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1 종 설 과민성방광 Overactive Bladder 대한비뇨기과학회지제 48 권제 12 호 2007 Kyu-Sung Lee, Young-Suk Lee From the Department of Urology, Sungkyunkwan University School of Medicine, Seoul, Korea Overactive bladder (OAB) is a symptom syndrome including urinary urgency with or without urinary incontinence, usually with frequency and nocturia. Urgency, defined as the compelling feeling of impending incontinence that is difficult to defer, is the cornerstone symptom of OAB. The diagnosis is based on symptoms alone and assumes no underlying pathology. Approximately 12.2% of the adult population experience OAB in Korea. The syndrome is now recognized as a chronic debilitating condition that negatively affects the quality of life. Often the patients have a restricted social life and an increased risk for depression. Despite increased awareness in recent years, OAB remains an underreported condition. Continued evolution of our understanding of the pathophysiology of OAB has identified contributory mechanisms, which has in turn established structured evidence-based managements. Treatment of OAB is aimed at relief of symptoms and improving quality of life. Conservative treatments combined with antimuscarinic drugs are the main treatment for OAB. There are many antimuscarinics available, with several under development, which have different specificities for the muscarinic receptors. Other drugs have also been tried but with limited success. Behavioral therapy combined with pharmacological therapy often will bring about acceptable outcomes for patients with OAB. Modalities such as botulinum toxin injections, neuromodulation, and various surgical interventions also are showing encouraging results in more refractory patients. Further research into the basic science of the condition is required to identify the true cause of OAB, allowing new targeted treatments to be established. (Korean J Urol 2007;48: ) Key Words: Overactive bladder, Pathophysiology, Behavioral therapy, Pharmacological therapy, Surgical therapy 성균관대학교의과대학비뇨기과학교실 이규성ㆍ이영숙 교신저자 : 이규성성균관대학교의과대학삼성서울병원비뇨기과서울시강남구일원동 50 번지 TEL: FAX: ksleedr@skku.edu 과민성방광의정의 2002년 International Continence Society (ICS) 는과민성방광을, 절박성요실금 (urge incontinence) 유무에관계없이요절박 (urgency) 이있는증상군으로, 대개빈뇨와야간뇨를동반하는것으로정의하였다 (Table 1). 1 또한이러한증상을야기할수있는감염, 대사장애나다른기저질환은없어야한다. 한편, 이전에사용하던배뇨근과활동성 (detrusor overactivity) 의개념은요역동학검사에서불수의적배뇨근수축이확인되는경우로제한하였다. 한연구에의하면 과민성방광증상이있는환자중 64% 에서만배뇨근과활동성을확인할수있었을뿐아니라, 증상이없는환자의 30% 이상에서배뇨근과활동성을관찰할수있었다고하였다. 2 이와같이요역동학검사소견과증상이일치하지않고, 모든환자에게요역동학검사를시행하기어려운점을감안하여증상에기초한정의를제안하게되었다. 새로운정의에서과민성방광을규정하는가장중요한증상은요절박 (urgency) 이다. 최근 Abrams 등 3 은주관적인욕망을뜻하는 urge 보다배뇨를미루지못하는비정상적인상황을뜻하는 urgency 의개념을도입하여 urge incontinence 역시 urgency incontinence 로표현하는것이바람직 1191

2 1192 대한비뇨기과학회지 : 제 48 권제 12 호 2007 Table 1. The standardization of terminology in lower urinary tract function 1 Terms Overactive bladder syndrome Increased daytime frequency Nocturia Urgency Urge urinary incontinence Definitions Urgency, with or without urge incontinence, usually with frequency and nocturia Complaint by the patient who considers that he/she voids too often by day. This term is equivalent to pollakisuria used in many countries. Complaint that the individual has to wake at night one or more times to void. Complaint of a sudden compelling desire to pass urine which is difficult to defer. Complaint of involuntary leakage accompanied by or immediately preceded by urgency. Fig. 1. Overactive bladder and urinary incontinence. SUI: stress urinary incontinence, MUI: mixed urinary incontinence, UUI: urge urinary incontinence. 하다고제안하였다. 또한빈뇨를나타내는 frequency 는야간뇨 nocturia 와구분하여 increased daytime frequency 라는용어를사용할것을제안하기도했다. 절박성요실금은일부과민성방광환자에서동반되기도하는데절박성요실금환자의일부는복압성요실금 (stress incontinence) 이동반된복합성요실금 (mixed urinary incontinence) 을가지기도한다. 이러한환자를 OAB-wet라고하는반면, 요실금이없는환자는 OAB-dry로정의한다 (Fig. 1). 과민성방광의병인 방광은평활근으로구성되어있고배뇨기능은신경계에의해조절되기때문에과민성방광은평활근과신경계의이상으로발생할수있다. 지금까지연구된결과들을종합하면, 과민성방광이나배뇨근과활동성을일으키는원인으로생각되는기전은몇가지로요약할수있다. 첫번째는배뇨근이상에의한것으로, 원인에관계없이배뇨근이부분적으로탈신경되면배뇨근에변화가오고세포간흥분도나전기결합이증가하여배뇨근의한부분에서수축 (micromotion) 이일어나고이수축은방광벽을따라전달되어결국방광전체의근수축을야기하게된다는이론이다. 4 이러한현상은배뇨근세포간의 protrusion junction과 ultra-close abutments의변화와관련있으며수축을전달하는 gap junction의증가와도관련이있다. 방광출구폐색이나노화에의한배뇨근변화에서도이같은현상을관찰할수있다. 5,6 두번째이론은신경인성원인으로대뇌나척수의억제신경경로에손상을입었거나, 방광의구심신경말단이감작되면원시배뇨반사가재출현하여배뇨근과활동성이일어난다는것이다. 7 신경인성원인으로억제성신경전달에이상이발생하는연수상부대뇌의병변이나, 원시척수-방광반사를일으키는축삭손상, C-fiber에의한천수신경의새로운반사경로형성, 방광의구심신경말단의감작등이원인이된다. 따라서다발성경화증이나뇌혈관질환, 파킨슨질환등이과민성방광과배뇨근과활동성을일으키는신경인성원인이될수있다. 세번째가설은비교적최근개념으로, 하나의신경절이담당하는영역의배뇨근을 autonomous module 로정의하여설명한다. 8 이러한 module들은배뇨근내신경절과간질세포들로구성된 peripheral myovesical plexus 에의해조절된다. 그러나병적인상태에서는충전기동안과도한흥분신호로인해 module들의자율성이병적으로증가하고이로인해배뇨근과활동성이나타난다. 배뇨근이상에의한기전과비슷하게이해될수있으나, 그기전이보다광범위하다. 여기에서는증가된충전감각이나배뇨근과활동성과관련된모든구조적, 기능적변화들이말초에서통합된다고설명하고있다 (Fig. 2). 따라서 module들간의신호전달을비정상적으로증가시키는것은배뇨근과활동성의원인이될수있다고말한다. 네번째이론은신경전달물질의이상으로, 과민성방광과우울증의관련성에서시작한다. 이미많은연구에서요실금환자들의우울증발생률이대조군에비해높은것이밝혀졌다. 몇연구에서주목할만한사실은, 복압성요실금환자의우울증발생률은약 13% 로대조군과유사했던반면, 절박성및복합성요실금환자의우울증발생은약 42% 로대조군에비해높게나타났다. 9 이밖의다른연구들도요실금환자의우울증이단순히요의유출에의한것이아니라요절박증상과더욱관련되어있음을시사하였다. 10,11 비록이들간의인과관계에대해서는밝혀지지

