DRUG-INDUCEDHYPERKALEMIA

To the Editor:In his review article on drug-in-

duced hyperkalemia, Perazella (1) re-fers to nutritional supplements andherbal remedies as possible precipi-tants of hyperkalemia. Because theuse of these alternative medicines isremarkably high in the United States(2), I would like to draw attention tothe pathogenesis and clinical impactof one such group of drugs whose usemay result in clinically significant hy-perkalemia. Extracts from the driedskin of toads (Bufo) are used in herbalmedicines today by the Chinese (whocall it Chan Su) and by the Japanese(who call it Senso) to treat congestivecardiac failure. Chan Su is also a ma-jor component of the traditional Chi-nese medicines Liu-Shen-Wan andkyushin. Their use dates back to an-cient times when physicians pre-scribed dried toad skins to treatdropsy (edema) and as a cardiotonic,even before digitalis was introduced(3). These drugs are also used to treattonsillitis, sore throat, and furunclesbecause of their proposed anesthetic,anti-inflammatory, and antibiotic ac-tions.

The cardioactive bufadienolidesteroid aglycones (bufagins) and theirderivatives (bufotoxins) isolated fromtoad skin are structurally analogousto the well-known plant cardiac gly-cosides, such as digitalis (3). Bothhave the configuration essential forcardiac activity and, therefore, thesame pharmacologic and toxicologicactions (3). Because the chemicalstructure of bufadienolides is similarto that of digoxin, Chinese medicinescontaining these toad compoundsfrequently interfere with digoxin im-munoassays (4). The pharmacologicreceptor for both toad and plantcardiac glycosides is the membrane-bound Na-K-ATPase (5). Bufadienol-ides, similar to digitalis in toxic doses,may cause analogous extracardiac ef-fects (like nausea, emesis, diarrhea,

and a bitter taste), bradycardia, andultimately asystole (3,6). Administer-ing commercially available digoxin-specific antibodies may antagonizesome of the cardiotoxic effects of toadvenoms (7). Significant poisoningfrom toad toxins may result in hyper-kalemia (8), as occurs from acute in-gestion of other cardiac glycosides.Although the general populationconsiders these unconventional over-the-counter traditional Chinese med-icines to be safe, serious toxic effectsincluding fatalities have been docu-mented in the literature (9,10).

Liron Pantanowitz, MDDepartment of Pathology

Beth Israel Deaconess Medical CenterHarvard Medical School

Boston, Massachusetts

1. Perazella MA. Drug-induced hyperkalemia:old culprits and new offenders. Am J Med.2000;109:307314.

2. Eisenberg DM, Kessler RC, Foster C, et al.Unconventional medicine in the UnitedStates. Prevalence, costs, and patterns ofuse. N Engl J Med. 1993;328:246 252.

3. Pantanowitz L, Naude TW, Leisewitz A.Noxious toads and frogs of South Africa. SAfr Med J. 1998;88:1408 1414.

4. Dasgupta A, Biddle DA, Wells A, Datta P.Positive and negative interference of theChinese medicine Chan Su in serumdigoxin measurement. Am J Clin Pathol.2000;114:174 179.

5. Cruz JS, Matsuda H. Arenbufagin, a com-pound in toad venom, blocks (Na)-Kpump current in cardiac myocytes. EurJ Pharmacol. 1993;239:223226.

6. Otani A, Palumbo N, Read G. Pharmaco-dynamics and treatment of mammals poi-soned by Bufo marinus toxin. Am J VetRes. 1969;30:18651872.

7. Bagrov AY, Roukoyatkina NI, FederovaOV, et al. Digitalis-like and vasoconstric-tor effects of endogenous digoxin-like fac-tor(s) from the venom Bufo marinus toad.Eur J Pharmacol. 1995;234:165172.

8. Pantanowitz L. Amphibian alert. J TropPed. 1999;45:123124.

9. Kwan T, Paiusco AD, Kohl L. Digitalis tox-icity caused by toad venom. Chest. 1992;102:949 950.

10. Ko RJ, Greenwald MS, Loscutoff SM, et al.Lethal ingestion of Chinese herbal tea con-taining Chan Su. West J Med. 1996;164:7175.

The Reply:As noted by Dr. Pantanowitz, a

number of herbal or natural remediesmay be unsafe for general humanconsumption. This is particularlytrue for patients with underlying re-nal disease. Some herbal productshave been noted to cause renal failure(Aristolochia spp) and kidney stones(Ma-Huang-Ephedra spp) in normalhosts (1,2). However, certain medici-nal herbs may induce potentially lifethreatening hyperkalemia in patientswith underlying risk factors (chronicrenal insufficiency, hypoaldosteron-ism, use of other potassium-alteringmedications) for this electrolyte dis-order. Examples include herbs orjuices, such as noni juice (Morindiacitrifolia), alfalfa (Medico sativa), dan-delion (Taraxacum officinale), horse-tail (Equisetum arvense), and nettle(Urtica dioica), that contain largeamounts of potassium (3,4). Patientswith impaired renal potassium han-dling can develop severe hyperkale-mia after ingesting these substances.In addition to the herbs pointed outby Dr. Pantanowitz, Na-K-ATPaseimpairment by the digoxin-like sub-stances contained in milkweed, lily ofthe valley, Siberian ginseng, and haw-thorne berries may also precipitatehyperkalemia in at-risk patients (5,6).It is therefore prudent that practi-tioners who care for patients whoconsume these products become fa-miliar with the associated adverseeffects. Furthermore, the FDA shouldbe allowed to enforce the same drugstandards for herbal remedies andnatural products available in the mar-ketplace that are required for othermedications.

Mark A. Perazella, MDDepartment of Medicine

Yale University School of MedicineNew Haven, Connecticut

1. Vanherweghem JL, Depierreux M, Tiele-mans C, et al. Rapidly progressive intersti-tial renal fibrosis in young women: associa-tion with slimming regimen includingChinese herbs. Lancet. 1993;341:387391.

2. Powell T, Fu Hsu F, Turk J, Hruska K. Ma-

Letters to the Editor

334 March 2002 THE AMERICAN JOURNAL OF MEDICINE Volume 112