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1 병원약사회지 (2016), 제 33 권제 1 호 J. Kor. Soc. Health-Syst. Pharm., Vol. 33, No. 1, 20 ~ 30 (2016) Original Article 노인의료센터와일반병동의약물유해반응비교분석 박태영, 허새미, 서예원, 최경숙, 이은숙, 김광일 a 분당서울대학교병원약제부, 노인의료센터 a Comparative Analysis of Adverse Drug Events between Geriatric and Common Wards Tae-young Park, Sae-mi Heo, Ye-won Seo, Kyung-sook Choi, Eun-sook Lee and Kwang-il Kim a Department of Pharmacy, Seoul National University Bundang Hospital 300, Gumi-dong, Bundang-gu, Seongnam-city, Gyeonggi-do, , Korea Abstract : Background : Adverse drug events (ADEs) are medication-related problems that threaten patients safety and increase the length of stay in hospital settings. Especially, geriatric patients are at high risk for ADEs due to comorbidities, polypharmacy and altered pharmacodynamic and pharmacokinetic properties. The geriatric center (GC) of Seoul National University Bundang Hospital (SNUBH) has a designated charged pharmacist and runs a multi-disciplinary team to prevent ADEs and provide safe treatment. In addition, an ADE reporting and surveillance system has been implemented as an effort to prevent ADEs through all departments in SNUBH. Objectives : In order to assess the effect of a designated-pharmacist in GC on ADE prevention, ADE 투고일자 ; 심사완료일자 ; 게재확정일자 교신저자박태영 Tel: @snubh.org

2 박태영 : 노인의료센터와일반병동의약물유해반응비교분석 reports and surveillance signals were collected and analyzed. Methods : A retrospective database review of reported ADEs and ADE surveillance signals was conducted. Reported ADEs were reviewed by pharmacists in the ADE task team to measure causality. Potentially inappropriate medications (PIMs) uses in older adults were determined using the SNUBH geriatric medication guideline. ADE surveillance signals that were judged to be unrelated to ADE by the pharmacists involved were excluded. Results : Among 10,710 inpatients 43 ADEs were reported during the 3-month study period, all of which were from non-gc wards. A total of 77 and 6,819 ADE surveillance signals were reported from 12 geriatric and 708 common ward patients respectively. Polypharmacy were less common and PIMs administered were lower at GC. Conclusion : The frequency of ADE surveillance signals and PIMs uses reported by the multi-disciplinary team involving designated geriatric pharmacists has positive effects on the prevention of ADEs. [Key words] Adverse drug events, Geriatric patients, Designated-pharmacists 1. 배경약물유해반응은치료과정에서환자안전을위협하고입원환자의재원일수를증가시켜의료비증가에기여하는약물관련문제중하나이다. 1),2) 약사의처방중재활동참여는투약과오를예방하는첫단계로이러한약물유해반응예방및환자안전과진료비감소에기여한다. 3),4) 특히노인환자는병존질환과이로인한다약제복용, 약동학, 약력학적특성변화등의요인으로약물유해반응에노출위험이더높다는것이알려져있다. 5)-7) 이러한약물관련문제의예방및안전하고효과적인 치료를위해분당서울대병원노인의료센터는노인전담약사를포함하는다학제팀의료를시행하고있다. 노인전담약사는해당업무를맡은 3년차이상의임상약사 1명과전공약사 (post graduate year 2 or PGY2) 1명으로구성되어있으며노인의료센터환자의입원부터입원치료과정및퇴원후까지환자의안전하고효율적인약물요법시행에관여하고있다. 병원차원에서는약물유해반응보고및감시시스템을통해해당내용공유및이를통한재발방지, 능동적모니터링기반을마련하고있다. 본연구에서는원내약물유해반응보고현황과약물유해반응감시시스템을검토하여노인전담약사가참

