A Review of Drug-Induced Hyponatremia
George Liamis, MD, Haralampos Milionis, MD, and Moses Elisaf, MD Hyponatremia (defined as a serum sodium level Ͻ 134 mmol/L) is the most common electrolyte abnormality in hospitalized patients. Certain drugs (eg, diuretics, antidepressants, and antiepileptics)have been implicated as established causes of either asymptomatic or symptomatic hyponatremia.
However, hyponatremia occasionally may develop in the course of treatment with drugs used ineveryday clinical practice (eg, newer antihypertensive agents, antibiotics, and proton pump inhibitors).
Physicians may not always give proper attention in time to undesirable drug-induced hyponatremia.
Effective clinical management can be handled through awareness of the adverse effect of certainpharmaceutical compounds on serum sodium levels. Here, we review clinical information about theincidence of hyponatremia associated with specific drug treatment and discuss the underlying patho-physiologic mechanisms.
Am J Kidney Dis 52:144-153. 2008 by the National Kidney Foundation, Inc. INDEX WORDS: Adverse drug reaction; hyponatremia; sodium homeostasis; syndrome of inappropriate
secretion of antidiuretic hormone; water homeostasis.
Hyponatremia (defined as a serum sodium
level Ͻ 134 mmol/L) is a common electro- OF HYPONATREMIA
lyte disturbance in clinical practice that is associ- Hyponatremia is ascribed to either water reten- ated with considerable morbidity and mortal- tion or (less often) loss of effective solute (so- ityDrugs are a common cause of electrolyte dium plus potassium) in excess of water. Be- abnormalities, and a careful drug history is essen- cause the capacity for water excretion normally tial in patients with electrolyte abnormalities.
is so great, retention of water resulting in hypona- One of the more common electrolyte abnormali- tremia takes place only in the presence of condi- ties that may be drug induced is hyponatremia. A tions that impair renal excretion of water. An thorough understanding of the pathophysiologi- exception to this rule is primary polydipsia, in cal process of drug-induced hyponatremia and which the excessive water intake can overwhelm associated risk factors is of great importance for even normal excretory capacity. Given that sup- prevention and prompt and effective intervention pression of arginine vasopressin (antidiuretic hor- in this potentially life-threatening disturbance.
mone [ADH]) secretion is essential for the excre- Here, we review clinical information about the tion of any water load, the presence of high incidence of hyponatremia associated with spe- serum ADH concentrations is the sine qua non cific drug treatment and discuss the underlying for the development and maintenance of hypona- pathophysiological mechanisms and therapeutic tremia. Virtually all causes of hyponatremia (ex- cept renal failure and primary polydipsia) arecharacterized by an excess of ADH (despite thepresence of hypotonicity), most frequently causedby syndrome of inappropriate ADH secretion From the Department of Internal Medicine, School of (SIADH) or effective circulating volume deple- Medicine, University of Ioannina, Ioannina, Greece. tion (which is a normal stimulus to ADH secre- Received November 13, 2007. Accepted in revised form March 3, 2008. Originally published online as doi: 10.1053/j.ajkd.2008.03.004 on May 8, 2008. Address correspondence to Moses Elisaf, MD, Professor creates an osmotic gradient between extracellu- of Medicine, Department of Internal Medicine, School of lar and intracellular fluid in brain cells, causing Medicine, University of Ioannina, 45110 Ioannina, Greece. movement of water into cells. Therefore, symp- toms of hyponatremia (predominantly neurologi- 2008 by the National Kidney Foundation, Inc.
