{"id":510,"date":"2017-05-02T09:41:33","date_gmt":"2017-05-02T06:41:33","guid":{"rendered":"https:\/\/tatd.org.tr\/tatdtoks\/2021\/09\/17\/n-asetil-sistein-kullanimi-yalniz-parasetamol-zehirlenmeleri-ile-sinirli-degildir\/"},"modified":"2021-11-10T22:35:24","modified_gmt":"2021-11-10T19:35:24","slug":"n-asetil-sistein-kullanimi-yalniz-parasetamol-zehirlenmeleri-ile-sinirli-degildir","status":"publish","type":"post","link":"https:\/\/tatd.org.tr\/toksikoloji\/2017\/05\/02\/n-asetil-sistein-kullanimi-yalniz-parasetamol-zehirlenmeleri-ile-sinirli-degildir\/","title":{"rendered":"N- asetil sistein kullan\u0131m\u0131 yaln\u0131z parasetamol zehirlenmeleri ile s\u0131n\u0131rl\u0131 de\u011fildir."},"content":{"rendered":"
\n\n\n
<\/td>\n1970\u2019 lerin ba\u015f\u0131nda bilim insanlar\u0131 parasetamol (asetaminofen) al\u0131m\u0131ndan sonra hayvan modellerinde k\u0131saca NAPQI olarak bildi\u011fimiz N-acetyl-p-benzoquinone imine metabolitinin birikti\u011fini tespit ettiler. Bu toksik metabolit normalde glutatyon ile konjuge edilir\u00a0ancak\u00a0 fazla miktarda parasetamol al\u0131nd\u0131\u011f\u0131 zaman\u00a0 (intihar ama\u00e7l\u0131 al\u0131m\u0131 gibi) v\u00fccuttaki glutatyon rezervi NAPQI tamam\u0131n\u0131 metabolize edemez. Sonu\u00e7ta hepatositlerde direkt nekroz geli\u015fir. Hatta altta yatan \u015fartlar uygun ise akut toksik hepatit dahi geli\u015febilir. Bu bilgi \u0131\u015f\u0131\u011f\u0131nda \u00a0glutatyon depolar\u0131n\u0131 parasetamol zehirlenmesi olan hastalarda art\u0131rarak tedavi etmek \u00a0veya akut hepatik toksiteyi \u00f6nlemek yollar\u0131 ara\u015ft\u0131r\u0131ld\u0131. \u00d6nce g\u00f6r\u00fcld\u00fc ki karaci\u011ferde glutatyon konsantrasyonunu art\u0131rmak i\u00e7in iki tedavi y\u00f6ntemi vard\u0131; ya metyonin veya sisteamin tedavisi yap\u0131labilirdi. Ancak her iki maddenin \u00f6nemli kendilerine ait yan etkileri mevcuttu. Flushing, bulant\u0131, kusmadan ba\u015flay\u0131p depresyona dek geni\u015fleyen yan etki spektrumlar\u0131 olan bu maddeler insanlarda tedaviye uygun bulunmad\u0131. Ancak \u00fc\u00e7\u00fcnc\u00fc madde olarak denenen N-acetylcysteine (NAC) ise major yan etkilere sebep olmadan karaci\u011ferdeki glutatyon depolar\u0131n\u0131 yenileyen bir antidot oldu.<\/td>\n<\/tr>\n<\/tbody>\n<\/table><\/div>\n

