Unit9:药物不良反应的分析评价 主讲教师:朱畴文助理教师:高虹 授课时间:2010年4月20日(1班);2010年4月23日(2班) 教学目的:掌握和熟悉药物不良反应的研究、评价和应用的原则及方法 二、教学内容 1.了解药物不良反应研究的历史和进展—药物流行病学 2.掌握药物不良反应的定义、重要意义和有关监测研究的主要基本方法 3.初步掌握药物不良反应的确定方法(宏观和微观评价) 4.熟悉流行病学中各种相关性或因果研究方法的特点(带复习性质) 5.了解药物不良反应监测、药物流行病学的应用及前景 三、教学重点:药物不良反应的研究方法 四、教学难点:药物不良反应的判断 五、中文和英文关键词 Adverse drug reaction药物不良反应 Pharmacoepidemiology药物流行病学 Causal Association因果关联 六、阅读文献: 中文 1.朱畴文第三篇第18章不良反应。于:《循证医学与临床实践》(第2版), 王吉耀主编,北京科学出版社2006 MiX:(all in: "Strom BL ed, Pharmacoepidemiology(2 ed), Chichester: John Wiley &Sons,1994) 2. Brian L. Strom. What is Pharmacoepidemiology? 3. Brian L. Strom. Study designs available for pharmacoepidemiology studies 4. Brian L Strom. When should one perform pharmacoepidemiology studies? 5. Brian L. Strom. How should one perform pharmacoepidemiology studies? Choosing among the available alternatives 七、讨论思考题: (一)微观判断:使用 Naranjo模式和我国卫生部ADR中心评分法,推断如下 临床病例发生药物不良反应的可能性 位29岁的女性在过去一周已经接受 nitrofurantoin(酶要因)治疗2 次。在她服下第3次治疗的第1片药的4小时后,她出现发热(39C) 呼吸容迫和呕吐。她随即停了药,一天后她的全科医师开了胸片检查, 发现为“过敏性肺炎”的表现。她的白细胞稍增多(12*10~9L)伴9% 嗜酸性细胞。数日后,患者完全康复 第166页
Unit 9：药物不良反应的分析评价 主讲教师：朱畴文 助理教师：高虹 授课时间：2010 年 4 月 20 日（1 班）；2010 年 4 月 23 日（2 班） 一、教学目的：掌握和熟悉药物不良反应的研究、评价和应用的原则及方法 二、教学内容： 1. 了解药物不良反应研究的历史和进展—药物流行病学 2. 掌握药物不良反应的定义、重要意义和有关监测研究的主要基本方法 3. 初步掌握药物不良反应的确定方法（宏观和微观评价） 4. 熟悉流行病学中各种相关性或因果研究方法的特点（带复习性质） 5. 了解药物不良反应监测、药物流行病学的应用及前景 三、教学重点：药物不良反应的研究方法 四、教学难点：药物不良反应的判断 五、中文和英文关键词 Adverse Drug Reaction 药物不良反应 Pharmacoepidemiology 药物流行病学 Causal Association 因果关联 六、阅读文献： 中文 1. 朱畴文 第三篇第 18 章 不良反应。于：《循证医学与临床实践》（第 2 版）， 王吉耀主编，北京 科学出版社 2006 英文：(all in: “Strom BL ed, Pharmacoepidemiology (2nd ed), Chichester: John Wiley & Sons, 1994”) 2. Brian L. Strom. What is Pharmacoepidemiology? 3. Brian L. Strom. Study designs available for pharmacoepidemiology studies. 4. Brian L. Strom. When should one perform pharmacoepidemiology studies? 5. Brian L. Strom. How should one perform pharmacoepidemiology studies? Choosing among the available alternatives 七、讨论思考题： （一）微观判断：使用 Naranjo 模式和我国卫生部 ADR 中心评分法，推断如下 临床病例发生药物不良反应的可能性 一位 29 岁的女性在过去一周已经接受nitrofurantoin（呋喃妥因）治疗 2 次。在她服下第 3 次治疗的第 1 片药的 4 小时后，她出现发热（39o C）、 呼吸窘迫和呕吐。她随即停了药，一天后她的全科医师开了胸片检查， 发现为“过敏性肺炎”的表现。她的白细胞稍增多（12*10^9/L）伴 9% 嗜酸性细胞。数日后，患者完全康复。 第 166 页
aranjo's Adverse drug reaction Probability Scale 问题 是否不知道分值 以前有类似的报道吗? 2不良事件是在应用可疑药物之后出现的吗? 3当撤药后或应用特定的对抗药后不良反应有所+10 好转吗? 4当再次用药后,不良反应又出现吗? 5有其他非药物因素可引起该不良反应吗? 1+2 6使用安慰剂后,不良反应再次出现了吗? 0000 7药物血(或其他体液)浓度达到中毒浓度了吗?+10 8增加(或减少)药物剂量,不良反应加重或减轻)+10 9病人以前暴露于该药或同类药有类似的反应吗?+10 10该不良事件可被其他客观证据证明吗? 合计 判断标准:总分≥9肯定( definite),5-8很可能( probable) 1-4可能( possilbe),≤0可疑( doubtful) 我国卫生部ADR中心推荐的评分法 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? 肯定 很可能 2+++ 可能 可疑 +++ 士士+ 士士 ? 不可能 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 问 A.你的评分多少? B.这两个模式有什么主要缺点或弱点? C.你有什么建议? (二)宏观评价 A.各种用于因果关联研究的流行病学设计方法有什么各自的优点和缺点? 如:病例报告,病例系列,病例对照硏究,队列硏究,随机临床试验, 荟萃分析 B.药物不良反应的研究主要运用哪些方法? 第167页
Naranjo’s Adverse Drug Reaction Probability Scale 问题 是 否 不知道 分值 1 .以前有类似的报道吗? +1 0 0 2 不良事件是在应用可疑药物之后出现的吗？ +2 -1 0 3 当撤药后或应用特定的对抗药后不良反应有所 好转吗？ +1 0 0 4 当再次用药后，不良反应又出现吗? +2 -1 0 5 有其他非药物因素可引起该不良反应吗? -1 +2 0 6 使用安慰剂后,不良反应再次出现了吗? -1 +1 0 7 药物血(或其他体液)浓度达到中毒浓度了吗？ +1 0 0 8 增加(或减少)药物剂量，不良反应加重(或减轻) 了吗? +1 0 0 9 病人以前暴露于该药或同类药有类似的反应吗? +1 0 0 10 该不良事件可被其他客观证据证明吗? +1 0 0 合计 判断标准: 总分≥9 肯定(definite); 5-8 很可能(probable); 1-4 可能(possilbe); ≤0 可疑(doubtful) 我国卫生部 ADR 中心推荐的评分法 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? 1 2 3 4 5 肯定 + + - + + 很可能 + + - + + 可能 + + ± ± ? 可疑 + - ± ± ? 不可能 - - + - - 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 问： A. 你的评分多少？ B. 这两个模式有什么主要缺点或弱点？ C. 你有什么建议？ （二）宏观评价： A. 各种用于因果关联研究的流行病学设计方法有什么各自的优点和缺点？ 如：病例报告，病例系列，病例对照研究，队列研究，随机临床试验， 荟萃分析 B. 药物不良反应的研究主要运用哪些方法？ 第 167 页
C.为什么? 八、参考书及文献目录 1.《循证医学与临床实践》(第2版),王吉耀主编,科学出版社 2. Brian L. Strom, ed. Pharmacoepidemiology(2 ed), Chichester: John Wiley Sons. 1994 3. Brian L. Strom, Stephen E. Kimmel, eds. Textbook of Pharmacoepidemiology John Wiley&Sons(Asia), Singapore,2008(药物流行病学教程,主译曾繁 典施侣元詹思延) 第168页
C. 为什么？ 八、参考书及文献目录 1. 《循证医学与临床实践》（第 2 版），王吉耀主编，科学出版社 2. Brian L. Strom, ed. Pharmacoepidemiology (2nd ed), Chichester: John Wiley & Sons, 1994” 3. Brian L. Strom, Stephen E. Kimmel, eds. Textbook of Pharmacoepidemiology, John Wiley & Sons (Asia), Singapore, 2008 （药物流行病学教程，主译 曾繁 典 施侣元 詹思延） 第 168 页
What is Pharmacoepidemiology BRIAN L. STROM University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA a desire to take medicine is, perhaps, the great fields. The history of drug regulation will then be feature which distinguishes man from other ani. briefly and selectively reviewed, focusing on the Sir william Osler. 1891 US experience as an example, demonstrating how it has led to the development of this new field In recent decades, modern medicine has been bles- Next the current regulatory process for the sed with a pharmaceutical armamentarium which approval of new drugs will be reviewed, in order is much more powerful than what it had before. to place the use of pharmacoepidemiology and Although this has given us the ability to provide postmarketing drug surveillance into proper much better medical care for our patients, it has spective. Finally, the potential scientific and per- also resulted in the ability to do much greater ical contributions of pharmacoepidemiology harm. It has also generated an enormous number be discussed of product liability suits against pharmaceutical manufacturers, some appropriate and others inap- propriate.In fact, the history of drug regulation parallels the history of major adverse drug reac- DEFINmION OF tion"disasters. "Each change in pharmaceutical PHARMACOEPIDEMIOLOGY law was a political reaction to an epidemic of Pharmacoepidemiology is the study of the use/of adverse drug reactions. The harm that drugs can and the effects of drugs in large numbers of cause has also led to the development of the field people. The term pharmacoepidemiology con- of pharmacoepidemiology, which is the focus of tains two components: "pharmaco"and"epide this book. More recently, the field has begun to miology "In order to better appreciate and expand its focus to include issues other than understand what is and what is not included in adverse reactions, as well this new field, it is useful to compare its scope to To clarify what is, and what is not, included that of other related fields. The scope of pharma within the discipline of pharmacoepidemiology, coepidemiology will first be compared to that of this chapter will begin by defining pharmacoepi- clinical pharmacology, and then to that of epide- demology, differentiating it from other related molo Pharmacoepidemiology(Second edition). Edited by Brian L Strom 第169页
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PHARMACOEPIDEMIOLOGY PHARMACOEPIDEMIOLOGY VS CLINICAL does not normally involve or require the mea PHARMACOLOGY surement of drug levels. However, pharmacoepi demology can be used to shed light on the Pharmacology is the study of the effects of drugs. pharmacokinetics of a drug, such as exploring Clinical pharmacology is the study of the effects whether aminophylline is more likely to cause e of drugs in humans (see also Chapter 4).Phar- nausea when administered to a patient simulta- macoepidemiology can be considered, therefore, neously taking cimetidine. However, this is a to fall within clinical pharmacology. In attempt- relatively unusual application of the field ing to optimize the use of drugs, one central