3 이규성ㆍ이영숙 : 과민성방광 1193 Fig. 2. Detrusor module inputs. 8 Ganglion has integrative circuit (1), that receives inputs from neighbouring modules (2), interstitial cells (3), afferent collaterals (4), and other pelvic organs (5). These inputs collectively affect the likelihood of contraction of module, which can thereby show autonomous activity, irrespective of the primary sacral efferents (6). SNS: sympathetic nervous system. 않았지만공통된신경화학적기전을가지고있을것으로생각할수있다. 우울증이 serotonin (5-HT) 과관련이있다는것은이미알려져있으며배뇨에도영향을미치는것으로알려져있다. 여러동물실험에서중추신경계에 5-HT와 norepinephrine 같은단가아민이줄어들면빈뇨와과민성방광이야기된다는결과들을보고하였다. 12 이이론은항우울제를이용한과민성방광치료의근거가된다. 이상과같이, 배뇨근과활동성과과민성방광에대한여러발생기전들이연구되고있으나실제로, 배뇨근과활동성을일으키는기전과과민성방광증상을일으키는기전이다를수있다. 또한위에설명한이론들중하나의기전에의한것일수있고, 둘이상의기전이작용할수도있을것이며, 아직밝혀지지않은다른기전에의한것일수도있을것이다. 과민성방광의유병률및정신ㆍ사회적영향 새로운 ICS 정의를이용한과민성방광의유병률에대한보고는충분치않지만, 모든연령층에서발생가능하며, 남녀간유사한빈도를나타내고, 나이가들수록그빈도가증가하는경향을보인다. 13 유럽의 40세이상성인을대상으로한연구에서는약 16.6% ( 남성 : 15.6%, 여성 : 16.4%) 가과민성방광증상을가지는것으로보고하였으며, 14 미국의연구결과역시이와유사하였다. 10 한편, 대한배뇨장애요실금학 Fig. 3. Prevalence of overactive bladder by age and gender in Korea. 회에서는 2002년 ICS 정의를이용하여대한민국의 18세이상남녀 2,000명을대상으로과민성방광을비롯한하부요로증상의유병률을조사한결과, 과민성방광의전체유병률은 12.2% 였으며남자 (10.0%) 와여자 (14.3%) 에서비슷하게나타났다. 이결과는 2006년발표된캐나다를포함한유럽 4개국의유병률과도유사한것이다 ( 전체 : 11.8%, 남자 : 10.8%, 여자 : 12.8%). 15 또한, 연령이증가할수록유병률이증가하는것으로나타났는데 40세이상의경우, 전체유병률은 14.9% ( 남 : 11.2%, 여 : 18.4%) 인것으로나타났다 (Fig. 3). 이를토대로우리나라성인인구를고려하여산출한결과총 600만명가량이과민성방광증상을가지는것으로추산된다. 과민성방광증상을가지는환자들은사회활동및대인관계에서고립되기쉽고, 실제과민성방광이삶의질에미치는영향은당뇨보다더큰것으로나타났다 앞서언급한듯이과민성방광환자에서우울증의위험이높다는사실은이미여러연구에서입증되었다 또한절박성요실금환자의낙상위험은절박성요실금이없는군에비해 30% 가량높으며이로인한골절의위험도 3% 가량높은것으로나타났다. 24 과민성방광의진단 과민성방광을진단하는데가장중요한것은세심한병력청취이다. 비뇨기계병력은물론, 증상을야기할수있는모든가능한원인을함께고려하여야한다. Table 2에과민성방광증상을야기할수있는다양한원인과치료들을간략히설명하였다. 한편, 과민성방광환자들은요절박이나요실금등에대한 coping 행동을보일수있는데, 이런행

4 1194 대한비뇨기과학회지 : 제 48 권제 12 호 2007 Table 2. Conditions that can cause or contribute to symptoms of overactive bladder Conditions Mechanisms or effect Implications Lower urinary tract conditions Both sexes Urinary tract infection Inflammation with activation of sensory Treat infection before other interventions afferent innervation can result. are considered. Obstruction Obstruction can contribute to detrusor Consider surgical intervention. overactivity and urinary retention. Impaired bladder contractility Urinary retention and reduced functional Teach patients to enhance voiding bladder capacity can result. (e.g., Crede s method). Intermittent catheterization is helpful in selected patients. Bladder abnormalities or Intravesical abnormalities can Sterile hematuria and risk factors for inflammation (e.g., tumors, precipitate detrusor overactivity. bladder cancer should prompt further calculi, interstitial cystitis) evaluation. Women Estrogen deficiency Inflammation from atrophic vaginitis and Topical estrogen may ameliorate symptoms. urethritis can contribute to symptoms. Sphincter weakness Leakage of urine into proximal urethra Topical estrogen and pelvic-muscle exercises may precipitate urgency. may help strengthen the sphincter. Ability to inhibit detrusor by sphincter Periurethral injections or surgical procedures contraction may be diminished. may be helpful in selected patients. Men Prostate enlargement Benign or malignant prostate enlargement Evaluation and treatment for prostate can contribute to detrusor overactivity. cancer should be considered. Alpha-adrenergic blockers may improve symptoms. 5α-reductase inhibitors may reduce prostate size. Surgical removal of obstructing prostate may be indicated. Neurologic conditions Brain Stroke, Alzheimer s disease, Higher cortical inhibition of the bladder Management must include a means of multiinfarct dementia, other is impaired, causing neurogenic detrusor compensation for impaired cognition, dementias, Parkinson s disease, overactivity. impaired mobility, or both. multiple sclerosis Spinal cord Multiple sclerosis, cervical or Neurogenic detrusor overactivity or Presence of neurologic symptoms or lumbar stenosis or disk urinary retention can result. signs may require further evaluation. herniation, spinal cord injury Urodynamic testing is often indicated for diagnostic purposes. Peripheral innervation Diabetic neuropathy, Urinary retention and low functional History suggestive of nerve injury or nerve injury bladder capacity can result. neurologic signs require further evaluation. Systemic conditions Congestive heart failure, Volume overload can contribute to Proper timing of diuretics may ameliorate venous insufficiency urinary frequency and nocturia symptoms. when patient is supine. Use of leg elevation, support hose, and salt restriction may be helpful.

5 이규성ㆍ이영숙 : 과민성방광 1195 Table 2. Continued Conditions Mechanisms or effect Implications Diabetes mellitus Poor blood glucose control can contribute Improved blood glucose control may to osmotic diuresis and polyuria. ameliorate symptoms. Sleep disorders (sleep apnea, Sleep disorders can contribute to nocturia. Reports of sleep disruption or heavy periodic leg movements) snoring may require further evaluation. Abnormalities of arginine Impaired secretion or action of vasopressin Carefully selected patients may benefit vasopressin may cause polyuria and nocturia. from desmopressin therapy. Functional and behavioral conditions Excess intake of caffeine, Polyuria and urinary frequency can result. Modification of fluid intake is critical alcohol; polydipsia for successful management. Poor bowel habits and Fecal impaction can contribute to An appropriate bowel regimen will reduce constipation symptoms. the incidence of fecal impaction. Impaired mobility (e.g., in Impaired mobility can interfere with Treatment of underlying disorders, including patients with degenerative toileting ability and precipitate physical therapy, should be optimal; joint disease, Parkinson s urge incontinence. the use of urinals, bedside commodes, disease, severe osteoporosis, and bedpans can be helpful. or muscle weakness) Psychological conditions Chronic anxiety and learned voiding The diagnosis should be considered on dysfunction can cause symptoms of the basis of a patient s history and overactive bladder. physical examination. Side effects of medication Diuretics, especially rapid-acting Diuretics cause a rapid increase in bladder Changing to a longer-acting diuretic, agents volume, which may precipitate urgency altering the timing of the dose, or and detrusor overactivity. discontinuing the drug, if appropriate, can ameliorate symptoms. Anticholinergic agents, narcotics, These agents decrease bladder contractility Such drugs should be discontinued calcium-channel blockers and may cause urinary retention, with whenever feasible. a decreased functional bladder capacity. Cholinesterase inhibitors These agents could theoretically contribute No clinical studies have documented such to detrusor overactivity by increasing effects, but they should be considered in acetylcholine levels. patients in whom symptoms develop after the initiation of one of these agents. 동들이면에숨은증상들을알아내는것은그것이환자의삶의질에미치는영향을평가하는데도움을준다. 예를들면요절박을대비해항상가까운화장실위치를기억해둔다거나, 요실금을숨기기위해어두운색옷을입는다든지, 요실금을피하기위해소변을자주보는것등이있다. 배뇨일지는배뇨횟수와배뇨량뿐아니라배뇨형태에대한정보를제공하는유용한도구이다. 배뇨일지의작성기간에대해서는몇가지의견이있지만, 3일간의배뇨일지는치료효과와환자의증상을반영하는데 7일배뇨일지와비슷한신뢰도를가지면서환자의순응도가높아임상에서는일반적으로 3일배뇨일지를이용한다. 25 과민성방광진단에요절박의중요성이강조되면서최근에는배뇨일지에요절박정도를함께기록하기도한다. 저자의경우, 요절박정도를 5단계로분류한 Urinary Sensation Scale을배뇨일지에포 함하여매배뇨시마다환자가직접작성하도록하고있다. 최근에는이와같은설문지들이진료와임상연구에이용되기도하는데이에대해서는후반부에별도로다루었다. 다음으로, 비뇨생식기및골반검사, 직장수지검사등신체검사를통해원인이되는질환이있는지조사한다. 요검사는감염이나혈뇨등을감별하기위해반드시실시한다. 신경질환이있거나, 치료에반응을안하는경우, 진단이모호한경우, 침습적인치료를계획하고있는경우에는기본검사이외에추가적인검사가필요하다. 당뇨나척추질환, 전립선비대증과같이요폐색을일으킬위험요인을가지고있는환자에게는배뇨후잔뇨측정이유용하다. 전통적으로도뇨를통해잔뇨를측정하였으나임상적으로의미있는양의잔뇨를측정하는데는초음파를이용한방법이비침습적일뿐아니라 90% 이상의정확도를나타내는것으

