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1 약인성간손상 개원의연수강좌 분당서울대학교병원내과정숙향

2 약인성간손상의중요성 2002년, 등록된 chemical 수 > 360만개, 매일 400개이상등록추가 미국 FDA approved drugs > 1만개 대체보완요법의사용빈도증가 약인성간손상증례는앞으로지속적으로증가할것임 입원환자의황달원인중 2% 는약제에의함 급성간부전례의 20% 정도가약제에의함 약인성간손상은거의모든종류의간질환으로나타날수있음

3 급성간부전에서약인성간손상의중요성 AAP/ Other Drugs HAV/ HBV Shock/ Others Indeter Argentina, 96-01, n=83 0 / 14% 8 / 22% 0 / 31% 25% Denmark, 73-90, n= / 17% 2 / 31% 3 / 13% 15% France, 72-90, n=502 2 / 17% 4 / 32%? / 27% 18% India, 87-93, n=423 0 / 5% 2 / 31% 0 / 62% 0 Japan, 92-99, n=38 0 / 0 3 / 18% 0 / 8% 71% UK, 93-94, n= / 2% 2 / 2% 3 / 9% 8% USA, 94-96, n= / 12% 7 / 10% 3 / 33% 15% USA, 98-01, n= / 13% 4 / 7% 6 / 15% 17%

4 약의간내대사과정 Uptake: sinusoidal mb. TP Metabolism Canalicular mb. TP Phase I (CYPs) :SER toxification Phase II (conjugation) : cytosol detoxification Phase III (efflux)

5 약인성간손상의병인론 (1) Drug metabolite Covalent binding Oxidative stress Metabolite Haptenization Mitochondria Bioenergetic Catastrophe: ATP Organellar stress, Altered signal transduction/ gene exp. Mitochondria Adaptive / Innate immune response sensitization Necrosis Apoptosis

6 약인성간손상의병인론 (2) 내인성간독성 용량-의존적 예측가능 재현가능 간소엽의특정부위침범 짧은잠복기 ( 수시간-수일 ) 예 : acetaminophen 특이반응성간독성 용량 - 비의존적 예측불가능 치료용량에서도가능 긴잠복기 ( 수주 - 수개월 ) 면역학적특이반응 대사성특이반응 ( 대사효소장애, 유전적다형성 ) 예 : phenytoin, INH

7 약인성간독성의병인론 (3) 약제에의한요인 toxic potential, reactive metabolite, mitochondria effects 숙주에의한요인 Age Gender Race Renal ds, Liver ds, Obesity, HIV/AIDS Alcohol Genetic polymorphism or defects: P450 2D6(perhexiline maleate), Urea cycle(valproate), mitochondrial beta-oxidation(valproate, ASA), UDP glucuronosyl transferase(aap)

8 약인성간손상의임상양상 by CIOMS (Council for International Organization of Medical Sciences) 간손상 : ALT, 총빌리루빈, ALP 중하나이상이정상상한치의 2 배이상인경우 급성 / 만성약인성간손상 : 3(-6) 개월기준 심한간손상 : 황달, PT 연장 (INR>1.5), 간성혼수 ALT Hepatitis Cholestasis ALP (Alkaline P-tase) Mixed >2N in ALT alone or ALT/ALP ratio 5 >2N in ALP alone or ALT/ALP ratio 2

9 약인성간손상의병리양상 Acute Hepatitis acetaminophen Isoniazid, halothane ketoconazole troglitazone Acute Cholestasis augmentin/ EM sulindac/piroxicam estrogen allopurinol NASH MTX amiodaron tamoxifen valproate Chronic Hepatitis methyl dopa MTX nitrofurantoin minocycline Chronic Cholestasis (ductopenic) Same Others VOD (ChemoTx) Tumors (estrogen, aflatoxin, vinyl chloride)

10 약인성간독성의진단 (1) 간기능이상환자에서복용한약에관한병력을자세히얻을것 정확한진단보다는의심되는약물을빨리찾아내어늦기전에약을중단하는것이중요함

11 약인성간독성의진단 (2) 임상적특징과잠복기 : 복용후 5-90 일이내발생 약을중단했을때호전여부 : 중단후 8 일이내 ALT 50%, Bilirubin 50% 감소 다른원인에의한간손상을배제 : 바이러스성간염, 자가면역성간염, 담도페쇄성질환, 대사성질환등 ( 의도치않은 ) 재투여시악화 상황증거에근거한진단이라정확성이떨어짐 Scoring system RUCAM scoring system, Maria/ Victorino system

