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1 대한배뇨장애요실금학회지 J Korean Continence Soc 2008;12:133-8 원저 뇌질환을동반한과민성방광환자에서 tolterodine 투여후인지기능의변화 동아대학교의과대학비뇨기과학교실, 1 김원묵기념봉생병원신경과 김태효 박민정 1 조원열 The Change of Cognitive Function after Administration of Tolterodine in Brain Disease Patients with Overactive Bladder Tae Hyo Kim, Min Jung Park 1, Won Yeol Cho From the Department of Urology, College of Medicine, Dong-A University 1 Bongseng Memorial Hospital, Busan, Korea Puropose: It is known that anticholinergics induces cognitive dysfunction and may aggravate the state of it. Tolterodine tartrate (detrusitol R ) is a widely known selective anticholinergics to bladder, which does not cause a cognitive dysfunction. This study was designed to analyze the change of cognitive function of brain disease patients, whom are taking anticholinesterase inhibitor with tolterodine for overactive bladder (OAB). Material and methods: From January 2001 to December 2004, with the patients whom have been followed for the brain disease in the department of neurology, we have analyzed 79 patients with tolterodine administered for OAB. We used K-MMSE (Korea minimental status examination) and SNSB (seoul neuropsychological screening battery) to analyze the state of cognition. Mean age of patients was 67.3±4.5 (yrs), mean administration period was 4.7±9.5 (mon). Results: 7 patients made complaints for the decline of memory, 2 of them with Parkinsonism and 2 with cerebral infarction, 1 with progressive supranuclear palsy and, 2 dementia with lewy body (DLB). Patients with DLB was excluded in this study because the disease had fluctuation of cognitive function. Conclusions: The result of these studies demonstrates tolterodine tartrate caused the decline of cognitive function in only a few patients with brain disease. We concluded that prospective studies are needed to change the cognitive functions of the brain disease patients with OAB after administration of tolterodine tartrate. (J Korean Continence Soc 2008;12:133-8) Key Words: Tolerodine tartrate, Overactive bladder, Cognition, Brain disease 접수일자 : 2008 년 4 월 15 일, 수정일자 : 2008 년 7 월 25 일, 채택일자 : 2008 년 7 월 29 일교신저자 : 조원열, 동아대학교의과대학비뇨기과학교실, 부산시서구동대신동 3 가우 Tel: , Fax: , urogate@daunet.donga.ac.kr * 이논문은동아대학교학술연구비지원에의하여연구되었음. Vol. 12, No. 2,

