今日の臨床サポート

循環器薬の副作用

著者: 森田英晃 大阪医科薬科大学 循環器内科

監修: 今井靖 自治医科大学 薬理学講座臨床薬理学部門・内科学講座循環器内科学部門

著者校正/監修レビュー済:2021/07/07
参考ガイドライン:
  1. 日本高血圧学会高血圧治療ガイドライン作成委員会編:高血圧治療ガイドライン2019、ライフ・サイエンス出版、2019
  1. 日本循環器学会/日本不整脈心電学会合同ガイドライン:2020年改訂版 不整脈薬物治療ガイドライン
患者向け説明資料

概要・推奨   

  1. 薬には本来の治療目的とする主作用だけでなく、有害であるかどうかにかかわらず目的以外の作用として副作用がある。
  1. 副作用:薬物との因果関係が疑われる、又は関連が否定できないもの。有益なこともある。
  1. 薬物有害反応:有害かつ意図されない反応で、予防、診断、治療または機能改善のために通常量で発現する作用。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
森田英晃 : 特に申告事項無し[2021年]
監修:今井靖 : 講演料(第一三共株式会社)[2021年]

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 循環器薬は長期間にわたり服用することが多い薬剤である。加齢、疾病などにより腎機能、肝機能低下が進行し副作用が出現することがある。加齢とともに洞機能、房室伝導障害が進行した場合、徐脈性不整脈が出現するため、自宅血圧での脈拍数の変化に注意が必要である。
  1. 副作用出現時には原則、薬剤中止が必要であるが、高K血症、徐脈、低血圧、心室頻拍などの緊急対応が必要な副作用も少なくない。各種循環器薬の作用、副作用を熟知した上で、適切な処方を心がける必要がある。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: C D Furberg, B M Psaty, J V Meyer
雑誌名: Circulation. 1995 Sep 1;92(5):1326-31. doi: 10.1161/01.cir.92.5.1326.
Abstract/Text BACKGROUND: The purpose of this study was to assess the effect of the dose of nifedipine, a dihydropyridine calcium antagonist, on the increased risk of mortality seen in the randomized secondary-prevention trials and to review the mechanisms by which this adverse effect might occur.
METHODS AND RESULTS: We restricted the dose-response meta-analysis to the 16 randomized secondary-prevention trials of nifedipine for which mortality data were available. Recent trials of any calcium antagonist and formulation were also reviewed for information about the possible mechanisms of action that might increase mortality. Overall, the use of nifedipine was associated with a significant adverse effect on total mortality (risk ratio, 1.16, with a 95% CI of 1.01 to 1.33). This summary estimate fails to draw attention to an important dose-response relationship. For daily doses of 30 to 50, 60, and 80 mg, the risk ratios for total mortality were 1.06 (95% CI, 0.89 to 1.27), 1.18 (95% CI, 0.93 to 1.50), and 2.83 (95% CI, 1.35 to 5.93), respectively. In a formal test of dose response, the high doses of nifedipine were significantly associated with increased mortality (P = .01). While the mechanism of this adverse effect is not known, there are several plausible explanations, including the established proischemic effect, negative inotropic effects, marked hypotension, recently reported prohemorrhagic effects attributed to antiplatelet and vasodilatory actions of calcium antagonists, and possibly proarrhythmic effects.
CONCLUSIONS: In patients with coronary disease, the use of short-acting nifedipine in moderate to high doses causes an increase in total mortality. Other calcium antagonists may have similar adverse effects, in particular those of the dihydropyridine type. Long-term safety data are lacking for most calcium antagonists.