1988\u2019 de New England Journal of Medicine\u2019 de yay\u0131nlanan Smilkstein\u2019 in makalesi \u015fimdi de \u00f6nemli bir tedavi olan \u00a0NAC tedavisini ba\u015flatan bir yaz\u0131 oldu.\u00a0<\/strong>\u00a0Oral NAC tedavisi yap\u0131lm\u0131\u015f 2540 parasetamol zehirlenmesi hastas\u0131nda bu antidotun etkisi g\u00f6sterildi. \u00c7al\u0131\u015fmada AST veya ALT d\u00fczeyleri ciddi karaci\u011fer hasar\u0131 olan hastalarda kar\u015f\u0131la\u015ft\u0131r\u0131ld\u0131. Parasetamol al\u0131m\u0131ndan sonra 10 saat i\u00e7inde NAC tedavisi alanlarda %6.1 ve 10- 24 saat sonra NAC tedavisi alanlarda ise %26.4 oran\u0131nda AST veya ALT d\u00fczeylerinde istenmeyen etki olarak 1000 IU \u00fczerinde olacak \u015feklide art\u0131\u015f g\u00f6r\u00fcld\u00fc. Geri kalan hastalar ise NAC tedavisinden faydaland\u0131lar. Yani yazarlara g\u00f6re bu sonu\u00e7lar NAC tedavisine\u00a0 parasetamol zehirlenmesi olan hastalarda ilk 8 saat i\u00e7inde ba\u015flamak gerekti\u011fini \u00a0kan\u0131tl\u0131yordu.<\/p>\n

\"\"<\/p>\n

Daha sonra yap\u0131lan di\u011fer \u00e7al\u0131\u015fmalarda intraven\u00f6z NAC tedavisinin parasetamol ile ind\u00fcklenen karaci\u011fer yetmezli\u011finde faydal\u0131 oldu\u011fu g\u00f6sterildi. NAC tedavisinin mortaliteyi %21 azaltt\u0131\u011f\u0131 Lancet\u2019 te 1990 y\u0131l\u0131nda Harrison taraf\u0131ndan yay\u0131nland\u0131. Plasebo kontrollu yapt\u0131\u011f\u0131 \u00e7al\u0131\u015fmada ise Keays ve arkada\u015flar\u0131 NAC\u2019\u0131n mortaliteyi azaltmas\u0131n\u0131n yan\u0131nda serebral \u00f6demi ve inotrop gerektiren \u015fiddetli hipotansiyon tablosunu parasetamol zehirlenemesinde azaltt\u0131\u011f\u0131n\u0131 yazd\u0131. NAC tedavisini glutatyon depolar\u0131n\u0131 d\u00fczeltmesi yan\u0131 s\u0131ra antienflamatuar, antioksidan, inotropik ve vazodilatasyon etkileri oldu\u011fu, vital organlarda mikrovaskuler dola\u015f\u0131m\u0131 d\u00fczeltti\u011fi de g\u00f6sterildi. Bu bilgiler sonucunda doksanl\u0131 y\u0131llardan beri t\u00fcm d\u00fcnyada parasetamol zehirlenmesinde NAC antidot olarak kullan\u0131ma girmi\u015ftir.<\/p>\n

NAC bu kadar etkili olarak parasetamol zehirlenmelerinde kullan\u0131labiliyorsa acaba di\u011fer parasetamol d\u0131\u015f\u0131 toksik hepatit veya karaci\u011fer yetmezli\u011fi tablosunda kullan\u0131labilir mi?<\/strong><\/p>\n

Bu soru \u00f6zellikle gastroenteroloji biliminde s\u0131k g\u00fcndeme geliyor. Akut karaci\u011fer yetmezli\u011fi nedenlerine bak\u0131l\u0131rsa ABD s\u0131ralama \u015f\u00f6yledir; parasetamol %50, idiosinkratik ila\u00e7lar %12, hepatit B %7, otoimmun hepatit \u00a0%5 ve \u00a0hepatit A %3. Ancak hastalar\u0131n yakla\u015f\u0131k %15\u2019\u00a0 inde neden bulunam\u0131yor. Bu hastalar\u0131n hepsinin de Acil T\u0131p ile ilgili oldu\u011funu da hat\u0131rlatmak isterim \u00e7\u00fcnk\u00fc ya acil servise direkt \u00a0ba\u015fvuruyorlar veya tedavilerinin bir k\u0131sm\u0131nda acil t\u0131p kliniklerinde bulunuyorlar.\u00a0 Parasetamol d\u0131\u015f\u0131 nedenlerden dolay\u0131 olu\u015fan akut karaci\u011fer yetmezli\u011finde olan hastalar \u00a0antidot \u015fans\u0131 olmad\u0131\u011f\u0131 i\u00e7in y\u00fcksek morbidite ve mortalite oranlar\u0131na sahiptirler.<\/p>\n