cal) are attributed to cerebral edema. Moreover, they are related to both the severity and rapidity American Journal of Kidney Diseases, Vol 52, No 1 (July), 2008: pp 144-153 Hyponatremia Due to Drug Treatment Table 2. Rare Causes of Drug-Induced Hyponatremia
ponatremic patients at risk of neurological com-plications caused by acute cerebral edema are postoperative menstruating women, elderly women on thiazide therapy, children, psychiatric 3,4-Methylenedioxymethylamphetamine Antibiotics DRUG-INDUCED HYPONATREMIA
Hyponatremia related to drug treatment can be caused by dozens, perhaps hundreds, of medica- tions. Because hyponatremia can have many Table 1. Principal Causes and Underlying
Mechanisms of Drug-Induced Hyponatremia
Drugs affecting sodium and water homeostasis other causes, the diagnosis of drug-induced hypo- As shown in evidence from small studies and case reports, drugs may cause hyponatremia by affecting sodium homeostasis and water ho- Tricyclic antidepressants (amitryptiline, meostasis. Clinical information about the inci- dence and pathophysiological process of hypona- tremia of the most commonly offending agents is from occasionally reported cases also are pre- Drugs Affecting Sodium and Water Homeostasis
Diuretic Treatment
Vinca alkaloids (vincristine, Platinum compounds (cisplatin, causes of hyponatremia, with an estimated inci- dence of 11% in 1 series of 114 geriatric pa- Miscellaneous (methotrexate, interferon ␣ and ␥, diuretics are the most common cause of commu- nity-developed hyponatremiaDiuretic-induced hyponatremia is caused almost exclusively by thiazide or thiazide-like agentsLoop diuret- ics, by inhibiting sodium chloride reabsorption in the thick ascending limb of the loop of Henle, reduce the osmolarity of the medullary intersti- tium. Consequently, loop diuretics rarely are asso- ciated with hyponatremia because they impair both the renal concentrating and diluting mechanisms Conversely, thiazide diuretics acting solely in the distal tubules do not interfere with urinary concen- tration and the ability of ADH to promote water retention, which is the critical point for the develop- Abbreviation: ADH, antidiuretic hormone.
It should be noted that hyponatremia also cently, we validated this concept, and serum uric follows indapamide administration, as well as acid levels that could differentiate the 2 subgroups the combination of hydrochlorothiazide and of diuretic-induced hyponatremia also were de- rothiazide and amiloride appears to increase the acid level less than 4 mg/dL (Ͻ238 ␮mol/L) risk of hyponatremia. This increase probably is showed a biochemical profile consistent with an caused by the additional effect of amiloride on SIADH-like state, whereas patients with a serum the renal handling of sodium. Amiloride has a uric acid level of 4 mg/dL or greater had a direct effect on the collecting tubule, increasing biochemical profile compatible with extracellu- sodium loss. Effects of thiazides are mainly on lar volume depletion. Recognition of these 2 the distal tubule; therefore, the combination com- profiles aids the evaluation and management of pounds the urinary loss of sodium. Moreover, patients. In patients with extracellular volume amiloride, which spares potassium, aggravates depletion, normal saline solution with or without thiazide-induced hyponatremia as a consequence potassium chloride should be administered intra- of potassium retention by exchanging it for so- venously to correct hypovolemia and hypokale- dium in the distal tubule. Thus, sodium defi-ciency has been implicated as the major etiologic mia, if present. Conversely, in patients with an factor of hyponatremia induced by the combina- SIADH-like state who present with severe symp- tomatic hyponatremia, the treatment consists of Despite numerous studies, the pathophysiologi- hypertonic sodium chloride solution (3%) admin- cal mechanisms underlying diuretic-induced hy- istration, along with water restriction.
ponatremia are unclear. Among the implicated The diagnosis of diuretic-induced hyponatre- mechanisms, the most important are as follows: mia is based on a history of diuretic use and the (1) excess renal loss of effective solutes (potas- finding that hyponatremia resolved after discon- sium plus sodium) compared with water losses tinuing the offending agent. However, achieve- resulting from both diuretic-induced electrolytes ment of normonatremia and full recovery of losses and ADH-induced water retention; (2) diluting ability may be delayed for 1 to 2 weeks diuretic-induced volume depletion that appropri- after drug withdrawal. Consequently, in patients ately stimulates ADH secretion; (3) the coexis- with diuretic-induced hyponatremia and an tent hypokalemia leading to a transcellular cation SIADH-like profile, unless there is strong evi- exchange in which potassium leaves the cells to replenish the extracellular stores, whereas so- SIADH, a comprehensive diagnostic evalua- dium moves into cells to preserve electroneutral- tion should be postponed for 2 to 3 weeks.