PMID 7648682  Circulation. 1995 Sep 1;92(5):1326-31. doi: 10.1161/01.・・・
著者: Harikrishna Makani, Sripal Bangalore, Jorge Romero, Nay Htyte, Ronaldo S Berrios, Hetal Makwana, Franz H Messerli
雑誌名: J Hypertens. 2011 Jul;29(7):1270-80. doi: 10.1097/HJH.0b013e3283472643.
Abstract/Text OBJECTIVE: Peripheral edema is considered to be a common and annoying adverse effect of calcium channel blockers (CCBs). It has been thought to occur secondary to arteriolar dilatation causing intracapillary hypertension and fluid extravasation. We aimed to evaluate the incidence and withdrawal rate of peripheral edema with CCBs.
METHODS: A systematic search was made in PubMed, EMBASE and CENTRAL from 1980 to January 2011 for randomized clinical trials reporting peripheral edema with CCBs in patients with hypertension. Trials enrolling at least 100 patients in the CCB arm and lasting at least 4 weeks were included in the analysis. Both the incidence and withdrawal rate due to edema were pooled by weighing each trial by the inverse of the variance. Head-to-head comparison was done to evaluate the risk of edema between newer lipophilic dihydropyridine (DHP) CCBs and older DHPs.
RESULTS: One hundred and six studies with 99 469 participants, mean age 56 ± 6 years, satisfied our inclusion criteria and were included in this analysis. The weighted incidence of peripheral edema was significantly higher in the CCBs group when compared with controls/placebo (10.7 vs. 3.2%, P < 0.0001). Similarly, the withdrawal rate due to edema was higher in patients on CCBs compared with control/placebo (2.1 vs. 0.5%, P < 0.0001). Both the incidence of edema and patient withdrawal rate due to edema increased with the duration of therapy with CCBs reaching 24 and 5%, respectively, after 6 months. The risk of peripheral edema with lipophilic DHPs was 57% lower than with traditional DHPs (relative risk 0.43; 95% confidence interval 0.34-0.53; P < 0.0001). Incidence of peripheral edema in patients on DHPs was 12.3% compared with 3.1% with non-DHPs (P < 0.0001). Edema with high-dose CCBs (defined as more than half the usual maximal dose) was 2.8 times higher than that with low-dose CCBs (16.1 vs. 5.7%, P < 0.0001).
CONCLUSION: The incidence of peripheral edema progressively increased with duration of CCB therapy up to 6 months. Over the long term, more than 5% of patients discontinued CCBs because of this adverse effect. Edema rates were lower with both non-DHPs and lipophilic DHPs.

PMID 21558959  J Hypertens. 2011 Jul;29(7):1270-80. doi: 10.1097/HJH.0・・・
著者: Rachel D Savage, Jessica D Visentin, Susan E Bronskill, Xuesong Wang, Andrea Gruneir, Vasily Giannakeas, Jun Guan, Kenneth Lam, Miles J Luke, Stephanie H Read, Nathan M Stall, Wei Wu, Lynn Zhu, Paula A Rochon, Lisa M McCarthy
雑誌名: JAMA Intern Med. 2020 May 1;180(5):643-651. doi: 10.1001/jamainternmed.2019.7087.
Abstract/Text Importance: Calcium channel blockers (CCBs) are commonly prescribed agents for hypertension that can cause peripheral edema. A prescribing cascade occurs when the edema is misinterpreted as a new medical condition and a diuretic is subsequently prescribed to treat the edema. The extent to which this prescribing cascade occurs at a population level is not well understood.
Objective: To measure the association between being newly dispensed a CCB and subsequent dispensing of a loop diuretic in older adults with hypertension.
Design, Setting, and Participants: A population-based cohort study was performed using linked health administrative databases of community-dwelling adults 66 years or older with hypertension and new prescription drug claims from September 30, 2011, to September 30, 2016, in Ontario, Canada. The dates of analysis were September 1, 2018, to May 30, 2019.
Exposures: Individuals who were newly dispensed a CCB were compared with the following 2 groups: (1) individuals who were newly dispensed an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and (2) individuals who were newly dispensed an unrelated medication.
Main Outcomes and Measures: Hazard ratios (HRs) with 95% CIs were estimated for individuals who were dispensed a loop diuretic within 90 days of follow-up using Cox proportional hazards regression models.
Results: The cohort included 41 086 older adults (≥66 years) with hypertension who were newly dispensed a CCB, 66 494 individuals who were newly dispensed another antihypertensive medication, and 231 439 individuals who were newly dispensed an unrelated medication. At index (ie, the dispensing date), the mean (SD) age was 74.5 (6.9) years, and 191 685 (56.5%) were women. Individuals who were newly dispensed a CCB had a higher cumulative incidence at 90 days of being dispensed a loop diuretic than individuals in both control groups (1.4% vs 0.7% and 0.5%, P < .001). After adjustment, individuals who were newly dispensed a CCB had increased relative rates of being dispensed a loop diuretic compared with individuals who were newly dispensed an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (HR, 1.68; 95% CI, 1.38-2.05 in the first 30 days after index [days 1-30]; 2.26; 95% CI, 1.76-2.92 in the subsequent 30 days [days 31-60]; and 2.40; 95% CI, 1.84-3.13 in the third month of follow-up [days 61-90]) and individuals who were newly dispensed unrelated medications (HR, 2.51; 95% CI, 2.13-2.96 for 1-30 days after index; 2.99; 95% CI, 2.43-3.69 for 31-60 days after index; and 3.89; 95% CI, 3.11-4.87 for 61-90 days after index). This association persisted, although slightly attenuated, from 90 days to up to 1 year of follow-up and when restricted to a subgroup of individuals who were newly dispensed amlodipine.
Conclusions and Relevance: Many older adults with hypertension who are newly dispensed a CCB subsequently receive a loop diuretic. Given how widely CCBs are prescribed, interventions are needed to raise clinicians' awareness of this common prescribing cascade to reduce the prescribing of potentially unnecessary medications that may cause harm.

