含Digoxin處方其藥物交互作用之研究

中文摘要 藥物交互作用，通常會造成治療失敗以及副作用的產生，所以近年來在臨床上逐漸受到重視。由於藥物品項的日益增加，不僅提供更多治療藥物的選擇，同時也增加了許多藥品併用的機會，尤其罹患一種以上的慢性疾病者。老年病患之肝、腎功能及新陳代謝的改變，再加上少數醫師多藥療法（Polypharmacy）的治療習慣，產生藥物交互作用的可能性就更高了。藥物在體內產生的藥效常因濃度的不同，而引起不一樣的藥理反應。併用其他藥物可能增強或減弱其預期的藥效，若能獲得正面的協同效果自然是相得益彰，但若是造成負面的交互作用，這便不是我們所希望看見的，尤其是一些治療指數（Therapeutic index：TI）低的藥物如Digoxin、Warfarin、Theophylline等，當併用其他藥物時更需要定時地監測其血中濃度。嚴重的藥物交互作用常會導致不可預期的後果，造成病患極大的危險，甚至死亡。 Digoxin被使用在充血性心衰竭，其臨床有效劑量已接近中毒劑量，所以其治療指數相當低，其藥物交互作用更受重視。故本研究針對處方中Digoxin與其他藥物產生交互作用的發生率及相關因子加以探討，以及經由瞭解藥物交互作用發生的作用機轉，探討其發生的嚴重度，以期進一步提醒醫師在臨床上對病患的檢查追蹤，使病患可以獲得較佳的醫療服務。 處方上常見Digoxin與利尿劑合併使用來治療充血性心臟衰竭，而利尿劑的合併使用會改變血鉀濃度，進而影響Digoxin的毒性。此外，Digoxin與留鉀利尿劑、血管加壓素轉化酶抑制劑（Angiotensin converting enzyme inhibitors；ACEIs）或鉀離子補充劑的合併使用，是否改變血鉀濃度而影響Digoxin毒性？均有待探討。本研究是依Digoxin合併不同的利尿劑、鉀離子補充劑或ACEIs加以分組，進行血鉀濃度的比較分析，以探討這些藥物對Digoxin毒性的影響，以及評估這些藥物在臨床上與Digoxin併用之利弊。此外亦探討處方中其他藥物間的交互作用，以期結果能提供醫事人員有益的參考，減少交互作用所產生的危險。 本研究收集民國90年1月1日至1月31日間含有Digoxin藥物處方，共計440張處方，藥品品項數共30231筆。藥物交互作用的發生率為4.36 %，若只估計具臨床意義的交互作用（一到三級）則有2.84 %；研究對象中，男性佔228例（51.8 %），女性佔212例（48.2 %），其年齡分佈以老年病患為主，其中60〜79歲有256例（58.2 %）為最多，80歲以上者93例（21.2 %）為其次。研究的處方中，其藥品品項數以七種品項為最多，有72例（16.4 %），八種品項為其次，有62例（14.1 %）。研究結果顯示，藥物交互作用的發生與藥品品項數呈現正的相關（相關係數r＝0.593），與病患的年齡呈現低度但具顯著的相關，但與性別則無相關性。 Digoxin與藥物交互作用的發生率為2.32 %，共有701組藥物交互作用的產生，若只估計具臨床意義的第一級到第三級的交互作用則有411組，佔了1.36 %。與Digoxin產生交互作用的藥物之數量及其嚴重度分析中，利尿劑與Digoxin的交互作用佔了260例，而Furosemide即佔了201例，屬於第二級交互作用。Thiazide類利尿劑（Trichlormethiazide，Indapamide，Benzyldihydrochlorthiazide）與Digoxin呈現一級的藥物交互作用，共有40例。第二大類為Digoxin與制酸劑的併用，佔了123例，屬於第四級；其次為Digoxin與β-阻斷劑（Carvedilol，Atenolol，Labetalol，Propranolol，Satalol，Bisoprolol）有59例，Digoxin與Amiodarone交互作用有28例，皆屬於第二級的交互作用。 除Digoxin外，藥物間交互作用的發生率為2.04 %，共有616組藥物交互作用的產生，若只估計具臨床意義的第一級到第三級的交互作用則有447組，佔了1.40 %。所產生的交互作用組別其數量及其嚴重度分析中，第一級的藥物交互作用以Aspirin與Ticlopidine及銀杏葉萃取物（Ginkgo biloba extract）佔最多，各佔了6例及5例；抗凝血劑Warfarin與抗血小板凝集藥物的交互作用皆屬於一級，共佔了4例。ACEIs ─ Enalapril，Captopril，Perindopril與Spironolactone的交互作用共有5例；ACEIs與鉀離子補充劑的併用有4例。Furosemide與Aspirin交互作用有62例，其次為Aspirin與制酸劑及氧化鎂的交互作用，各佔56例及34例，皆屬於第二級的交互作用。二級交互作用的另一大類為Loop及Thiazide類利尿劑與ACEIs的併用，共有98例；而Aspirin與降血糖藥物的交互作用共佔了21例。 血鉀正常濃度為3.5 - 5.0 meq/l，血鉀過低或過高皆會導致心律不整，病歷對照的結果顯示，在單獨使用Digoxin這組，其平均血鉀濃度為4.06 meq/l（95 % CI：3.92 — 4.20 meq/l），其中有1人（2.9 %）發生低血鉀現象；Digoxin + Trichlormethiazide的平均血鉀濃度值為最低（血鉀濃度為3.35 meq/l，95 % CI：1.68 - 4.02 meq/l），除了與Digoxin + Furosemide + KCl這組顯示無統計上的差異外，與其它各組的平均血鉀濃度比較皆有統計上的差異（P < 0.05），且其中75 % 有低血鉀（血鉀濃度 < 3.5 meq/l）；在Digoxin + Furosemide 這組平均血鉀濃度亦呈現較低的情形（3.93 meq/l；95 % CI：3.72 - 4.13 meq/l），低血鉀情形佔了其中的17.8 %，而在Digoxin + Moduretic®（Amiloride + Hydrochlorthiazide）這組則無血鉀異常的現象。 在合併使用Digoxin + Furosemide + KCl的結果，其平均血鉀濃度為3.80 meq/l（95 % CI: 3.58 - 4.02 meq/l），與Digoxin + Furosemide + ACEIs及Digoxin + Moduretic®兩組皆有統計上的差異（P < 0.05）；其血鉀濃度的提昇並不如預期的高，且亦有30.8 %發生低血鉀異常的情形。 綜合以上結果可知Trichlormethiazide的確會造成低血鉀，可能會加強Digoxin造成心室纖維顫動之毒性，而臨床上亦觀察到較少單獨開立此類的處方，而以併用留鉀利尿劑為較常見。Furosemide為最強之利尿劑，理應較Thiazides利尿劑易降低血鉀，但追蹤血鉀結果仍在正常血鉀範圍內，所以在臨床上其加強Digoxin毒性可能比預期低。此外Thiazide和Loop利尿劑併用ACEI，或留鉀利尿劑均可防止血鉀濃度的下降。令人訝異的是，鉀離子補充劑併用Furosemide並無法有效提昇血鉀，甚至有30.8 % 病人呈現低血鉀，此點值得更進一步謹慎的探討。藥物交互作用嚴重度分析結果顯示，在處方中屬於二級（含）以上之藥物交互作用仍有相當高的比例存在，可見藥物交互作用尚未受到醫師和藥師重視。

