Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control studyBMJ 2011; 343 doi: https://doi.org/10.1136/bmj.d5228 (Published 12 September 2011) Cite this as: BMJ 2011;343:d5228
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The recent research paper by Antoniou et al and editorial by Wei et
al highlighted the risk of significant hyperkalaemia when co-trimoxazole
(Septrin) and spironolactone are taken together. However, the association
of hyperkalaemia with the antibiotic Septrin was recognised much earlier,
when it was used regularly in HIV positive patients with AIDS who were
also receiving intravenous or inhaled pentamidine as treatment or
prophylaxis for pneumocystis carinii infection1. It is worthwhile
considering the likely mechanism of this interaction, because it explains
the increased risk of hyperkalaemia when co-trimoxazole, or rather its
trimethoprim component, is given with spironolactone or any other drug
that may interfere with renal potassium excretion directly or by
decreasing glomerular filtration rate (GFR).
What trimethoprim and pentamidine have in common is their weakly
basic property due to positively charged and weakly basic amino groups
attached to heterocyclic ring structures, which makes them similar in
structure to the widely used potassium-sparing diuretic amiloride (and
also triamterene)2,3. Amiloride blocks the epithelial sodium ion channel
ENaC, which is responsible for sodium reabsorption in the distal nephron
of the kidney. ENaC also indirectly controls potassium secretion and
excretion in the urine, and it is stimulated by aldosterone; both
spironolactone and amiloride inhibit ENaC (although by different
mechanisms and so their inhibitory effect is additive) and thereby reduce
Thus, it might be expected that co-prescription of co-trimoxazole, or
trimethoprim, with spironolactone could cause significant hyperkalaemia,
especially on a background of the mild renal impairment often found in
elderly patients. However, it is also worth noting that trimethoprim
interferes with creatinine secretion (cf. cimetidine), which may lead to a
spurious rise in serum creatinine concentration than can be misinterpreted
as a fall in GFR.
Finally, the basis of the observed weaker association of
nitrofurantoin and spironolactone co-prescription with hyperkalaemia is
less certain; while nitrofunrantoin may impair aldosterone production and
release from adrenal cells4, this finding has not been replicated in
laboratory or clinical studies, to our knowledge.
Stephen B Walsh, Christopher M Laing and Robert J Unwin,
UCL Centre for Nephrology,
Royal Free Campus and Hospital,
Rowland Hill Street
London NW3 2PF
Competing interests: None declared
1. Greenberg S, Reiser IW, Chou SY, Porush JG. Trimethoprim-
sulfamethoxazole induces reversible hyperkalemia. Ann Intern Med
2. Velazquez H, Perazella MA, Wright FS, Ellison DH. Renal mechanism
of trimethoprim-induced hyperkalemia. Ann Intern Med 1993;119(4):296-301.
3. Schlanger LE, Kleyman TR, Ling BN. K(+)-sparing diuretic actions
of trimethoprim: inhibition of Na+ channels in A6 distal nephron cells.
Kidney Int 1994;45(4):1070-6.
4. Jager LP, de Graaf GJ, Widjaja-Greefkes HC. Differential effects
of nitrofurans on the production/release of steroid hormones by porcine
adrenocortical cells in vitro. Eur J Pharmacol 1997;331(2-3):325-31.
Competing interests: No competing interests