PMID 32091538  JAMA Intern Med. 2020 May 1;180(5):643-651. doi: 10.100・・・
著者: Harikrishna Makani, Sripal Bangalore, Jorge Romero, Omar Wever-Pinzon, Franz H Messerli
雑誌名: Am J Med. 2011 Feb;124(2):128-35. doi: 10.1016/j.amjmed.2010.08.007.
Abstract/Text BACKGROUND: Peripheral edema is a common adverse effect of calcium channel blockers. The addition of a renin-angiotensin system blocker, either an angiotensin-converting enzyme inhibitor or an ARB, has been shown to reduce peripheral edema in a dose-dependent way.
METHODS: We performed a MEDLINE/COCHRANE search for all prospective randomized controlled trials in patients with hypertension, comparing calcium channel blocker monotherapy with calcium channel blocker/renin-angiotensin system blocker combination from 1980 to the present. Trials reporting the incidence of peripheral edema or withdrawal of patients because of edema and total sample size more than 100 were included in this analysis.
RESULTS: We analyzed 25 randomized controlled trials with 17,206 patients (mean age 56 years, 55% were men) and a mean duration of 9.2 weeks. The incidence of peripheral edema with calcium channel blocker/renin-angiotensin system blocker combination was 38% lower than that with calcium channel blocker monotherapy (P<.00001) (relative risk [RR] 0.62; 95% confidence interval [CI], 0.53-0.74). Similarly, the risk of withdrawal due to peripheral edema was 62% lower with calcium channel blocker/renin-angiotensin system blocker combination compared with calcium channel blocker monotherapy (P=.002) (RR 0.38; 95% CI, 0.22-0.66). ACE inhibitors were significantly more efficacious than ARBs in reducing the incidence of peripheral edema (P<.0001) (ratio of RR 0.74; 95% CI, 0.64-0.84) (indirect comparison).
CONCLUSION: In patients with hypertension, the calcium channel blocker/renin-angiotensin system blocker combination reduces the risk of calcium channel blocker-associated peripheral edema when compared with calcium channel blocker monotherapy. ACE inhibitor seems to be more efficacious than ARB in reducing calcium channel blocker-associated peripheral edema, but head-to-head comparison studies are needed to prove this.

Copyright © 2011 Elsevier Inc. All rights reserved.
PMID 21295192  Am J Med. 2011 Feb;124(2):128-35. doi: 10.1016/j.amjmed・・・
著者: Ranjan Shetty, G Vivek, Kushal Naha, Anil Tumkur, Abhinav Raj, K L Bairy
雑誌名: N Am J Med Sci. 2013 Jan;5(1):47-50. doi: 10.4103/1947-2714.106203.
Abstract/Text BACKGROUND: Ankle edema is a common adverse effect of amlodipine, an L-type calcium channel blocker (CCB). Cilnidipine is a newer L/N-type CCB, approved for treatment of essential hypertension.
AIM: This study was designed to determine whether cilnidipine can produce resolution of amlodipine-induced edema while maintaining adequate control of hypertension.
MATERIALS AND METHODS: A prospective study was performed on 27 patients with essential hypertension with amlodipine-induced edema. Concomitant nephropathy, cardiac failure, hepatic cirrhosis, or other causes of edema, and secondary hypertension were excluded by appropriate tests. Amlodipine therapy was substituted in all the cases with an efficacy-equivalent dose of cilnidipine. Clinical assessment of ankle edema and measurement of bilateral ankle circumference, body weight, blood pressure, and pulse rate were performed at onset of the study and after 4 weeks of cilnidipine therapy.
RESULTS: At completion of the study, edema had resolved in all the patients. There was a significant decrease in bilateral ankle circumference and body weight (P < 0.001). There was no significant change in mean arterial blood pressure and pulse rate.
CONCLUSIONS: Therapy with cilnidipine resulted in complete resolution of amlodipine-induced edema in all the cases without significant worsening of hypertension or tachycardia. Cilnidipine is an acceptable alternative antihypertensive for patients with amlodipine-induced edema.