ity; (4) direct inhibition of urinary dilution by However, taking into consideration that thia- diminishing sodium chloride reabsorption in the zides may aggravate the hyponatremia induced renal tubules; (5) stimulation of thirst; (6) magne- sium depletion; and (7) excessive ADH secre- proach if even mild hyponatremia persists af- mia occasionally is observed as an idiosyncraticreaction, particularly in subjects who consume Drugs Affecting Water Homeostasis
large quantities of waterMost cases of thiazide-induced hyponatremia occur in elderly patients, Except for diuretics, several other drugs that impair the renal diluting capacity also can induce subjects with low body mass appear to be more ways drugs can affect water homeostasis: they There are 2 groups of patients with diuretic- can increase ADH secretion centrally, potentiate induced hyponatremia, one consistent with extra- the effect of endogenous ADH at the renal me- cellular volume depletion and another that simu- dulla, and reset the osmostat, thus lowering the lates SIADH. Serum uric acid level has been proposed as an index to discriminate between of the most important offending agents are re- Hyponatremia Due to Drug Treatment Drugs that Increase ADH Secretion Centrally
Oxcarbazepine is a 10-keto analogue of car- Psychotropic agents. Psychotropic agents have
bamazepine and is a useful drug in treating often been implicated in the cause of hyponatre- patients with the same seizure types, but it may mia, including both antidepressants (tricyclics, se- have an improved toxicity profile. However, lective serotonin reuptake inhibitors [SSRIs], and the prevalence of hyponatremia, as well as the monoamine oxidase inhibitors) and antipsychotic frequency of severe hyponatremia, is greater in drugs (phenothiazines and butyrophenones) patients treated with oxcarbazepine than with hyponatremia is believed to be the development can cause hyponatremia, possibly because of of SIADH. However, it should be emphasized that low serum sodium levels in emotionally Antineoplastic agents. Vincristine and, less of-
disturbed or psychotic patients may not be a ten, vinblastine are associated with hyponatre- direct consequence of these medications. Among the most frequent causes of hyponatremia in this tor control of ADH secretion through a direct toxic effect on the neurohypophysis and hypotha- and the compulsive water drinking. Primary poly- lamic system. That peripheral neuropathy often dipsia is prominent in patients with psychosis, is observed in patients with vinca alkaloid– affecting nearly 7% of patients with schizophre- related SIADH is indirect evidence for this neu- the sensation of a dry mouth caused by psycho- Hyponatremia associated with platinum com- tropic drugs (especially phenothiazines) may con- pounds is described more frequently with cispla- tin than with carboplatinThe possible under- causality between psychotropic agents and hypo- lying pathophysiological mechanisms by which natremia was shown more persuasively with an- cisplatin induces hyponatremia are SIADH and tidepressants and mainly with SSRIs, which cause renal salt wastingCisplatin-induced hyponatre- hyponatremia more frequently than other antide- mia often is combined with hypomagnesemia, pressant drugs. The incidence of hyponatremia hypokalemia, and hypocalcemia, with increased caused by SSRIs varies widely from 0.5% to magnesium, potassium, and calcium renal losses, 32%. In the majority of cases, hyponatremia respectively. This constellation of electrolyte dis- occurs within the first few weeks of the onset of turbances (observed only rarely in patients with therapy, whereas the normonatremia is achieved SIADH) is believed to be mediated by cisplatin- within 2 weeks after drug withdrawal. Older age related tubular necrosis. The incidence of hypo- and concomitant use of diuretics are the most natremia secondary to cisplatin can be as high as important risk factors for the development of 43%. However, it is difficult to define precisely given that the majority of cases described are in Antiepileptics. Hyponatremia has repeatedly
