TO THE EDITOR:
Hyponatraemia is frequently observed and usually caused by drugs.
Fluconazole induced hyponatraemia remains under-reported.
An 82-year-old woman was admitted for rehabilitation. Past medical
history was significant for hypertension, hypothyroidism, cervical
stenosis and unilateral hydronephrosis. Drug history included lisinopril
5mg, levothyroxine 100mcg, amitriptyline 10mg and cefalexin 125mg. The
patient was euvolaemic and examination was unremarkable. Routine
haematology and biochemistry were normal.
During the first 24 hours the patient developed vomiting and dyspepsia.
Body computerised tomography demonstrated unchanged hydronephrosis and
no malignancy. She was empirically treated for urosepsis with
intravenous co-amoxiclav and fluids. Within 24 hours serum sodium (Na)
dropped from 134mmol/L to 128mmol/L which was attributed to
overhydration and vomiting. Oesophago-gastro-duodenoscopy on day 6
revealed gastritis and oesophageal candidiasis. On day 7 she was
prescribed fluconazole 50mg and lansoprazole 30mg daily for 14 days.
Symptoms rapidly subsided, but Na continued to decline (Figure 1).
Plasma glucose, lipids, protein, inflammatory markers and tests for
thyroid, adrenal and renal function were found normal. Serum osmolality
was 267mmol/L, urine osmolality 267mmol/L and urine Na 50mmol/L
confirming syndrome of inappropriate anti-diuretic hormone secretion
(SIADH) (Table 1).
Fluconazole was stopped and lansoprazole was substituted for famotidine
(a histamine H2-receptor antagonist) on day 20 when Na was 121mmol/L,
and daily fluid intake was restricted to 1L. Slow release salt tablets
were also prescribed. 3 days after stopping both medications (on day 23)
and with continued fluid restriction, Na dropped to 119mmol/L. Repeat
serum osmolality was 257mOsmol/kg, urine osmolality 418mOsmol/kg and
urine Na 33mmol/L confirming ongoing SIADH. Demeclocycline was
prescribed on day 26 to counteract SIADH, and fluid intake was
restricted to 750ml. This regimen was continued for 14 days.
7 days after cessation of fluconazole (on day 27), Na gradually
increased. On day 38 (18 days after stopping fluconazole) Na was
127mmol/L and the patient remained well. Demeclocycline was stopped on
day 40. On follow up, 5 weeks after stopping fluconazole, Na was
132mmol/L and the patient was asymptomatic.
Causes of hypotonic hyponatremia in a euvolemic patient include
glucocorticoid deficiency, thyroid dysfunction, hyperlipidaemia
(pseudo-hyponatraemia), SIADH or drugs. Our patient had been on
long-term treatment with amitriptyline and lisinopril, and lansoprazole
was replaced with famotidine early. Although proton pump inhibitors can
cause hyponatraemia through SIADH, lansoprazole is the least likely
agent to do so, and the effect is readily reversible on cessation of the
culprit drug [1]; consequently, ongoing hyponatraemia cannot be
credited to these medications. In light of biochemical analyses and
elimination of other causes, the most likely cause of hyponatraemia in
our patient was fluconazole induced SIADH. Arguably, lansoprazole may
have contributed to the biochemical diagnosis of SIADH.
Fluconazole belongs to azole group of antifungals. After its approval in
1990, it soon became recognized as the more stable and less toxic azole
antifungal when compared to ketoconazole and itraconazole. The half-life
of fluconazole is 30 hours and it takes 6-10 days of daily dosing to
reach a steady state in serum and around 11 days for its elimination
from the body [2]. Lansoprazole, a proton pump inhibitor, has
excellent and rapid absorption and reaches peak plasma levels in 1.7
hours. Although in older adults, clearance is decreased, the mean
half-life remans between 1.9 and 2.9 hours [3]. Importantly,
lansoprazole does not accumulate in the body and peak plasma levels
remain unaltered by multiple dosing [4]. This makes it an unlikely
culprit for ongoing hyponatremia. Causality assessment via Naranjo
algorithm demonstrated probable adverse effect (> 5/10) in
favour of fluconazole.
In vitro and preclinical in vivo studies have reported that fluconazole
increases osmotic water transport in renal collecting ducts, thus
corroborating an antidiuretic action [5]. This, alongside its
pharmacokinetic data, supports the potential of fluconazole to
precipitate a prolonged state of hyponatraemia. However, to date, no
substantial clinical data are available to validate this proposed
mechanism, and there are few reports suggesting a causal link between
fluconazole and hyponatraemia. Our case is unique in that hyponatraemia
was profound and protracted and likely attributable to fluconazole.
Research to elucidate the role of fluconazole in the aetiology of
hyponatraemia is awaited.