PMID 23378956  N Am J Med Sci. 2013 Jan;5(1):47-50. doi: 10.4103/1947-・・・
著者: Z H Israili, W D Hall
雑誌名: Ann Intern Med. 1992 Aug 1;117(3):234-42. doi: 10.7326/0003-4819-117-3-234.
Abstract/Text OBJECTIVE: To review available information on cough and angioneurotic edema associated with angiotensin-converting enzyme (ACE) inhibitors.
DATA SOURCES: All relevant articles from 1966 through 1991 were identified mainly through MEDLINE search and article bibliographies.
STUDY SELECTION: More than 400 articles were identified; 200 reporting incidence or possible mechanisms for the side effects or both were selected.
DATA EXTRACTION AND SYNTHESIS: All pertinent information, including incidence and mechanisms of ACE inhibitor-induced cough and angioedema, was reviewed and collated.
CONCLUSIONS: Cough occurs in 5% to 20% of patients treated with ACE inhibitors, recurring with reintroduction of the same or another ACE inhibitor. It is more common in women. The mechanism may involve accumulation of prostaglandins, kinins (such as bradykinin), or substance P (neurotransmitter present in respiratory tract C-fibers); both bradykinin and substance P are degraded by ACE. A 4-day trial of withdrawal of the ACE inhibitor or temporary substitution of another class of antihypertensive agent inexpensively and easily ascertains if the ACE inhibitor caused the cough. Change to another ACE inhibitor or additive therapy with nonsteroidal anti-inflammatory drugs is not recommended. Prompt recognition of ACE inhibitor-related cough can prevent unnecessary diagnostic testing and treatment. Angioedema occurs in 0.1% to 0.2% of patients receiving ACE inhibitors. The onset usually occurs within hours or, at most, 1 week after starting therapy. The mechanism may involve autoantibodies, bradykinin, or complement-system components. Treatment involves first protecting the airway, followed by epinephrine, antihistamines, and corticosteroids if needed. Therapy is then resumed with an alternate class of antihypertensive agent.

PMID 1616218  Ann Intern Med. 1992 Aug 1;117(3):234-42. doi: 10.7326/・・・
著者: B Pitt, F Zannad, W J Remme, R Cody, A Castaigne, A Perez, J Palensky, J Wittes
雑誌名: N Engl J Med. 1999 Sep 2;341(10):709-17. doi: 10.1056/NEJM199909023411001.
Abstract/Text BACKGROUND AND METHODS: Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes.
RESULTS: The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients.
CONCLUSIONS: Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure.

PMID 10471456  N Engl J Med. 1999 Sep 2;341(10):709-17. doi: 10.1056/N・・・
著者: Bertram Pitt, Willem Remme, Faiez Zannad, James Neaton, Felipe Martinez, Barbara Roniker, Richard Bittman, Steve Hurley, Jay Kleiman, Marjorie Gatlin, Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators
雑誌名: N Engl J Med. 2003 Apr 3;348(14):1309-21. doi: 10.1056/NEJMoa030207. Epub 2003 Mar 31.
Abstract/Text BACKGROUND: Aldosterone blockade reduces mortality and morbidity among patients with severe heart failure. We conducted a double-blind, placebo-controlled study evaluating the effect of eplerenone, a selective aldosterone blocker, on morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.
METHODS: Patients were randomly assigned to eplerenone (25 mg per day initially, titrated to a maximum of 50 mg per day; 3319 patients) or placebo (3313 patients) [correction] in addition to optimal medical therapy. The study continued until 1012 deaths occurred. The primary end points were death from any cause and death from cardiovascular causes or hospitalization for heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia.
RESULTS: During a mean follow-up of 16 months, there were 478 deaths in the eplerenone group and 554 deaths in the placebo group (relative risk, 0.85; 95 percent confidence interval, 0.75 to 0.96; P=0.008). Of these deaths, 407 in the eplerenone group and 483 in the placebo group were attributed to cardiovascular causes (relative risk, 0.83; 95 percent confidence interval, 0.72 to 0.94; P=0.005). The rate of the other primary end point, death from cardiovascular causes or hospitalization for cardiovascular events, was reduced by eplerenone (relative risk, 0.87; 95 percent confidence interval, 0.79 to 0.95; P=0.002), as was the secondary end point of death from any cause or any hospitalization (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.98; P=0.02). There was also a reduction in the rate of sudden death from cardiac causes (relative risk, 0.79; 95 percent confidence interval, 0.64 to 0.97; P=0.03). The rate of serious hyperkalemia was 5.5 percent in the eplerenone group and 3.9 percent in the placebo group (P=0.002), whereas the rate of hypokalemia was 8.4 percent in the eplerenone group and 13.1 percent in the placebo group (P<0.001).
CONCLUSIONS: The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.

