but it is currently not rec- the severity and duration of hyponatremia and its symptoms.1 ommended due to the potential for adverse events and a lack of Typically in drug-induced SIADH, the hyponatremia will be chronic and asymptomatic. In these instances, water should be With respect to SSRI-induced SIADH, cross-sensitivity restricted (500–1000 mL/day), and this measure alone may be among agents has been reported, but published data are scarce.4,12 adequate. It may be necessary to add furosemide to increase the Caution should be used if any SSRI is to be re-initiated.12 Moni- excretion of free water and if needed, replace salt and volume by toring of serum sodium concentrations at baseline and 1 to 2 administering 0.9% sodium chloride intravenously.4 For severely weeks after initiation of SSRIs may be warranted in individuals hyponatremic and symptomatic patients, administration of at risk of SIADH.13 For elderly patients taking an SSRI and pre- hypertonic saline (3%) may be appropriate. Serum sodium senting with sudden or unexplained mental status changes (e.g., should not increase by more than 1 to 2 mmol/L per hour or 8 delirium, lethargy, confusion) or nausea, measurement of serum to 10 mmol/L in the first 24 hours, as there is a risk of osmotic In cases in which removal of the offending agent is not possi- ble, treatment options include demeclocycline (a tetracycline Many medications have been associated with SIADH; however, derivative), oral urea, and lithium. Demeclocycline, currently the actual incidence of drug-induced SIADH is estimated to be available through Health Canada’s Special Access Program, very low.4 Symptoms of SIADH are linked to the degree of reduces urine osmolality and increases serum sodium levels; hyponatremia, and most drug-induced cases are mild in nature.1,4 C P J / R P C • N O V E M B E R / D E C E M B E R 2 0 0 7 • V O L 1 4 0 , N O 6 Removal of the offending agent is the most effective treatment.
This article was written by Erika Jones, a phar- In the case of SSRIs, extreme caution should be used when O V R D I S macist at The Ottawa Hospital, and reviewed
switching to another agent of that class. Other treatment alter- by Norma Lynn Pearson and Mirella Giudice natives include demeclocycline, urea, and lithium. While it is S R I P O with the Ottawa Valley Regional Drug Infor-
important to be aware of this possible adverse effect, it is proba- mation Service at The Ottawa Hospital. bly not necessary to counsel all patients on the risk of SIADH.4 References
1. Ellison DH, Berl T. The syndrome of inappropriate antidiuresis. N Engl J Med
8. Yokoyama Y, Shigeto T, Futagami M, Mizunuma H. SIADH following carbo-
platin-paclitaxel administration in a patient with recurrent ovarian cancer. Eur J 2. Palmer BF, Gates JR, Lader M. Causes and management of hyponatremia. Ann
Gynaecol Oncol 2005;26(5):531-2.
Pharmacother 2003;37:1694-702.
9. Collins A, Anderson J. SIADH induced by two atypical antipsychotics. Int J Geri-
3. Rose BD. Causes of the SIADH. In: Rose BD, ed. UpToDate [electronic data-
10. Liu BA, Mittmann N, Knowles SR, Shear NH. Hyponatremia and the syn-
4. Foote EF. Syndrome of inappropriate antidiuretic hormone secretion and dia-
drome of inappropriate secretion of antidiuretic hormone associated with the use betes insipidus. In: Tisdale JE, Millder DA, eds. Drug-induced diseases, preven- of selective serotonin reuptake inhibitors: a review of spontaneous reports. CMAJ tion, detection and management. Bethesda, MD: American Society of Health-Sys- 11. AHFS Drug Information. Snow EK, ed. Bethesda MD: American Society of
5. Spigset O, Hedenmalm K. Hyponatremia and the syndrome of inappropriate
antidiuretic hormone secretion (SIADH) induced by psychotropic drugs. Drug 12. Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reup-
take inhibitors in older adults. Ann Pharmacother 2006;40:1618-22.
6. Reactions Database 1983-2007/04. WebSPIRS Version 5.12. Ovid Technologies.
13. Fabian TJ, Amico JA, Kroboth PD, et al. Paroxetine-induced hyponatremia in
7. DRUGDEX® System. Thomson Micromedex. Greenwood Village, Colorado
older adults: a 12-week prospective study. Arch Intern Med 2004;164:327-32.
C P J / R P C • N O V E M B E R / D E C E M B E R 2 0 0 7 • V O L 1 4 0 , N O 6



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