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Drug-induced hyperkalemia

      To the Editor:
      In his review article on drug-induced hyperkalemia, Perazella (
      • Perazella M.A.
      Drug-induced hyperkalemia old culprits and new offenders.
      ) refers to nutritional supplements and herbal remedies as possible precipitants of hyperkalemia. Because the use of these “alternative” medicines is remarkably high in the United States (
      • Eisenberg D.M.
      • Kessler R.C.
      • Foster C.
      • et al.
      Unconventional medicine in the United States. Prevalence, costs, and patterns of use.
      ), I would like to draw attention to the pathogenesis and clinical impact of one such group of drugs whose use may result in clinically significant hyperkalemia. Extracts from the dried skin of toads (Bufo) are used in herbal medicines today by the Chinese (who call it Chan Su) and by the Japanese (who call it Senso) to treat congestive cardiac failure. Chan Su is also a major component of the traditional Chinese medicines Liu-Shen-Wan and kyushin. Their use dates back to ancient times when physicians prescribed dried toad skins to treat dropsy (edema) and as a cardiotonic, even before digitalis was introduced (
      • Pantanowitz L.
      • Naudé T.W.
      • Leisewitz A.
      Noxious toads and frogs of South Africa.
      ). These drugs are also used to treat tonsillitis, sore throat, and furuncles because of their proposed anesthetic, anti-inflammatory, and antibiotic actions.
      The cardioactive bufadienolide steroid aglycones (bufagins) and their derivatives (bufotoxins) isolated from toad skin are structurally analogous to the well-known plant cardiac glycosides, such as digitalis (
      • Pantanowitz L.
      • Naudé T.W.
      • Leisewitz A.
      Noxious toads and frogs of South Africa.
      ). Both have the configuration essential for cardiac activity and, therefore, the same pharmacologic and toxicologic actions (
      • Pantanowitz L.
      • Naudé T.W.
      • Leisewitz A.
      Noxious toads and frogs of South Africa.
      ). Because the chemical structure of bufadienolides is similar to that of digoxin, Chinese medicines containing these toad compounds frequently interfere with digoxin immunoassays (
      • Dasgupta A.
      • Biddle D.A.
      • Wells A.
      • Datta P.
      Positive and negative interference of the Chinese medicine Chan Su in serum digoxin measurement.
      ). The pharmacologic receptor for both toad and plant cardiac glycosides is the membrane-bound Na-K-ATPase (
      • Cruz J.S.
      • Matsuda H.
      Arenbufagin, a compound in toad venom, blocks (Na+)-K+ pump current in cardiac myocytes.
      ). Bufadienolides, similar to digitalis in toxic doses, may cause analogous extracardiac effects (like nausea, emesis, diarrhea, and a bitter taste), bradycardia, and ultimately asystole (
      • Pantanowitz L.
      • Naudé T.W.
      • Leisewitz A.
      Noxious toads and frogs of South Africa.
      ,
      • Otani A.
      • Palumbo N.
      • Read G.
      Pharmacodynamics and treatment of mammals poisoned by Bufo marinus toxin.
      ). Administering commercially available digoxin-specific antibodies may antagonize some of the cardiotoxic effects of toad venoms (
      • Bagrov A.Y.
      • Roukoyatkina N.I.
      • Federova O.V.
      • et al.
      Digitalis-like and vasoconstrictor effects of endogenous digoxin-like factor(s) from the venom Bufo marinus toad.
      ). Significant poisoning from toad toxins may result in hyperkalemia (
      • Pantanowitz L.
      Amphibian alert.
      ), as occurs from acute ingestion of other cardiac glycosides. Although the general population considers these unconventional over-the-counter traditional Chinese medicines to be safe, serious toxic effects including fatalities have been documented in the literature (
      • Kwan T.
      • Paiusco A.D.
      • Kohl L.
      Digitalis toxicity caused by toad venom.
      ,
      • Ko R.J.
      • Greenwald M.S.
      • Loscutoff S.M.
      • et al.
      Lethal ingestion of Chinese herbal tea containing Ch’an Su.
      ).

      References

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        Drug-induced hyperkalemia.
        Am J Med. 2000; 109: 307-314
        • Eisenberg D.M.
        • Kessler R.C.
        • Foster C.
        • et al.
        Unconventional medicine in the United States. Prevalence, costs, and patterns of use.
        N Engl J Med. 1993; 328: 246-252
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        • Naudé T.W.
        • Leisewitz A.
        Noxious toads and frogs of South Africa.
        S Afr Med J. 1998; 88: 1408-1414
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        • Biddle D.A.
        • Wells A.
        • Datta P.
        Positive and negative interference of the Chinese medicine Chan Su in serum digoxin measurement.
        Am J Clin Pathol. 2000; 114: 174-179
        • Cruz J.S.
        • Matsuda H.
        Arenbufagin, a compound in toad venom, blocks (Na+)-K+ pump current in cardiac myocytes.
        Eur J Pharmacol. 1993; 239: 223-226
        • Otani A.
        • Palumbo N.
        • Read G.
        Pharmacodynamics and treatment of mammals poisoned by Bufo marinus toxin.
        Am J Vet Res. 1969; 30: 1865-1872
        • Bagrov A.Y.
        • Roukoyatkina N.I.
        • Federova O.V.
        • et al.
        Digitalis-like and vasoconstrictor effects of endogenous digoxin-like factor(s) from the venom Bufo marinus toad.
        Eur J Pharmacol. 1995; 234: 165-172
        • Pantanowitz L.
        Amphibian alert.
        J Trop Ped. 1999; 45: 123-124
        • Kwan T.
        • Paiusco A.D.
        • Kohl L.
        Digitalis toxicity caused by toad venom.
        Chest. 1992; 102: 949-950
        • Ko R.J.
        • Greenwald M.S.
        • Loscutoff S.M.
        • et al.
        Lethal ingestion of Chinese herbal tea containing Ch’an Su.
        West J Med. 1996; 164: 71-75

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