3 JKSHP, VOL.33, NO.1 (2016) 여하는다학제팀의료가약물유해반응예방에미치는효과를분석하고효율적인예방방안을모색하고자하였다. 2. 연구방법전자의무기록의후향적검토를통해 2014년 3월 1일부터 5월 31일까지원내전산시스템에기록된약물유해반응보고및약물유해반응감시시그널중 65 세이상의노인환자정보를분석하였다. 비교분석을위해노인전담약사에의한약물관리노력이이루어지고있는노인의료센터와전담약사가없는일반병동으로구분하였으며약물유해반응발생보고현황과원인약물, 감시시그널및해당환자들의기본특성, 약물유해반응발생위험인자정보를수집하였다. 보고된약물유해반응은인과성평가를위해약물유해반응담당약사들에의해재검토가이루어졌으며이때사용된 Naranjo scale score (Table 1) 를지표로 possible(1-4) 이상에해당하는보고건을약물유해반응발생으로간주하였다. 약물유해반응감시시그널중분복또는반복투여에따른동일 ( 日 ), 동약제에대한중복시그널을제외하였다. 약물유해반응과관련성이희박하다고판단되는시그널역시제외하였으며사망임박환자의다장기손상또는교통사고등의외상에의한급격한혈액학적수치악화에따른시그널등이이에해당한다. 그외시스템구조상보고되는치료약물농도감시 (TDM) 미자문및호산구증가증관련시그널을제외하였으며응급실입원중보고된약물유해반응역시제외하였다. 약물유해반응발생위험인자로생각되는노인부적절약물복용과다약제복용여부를검토하였다. 노인부적절약물기준은 Beers criteria와 STOPP (Screening Tool of Older Person s Prescriptions) criteria를기반으로한분당서울대병원노인약물가이드라인 (2012) 을적용하였다. 약제복용은보고가이루어진해당일의수액을제외한실제투여된약물의 Table 1. Naranjo algorithm 연령구분 Yes No Don t know or not done Are there previous conclusive reports on this reaction? Did the adverse events appear after the suspected drug was given? Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given? Did the adverse reaction appear when the drug was re-administered? Are there alternative causes that could have caused the reaction? Did the reaction reappear when a placebo was given? Was the drug detected in any body fluid in toxic concentrations? Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? Did the patient have a similar reaction to the same or similar drugs in any previous exposure? Was the adverse event confirmed by any objective evidence? Sum of scores 9 = definite ADE 5-8 = probable ADE 1-4 = possible ADE 0 = doubtful ADE

4 박태영 : 노인의료센터와일반병동의약물유해반응비교분석 수로결정하였으며관류, 인공물삽입 (e.g., 관절내 cement mix) 에사용되는약물은제외하였다. 3. 연구결과연구기간동안노인의료센터 140명, 일반병동 10,570명의총 10,710명의환자에대해입원치료가이루어졌으며일반병동에서만 43건의약물유해반응이보고되었다. 약물유해반응이보고된환자의평균복용약물수는약 9.3종이었으며 23% 에서노인부적절약물을복용중이었다 (Table 2). 노인의료센터약물유해반응보고건수가없어수치적비교는어려웠다. 보고된약물유해반응유발약물중항감염약물보고빈도가가장높았으며사용량이많은 vancomycin, ceftriaxone, piperacillin/tazobactam의약물유해반응발생비율이높았다. 그외대사계, 신경계, 호흡계, 비뇨기계작용약물및조영제가포함되어있었으며노인부적절약물도포함되어있었다 (Table 2). 보고된약물유해반응증상은보편적인약물유해반응발생빈도와마찬가지로 dose-related (type A), nondose-related (type B) 반응이모두를차지했으며 8) Naranjo scale score은 possible, probable에해당하는경우가많았다 (Table 3). 다른약물유해반응감시시스템을통해노인의료센터, 일반병동의 12건, 708건의환자에서각각 140건, 10,570건의시그널이보고되었다 ( 환자수의경우동일환자의시간차가있는상이약물에대한상이시그널은중복하여집계하여건이라는표현을사용하였다 ). 이는환자 1건당 6.4건, 9.6건의시그널보고에해당하며노인의료센터의환자당보고건수가더적음을알수있었다. 평균복용약물수는큰차이를보이지않았으며노인부적절약물복용환자비율은 17.7%, 23.0% 로노인의료센터가더적었다. 퇴원시처방약수나노인부적절약물포함비율역시큰차이가없었다 (Table 4). 노인의료센터에서보고된약물유해반응감시시그널은 methylprednisolone 투여, anti-diarrhea 투여, 신기능저하환자에서의신독성약물사용의빈도가높았다. 그외약물에의한고혈당, 백혈구감소증, 과민반응, 신기능저하, 독성, 혈소판감소증등과관련 Table 2. Characteristics of Patients Reported in Adverse Drug Events Recording System 구분 약물유해반응보고 (n=43) 연령 ( 세 ) 74.8 ± 5.4 성별 남성 ( 건 ) 25 여성 ( 건 ) 18 신장 (cm) ± 8.4 체중 (kg) 56.2 ± 12.0 간수치이상 ( 건, LFT > 40 U/L)* 11 신기능이상 ( 건, egfr < 60 ml/min/1.73 m 2 )* 된시그널이포함되어있었다 (Table 5). 일반병동의경우혈소판감소, methylprednisolone 투여, bilirubin 수치증가관련시그널의빈도가가장높았으며세항목이전체의약 60% 를차지했다. 해당환자와보고시그널수가많은만큼다양한 18 신대체요법적용 9 복용약물수 9.3 ± 4.2 노인부적절약물복용 ( 건 ) 10 (Hydroxyzine 2 건, ketoprofen 1 건, ketorolac 2 건, metoclopramide 1 건, terazosin 1 건, zolpidem 1 건 ) 퇴원처방약수 6.8 ± 3.6 퇴원시노인부적절약물처방 7 (Chlorpheniramine 2 건, clonazepam 2 건, metoclopramide 1 건, zolpidem 2 건 ) 재원일수 ( 일 ) 31.5 ± 24.2 병원재방문환자수 ( 건 ) 16 *ADE 보고일기준또는최근 5일이내기준 ADE 보고일기준 사망 9건제외

