대한요로생식기감염학회지 : 제2권제2호 2007년 10월 Korean J UTII Vol.2, No.2, October 2007 종설 만성전립선염 / 만성골반통증후군에서 알파차단제치료의역할 가톨릭대학교의과대학비뇨기과학교실 최아람 한창희 [Abstract] Role of Alpha Blocker Therapy for Chronic Prostatitis/ Chronic Pelvic Pain Syndrome A-Ram Choi, Chang Hee Han From the Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Korea Prostatitis is a common medical diagnosis. The etiology of this symptomatic syndrome can be an acute or chronic bacterial infection, a noninfectious initiator, or iatrogenic heat or radiation. Alpha-blocker therapy has been advocated, with various levels of evidence, as a treatment modality for all categories of the prostatitis syndromes. From a pharmacological standpoint, the alpha blockers used in urology are not interchangeable. These drugs may work by different mechanisms and with different efficacy in patients with lower urinary tract symptoms related to benign prostatic hyperplasia and in those with symptoms of Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS). This article reviews the rationale for alpha blockers in patients with CP/CPPS. (Korean J UTII 2007;2:136-142) Key Words: Chronic prostatitis, Alpha blocker 서 전립선비대증과관련된하부요로증상의치료에있어알파차단제의효과는이미입증되어있으며현재까지가장널리사용되고있는치료법이다. 또한전립선비대증과관련된하부요로증상이외의비뇨기질환, 예를들어방광출구폐색, 신경인성방 론 교신저자 : 한창희, 가톨릭대학교의과대학비뇨기과학교실경기도의정부시금오동 65-1 Tel: 031-820-3546, Fax: 031-847-6133 E-mail: urohan@catholic.ac.kr 136 광, 간질성방광염, 여성및젊은남성에서의하부요로증상등에서도사용되고있으나아직까지그효과를입증할만한명확한근거자료는없다. 전립선염은전립선비대증다음으로알파차단제가흔히사용되는비뇨기과질환이다. 임상적으로진단된전립선염환자는거의모두가치골상부, 회음부, 골반, 음경혹은고환의통증을가지고있으며, 정도의차이는있지만빈뇨, 야간빈뇨, 절박뇨등의요저장 ( 자극 ) 증상과요주저, 약뇨, 단속뇨, 배뇨후점적등배뇨 ( 폐색 ) 증상을가지고있다. 급성세균성전립선염 (category I) 에서는심한요폐색증상
최아람외 : 만성전립선염 / 만성골반통증후군에서알파차단제치료의역할 137 의개선을위해사용될수있고, 1 만성세균성전립선염 (category II) 에서는항생제와함께병용투여함으로써항생제단독치료에비해재발의위험을줄일수있다는보고가있다. 2 무증상전립선염 (category IV) 의경우에는아직까지알파차단제사용의정당성을입증할근거가없으나전립선비대증에서전립선염이동반된경우급성요폐등과같은장기적합병증의발생위험이높다는보고가있으며, 3 이는전립선비대증치료에있어알파차단제의또다른역할이있을수있음을시사한다. 한편만성전립선염 / 만성골반통증후군 (category III) 은가장흔하고치료가어려운전립선염의하나로여러가지의전통적치료법들이소개되었으나어느하나우수한효과가입증되지는못하였다. 4-6 그러나알파차단제의경우하부요로증상및통증을효과적으로개선시켜삶의질을향상시킬수있다는여러임상연구결과들이보고되고있다. 7-10 이에저자들은만성전립선염 / 만성골반통증후군치료에있어알파차단제사용의이론적근거와구체적으로보고된자료에대해정리하고자한다. 본론 1. 