6 1196 대한비뇨기과학회지 : 제 48 권제 12 호 2007 로알려져있다. 26 혈뇨를보이거나방광암의위험이있는환자에게는방광경검사와요세포검사를시행한다. 과민성방광의진단에요역동학검사를실시하는것은아직까지논란의여지가있으나, 증상이비특이적이고치료에반응하지않거나침습적인치료를계획중인경우에는정확한방광기능의평가를위해시행한다. 예전에는충만기동안비자발적인배뇨근수축압력이 15cmH 2O 이상상승한경우에배뇨근과활동성으로진단했으나최근에는환자가배뇨를억제하고있는동안요절박이나요실금에동반되어배뇨근수축이발생하면배뇨근과활동성으로진단한다. 과민성방광의치료과민성방광증상은감염이나방광출구폐색, 방광결석, 방광암등교정가능한원인에의해서도발생할수있으므로이러한유발요인들을찾아내어치료하는것이중요하다. 전립선비대증과과민성방광이동반된환자의경우, 경요도절제술로방광출구폐색이소실되면약 2/3의환자에서과민성방광증상이호전되는것으로알려져있다. 27 또요실금수술로인한요도폐쇄로발생한배뇨근과활동성을가지는여성환자에서요도박리를시행했을경우 60-80% 의환자에서배뇨근과활동성이호전되는것으로나타났다. 28 그러나원인질환을치료하는것이불가능할경우에치료목적은행동요법이나자기장치료, 약물요법, 신경조정술또는수술적방법등을통해불수의적배뇨근수축을감소시키는것이다. 과민성방광의일차적치료법은행동치료와약물요법이다. 이두가지방법은단독으로사용하는것보다병용하는것이더효과적이기때문에동시에, 혹은단계적으로병용하여치료한다. 일반적으로복합요법으로 50-80% 정도에서요절박이감소하고절박성요실금이호전되는것으로알려져있다. 29,30 1. 행동치료 (Behavioral therapy) (Fig. 4) 환자들에게방광의기능을교육하고, 적절한수분섭취 Fig. 4. Behavioral therapy for overactive bladder. ( 카페인제한, 적정양의수분섭취, 수분섭취시간조절 ) 와변비치료, 금연, 체중조절등생활습관을개선 (life style modifications) 하도록하는것은과민성방광의중요한기본치료이다. 또한정상적인배뇨기전과간격을설명하여본인의잘못된배뇨형태를이해시키고방광훈련의효과를설명하는것은동기를유발하여치료의효과를높이는데도움을준다. 실제로많은무작위위약대조군연구에서나타나는위약효과는배뇨일지를비롯한교육에의한것일가능성이높다. 골반근육운동 (pelvic muscle exercise) 이나방광재훈련 (bladder retraining) 은인지능력이정상이고동기가유발된환자들에게효과적인치료법이다 한대조군연구에서는방광재훈련과골반근육운동이유사한효과를나타냈다고보고하였다. 두방법의병합요법에대한효과는확실치않으며추가연구가필요한실정이다. 한편, 다른연구에서는방광재훈련의장기간성적은방광재훈련과골반근육운동을병합한효과와유사하였다고밝혔다. 방광재훈련단독요법과약물요법및물리치료를병합한요법의효과비교에대해서는추가적인무작위대조군연구가필요하다. 31,34 위와같은행동치료는경미한증상의치료에는단독으로사용되지만, 약물치료와병행할경우효과가증대되는것으로알려져있다. 29,30 또한행동치료에있어성공을예측하는중요한인자는치료에대한환자의순응도이므로환자에게동기를유발하는것이매우중요하다. 2. 약물치료 (Pharmacological therapy) (Table 3) 매우다양한약물들이과민성방광및배뇨근과활동성의치료에사용되고있다. 그러나임상에서사용되고있는대부분의약물들이무작위대조군연구가아닌기초적인임상연구결과를근거로사용되고있다. 뿐만아니라, 많은과민성방광연구에서위약에대한반응이높게나타나치료약물과위약간효과에임상적으로유의한차이가있는지판단하기어려운단점도있다. 과민성방광의약물치료는중추와말초를대상으로한다. 대표적인중추신경억제신경전달물질인 gamma-amino butyric acid (GABA) 를대상으로한 baclofen은과거원발성배뇨근과활동성의치료에사용되었던 GABA 항진제이다. 삼환계항우울제는부분적으로 noradrenalin을말초에서차단하는작용을가진다. Dopamine 항진제의정확한기전이나효과가밝혀지지는않았지만, dopamin은파킨슨병환자의과민성방광증상과연관이있을것으로생각한다. 한편, 과민성방광치료의말초대상은방광의무스카리닉수용체, 베타-교감신경수용체와 Ca 2+ 채널, K + 채널과같은이온채널, vallinoid 수용체와같은감각신경수용체와 prostanoid 등이있으며투여방법에따라경구투여와방광