Copyright 2003 Massachusetts Medical Society
PMID 12668699  N Engl J Med. 2003 Apr 3;348(14):1309-21. doi: 10.1056/・・・
著者: Katsuyuki Ando, Hiroshi Ohtsu, Shunya Uchida, Shinya Kaname, Yoshihiro Arakawa, Toshiro Fujita, EVALUATE Study Group
雑誌名: Lancet Diabetes Endocrinol. 2014 Dec;2(12):944-53. doi: 10.1016/S2213-8587(14)70194-9.
Abstract/Text BACKGROUND: Renin-angiotensin system inhibitors have renoprotective effects in patients with chronic kidney disease, but most patients treated with these drugs have residual urinary albumin excretion. Some small clinical studies show that mineralocorticoid receptor blockade reduces albuminuria. Our study aimed to examine the beneficial effects of addition of a selective aldosterone antagonist, eplerenone, to renin-angiotensin system inhibitors in hypertensive patients with non-diabetic chronic kidney disease.
METHODS: In this double-blind, randomised, placebo-controlled trial, we enrolled hypertensive patients, aged 20–79 years, with albuminuria (urinary albumin-to-creatinine ratio [UACR] in the first morning void urine of 30–599 mg/g), an estimated glomerular filtration rate of 50 mL/min per 1·73 m2 or more, and who had received an angiotensin-converting enzyme inhibitor, an angiotensin receptor blocker, or both, for at least 8 weeks. Participants were from 59 clinics and hospitals in Japan. Eligible patients were randomly assigned (1:1), stratified by baseline characteristics, to either low-dose eplerenone (50 mg/day) or placebo, with continuation of standard antihypertensive treatment to attain therapeutic goals (<130/80 mm Hg) for 52 weeks. We assessed efficacy in all patients who received allocated treatment, provided a baseline and post-treatment urine sample, and remained in follow-up. We assessed safety in all patients who received allocated treatment. The primary efficacy measure was percent change in UACR in the first morning void urine at week 52 from baseline. The trial is registered at the clinical trials registry of University Hospital Medical Information Network (UMIN), trial identification number UMIN000001803.
FINDINGS: Between April 1, 2009, and March 31, 2012, we randomly allocated 170 patients to the eplerenone group and 166 patients to the placebo group. In the primary efficacy analysis, mean percent change in UACR from baseline was −17·3% (95% CI −33·65 to −0·94) for 158 patients in the eplerenone group compared with 10·3% (−6·75 to 22·3) for 146 patients in the placebo group (absolute difference −27·6% [–51·15 to −3·96]; p=0·0222). In the safety analyses, 53 (31%) of 169 patients in the eplerenone group had adverse events (five serious), as did 49 (30%) of 163 in the placebo group (seven serious). Although mean serum potassium concentration was higher in the eplerenone group than the placebo group, severe hyperkalaemia (>5·5 mmol/L) was not recorded in either group.
INTERPRETATION: Addition of low-dose eplerenone to renin-angiotensin system inhibitors might have renoprotective effects through reduction of albuminuria in hypertensive patients with non-diabetic chronic kidney disease, without serious safety concerns.
FUNDING: Pfizer.

PMID 25466242  Lancet Diabetes Endocrinol. 2014 Dec;2(12):944-53. doi:・・・
著者: Ahmed Hassaan Qavi, Rida Kamal, Robert W Schrier
雑誌名: Int J Nephrol. 2015;2015:975934. doi: 10.1155/2015/975934. Epub 2015 Jul 29.
Abstract/Text Diuretics play significant role in pharmacology and treatment options in medicine. This paper aims to review and evaluate the clinical use of diuretics in conditions that lead to fluid overload in the body such as cardiac failure, cirrhosis, and nephrotic syndrome. To know the principles of treatment it is essential to understand the underlying pathophysiological mechanisms that cause the need of diuresis in the human body. Various classes of diuretics exist, each having a unique mode of action. A systemic approach for management is recommended based on the current guidelines, starting from thiazides and proceeding to loop diuretics. The first condition for discussion in the paper is cardiac failure. Treatment of ascites in liver cirrhosis with spironolactone as the primary agent is highlighted with further therapeutic options. Lastly, management choices for nephrotic syndrome are discussed and recommended beginning from basic sodium restriction to combined diuretic therapies. Major side effects are discussed.