2 김태효 박민정 조원열 서론과민성방광은요절박과함께빈뇨나야간뇨혹은절박성요실금등의증상을호소하는질환이다 (1). 과민성방광의유병율은나이가들면서증가하고, 65세이상인구중에서는약 25% 에서과민성방광을가진다 (2). 항콜린제는과민성방광의치료에효과적이긴하나구갈이나변비, 시야혼탁과같은다양한부작용이있으며, 이로인하여약물투여를중지하는경우도있다 (3). 항콜린제에의해발생하는다양한부작용은방광외의다양한장기에존재하는무스카린아세틸콜린성수용체 (muscarinic acetylcholine receptor) 에의해발생하며 (4), 대부분의항콜린제는말초조직에작용하는것으로알려져있지만, 중추신경조직에작용하는사례도보고되고있다. 중추신경계에주로존재하며콜린성신경원 (cholinergic neuron) 은인지능력과기억력에중요한역할을하며 (5), 특히지각능력이저하되어있는노인의경우자신의지각능력에대해잘인식하지못하는경우가많고, 이로인해항콜린제를복용할경우중추신경계의부작용이발생할수있다 (6). Oxybutynin의경우, 건강한노인에서장기기억과정신활동의능력에장애가발생할수있는것으로보고되었고 (7), 파킨슨병환자에서도심각한장애를유발된예가보고되었다 (8). 그외에도스코폴라민 (scopolamine) 과같은항콜린제는알쯔하이머치매를가진환자에서인지능력의심각한부작용을일으킬수있는것으로알려져있다 (9). 이상의보고에서과민성방광의표준치료제로사용되는항콜린제들은뇌질환을가진환자에서인지능력을악화시킬수있다. 저자들은뇌질환을동반한과민성방광환자에서 tolterodine을복용한후인지능력의변화에대하여알아보고자하였다. 대상및방법 동반될수있는뇌질환을가진경우, 2) 최소 4주이상 tolterodine을복용한경우, 3) 약물복용전, 후의 K-MMSE (Korean Mini-mental state examination) 나 SNSB (Seoul neruopsychological screening battery) 검사등으로인지기능평가가있는경우, 4) 인지기능에대한검사를수행할수있을정도의이해력을가진환자, 5) 객관적인상황을기술할수있는보호자가있는경우를대상자로선정하였다. 결과분석은약물복용후인지기능저하나기억력감소등의증상을보호자보고를통하여수집하였고, 인지기능평가는 K-MMSE 를시행하였으며, 가능한경우에는 SNSB를함께시행하여약물복용후, 그리고중단후의결과를각각비교하였다. MMSE는 5~10분정도의짧은시간에전반적인인지기능을평가하고측정할수있도록고안된검사로서치매를탐지하는데있어신뢰도와타당도가입증되었고다른인지기능검사와도높은상관관계를보이는등우수성과임상적인편리함때문에여러가지인지기능선별검사중가장널리사용되고있는검사이다. K-MMSE ( 한국판 MMSE) 는우리나라노인들에게사용할목적으로원래문항들을가능한그대로유지하여번안하여만들어진것으로치매환자를대상으로타당도연구가되어있다 (10). SNSB는종합적인신경심리검사배터리로서인지기능전반을모두평가하는다양한검사들로구성되어있다 (11). 인지영역별로는주의집중능력, 언어및그와관련된기능, 시공간기능, 기억력및전두엽 / 집행기능의 5가지인지영역을평가하고있는데포함된검사들은국내노인을대상으로표준화연구를수행하였다. 인지영역에대한검사들외에도피검자의정서적상태가인지적기능에어떤영향을미치고있는지에대한정보를제공하는 Geriatric Depression Scale (GDS) 과 Barthel Activity of Daily Living (B-ADL) 이포함되어있으며, 피검자와보호자의보고를종합하여최종적으로치매심각도를평정하는 Clinical Dementia Rating Scale (CDR) 이포함되어있다. 2001년 1월부터 2004년 12월까지본원신경과에서뇌질환으로치료중인환자에서요절박과빈뇨의증상이있어비뇨기과로전과된환자중최소 3개월이상 tolterodine을복용한 79명을대상으로하였다. 약물복용후인지기능의변화는후향적으로의무기록을통하여분석하였다. 다음과같은적응증을가진경우는연구대상으로포함시켰다. 1) 알쯔하이머치매나파킨슨병, 뇌경색등인지기능장애가 결과환자들의평균연령은 67.3±4.5세였고평균추적관찰기간은 4.7±12.6개월이었다. 79명중 7명에서인지기능의저하를보여 tolterodine 복용을중단하였다. 7명중 2명은루이바디치매 (lewy body dementia) 로이질환의경우, 증상자체로인지기능의주기적인변동을보이므로결과에서제외하였 134 대한배뇨장애요실금학회지