만성전립선염 / 만성골반통증후군환자에서알파차단제사용의이론적근거만성전립선염 / 만성골반통증후군환자에서알파차단제치료는다음의네가지임상양상에근거한다 : (1) 일부전립선염환자들은전립선비대증과관련된배뇨장애혹은방광출구폐색증상을겪고있을것으로생각되고 11-12 (2) 알파차단제는배뇨장애와방광출구폐색증상개선에효과가있음이입증되었으며 (3) 전립선염증상과하부요로증상을동시에경험하는일부환자들에서알파차단제치료가 효과적이며 12-14 (4) 비뇨기과의사들은다양한질환 에대한알파차단제사용경험이많다는점이다. 상기사실들을근거로많은비뇨기과의사들이만성전립선염 / 만성골반통증후군환자들에게알파차단제를경험적으로처방하게되었으며임상적으로많은환자에서알파차단제치료후증상이호전되 는양상이관찰되었다. 2. 하부요로에대한알파차단제의약리기전알파와베타수용체는혈관, 척수, 전립선, 방광, 배뇨근등여러조직에분포되어있다. 특히비뇨생식기계에알파수용체가많이분포되어있어비뇨생식기질환의치료에선택적인여러약물들이개발되었다. 분자구조학적으로알파 1 과알파 2 라는두개의알파수용체가존재하며이들은각각 3가지의아형즉, 알파 1a, 알파 1b, 알파 1d 와알파 2a, 알파 2b, 알파 2c 가있다는사실이밝혀졌다. 15 이알파수용체들은 G 단백질매개 (G-protein-linked) 수용체군에속하는데알파자극제들은이차전달체계 (second messenger system) 를통해세포의활동을변화시켜카테콜아민치를변화시키고다양한반응을유도한다. 알파 1 아드레날린수용체들은대부분평활근, 심장, 정관, 뇌, 전립선등의연접후 (postsynaptic) 세포들에분포되어있다. 16-18 알파차단제에대한약리학및약물역동학적이해가넓어짐에따라비뇨생식기질환, 특히전립선비대증에효과적인많은약제들이개발되었으며아울러이약제들은만성전립선염 / 만성골반통증후군을포함한다른여러비뇨기질환에도효과를나타낸다 (Table 1). 그러나현재까지상용화된알파차단제들은약리학적으로다양한부위에작용을하고임상적으로동등한효과를예측하기어렵다는문제점이있다. 3. 여러연구자료및논란만성전립선염 / 만성골반통증후군치료에서알파차단제사용의당위성을입증하는사실들은여전히논란의여지로남아있는상태이다. 가장논란의여지가되는것은만성전립선염 / 만성골반통증후군환자들에게서알파차단제치료로호전될수있는방광출구폐색이나배뇨장애가있느냐하는문제이다. 1970년대초부터요역동학검사를통해방광경부기능이상 / 방광경부폐색에의해유발된만성전립선염을확인할수있다는사실을여러연구자들이제시하였
138 대한요로생식기감염학회지 : 제 2 권제 2 호 2007 년 10 월 Table 1. Alpha blockers evaluated clinically for treating lower urinary tract symptoms Category Agents Site of action Non-selective Selective α 1 phentolamine phenoxybenzamine labetalol α-difluoromethyl-orthinine terazosin doxazosin alfuzosin peripheral alpha receptors, vascular smooth muscle bladder trigone, urethra prostatic capsule Main indications hypertension BPH hypertension Major side effects orthostatic hypotension. reflex tachycardia, nasal stuffiness, retrograde ejaculation orthostatic hypotension Selective α 1a tamsulosin prostatic capsule BPH retrograde ejaculation Selective α 1d naftopidil bladder smooth muscle BPH orthostatic hypotension BPH: benign prostatic hyperplasia 다. 18-27 즉, 비정상적배뇨가고압의난류성 (turbulent) 요류를유발하고이로인해소변의전립선관내로의역류혹은전립선내항체의침착을유도하여통증과다른증상을유발한다는개념으로, 22,24,28-32 비대조군연구결과이러한환자들은내시경하절개, 경요도전립선절제술, 전립선의풍선확장술등의시술을통해서효과를볼수있다고보고하였다. 23,24,30,33-36 또한이러한환자들은알파차단제로도효과를볼수있는환자들로생각되어졌다. 이와는상반된결과로, 다른연구자들은요역동학검사에서폐색소견을보였던환자들이알파차단제에효과를나타내지않았다는사실에미루어알파차단제들이그다지효과를나타내지않았다는결론을발표하였다. Mayo 등 37 은하부요로증상을주소로요역동학검사센터를방문한 18~51세의남자환자들의증상및요역동학검사소견과임상적으로전립선염으로진단된환자들의증상및요역동학검사소견을비교하였다. 