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NARRATIVE REVIEW

A Review of Drug-Induced Hyponatremia


George Liamis, MD, Haralampos Milionis, MD, and Moses Elisaf, MD

Hyponatremia (defined as a serum sodium level ! 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 in
everyday 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 certain
pharmaceutical compounds on serum sodium levels. Here, we review clinical information about the
incidence 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.

H yponatremia (defined as a serum sodium


level ! 134 mmol/L) is a common electro-
lyte disturbance in clinical practice that is associ-
PATHOGENETIC ASPECTS
OF HYPONATREMIA
Hyponatremia is ascribed to either water reten-
ated with considerable morbidity and mortal-
tion or (less often) loss of effective solute (so-
ity.1,2 Drugs 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-
implications. cept renal failure and primary polydipsia) are
characterized by an excess of ADH (despite the
presence of hypotonicity), most frequently caused
by 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 tion).1,3
March 3, 2008. Originally published online as doi:
10.1053/j.ajkd.2008.03.004 on May 8, 2008. A decrease in serum sodium concentration
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-
E-mail: egepi@cc.uoi.gr
© 2008 by the National Kidney Foundation, Inc.
toms of hyponatremia (predominantly neurologi-
0272-6386/08/5201-0020$34.00/0 cal) are attributed to cerebral edema. Moreover,
doi:10.1053/j.ajkd.2008.03.004 they are related to both the severity and rapidity

144 American Journal of Kidney Diseases, Vol 52, No 1 (July), 2008: pp 144-153
Hyponatremia Due to Drug Treatment 145

of decrease in serum sodium levels.2,4-6 Hy- Table 2. Rare Causes of Drug-Induced Hyponatremia
ponatremic patients at risk of neurological com-
Antihypertensive agents
plications caused by acute cerebral edema are Angiotensin-converting enzyme inhibitors62
postoperative menstruating women, elderly Amlodipine63
women on thiazide therapy, children, psychiatric Immune globulin (intravenous)64,65
polydipsic patients, and hypoxemic patients.7 3,4-Methylenedioxymethylamphetamine (ecstasy)66,67
Antibiotics
DRUG-INDUCED HYPONATREMIA Trimethoprim-sulfamethoxazole,68 ciprofloxacin,69
cefoperazone/sulbactam,70 rifabutin71
Hyponatremia related to drug treatment can be Antiarrhythmic
caused by dozens, perhaps hundreds, of medica- Amiodarone,72 lorcainide,73 propafenone74
Theophylline75
tions. Because hyponatremia can have many
Proton pump inhibitors76
Bromocriptine77
Table 1. Principal Causes and Underlying Terlipressin78
Mechanisms of Drug-Induced Hyponatremia Duloxetine79
Fluorescein angiography80
Drugs affecting sodium and water homeostasis Bupropion81
Diuretics
Thiazides8-18
Indapamide19
Amiloride other causes, the diagnosis of drug-induced hypo-
Loop diuretics8,14 natremia can easily be overlooked.
Drugs affecting water homeostasis As shown in evidence from small studies and
Increased hypothalamic production of ADH case reports, drugs may cause hyponatremia by
Antidepressants
Tricyclic antidepressants (amitryptiline,
affecting sodium homeostasis and water ho-
protriptyline, desipramine)20 meostasis. Clinical information about the inci-
Selective serotonin reuptake inhibitors21-25 dence and pathophysiological process of hypona-
Monoamine oxidase inhibitors26 tremia of the most commonly offending agents is
Antipsychotic drugs presented first (Table 1). Rarer causes derived
Phenothiazines (thioridazine, trifluoperazine)27,28
Butyrophenones (haloperidol)29
from occasionally reported cases also are pre-
Antiepileptic drugs sented (Table 2).
Carbamazepine,30-35 oxcarbazepine,33,36,37
sodium valproate38 Drugs Affecting Sodium and Water Homeostasis
Anticancer agents Diuretic Treatment
Vinca alkaloids (vincristine, vinblastine)39-42
Platinum compounds (cisplatin, carboplatin)42-44 Diuretics make up one of the most common
Alkylating agents (intravenous causes of hyponatremia, with an estimated inci-
cyclophosphamide,45-47 melphalan,48 dence of 11% in 1 series of 114 geriatric pa-
ifosfamide49)
tients.8,9 Interestingly, we recently showed that
Miscellaneous (methotrexate, interferon ! and ",
levamisole, pentostatin, monoclonal diuretics are the most common cause of commu-
antibodies)42,50 nity-developed hyponatremia.10 Diuretic-induced
Opiates51 hyponatremia is caused almost exclusively by
Potentiation of ADH effect thiazide or thiazide-like agents.8,11-17 Loop diuret-
Antiepileptic drugs
ics, by inhibiting sodium chloride reabsorption
Carbamazepine,30-33 lamotrigine52
Antidiabetic drugs in the thick ascending limb of the loop of Henle,
Chlorpropamide,53-55 tolbutamide56 reduce the osmolarity of the medullary intersti-
Anticancer agents tium. Consequently, loop diuretics rarely are asso-
Alkylating agents (intravenous cyclophosphamide)46 ciated with hyponatremia because they impair both
Nonsteroidal anti-inflammatory drugs57-60
the renal concentrating and diluting mechanisms.8,14
Reset osmostat
Antidepressants Conversely, thiazide diuretics acting solely in the
Venlafaxine61 distal tubules do not interfere with urinary concen-
Antiepileptic drugs tration and the ability of ADH to promote water
Carbamazepine33 retention, which is the critical point for the develop-
Abbreviation: ADH, antidiuretic hormone. ment of hyponatremia.
146 Liamis, Milionis, and Elisaf

