Medications and the Perils of Too Little Sodium in the Blood

Many people with hypertension or congestive heart failure have been told by their physicians to avoid eating high sodium foods to help control their disease.

This is sound advice. Nonetheless, some people develop hyponatremia, a potentially life-threatening disorder in which there is too little sodium in the blood.

A recent review of drug-induced hyponatremia in the American Journal of Kidney Diseases presented compelling evidence that drug-induced hyponatremia is more common than many people believe. Greater awareness on the part of both health professionals and patients is important, because early recognition may allow application of corrective measures to prevent serious adverse outcomes.

In this article we describe the types of people who are predisposed to hyponatremia, what medications may lead to this disorder and what symptoms to look for if you think you may be at risk.

What are the major risk factors of hyponatremia?

Old Age. Older people are at increased risk of hyponatremia for several reasons. Kidney function declines with age, and the kidneys are important in regulating sodium excretion in the urine. Thus, the ability of older people to compensate for factors that reduce blood sodium may be compromised. Low body weight also may be a risk factor, which is probably why elderly women appear to be at particular risk. In addition, older people may have diseases, accidents or surgery that predispose them to hyponatremia. Finally, older people take more medications than younger people, and they also take more of the types of medications that can make them more susceptible to hyponatremia.

Diseases. Patients with diseases such as pneumonia, congestive heart failure, cirrhosis, certain malignancies and other diseases such as epilepsy may be at increased risk of hyponatremia.

Trauma and Surgery. People who have sustained severe trauma, especially to the head, are at increased risk of hyponatremia. The same applies to patients who have undergone neurosurgery. The trauma of prolonged strenuous exercise also can put patients at risk.

What medications can cause hyponatremia?

Several commonly used medications have been associated with this condition. Problems are more likely to occur when the person also has other risk factors such as those described above, or are taking more than one medication that can cause hyponatremia.

Diuretics. Thiazide diuretics such as hydrochlorothiazide are useful and inexpensive drugs for the treatment of hypertension and other cardiovascular disorders, so they continue to be commonly used.

Thiazide diuretics are probably at the top of the list of drugs causing hyponatremia. Thiazide diuretics are designed to increase sodium elimination in the urine, so it makes sense that they could increase the risk of hyponatremia. In most cases of thiazide diuretic-induced hyponatremia, the patient has other risk factors for hyponatremia such as the diseases listed above or they are also using other drugs that can cause hyponatremia.

Related diuretics such as hydrochorothiazide and amiloride (MODURETIC) and indapamide also have been associated with hyponatremia. However, loop diuretics such as furosemide (LASIX) appear less likely to cause hyponatremia than thiazide diuretics and are sometimes used to treat hyponatremia. See Table 2 for a complete list of thiazide diuretics.

Selective serotonin reuptake inhibitors (SSRIs). The popular SSRIs and selective serotonin/ norepinephrine reuptake inhibitors (SNRIs) used for depression and other psychiatric disorders have been associated with hyponatremia in a number of studies and case reports.

The results of epidemiologic studies suggest that the risk may be higher than commonly believed. In one study of paroxetine (PAXIL), for example, hyponatremia developed in 12 percent of people within 12 weeks of starting paroxetine. Detection of SSRI/SNRI-induced hyponatremia by doctors and others may be hampered by the fact that hyponatremia can cause symptoms that mimic depression such as loss of appetite, fatigue and lethargy. See Table 1 for a complete list of SSRIs and SNRIs.

There is some evidence that tricyclic antidepressants, not listed above, can also produce hyponatremia, but based on available data the risk seems lower than with SSRIs. Mirtazapine (REMERON) may be less likely to cause hyponatremia than SSRIs, but there are isolated case reports of hyponatremia with mirtazapine, so the jury is still out on this one.

Antipsychotic medications. Antipsychotic medications such as thioridazine (MELLARIL), trifluoperazine (STELAZINE) and haloperidol (HALDOL) have been associated with hyponatremia. Nonetheless, in some instances it may be difficult to sort out whether the medications or the disease is responsible in these cases, because psychotic patients may be predisposed to hyponatremia if their particular psychoses cause compulsive water drinking and/or their antipsychotic medications cause dry mouth.

Antiepileptic medications. Carbamazepine (TEGRETOL) and oxcarbazepine (TRILEPTAL) have been associated with hyponatremia in a number of cases. As with SSRI-induced hyponatremia, the risk appears greater in the elderly and those taking other drugs that can also cause hyponatremia. Keep in mind that several of the symptoms of hyponatremia are also classic symptoms of carbamazepine toxicity, such as nausea, anorexia, lethargy and headache. There is some evidence that other antiepileptic medications such as lamotrigine (LAMICTAL) and valproic acid (DEPAKOTE) may increase the risk of hyponatremia. It is possible that epilepsy itself may contribute to the low blood sodium levels in these cases, but more study is needed on this point.

Chemotherapy drugs. Several chemotherapy drugs have been associated with hyponatremia, including vincristine (ONCOVIN), vinblastine (VELBAN), cisplatin and cyclophosphamide (CYTOXAN, NEOSAR). Factors contributing to the hyponatremia in some of these cases include increased fluid intake (which may be recommended for cyclophosphamide), and chemotherapy- induced nausea, which can cause release of a hormone (antidiuretic hormone) that reduces water excretion in the urine.

Other drugs. A number of other drugs have been associated with hyponatremia, including narcotic analgesics, such as morphine; antidiabetic drugs, such as chlorpropamide or tolbutamide; nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (MOTRIN); the hormone oxytocin; ACE (angiotensin-converting enzyme) inhibitors, such as enalapril (VASOTEC); “ecstasy” (MDMA); co-trimoxazole (SEPTRA, BACTRIM); amiodarone (CORDARONE); theophylline; and proton pump inhibitors such as omeprazole (PRILOSEC). Many of these drugs are widely used, however, and the incidence of hyponatremia is probably low.

What are the symptoms of hyponatremia?

One of the problems with detecting hyponatremia is that early symptoms are often nonspecific and can be caused by many other factors. Mild symptoms include nausea, loss of appetite, fatigue, lethargy, muscle cramps and headache. These nonspecific symptoms may be accompanied by confusion and disorientation, which is especially problematic in the elderly where confusion may be attributed to onset of — or worsening of — dementia. More severe hyponatremia can be dangerous, and can produce delirium, seizures, coma and respiratory arrest.

Can hyponatremia be treated?

Yes, once hyponatremia has been diagnosed, it can usually be corrected it if is detected early. The drugs that caused the hyponatremia are usually stopped, and that is often enough to correct mild cases. Other measures such as fluid restriction may also be useful for some people. More severe cases may require more intensive treatments, including intravenous use of high-sodium fluids.

What You Can Do

Because hyponatremia appears to be underdiagnosed, both patients and health professionals should be alert for this disorder in patients who are at higher risk. Most cases of antidepressant-induced hyponatremia occur within the first three weeks of therapy, so measuring serum sodium three weeks after starting therapy would be useful.

Although this is not currently a routine practice, one could argue that it should be done in elderly patients or those with other risk factors, such as those already receiving thiazide diuretics. In any case, both patients and health professionals should be alert for the onset of symptoms that may signal the onset of hyponatremia if the patient is predisposed to this disorder as a result of their drug therapy or diseases.  

* Do Not Use in Worst Pills, Best Pills
** Limited Use in Worst Pills, Best Pills

* Do Not Use in Worst Pills, Best Pills
** Limited Use in Worst Pills, Best Pills
*** Do Not Use for 7 Years After FDA Approval (2009) in Worst Pills, Best Pills