하부요로증상을주소로요역동학검사를시행하였던 201명중 37명 (18%) 에서만이심한통증을호소하여만성전립선염으로진단되었고이들중 4 명 (11%) 만이폐색소견을보였으며, 전립선염으로진단된 123명의환자들중 2명 (1.6%) 만폐색소견을보였고 1명 (0.8%) 은폐색이의심되는소견을보였다고보고하였다. 이를뒷받침하는최근연구로만성전립선염 / 만성골반통증후군환자에있어서알파차단제와위약치료를비교하는대규모의무작위임상 시험결과가보고되었는데임상증상과요역동학검사소견간에는상관관계를보이지않는것으로나타났다. 38 이들의연구에의하면알파차단제가요역동학검사지표의개선이외에다른기전으로만성전립선염 / 만성골반통증후군의치료에효과적이었다고보고하고있다. 즉, 특정알파 1 차단제는전립선과방광경부이외의부위에작용하는데이작용부위들이만성전립선염 / 만성골반통증후군을치료하는데중요한역할을하는것일수도있다고주장하고있다. Mehik 등 39 은만성전립선염 / 만성골반통증후군환자는대부분전립선내압이증가된소견을보였다고보고하였다. 만성비세균성전립선염으로진단된 42명의환자들과비뇨기과적인질환이없는 12명을비교한결과만성비세균성전립선염환자들에있어서대조군에비해전립선내압이유의하게증가되어있음을보여주었다. 이들은전립선내압이증가된것은조직저항성이증가되거나조직미세혈류환경이좋지않음을반영하는것이며이론적으로알파차단제들은배뇨에영향을주지않으면서그와같은병태생리학적과정을개선시킬것으로추측하였다. 4. 만성전립선염 / 만성골반통증후군의알파차단제치료에대한임상시험들만성전립선염 / 만성골반통증후군치료에있어알
최아람외 : 만성전립선염 / 만성골반통증후군에서알파차단제치료의역할 139 파차단제사용의당위성은 alfuzocin, 2 terazosin, 40 phnoxybenzamine, 7,8 tamsulosin 10 등을사용한일부비대조임상시험들에서입증되었었다. 그러나이임상시험들은연구자마다진단기준이나포함 / 배제기준이각기다르고, 치료효과판정의기준또한달라서로간에비교하는데문제가있다. 1999년 NIH 전립선염증상지수 (NIH-CPSI) 가개발됨으로 써 41 만성전립선염 / 만성골반통증후군환자에서증 상이나치료반응을보다객관적이고통일된기준하에평가할수있게되었으며, 이를이용한알파차단제의효과에대한 4개의무작위, 위약-대조임상시험결과가보고되었다 (Fig. 1). 그러나이들연구또한반응군의기준이다소달라서로를비교하는데어려움이있다. Cheah 등 38 은 86명의만성전립선염 / 만성골반통증후군환자에서비선택적알파 1 차단제로알려져있는 terazosin의효과에대한 14주간의무작위, 위약- 대조임상시험을시행하였다. 기저치와비교했을때치료군과대조군모두에서유의한개선효과를보였으나 terazosin 치료군에서평균증상점수가 50% 감소된반면위약군에서는 37% 감소만이관찰되어 terazosin 사용이효과적이라고보고하였다. Mehik 등 42 은 40명의만성전립선염 / 만성골반통증 후군환자를대상으로알파 1a 차단제로알려진 alfuzosin의효과에대한 6개월간의무작위, 위약-대조임상시험을시행하였다. 대조군에비해 alfuzosin 치료군에서유의하게증상이개선되었으며, 이러한개선효과는치료 4개월부터확실해지기시작해서 6개월에더욱유의한개선효과를나타내었다. 그러나 6개월간의치료후양군모두에서점차치료효과가감소되었으며위약군에서보다빨리감소되었다고보고하였다. 한편 NIH-Chronic Prostatitis Collaborative Research network (NIH- CPCRN) 에서는만성전립선염 / 만성골반통증후군증상이 2년미만인환자들중에서이전에알파차단제를사용한적이없는환자들을대상으로 alfuzosin과위약치료를비교하는총 12주간의무작위임상시험을진행중이며이연구는이전에치료를받지않았던만성전립선염 / 만성골반통증후군환자에대한선택적알파 1a 차단제의효과에대해중요한정보를줄것으로기대된다. Nickel 등 43 은 58명의만성전립선염 / 만성골반통증후군환자를대상으로 tamsulosin의효과를평가하기위한이중맹검, 무작위, 위약-대조다기관임상시험을시행하였다. 