藥品不良反應(yīng)基礎(chǔ)知識匯總和基本的概念

1、藥品不良反應(yīng)基礎(chǔ)知識匯總和基本的概念藥物不良反應(yīng)的定義Adverse Drug Reaction，ADR質(zhì)量合格藥品在正常用法用量情況下出現(xiàn)的與用藥目的無關(guān)的或意外的有害反應(yīng)。(藥品不良反應(yīng)監(jiān)察管理辦法及WHO定義)ADR辨析藥物濫用（吸毒）超量誤用偽劣藥品差錯(cuò)、事故(未按規(guī)定方法用藥)more ADRs = better care特殊情形 臨床試驗(yàn)中新藥其治療劑量尚未確定時(shí)所有有害而非所期望的且與藥品應(yīng)有因果關(guān)系的反應(yīng)，視為藥品不良反應(yīng)。中藥: ADR概念的困惑質(zhì)量合格藥品在正常用法用量情況下出現(xiàn)的與用藥目的無關(guān)的或意外的有害反應(yīng)。建立中藥質(zhì)量標(biāo)準(zhǔn)是實(shí)現(xiàn)中藥現(xiàn)代化的重要內(nèi)容辯證論治是中醫(yī)治療

2、學(xué)的精髓，更強(qiáng)調(diào)個(gè)體化中醫(yī)證侯與西醫(yī)疾病間既相聯(lián)系又有區(qū)別中醫(yī)治療學(xué)有自己獨(dú)特的醫(yī)理指導(dǎo)中藥不同制劑引起ADR的比率%特殊情形 中藥ADR經(jīng)注冊上市流通的中藥制品在正常用藥情況下引起的與治療無關(guān)且不利于病人的反應(yīng)。中西醫(yī)“ADR”觀念的沖突西醫(yī)：理想的藥物-高效低毒，在正常用法用量下也會發(fā)生ADR，追求低毒安全的藥品；中醫(yī)：藥本身有大、中、小毒，正確駕馭便能“以毒攻毒”，追求正確的用藥方法，發(fā)生ADR說明用法不當(dāng)。特殊情形 治療無效表現(xiàn)：原有疾病控制不良、惡化爭議：ADR符合定義非ADR屬于有效性范疇Case by case 選藥不對癥，相當(dāng)于無治療產(chǎn)生耐受性，耐藥性藥物促進(jìn)疾病進(jìn)展不良事件/

3、不良經(jīng)歷adverse drug event / experience，ADE藥物治療期間所發(fā)生的任何不利的醫(yī)療事件或經(jīng)歷，該事件/經(jīng)歷并非一定與該藥有因果關(guān)系。AE ADE ADRADE概念的實(shí)際意義ADE與用藥的因果關(guān)系常不能馬上確立對ADE”可疑即報(bào)”最大限度降低人群用藥風(fēng)險(xiǎn)ADE包括了偽劣藥、誤用、事故等造成的損害，可揭示醫(yī)療系統(tǒng)存在的缺陷，是藥物警戒關(guān)注的對象Preventabilitythe drug(s) involved in the ADR is NOT considered appropriate for the patients clinical condition (用

4、途不當(dāng))the dose, route, or frequency of administration was NOT appropriate for the patients age, weight, or disease state (用法不當(dāng))Preventabilityrequired therapeutic drug monitoring or other necessary laboratory tests were NOT performed or not performed frequently enough (監(jiān)測不當(dāng))there was a history of aller

5、gy or previous reaction to the drug (忽略藥史)a known drug interaction was the suspected cause of the reaction (相互作用)Preventabilitya serum drug concentration above the therapeutic range was documented (血濃過限)noncompliance poor was associated with the reactionfor outpatient only (依從性低)a medication error w

6、as associated with the reaction (用藥差錯(cuò))非預(yù)期不良反應(yīng)Unanticipated adverse reaction根據(jù)藥物特性預(yù)料不到的ADR；性質(zhì)和嚴(yán)重程度與文獻(xiàn)報(bào)道或上市批文不一致的ADR;藥品不良反應(yīng)監(jiān)測管理辦法術(shù)語“新的藥品不良反應(yīng)” 是指藥品使用說明書或有關(guān)文獻(xiàn)資料上未收載的不良反應(yīng)。Shanghai: sharp increase in ADR reports 03000600090001200020012002200320042005Number of reportsNumber of ADR reports received in Shang

7、hai ADR Monitoring Center since 2001上海市SRS數(shù)據(jù)庫中新的嚴(yán)重ADR報(bào)告建立和更新已知ADR庫 !信號 (signal) 是指關(guān)于一種不良事件與某一藥品間可能存在的因果關(guān)系的報(bào)道信息。應(yīng)是此前未知的或尚未充分證實(shí)的。意義:形成假說供一步研究，并使ADR得到早期預(yù)警產(chǎn)生信號是不良反應(yīng)監(jiān)測工作的一項(xiàng)基本任務(wù)。藥品不良反應(yīng)監(jiān)測管理辦法中采用的術(shù)語“可疑不良反應(yīng)”是指懷疑而末確定的不良反應(yīng)，與信號的概念相近。captopril induced cough (WHO-17 years)Shanghai: Top 5 most intensive signalsRan

8、k drug event frequency SI 1 flavoxate pancytopenia hydrochloride 2 andrographolide acute renal injection failure 3 絲裂霉素 paralytic ileus 4 31.03 4 valproate fibrinogenopenia 4 29.04 5 cefradine hematuria 39 23.63 信號的發(fā)布信號強(qiáng)度(頻率性質(zhì))與措施弱信號強(qiáng)信號注意觀察以搜集更多信息增加特別的化驗(yàn)檢查項(xiàng)目組織各方面的相關(guān)專家進(jìn)行研討發(fā)起專門的臨床試驗(yàn)、毒理學(xué)或流行病學(xué)研究在藥物試驗(yàn)手冊及

9、有關(guān)資料中增加該AE中止臨床試驗(yàn) / 停止藥物使用ADR程度分級 (severity)輕度：輕度不適，不影響正常功能，一般不需特別處理。中度：明顯的不適，影響日?；顒?，需要減量/撤藥或做特殊處理。重度：不能從事日?；顒樱瑢ΠY治療不緩解，需立即撤藥或做緊急處理。 ADE的嚴(yán)重性 (seriousness)反映ADE對生存的重要程度; 癥狀性/嚴(yán)重的Serious adverse event, SAE:死亡；立即威脅生命；需住院治療或延長住院時(shí)間；永久或顯著性殘疾、失能;導(dǎo)致先天畸形或出生時(shí)缺陷。一般情況下必須在嚴(yán)重不良事件發(fā)生后24小時(shí)內(nèi)向有關(guān)部門報(bào)告 ADE發(fā)生時(shí)間分類從最后一次給藥至首次出現(xiàn)

10、ADE的時(shí)間急性：0-60分鐘；占4.3%亞急性：1-24小時(shí)；占86.5%潛伏性: 1天數(shù)周；占3.5%ADR發(fā)生頻率描 述發(fā)生頻率很常見 (very common) 10%常見 (common, frequent) 1% 并 10%不常見，偶見 (uncommon, infrequent) 0.1% 并 1%罕見 (rare) 0.01% 并 0.1%極罕見 (very rare)9 肯定; 5-8 很可能; 4 可能; 4 可疑WHO-烏普薩拉監(jiān)測中心因果關(guān)系評估系統(tǒng) 關(guān) 聯(lián)評估標(biāo)準(zhǔn)肯定不良事件或?qū)嶒?yàn)室檢查異常與用藥之間有合理的時(shí)間關(guān)系不能用疾病或其他藥物解釋撤藥反應(yīng)陽性不良事件有明確的

11、藥理學(xué)或癥狀特征(如客觀、特異的臨床表現(xiàn)或公認(rèn)的藥理學(xué)現(xiàn)象)再激發(fā)反應(yīng)陽性(必要時(shí))很可能不良事件或?qū)嶒?yàn)室檢查異常與用藥之間有合理的時(shí)間關(guān)系不太可能歸因于疾病或其他藥物有合理的撤藥臨床反應(yīng)未要求再激發(fā)可能不良事件或?qū)嶒?yàn)室檢查異常與用藥之間有合理的時(shí)間關(guān)系也可以用疾病或其他藥物解釋撤藥方面的信息缺乏或不清楚不可能不良事件或?qū)嶒?yàn)室檢查異常與用藥之間的時(shí)間關(guān)系不大可能 （但也并非絕無可能）疾病或其他藥物也能提供合理的解釋條件性/未分類有不良事件或?qū)嶒?yàn)室檢查異常作出合適的評估需要更多資料其他資料尚在檢查中不能評估/不能分類報(bào)告提示了一個(gè)不良反應(yīng)因信息不足或相互矛盾不能作出判斷資料無法補(bǔ)充或核實(shí)我國衛(wèi)生

