BPH TEDAVİSİNDE ALFA-ADRENERJİK BLOKERLER Op. Dr. Tümay İPEKÇİ Antalya Eğitim ve Araştırma Hastanesi Üroloji Kliniği Ürolojik Cerrahi Derneği Batı Akdeniz Şubesi Toplantısı The Marmara Otel Antalya 5 Nisan 2013

α-RESEPTÖR BLOKAJI; Alfa-bloker kullanımının rasyoneli; BPH patofizyolojisinin prostatik düz kaslardaki alfa1 adrenerjik reseptörler (AR) aracılığı ile oluşturulan MÇO olduğu hipotezine dayanmaktadır. Alfa blokerler : Mesane çıkımındaki düz kası gevşeterek, Detrüssör instabilitesini azaltarak, Mesane çıkım obstrüksiyonuna bağlı oluşan mesane duvar kalınlaşmasını azaltarak, semptomları düzeltir. Literatür 2

Alfa Adrenoreseptör Hedef Organları Alfa 1 A: Mesane boynu ve prostat düz kas Alfa 1 B: Arter düz kas Alfa 1 D: Mesane düz kas α -1A reseptör , alt üriner sistemdeki dominant reseptör alt tipidir. Düz kas kasılmasından temel sorumlu reseptör alt tipidir.

αlfa-adrenoreseptör hedef organlari Alfa- adrenoreseptörler Norepinefrin gerialımı Prostat selektif ? Prostat düz kas tonusu Vazokonstrüktör tonus Mesane Roger S Kirby: Atlas of prostatic diseaseas, s:52, 1997

Alt Üriner Sistemdeki αlfa-reseptörler mesane boynu ve üretrada yoğundur

Kanıtlanmış Etkinlikleri mevcuttur : ALFA BLOKERLER Kanıtlanmış Etkinlikleri mevcuttur : -IPSS (%30-40↓) -Akım hızı (%18-24↑) Çabuk Etkilidir (ilk 48 saatte), Semptomatik düzelme ilk 2-3 haftada oluşmaktadır. Madersbacher S,Marszalek.Europ. Urol.51 (2007)1522-1533

Avrupa’ da toplam 19 ülkede 11.6 milyon reçete %11-41 alfa bloker %2-20 5ARI %0-20 fitoterapi Cornu et.al. Eur. Urol. 2010

Avrupada Lisansli Alfa Blokerler Alfuzosin IR Alfuzosin SR Alfuzosin XL Doxazosin IR Doxazosin GITS Tamsulosin MR Tamsulosin OCAS Terazosin Silodosin

Tedavi Zamanlaması İPSS 0-7 Hafif 8-18 Orta 19> Şiddetli Yaşam kalitesi

IPSS semptom skoru 0-7 Hafif derecede semptomatik 8-19 Orta derecede semptomatik 20- 35 Ciddi derecede semptomatik

Tedavi Zamanlaması 456 olgu 5 yıl izlem %72.5 Tedavi yok %26 Medikal %1.5 TUR P Temml C 2003 European Urology, Volume 43, Issue 4, Pages 374-380

The natural history of lower urinary tract symptoms over five years. Temml C, Brössner C, Schatzl G, Ponholzer A, Knoepp L, Madersbacher S; Prostate Study Group of the Austrian Society of Urology. Source Department of Preventive Health, City of Vienna, Vienna, Austria. Abstract OBJECTIVES: To assess the natural history of lower urinary tract symptoms (LUTS) in a cohort of previously untreated men over five years. METHODS: Men participating in a health-screening project completed the International Prostate Symptom Score (IPSS) in 1996. In 2001, men older than 45 years with no prostate surgery or LUTS-specific medication before 1996 completed the IPSS plus a questionnaire on several aspects of LUTS. At the same time, all men underwent a health examination in 1996 and 2001. RESULTS: A total 456 men aged 52+/-12 years (range: 40-84) at baseline completed the 5-year follow-up. Mean IPSS increased from 4.6 to 5.5 (+20%; p<0.0001) and the IPSS-Ql from 0.8 to 1.1 (+38%; p<0.0001) over five years. Progression of IPSS and IPSS-Ql were highly correlated. No change of IPSS was reported by 19%, a worsening by 50% and an improvement by 31%. Not all aspects of LUTS progressed in a similar pattern, storage symptoms had a higher tendency to improve over time. Medical therapy was initiated in 7%, 39% and 67% of those with mild, moderate or severe LUTS at baseline, respectively. In a multivariate analysis age and degree of being bothered by LUTS were independent predictors for initiation of therapy. CONCLUSIONS: This 5-year longitudinal study of men without previous LUTS treatment demonstrates the slow nature of the disease's progression. Not all aspects of LUTS progress in a similar pattern. Initiation of therapy is influenced by patient age and by the degree of being bothered by LUTS.

Tedavi Zamanlaması 397 olgu İPSS < 8 AUR %4.9 Djavan 2004 Progresyon 24 ay %24 48 ay %31 AUR %4.9 TUR P %0.6 Djavan 2004 Urology Volume 64, Issue 6 , Pages 1144-1148, December 2004

Longitudinal study of men with mild symptoms of bladder outlet obstruction treated with watchful waiting for four years. Djavan B, Fong YK, Harik M, Milani S, Reissigl A, Chaudry A, Anagnostou T, Bagheri F, Waldert M, Kreuzer S, Fajkovic H, Marberger M. Source Department of Urology, University of Vienna, Vienna, Austria. bdjavan@hotmail.com Abstract OBJECTIVES: To determine the risk of clinical progressions in men with mild lower urinary tract symptoms of bladder outlet obstruction and identify the predictors for progression in this group of men. METHODS: A total of 397 men who presented to the urology clinics with mild symptoms of bladder outlet obstruction (International Prostate Symptom Score less than 8) were analyzed in this longitudinal study conducted during a 4-year period. They began with the watchful waiting protocol and were followed up every 3 months for 48 months. Age, International Prostate Symptom Score (IPSS), divided into obstructive symptom score and irritative symptom score, serum prostate-specific antigen level, total prostate volume, transitional zone volume, urinary flow rates, and postvoid residual urine volume were documented. RESULTS: The cumulative incidence of clinical progression, defined as worsening of the IPSS with migration to the moderate symptom group (IPSS 8 to 18) or severe symptom group (IPSS 19 to 35) and an increase in IPSS of more than 2 points, was 6%, 13%, 15%, 24%, 28%, and 31% at 6, 12, 18, 24, 36, and 48 months, respectively. Nineteen patients (4.9%) developed acute urinary retention within the 48-month follow-up period. Of these 19 patients, only 2 (0.6%) required transurethral resection of the prostate. The variables of importance for disease progression in the artificial neural network analysis were, in order of statistical significance, prostate-specific antigen level, obstructive symptom score, and transitional zone volume. CONCLUSIONS: The risk for men with mild symptoms of bladder outlet obstruction to progress clinically and develop complications such as acute retention of urine is moderate. Prostate-specific antigen, obstructive symptom score, and transitional zone volume were identified as important risk factors.

Tedavi Zamanlaması 2 yıl Alfa bloker % Plasebo AUR 2.1 1.8 Cerrahi 5.1 6.5 Semptom ↑ 11.7 16.8 Rooehrborn CG 2006 BJU Int. 2006 Apr;97(4):734-41