2주의 washout 기간을거쳐 6 주간 tamsulosin 또는위약을매일 1회투여하였고, Tamsulosin Terazosin n=98; 6 weeks P<.05 n=86; 14 weeks Tamsulosin Alfuzosin P<.05 P<.05 n=57; 6 weeks n=37; 24 weeks 0-2 -4-6 -8-10 -12-14 -16 Fig. 1. Results from the 4 randomized, placebo-controlled trials available in the literature comparing α-blocker therapy with placebo in chronic prostatitis/chronic pelvic pain syndrome. The bar graphs describe the delta between the end-of-treatment National Institutes of Health-Chronic Prostatitis Symptom Index score and the baseline score in each group. Data from Cheah PY et al, 38 Mehik A et al, 42 Nickel JC et al, 43 and Alexander RB et al. 44
140 대한요로생식기감염학회지 : 제 2 권제 2 호 2007 년 10 월 투여 15일과 45일째 NIH-CPSI를이용하여효과를평가하였다. 위약군에비해 tamsulosin 치료군에서유의한치료효과를보였는데 tamsulosin 치료군에서는 52% 에서치료반응이나타난반면위약군에서는 33% 만이치료반응을보였으며, 치료전 NIH-CPSI 총점수가높았던환자, 즉증상이중등도이상으로심했던환자에서보다큰효과를나타내었다. 한편 NIH-CPCRN에서는 44 196명의만성전립선염 / 만성골반통증후군환자를대상으로 ciprofloxacin, tamsulosin 및 ciprofloxacin과 tamsulosin 병합치료의효과를비교하기위한 6주간의무작위, 위약-대조, 3상임상시험을시행하였는데, 위에서언급한 3가지의임상연구결과와는다르게이연구에서는 tamsulosin 치료가위약치료에비해유의한개선효과를보이지않았다. 그러나이와같은결과는대상환자군이알파차단제효과에대한긍정적결과를보인위의 3가지연구에비해증상이더욱오래된만성환자들로이전에알파차단제를포함한많은치료를받았던환자들이었기때문으로생각한다. Dimitrakov 등 6 은상기 4개의임상시험을메타분석한결과를보고하였는데, 호전에대한 pooled relative risk값이 0.57로 (95% 신뢰구간 0.24-0.91, p=0.10) 만성전립선염 / 만성골반통증후군에서알파차단제치료가중등도의효과를보인다고보고하였다. 그러나상기 4개의임상시험들은각기작용위치와작용기전이서로다른 3가지의알파차단제들을사용하였다는문제점과함께연구디자인, 치료기간, 대상환자군에있어서중요한차이가있어이를통합하여정확한결과를도출하기에는제약이있다. 결론알파차단제가만성전립선염 / 만성골반통증후군치료에효과적치료법중의하나임이양질의여러임상연구들을통해증명되고있으며, 임상적으로도많은만성전립선염 / 만성골반통증후군환자들이알파차단제치료에좋은반응을보인다. 위에서언급되었던최근연구자료들을통해다음과같은결론을추론해볼수있다. (1) 임상연구디자인에있어제기되는중요한 문제점들이해소되고있으며, 이에따라더많은양질의연구가촉진될것이다. (2) 전에치료를받지않았거나처음진단된만성전립선염 / 만성골반통증후군환자들이장기간치료를받았고기존치료에반응하지않았던환자들보다알파차단제들에좋은치료효과를보이고있다. (3) 만성전립선염 / 만성골반통증후군환자에서알파차단제치료는 6주미만의단기치료보다 12주에서 6개월까지의장기치료가보다우수한것으로생각한다. (4) 만성전립선염 / 만성골반통증후군치료에서는선택적알파 1 차단제보다덜선택적인약제들이치료효과가더우수한것으로생각된다. 아울러만성전립선염 / 만성골반통증후군치료에있어알파차단제의역할을규명하기위해서는다음 4 가지의중요한의문에대한규명이필요할것으로생각된다. (1) 만성전립선염 / 만성골반통증후군에서알파차단제의치료효과를담당하는위치와수용체를규명해야한다. 아마도그위치는전립선, 방광, 척수, 혹은다른해부학적위치일것으로생각되며, 이러한위치와수용체들은전립선비대증과관련된하부요로증상에관여하는위치와수용체들과는다를것이다. (2) 최적의알파차단제는무엇이고치료기간은얼마가좋은가에대한규명이필요하다. (3) 알파차단제를단독으로사용하는것이좋은지, 다른치료와병합하여사용하는것이좋은지를규명해야한다. (4) 만성전립선염 / 만성골반통증후군의자연경과기간중알파차단제치료의적기는언제인지를규명해야한다. 즉, 알파차단제를초기에사용하는것이좋을지, 아니면항생제요법혹은다른여러치료에실패한경우 2차적으로사용하는것이좋을지를규명해야한다. REFERENCE 1. Neal DE. Treatment of acute prostatitis. In: Nickel
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