been associated with carbamazepine therapy Another drug that deserves emphasis is cyclo- Carmabazepine can induce hyponatremia by in- phosphamide. This alkylating agent, when admin- creasing ADH release from the neurohypophy- istered intravenously, can cause hyponatremia, sis. The incidence of carbamazepine-induced hy- impairing water excretion by potentiating the ponatremia ranged widely from 4.8% to 41.5%, effect of ADH and possibly by increasing its release. Patients on cyclophosphamide therapy Specifically, this electrolyte disturbance fre- are at high risk of developing hyponatremia quently was encountered in the elderly or sub- because they are encouraged to drink large jects who simultaneously used other medications amounts of fluids to maintain high urine output known to cause hyponatremia (mainly diuret- as an effort to prevent chemical cystitis. The combination of both increased ADH effect and effects of carbamazepine correlated with carbam- water intake can induce potentially life-threaten- azepine dose, serum carbamazepine level, and ing water intoxication. Administration of iso- tonic saline solution instead of using water is an appropriate measure to minimize the incidence Nonsteroidal anti-inflammatory drugs. Nonste-
roidal anti-inflammatory drugs (NSAIDs) de- It should be emphasized that in patients with crease water excretion by potentiating the ef- chemotherapy-related hyponatremia, chemo- fect of ADH. This is caused by a decrement in therapy-induced nausea may have an important renal prostaglandin synthesis because prosta- role because nausea is a potent stimulus to ADH glandin normally is an inhibitor of ADH ac- release. Moreover, immunomodulators, includ- tion. It should be noted that hyponatremia ing interferon, interleukin 2, and levamisole, as attributable exclusively to NSAIDs is rare, well as monoclonal antibodies, also were shown probably because prostaglandin inhibition also mechanism in the majority of cases seems to trally. However, volume-depleted patients or be SIADH. Finally, methotrexate in high doses those with SIADH simultaneously using this can cause hyponatremia. A toxic effect on the group of medications have increased risk of neurosecretory areas of the cerebrum, as well as alteration of the distribution of body fluid appears that NSAIDs are a risk factor for hypona- volumes, was proposed as a possible explana- tion of methotrexate-induced hyponatremia This association was described during military Analgesics. Morphine and other opiates have
operations and desert hikes. Such individuals often been implicated as a cause of hyponatremia, also may be using NSAIDs, which can impair the possibly by directly enhancing ADH releaseIn excretion of free water. Ultramarathon and mara- addition, indirect stimulation of ADH secretion thon runners may replace their dilute, but sodium- caused by opiate-induced nausea or hypotension containing, sweat losses with excessive amounts of hypotonic solutions, with the net effect of adecrease in plasma sodium concentration. How- Drugs that Potentiate the Effect of Endogenous
ever, the risk of hyponatremia in runners using ADH at the Renal Tubule Level
Antiepileptic drugs. It was proposed that car-
Drugs that Reset the Osmostat
bamazepine may cause hyponatremia by increas- Hyponatremia caused by a reset osmostat syn- ing renal sensitivity to normal plasma ADH drome variant of SIADH has been described lafaxine, a serotonin and norepinephrine re- Hypoglycemic agents. Chlorpropamide, which
is now rarely used in the treatment of patientswith diabetes mellitus, can cause hyponatremia Drugs Inducing Labor
in approximately 4% to 6% of patients with Oxytocin, used to induce labor or abortion, clinical characteristics of SIADH. Elderly pa- has significant antidiuretic activity. Therefore, tients concomitantly using diuretics have greater when administered with excess electrolyte-free amide can cause hyponatremia by decreasing by decreasing the amount of water given and ing that although fluid retention is a common using isotonic saline, rather than dextrose and adverse effect of both thiazolidinediones (piogli- water. Moreover, administration of exogenous tazone and rosiglitazone), hyponatremia related ADH (as part of the treatment of patients with to these drugs was not reported yet. Finally, there gastrointestinal hemorrhage) also can cause hy- is only 1 case report with metformin-related ponatremia. Finally, hyponatremia can be in- duced by desamino-8-D-AVP (an analogue of Anticancer agents. In addition to increasing