2009 y\u0131l\u0131nda yap\u0131lan \u00e7al\u0131\u015fmada Parasetamol d\u0131\u015f\u0131 akut karaci\u011fer yetmezli\u011fi olan 47 hastada NAC denenmi\u015f ve NAC alan hastalarda almayan hastalara g\u00f6re (53.2% versus 72.7%, p=0.05) daha az mortalite saptanm\u0131\u015ft\u0131r. Ayr\u0131ca Lee ve arkada\u015flar\u0131 taraf\u0131ndan yap\u0131lan ve a\u015fa\u011f\u0131da tasar\u0131m\u0131 bulunan \u00a0\u00f6nemli bir \u00e7al\u0131\u015fmada NAC kullan\u0131m\u0131n\u0131n karaci\u011fer transplant\u0131 gereksinimi s\u00fcresi \u00fczerinde olumlu\/ olumsuz\u00a0 etkisi ara\u015ft\u0131r\u0131lm\u0131\u015ft\u0131r (\u015eekil 1)<\/strong>. Transplant aday\u0131 olan 173 hastada plasebo kontrollu sonu\u00e7lara g\u00f6re NAC tedavisi alanlarda transplant olmadan \u00a0ya\u015fam s\u00fcresi plaseboya g\u00f6re daha uzundur (40% versus 27%, p=0.043). Alt gruplar\u0131n Kaplan- Meier e\u011frisine g\u00f6re da\u011f\u0131l\u0131m\u0131 a\u015fa\u011f\u0131dad\u0131r (\u015eekil 2).<\/strong><\/p>\n

\"\"
\n\u015eekil 1<\/em><\/strong>. Lee ve arkada\u015flar\u0131 taraf\u0131ndan tasarlanan \u00e7al\u0131\u015fma \u015femas\u0131. Gastroenterology. 2009;137(3):856-864<\/em><\/p>\n

\"\"
\n\u015eekil 2.<\/em><\/strong> Hastalar\u0131n alt gruplar\u0131na g\u00f6re 365 g\u00fcn i\u00e7inde transplantasyon veya \u00f6l\u00fcm oranlar\u0131. Burada Kaplan Meier e\u011frisinde\u00a0 g\u00f6r\u00fcld\u00fc\u011f\u00fc gibi en iyi ya\u015fam s\u00fcresi mavi \u00e7izgi ile g\u00f6sterilen NAC I-II grubudundad\u0131r.\u00a0 Di\u011fer \u00fc\u00e7 grup ile k\u0131yasland\u0131\u011f\u0131 zaman transplant olmadan ya\u015fam s\u00fcresi en fazla bu gruptad\u0131r; p= 0.017.<\/em><\/p>\n

Ayn\u0131 kohortta yap\u0131lan sub- grup analizinde\u00a0 g\u00f6r\u00fclm\u00fc\u015ft\u00fcr ki NAC\u2019\u0131n bu koruyucu etkisi West Haven ensefalopati Koma \u00a0grade I-II hastalarda daha ileri klinik tablolara g\u00f6re daha anlaml\u0131d\u0131r. 2013\u2019 te ise Singh yine ayn\u0131 kohort i\u00e7in bir analiz daha yapt\u0131 Koma grade I-II ile Koma III-IV gruplar\u0131n\u0131 k\u0131yaslad\u0131\u011f\u0131nda \u015fu sonuca ula\u015ft\u0131: Grade I-II olan grupta NAC tedavisi ile bilirubin ve ALT d\u00fczeyleri \u00f6nemli bir \u015fekilde d\u00fczelmektedir. Bu kohortta Grade II- IV say\u0131lar\u0131 analiz i\u00e7in k\u00fc\u00e7\u00fck oldu\u011fundan sonu\u00e7lar \u00a0ne yaz\u0131k ki pek \u00f6nemli bulunmad\u0131.<\/p>\n