7 이규성ㆍ이영숙 : 과민성방광 1197 Table 3. Drugs used to treat symptoms of overactive bladder* Level of Drug Usual adult dose evidence/grade of Comments recommendation Drugs with predominantly anticholinergic or antimuscarinic effects Oxybutynin mg thrice daily orally (short-acting) 1/A Long-acting and transdermal preparations have fewer 5-30mg daily orally (long-acting) side effects than short-acting preparations. 36mg over a 96hr period (transdermal) The transdermal patch can cause local skin irritation in some patients. Propiverine 20-40mg daily orally 1/A The drug has complex pharmacokinetics with several active metabolites; it is not currently available in the United States. Tolterodine 1-2mg twice daily orally (short-acting) 1/A The long-acting and short-acting preparations have 4mg daily orally (long-acting) similar efficacy. Trospium 20mg twice daily orally 1/A The agent is a quaternary ammonium compound, which does not cross the blood-brain barrier and may have fewer cognitive side effects than other anticholinergic agents; it is not currently available in the United States. Solifenacin 5, 10mg daily orally 1/A Long-acting tertiary amine with some selectivity for M3 receptors Darifenacin 7.5, 15mg daily orally 1/A Tertiary amine with moderate lipophilicity and selective M3 receptor antagonist Estrogen (for women) Vaginal estrogen Approximately 0.5g cream applied 4/D Local vaginal preparations are probably more effective preparations topically nightly for 2 wk, then twice than oral estrogen, but definitive data on per week. effectiveness are lacking. Estradiol ring, replaced every 90 days Estradiol, 1 tablet daily for 2 wk, then 1 tablet twice a week Alpha-adrenergic antagonists (for men) Alfuzosin 10mg thrice daily orally 4/D These agents are useful in men with benign Doxazosin 1-8mg daily orally prostatic enlargement. Prazosin 1-10mg twice daily orally Postural hypotension can be a serious side effect. Tamsulosin mg daily orally Doses must be increased gradually to facilitate Terazosin 1-10mg orally each day at bedtime tolerance. Other drugs Imipramine 10-25mg thrice daily orally 2/C This agent may be useful for mixed urge-stress incontinence; it can cause postural hypotension and bundle-branch block. Desmopressin 20-40μg of intranasal spray 1/B The intranasal spray is used for primary nocturnal daily at bedtime enuresis in children; hyponatremia occurs commonly mg orally 2 hr in older adults, and serum sodium levels must be before bedtime monitored closely. *Not all drugs listed in this table have proven efficacy specifically for symptoms of overactive bladder. Levels of evidence are based on the Oxford System: a score of 1 indicates evidence from randomized, controlled trials; a score of 2 evidence from good-quality prospective cohort studies; a score of 3 evidence from good-quality retrospective case control studies; and a score of 4 evidence from good-quality case series. The grade of recommendations is based on the definitions used by the International Consultation on Urological Diseases: A indicates consistent level 1 evidence; B consistent level 2 or 3 evidence or major evidence from randomized, controlled trials; C level 4 evidence or major evidence from level 2 or 3 studies or expert opinion based on the Delphi method; and D inconclusive, inconsistent, or nonexistent evidence or evidence based on expert opinion only. The rating is for symptoms of overactive bladder, not for overall symptoms of benign prostatic hyperplasia.

8 1198 대한비뇨기과학회지 : 제 48 권제 12 호 2007 내투여로나눌수있다. 1) 항무스카린약물 (Antimuscarinic drugs): 항무스카린약물은 acetylcholine이무스카린수용체에작용하는것을경쟁적으로억제하기때문에부교감신경전달이없는소변저장기에불수의적배뇨근수축을억제한다. 그러나배뇨를위하여방광이수축하는단계에서는많은양의 acetylcholine이분비되기때문에치료용량의항무스카린약물은배뇨시배뇨근수축에는영향을미치지않아방광의수축력이정상인경우배뇨후잔뇨량을증가시키지않는다. 그러나배뇨근수축력이약한환자에게사용시잔뇨량이증가하거나요폐가발생할수있다. 무스카린수용체는배뇨근뿐아니라요상피세포에도분포하는데이수용체가배뇨에영향을미치는지는아직까지확실히밝혀지지않았다. 35 Yoshida 등 36 은배뇨근에서 acetylcholine이분비되는것을발견하였으며이것은 tetrodotoxin 에의해억제되지않고요상피를제거하였을때현저히감소하는것으로나타났다. 결과적으로, 분비된 acetylcholine 은신경에서유래한것이아니며부분적으로는요상피세포에서분비된것이라고결론내렸다. 따라서저장기에 acetylcholine은신경뿐아니라요상피세포와같은신경계이외의장소에서도분비되어요상피하층과배뇨근에있는구심신경을직접, 간접적으로흥분시킨다. 이러한기전은과민성방광의병태생리를설명하는데중요할뿐아니라항무스카린약물치료의목표가되기도한다 (Fig. 5). 이러한약 물로는 tolterodine, trospium, darifenacin, solifenacin 등이있다. Tolterodine은비선택적항무스카린약물로알려져있지만몇몇동물실험결과침샘에대한친화도보다방광에대한친화도가더높은것으로나타났다. Oxybutynin-extended release (ER) (10mg/d) 과 tolterodine-er (4mg/d) 의효과와부작용을비교분석한위약대조군연구인 overactive bladder: performance of extended-release agents (OPERA) 37 에의하면, 요실금발생빈도를감소시키는데는두약물의효과가비슷하였고빈뇨에대한효과는 oxybutynin이 tolterodine보다좋았다 (p=0.003). 입마름발생률은각각 29.7% 와 22.3% 로 tolterodine에서낮았으며부작용으로인한탈락률은두군이비슷하였다. Tolterodine-ER과 immediate release (IR), 위약간대조연구에따르면입마름증상은각각 23%, 30% 와 10% 로 tolterodine-er에서 IR보다낮게발생하였다. 38 Tolterodine은현재과민성방광치료제중전세계에서가장많이사용되고있는약물이다. Trospium chloride는다른비선택적항무스카린약물과비슷한효과를가지는비활성 4가아민으로뇌-혈관장벽을통과하지못한다. 따라서중추신경부작용이적고다른약물과상호작용이적어하루두번복용해야하는번거로움에도불구하고고령환자의과민성방광및절박성요실금치료에유용한약물이다. 39,40 Darifenacin은 M 1,2,4,5 수용체에비해방광에콜린성신호를전달하는 M 3 수용체에선택적으로작용하는항무스카 Fig. 5. Bladder effects of antimuscarinics. By inhibiting the effects of acetylcholine, generated from non-nervous sources (urothelium) or leaking from cholinergic nerves during the filling phase, antimuscarinics may inhibit detrusor overactivity and urgency.

9 이규성ㆍ이영숙 : 과민성방광 1199 린제로비선택적항무스카린약물에서발생하는부작용을줄일수있을것으로기대되었다. Haab 등 41 에의하면 darifenacin 7.5mg/d과 15mg/d은치료 2주에위약에비해요실금횟수, 배뇨횟수, 급박뇨의정도및횟수를유의하게감소시켰다고보고했다. 반면, 과민성방광으로인한야간뇨는감소시키지못했다. 가장흔한부작용은경도및중등도의입마름과변비였으며, 중추신경계와심장에대한안전성은위약과비슷하게나타났다. Chapple 42 이 darifenacin에대해연구한결과, 효과는용량의존적이었으며, 7.5mg/d와 15mg/d 복용시요실금횟수는각각 8.8회 (68.4%), 10.6회 (76.8%) 감소하였다. 또한, 65세이상고령환자를대상으로시행한연구결과, darifenacin 복용환자의인지도감소는위약복용환자와차이가없었다. 43 이것은 M 3 수용체에대한 darifenacin의친화도가 M 1 에대한친화도보다 5배가량높기때문일것으로생각한다. 인간재배합무스카리닉수용체를이용한연구에따르면, darifenacin의 M 3 수용체에대한친화도는 M 1 의 9배, M 5 의 12배, M 2 나 M 4 의 59배정도로나타났다 (Fig. 6). 44 Solifenacin은 2004년유럽에서출시된경쟁적무스카린차단제로 3가아민이다. 비교적 M 3 수용체에선택적으로작용하여 oxybutynin이나 tolterodine에비해입마름등의부작용이적었다. 45 Chapple 등 46 은최근연구결과, 서방형 tolterodine에비해 solifenacin이요실금횟수를감소시키는데효과적이라고보고하였다. Atropine (dl-hyoscyamine) 은약물의부작용으로인해과민성방광이나절박성요실금치료에거의사용되지않는다. 그러나신경인성배뇨근과활동성이있는환자의치료에방광내 atropine 주입술은전신부작용을야기하지않고방광용적을늘일수있다고한다. 47,48 Fig. 6. M3/M2 receptor selectivity for darifenacin compared with other antimuscarinics. *Inhibition constant ratio (Ki) muscarinic receptor subtypes. 2) 복합작용제 (Drugs with mixed action): 항무스카린효과이외에평활근이완, 국소마취효과등배뇨근에직접적인효과를보이는약제로, 약효는대부분항무스카린효과에의한다고해석된다. 평활근이완효과는 Ca 2+ channel 차단에의해발생한다. 약물로는 oxybutynin chloride와 propiverine HCl 등이있으며부작용은다른항무스카린약물과유사하다. Oxybutynin은과민성방광치료에가장오랫동안사용되는약물중하나로, 위장관에서쉽게흡수되어간의 cytochrome P-450에의해대사되는 3가아민이다. 첫번째대사물질인 N-desethyloxybutynin (DEO) 은 oxybutynin의부작용을나타내는원인물질로생각된다. Oxybutynin은항무스카린작용이외에직접적인근이완작용과국소마취효과를갖는다. 직접적인근이완효과는방광내주입술의근거가된다. 49,50 방광내주입술은배뇨근에서높은약물농도를얻을수있고전신부작용을피할수있다는생각에서시작되었으며경구투여가힘든경우에유용하다. 50,51 Oxybutinine-ER은부작용의원인물질인 DEO의생성을줄여환자의약물순응도를높이고자개발되었다. 삼투압을이용하여 24시간동안대장에서흡수되도록만들어진이제재는 cytochrome P-450에의해대사되지않아 oxybutynin-ir 에비해입마름이적을것으로예상되었다. 비록 first-pass metabolism 시에 DEO가생성되기는하지만, 여러연구에서 ER 제재가 IR 제재에비해입마름이적었다고보고하였다. 52 흥미로운한연구에의하면, oxybutynin-ir과 tolterodine-ir을복용한지 2시간후침분비량은현저히감소하였으며이후서서히증가한반면, oxybutynin-er을복용한후의침분비량은복용전과동일했다 년에는패치형 oxybutynin이미식약청승인을얻었다. 제 3상연구에의하면, 하루 3.9mg이유리되는패치형 oxybutynin은 tolterodine- ER보다효과적이며부작용발생빈도는낮았다. 54 가장흔한부작용으로는부착부위의소양감과발적이며, 전신부작용중가장흔한것은입마름으로두연구에서각각 4.1% 와 9.6% 로보고되었다. 54,55 우리나라에서는아직패치형 oxybutynin이사용허가를받지못하였다. Propiverine은항무스카린효과와더불어 Ca 2+ 차단작용을가지고있다. 56,57 Oxybutinine과마찬가지로과민성방광및배뇨근과활동성에대한효과는주로항무스카린효과에의한것으로생각된다. Dorschner 등 58 은 propiverin은급박뇨나빈뇨뿐아니라절박성요실금과복합성요실금도호전시켰다고발표했다. 현재까지밝혀진바에의하면 Flavoxate는 Ca 2+ 차단작용과마취효과를가지는반면, 항무스카린효과는미미한것으로알려진다. 마취쥐의지주막하와뇌실에 flavoxate를