5 JKSHP, VOL.33, NO.1 (2016) Table 3. Reported Adverse Drug Events 약물구분 증상 문헌발현율 Naranjo scale score Antiinfectives Antifungal agents Amphotericin-B renal function abnormality (probable) Fluconazole rash (possible) Cephalosporins Ceftriaxone fever (possible) LFT abnormality (possible) neutropenia (probable) rash (possible) thrombocytopenia (possible) Ceftazidime rash (probable) Penicillins Piperacillin/Tazobactam neutropenia (probable) neutropenia (possible) thrombocytopenia (possible) thrombocytopenia (possible) Quinolones Moxifloxacin fever (possible) rash (possible) Sulfa drugs Sulfamethoxazole/trimethoprim rash (possible) thrombocytopenia reported 3 (possible) Others Colistimethate Scr raised reported 4 (possible) itching, Scr raised reported 3 (possible) Teicoplanin leukopenia reported 7 (probable) hypersensitivity (probable) Vancomycin drug fever (possible)

6 박태영 : 노인의료센터와일반병동의약물유해반응비교분석 약물구분 증상 문헌발현율 Naranjo scale score fever reported 3 (possible) leukopenia (definite) leukopenia (probable) neutropenia (probable) rash (possible) rash (probable) thrombocytopenia (probable) Metabolic system Gout drugs Allopurinol rash (possible) Nervous system Anti-dementia drug Donepezil rash (probable) Antiepileptics Diphenylhydantoin hypersensitivity syndrome (possible) rash (possible) NSAIDs Ketorolac angioedema (probable) edema (probable) pruritus (probable) rash (probable) Opioids Oxycodone dizziness (possible) Respiratory system Bronchodilator Tulobuterol palpitation (probable) Mucolytics Ambroxol nausea and vomiting reported 4 (possible) Others Contrast media Contrast cyanosis reported 4 (possible) erythema reported 4 (possible) rash, pruritus (possible) Genitourinary system Silodosin rash (probable)

7 JKSHP, VOL.33, NO.1 (2016) Table 4. Characteristics of Patients Reported in Adverse Drug Events Surveillance System 구분 노인의료센터 (n=12) 일반병동 (n=708) 연령 ( 세 ) 81.5 ± ± 7.1 성별남성 ( 건 ) 여성 ( 건 ) 신장 (cm) ± ± 11.4 체중 (kg) 45.6 ± ± 8.6 간수치이상 ( 건, LFT > 40 U/L)* 신기능이상 ( 건, egfr < 60 ml/min/1.73 m2)* 복용약물수 8.9 ± ± 4.2 노인부적절약물복용 ( 건 ) 2 (Hydroxyzine, ibuprofen 1건, zolpidem 1건 ) 180 (24종 ) 퇴원처방약수 7.1 ± ± 4.0 퇴원시노인부적절약물처방 재원일수 ( 일 ) 24.8 ± ± 26.5 병원재방문환자수 ( 건 ) 시그널발생률 ( 건 / 명 ) *ADE 보고일기준또는최근 5일이내기준 ADE 보고일기준 aceclofenac 4건, alprazolam 3건, amiodarone 14건, amitriptyline 3건, chlorpheniramine 18건, clonazepam 16건, diazepam 4건, doxazosin 10건, etizolam 2 건, flecainide 1건, flunitrazepam 1건, hydroxyzine 6건, ibuprofen 2건, ketoprofen 21건, ketorolac 29건, lorazepam 9건, megestrol 11건, metoclopramide 27건, nabumetone 1건, perphenazine 1건, propafenone 3건, terazosin 1건, triprolidin 1건, zolpidem 24건 Table 5. Adverse Drug Events Surveillance Signals in the Geriatric Center 약물유해반응감시시그널 빈도 Methylprednisolone (anaphylactic shock or asthma due to drug use) 18 Anti-diarrhea (drug-induced diarrhea) 16 BUN > 50 mg/dl AND receiving nephrotoxin (nephrotoxicity related to drug use) 14 Glucose > 126 mg/dl AND Diagnosis of diabetes, etc. (hyperglycemia related to drug use) 7 WBC count, Blood < 3x10 3 / μl (drug-induced leukopenia) 6 Anti-histamine (drug-induced hypersensitivity) 5 SrCr 0.5 over admission baseline AND receiving nephrotoxin (nephrotoxicity related to drug use)

