Understanding Hypernatremia
Hypernatremia is an electrolyte disorder characterized by an elevated sodium concentration in the blood, specifically a serum level exceeding 145 mEq/L [1.3.4, 1.4.5]. This condition signifies a deficit of total body water relative to the body's total sodium content, leading to hyperosmolality [1.7.3]. In most clinical scenarios, hypernatremia results from net water loss or a failure to replace ongoing water losses, which can be exacerbated by impaired thirst mechanisms or an inability to access water [1.3.1]. Less commonly, it can be caused by a large intake of sodium [1.3.1]. The body's primary defense against hypernatremia is the stimulation of thirst and the renal conservation of water, a process mediated by the antidiuretic hormone (ADH), also known as vasopressin [1.2.3]. Certain medications can disrupt this delicate balance, leading to drug-induced hypernatremia.
Mechanisms of Drug-Induced Hypernatremia
Drugs typically cause hypernatremia through two primary pathophysiological pathways: inducing excessive water loss or causing a hypertonic gain of sodium [1.2.6, 1.3.4].
Promoting Renal Water Loss (Nephrogenic Diabetes Insipidus)
The most common mechanism is the induction of nephrogenic diabetes insipidus (NDI). In this condition, the kidneys' collecting ducts become resistant to the effects of ADH [1.6.3]. ADH normally promotes water reabsorption by increasing the insertion of aquaporin-2 (AQP2) water channels into the kidney tubules [1.3.2]. When this signaling is impaired, the kidneys are unable to concentrate urine, leading to the excretion of large volumes of dilute urine (polyuria), which results in a net loss of free water and a subsequent rise in serum sodium [1.3.2, 1.6.6].
Promoting Sodium Gain or Other Water Losses
Some medications directly increase the body's sodium load. This can occur through the administration of hypertonic sodium solutions, such as hypertonic saline or sodium bicarbonate, often used in critical care settings [1.2.6]. Other drugs, like osmotic laxatives, cause water loss through the gastrointestinal tract, which, if not matched by fluid intake, can lead to dehydration and hypernatremia [1.2.6].
Common Medications Causing Hypernatremia
A variety of medications across different classes are implicated in causing hypernatremia.
Lithium
Lithium is the most well-known and frequent cause of drug-induced NDI, affecting a significant percentage of patients on long-term therapy [1.2.6, 1.6.1]. It impairs the kidney's ability to concentrate urine by inhibiting signaling pathways downstream of the vasopressin receptor, which leads to a downregulation of AQP2 water channels [1.3.2, 1.6.3]. This effect is often reversible upon discontinuation of the drug, but in some cases of prolonged use, it can be permanent [1.2.6, 1.6.6].
Diuretics
- Loop Diuretics (e.g., Furosemide, Torsemide): These agents are a common cause of hypernatremia, especially in the elderly [1.2.1]. They work by inhibiting the Na-K-2Cl cotransporter in the thick ascending limb of the loop of Henle, which impairs the generation of the medullary concentration gradient necessary for water reabsorption. This leads to a loss of free water in excess of salt [1.2.1, 1.5.5].
- Osmotic Diuretics (e.g., Mannitol): Mannitol is an osmotically active agent that is filtered by the glomerulus but not readily reabsorbed. It increases urine output by drawing water into the renal tubules, leading to osmotic diuresis and potential free water loss [1.2.6, 1.7.6].
Other Implicated Drugs
- Amphotericin B: This antifungal agent is nephrotoxic and can induce NDI by damaging renal tubules and impairing the kidney's response to ADH [1.2.6, 1.6.4].
- Lactulose: An osmotic laxative used to treat constipation and hepatic encephalopathy, lactulose can cause significant diarrhea, leading to gastrointestinal water loss and hypernatremia if fluid intake is inadequate [1.2.6].