Abstract In recent years, the drug interaction has been concerned gradually as it often leads to failures in treatments and unwanted side effects. Today, following the increase in numerous drug categories, not only the choices of drugs became abundant, the opportunities of treatments with different drug combinations also greatly enhanced, especially in patients who have more than one chronic disease. The possibilities of drug interactions again got higher in aged patients whose liver and kidney functions changed in plus of the polypharmacy treatments accustomed to physicians. Drug effects may differ according to its’ serum concentration and causing different pharmacology effects. Combination of drugs can either enhance or lower the effects; thus if the interactions proves to be positive synergism then we may well to see the multiplying effects, but on the other hand, it’s not we expect that negative drug interactions effects. Closely monitor the serum concentration, particularly in combine with some drugs that are low Therapeutic index. Unexpected effects of drug interactions may jeopardize patients’ health, even death. Digoxin is mostly used in congestive heart failure; the TI is low and the effective dosage is nearly to the toxic dosage; its tendency in drug interaction is even more emphasized. Hence this research aimed at exploring the drug interaction possibilities and related factors of Digoxin. And through the understanding of drug interaction mechanism and severity, make it a reminder for doctors in following their patients clinically, thus providing better medical services for patients. Digoxin combined with diuretics to treat CHF is common in prescriptions; the addition of diuretics can alter the serum potassium concentration and ultimately affecting the toxicity of Digoxin. In addition, does the serum potassium concentration change when Digoxin combined with potassium-sparing diuretics, ACEIs or potassium supplements? Under different groupings of Digoxin combined with diuretics, ACEIs or potassium supplements, we compared the serum potassium and analysis for understanding affections of the above drugs have on Digoxin toxicity, evaluating the clinical benefits of the combinations. Expect the results could be the beneficial references for medical personnel and reduce the damage generated from interactions. This study collected prescriptions contained Digoxin during the period of 1/1/2001 to 1/31/2001, there were 440 samples and 30,231 drugs. The prevalence of the drug interaction was 4.36% and 2.84% for with clinical significance interactions (severity 1 to 3). There were 228 (51.8%) male and 256 (48.2%) female; among them, the largest group of 256 people was between the age of 60 and 79 (58.2%), next was the group of 93 with ages over 80 (21.2%). There were 72 samples (16.4%) had 7 different kinds of drugs in prescriptions, and 62 samples (14.1%) had 8. According to the results, the prevalence of drug interaction displayed a positive correlation with the numbers of drugs (r = 0.593), there was significant but low correlation with patients’ age, and there were no correlation with gender. The prevalence of drug interactions with Digoxin was 2.32% with a total of 701 sets, and 411 sets in severity 1 to 3, which was 1.36%. In the analysis the numbers of drug interactions with Digoxin and their severity, within the 260 interactions between diuretics and Digoxin, Furosemide along took up 201 samples and was classified as severity 2; Thiazide diuretics（Trichlormethiazide, Indapamide, Benzyldihydrochlorthiazide） combined with Digoxin had shown severity 1 interactions with a total of 40 samples. Digoxin combined with antacids had 123 samples classified in the forth severity, and next was the Digoxin combined with β-blocker with 59 samples, Amiodarone had 28 samples classified in severity 2. The prevalence of drug interactions except Digoxin was 