8 박태영 : 노인의료센터와일반병동의약물유해반응비교분석 약물유해반응감시시그널 빈도 Vancomycin peak > 40 mg/l, trough > 10 mg/l (vancomycin toxicity) 2 Platelet count, Blood < 100K / μl (drug-induced thrombocytopenia) 2 Atropine (reversal agent) 1 Diagnosis of Drug induced osteoporosis with pathological fracture 1 Diagnosis of Drug-induced diabetes mellitus 1 Anti-emetics (drug-induced nausea/vomiting) 1 총계 77 Table 6. Adverse Drug Events Surveillance Signals in Common wards 약물유해반응감시시그널 빈도 Platelet count, Blood < 100K / μl (drug-induced thrombocytopenia) 2,399 Methylprednisolone (anaphylactic shock or asthma due to drug use) 920 Bilirubin, total > 3 mg/dl (hepatotoxicity related to drug use) 605 BUN > 50 mg/dl AND receiving nephrotoxin (nephrotoxicity related to drug use) 559 AST > 150 U/L (hepatotoxicity related to drug use) 307 Anti-diarrhea (drug-induced diarrhea) 296 SrCr 0.5 over admission baseline AND receiving nephrotoxin (nephrotoxicity related to drug use) 255 WBC count, Blood < 3x10 3 / μl (drug-induced leukopenia) 203 Anti-emetics (drug-induced nausea and vomiting) 162 Epinephrine AND receiving with corticosteroids (drug-induced hypersensitivity) 145 Vancomycin peak > 40 mg/l, trough > 10 mg/l (vancomycin toxicity) 141 ALP > 350 U/L (hepatotoxicity related to drug use) 128 Anti-histamine (drug-induced hypersensitivity) 114 ALT > 150 U/L (hepatotoxicity related to drug use) 111 Glucose < 60 mg/dl (hypoglycemia related to drug use) 89 Hydrocortisone (drug-induced hypersensitivity) 69 Polystyrene sulfonate Ca (hyperkalemia related to drug use) 68 K > 6.0 mmol/l (drug-induced hyperkalemia)

9 JKSHP, VOL.33, NO.1 (2016) 약물유해반응감시시그널 빈도 aptt > 3 X hospital`s upper limits (anticoagulant overdose) 35 Atropine (reversal agent) 33 Diagnosis of Drug-induced parkinsonism 26 Diagnosis of Drug intoxication 12 Gentamicin peak > 10 mg/l, trough >2 mg/l (gentamicin toxicity) 12 Tobramycin peak > 10 mg/l, trough >2 mg/l (tobramycin toxicity) 8 PT (InR) > 3.5 (anticoagulant overdose) 8 Flumazenil (benzodiazepine toxicity) 7 Digoxin > 1.5 ng/ml (digoxin toxicity) 6 Glucose > 126 mg/dl AND Diagnosis of diabetes, etc. (hyperglycemia related to drug use) 6 Diagnosis of Drug toxicity 6 Diagnosis of Sedative, hypnotic or anxiolytic intoxication 6 Diagnosis of Drug-induced hepatitis 5 Phenytoin > 20 μg /ml (phenytoin toxicity) 4 Amikacin peak > 25 mg/l, > 10 mg/l 4 Alteplase 4 Dextrose 50% in water AND Glucose < 70mg/dL (hyperglycemia related to drug use) 3 Protamine (heparin reversal) 3 Diagnosis of Drug-induced interstitial pneumonia 3 Topical steroid AND Drug eruption (drug-induced rash) 3 Vitamin K (anticoagulants overdose) 3 Valproic acid > 100 μg /ml (valproic acid toxicity) 2 Diagnosis of Drug-induced myopathy 2 Diagnosis of Drug induced hypercalciuria 2 Diagnosis of Acute renal failure due to other drug 1 Naloxone (opioid overdose) 1 Diagnosis of Inhalant intoxication 1 Diagnosis of Drug-induced cataract 1 Cyclosporine > 500 μg /L (cyclosporine toxicity) 1 총계 6,