PMID 26294976  Int J Nephrol. 2015;2015:975934. doi: 10.1155/2015/9759・・・
著者: Meng-Ting Wang, Chen-Yi Su, Agnes L F Chan, Pei-Wen Lian, Hsin-Bang Leu, Yu-Juei Hsu
雑誌名: Br J Clin Pharmacol. 2010 Aug;70(2):258-67. doi: 10.1111/j.1365-2125.2010.03687.x.
Abstract/Text WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Increased frequency of electrolyte abnormalities and cardiac arrhythmias among patients exposed to digoxin-diuretic interactions has been well-documented in numerous descriptive studies. * Nonetheless, a clear causal relationship has not been established in these studies. WHAT THIS STUDY ADDS * The risks of digoxin intoxication associated with use of digoxin in combination with any diuretic use, types of diuretics, combinations of diuretics, and individual diuretics were quantified using a population-based nested case-control study design. * The combined therapy of digoxin with any diuretic is associated with a 3.08-fold increase in the risk of digoxin intoxication. * Regarding diuretic class, the risk carried by loop diuretics is greater than that of thiazides or potassium-sparing diuretics, and the risk varies with different combinations of diuretic classes and individual diuretics. AIMS To quantify the digoxin intoxication risk associated with exposure to digoxin-diuretic interactions, and evaluate whether the risk varies by diuretic type, individually or in combination. METHODS This was a population-based nested case-control study in which data from the National Health Insurance Research Database (NHIRD) in Taiwan were analysed. RESULTS The study cohort comprised 154 058 heart failure (HF) patients taking digoxin between 2001 and 2004, in whom digoxin intoxication requiring a hospitalization (ICD-9 code 972.1) occurred in 595 cases. A total of 28 243 matched controls were also selected for analysis. Cases were 3.08 times (adjusted OR 3.08, 95% CI 2.50, 3.79) more likely to have been prescribed diuretic medication in the previous month than controls. Regarding the class of diuretics, loop diuretics carried the greatest risk (adjusted OR 2.97, 95% CI 2.35, 3.75), followed by thiazides (OR 2.36, 95% CI 1.70, 3.29) and potassium-sparing diuretics (OR 1.72, 95% CI 0.83, 3.56). The risk was also observed to vary with different combinations of diuretics, and the loops/thiazides/potassium-sparing diuretics combination carried the greatest risk (adjusted OR 6.85, 95% CI 4.93, 9.53). Among the individual diuretics examined, hydrochlorothiazide carried the greatest risk (adjusted OR 4.63, 95% CI 2.50, 8.57). CONCLUSIONS This study provided empirical evidence that digoxin-diuretic interactions increased the risk of hospitalization for digoxin intoxication in HF patients. The risk was particularly high for concomitant use of digoxin with a combination of loop diuretics, thiazide and potassium-sparing diuretics. The combined use of digoxin and diuretics should be avoided if possible.

PMID 20653679  Br J Clin Pharmacol. 2010 Aug;70(2):258-67. doi: 10.111・・・
著者: D Tzivoni, S Banai, C Schuger, J Benhorin, A Keren, S Gottlieb, S Stern
雑誌名: Circulation. 1988 Feb;77(2):392-7.
Abstract/Text Twelve consecutive patients who developed torsade de pointes (polymorphous ventricular tachycardia with marked QT prolongation, TdP) over a 4 year period were treated with intravenous injections of magnesium sulfate. In nine of the patients a single bolus of 2 g completely abolished the TdP within 1 to 5 min, and in three others complete abolition of the TdP was achieved after a second bolus was given 5 to 15 min later. Nine of the patients also received continuous infusion of MgSO4 (3 to 20 mg/min) for 7 to 48 hr until the QT interval was below 0.50 sec. In nine of the 12 patients the TdP was induced by antiarrhythmic agents. The QT interval preceding TdP ranged from 0.54 to 0.72 sec. After the MgSO4 bolus, which prevented the recurrence of TdP, no significant changes were observed in the QT interval. There were no side effects of this treatment. In eight of the 12 patients potassium levels before the TdP were below 3.5 meq/liter; magnesium levels were available in eight patients before TdP, and were normal in all. Five additional patients with polymorphous ventricular tachycardia but normal QT intervals (non-TdP patients) received two to three boluses of MgSO4. This treatment was ineffective in all, but they responded to conventional antiarrhythmic therapy. Thus, MgSO4 is a very effective and safe treatment for TdP, and its application is rapid and simple. Its use is therefore recommended as the first line of therapy for TdP.