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-
amiloride.19,82 The combination of hydrochlo- fined.10 Specifically, patients with a serum uric
rothiazide and amiloride appears to increase the acid level less than 4 mg/dL (!238 #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-
mia, if present. Conversely, in patients with an
ciency has been implicated as the major etiologic
SIADH-like state who present with severe symp-
factor of hyponatremia induced by the combina-
tion of amiloride plus thiazide.82 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 dence to suggest an underlying cause for
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- by SIADH, an evaluation is a prudent ap-
sium depletion; and (7) excessive ADH secre- proach if even mild hyponatremia persists af-
tion.8,11-18 Furthermore, acute severe hyponatre- ter this diagnostic waiting period.
mia occasionally is observed as an idiosyncratic
reaction, particularly in subjects who consume Drugs Affecting Water Homeostasis
large quantities of water.11 Most cases of thiazide-
induced hyponatremia occur in elderly patients, Except for diuretics, several other drugs that
with a female predominance.8,13,16 Furthermore, impair the renal diluting capacity also can induce
subjects with low body mass appear to be more hyponatremia (Table 1). There are 3 possible
prone to this complication.8 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 threshold for ADH secretion (Table 1). Several
proposed as an index to discriminate between of the most important offending agents are re-
these 2 pathophysiological constructs.83,84 Re- viewed here.
Hyponatremia Due to Drug Treatment 147

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).20-29 patients treated with oxcarbazepine than with
The mechanism by which these drugs cause carbamazepine.33,36,37 Finally, valproic acid
hyponatremia is believed to be the development can cause hyponatremia, possibly because of
of SIADH. However, it should be emphasized SIADH.39
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 mia.39-42 These drugs alter the normal osmorecep-
the most frequent causes of hyponatremia in this tor control of ADH secretion through a direct
population are the underlying psychosis itself85 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-
nia.86,87 In addition to the underlying psychosis, rological toxicity.39
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-
tribute to the increase in water intake.28 Thus, tin than with carboplatin.42,43 The 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 wasting.44 Cisplatin-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
hyponatremia associated with SSRIs.23-25 given that the majority of cases described are in
Antiepileptics. Hyponatremia has repeatedly case reports.42,43
been associated with carbamazepine therapy.30-35 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
depending on the patient population studied.33-35 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
ics).33-35 It is noteworthy that the hyponatremic 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-
lower initial serum sodium concentration.33-35 tonic saline solution instead of using water is an
148 Liamis, Milionis, and Elisaf

appropriate measure to minimize the incidence Nonsteroidal anti-inflammatory drugs. Nonste-