10 1200 대한비뇨기과학회지 : 제 48 권제 12 호 2007 주입한실험결과, flavoxate의배뇨반사억제는뇌에존재하는 pertussis toxin-sensitive G-protein 을통해작용할것으로생각한다. 59 Oxybutynin을비롯한다른약물에비해부작용발생이낮음에도불구하고, 절박요실금을비롯한과민성방광에대한 flavoxate의효과는다른약물과비견할만한효과가입증되지않았다. 여러문헌을분석한결과항무스카리닉약물은과민성방광에효과적이고안전한약제로여겨진다. 60 약제간효과의차이는약제간비교연구가부족하여판단하기어려우나여러약제의효과는유사한것으로알려져있다. 항무스카리닉약물의효과적인치료기간은아직까지알려지지않았으며환자마다그원인이다양하기때문에치료에반응하는정도도다양하다. 일반적으로약물의효과는 2주내에발생하고 6개월까지사용하는경우더욱증가한다. 얼마나오랫동안약물을사용하여야하는지에대해서는확실히알려져있지않다. Choo 등 61 에의하면 3개월간항콜린제치료후증상이호전되어약물을중단한경우, 약 35% 의환자에서는증상이재발하여재치료가필요하였다. 이연구에의하면재치료의위험인자는고령, 중증의요절박및배뇨근 과활동성의유무등이었다. 또한, 신경질환이원인인경우, 절박성요실금이있는경우에도지속적인약물투여가필요할것이다. 그외의경우는 3-6개월간치료후약물을중단하고증상을관찰하면서재치료여부를결정할수있을것이다. 3) 삼환계항우울제 (Tricyclic antidepressants): 삼환계항우울제는항무스카린효과, 진정및항히스타민효과, 교감신경말단부의 serotonin과 noradrenaline의재흡수를억제하여알파1-교감신경을자극하는효과들이있다. 62 따라서하부요로에서요저장을촉진하는작용으로방광수축력을감소시키고괄약근저항을증강시키는이중작용을할것으로생각한다. 약물로는 imipramine HCl. amitriptyline HCl, doxepin 등이있다. Imipramine은소아의유뇨증치료에효과적인것으로알려져있지만 QT 증가와같은심혈관계부작용이있다. 63,64 요실금치료에 imipramine의효과에대한몇몇연구가있었으나위약에비해임상적으로의미있는효과를나타내지는못했다. 65,66 소아의유뇨증을제외한배뇨장애치료제로서 imipramine의효과와위험성에대해서는충분한연구가없는실정이다. Table 4. Examples of classes of drugs under investigation for the treatment of symptoms of overactive bladder Drug classes and actions Examples Comments Drugs used for other conditions Calcium-channel blockers Diltiazem Agents inhibit bladder contraction by decreasing calcium available for Nifedipine smooth-muscle contraction; there is no evidence that these agents are Verapamil effective for symptoms of overactive bladder. Inhibitors of prostaglandin Flurbiprofen Prostaglandins may increase the contraction of bladder smooth muscle; synthesis no currently available agents have proven efficacy. g-aminobutyric acid-receptor Baclofen Stimulation of g-aminobutyric acid receptors inhibits the voiding reflex. agonists Neuromuscular-junction inhibition Botulinum toxin Botulinum toxin A injections have been used for refractory symptoms. of acetylcholine release of acetylcholine release Drugs in development Potassium-channel openers Pinacidil These agents decrease spontaneous detrusor-muscle contractions and Cromakalim can have clinically significant effects on blood pressure; potassium-channel gene therapy has also been studied. Serotonergic agonists Duloxetine The central serotonergic effects of these agents increase urethral striated sphincter-muscle tone. Vanilloids and other Capsaicin These agents cause desensitization of unmyelinated C fibers; afferent-nerve inhibitors Resiniferatoxin other afferent-nerve inhibitors may be useful. Dopamine-D1-receptor agonists Pergolide D1-receptor stimulation inhibits the voiding reflex. Nerve growth factor inhibitors Nerve growth factor modulates sensory afferent function; antibody-based gene therapy to suppress nerve growth factor has also been studied. Enkephalins Opioid peptides, including enkephalin, suppress the voiding reflex; therapy with the herpes simplex virus proenkephalin gene has been studied.

