Stay alert to drugs that cause hyponatremia

Questions are coming up about medications-induced hyponatremia. Low sodium levels are the most common electrolyte disturbance. Symptoms are rare with mild drops below 135 mEq/L that develop over time. But severe or rapid drops in sodium below 125 mEq/L can cause coma or seizures.

Plus, chronically low sodium in older patients is linked with cognitive impairment, falls, and fractures. Hundreds of medications list low sodium as a possible side effect, often based on limited evidence. Know when to be proactive...

• High-risk patients. Be on the lookout for medication-induced hyponatremia in the elderly or patients with low body weight. Medications linked with hyponatremia may also "tip the balance" in patients at risk for low sodium, such as in heart failure, renal or liver disease, uncontrolled hypothyroidism, or malnourishment.
• Medication culprits. Watch for hyponatremia with SSRIs (e.g., Cipralex), SNRIs (e.g., Efexor), and diuretics, especially thiazides. These are the most common medication causes. Look for other likely culprits, such as antipsychotics, tricyclics, tramadol, desmopressin (Minirin, Omegapress), carbamazepine (Tegretol) and oxcarbazepine (Trileptal). Try to limit doses of these, especially in high-risk patients. And generally, avoid combining desmopressin with other risky medications.
• Monitoring and education. Be especially cautious in high-risk patients or with risky combos, such as an SSRI or SNRI plus a thiazide. In these cases, consider checking sodium at baseline and usually one to two weeks after starting or changing a dose and educate high-risk patients to report symptoms such as confusion, headache, or nausea. Get our note, "Best approach for treating HYPOnatremia" to know how to manage hyponatremia.

Table (1). Medications induced Hyponatremia
Clinical Question	Information
Common medications that have been associated with hyponatremia	Antiarrhythmics: amiodarone, propafenone Antibiotics: ciprofloxacin, rifabutin, trimethoprim/sulfamethoxazole Anticonvulsants, particularly carbamazepine and oxcarbazepine. Gabapentin, eslicarbazepine, lamotrigine, levetiracetam, and valproate have also been implicated. Antidepressants, particularly SSRIs and venlafaxine. Duloxetine, mirtazapine, bupropion, and TCAs, have also been implicated. Antidiabetic agents: chlorpropamide, tolbutamide Antihypertensives: ACEI, amlodipine (extremely rare, if at all) Antipsychotics: phenothiazines (thioridazine, trifluoperazine), clozapine, haloperidol DIURETICS: thiazides especially, but also loops, and amiloride when combined with hydrochlorothiazide. Diuretics are the most common cause of hyponatremia in the outpatient setting. Chemotherapy: carboplatin, cisplatin, cyclophosphamide, ifosfamide, levamisole, melphalan, methotrexate, vincristine Desmopressin Laxatives Nicotine NSAIDs Oxytocin Proton pump inhibitors Theophylline (rare) Tramadol
Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ADH = antidiuretic hormone; NSAID = nonsteroidal anti-inflammatory drug; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant

REFERENCES

• Henry DA. In The Clinic: Hyponatremia. Ann Intern Med. 2015 Aug 4;163(3):ITC1-19. Available at: https://www.acpjournals.org/doi/10.7326/AITC201508040

  Ramos-Levi AM, Duran Rodriguez-Hervada A, Mendez-Bailon M, Marco-Martinez J. Drug-induced hyponatremia: an updated review. Minerva Endocrinol. 2014 Mar;39(1):1-12. Available at: https://www.minervamedica.it/en/journals/minerva-endocrinology/article.php?cod=R07Y2014N01A0001&acquista=1 or https://pubmed.ncbi.nlm.nih.gov/24513599

  Lu X, Wang X. Hyponatremia induced by antiepileptic drugs in patients with epilepsy. Expert Opin Drug Saf. 2017 Jan;16(1):77-87. Available at: https://www.tandfonline.com/doi/abs/10.1080/14740338.2017.1248399?journalCode=ieds20

  De Picker L, Van Den Eede F, Dumont G, Moorkens G, Sabbe BG. Antidepressants and the risk of hyponatremia: a class-by-class review of literature. Psychosomatics. 2014 Nov-Dec;55(6):536-47. Available at: https://www.sciencedirect.com/science/article/pii/S0033318214000152?via%3Dihub