- Sodium-Containing Medications: Administration of hypertonic saline (3% NaCl), sodium bicarbonate, or antibiotics with high sodium content (like piperacillin-tazobactam) can directly lead to a hypertonic sodium gain [1.2.6, 1.3.7, 1.5.5]. Sodium polystyrene sulfonate, a resin used to treat hyperkalemia, exchanges potassium for sodium in the gut, which can increase sodium levels [1.8.2, 1.8.5].
- Demeclocycline: A tetracycline antibiotic that is a known cause of NDI. This side effect is so reliable that it has been used therapeutically to treat hyponatremia caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH) [1.2.6, 1.6.5].
Comparison of Common Drug Classes
| Drug Class | Examples | Primary Mechanism of Hypernatremia | Common Clinical Use |
|---|---|---|---|
| Antimanic Agents | Lithium | Induces nephrogenic diabetes insipidus (NDI) by downregulating AQP-2 water channels [1.3.2]. | Bipolar disorder [1.6.1]. |
| Loop Diuretics | Furosemide, Bumetanide | Promotes electrolyte-free water excretion by impairing the renal concentrating mechanism [1.2.1]. | Heart failure, edema, hypertension [1.2.1]. |
| Osmotic Diuretics | Mannitol | Causes osmotic diuresis, leading to renal water loss [1.2.6]. | Reduction of intracranial pressure [1.2.6]. |
| Antifungals | Amphotericin B | Induces NDI through direct renal tubule toxicity [1.2.6, 1.6.4]. | Severe systemic fungal infections [1.6.3]. |
| Osmotic Laxatives | Lactulose, Sorbitol | Induces osmotic diarrhea, causing gastrointestinal free water loss [1.2.6]. | Hepatic encephalopathy, constipation [1.2.6]. |
| Hypertonic Solutions | 3% Saline, Sodium Bicarbonate | Direct administration of a hypertonic sodium load [1.2.6]. | Treatment of severe hyponatremia, metabolic acidosis [1.2.6]. |
Clinical Presentation and Management
Symptoms of hypernatremia are primarily neurological and result from brain cell shrinkage due to the osmotic shift of water out of brain cells [1.7.6]. Early symptoms can include lethargy, weakness, and intense thirst [1.5.4]. As the condition worsens, it can lead to confusion, muscle twitches, seizures, coma, and even death [1.5.4, 1.5.6]. The severity of symptoms often correlates with the acuity and magnitude of the serum sodium increase [1.2.6].
Management of drug-induced hypernatremia involves several key steps:
- Identify and Discontinue the Offending Drug: This is the most critical first step whenever possible [1.5.2].
- Correct the Water Deficit: The primary treatment is the replacement of free water [1.5.4]. This is typically done using oral water if the patient is conscious and able to drink, or with intravenous (IV) hypotonic fluids like 5% dextrose in water (D5W) or 0.45% saline [1.5.3, 1.5.5].
- Correct Slowly: In cases of chronic hypernatremia (present for >48 hours), the correction must be done slowly to avoid cerebral edema, a potentially fatal complication that occurs when water moves back into brain cells too quickly [1.5.1, 1.5.6]. The goal is typically to lower the serum sodium by no more than 0.5 mEq/L/hour, or less than 12 mEq/L over a 24-hour period [1.5.3, 1.5.6].
- Monitor Closely: Frequent monitoring of serum electrolytes (every 2-4 hours initially) is essential during correction to ensure the rate is appropriate [1.5.3, 1.5.6].
Conclusion
Drug-induced hypernatremia is a significant clinical concern, particularly in vulnerable populations such as the elderly and critically ill [1.3.2]. A wide range of medications, from lithium and diuretics to laxatives and certain antibiotics, can disrupt sodium and water homeostasis. Awareness of which drugs cause hypernatremia, understanding their underlying mechanisms, and recognizing the signs of this disorder are paramount for prevention. When it does occur, prompt identification of the causative agent and careful, methodical correction of the water deficit are essential to prevent the severe morbidity and mortality associated with this electrolyte imbalance [1.2.6].
For further reading, an authoritative overview can be found at: A review of drug-induced hypernatraemia, via the National Center for Biotechnology Information [1.2.6, 1.3.2, 1.3.4]
