과민성방광을동반한전립선비대증환자의치료에서알파차단제와저용량 Propiverine Hydrochloride 병용투여의효과및안전성 The Efficacy and Safety of Combination Therapy with Alpha-Blocker and Low-Dose Propiverine Hydrochloride for Benign Prostatic Hyperplasia Accompanied by Overactive Bladder Symptoms Kang Il Seo, Sung Zoo Hong, Jong Bouk Lee From the Department of Urology, National Medical Center, Seoul, Korea Purpose: We evaluated the efficacy and safety of combined therapy with an alpha-blocker (tamsulosin 0.2 mg) and low-dose anti-cholinergics (propiverine HCl 10 mg) in patients with benign prostatic hyperplasia (BPH) accompanied by overactive bladder (OAB) symptoms. Materials and Methods: This prospective study enrolled 119 male patients with lower urinary tract symptoms (LUTS) with prostate volume of 20 ml or greater, International Prostate Symptom Score (IPSS) of more than 8, and OAB symptoms from May 2007 to April 2008. Patients with post-void residual volume (PVR) over 100 ml were excluded. Among these patients, 74 patients were treated with tamsulosin 0.2 mg plus propiverine HCl 10 mg (group A) and 45 patients were treated with tamsulosin 0.2 mg only (group B). The clinical parameters, including IPSS, quality of life (QoL) score, uroflowmetry, and PVR were re-evaluated after 3 months. Results: A total of 115 patients, including 70 in group A and 45 in group B, completed the study. IPSS, QoL score, voided volume, maximum flow rate (Qmax), and PVR showed significant improvement after 3 months of treatment (p<0.05). Baseline characteristics between the 2 groups were not significantly different for any parameter (p>0.05). Changes in the QoL score were 1.9±1.1 and 1.5±0.9 for group A and group B, respectively (p=0.043). Changes in all other parameters were not significantly different between the 2 groups (p>0.05). Conclusions: For those patients with LUTS due to BPH and concomitant OAB, combination therapy with an alpha-blocker (tamsulosin 0.2 mg) and low-dose anti-cholinergics (propiverine HCl 10 mg) may be a reasonable and effective therapeutic option as an initial therapy. (Korean J Urol 2009;50:1078-1082) Key Words: Prostatic hyperplasia, Overactive urinary bladder Korean Journal of Urology Vol. 50 No. 11: 1078-1082, November 2009 DOI: 10.4111/kju.2009.50.11.1078 국립의료원비뇨기과 서강일ㆍ홍성주ㆍ이종복 Received:May 25, 2009 Accepted:October 5, 2009 Correspondence to: Jong Bouk Lee Department of Urology, National Medical Center, 243, Euljiro, Jung-gu, Seoul 100-799, Korea TEL: 02-2262-4718 FAX: 02-2274-6601 E-mail: nmcuro@hanmail.net C The Korean Urological Association, 2009 가하는것으로보고되고있다 [4,5]. 