PMID 3338130  Circulation. 1988 Feb;77(2):392-7.
著者: Akshay Gupta, Andrew T Lawrence, Kousik Krishnan, Clifford J Kavinsky, Richard G Trohman
雑誌名: Am Heart J. 2007 Jun;153(6):891-9. doi: 10.1016/j.ahj.2007.01.040.
Abstract/Text Drug-induced long QT syndrome is characterized by a prolonged corrected QT interval (QTc) and increased risk of a polymorphic ventricular tachycardia known as torsade de pointes (TdP). We review mechanisms, predispositions, culprit agents, and management of this potentially fatal phenomenon. Virtually all drugs that prolong QTc block the rapid component of the delayed rectifier current (I(kr)). Some drugs prolong QTc in a dose-dependent manner, others do so at any dose. Most patients that develop drug-induced TdP have underlying risk factors. Female sex is the most common. Implicated drugs include class 1A and III antiarrhythmics, macrolide antibiotics, pentamidine, antimalarials, antipsychotics, arsenic trioxide, and methadone. Treatment for TdP includes immediate defibrillation for hemodynamic instability and intravenous magnesium sulfate. Potassium levels should be maintained in the high normal range, and all QT prolonging agents must be promptly discontinued.

PMID 17540188  Am Heart J. 2007 Jun;153(6):891-9. doi: 10.1016/j.ahj.2・・・
著者: Atsushi Sekiguchi, Takayuki Kashiwagi, Akemi Ishida-Yamamoto, Hidetoshi Takahashi, Yoshio Hashimoto, Hiroshi Kimura, Mikiko Tohyama, Koji Hashimoto, Hajime Iizuka
雑誌名: J Dermatol. 2005 Apr;32(4):278-81. doi: 10.1111/j.1346-8138.2005.tb00762.x.
Abstract/Text A 66-year-old man developed a fever of 38 degrees C and generalized pruritic rash about one month after mexiletine hydrochloride administration for ventricular tachycardia. The rash appeared as edematous erythema and papules with purpura on the lower extremities. Liver dysfunction, leukocytosis, and atypical lymphocytes were also present. Elevated antibody titer against human herpes virus 6 (HHV-6) was detected during the course of the disease (1:20 -> 1:640). The patient was diagnosed as having drug-induced hypersensitivity syndrome (DIHS) due to mexiletine. Discontinuation of the mexiletine administration and systemic corticosteroid treatment led to a temporary improvement, but tapering the corticosteroid dose twice led to recrudescence. Simultaneous with the recrudescence, elevated antibody titers against HHV-6 and cytomegalovirus were detected, as well as viral DNA in the blood, suggesting that these two viruses may have been involved in the recrudescence. The patient died of myocarditis, most likely related to cytomegalovirus. Our case indicates that, in addition to HHV-6, other herpes viruses such as cytomegalovirus can be reactivated in DIHS and may modify the clinical disease activity.