2.04% with a total of 616 sets, and 447 sets in severity 1 to 3, which was 1.40%. In the analysis of numbers of drugs interactions and their severity, Aspirin and Ticlopiddine/Ginkgo Biloba Extract had the most drug interactions, which were 6 and 5 samples; The interaction of Warfarin and anti-platelet drug were classified in severity 1 that had 4 samples. Interactions of ACEIs— Enalapril, Captopril, Perindopril with Spironolactone had 5 samples; the combination of ACEIs and potassium supplements had 4 samples. Furosemide and Aspirin had the most interaction totaling 62 samples. Next was the interaction between Aspirin and antacids / magnesium oxide with 56 and 34 samples respectively, classified as second severity interaction. Another significant category in severity two was the combination of Loop/ Thiazide diuretics and the Aspirin with a total of 98 samples, the Aspirin and antidiabetics with 21 samples. The normal serum potassium concentration is 3.5 - 5.0 meq/l, either hypokalemia or hyperkalemia may cause cardiac arrhythmia. The results of case control study demonstrated the mean serum potassium was 4.06 meq/l (95% CI: 3.92 - 4.20 meq/l) in the group took Digoxin. Among them, one patient had developed hypokalemia (serum potassium < 3.5 meq/l). The Digoxin + Trichlormethiazide had the lowest serum potassium concentration (mean serum potassium was 3.35 meq/l, 95% CI: 1.68 - 4.02 meq/l). There were significant differences when compared with other groups’ mean serum potassium (P < 0.05) except the group of Digoxin + Furosemide + KCl. And in the group of Dioxin + Trichlormethiazide, there was 75% had hypokalemia. The group, Digoxin + Furosemide, also had lower mean serum potassium concentration (3.93 meq/l, 95% CI: 3.72 - 4.13 meq/l), and hypokalemia took up about 17.8%. There was no abnormal serum potassium appeared in the group of Digoxin + Moduretic® (Amiloride + Hydrochlorthiazide). The result of combining Digoxin + Furosemide + KCl had shown the mean serum potassium concentration of 3.80 meq/l (95% CI: 3.58 — 4.02 meq/l), which was significant different with the groups of Digoxin + Furosemide + ACEIs and Digoxin + Moduretic (P < 0.05). Additionally, compared the groups of Digoxin + Furosemide and Digoxin + Furosemide + potassium supplement, the results had shown that the group with supplementing potassium had lower serum potassium than the one without; and the percentage of hypokalemia was also higher (30.8% : 17.9%). Conclusion: Trichlormethiazide could cause hypokalemia and might enhance the ventricular fibrillation of Digoxin toxicity. Doctors seem to notice the fact. and there were less such prescriptions. Furosemide is the most powerful diuretic and should be more efficacies to lower the serum potassium than the Thiazides; but, in the study, the serum potassium kept within the normal range. Therefore, the effect of enhancing Digoxin’s toxicity can be actually lower than the expected in the clinical. Furthermore, Thiazide and Loop diuretics combined with ACEIs or potassium-sparing diuretics could prevent the drop of serum potassium. And surprisingly, potassium supplements combined with Furosemide couldn’t raise the serum potassium effectively, and there was 30.8 % of the patients had hypokalemia; this will be a subject for further researches. The results from interaction severity analysis had shown high percentage for even severity 2 in the prescriptions; Drug interaction doesn’t seem to have been aware to the doctors and the pharmacists.