12 RUCAM Scoring System: CIOMS scale (Council for International Organizations of Medical Sciences) Rousel UCLAF Causality Assessment Method latency : 투여시작후 5-90day/ 투여종료후 15day rate of resolution on withdrawal : ALT/ALP 50% reduction for 8d/1mo. risk factors: alcohol, old age concomitant drugs exclusion of competing causes : viral hepatitis, bile duct obstruction, alc. etc tract record of the drug response to rechallenge Probability of association between drug and liver injury: Score range: -5 ~ +14 Exclude -5-0, Unlikely 1-2, Possible 3-5 Probable 6-8, Highly probable >8

13 독성간손상 : 우리나라다기관연구 , 7 개대학병원, 입원한독성간염환자 76 명 나이 : 54 ± 28 (23-81 세 ), 남녀비 : 26/50 원인 : 한약 (44.7%), 한약재 (13.2%) 민간요법, 건강식품 (25.0%) 약국매약 (1.3%), 의사처방 (14.5%), 불명 (1.3%) 복용기간 : 43 ±82 (2-163 일 ) 검사소견 : AST 907 ( ), ALT 996 ( ), ALT 304 ( ), TB 8.8 (0.5-41) RUCAM score: 7.5 ±3.2 (4-11) 사망례 : 2/72 : CH-B+herb, Anti-Tbc med+herb

14 Acetaminophen (AAP) (1) AAP Conjugation : sulfate glocuronate CYP450: 2E1, 1A2, 3A4 NAPQI: Toxic metabolite Conjugation with GSH ->Cysteine derivatives Covalent binding to cell proteins Oxidative stress Renal excretion Cell death Disruption of cell Ca++ homeostasis NAPQI:N-acetyl- p-benzoquinone imine GSH: glutathione

15 Acetaminophen (AAP)(2) 어른에서는 7.5g 이상복용시간독성유발, 20g 이상복용시사망 2-6g 을수개월 - 수년복용시에만성간독성예도있음 병리적으로는 zone 3 necrosis, 염증반응은거의없음 간독성을악화시키는요인 금식, 음주, 동시복용약제 (isoniazid, phenytoin, phenobarbital, carbamazepine, zidovudine, etc.) FDA guideline: not use after consuming > 3 drinks (alcohol 36g) daily 어린이, 일찍발견되어해독제사용한예에서예후가좋음 복용후 시간이내 N-acetylcystein 을주면예후가좋음

16 Acetaminophen (AAP)(3) 임상양상 복용후 24 시간 : nausea, vomiting, diaphoresis 복용후 2-4 일 : 무증상 (latency period) 복용후 3-10 일 : 간부전, 신부전 회복기혹은사망 Serum AAP level correlates with liver damage 치료 위장세척 ( 복용후 1-3 시간 ) N-acetylcysteine PO/ IV within 16hr of ingestion Stimulate hepatic production of reduced glutathione PO: 140mg/kg 70mg/kg q 4hr x 17 doses Rash, diarrhea, anaphylactoid reaction Methionine (2.5g loading 2.5g q 4hr x 4), cimetidine

17 NASID/ COX-2 inhibitor/ Anti-rheumatoid Aspirin: >2-6g/day, pt s having connective ts.ds.( 고위험군 ) * Reye s synd.: microvesicular hepatic steatosis, acute encephalopathy, inborn error of mitochondrial enzymes 대부분 NASIDs: idiosyncratic, hepatocellular injury, 복용중단하면예후는양호함 Celecoxib: 다른 NASID보다간독성빈도가낮은편 Allopurinol: systemic side effect에비해간독성은드문편, 복용후 1-5주후에발진, 발열, 호산구증다증등을동반, 병리적으로 granuloma 형성 Methotrexate: stellate cell activation, hepatic fibrosis, 간조직검사상중등도이상의간섬유화가있을시는반드시중단

18 Anti-microbials/Anti-Tbc drugs Amoxicillin-clavulinic acid (cholestasis), oxcillin Cephalosporin: extremely rare Erythromycin, Quinolones: cholestasis Tetracyclin, minocyclin: microvesicular steatosis, AIH-like Ketoconazole, fluconazole, terbinafine: hepatocellular injury Isoniazid: 첫 3개월에 10-20% 의환자에서 ALT상승, 약을계속써도대부분정상화됨, 고령, 과음주자, HBV, HIV 감염자에서위험 Rifampin: potent CYP450 inducer, inhibitor of bilirubin uptake, isoniazid 간독성을증가시킴 Pyrazineamide: 항결핵제중에서가장간독성이큼. INF+RFP+PZA 함께쓰면간독성악화

