Hyponatremia: Evolving diagnostics and emerging therapeutics in clinical practice

Table 1 Medications associated with syndrome of inappropriate antidiuretic hormone or hyponatremia

Drug class	Examples	Proposed mechanism	Clinical notes
Antidepressants	SSRIs (sertraline, fluoxetine, paroxetine), SNRIs (venlafaxine, duloxetine), tricyclics (amitriptyline), mirtazapine	Enhanced ADH release or potentiation of its renal effect	Most frequent cause in older adults, especially underweight women
Antipsychotics	Haloperidol, risperidone, olanzapine, quetiapine	Dopaminergic and serotonergic modulation of ADH	Risk increases with concomitant antidepressants
Antiepileptics/mood stabilizers	Carbamazepine, oxcarbazepine, valproate, lamotrigine	Increased ADH release and sensitivity at renal V2 receptor	Carbamazepine is a classic cause of chronic SIADH
Chemotherapeutic/oncologic agents	Cyclophosphamide, vincristine, cisplatin, ifosfamide	Direct stimulation of ADH release or renal tubular toxicity	Often transient; risk rises with concomitant nausea or stress
Analgesics	Opioids (morphine, tramadol), NSAIDs	Opioids increase ADH release; NSAIDs potentiate its action by reducing prostaglandin inhibition	Particularly relevant postoperatively
Diuretics	Thiazides (hydrochlorothiazide, indapamide)	Impaired urinary dilution, sodium loss	Responsible for up to 90% of diuretic-induced hyponatremia
Antineoplastic/immunomodulators	Interferon-α, cyclophosphamide, vincristine	Hypothalamic or renal effect on ADH	Usually dose-dependent
Other agents	Desmopressin, chlorpropamide, ecstasy (MDMA)	Direct V2 receptor agonism or ADH secretion	Seen in recreational drug users and hospitalized patients receiving DDAVP

SSRI: Selective serotonin reuptake inhibitor; SNRI: Serotonin-norepinephrine reuptake inhibitor; ADH: Antidiuretic hormone; SIADH: Syndrome of inappropriate antidiuretic hormone secretion; NSAID: Non-steroidal anti-inflammatory drug; MDMA: 3,4-methylenedioxymethamphetamine; DDAVP: 1-deamino-8-D-arginine vasopressin.

Table 2 Comparison of syndrome of inappropriate antidiuretic hormone, cerebral salt wasting, and reset osmostat

Feature	SIADH	Cerebral salt wasting	Reset osmostat
Volume status	Euvolemic	Hypovolemic (true salt loss)	Euvolemic
Plasma sodium	Low	Low	Mildly low but stable
Urine sodium	> 30 mmol/L	> 30 mmol/L	Variable
Urine osmolality	> 100 mOsm/kg	> 100 mOsm/kg	Normal dilution capacity maintained
Serum uric acid	Low	Low	Normal or low-normal
Fractional excretion of uric acid	Elevated during hyponatremia (> 12%), normalizes after correction	Remains elevated after correction	Normal (< 11%)
Fractional excretion of sodium	> 0.5%-1% (inappropriately high for euvolemia)	> 1%-2% (due to true renal salt loss)	Normal or slightly increased
Fractional excretion of urea	> 55%-60%	> 60%-70%	Normal (< 35%)
Response to isotonic saline	No improvement or worsens hyponatremia	Improves serum sodium and volume	No major change
ADH secretion pattern	Inappropriate, independent of osmolality	Appropriate (secondary to hypovolemia)	Reset to a lower threshold
Volume markers (BUN, hematocrit)	Normal	Elevated (due to hypovolemia)	Normal
Treatment approach	Fluid restriction, salt tablets, urea, vaptans	Volume and salt repletion ± fludrocortisone	Usually none; avoid overcorrection
Typical setting	Pulmonary disorders, malignancy, CNS disease, drugs	CNS injury, subarachnoid hemorrhage, neurosurgery	Chronic illness, elderly, pregnancy, tuberculosis, carcinoma

ADH: Antidiuretic hormone; BUN: Blood urea nitrogen; CNS: Central nervous system.