과민성방광으로인한 서 론 저장증상은배뇨증상보다더큰고통을줄수있으며 [6], 과민성방광을동반한전립선비대증의경우알파차단제단 전립선비대증으로인한방광출구폐색이존재하는경우 독치료만으로는충분한치료효과를얻기어렵다. 이러한 50-75% 에서는과민성방광을동반하며, 전립선비대증을치 이유로전립선비대증에동반된과민성방광환자에서항콜 료한후에도과민성방광이약 38% 에서는지속되는것으로 린제사용이시도되고있다. 이전의많은연구에서알파차 알려져있다 [1-3]. 또한연령이높거나하부요로폐색이심 단제와항콜린제병합요법의효과및안전성은확인되었으 할수록전립선비대증으로인한과민성방광의발생률도증 나 [7-13], 아직까지도항콜린제에의한잔뇨의증가및요 1078
Kang Il Seo, et al:combination of α-blocker and Low Dose Propiverine in BPH/OAB 1079 폐의위험성으로인해실제임상에서는알파차단제단독처방으로호전정도를파악한후필요시병합치료로전환하는경우가많은실정이다. 이에저자들은과민성방광을동반한전립선비대증환자에서알파차단제 (tamsulosin 0.2 mg) 와함께저용량항콜린제 (propiverine HCl 10 mg) 를처음부터같이투여하여그안전성및효과를알아보고자하였다. 대상및방법 2007년 5월부터 2008년 4월까지하부요로증상으로내원한전립선비대증환자중과민성방광이동반된 119명을대상으로하였다. 모든환자에서병력청취, IPSS 및삶의질점수 (quality of life; QoL), 직장수지검사, 요검사, 혈중전립선특이항원 (prostate-specific antigen; PSA), 요속및잔뇨측정검사, 경직장전립선초음파등을시행하였다. 구체적인포함기준은 IPSS가 8점이상이고직장수지검사와경직장초음파검사에서전립선비대가확인된환자를대상으로하였으며, 최근 3개월이내알파차단제를비롯한약물치료를받았거나전립선수술, 비뇨기계의종양, 신인경성방광, 요도협착등의병력을가진경우나잔뇨량이 100 cc 이상인경우에는대상에서제외하였다. 과민성방광은 Kaplan 등의기준 [13] 에따라국제전립선증상점수 (International Prostate Symptom Score; IPSS) 4번째항목 (urgency) 에서 3점이상을나타내는경우로정의하였다. 대상을두군으로나누어 1군 (74 명 ) 은 tamsulosin 0.2 mg과 propiverine HCl 10 mg을병합하여저녁에투여하였고, 2군 (45명) 은 tamsulosin 0.2 mg만단독투여하였다. 3개월뒤모든환자들에게 IPSS, 요속및잔뇨측정검사를다시시행하여투여전후의임상적인변화를비교하였다. 통계학적검증은윈도우용 SPSS 12.0의 paired t-test, independent t-test를사용하여분석하였고, p값이 0.05 미만인경우통계적으로유의한것으로평가하였다. B군사이에연령, PSA 수치, 전립선용적, IPSS, 배뇨및저장증상영역점수, 삶의질점수, 최대요속, 평균배뇨량및잔뇨량등에있어서유의한차이가없었다 (Table 1). 약제투여후두군모두 IPSS, 배뇨및저장증상영역점수, 삶의질점수, 최대요속, 평균배뇨량및잔뇨량등에서각각유 의한호전을나타냈다 (p<0.05). 두군간변화량은대부분큰차이를보이지않았으나, 삶의질점수변화폭에서 A군 1.9±1.1, B군 1.5±0.9로유의한차이를보였다 (p=0.043) (Table 2). 또한, 저장증상영역점수에서 A군 3.8±3.0, B군 3.0±3.3로비록통계적인유의성은없었으나병합투여군에서더호전되는결과를나타냈다 (p=0.151). 