19 Hypolipidemic/ Anticoagulants HMG-CoA Reductase (Statin) Dose-related, LFT abnormality in 5% for simvastatin, pravastatin No reports with cerivastatin, fluvastatin LFT monitoring: cost-effective? Fibrates Cholestasis, hepatitis, granulomatous change Mitochondrial damage, lithogenic (cholesterol gallstones) Niacin/ Nicotinic acid Dose-related, sustained- release form 에서심한경향 Heparin/ Coumarin derivatives

20 Anti-Hypertensive/-arrythmic Drugs ACEI / ARA: cholestatic injury Beta-Blocker: rare, labetalol (hepatocellular) Calcium-channel blocker: rare Diuretics: very rare Methyl-dopa safe in pregnancy, acute hepatocellular injury-chronic hepatitis resembling autoimmune hepatitis with autoimmune phenomena Hydralazine Safe in pregnancy, hepatocellular type * Amiodarone Phospholipidosis, pseudoalcoholic liver ds. with steatosis

21 Estrogens cholestasis cholesterol gallstone formation Hormones hepatic tumors (adenoma, FNH, carcinoma?, hemangioendothelioma) Budd-Chiari synd. Tamoxifen: NASH, cholestasis Androgens: cholestasis, peliosis, hepatic tumors Glucocorticoids : steatosis/ NASH Anti-thyroid drugs PTU: LFT abnormality in 25% with fever, rash, arthralgia Methimazole: cholestasis

22 Oral hypoglycemic agents Sulfonylurea: 투여 1 개월내발생, rare, cholestatic type Biguanide: rare, cause lactic acidosis/ low hepatotoxicity α-glucosidase inhibitor: ALT >3N in 3% Thiazolidinediones: PPAR-γ agonists Troglitazone: fatal hepatotoxicity, withdrawn from market Rosiglitazone: case of ALF+ Pioglitazone: less hepatotoxicity Monitor LFT q 2Mo for the 1st 12Mo. Discontinue if ALT>3N Effect of monthly monitoring: questionable

23 그외상용약제 위산분비억제제 H2 blocker: cholestasis, hepatitis, CMT > Ranitidine, Famotidine PPI: rare 항히스타민제 Cetrizine, terfenadine, chlorpheniramine

24 한약, 민간요법등에의한간손상 Pyrrolizidine alkaloids: VOD (Venoocclusive disease) Senecio, symphytum(comfrey), Crotalaria, Heliotropium 체중감량용약제 Germander(Teucrium), lipokinetix, 중국산체중감량식품 중국산한약재 기타 작약, 용담, 시호, 백선, 마황, 진부환, 황련, 등 Greater celandine( 애기똥풀추출물 ) Pennyroyal oil( 박하 ) Ackee fruit, artichoke( 채소뿌리일종 ), kava, cycasin( 소철류열매성분 ), senna( 변비치료제 ), mistletoe( 겨우사리 ), Chaparral( 떡갈나무일종 )

25 건강기능식품과타약제간의약물상호반응의예 St. John s wort (Hypericum perforatum) Used as antidepressant Hyperporin binds to nuclear receptor (PXR) CYP3A4, MDR1 expression interaction with cyclosporin; lower blood conc. in liver transplantation recipient organ rejection risk Grapefruit juice, lime juice Bergamottin ingredient: Suppression of CYP3A4 digoxin toxicity

26 간손상이없는한약재 Aloe: wound healing Chamomile: insomnia, antiseptic Cranberry: urinary tract infection Dandelion root: diuretic Feverfew: arthritis, migraines Garlic: cholesterol-lowering, anti-hypertensive Ginger: concentration, increase stamina Gingko biloba: memory improvement, claudication Ginseng: stimulant Peppermint: analgesic Glucosamine; arthritis

27 내용정리 날로증가하는약제사용과함께약의주대사기관인간손상도증가하고있다. 처방약제의간손상가능성을염두에두고, 간손상을조기진단하여원인약제를조기중단하는것이중요하다. 여러약물간의상호작용, 대체요법제의사용도의사가관리해야할부분이다.

28 약물정보탐색에유용한사이트

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<B0E6C8F1B4EBB3BBB0FAC0D3BBF3B0ADC1C E687770> 개원의와함께하는임상강좌 2011 신기능저하환자에서의약물처방 경희대학교의과대학신장내과학교실 정경환 내용 1. 국내만성콩팥병환자현황 2. 만성콩팥병환자에서의약물대사 3. 신기능의판단 4. 신기능감소에따른약물처방의실제 국내만성콩팥병환자현황 68 개원의와함께하는임상강좌 2011 정경환 : 신기능저하환자에서의약물처방 Prevalence of ESRD, 2008 1031.6