药品不良反应基础知识汇总和基本的概念

1、药品不良反应基础知识汇总和基本的概念药物不良反应的定义Adverse Drug Reaction，ADR质量合格药品在正常用法用量情况下出现的与用药目的无关的或意外的有害反应。(药品不良反应监察管理办法及WHO定义)ADR辨析药物滥用（吸毒）超量误用伪劣药品差错、事故(未按规定方法用药)more ADRs = better care特殊情形 临床试验中新药其治疗剂量尚未确定时所有有害而非所期望的且与药品应有因果关系的反应，视为药品不良反应。中药: ADR概念的困惑质量合格药品在正常用法用量情况下出现的与用药目的无关的或意外的有害反应。建立中药质量标准是实现中药现代化的重要内容辩证论治是中医治疗

2、学的精髓，更强调个体化中医证侯与西医疾病间既相联系又有区别中医治疗学有自己独特的医理指导中药不同制剂引起ADR的比率%特殊情形 中药ADR经注册上市流通的中药制品在正常用药情况下引起的与治疗无关且不利于病人的反应。中西医“ADR”观念的冲突西医：理想的药物-高效低毒，在正常用法用量下也会发生ADR，追求低毒安全的药品；中医：药本身有大、中、小毒，正确驾驭便能“以毒攻毒”，追求正确的用药方法，发生ADR说明用法不当。特殊情形 治疗无效表现：原有疾病控制不良、恶化争议：ADR符合定义非ADR属于有效性范畴Case by case 选药不对症，相当于无治疗产生耐受性，耐药性药物促进疾病进展不良事件/

3、不良经历adverse drug event / experience，ADE药物治疗期间所发生的任何不利的医疗事件或经历，该事件/经历并非一定与该药有因果关系。AE ADE ADRADE概念的实际意义ADE与用药的因果关系常不能马上确立对ADE”可疑即报”最大限度降低人群用药风险ADE包括了伪劣药、误用、事故等造成的损害，可揭示医疗系统存在的缺陷，是药物警戒关注的对象Preventabilitythe drug(s) involved in the ADR is NOT considered appropriate for the patients clinical condition (用

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

5、gy or previous reaction to the drug (忽略药史)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 (血浓过限)noncompliance poor was associated with the reactionfor outpatient only (依从性低)a medication error w

6、as associated with the reaction (用药差错)非预期不良反应Unanticipated adverse reaction根据药物特性预料不到的ADR；性质和严重程度与文献报道或上市批文不一致的ADR;药品不良反应监测管理办法术语“新的药品不良反应” 是指药品使用说明书或有关文献资料上未收载的不良反应。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数据库中新的严重ADR报告建立和更新已知ADR库 !信号 (signal) 是指关于一种不良事件与某一药品间可能存在的因果关系的报道信息。应是此前未知的或尚未充分证实的。意义:形成假说供一步研究，并使ADR得到早期预警产生信号是不良反应监测工作的一项基本任务。药品不良反应监测管理办法中采用的术语“可疑不良反应”是指怀疑而末确定的不良反应，与信号的概念相近。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 丝裂霉素 paralytic ileus 4 31.03 4 valproate fibrinogenopenia 4 29.04 5 cefradine hematuria 39 23.63 信号的发布信号强度(频率性质)与措施弱信号强信号注意观察以搜集更多信息增加特别的化验检查项目组织各方面的相关专家进行研讨发起专门的临床试验、毒理学或流行病学研究在药物试验手册及

9、有关资料中增加该AE中止临床试验 / 停止药物使用ADR程度分级 (severity)轻度：轻度不适，不影响正常功能，一般不需特别处理。中度：明显的不适，影响日常活动，需要减量/撤药或做特殊处理。重度：不能从事日常活动，对症治疗不缓解，需立即撤药或做紧急处理。 ADE的严重性 (seriousness)反映ADE对生存的重要程度; 症状性/严重的Serious adverse event, SAE:死亡；立即威胁生命；需住院治疗或延长住院时间；永久或显著性残疾、失能;导致先天畸形或出生时缺陷。一般情况下必须在严重不良事件发生后24小时内向有关部门报告 ADE发生时间分类从最后一次给药至首次出现

10、ADE的时间急性：0-60分钟；占4.3%亚急性：1-24小时；占86.5%潜伏性: 1天数周；占3.5%ADR发生频率描 述发生频率很常见 (very common) 10%常见 (common, frequent) 1% 并 10%不常见，偶见 (uncommon, infrequent) 0.1% 并 1%罕见 (rare) 0.01% 并 0.1%极罕见 (very rare)9 肯定; 5-8 很可能; 4 可能; 4 可疑WHO-乌普萨拉监测中心因果关系评估系统 关 联评估标准肯定不良事件或实验室检查异常与用药之间有合理的时间关系不能用疾病或其他药物解释撤药反应阳性不良事件有明确的

11、药理学或症状特征(如客观、特异的临床表现或公认的药理学现象)再激发反应阳性(必要时)很可能不良事件或实验室检查异常与用药之间有合理的时间关系不太可能归因于疾病或其他药物有合理的撤药临床反应未要求再激发可能不良事件或实验室检查异常与用药之间有合理的时间关系也可以用疾病或其他药物解释撤药方面的信息缺乏或不清楚不可能不良事件或实验室检查异常与用药之间的时间关系不大可能 （但也并非绝无可能）疾病或其他药物也能提供合理的解释条件性/未分类有不良事件或实验室检查异常作出合适的评估需要更多资料其他资料尚在检查中不能评估/不能分类报告提示了一个不良反应因信息不足或相互矛盾不能作出判断资料无法补充或核实我国卫生

12、部ADR中心推荐的评分法(1994年版)根据对以下5个问题的回答:1. 开始用药的时间和不良反应出现的时间有无合理的先后关系?2. 所怀疑的不良反应是否符合该药品已知不良反应的类型?3. 所怀疑的不良反应是否可用并用药的作用,病人的临床状态或其他疗法的影响来解释?4. 停药或减量后,反应是否减轻或消失?5. 再次接触可疑药品是否再次出现同样的反应?判定药物与ADR的关系-+-不可能？-+怀疑？+可能？+-+很可能+-+肯定54321说明: + 表示肯定; -表示否定； 表示难以肯定或否定； ？表示情况不明小 结ADR 是药物治疗中的自然风险毒副作用 ADRADE 具有实际的监测意义信号 提示潜

13、在的ADR，由ADR报告产生新的、严重ADR 具有更高的报告价值药源性疾病 是有明确因果关系的药物损害ADR的因果关系评估困难，常以关联度表达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