3 뇌질환을동반한과민성방광환자에서 tolterodine 투여후인지기능의변화 다. 그외 2명은파킨슨병이었고, 2명은알츠하이머치매, 1명은진행성핵상마비 (progressive supranuclear palsy) 였다 (Table 1). Tolterodine 복용후인지기능의저하를보인 5명의평균연령은 66.0±5.0세이었고, 평균 tolterodine 사용기간은 1.6±1.4개월이었다 (Table 2). Tolterodine 사용전의평균 K-MMSE 점수는 23.8±4.02 이었고, tolterodine 사용후에는 20±4.74, tolterodine 중단후에는 23.6±3.85였다 (Table 3). SNSB 검사의경우는약물사용후, 중단후에두차례시행한환자가 2명이었다. 한환자에서는파킨슨병환자로언어및시각적기억력과전두엽기능에서통계적으로의미있는변화를보였다. 다른환자는알쯔하이머치매로전반적인인지기능저하가있는가운데전두엽기능검사에서각각 Table 1. The characteristics of patients No. of patients Sex (M/F) Mean age (yr.) Duration of tolterodine use (mos.) Associated brain diseases Cerebral infarction Parkinson disease Alzheimer disease Multiple system atrophy Progressive supranuclear palsy Dementia with lewy body 79 32/ ± ± Table 2. The characteristics of patients who showed the change of cognitive function after use of tolterodine for OAB No. of patients (%) Sex (M/F) Age (yrs.) Duration of tolterodine use (mos.) Cognitive dysfunction Cerebral infarction Parkinson disease Dementia with lewy body* Progressive supranuclear palsy K-MMSE Before using Tolterodine After using Tolterodine After stop using Tolterodine 2/ ± ± 1.4 7/79 (8.9) 2 (2.5) 2 (2.5) 2 (2.5) 1 (1.3) 25.2 ± ± ± 4.9 * OAB: Over Active Bladder * K-MMSE: Korean Mini-mental state examination) tolterodine 사용시, 중단후의의미있는변화소견을보였다 (Table 4). Table 3. The change of K-MMSE score in patients who presented the symptoms of cognitive dysfunction after use of tolterodine for OAB Patient before use of To 고 과민성방광증상은약물의중추신경계증상을더욱악화시킬수있는것으로알려져있다. 예를들면, 야간뇨증상은수면장애를유발하게되므로, 정신건강에해로움을줄수있고 (12), 요절박과야간뇨는노인에서낙상이나골절의위험을증가시킬수있다 (13). 인지기능에장애를가져올수있는약물은과민성방광증상과연관되어낙상의위험을증가시키지만, 반대로항콜린제를사용함으로써화장실로뛰어가다낙상을입을가능성을감소시킬수있다는점도반드시고려해야한다. 약물로인한인지기능장애는노인에서흔히관찰할수있다 (14). 이와연관된약물로는벤조다이아제핀, 오피오이드, 삼환계항우울제, 항콜린제등이다 (15). Blazer 등 (16) 은 1년이상, 1가지이상의항콜린특성을가진약물을복용하는사람들과 5가지이상의항콜린제를복용하는사람들을비교분석하여, 신경이완제나삼환계항우울제를복용하는환자에서항콜린효과를최소화해서처방할필요는없다고보고하였다. 항무스카린제인스콜폴라민은언어학습에문제를야기하며, 심한경우자유연상을지연시키는것으로알려진약제이지만, 실제로이약물은기억재생에영향을거의미치지않는다 (17). 과민성방광의치료에쓰이는대부분의항콜린제는 3차또는 4차아민이다 (18). 4차아민계열인 trospium chloride 는강한극성과낮은지용성을가지고있어 tolterodine after use of To after stop of To A B C D E * To: toletrodine 찰 Vol. 12, No. 2,

4 김태효 박민정 조원열 Table 4. The change of SNSB score in patients who presented the symptoms of cognitive dysfunction after use of tolterodine for OAB SNSB items-patient B post prescription stop prescription Digit span: forward/backward 5/3 7/4 Korean Boston Naming Test Copying of Rey Complex Figure Test Seoul Verbal learning test - delayed recall 3 7 Rey Complex Figure Test - delayed recall 7 15 Controlled Oral Word Association - letter item 14 (-) 17 Stroop Test - color reading SNSB items-patient D post prescription