10 박태영 : 노인의료센터와일반병동의약물유해반응비교분석 시그널이보고되었다 (Table 6). 방효과를기대할수있을것으로사료된다. 4. 고찰및결론 참고문헌 본연구는노인전담약사가참여하는다학제팀의료의약물유해반응예방효과를분석하고자원내약물유해반응보고내역과감시시그널내역, 해당환자의약물유해반응발생위험인자를검토하였다. 약물유해반응보고의경우짧은연구기간과보고건수의한계로통계적비교는어려우나단기간의수치비교시노인의료센터환자에서약물유해반응발생이더적었다. 증상이경미하여환자와의료진에인지되지않았거나예상가능한약물유해반응에대해의료진이적절하게대처한사례들이보고되지않았을가능성이있어해당사례까지포함하는더욱체계적인연구가필요하다. 약물유해반응감시시스템은각 screening 항목의기준에부합하는환자와해당내역이자동으로보고되어전산시스템에기록된다. 각환자의세부적인기저상태가고려되지않기때문에시그널의보고와약물유해반응발생이필연적으로대응된다고판단하기는어렵다. 그러나각시그널의특성상약물유해반응에더취약한환자상태를반영한다고볼수있으며약물유해반응예방의능동적모니터링도구로써의미가있다. 이번연구에서보고된약물유해반응보고환자의약 50% 는감시시그널에도보고되어있었다. 환자당보고된시그널수가일반병동보다노인의료센터에서더적었으며이는다장기급성내과환자의특성에도불구하고약물유해반응발생에덜취약한상태로관리되고있다고판단된다. 앞서언급한대로각환자의상태를고려한개별적시그널의검토의부재가본연구의한계이며향후원내에서는보고된전체시그널에대해개별적분석및예방효과를확인할계획에있다. 아울러시그널을이용한전담약사의처방중재활동에대한기록및연구가이루어진다면전담약사의팀의료참여효과를간접적으로입증할수있을것으로사료된다. 본연구는노인의료센터에서의전담약사참여효과를언급하고있으나담당약사제도에의한약사의처방중재활동이치료에미치는긍정적효과를고려할때해당제도의타과에의적용을통해서도약물유해반응예 1) Barbara L. Kass : Reducing and preventing and adverse drug events to decrease hospital costs. Agency for Healthcare Research and Quality. findings/factsheets/errors-safety/ aderia/ade.html. Published March, ) Koo H.Y. : Effects of adverse drug reactions detected using monitoring program on the length of stay and charges in the hospital setting. Doctoral disseration, Thesis for Medicine, Seoul National University (2009) 3) Michael J. Dooley, Karen M. Allen, Christopher J. Doecke, Kirsten J. Galbraith, George R. Taylor, Jennifer Bright and Dianne L. Carey : A prospective multicentre study of pharmacist initiated changes to drug therapy and patient management in acute care government funded hospitals. Br J Clin Pharmacol, 57, (2004) 4) Lucian L. Leape, David J. Cullen, Margaret Dempsey Clapp, Elisabeth Burdick, Harold J. Demonaco, Jeanette Ives Erickson and David W. Bates : Pharmacist participation on physician rounds and adverse drug events in the intensive care unit. JAMA, 282, (1999) 5) Kathrin M. Cresswell, Bernard Fernando, Brian Mckinstry and Aziz Sheikh : Adverse drug events in the elderly. Br Med Bull, 83(1), (2007) 6) Balamurugan Tangiisuran, Juliet Wright, Tischa Van Der Cammen, Chakravarathi Rajkumar. : Adverse drug reactions in elderly: Challenges in identification and improving preventative strategies. Age and Ageing, 38, (2009)

11 JKSHP, VOL.33, NO.1 (2016) 7) 김형숙, 서예원, 이정화, 이은숙, 이병구, 신완균, 박명숙, 김광일 : 노인의료센터입원환자의약물유해반응현황및위험인자분석. J. Kor. Soc. Health-Syst. Pharm., 25(4), (2008) 8) 이병재 : 약물유해반응 (Adverse drug reaction) J. Kor. Soc. Health-Syst. Pharm., 26(3), (2009)

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract