Nephrotoxicdrugs-台湾肾脏医学会课件.ppt

1、Nephrotoxic Drugs中國醫藥大學北港附設醫院曾裕雄 全民健康保險雙月刊第85期(99年5月號)台灣腎臟病現況 腎臟病已成台灣新國病，洗腎人數突破6萬人 扣除死亡，每年約以2,000人的速度淨增加 全球慢性腎臟病盛行率為10-12，台灣為11.9，亦即平均每10人中至少有1人罹患慢性腎 溫啟邦研究室,2008 43是糖尿病患合併症、腎絲球腎炎占20，高血壓合併症占15，不當用藥及老化占12，其他原因占10Drugs cause approximately 20 percent of community-and hospital-acquired episodes of acute

2、renal failureCynthia A.Naughton,PharmD,BCPS North Dakota State University College of Pharmacy,Nursing,and Allied Sciences in FargoPossible Mechanisms Altered intraglomerular hemodynamics Tubular cell toxicity Inflammation Crystal nephropathy Rhabdomyolysis Thrombotic microangiopathy.Risk Factors-pat

3、ients Age&Sex Previous renal disease DM,multiple myeloma,lupus,Proteinuric disease Salt retaining disease(liver cirrhosis,heart failure)Acidosis or K or Mg depletion Hyperuricemia or hyperuricosuria Kidney transplantationRisk factors-Drugs Inherent nephrotoxic effects Dose During,frequency,and form

4、of administration Repeated exposure Drug intoxicationOlderMultiple comorbilities&DrugsDiagnostic&therapeutic procedures The situation We meetAcute interstitial nephritis Etiology:Drug Antibiotic NSAIDs Diuretics:furosemide,Thiazide Cimetidine Allopurinol Proton pump inhibitor Infection:Idiopathic Au

5、toimmune disease Sarcoidosis,SLE,Sjogrens syndrome Tubulointerstitial nephritis and uveitis(TINU)syndromeDrug induced interstitial nephritis Diagnosis Renal biopsy History of drug exposure 3-5 days after second exposure Several weeks to many months after first exposure Rifampin:One day NSAIDs:18 mon

6、ths S/S:Allergic Urine sediment White cell Red cell White cell castsAllergic interstitial nephritis An idiosyncratic reaction Antibiotic are the most common causes Penicillins Cephalosporins Fluoroquinolone Symptoms and signs Rash Fever Eosinophilia Triad:10%Progressive renal failureNephrotoxic drug

7、s Antibiotics Chemotherapy and Immunosuppressants Heavy Metals Anti-Hyperlipidemics Chemotherapy Miscellaneous Drugs Drugs of abuseAntibiotics Aminoglycosides Sulfonamides Amophotericin B Levofloxacin Rifampin Tetracycline Acyclovir Pentamidine Penicilline Cephalosporine CiprofloxacinAminoglycosides

8、 Pathogenesis Tubular cell toxicity Risk factors:Duration of therapy is 10 days Trough concentrations 2 g/mL maintaining trough levels at 1 g/mL or less GentamicinAmikin,Tobramycin Prevention:Single daily doseSulfonamides Crystal nephropathy Insoluble in acid urine Risk:7%in pH 7.15 Sulfadiazine sol

9、ubility more than 20-fold Amphotericin B Pathogenesis Tubular cell toxicity Renal vasocontriction Dose-dependent nephrotoxicity Irreversible if cumulative dose 4g Rates of acute renal failure 49%-65%15%:hemodialysis Prevention:Liposomal formulation(AmBisome)Stop if 25%increment of serum CrAcyclovir

10、Crystal nephropathy Most common:Ua and Acyclovir Ganciclvir:little or no risk Birefringent needle-shaped acyclovir crystals can be seen in the urine Complete recovery typically occurs within four to nine days after acyclovir is discontinued Prevention Prior hydration:urine output75 ml/h Slow drug in

11、fusion for 1-2 hrsChemotherapy and Immunosuppressants Cisplantin Methotrexate Mitomycin Cyclosporine IfosphamideCisplantin Pathogenesis Tubular cell toxicity Proximal tubule(S3)：fanconi like syndrome Vasoconstriction Proinflammation Dose dependent Prevention Carboplatin:less nephrotoxic analog Isoto

12、nic saline 1000cc of isotoic saline+20 meg KCl+2g MgSO4 1000cc 2-3 hrs before cisplatin treatment 500 cc 2 hrs after cisplatin treatmentMethotrexate Crystal nephropathy 90%excreted unchanged in urine Insoluble in acid urine Poor dialyzable and large volume distribution Reversible in almost all cases

13、 within one to three weeks Prevention Hydration Urine pH7.0 Increase solubility as much as 10 fold 1000 cc D5W+44-66 meg NaHCO3 3 L/day 12 hrs befor and 24-48 hrs afterMitomycin-C Thrombotic microangiopathyCyclosporine&Tacrolimus Pathogenesis Altered intraglomerular hemodynamics Thrombotic microangi

14、opathy Acute nephrotoxicity Oliguric TIN Dose dependent Chronic nephrotoxicity Less dose dependentHeavy Metals Lead Cadmium Mercury Lithium Arsenic Bismuth為何藥物,毒物,重金屬容易傷害腎臟 High Blood Flow Increase delivery to kidney Organic solute and ion transporters Increase entry to renal parenchyma Intracellula

15、r xenobiotic metabolizing enzymes Local release of toxic metabolites Concentrate urine Facilitate precipitation or crystallization為何重金屬容易傷害腎臟 Defense mechanisms of the Kidney Glutathione(GSH)Bind free metals via sulfhydryl groups GSH-Metal in the kidney release Metal to entry into cell Induced by g-

16、glutamyltransferase/cysteinyl glycinase Metallothionein(MT)Low molecular weight protein rich in cysteinyl residues MT-Metal in liver deliver slowly to kidney Release metal in kidneyHeavy Metal nephropathyAcute Renal failureNephrotic syndromeChronic interstitial nephritisArsenic 砷 BismuthBismuthBismu

17、th鉍GoldCadmiumCadmium鎘MercuryChromiumChromium鉻Nickel鎳CopperCopper銅IronGoldLeadIronLithiumLeadMercuryMercuryPlatinum鉑SilverSiliconUranium鈾UraniumLead nephropathy Most common and nephrotoxic metal Lead&Cadmium Environment and industry USA:removed from gasoline(since 1973)and house paint(1978)Toxic blo

18、od level Decrease with timeNHANES1976-19801988-19911999-2002Mean blood lead level (Ug/dl)12.82.81.64AdultChild80 mg/dl40mg/dlLead nephropathy Acute Renal failure Chronic interstitial nephritis Proximal tubule Nuclear inclusion body in proximal tubule Absent or minimal albuminuria Hyperuricemia Inhib

19、it uric acid secretion 50%have goutLead nephropathyRenal failureGoutHypertensionExposureChronic Lead toxicity-Diagnosis Bone X-ray fluorescence EDTA stimulation Test 1 gm x2 Collect urine Result Positive:650 mgNormal GFRCr1.5 mg/dl24 hr urine48-72 urineCadmium ToxicityAcuteChronicPulmonary FailureGI

20、 toxicityBone:Mixed OsteoporosisAnd osteomalaciaKidneyCancer日本神通川(Jinzu river)鎘污染 -1950痛痛病 Itai-Itai disease(Ouch ouch disease)痛痛病 Itai-Itai disease 三井金屬礦業經營的富山縣神岡礦山,大量排放鎘，導致神通川及其支流的污染 直至1955年，鎘才被荻野昇醫生和同僚懷疑是致病的原因。荻野醫生也創造了痛痛病一詞Cadmium nephropathy Environment and industry Proximal tubule Fanconi syndr

21、ome Type 1 RTA Hypercalciuria Excretion of tubular protein Beta 2-microglobulin retinol binding protein alfa 1-microglobulin NAG(N-acetyl-b-D-glucosaminidase)Outcome:irreversibleNephrolithiasisMercury The principal organ systems the central nervous system:ataxia,tremor,brain atrophy the kidneys Huma

22、n exposure amalgam fillings(汞合金補牙)are the most important source of inorganic mercury the average exposure from dental amalgam is approximately 10 g/day normal value less than 5 g/L in blood fish are the most important source of methylated or organic mercury Salt water:shark,swordfish,and tuna(金槍魚)Ca

23、se:Minamata disease(水俣病水俣病)-1956Minamata disease(水俣病水俣病)-1956 新日本窒素肥料（窒素，即氮）於水俁（音：予）工場生產氯乙烯與醋酸乙烯，其製程中需要使用含汞的催化劑。由於該工廠任意排放廢水，這些含汞的劇毒物質流入成海，被水中生物所食用，並轉成甲基氯汞（化學式CH3HgCl）与二甲汞（化學式(CH3)2Hg）等有機汞化合物 人類食用遭污染的魚蝦致病Minamata disease(水俣病水俣病)-1956經過經過 1950年，有大量的海魚成群在水俣湾海面游泳，任人網捕，海面上常見死魚、海鳥屍體 1952年，水俁當地許多貓隻出現不尋常現象，

24、走路顛顛跌跌，甚至發足狂奔，當地居民稱【跳舞病】1953年1月有貓發瘋跳海自殺，一年內，投海自殺的貓總數達五萬多隻。接著，狗、豬也發生了類似的發瘋情形 1956年4月21日，來自入江村的小女孩田中靜子成為第一位患病者，被送至窒素公司（Chisso Minamata Chemical Company）附屬醫院，病況急速惡化，一個月後雙眼失明，全身性痙攣，不久死亡。死者二歲的妹妹也罹患相同的病症Minamata disease(水俣病水俣病)-1956定名定名 1959年，熊本大學醫學部水俁病研究班發表研究報告 原因為當地窒素工場所排出的有機水銀 1932至1966年間有數百噸的汞被排入水俁灣 1

25、960年正式將甲基汞中毒所引起的工業公害病，定名為水俁病 1966年新潟又爆發水俁病，史稱第二水俁病，這次的禍首是昭和電工 1997年10月，由官方所認定的受害者高達12,615人，當中有1,246人已死亡Mercury Nephrotic syndrome usually reversible,although it may take several months Tubular dysfunction Acute ChronicLithium Treatment of manic depressive illness High mortality rate 25%with an acute

26、 overdose 9%in patients intoxicated during maintenance therapyprophylactictreatment IntoxicationMildModerateSeverePlasma level mEq/L 0.6 to 1.2 1.0 to 1.5 1.5 to 2.5 2.5 to 3.5 3.5Lithium Almost completely excreted by the kidneys.Most of the filtered lithium is reabsorbed in the proximal tubule appr

27、oximately 20 percent being excreted in the urine.Lithium reabsorption follows that of sodium Risk factor of lithium intoxication volume depletion renal ischemiaLithium Inflammation Chronic interstitial nephropathy Nephrogenic diabetes insipidus Minimal change glomerulonephropathy Other Neuromuscular

28、 irritability Confusion GoiterArsenic Elemental(0),arsenite(trivalent,+3),and arsenate(pentavalent,+5)Trivalent Arsenic or arsenite compounds Earths crust and numerous ores（礦石）Acute high-dose exposure gastrointestinal system dehydration,hypotension,irregular pulse and cardiac instability shock,acute

29、 respiratory distress syndrome,and sometimes death(600 mcg per kg body weight per day or higher)Lower dose chronic arsenic exposure peripheral neurologic and skin manifestations distal paresthesias,followed rapidly by an ascending sensory loss and weakness Hyperpigmentation or hypopigmentationArseni