PMID 15863850  J Dermatol. 2005 Apr;32(4):278-81. doi: 10.1111/j.1346-・・・
著者: D S Echt, P R Liebson, L B Mitchell, R W Peters, D Obias-Manno, A H Barker, D Arensberg, A Baker, L Friedman, H L Greene
雑誌名: N Engl J Med. 1991 Mar 21;324(12):781-8. doi: 10.1056/NEJM199103213241201.
Abstract/Text BACKGROUND AND METHODS: In the Cardiac Arrhythmia Suppression Trial, designed to test the hypothesis that suppression of ventricular ectopy after a myocardial infarction reduces the incidence of sudden death, patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The use of encainide and flecainide was discontinued because of excess mortality. We examined the mortality and morbidity after randomization to encainide or flecainide or their respective placebo.
RESULTS: Of 1498 patients, 857 were assigned to receive encainide or its placebo (432 to active drug and 425 to placebo) and 641 were assigned to receive flecainide or its placebo (323 to active drug and 318 to placebo). After a mean follow-up of 10 months, 89 patients had died: 59 of arrhythmia (43 receiving drug vs. 16 receiving placebo; P = 0.0004), 22 of nonarrhythmic cardiac causes (17 receiving drug vs. 5 receiving placebo; P = 0.01), and 8 of noncardiac causes (3 receiving drug vs. 5 receiving placebo). Almost all cardiac deaths not due to arrhythmia were attributed to acute myocardial infarction with shock (11 patients receiving drug and 3 receiving placebo) or to chronic congestive heart failure (4 receiving drug and 2 receiving placebo). There were no differences between the patients receiving active drug and those receiving placebo in the incidence of nonlethal disqualifying ventricular tachycardia, proarrhythmia, syncope, need for a permanent pacemaker, congestive heart failure, recurrent myocardial infarction, angina, or need for coronary-artery bypass grafting or angioplasty.
CONCLUSIONS: There was an excess of deaths due to arrhythmia and deaths due to shock after acute recurrent myocardial infarction in patients treated with encainide or flecainide. Nonlethal events, however, were equally distributed between the active-drug and placebo groups. The mechanisms underlying the excess mortality during treatment with encainide or flecainide remain unknown.

PMID 1900101  N Engl J Med. 1991 Mar 21;324(12):781-8. doi: 10.1056/N・・・
著者: Yuichiro Yamada, Tsuyoshi Shiga, Naoki Matsuda, Nobuhisa Hagiwara, Hiroshi Kasanuki
雑誌名: Circ J. 2007 Oct;71(10):1610-6. doi: 10.1253/circj.71.1610.
Abstract/Text BACKGROUND: Amiodarone-induced pulmonary toxicity (APT) is the most serious side-effect of amiodarone, and its detection and prevention are extremely important. This study was designed to evaluate the incidence and clinical risk factors of APT, and the utility of a pulmonary function test or serum KL-6 assay to predict pulmonary toxicity in Japanese patients receiving low-dose amiodarone.
METHODS AND RESULTS: Five hundred consecutive patients receiving amiodarone were retrospectively evaluated. Mean follow-up period was 48 months and mean maintenance dose was 141 mg daily. Cumulative incidence of APT was 4.2%, 7.8%, and 10.6% at 1, 3, and 5 years, respectively. On multivariate analysis, age at the start (hazard ratio (HR) =1.48, 95% confidence interval (CI) 1.13 to 1.93) was a significant pretreatment risk factor. Age (HR =1.64, 95% CI 1.29 to 2.09), maintenance dose (HR =1.90, 95% CI 1.45 to 2.49) and plasma monodesethylamiodarone concentration (HR =1.30, 95%CI 1.08 to 1.58) were risk factors. Sensitivity and specificity in screening with measurement of percent predicted diffusion capacity of carbon monoxide, > or =15% individual decrease, were 68% and 69%, and for > or =20% individual decrease, were 59% and 74%, whereas those in screening with serum KL-6 assay, > or =500 U/ml, were 25% and 91%, respectively.
CONCLUSIONS: Even at low dose, amiodarone shows substantial pulmonary toxicity. Higher age and higher maintenance dose are risk factors. Further decreasing the maintenance dose of amiodarone should be considered in order to reduce the incidence of pulmonary toxicity, at least in Japanese patients.

PMID 17895560  Circ J. 2007 Oct;71(10):1610-6. doi: 10.1253/circj.71.1・・・
著者: W D Pitcher
雑誌名: Am J Med Sci. 1992 Mar;303(3):206-12. doi: 10.1097/00000441-199203000-00012.
Abstract/Text Amiodarone is an effective antiarrhythmic agent whose utility is limited by many side-effects, the most problematic being pneumonitis. The pulmonary toxicity of amiodarone is thought to result from direct injury related to the intracellular accumulation of phospholipid and T cell-mediated hypersensitivity pneumonitis. The clinical and radiographic features of amiodarone-induced pulmonary toxicity are characteristic but nonspecific. The diagnosis depends on exclusion of other entities, such as heart failure, infection, and malignancy. While withdrawal of amiodarone leads to clinical improvement in majority of cases, this is not always possible or advisable. Dose reduction or concomitant steroid therapy may have a role in selected patients.

PMID 1595783  Am J Med Sci. 1992 Mar;303(3):206-12. doi: 10.1097/0000・・・

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