CASE REPORT Hyperkalemia Induced by the Calcium Channel Blocker, Benidipine Takuroh Imamura, Yunosuke MATSUURA,Toshiro Nagoshi, Tetsunori ISHIKAWA, Haruhiko DATE, Toshihiro Kita, Akihiko Matsuyama, Takeshi Matsuo and Tanenao Eto Abstract oped hyperkalemia during treatment with CCBswere con- comitantly prescribed other drugs (5, 6, 8, 10) and had A 73-year-old hypertensive, non-diabetic woman with- chronic renal failure (7, 9) or underlying hypoaldosteronism out obvious renal dysfunction had frequently been (ll), the etiology of hyperkalemia has appeared hyperkalemic over four years after receiving antihy- multifactori al. pertensive drugs including the calcium channel blocker The CCB, benidipine, has been widely prescribed for (CCB) benidipine. One week after all medications were hypertensive patients in Japan since 1991. A few post-market accidentally discontinued, the serum potassium level re- surveys have noted that hyperkalemia is a likely side effect turned to normal. After we obtained the informed con- of benidipine in hypertensive Japanese patients (12-14). sent of the patient, benidipine alone was administered However, the relationship between benidipine and hyper- again for over two weeks and hyperkalemia developed kalemia has not been clearly defined. Since this side effect is once more. This previously uncommonside effect of relatively minor, a CCBis apt to be overlooked as a cause of hyperkalemia induced by benidipine is not very serious hyperkalemia in clinical situations. Weemphasize the need but it is apt to be overlooked. Since CCBsare nowwidely for medical awareness of this side effect of CCB. prescribed, the development of hyperkalemia should be considered. (Internal Medicine 42: 503-506, 2003) Case Report A 73-year-old hypertensive, non-diabetic woman was Key words: hyperkalemia, benidipine, calcium channel treated with 120 mg of verapamil and 0.25 mg of reserpine blocker, potassium, side effect from 1994. A complete atrioventricular block (CAVB)asso- ciated with a heart rate of 45 beats/min developed in May 1996, so verapamil was discontinued and 1 mgof cilazapril and 1.5 mg of rescimanine were administered instead. Introduction However, CAVBdid not improve and she was admitted to our hospital for pacemaker implantation. Although all drugs Hyperkalemia, defined as a serum potassium concentra- except for cilazapril were discontinued after admission, tion greater than 5.0 mEq//, occurs as a result of increased CAVBcontinued. An electrophysiological study showed an potassium release from cells, decreased renal loss or in- intra-Hissian block and a minimal heart rate of 37 beats/min, creased potassium intake (1). Drugs can cause hyperkalemia so a permanent pacemaker (VVI) was implanted in August through either of the above mechanisms (2). Antihyper- 1996. She was treated with 1 mg of cilazapril alone during tensive drugs such as spironolactone, angiotensin-converting admission and serum potassium levels during these admis- enzyme inhibitor (ACEI) and angiotensin receptor blocker sion periods ranged from 3.8 to 4.7 mEq// with controlled (ARB) quite often cause this condition (1-4). Although cal- blood pressure. The serum levels of sodium, chloride, cium channel blockers (CCBs) are not knownfor inducing creatinine (Cr) and blood urea nitrogen (BUN) during these hyperkalemia, several investigators have reported an associa- periods were 143-146 mEq//, 104-108 mEq//, 0.7-0.9 mg/ tion between hyperkalemia and verapamil (5-9) as well as d/ and 14.2-23.7 mg/d/, respectively. Arterial blood pH and diltiazem (10, ll). However, since most patients who devel- bicarbonate values were 7.416 and 23.3 mEq//, respectively. From the First Department of Internal Medicine, Miyazaki Medical College, Miyazaki Received for publication November 1 1, 2002; Accepted for publication March 3, 2003 Reprint requests should be addressed to Dr. Takuroh Imamura, the First Department of Internal Medicine, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692 Internal Medicine Vol. 42, No. 6 (June 2003) 503 IMAMURAet al However, blood pressure became elevated after discharge, so inhaler for the cough. Her blood pressure was controlled dur- 4 mgof benidipine and 25 mgof spironolactone in addition ing bed rest without antihypertensive drugs. The serum level to 1 mg of cilazapril were administered from October 1996 of potassium was in the normal range between 3.9 and 4.4 by her general practitioner. The initial serum potassium level mEq// during these periods, suggesting that hyperkalemia in identified by the physician was 5.0 mEq// in February 1998, this patient had been induced by the drugs prescribed before so he discontinued spironolactone and cilazapril and pre- this episode. Values for plasma aldosterone (171 pg/m/), scribed