\"\"Ancak en son 2015\u2019 te Hu ve arkada\u015flar\u0131 bir\u00a0 meta-analiz yapt\u0131. D\u00f6rt klinik \u00e7al\u0131\u015fmadan elde ettikleri 331 NAC tedavisi alan hasta\u00a0 ile 285 kontrol hastas\u0131n\u0131n verilerini k\u0131yaslad\u0131klar\u0131 zaman\u00a0 \u015fu sonu\u00e7lara ula\u015ft\u0131lar;<\/p>\n

    \n
  1. NAC alan hastalar ile kontrol gurubu aras\u0131nda sa\u011f kal\u0131m fark\u0131 yoktur [71% versus 67%; 95% CI, 1.16 (0.81-1.67); p=0.42].<\/li>\n
  2. Ama \u00e7ok \u00f6nemli derecede karaci\u011ferin sa\u011fl\u0131kl\u0131 kal\u0131m\u0131 [41% versus 30%; 95% CI, 1.61 (1.11-2.34); p=0.01] g\u00f6zlenmi\u015ftir.<\/li>\n
  3. Transplantasyon sonras\u0131 sa\u011f kal\u0131m ise hastalarda artmaktad\u0131r\u00a0 [85.7% versus 71.4%; 95% CI, 2.44 (1.11-5.37); p=0.03].<\/li>\n
  4. NAC tedavisi sonucunda \u00a0kar\u015f\u0131la\u015f\u0131lan gastrointestinal yan etkiler hesaba al\u0131nd\u0131\u011f\u0131nda parasetamol d\u0131\u015f\u0131nda nedenlerden dolay\u0131 akut karaci\u011fer yetmezli\u011fi olan hastalarda Yarar\/Zarar oran\u0131 NAC kullan\u0131m\u0131 lehinedir.<\/li>\n<\/ol>\n

    The American Association for the Study of Liver Diseases (AASLD)<\/strong> bu konuda \u00f6nerilerini \u015f\u00f6yle s\u0131ralamaktad\u0131r:<\/p>\n

      \n
    1. NAC kullan\u0131m\u0131 akut karaci\u011fer yetmezli\u011fi vakalar\u0131nda e\u011fer etken muhtemelen parasetamol ise \u00f6nerilir (D\u00dcZEY III \u00f6neri)<\/strong><\/li>\n
    2. Aminotransferaz enzimlerinin y\u00fcksek oldu\u011fu ve e\u011fer parasetamol zehirlenmesini bize hat\u0131rlatan durum varsa uygulan\u0131r (D\u00dcZEY III \u00f6neri).<\/strong> Burada ek bir konuya dikkat \u00e7ekmek isterim Parasetamol d\u00fczeyi bak\u0131lmas\u0131 ile ilgili bir \u00f6neri yok. Sadece klinik \u015f\u00fcphe mevcut ise uygulama m\u00fcmk\u00fcn.<\/em><\/strong><\/li>\n
    3. AASLD \u00f6nerisine g\u00f6re\u00a0 (D\u00dcZEY I)<\/strong> t\u00fcm ilaca ba\u011fl\u0131 akut karaci\u011fer yetmezliklerinde \u00a0(toksik hepatit tablolar\u0131) NAC tedavisi faydal\u0131d\u0131r.<\/li>\n<\/ol>\n

      SONU\u00c7:<\/strong><\/p>\n

      \u00c7e\u015fitli yazarlar \u00f6zellikle bu \u00f6nerilerden\u00a0 dolay\u0131 hastalar\u0131n ilk ba\u015fvurdu\u011fu acil servislerde Parasetamol d\u0131\u015f\u0131 nedenler ile olu\u015fan akut karaci\u011fer yetmeli\u011finde de \u00a0NAC tedavisini \u00f6neriyorlar. Acil T\u0131p \u00e7al\u0131\u015fanlar\u0131 olarak bizlerin West Haven ensefalopati Koma \u00a0grade I-II de NAC tedavisi ba\u015flamam\u0131z ve \u00f6zellikle karaci\u011fer nakline kadar bekleme s\u00fcresine katk\u0131da bulunmam\u0131z \u00f6zellikle \u00f6nerilmektedir. \u00d6zellikle toksik hepatit ve buna ba\u011fl\u0131 ensefalopatide NAC tedavisini AASLD \u00f6nerisi ile uygulayal\u0131m.<\/p>\n