stop prescription Digit span: forward/backward 3/2 4/2 Korean Boston Naming Test Copying of Rey Complex Figure Test 6 7 Seoul Verbal learning test - delayed recall 2 2 Rey Complex Figure Test - delayed recall 1 4 Controlled Oral Word Association - letter item 2 7 Stroop Test - color reading *SNSB: Seoul Neruopsychological Screening Bettery 이나 oxybutynin 등의 3차아민계열약물보다중추신경제효과는적다. 3차아민계열임에도불구하고 tolterodine은낮은지용성을가지고 (1/30 이하 ) (19), oxybutynin보다분자구조가커서중추신경계로침투할가능성이적다 (19). 이에반해높은지용성과중립성, 그리고작은분자구조를가진 oxybutynin은중추신경계로침투가잘된다. 이상의사실은 108명의건강한지원자에게 tolterodine, oxybutynin과 trospium chloride 및위약을투여하여이중맹검법을이용한메타분석을시행한실험에서입증되었다 (21). 또한 oxybutynin은 tolterodine이나 trospium chloride에선볼수없었던운동조화기능, 반응시간, 지각정확도, 집중력, 불면증에서악영향을주는것으로보고하였고, oxybutynin이 tolterodine보다쉽게중추신경계에영향을미치며, trospium chloride는혈관뇌장벽을통과하지않는다고보고하였다. 과민성방광의치료제중 tolterodine은다양한연구가가장많이진행된 3차아민계약물로, 건강한지원자에서표준치료용량이상으로 (12.8mg) 약물을복용한경우에서도중추신경계부작용이없는것으로알려져있다 (20). 또한 Malone- Lee 등 (21) 이과민성방광이있는 177명의노인에 게시행한 4주간의연구에서중추신경계부작용은 5~7% 로보고하였고, tolterodine IR과 oxybutynin ER을비교한경우에서도둘다비슷한비율의중추신경계부작용을보고하였다 (22). 가장최근에는 tolterodine ER과 oxybutynin IR의효능과지속성에대해일본과한국의과민성방광환자를대상으로비교분석한결과가보고되었다 (23). Tolterodine ER을복용한환자에서전반적인부작용이적은것으로보고되었는데, 주목할점은 oxybutynin IR을복용한경우중추신경계부작용의발생률이 12.7%, 위약을복용한경우에서는 11.5% 이고 tolterodin ER을복용한경우는중추신경계부작용이 8.4% 였다는점이다. Tolterodine이나 oxybutynin을복용한경우에서나타나는중추신경계부작용은기억력저하와연관이있으며 (24), oxybutynin은 M1 수용체에작용하므로, 기억력저하는일련의무스카리닉반응과정의변화로인해발생하는것으로추정된다. 이러한가설은 M1 수용체가결핍된쥐에서기억력의특정영역이심각하게훼손되어있는것을보여주는것이근거가된다 (25). 본연구에서기억력저하를비롯하여인지기능의저하를보고한예는 79명중 5명으로 9% 에못미치고이는기 136 대한배뇨장애요실금학회지

5 뇌질환을동반한과민성방광환자에서 tolterodine 투여후인지기능의변화 존의보고와유사한것으로보인다. 하지만후향적연구로이루어져 tolterodine 사용으로인한인지기능의변화를환자나보호자의보고가있었던경우에만주목하여평가하였기에미비한변화가있었던경우는그변화를인지하지못하여적게보고되었을가능성이충분히있을것으로생각한다. MMSE는치매의선별검사로서뿐만아니라치매의진행을추적관찰할때에도널리쓰이는검사로대개치매환자의경우에서도 1년에 2~3점정도의저하를보이는것으로알려져있다 (26). 본연구의관찰기간인 4.7개월내에평균 3.6점정도의현저한변화를보인것은질병의일반적경과라고볼수없고약물복용이원인으로작용한것으로판단할수있었다. SNSB를시행한파킨슨병환자는기억력을평가하는 Seoul Verbal Learning Test (SVLT), Rey Complex Figure Test (Rey CFT) 의지연회상항목과전두엽기능검사인스트룹항목에서동일연령과학력을가진경우에비해 1.5 표준편차미만의수행을보여인지기능의저하가있었고, tolterodine을중단하고나서시행한검사에서는평균에미치지못했던항목들에서모두정상수준의수행을보였다. 다른한명은알쯔하이머치매환자로시공간능력, 기억력, 전두엽기능을평가하는여러가지검사에서전반적으로낮은수행을보여다발성인지장애가있는데그중전두엽기능검사인글자유창성과스트룹검사에서는약물중단후에높은수행을보여정상범주에속하는변화를보였고, 나머지항목에서는약물중단후에도통계적으로의미있는뚜렷한차이는보이지않았다. 인지기능검사수행능력에서뚜렷한차이를보여이를 tolterodine 복용으로인한인지기능저하가약물중단후에다시회복되었을것이라판단하였다. 