various antihypertensive regimens with continuous plasma renin activity (0.53 ng/m//h), renal function (Cr: 0.7 benidipine. The physician also advised her to minimize fruit -0.9 mg/dZ, BUN: 13-19 mg/d/) and liver function without and vegetable consumption. However, her serum potassium medication were normal. Informed consent was obtained level remained high (4.9 to 6.2 mEq//) despite the admini- from the patient and her family to administer 4 mg of stration of 20 mg of furosemide (Fig. 1). Probucol (250 mg) benidipine and 2 mg of azelastine on September 29, 2001. was initiated from July 1999 because of hypercholesterole- She was also advised to consumea balanced diet to mini- mia and 2 mgof azelastine was administered in addition to mize the effects on the serum potassium levels during the benidipine and furosemide from July 2000 because of occa- trial. Three weeks later, serum potassium levels increased sional itching. The serum levels of sodium, chloride, Cr and from 4.1 to 5.7 mEq//. Benidipine alone was administered BUNwhile receiving benidipine were 141-144 mEq//, 102- from October 19 to November 5, 2001. The serum potassium 104 mEq//, 1.0-1.1 mg/d/ and 18-24 mg/dZ, respectively. level reached 5.7 mEq// again on November 5, 2001 then de- Liver dysfunction and hemolysis were also absent. creased to 4.5 mEq// three weeks after substituting The patient presented flu-like symptoms associated with a amlodipine for benidipine. Amlodipine and azelastine were severe repetitive cough on August 15, 2001. All medications continuously administered without the recurrence of were discontinued and she was prescribed with a procaterol hyperkalemia for up to 8 months of follow-up. These find- [ Benidipine 4 mg ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^B I E Spironolactone 25 mg =3 K Cilazapril 1 mg \$$oc$ssssx^ Delapril 15milIIIIIIIllIII mg fygJLAJjLjyvjUl*''III1111ItII I Prazosin 1 mg R§X?888g§> «-*å » « '/////////////Ztftf' Serum K Probucol 250 mg concentration V////////////////A fl K£^/^X<a (mEq//) Azelastine 2 mg ^^^^^^^^ [J ¥%%//$, m Amlodipine 5 mg r^^^^^VS <l (nodata) uN V^ 3.0 - July/96 July/97 July/98 July/99 July/00 July/01 July/02 Figure 1. Changes in serum potassium levels and prescribed medications during 6 years of follow-up. Serum potassium levels before administration of benidipine and spironolactone were between 3.8 and 4.7 mEq//. However, the first charted record of serum potassium levels after the initiation of benidipine therapy was 5.0 mEq// followed by 5.3 to 6.2 mEq//. The level fell to 4.9 mEq// only once during benidipine therapy immediately after starting furosemide. After discontinuing benidipine, the serum level of potassium dropped to the normal range. Levels then increased from 4.1 to 5.7mEq// three weeks after starting benidipine and azelastine therapy and reached 5.7 mEq// again after 17 days of manidipine alone. Three weeksafter amlodipine was substituted for benidipine, serum potassium levels decreased to 4.5mEq//. Amlodipine and azelastine were con- tinuously administered without recurrence of hyperkalemia for up to 8 months of follow-up. 504 Internal Medicine Vol. 42, No. 6 (June 2003) B enidipine-induced Hyperkalemia ings indicated that hyperkalemia in this patient was caused sterone secretion in response to potassium and angiotensin II by benidipine. stimuli. Although the molecular events relating to cellular calcium entry and aldosterone biosynthesis remain unclear, Discussion aldosterone secretion induced by potassium stimulation in vivo is also suppressed by nisoldipine (20). Doses of A 73-year-old hypertensive, non-diabetic womanwithout verapamil far larger than those used in clinical practice non- obvious renal dysfunction and hypoaldosteronism had two specifically inhibit at least two steps of the aldosterone bio- episodes of hyperkalemia while undergoing benidipine ther- synthetic pathway in vitro (21, 22). The findings of these in apy. Both episodes were reversed upon withdrawal of the vitro and in vivo studies suggest that benidipine could have drug. Several drugs including benidipine were prescribed to inhibited the biosynthesis and secretion of aldosterone in the the patient over the five years during the first episode and present patient. However, since the plasma aldosterone level benidipine alone was prescribed for over 2 weeks during the was not measured in this patient while undergoing benidi- second episode. These clinical courses suggested that the pine therapy, wecannot conclude that the hyperkalemia in- hyperkalemia in this patient was induced by benidipine. duced by benidipine is via the inhibition of aldosterone Knowndrugs that maycause hyperkalemia include ACEI, biosynthesis and secretion. Furthermore, the fact that our pa- ARB, beta-blocker, cyclosporin,