병합투여군을환자의나이 (70세이상 / 미만 ), 전립선크기 (30 ml 이상 / 미만 ), 혈청 PSA (2.0 ng/ml 이상 / 미만 ), 초기잔뇨량 (40 ml 이상 / 미만 ) 등의임상인자들로대상환자들을양분하여그결과를비교하였을때 [14-17], 각각의인자는약물치료의 Table 1. Baseline demographics and characteristics between the groups (Mean±SD) Group A Group B Age (years) Prostate volume (cc) PSA (ng/ml) IPSS Storage symptoms Voiding symptoms QoL score Qmax (ml/sec) Voided volume (ml) PVR (ml) 67.3±7.8 30.9±9.2 2.0±1.9 21.9±7.0 9.9±3.2 12.1±4.7 4.4±0.7 10.4±3.9 210.0±78.9 37.1±10.1 66.3±8.2 31.5±8.2 1.7±1.8 21.1±7.8 9.6±3.5 11.5±5.1 4.5±0.7 11.3±4.5 220.4±96.8 34.3±10.7 0.534 0.721 0.416 0.588 0.667 0.508 0.757 0.228 0.534 0.165 PSA: prostate-specific antigen, IPSS: International Prostate Symptom Score, QoL score: quality of life score, Qmax: maximum flow rate, PVR: post-void residual volume, a : statistical significance was done by independent t-test 결과전체 119명의대상환자중치료 3개월후에추적관찰이가능하였던총 115명을대상으로분석하였다. 중간탈락의원인으로는외래추적관찰이되지않은경우가 3명, 환자가임의로약복용을중단한경우가 1명이었다. 대상환자의평균연령은 66.9±7.9세였으며혈청 PSA는 1.9±1.8 ng/ml, 평균전립선용적은 30.9±8.1 ml였다. IPSS는 21.6±7.3, 배뇨증상영역점수는 11.9±3.2, 저장증상영역점수는 9.8±4.7, 삶의질점수는 4.5±0.7, 최대요속은 10.7±3.8 ml/sec, 평균배뇨량은 214±78.9 ml, 잔뇨량은 36±10.1 ml였다. 치료전 A군과 Table 2. Changes in each parameters after 3 months (Mean±SD) Group A Group B IPSS Storage symptoms Voiding symptoms QoL score Qmax (ml/sec) Voided volume (ml) PVR (ml) 8.4±5.6 3.8±3.0 4.7±3.8 1.9±1.1 2.7±3.3 57.8±63.9 11.3±13.0 7.92±6.4 3.0±3.3 5.0±4.3 1.5±0.9 2.9±4.0 48.8±52.4 12.2±12.9 0.587 0.151 0.860 0.043 0.808 0.437 0.707 IPSS: International Prostate Symptom Score, QoL score: quality of life score, Qmax: maximum flow rate, PVR: post-void residual volume, a : statistical significance was done by independent t-test
1080 Korean Journal of Urology vol. 50, 1078-1082, November 2009 Table 3. Differences in changes in clinical parameters according to the patient s age, prostate volume, initial PSA value, and PVR IPSS QoL score Qmax (ml/sec) PVR (ml) Age (years) <70 (n=41) 70 (n=29) Prostate volume (ml) <30 (n=42) 30 (n=28) PSA (ng/ml) <2 (n=45) 2 (n=25) Initial PVR (ml) <40 (n=42) 40 (n=28) 8.3±6.2 8.5±4.6 0.849 7.7±5.8 9.2±5.3 0.254 7.8±5.6 9.3±5.5 0.252 8.6±5.7 7.9±5.4 0.618 2.0±1.2 1.9±0.9 0.589 1.9±1.1 2.1±1.0 0.471 1.9±1.0 2.0±1.1 0.884 1.9±1.1 2.0±1.1 0.658 2.6±3.9 2.8±2.0 0.819 2.7±3.1 2.5±3.7 0.804 2.7±3.6 2.7±2.8 0.993 2.9±3.6 2.6±2.9 0.727 11.7±11.4 10.6±15.3 0.716 10.5±14.4 12.5±10.6 0.536 10.9±13.6 11.9±12.1 0.754 9.9±9.4 13.2±17.3 0.299 PSA: prostate-specific antigen, PVR: post-void residual volume, IPSS: International Prostate Symptom Score, QoL score: quality of life score, Qmax: maximum flow rate, a : statistical significance was done by independent t-test 효과에영향을미치지않는것으로나타났다 (Table 3). 