12、部ADR中心推薦的評分法(1994年版)根據(jù)對以下5個(gè)問題的回答:1. 開始用藥的時(shí)間和不良反應(yīng)出現(xiàn)的時(shí)間有無合理的先后關(guān)系?2. 所懷疑的不良反應(yīng)是否符合該藥品已知不良反應(yīng)的類型?3. 所懷疑的不良反應(yīng)是否可用并用藥的作用,病人的臨床狀態(tài)或其他療法的影響來解釋?4. 停藥或減量后,反應(yīng)是否減輕或消失?5. 再次接觸可疑藥品是否再次出現(xiàn)同樣的反應(yīng)?判定藥物與ADR的關(guān)系-+-不可能？-+懷疑？+可能？+-+很可能+-+肯定54321說明: + 表示肯定; -表示否定； 表示難以肯定或否定； ？表示情況不明小 結(jié)ADR 是藥物治療中的自然風(fēng)險(xiǎn)毒副作用 ADRADE 具有實(shí)際的監(jiān)測意義信號 提示潛

13、在的ADR，由ADR報(bào)告產(chǎn)生新的、嚴(yán)重ADR 具有更高的報(bào)告價(jià)值藥源性疾病 是有明確因果關(guān)系的藥物損害ADR的因果關(guān)系評估困難，常以關(guān)聯(lián)度表達(dá)Case studyK.V, a 52-year-old woman with a 12-year history of non-insulin diabetes, is admitted with a 2-week history of nausea, anorexia, fatigue, and intense generalized pruritus. She noted dark urine , light colored stools, and

14、 yellow pigmentation of the skin about 10 days ago, which has gotten progressive worse.No fever, vomiting, abdominal pain or fatty food intolerance.She denies use of alcohol or recreational drugs or blood transfusion.Medical historydiabetespioglitazonepast 18 monthshypertensionhydrochlorothiazidepas

15、t 4 yearslisinoprilacute otitis mediaamoxicillin-clavulanic acidone month ago ,10-day courseLaboratory findingsAST43040ALT29440alkaline phosphatase1230U/LT:D bilirubin7.251mg/dL:106 mol/Lup to 0.994 and up to 14albumin 4.1g/dLLaboratory findingsComplete blood count, differential count are normal. Se

16、rologic tests for hepatitis A,B,C are negative.Ultrasound shows a normal biliary tract system, with no obstruction. Liver biopsy showed preserved normal liver architecture, marked centrilobular cholestasis with bile pigment in hepatocytes and canaliculi, and a mild portal inflammatory infiltrate wit

17、h an excess of eosinophiles.Diagnosis Cholestatic jaundiceHepatocellular damage.Mixed cholestatic-cytotoxic hepatic damage.Drug-induced hepatitisTreatment and PrognosisA 1200-calorie daily diet,with no added salt.All other drugs are discontinued.Cholestyramine(questran) 4g PO TIDTreatment and Progno

18、sisAST: 85U/LALT:214U/LAlkaline phosphatase: 288U/LT:D bilirubin 2.456:29Etiology: two questions How the drug-induced hepatitis be determined?What was the most likely etiology in K.V?How the drug-induced hepatitis be determined?Drug-induced hepatic injury should be suspected in every patient with ja

19、undice.A negative history of fever, abdominal pain, and fatty food intolerance rule out gallbladder disease in K.V.No history of alcohol and hepatitis serologic tests are negative.Negative ultrasound studies rule out extrahepatic obstructive jaundice.How the drug-induced hepatitis be determined?Dark

20、 urine ruled out unconjugated hyperbilirubinemia.AST elevation alone may be seen in injury to cardiac and skeletal muscles, but together with increased ALT, usually indicate hepatic origin.Eosinophils in the liver biopsy ,together with the rapid decline of AST, bilirubin concentration toward normal

21、when all drugs are withdrawn,supports the assessment of drug-induced hepatitis.Four possible drugs, which one?HCTZ is first ruled out.Allergic cholestatic jaundice is very rarely associated with thiazide diuretics.K.V has taken the drug for four years.Four possible drugs, which one?Lisinopril :like

22、other ACEI, can cause acute hepatocellular injury with mostly mixed hepatocelluar and cholestatic injury; Most cases are occur within 14 weeks of exposure.Thus lisinopril may not be the causative.Four possible drugs, which one?Pioglitazone has been reported a mixed cholestatic-cytotoxic injury, but not the same degree as its predecessor, troglitazone which was previously withdrawn from the market due to 90 cases of hepatotoxic effects.There is only one report of pi