ADH), which is used for either polyuria in pa- ADH release, intravenous cyclophosphamide can tients with central diabetes insipidus or bleeding cause hyponatremia by potentiating the effect of caused by platelet dysfunction (von Willebrand Hyponatremia Due to Drug Treatment Drug-induced Dilutional or
results if measured in undiluted samples (direct Translocational Hyponatremia
In some cases, the decrease in serum sodium Intravenous immune globulin frequently is levels is associated with normal or increased effec- administered in a 10% maltose solution. Maltose tive plasma osmolality, rather than hypo-osmolal- normally is metabolized by maltase in proximal ity. This was called dilutional or translocational tubules. However, in patients with renal failure, hyponatremia.Administration of hypertonic manni- maltose accumulates in extracellular fluid, in- tol is an example of pseudohyponatremia with creasing plasma osmolality and diminishing se- increased plasma osmolality. Mannitol (by increas- ing plasma osmolality) creates a transcellular os- locational (hyperosmotic) hyponatremia also can motic gradient, resulting in water movement out of be observed with sugar-containing intravenous the cells and decrease in serum sodium concentra- immune globulin administration. It appears that the magnitude of hyponatremia depends consid-erably on the degree of renal impairment during Rare Causes of Drug-induced Hyponatremia
intravenous immune globulin infusion. In the setting of impaired renal function, decreased sporadic case reports of numerous other drugs renal clearance of sucrose takes place, leading to that can cause hyponatremia. Some of these increased effective plasma osmolalityFinally, relatively rare causes of drug-induced hyponatre- intravenous administration of immune globulin also can cause hyponatremia because of asepticmeningitis-related Angiotensin-Converting Enzyme Inhibitors
It is worth mentioning that angiotensin-con- Amphetamines
verting enzyme (ACE) inhibitors in combinationwith furosemide were shown to correct hypona- tremia in patients with congestive heart failure.
amine (MDMA), also known as ecstasy, is a However, ACE inhibitors per se can cause hypo- increasingly recognized cause of severe hypona- natremia. A handful of cases of ACE inhibitor– tremia. MDMA and its metabolites were shown related hyponatremia was reportedThese drugs to induce enhanced ADH secretion from the inhibit the conversion of angiotensin I to angio- hypothalamus. The excessive water intake (to tensin II in peripheral tissue, but not the brain. In counteract hyperthermia) is common in MDMA the brain, angiotensin I is converted to angioten- users and is involved in the pathogenesis of sin II, which may stimulate thirst and the release of ADH. Additionally, ACE inhibitors induce anincrease in ADH secretion by delaying the degra- Co-Trimoxazole
Trimethoprim-sulfamethoxazole (co-trimox- Immune Globulin
azole) is known to cause hyperkalemia and,less frequently, hyponatremia. These electro- It is well known that hyperlipidemia or hyper- proteinemia can induce pseudohyponatremia. Fur- lyte disturbances take place more often in thermore, intravenous infusion of immune globu- lin increases the protein-containing nonaqueous methoprim-sulfamethoxazole and those with phase of plasma, with a consequent relative de- renal dysfunction. Trimethoprim acts as a po- crease in plasma water volume. Because sodium tassium-sparing diuretic by blocking the amilo- is present in only the aqueous phase, each unit ride-sensitive sodium channels in the distal volume of plasma measured has less sodium- tubule. Consequently, the mild hyponatremia containing water, and this is interpreted as hypo- observed in patients administered trimethoprim natremia. Newer methods using ion-selective should be attributed to ongoing sodium losses electrodes for the measurement of serum electro- that lead to hypovolemia and increased ADH lytes may avoid this problem and give accurate Amiodarone
physiological mechanism of hyponatremia is not Hyponatremia is a rare adverse effect of amio- entirely clear, but is believed to be SIADH.