11 이규성ㆍ이영숙 : 과민성방광 1201 새로운치료법 (Novel trends in treatment of OAB) (Table 4) 약리학적으로는작용부위에따른새로운약제들이연구되고있다. 운동신경계에작용하는약제로각각배뇨촉진작용을억제하거나, 배뇨억제작용을활성화하는방법이연구되고있고감각신경계에도마찬가지로각각구심성신경절이나신경로에작용하는약제들이연구되고있다. 작용수준에따라서도중추신경계 (cerebral cortex, midbrain, spinal cord) 나말초신경계 (efferent system, afferent system) 에작용하는약물에대한연구가이루어지고있다. 또한, 방광에보다선택적으로작용하거나부작용을줄이는약제전달방법과투입경로에대한연구도지속되고있다. 1. 세포막에작용하는약물 (Drugs acting on membrane channels) 배뇨근수축은세포외 Ca 2+ 이 Ca 2+ 채널을통해세포내로유입되거나, 세포내 Ca 2+ 의이동에의해발생하는것으로알려져있다. 따라서 L-type Ca 2+ 채널을차단하면세포외 Ca 2+ 유입을막아배뇨근과활동성을억제할수있을것이다. 배뇨근과활동성과절박성요실금을가지는노인환자에서 nimodipine의효과를관찰한결과, 위약과비교하여요실금의횟수나삶의질에효과를나타내지못했다. 현재까지과민성방광에대한 Ca 2+ 채널차단제의효과를입증할만한결과가나오지않았다. K + 채널은세포흥분을조절하는데중요한역할을한다. K + 채널을통해 K + 이유출되면세포막이과분극 (hyperpolarization) 되어 Ca 2+ 채널이열리는것을막게되고따라서세포내로 Ca 2+ 유입이줄어들어배뇨근이이완하게된다. 일세대 K + 채널개방제인 pinacidil은방광선택성이혈관선택성에비해낮았으나이후연구되고있는약물들은방광선택성이향상되고방광조직과배뇨근세포의수축을감소시켰다. 사람의방광에는 ATP-sensitive (K ATP), large conductance calcium-activated (BK Ca), small conductance (SK) K + 채널이존재하는것으로알려져있으며, 이들을과민성방광의치료대상으로하는연구가계속되고있다. 67 최근에는인간의방광근육세포에서 TREK-1 이 K + 채널로밝혀져이를대상으로한약물연구가진행중이다 A1-교감신경차단제 (Alpha1-adrenergic antagonists) A1-교감신경차단제는전립선평활근수축을억제하여방광출구폐색의역동적원인을해소한다. A1-교감신경수용체 (α1a, α1b, α1d) 중전립선에대한효과는 α1a-수용체에의해매개되며, 방광자극증상에대한효과는 α1d- 수용체에의해매개되는것으로생각하였다. 69 따라서 α1a 와 α1d에모두작용하는 tamsulosin은전립선비대증환자의방광자극증상도경감시킬수있을것으로여겨졌다. 70 그러나전립선비대증쥐모델을이용한실험결과 α1a-수용체에만선택적인약물역시배뇨근과활동성을감소시키는것으로나타났다. 71 이러한결과는아마도 α1-수용체가전립선뿐아니라방광과중추신경계및척수에도작용하기때문일것으로생각한다. 최근 α1-차단제가방광의자극신호와통증에반응하여감각신경에관여하는것으로알려졌다. 72 Yokohama 등 73 은 tamsulosin이요도의 C-fiber를억제하여방광의저장기능을향상시킨다고설명하여 α1-차단제가하부요로의감각신경에도관여함을증명하였다. 비록여러동물실험결과들을그대로인체에적용할수없다하더라도과민성방광의치료제로서 α1-교감신경차단제의효과들이제시되고있다. 3. β-교감신경작용제 (β-adrenoceptor agonists) β-교감신경수용체는방광체부에존재하며배뇨근이완을담당한다. 따라서 β-교감신경작용제는수년간과민성방광치료제로연구되었다. 인간과돼지의방광에는주로 β3-수용체가분포하며이것이배뇨근이완을매개한다. 74 새로운 β3-작용제인 GW427353는낮은농도에서는정상배뇨근의자발적수축을억제하고고농도에서는전기적으로유발된수축을억제한다. 75 최근에는요상피세포의 β-교감신경수용체도방광의수축과이완에관여한다는이론이제기되고있다. 한연구결과에의하면, β-작용제가요상피에작용하여요상피로부터억제물질을분비하고배뇨근수축을억제하는것으로나타났다. 76 비록이들수용체가배뇨근수축에작용하는기전이확실히밝혀지지않았지만 β-교감신경수용체는과민성방광치료의새로운대상으로연구되고있으며현재 phase II 임상시험이종료되었다 Prostaglandin 합성저해제 (Prostaglandin synthesis inhibitors) Eicosanoids는여러자극에의해요상피에서만들어져배뇨근과요상피에서분비되는것으로알려져있다. Prostaglandin이배뇨근수축과관련이있는것은여러실험에서입증되었지만이것이배뇨근과활동성을일으키는기전으로작용하는지는확실하지않다. 아마도배뇨근에직접작용하기보다는방광충전에따라구심신호를증가시켜방광의감각신경을감작하는것으로생각한다. 따라서 prostaglandin에의해적은용적에서도배뇨근수축이유발될수있을것이다. 이이론을근거로하여, prostaglandin 합성

12 1202 대한비뇨기과학회지 : 제 48 권제 12 호 2007 저해제는배뇨근과반사를효과적으로억제할수있을것으로생각하였다. 몇몇연구에서 Prostaglandin 합성저해제인 flurbiprofen이과민성방광증상은호전시키는것으로나타났으나, 오심, 구토, 두통, 소화기장애등부작용발생률이높았으며이에따른중도탈락률도높게나타났다. 78,79 현재높은부작용발생률과실험약물부족등으로과민성방광치료제로서 prostaglandin 합성저해제의역할에대한임상연구가부족한실정이다. 5. Tachykinins Tachykinin은중추와말초신경계에분포하는펩타이드군으로 substance P, neurokinin A, neurokinin B 등이있다. 방광에서는 capsaicin 민감성구심신경에서분비되며배뇨의감각축에관여한다. 또한신경전달물질을분비하고신경인성염증반응을매개하며평활근수축을촉진시킨다. 인간의방광에존재하는 neurokinin (NK) 는혈관내피세포에 NK1, 배뇨근에 NK2가주로존재한다. 몇몇연구에서 NK2 차단제가래트의배뇨근과활동성을감소시키는것으로나타났지만인간방광에대한연구는일관된결과를보여주지못했다. 한편방광뿐아니라척수와척수상부경로에도 tachykinin들이관여하는것으로나타나척수의 NK 수용체가새로운과민성방광치료의대상으로연구되고있다. 6. Vanilloid 수용체에작용하는약물 (Drugs acting on vanilloid receptor) 비선택적양이온채널의하나인 vanilloid 수용체 (TRPV1) 는방광의요상피와감각신경에서발견되며최근에는방광의과활동성과연관이있는것으로밝혀지고있다. 감각성요절박을가지는여성의방광삼각부에서 TRPV1 발현이증가된것을관찰할수있었다. 80 강력한신경독소인 capsaicin은 TRPV1에결합하여 C-fiber 구심로를탈감작시킨다. Capsaicin 방광내주입요법은그효과에비해급성통증과자극증상들로인해임상이용이제한적이다. 반면 Euphorbia resinfera라는식물에서추출한 resiniferatoxin 역시 TRPV1 의작용제로 C-fiber를탈감작시키지만 capsaicin에비해효과가월등하고부작용은적다. 81 Resiniferatoxin의방광주입술은국소자극증상은없지만효과의지속기간이짧다. 한연구에따르면, 저용량 (10nM) 을반복주입했을때 3개월에약 62%, 6개월에약 50% 환자에서효과가지속되었다. 82 다른연구에서는고용량 (50nM) 을 1회주입함으로써불응성배뇨근과반사에대한효과를 6개월까지연장할수있다고보고하였다. 83 최근에는새로운 vanilloid 수용체인 TRPA1이방광의감각신경에서발견되어요절박치료의새로운대상으로연구되고있다 Serotonin, noradrenaline 재흡수차단제 (Serotonin and norepinephrine reuptake inhibitors) Serotonin 수용체 (5-HT) 차단제는방광의부교감신경활성을억제하고교감신경과체신경의활동을증가시키는것으로밝혀졌다. 이러한작용은방광을이완시키고요도저항을높여요저장을촉진한다. Duloxetine hydrochloride는복압성요실금치료제로최초개발된약물로 5-HT와 noradrenaline 수용체가많이분포하고있는천추신경의 Onuf s 핵에서 serotonin과 noradrenaline의재흡수를억제한다. 이어 Onuf s 핵에위치하고있는음부신경을자극하여요도괄약근의수축력을증가시킨다. 여러연구에서 duloxetine의요실금에대한치료효과가보고되었으며삶의질또한유의하게호전시켰다. 85 가장흔한부작용은오심으로 3상연구에서약 25% 의환자가단기간오심을경험했으며 5% 의환자는이로인해약복용을중단하였다. 비록복압성요실금치료제로서개발되었지만복합성요실금과과민성방광치료제로서의역할이기대된다. 8. Botulinum toxin Clostridium botulinum에서발견된 botulinum toxin (BTX) 은 Soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) 단백인 SNAP-25 을절단하여콜린신경의시냅스전막에서 acetylcholne이소포로부터유리되는것을억제함으로써신경차단을일으킨다. BTX 에는 7가지종류가있으며임상에서사용되고있는것은 BTX-A이다. 여러연구에서신경인성및원발성배뇨근과반사에대한 BTX-A 방광내주입술의효과가입증되었다. 86,87 부작용으로는요폐가드물게보고된다. 적정용량과방광내주사위치에대해서는연구가계속진행중이다. 88,89 초기에 BTX은원심신경에작용하는것으로생각하였지만최근에는주로구심신경에작용하는것으로생각하고있다. Apostolidis 등 90 은 BTX-A가 acetylcoline뿐아니라 ATP와 substance P의유리를저해하고, 구심신경에서퓨린성수용체 (P2X3) 와 TRPV1의발현을억제한다고밝혔다. 이밖에여러신경전달물질들이 BTX-A의작용과연관된것으로알려지고있다. 작용기전에대한여러연구결과들을뒷받침하는근거들이필요하지만 BTX-A는약물치료에반응하지않는과민성방광의새로운치료법으로대두되고있다. 과민성방광의치료효과판정지난 10년간환자가보고하는치료성과 patient-reported