      Kaynaklar:<\/strong><\/p>\n

        \n
      1. Mitchell JR, Jollow DJ, Potter WZ, et al. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther. 1973;187(1):211-7.<\/li>\n
      2. Prescott LF, Sutherland GR, Park J, et al. Cysteamine, methionine, and penicillamine in the treatment of paracetamol poisoning. Lancet. 1976;2(7977):109-13.<\/li>\n
      3. Prescott LF, Newton RW, Swainson CP, et al. Successful treatment of severe paracetamol overdosage with cysteamine. Lancet. 1974;1(7858):588-92.<\/li>\n
      4. Smilkstein MJ, Knapp GL, Kulig KW, et al. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988;319(24):1557-62. (98)70501-3\/references<\/li>\n
      5. Harrison PM, Keays R, Bray GP, et al. Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Lancet. 1990;335(8705):1572-3.<\/li>\n
      6. Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ. 1991;303(6809):1026-9.<\/li>\n
      7. Lee WM. Etiologies of acute liver failure. Semin Liver Dis. 2008;28(2):142-52.<\/li>\n
      8. Fontana RJ, Hayashi PH, Gu J, et al. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014;147(1):96-108.e4.<\/li>\n
      9. Harrison PM, Wendon JA, Gimson AE, et al. Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med. 1991;324(26):1852-7.<\/li>\n
      10. Mumtaz K, Azam Z, Hamid S, et al. Role of N-acetylcysteine in adults with non-acetaminophen-induced acute liver failure in a center without the facility of liver transplantation. Hepatology International. 2009;3(4):563-570.<\/li>\n
      11. Lee W, Hynan L, Rossaro L, et al. Intravenous n-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009;137(3):856-864.<\/li>\n
      12. Singh S, Hynan LS, Lee WM, et al. Improvements in Hepatic Serological Biomarkers are Associated with Clinical Benefit of Intravenous N-Acetylcysteine in Early Stage Non-Acetaminophen Acute Liver Failure. Digestive diseases and sciences. 2013;58(5):1397-1402.<\/li>\n
      13. Hu J, Zhang Q, Ren X, et al. Efficacy and safety of acetylcysteine in \u201cnon-acetaminophen\u201d acute liver failure: A meta-analysis of prospective clinical trials. Clin Res Hepatol Gastroenterol. 2015; 39(5):594-9.<\/li>\n
      14. Lee WM, Larson AM, Stravitz RT. AASLD<\/strong> position paper: the management of acute liver failure: update 2011. Hepatology. September 2011.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

        Prof. Dr. Arzu Denizba\u015f\u0131<\/em><\/p>\n

        1970\u2019 lerin ba\u015f\u0131nda bilim insanlar\u0131 parasetamol (asetaminofen) al\u0131m\u0131ndan sonra hayvan modellerinde k\u0131saca NAPQI olarak bildi\u011fimiz N-acetyl-p-benzoquinone imine metabolitinin birikti\u011fini tespit ettiler. Bu toksik metabolit normalde glutatyon ile konjuge edilir ancak fazla miktarda parasetamol al\u0131nd\u0131\u011f\u0131 zaman (intihar ama\u00e7l\u0131 al\u0131m\u0131 gibi) v\u00fccuttaki glutatyon rezervi NAPQI tamam\u0131n\u0131 metabolize edemez<\/p>\n","protected":false},"author":1538,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"inline_featured_image":false,"_lmt_disableupdate":"","_lmt_disable":"","footnotes":""},"categories":[10014],"tags":[222,296,396],"class_list":["post-510","post","type-post","status-publish","format-standard","hentry","category-akademik-blog-yazisi","tag-karaciger","tag-n-asetil-sistein","tag-toksik"],"acf":[],"_links":{"self":[{"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/posts\/510","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/users\/1538"}],"replies":[{"embeddable":true,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/comments?post=510"}],"version-history":[{"count":0,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/posts\/510\/revisions"}],"wp:attachment":[{"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/media?parent=510"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/categories?post=510"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/tags?post=510"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}