darone therapy. SIADH is the possible underly- Salt-losing nephropathy has also been proposed ing mechanism. It was proposed that amiodarone as a possible mechanism of PPI-related hypona- might cause SIADH through its channel-modulat- tremia given that these drugs are now the most ing properties on neural or renal tissues. Amioda- common cause of drug-induced acute interstitial rone-induced hyponatremia occurs mainly dur- nephritis. However, causality between PPI- ing the first weeks of therapy or even during induced hyponatremia and renal salt wasting was the loading period. It is worth mentioning that SIADH also was reported in association withother antiarrhythmic drugs, such as lorcainide CONCLUDING REMARKS
Calcium Channel Antagonists
the course of treatment with drugs used in every-day clinical practice (eg, newer antihypertensive In theory, calcium channel antagonists with agents, antibiotics, and PPIs). It should be noted natriuretic properties could cause hyponatremia.
that patients may receive complex drug regimens A case of amlodipine-associated hyponatremia (eg, patients with diabetes mellitus) containing several candidates as the cause of hyponatremia.
received amiodarone, which had not been recog- Discontinuation of treatment with these agents nized as a cause of hyponatremia at the time of and avoidance of readministration is fully war- publication. Consequently, calcium channel an- ranted. It is recommended that patients with tagonist–related hyponatremia, if it exists, is ex- acute severely symptomatic hyponatremia (eg, seizures) should be treated in an aggressive but Theophylline
controlled fashion, whereas less symptomatic Theophylline-induced hyponatremia has rarely hyponatremia may be corrected at a slower been described. Theophylline inhibits solute re- absorption in both the proximal nephron and tic target in all cases to limit the increase in diluting segment, with a thiazide-like action.
serum sodium concentration to less than 12 Furthermore, theophylline can cause hypokale- mEq/L (Ͻ12 mmol/L) in the first day and less mia, especially in patients with acute intoxica- than 18 mEq/L (Ͻ18 mmol/L) in the first 2 days tion. Depletion of potassium is expected to con- of treatment, as well as avoid overcorrection of serum sodium concentration to greater than 140 concentration is determined by the ratio of “ex- mEq/L (Ͼ140 mmol/L) within the first 2 days of changeable” (ie, osmotically active) portions of the body’s sodium and potassium content to verse effect of certain pharmaceutical com- total-body water. It also was proposed that potas- pounds on serum sodium concentrations facili- sium depletion shifts sodium to the intracellular tates a rational clinical management.
space. Additionally, theophylline-associated SI-ADH is ACKNOWLEDGEMENTS
Proton Pump Inhibitors
Proton pump inhibitors (PPIs) also can cause hyponatremia. Currently, only 9 cases of PPI- REFERENCES
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Szemle DEMOKRÁCIA Az emberi egyenértékûség Krisztus- sal kezdõdik, ezért nincs és nem is lehet felebaráti de-mokrácia Krisztus és tanítása nélkül. (1974. július 1.)Ha a kisebbség erõlteti rá akaratát a többségre, eznem demokrácia, hanem egészen másvalami. (1948. Az igazi demokrácia alappillére, hogy sértetlen O R S Z Á G G Y Û L É S természetj

original article J ournal of A ndrological S ciences 2011;18:64-71 Up-to-date on erectile dysfunction and treatment V. Gentile, S. Salciccia, P. Fele*, G.M. Busetto Dipartimento di Scienze Ginecologico-Ostetriche e Scienze Urologiche, Sapienza Università di Roma, Italy; * Dipartimento di Scienze Ostetrico-Ginecologiche, Urologiche e Medicina della Riproduzione, Università Federi

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