13 이규성ㆍ이영숙 : 과민성방광 1203 outcomes (PRO) 에대한중요성이강조되면서다양한설문지들이개발되었다. 91,92 하부요로증상설문지들을적절히이용하는것은환자의증상파악과치료효과를판정하는데중요한정보를제공한다. 과민성방광환자를위한설문은크게불편지수 (bother score), 요절박, 삶의질에대한것으로나눌수있다. 불편지수에대한설문에는 Overactive Bladder Questionnaire (OAB-q) 의첫 8문항으로구성된 OAB-q Symptom Bother Scale 과 OAB Bother Rating Scale 이라고도불리는 Primary OAB Symptom Questionnaire (POSQ) 가있다. 새로운정의에따라요절박이과민성방광의주증상으로여겨지면서이것을측정하는것이증상과치료효과평가에중요하다. 요절박은빈뇨나요실금과달리단순한이차원적평가로는부족하다. 따라서요절박의유무나횟수뿐아니라증상의중증도가함께고려되어야한다. 그러기위해서먼저환자스스로정상적인배뇨욕구 urge 와비정상적인요절박 urgency 을구분할수있어야하며요절박정도를환자가이해하고기술할수있어야한다. 요절박정도를측정하는설문에는 urgency perception scale (UPS), Indevus Urgency Severity Scale (IUSS), Urinary Sensation Scale (USS) 등이있다. 삶의질에대한설문에는 Overactive Bladder Questionnaire (OAB-q), King s Health Questionnaire (KHQ), Urge Incontinence Impact Questionnaire (Urge-IIQ) 등이있다. OAB-q는과민성방광환자의삶의질을측정하기위해고안된설문으로앞서설명한 8개의불편지수와 25개의삶의질에대한평가항목으로구성된다. 항목을 19개로줄인 OAB-q shortened form (SF) 은편리하게사용할수있는장점이있다. 최근한연구에의하면 OAB-q의최소유효차이 (minimal importance difference: MID) 는 10점인것으로나타났다. 앞으로다양한외국어설문지들을번역하고한글판설문지의신뢰도및유효성을입증하는것이과제이다. 구폐색이발견되지않는다. 뿐만아니라전립선절제술후에도약절반가량의환자에서는과민성방광이소실되지않는다. 따라서전립선비대증에만초점을두던남성과민성방광의치료에도변화가필요하다. 전통적으로전립선폐색이있는남성에서항무스카린제는급성요폐를유발할위험이있어금기시되어왔다. 그러나최근연구결과, 대부분의항무스카린제는경쟁적길항제로, 아세틸콜린이과잉분비되는배뇨시에는항무스카린제의효과가감소하는것으로알려졌다. 따라서항무스카린제를고용량으로사용하지않은이상방광수축력을감소시킬수없으며, 배뇨압이나최대요속을감소시키지않는다. 최근여러연구에서남성과민성방광환자들을대상으로한항무스카린제의유효성과안전성이입증되고있다. 93 그러나항무스카린제는의미있는방광출구폐색이있거나배뇨근수축력이약한환자에서는배뇨증상을악화시키거나요폐를일으킬수있기때문에단독투여의안정성은완전히입증되지않았다. 이문제점을극복하기위해서는첫치료로 α1-아드레날린작용제를먼저투여하여방광출구폐색을해결한이후에항무스카린제를추가투여하는것이바람직할것이다. 또한, 배뇨근수축력이약한환자의경우항무스카린제를사용하면증상이악화되거나요폐의가능성이있으므로항무스카린제사용을고려하는경우요역동학검사를시행하여배뇨근수축력을평가하는것이필요하다. 실제임상에서요역동학검사를시행할수없는경우에는요속과배뇨후잔뇨량을기준으로치료원칙을정하는것이도움이된다. 배뇨후잔뇨량이많거나요속이아주낮은경우에는항무스카린제사용후요폐의가능성을염두에두고세밀히관찰하여야한다. 또한폐색이심한경우는항무스카린제에의한요폐의가능성이있어전립선비대증수술후과민성방광을치료하는것이바람직하다. 전립선비대증과동반된남성과민성방광의치료 난치성과민성방광의치료 여러역학조사결과남성의과민성방광유병률은여성과비슷하게보고되고있다. 전통적으로남성하부요로증상은전립선비대증과관련하여발생하는것으로생각되었다. 방광출구폐색이지속되면방광의허혈과콜라겐침착, 배뇨근활동의변화등으로배뇨근과활동성이나저활동성방광등과같은방광기능부전이동반된다. 한연구에의하면요역동학검사상방광출구폐색환자의 50% 에서배뇨근과활동성이관찰되었다고보고하였다. 그러나방광출구폐색이항상배뇨근과활동성의원인으로작용하지않으며다른원인에의해배뇨근과활동성이발생할수있다. 실제로상당수의하부요로증상을가지는남성환자에서방광출 과민성방광의일차적치료법은행동치료와약물치료이다. 이두가지방법은단독으로사용하는것보다병용하는것이더효과적이기때문에동시에, 혹은단계적으로병용하여치료한다. 일반적으로복합요법으로 50-80% 정도에서요절박이감소하고절박성요실금이호전되는것으로알려져있다. 하지만요절박이사라지거나완전한요자제에이르지못하여치료결과에만족하지않는경우가많고, 치료에반응하지않는경우도 20-50% 정도이다. 이런경우를난치성과민성방광이라한다.