of this complication.45-47 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
to induce hyponatremia.42 The underlying may directly suppress ADH secretion cen-
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 developing hyponatremia.57,58 Additionally, it
as alteration of the distribution of body fluid appears that NSAIDs are a risk factor for hypona-
volumes, was proposed as a possible explana- tremia in ultramarathon and marathon runners.59
tion of methotrexate-induced hyponatremia.50 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 release.51 In 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
may occur. of hypotonic solutions, with the net effect of a
decrease 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 NSAIDs was not shown in all studies.60
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
concentrations.30-33 Lamotrigine also may poten- after treatment with carbamazepine,33 and ven-
tiate renal tubule effects of ADH.52 lafaxine, a serotonin and norepinephrine re-
Hypoglycemic agents. Chlorpropamide, which uptake inhibitor.61
is now rarely used in the treatment of patients
with 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
risk of developing hyponatremia.53-55 Tolbut- water, hyponatremia is a possible conse-
amide can cause hyponatremia by decreasing quence.89-91 This complication can be prevented
renal free water clearance.56 It is worth mention- 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-
hyponatremia.88 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
ADH.46 disease).92,93
Hyponatremia Due to Drug Treatment 149

Drug-induced Dilutional or results if measured in undiluted samples (direct


Translocational Hyponatremia potentiometry).
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- rum sodium levels by means of dilution.64 Trans-
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
tion by means of dilution. 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
Apart from agents listed in Table 1, there are 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 osmolality.65 Finally,
relatively rare causes of drug-induced hyponatre- intravenous administration of immune globulin
mia are listed in Table 2. also can cause hyponatremia because of aseptic
meningitis-related SIADH.65
Angiotensin-Converting Enzyme Inhibitors
It is worth mentioning that angiotensin-con- Amphetamines
verting enzyme (ACE) inhibitors in combination
with furosemide were shown to correct hypona- Abuse of 3,4-methylenedioxymethylamphet-
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 reported.62 These 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 MDMA-induced hyponatremia.66,67
of ADH. Additionally, ACE inhibitors induce an
increase in ADH secretion by delaying the degra- Co-Trimoxazole
dation of bradykinin.
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-
lyte disturbances take place more often in
proteinemia can induce pseudohyponatremia. Fur-
thermore, intravenous infusion of immune globu- patients administered high doses of tri-
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 secretion.68
150 Liamis, Milionis, and Elisaf

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 not definitively proved yet.76
SIADH also was reported in association with
other antiarrhythmic drugs, such as lorcainide CONCLUDING REMARKS
and propafenone.72-74 Hyponatremia occasionally may develop in
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
has been reported.63 However, that patient also
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,
tremely rare.
seizures) should be treated in an aggressive but
Theophylline controlled fashion, whereas less symptomatic
hyponatremia may be corrected at a slower
Theophylline-induced hyponatremia has rarely
pace.94 Most authorities advocate as a therapeu-
been described. Theophylline inhibits solute re-
tic target in all cases to limit the increase in
absorption in both the proximal nephron and
serum sodium concentration to less than 12
diluting segment, with a thiazide-like action.
mEq/L (!12 mmol/L) in the first day and less
Furthermore, theophylline can cause hypokale-
than 18 mEq/L (!18 mmol/L) in the first 2 days
mia, especially in patients with acute intoxica-
of treatment, as well as avoid overcorrection of
tion. Depletion of potassium is expected to con-
serum sodium concentration to greater than 140
tribute to hyponatremia because sodium
mEq/L ("140 mmol/L) within the first 2 days of
concentration is determined by the ratio of “ex-
treatment.94 Nonetheless, awareness of the ad-
changeable” (ie, osmotically active) portions of
verse effect of certain pharmaceutical com-
the body’s sodium and potassium content to
pounds on serum sodium concentrations facili-
total-body water. It also was proposed that potas-
tates a rational clinical management.
sium depletion shifts sodium to the intracellular
space. Additionally, theophylline-associated SI-
ADH is probable.75 ACKNOWLEDGEMENTS
Support: None.
Proton Pump Inhibitors Financial Disclosure: None.
Proton pump inhibitors (PPIs) also can cause
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