Specifically, the field of pharmacoepidemiology principle of clinical pharmacology is that therapy has primarily concerned itself with the study of should be individualized, or tailored to the needs adverse drug effects. Adverse reactions have tra- of the specific patient at hand. This individuali- ditionally been separated into those which are zation of therapy requires the determination of a the result of an exaggerated but otherwise usual risk/benefit ratio specific to the patient at hand. pharmacological effect of the drug, so-called Doing so requires a prescriber to be aware of the Type A reactions, vs. those which are aberrant potential beneficial and harmful effects of the effects, so called Type B reactions. Type A reac- drug in question and to know how elements of tions tend to be common, dose-related, pre the patient' s clinical status might modify the dictable, and less serious. They can usually be probability of a good therapeutic outcome. For treated by simply reducing the dose of the drug example, consider a patient with a serious infec. They tend to occur in individuals who have one tion, serious liver impairment, and mild impair- of three characteristics. First, the individuals may ment of his or her renal function. In considering have received more of a drug than is customarily whether to use gentamicin to treat the infection, required. Second, they may have received a con it is not suficient to know that gentamicin has a ventional amount of the drug, but they may small probability of causing renal disease. A metabolize or excrete the drug unusually slowly, good clinician should realize that a patient who leading to drug levels that are too high. Third, has impaired liver function is at a greater risk of they may have normal drug levels, but for some suffering from this adverse effect than one with reason are overly sensitive to them. normal liver function. Pharmacoepidemiology In contrast, Type B reactions tend to be can be useful in providing information about the uncommon, not related to dose, unpredictable, beneficial and harmful effects of any drug, thus and potentially more serious. They usually permitting a better assessment of the risk/benefit require cessation of the drug. They may be due balance for the use of any particular drug in any to what are known as hypersensitivity reactions particular patient. or immunologic reactions. Alternatively, Type B Clinical pharmacology is traditionally divided reactions may be some other idiosyncratic reac- into two basic areas, pharmacokinetics and phar: tion to the drug, either due to some inherited macodynamics. Pharmacokinetics is the study of susceptibility(e.g glucose-6 hosphate dehy he relationship between the dose administered of drogenase deficiency) or due to some other a drug and the serum or blood level achieved. It mechanism. Regardless, Type B reactions are the deals with drug absorption, distribution, metabo- most difficult to predict or even detect, and major focus study of the relationship between drug level and- logic studies of adverse drug reactions drug effect. Together, these two fields allow one The usual approach to studying adverse drug to predict the effect one might observe in a reactions has been the collection of spontaneous patient from administering a certain drug regi- reports of drug-related morbidity or mortality men. Pharmacoepidemiology encompasses ele-(see Chapters 10 and 11). However, determining ments of both of these fields, exploring the effects causation in case reports of adverse reactions can achieved by administering a drug regimen. It be problematic(see Chapter 26), as can attempts 第170页
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