모든환자에서약물복용기간동안급성요폐는발생하지않았다. 병합투여군에서 10명 (14%) 의환자가구갈을호소하였으나투약을중단할정도는아니었으며, 6명 (9%) 의환자에서는투약후에도증상의호전이없었고이중 3명 (4%) 의환자에서잔뇨량이점진적으로증가하여 propiverine 투약을중단하고수술로전환하였다. 나머지 3명은증상의호전은없으나최대요속및잔뇨량의개선을보여투약을유지하였다. 폐색증상은개선되었으나저장증상이호전되지않았던 7명 (10%) 의환자에서는 propiverine을 20 mg으로증량하였으며, 이중 2명의환자에서증상의호전을보였다. 고찰무스카린수용체는방광을비롯하여뇌, 평활근, 분비샘등체내에널리분포되어있는데현재까지분자생물학적으로무스카린수용체에대한 5개의유전자가발견되었고각각의유전자와관련하여 5가지수용체가알려져있다 (M1- M5) [18]. 사람의방광에는주로 M2, M3 수용체가작용하나 M3 수용체가방광수축에가장중요한역할을하며, 아세틸콜린의작용으로 phosphoinositide를가수분해하여세포내칼슘농도가높아져평활근수축을유발하는것으로알려져있다 [19,20]. 항무스카린제는주로이러한무스카린수용체에작용하여불수의적방광수축을억제하고최대방광용량을증가시켜요절박, 절박성요실금등의증상을보 이는과민성방광의치료에사용되고있다. 그러나, 방광의수축력감소로잔뇨를증가시키거나요폐를발생시킬수있다는위험때문에현재미국이나유럽비뇨기과학회진료지침서에서는전립선비대증이확인된하부요로증상치료에항무스카린제를추천하고있지않다 [21,22]. 그럼에도불구하고, 항무스카린제는과민성방광증상을가지는전립선비대증치료에매우매력적인약물이며, 실제임상에서과민성방광의치료에흔히사용되고있다. 그중 darifenacin, solifenacin, tolterodine, trospium chloride는순수한항무스카린제인반면 oxybutynin은항무스카린제이면서직접적인근육이완작용을나타내고, propiverine은유일하게항무스카린효과뿐아니라칼슘조절작용을가져전립선평활근과배뇨근의수축을억제하는효과를기대할수있다 [20]. 전립선비대증에동반된과민성방광의치료에항무스카린제를사용한연구들을보면급성요폐를비롯한비뇨기계부작용의증가없이효과적이고안전하게투여할수있는것으로나타났다 [7-13]. Abrams 등은요역동학검사에서방광출구폐색과배뇨근과활동성을보이는전립선비대증환자에게항콜린제 (tolterodine 4 mg) 와위약을투여하여비교분석한결과, 항콜린제를사용한군에서급성요폐의발생률을증가시키지않으면서저장증상을유의하게호전시켰다고보고하였으며, 항콜린제사용군에서위약군에비해잔뇨량이 25 ml 더증가하였으나임상적의미는없었다고하였다 [7]. 또한, Athanasopoulos 등은요역동학검사에서방
Kang Il Seo, et al:combination of α-blocker and Low Dose Propiverine in BPH/OAB 1081 광출구폐색과배뇨근과활동성이모두확인된 50명의환자를대상으로 tamsulosin 0.4 mg 단독요법과 tolterodine 4 mg 을추가한병합요법과의무작위대조연구를시행하였으며, 병합치료군이단독요법군에비하여최대요속악화및잔뇨의증가없이삶의질을유의하게호전되었다고보고하였다 [8]. Lee 등도무작위대조연구를통해요역동학검사에서방광출구폐색을보이고과민성방광증상을호소하는 50명의환자에서 doxazosin 4 mg에 propiverine 20 mg을병합하여투여하였을때, 최대요속및배뇨증상에영향을미치지않으며저장증상에서유의한호전을보였다고하였으며, 부작용으로잔뇨량이 21 ml 증가하였으나잔뇨량이크지않아임상적으로의미있는양은아니었다고하였다 [9]. 이처럼방광출구폐색과배뇨근과활동성이동시에존재하는경우알파차단제와항콜린제의병합요법은안전하게이용될수있음이증명되었으나실제임상에서하부요로증상으로내원한모든환자에서약물요법을시작하기전에요역동학검사를시행한다는것은현실적으로어렵다. 또한, 하부요로증상을가진환자의약 20-40% 에서는배뇨근수축의장애를가지고있다고알려져있으나 [23-25], 요속검사만으로는방광출구폐색에서보이는증상과구별하기힘들다. 실제로 Hyman 등은저장증상을호소하는전립선비대증환자 160명에서요역동학검사를시행한결과 68명 (43%) 의환자에서배뇨근과활동성을, 45명 (28%) 의환자에서는배뇨근저활동성을가지고있는것으로진단하였으며, 50명 (31%) 의환자에서는방광출구폐색에배뇨근과활동성이동반되어있음을보고하였다 [23]. 