14 1204 대한비뇨기과학회지 : 제 48 권제 12 호 신경조정술 (Neuromodulation) 1) 말초신경의전기및자기장자극 : 말초신경을자극하여비정상적인배뇨척수반사를정상화하는것이목적이며배뇨근의억제반사경로를활성화한다. 자극의위치는천수신경, 음부신경, 경골신경등이이용되고전기나자기장으로자극한다. 체외자기장자극법 (extracorporeal magnetic stimulation) 은비침습적이라는장점이있다. Choe 등 94 은 48명의과민성방광환자에게체외자기장자극치료를시행하였는데, 치료 2주후약 69% 의환자에서요절박이소실되었으며 56% 에서빈뇨가, 50% 에서절박성요실금이소실되었다. 또한이들중 75% 이상은효과가최소 6개월이상지속되었다. 치료효과는여러연구에서입증되었으나장기치료성적은확실치않다. 2) 천수신경조절술 (Sacral neuromodulation): 1980년대초부터절박성요실금의치료로천수신경조절술이연구되어왔고 1981년기존의보존적인치료에반응하지않는환자를대상으로처음시행되었다. 95,96 최근에는그적응증이요절박, 특발성만성요폐, 골반통, 간질성방광염에까지확대되고있다. 천수신경을자극함으로써불안정한신경반사를억제하는것이치료의목표이다. A-delta 유수신경섬유, 특히 S3를자극함으로써요도괄약근과골반저를강화시키고배뇨근반사를억제하는효과를나타낸다. 동물실험결과, 음부구심섬유 (pudendal afferent) 를자극했을때절전부교감운동신경섬유 (parasympathetic pre-ganglionic motor neuron) 수준에서천수배뇨반사를억제함으로방광근에대한골반신경의활동성이억제되는것을관찰할수있었다. 또한골반신경절수준에서는하복신경 (hypogastric nerve) 이활성화되는것을관찰할수있었는데, 이는사람에서회음부를자극할때방광의활동성이억제되는기전과유사하다. 최근에는자가유치력이있는 tinned needle의사용으로시술이간편해졌다. 또한전통적으로자극하던천수신경보다음부신경의자극이더효과적이라는주장도있지만이것역시환자선정이성공을좌우하는주요한인자이다. 97 일반적으로기존치료에듣지않는과민성방광환자에서이시술을시행하였을때시술후 1년에 80-90%, 4년에 53-60% 의성공이보고되고있으며일부에서는완전한요자제상태까지도달하기도하였다. 98,99 합병증으로는이식부위통증으로자극기를제거한경우와전극이동등이보고되었다. 일반적으로장기추적시의효과는 50-60% 정도로예상되고있다. 저자의경우테스트자극을시행한환자중 70% 에서 50% 이상의증상호전이있었고, 영구적전기자극기를이식한 10명환자에서주간배뇨횟수는평균 17회에서 11회로, 야간배뇨횟수는 4회에서 2회로각각감소하 였으며, 기능적방광용적은 152ml에서 210ml로모두유의하게증가하였다. 100 특징적으로골반통증의정도도유의하게개선되었다. 2. 수술적치료주로신경인성이거나원인불명의과민성방광에서요절박이나빈뇨, 절박성요실금이심한경우혹은다른치료에내성이있는경우방광삼각부의구심성신경을파괴시켜방광수축의간격을늘리거나방광용적을증가시키는수술적치료를할수있다. 1) Bladder denervation procedure: 1950년대 Ingelman- Sundberg에의하여고안되었으며하복부신경총 (inferior hypogastric plexus) 을방광주위의광범위한박리로파괴하는수술이다. 질을통해간편히수술하는변형된 Ingelman- Sundberg 술식에의해좋은결과가보고되고있다. 수술여부를결정하기위해서는 bupivacaine을질전벽을통해방광삼각부아래에주사하고, 6-24시간동안절박성요실금이감소혹은소실되는지를확인하는술전검사가필요하다. 방광삼각부위치의질전벽에역 U 모양의절개를가하고질상피와방광주위근막을박리하여분리시키는방법이다. 이수술의결과는지속적이어서 28명환자에서수술후 44.1개월동안추적관찰한결과 68% 에서별다른합병증없이요절박과절박성요실금이완전 (54%) 혹은부분적 (14%) 으로소실되었다. 2) 배뇨근절제술 (Detrusor myomectomy or autoaugmentation): 배뇨근절제술혹은자가방광확대술은방광의점막층은유지하면서배뇨근을제거하는방법으로인공적인방광게실을형성하여방광용적과방광유순도를증가시킨다. 또한배뇨근을제거함으로써불수의적방광수축의강도와빈도를감소시킬수있다. 장을이용하는방광확대술에비해수술시간과회복기간이짧은장점이있지만수술술기를익히기가어렵다는단점이있다. 술후환자의주관적인증상은바로호전되지만점막으로이루어진게실은 3-6개월에거쳐크기가증가된다. 3) 방광확대술 (Augmentation cystoplasty): 방광의용적을늘려요저장능력을증가시키는것이목적이다. 그러나술후잔뇨가많이남기때문에자가도뇨를요하는경우가많다. 치료성적이높은반면합병증의발생비율이약 20% 정도로높은것이단점이다. 초기합병증으로소장누출, 봉합부요누출, 소장폐색, 장마비등, 장기합병증으로는방광결석, 고염소대사성산증, 소장폐색, 비타민 B12 결핍, 방광파열등이있다.

15 이규성ㆍ이영숙 : 과민성방광 1205 결 요절박, 빈뇨, 절박성요실금등을나타내는과민성방광은환자에게일상생활은물론, 사회적활동을위축시키는결과를초래한다. 최근환자가느끼는치료성과가중요시되면서환자가직접작성하도록고안된다양한종류의설문들이개발되어진단과치료에이용되고있다. 일차치료는약물요법과행동요법이고, 병행시치료효과를극대화할수있다. 약물로는항무스카린약물이주로사용된다. 최근에는운동신경계및감각신경계에작용하는약제들이연구되고있으며작용수준에따라서도중추신경계나말초신경계에작용하는약물에대한연구가이루어지고있다. 또한, 방광에보다선택적으로작용하거나부작용을줄이는약제전달방법과투입경로에대한연구도지속되고있다. 보존적요법으로치료되지않는과민성방광환자는요역동학검사를시행하여정확한병인을규명하는것이중요하다. 난치성과민성방광환자의경우에는 BTX-A, resiniferatoxin 등의방광주입술이나신경조정술등이연구되고있다. 론 REFERENCES 1. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21: Hashim H, Abrams P. Is the bladder a reliable witness for predicting detrusor overactivity? J Urol 2006;175: Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21: Brading AF. A myogenic basis for the overactive bladder. Urology 1997;50: Elbadawi A, Yalla SV, Resnick NM. Structural basis of geriatric voiding dysfunction. IV. Bladder outlet obstruction. J Urol 1993;150: Elbadawi A, Yalla SV, Resnick NM. Structural basis of geriatric voiding dysfunction. III. Detrusor overactivity. J Urol 1993;150: de Groat WC. A neurologic basis for the overactive bladder. Urology 1997;50(6A Suppl): Drake MJ, Mills IW, Gillespie JI. Model of peripheral autonomous modules and a myovesical plexus in normal and overactive bladder function. Lancet 2001;358: Zorn BH, Montgomery H, Pieper K, Gray M, Steers WD. Urinary incontinence and depression. J Urol 1999;162: Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, et al. Prevalence and burden of overactive bladder in the United States. World J Urol 2003;20: Melville JL, Katon W, Lentz G, Miller J, Fenner D. Prevalence of comorbid psychiatric illness and its impact on symptom perception, quality of life, and functional status in women with urinary incontinence. Am J Obstet Gynecol 2002;187: Lee KS, Na YG, Dean-McKinney T, Klausner AP, Tuttle JB, Steers WD. Alterations in voiding frequency and cystometry in the clomipramine induced model of endogenous depression and reversal with fluoxetine. J Urol 2003;170: Ouslander JG. Management of overactive bladder. N Engl J Med 2004;350: 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: Irwin DE, Milsom I, Hunskaar S, Reilly K, Kopp Z, Herschorn S, et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 2006;50: Komaroff AL, Fagioli LR, Doolittle TH, Gandek B, Gleit MA, Guerriero RT, et al. Health status in patients with chronic fatigue syndrome and in general population and disease comparison groups. Am J Med 1996;101: Kelleher CJ, Reese PR, Pleil AM, Okano GJ. Health-related quality of life of patients receiving extended-release tolterodine for overactive bladder. Am J Manag Care 2002;8(19 Suppl): S Liberman JN, Hunt TL, Stewart WF, Wein A, Zhou Z, Herzog AR, et al. Health-related quality of life among adults with symptoms of overactive bladder: results from a U.S. community-based survey. Urology 2001;57: Kobelt G. Economic considerations and outcome measurement in urge incontinence. Urology 1997;50(6A Suppl): Brown JS, Posner SF, Stewart AL. Urge incontinence: new health-related quality of life measures. J Am Geriatr Soc 1999;47: DuBeau CE, Kiely DK, Resnick NM. Quality of life impact of urge incontinence in older persons: a new measure and conceptual structure. J Am Geriatr Soc 1999;47: Dugan E, Cohen SJ, Bland DR, Preisser JS, Davis CC, Suggs PK, et al. The association of depressive symptoms and urinary incontinence among older adults. J Am Geriatr Soc 2000;48: Steers WD, Lee KS. Depression and incontinence. World J Urol 2001;19: Brown JS, Vittinghoff E, Wyman JF, Stone KL, Nevitt MC,

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