30、c Renal injury proteinuria,Hematuria acute tubular necrosisAnti-Hyperlipidemics Statins Gemfibrozil FenofibrateStatins Rhabdomyolysis The average incidence of hospitalization for rhabdomyolysis:0.44 per 10,000 patient-years(95%CI 0.20-0.84)for patients treated with atorvastatin,pravastatin,or simvas

31、tatin monotherapyGraham DJ:Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs JAMA 2004 Dec 1;292(21):2585-90 Pathogensis Volume depletion Tubular obstruction due to heme pigment casts Tubular injury from free chelatable ironMiscellaneous Chronic Stimulant Laxativ

32、e Radiographic contrast ACE inhibitors NSAIDs Aspirin Mesalamine Diuretics Allopurinol Cimetidine DilantinRadiographic contrast Pathogenesis Tubular cell toxicity Renal hemodynamic Ionic vs nonionic High-osmolal vs Iso-osmolalRadiographic contrast First generation-Ionic monomers,hyperosmolal Diatriz

33、oate,Iothalamate Second generation-Nonionic monomers,lower osmolal Iopamidol,Iohexol,Iopromide,Ioversol Newer agents-Nonionic dimers,iso-osmolal IodixanolRadiographic contrast Contrast associated(induced)nephropathy High risk CKD DM Prevention:Hydration(Normal saline or isotonic sodium bicarbonate)N

34、-AC(N-acetylcysteine)Mautone A:J Interv cardiol 2010 Feb;23(1):78-85Radiographic contrast Incidence 4-11%:Cr 1.5-4.0 mg/dl 50%:Cr4.0 mg/dl and DMACE Inhibitors+BowmansCapsule20 mmHgAfferent arterioleEfferentarterioleAngiotensin IIACEI s+XXNSAIDs Inflammation Acute interstitial nephropathy(proteinuri

35、a)Chronic interstitial nephropathy Hemodynamic Inhibition of prostaglandins systhesis Unproportional hyperkalemia Hyporeninemic hypoaldosteronism Papillary necrosis(Analgesic nephropathy)Salt and water retentionAnalgesic nephropathyFeartureIncidenceExcessive consumption100%Women80%Headache80%GI dist

36、urbance35%UTI40%Papillary Necrosis20%Papillary calcification65%Analgesic nephropathyAspirin Inflammation Chronic interstitial nephropathyDrugs of abuse Cocaine Cocaine-induced rhabdomyolysis is a significant cause of acute renal failure increased sympathomimetic activity vasospasm inhibition of the

37、reuptake of catecholamines at alpha adrenergic receptors high intracellular calcium levels in muscle cells台灣引發腎毒性的前五大可疑藥物全國藥物不良反應通報中心90-96年通報案例摘錄自財團法人台灣醫療改革基金會排名排名成份成份藥理分類藥理分類1Gentamicin抗生素2Vancomycin抗生素3Warfarin抗凝劑4Amphotericin B抗黴菌藥5Cyclosporin免疫調解劑如何保護腎臟 一般原則 力行健康生活 三少：少鹽、少糖、少油 三多：多纖維、多蔬果、多喝水 四不：

38、不抽煙、不憋尿、不熬夜、不吃來路不明的藥 一沒有：沒有鮪魚肚 治療原則 控制糖尿病 控制高血壓 因病使用具腎毒性藥物時，注意腎臟功能的變化 使用顯影劑做檢查時，注意檢查前後的腎臟功能 追蹤原則 40歲以後每年檢查一次 第1型糖尿病患發病五年後，每年一次尿液篩檢 第2型糖尿病診斷時，做尿液篩檢怎麼知道腎臟受損 用Serum Cr，帶入MDRD公式算eGFR 用Spot urine 測urine albumin/urine Cr ratio(ACR)Blood pressure 臨床症狀 泡、水、高、貧、倦4 變數怎麼算?找GFR calculator哪裡找?MDRD formula 的運用 分類系統適用於年輕人與老年人 新診斷出eGFR7 mmol/L)