압력요류검사를포함한요역동학검사만이방광출구폐색과배뇨근저활동성을구분하는유일한방법이나, 검사의번거로움과환자에대한침습성, 경제적인부담등으로약물치료시시행하기어려워요역동학검사없이항콜린제를같이투여하기에는부담이따른다. 또한, 다수의연구에서알파차단제와항콜린제의병합치료후최대요속이증가되지않거나, 잔뇨가증가되는부작용이보고되었다 [9,10]. 따라서 Han 등은전립선비대증환자 126명을대상으로한연구에서 tamsulosin 0.2 mg을 3개월간먼저투여하여폐색이적절히호전됨을확인한후자극증상의호전을보이지않는 29명의환자에게 propiverine 20 mg을병용투여하여성공적인결과를보고하였다 [11]. 순차적병용투여결과, 치료전과비교하여배뇨량, IPSS 및삶의질점수의유의한호전을보이면서최대요속및잔뇨량에는유의한변화가없었다고하였다. 저자들은요절박증상을포함하는하부요로증상으로내원한남성에서전립선초음파검사에서 20 cc 이상의전립선비대를보이고잔뇨량이 100 ml가넘지않는경우방광기능및방광출구폐색평가를위한요역동학검사없이초기약물치료로 tamsulosin 0.2 mg과 propiverine 10 mg을같이투여하였다. 약물투여전과비교하여 IPSS, 삶의질점수, 최대요속, 평균배뇨량및잔뇨량등에서유의한호전을보였으나 tamsulosin 단독투여군과비교하였을때최대요속및잔뇨량의 변화에서유의한차이를보이지는않았다. 이는항콜린제의용량을낮추어서사용함으로써알파차단제와정량의항콜린제를같이사용하였을때에비해상대적으로알파차단제의작용이우월하게나타남과동시에알파차단제단독요법에비해항콜린제를같이투여함으로써나타난배뇨량증가의효과로인해, 병합투여후에최대요속의증가및잔뇨량의감소를나타낼수있었던것으로생각한다. 본연구는비록환자수가많지않으나전향적으로시행되었으며, 환자의등록에큰제한을두지않아실제임상에서대상환자의선정및병합요법의시작시점등을결정함에있어유용한정보를제공할수있을것으로생각한다. 결 알파차단제 (tamsulosin 0.2 mg) 와저용량항콜린제 (propiverine HCl 10 mg) 의병용투여는잔뇨량증가, 최대요속및배뇨증상의악화없이과민성방광증상치료에효과적이었으며잔뇨량이많지않은전립선비대증환자에서처음부터안전하게사용할수있을것으로판단된다. 론 REFERENCES 1. Douchamps J, Derenne F, Stockis A, Gangji D, Juvent M, Herchuelz A. The pharmacokinetics of oxybutynin in man. Eur J Clin Pharmacol 1988;35:515-20. 2. Lepor H, Rigaud G. The efficacy of transurethral resection of the prostate in men with moderate symptoms of prostatism. J Urol 1990;143:533-7. 3. Knutson T, Edlund C, Fall M, Dahlstrand C. BPH with coexisting overactive bladder dysfunction--an everyday urological dilemma. Neurourol Urodyn 2001;20:237-47. 4. Oelke M, Baard J, Wijkstra H, de la Rosette JJ, Jonas U, Höfner K. Age and bladder outlet obstruction are independently associated with detrusor overactivity in patients with benign prostatic hyperplasia. Eur Urol 2008;54:419-26. 5. Wadie BS, Ebrahim el-he, Gomha MA. The relationship of detrusor instability and symptoms with objective parameters used for diagnosing bladder outlet obstruction: a prospective study. J Urol 2002;168:132-4. 6. Abrams P, Kelleher CJ, Kerr LA, Rogers RG. Overactive bladder significantly affects quality of life. Am J Manag Care 2000;6(11 Suppl):S580-90. 7. Abrams P, Kaplan S, De Koning Gans HJ, Millard R. Safety
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