결론과민성방광을치료하기위해항콜린제를쓸때콜린성기능과연관된뇌질환환자나치매가없더라도뇌질환이있는환자에서는더욱신중을기하여야한다. 즉, 인지기능의저하를동반한뇌질환환자에서는과민성방광으로인한증상이심하여약물을꼭써야할경우라면용량을줄이는것을고려하여야한다. 그리고처방한이후에는기억력과인지기능에대해주의깊은관찰을해야만한다. References 1) Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardization of terminology of lower urinary tract function: Report from the Standardization Sub-committee of the International Continence Society. Urology 2003;61: ) Milsom I, Abrams P, Cardozo L, Roberts RG, Thuroff J, Wein AJ. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 2001;87: ) Rovner ES, Wein AJ. Once-daily, extended-release formulations of antimuscarinic agents in the treatment of overactive bladder: A review. Eur Urol 2002;41:6-14 4) Caulfield MP, Birdsall NJ. International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 1998;50: ) Kopelman MD. The cholinergic neurotransmitter system in human memory and dementia: A review. Q J Exp Psychol A 1986;38: ) Morrison RL, Katz IR. Drug-related cognitive impairment: Current progress and recurrent problems. Annu Rev Gerontol Geiatr 1989;9: ) Katz IR, Sands LP, Bilker W, DiFilippo S, Boyce A, D'Angelo K. Identification of medications that cause cognitive impairment in older people: the case of oxybutynin chloride. J Am Geriatr Soc 1998;46:8-13 8) Bedard MA, Pillon B, Dubois B, Duchesne N, Masson H, Agid Y. Acute and long-term administration of anticholinergics in Parkinson s disease: specific effects on the subcortico-frontal syndrome. Brain Cogn 1999;40: ) Agnoli A, Martucci N, Manna V, Conti L, Fioravanti M. Effect of cholinergic and anticholinergic drugs on short-term memory in Alzheimer s dementia: a neuropsychological and computerized electroencephalographic study. Clin Neuropharmacol 1983;6: ) Kang Y, Na DL, Hahn SH. A validity study on the korean mini mental state examination (K-MMSE) in dementia patients. J Korean Neurol Assoc 1997;15: ) Kang Y, Na DL. Neuropsychological Screening Battery. Incheon:Human Brain Research & Conculting Co; ) Himashree G, Banerjee PK, Selvamurthy W. Sleep and performance-recent trends. Indian J Physiol Pharmacol 2002;46:6-24 Vol. 12, No. 2,

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페링야간뇨소책자-내지-16

페링야간뇨소책자-내지-16 야간뇨의진단과치료 - 실제적접근 - Reference 1. Choo MS, Ku JH, Park CH et al. Prevalence of Nocturia in a Korean Population Aged 40 to 89 Years. Neurourol Urodyn 2008; 27:60-64. 2. Weiss JP. Prevalence