Alfuzosin 10 mg once daily prevents overall clinical progression of benign prostatic hyperplasia but not acute urinary retention: results of a 2-year placebo-controlled study. Roehrborn CG. Source University of Texas, Southwestern Medical Center, Dallas, TX, USA. Abstract OBJECTIVES: To evaluate the effect of alfuzosin 10 mg once daily administered for 2 years on progression events in men with lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH). PATIENTS AND METHODS: In all, 1522 men at risk of having progression events from LUTS/BPH were randomized to receive alfuzosin 10 mg once daily (759) or placebo (763) for 2 years. Endpoints assessed were the occurrence of a first episode of acute urinary retention (AUR; primary) and the need for BPH-related surgery. Post hoc analyses included a deterioration in the International Prostate Symptom Score (IPSS) of > or = 4 points and overall clinical progression of BPH (occurrence of AUR and/or surgery and/or symptom deterioration). RESULTS: Over 2 years, symptom deterioration was the most common progression event (14.3%), followed by BPH-related surgery (5.8%) and AUR (2.0%). Alfuzosin did not reduce the risk of AUR (alfuzosin 2.1% vs placebo 1.8%, P = 0.82) but tended to reduce the risk of surgery (5.1% vs 6.5%, P = 0.18); the reduction in risk (RR) and 95% confidence interval with alfuzosin was 22 (-18 to 48)%; and significantly reduced the risk of symptom deterioration (11.7% vs 16.8%; P = 0.0013); the RR was 30 (10-46)%. The overall clinical progression of BPH was significantly lower with alfuzosin than with placebo (16.3% vs 22.1%, P < 0.001); RR 26 (9-40)%. Alfuzosin also significantly improved the IPSS (P = 0.017), quality of life (P < 0.001) and peak flow rate (P = 0.001) compared with placebo. Baseline levels of prostate-specific antigen (PSA) predicted both AUR and BPH-related surgery events, while the baseline postvoid residual urine volume predicted symptom deterioration. The incidence of adverse events with alfuzosin was comparable to that with placebo. CONCLUSIONS: Alfuzosin 10 mg once daily prevents the overall clinical progression of BPH, defined by the occurrence of a deterioration in IPSS of > or = 4 points and/or AUR and/or BPH-related surgery, but does not reduce the primary occurrence of AUR. Alfuzosin significantly improves LUTS and quality of life over 2 years, and is well tolerated.

Alfa 1 Blokerin Seçimi Kardiyovasküler sorunlar Anormal ejakulasyon İntraoperatif gevşek iris sendromu Halsizlik Baş dönmesi Baş ağrısı Nazal konjesyon

Alfa Blokerlerin Yan Etkileri (%) Baş dönmesi Hipotansiyon (postural) Asteni Baş ağrısı RE IFIS 12 15 7 6 1 Terazosin Doxazosin Alfuzosin Tamsulosin Silodosin 15 13 8 4 - 4 6 5 1 - 7 12 12 3 10 < 1 - 3,2 2,4 2,6 28,1 ? AUA Guideline on Management of BPH , 2010

Sonuç Alfa blokerlerin karşılıklı veya plasebo kontrollü çalışmalarında: Etkinliğin hepsinde benzer olduğunu ancak yan etkilerinin farklı olduğunu, Her beş ilacında BPH tedavisinde kullanılabileceğini, Terazosin ve doksazosinde vazodilatasyon, halsizlik hipotansiyon ve başdönmesi gibi kardiovasküler yan etkilerin belirgin fazla olduğunu, Alfa blokerlerin hastalığın progresyonuna ( AUR gelişme riskini azaltma) etkisi olmadığını,

Sonuç Akut retansiyonlu hastaları kısa zamanda sondadan kurtarmak için alfuzosin veya tamsulosinin uygun bir seçim olacağını, Tolarabilitelerinin daha iyi olması ve doz ayarlaması gerektirmediğinden normotansif hastalarda Alfuzosin ve tamsulosin in BPH tedavisinde iyi bir seçim olabileceğini, Ejekülasyon bozukluğunun tamsulosin ve özellikle silodosinde Alfuzosin den daha fazla olduğunu, Tamsulosin de ejekulasyon bozukluğu ve IFIS (intraoperatif floppy iris sendromu) göz önüne alınarak şahsa göre (örneğin; katarakt cerrahisi) ilaç seçimi kararı verilmesi gerektiğini, Tedavi modalitelerine, hastanın kişisel durumu değerlendirilerek karar verilmesi gerektiğini söylemek mümkündür.

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