药理学 Pharmacology By Dechang Zhang Department of Pharmacology, School of Basic Medicine, Peking Union Medical College

General Principles 绪论 Introduction 药物基因组学Pharmacogenetics 药物流行病学Pharmacoepidemiology 药物代谢动力学Pharmacokinetics 药物效应动力学Pharmacodynamics

What is Pharmacology? Pharmacology is the study of how drugs exert their effects on living systems.

What is Drug Drugs can be defined as chemical agents that interact with specific target molecules, thereby producing a biological effect. A drug can be defined as a chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect.

Drugs may be synthetic chemicals obtained from plants or animals, or products of genetic engineering.

What is Medicine A medicine is a chemical preparation, which usually but not necessarily contains one or more drugs, administered with the intention of producing a therapeutic effect. Medicines usually contain other substances (excipients, stabilisers, solvents, etc.) besides the active drug, to make them more convenient to use.

To count as a drug, the substance must be administered as such, rather than released by physiological mechanisms. Many substances, such as insulin or thyroxine, are endogenous hormones but are also drugs when they are administered intentionally.

In everyday parlance, the word drug is often associated with addictive, narcotic or mind-altering substances - an unfortunate negative connotation that tends to bias opinion against any form of chemical therapy.

Main factors for classifying drugs Pharmacotherapeutic actions (may be multiple) Pharmacologic actions (may be multiple) Molecular actions (both site and mechanism) Other factors (source and chemistry, etc.)

The origins of pharmacology: religion,animals and plants (Sheep, mandrake flowers and opium poppy head). (Frieze from the Palace of King Sargon II in Kharasabad, Mesopotamia , 800BC)

神农本草经记载了365种药物和许多方剂。很多仍然为现在所用。阿片作为麻醉剂，大黄作为泻药，苦艾驱虫，萝芙木镇静，高岭土治疗腹泻，麻黄治疗哮喘。

Most drugs in antiquity came from plants and animal pars of fluids Most drugs in antiquity came from plants and animal pars of fluids. Foxglove is the plant source of digoxin

Nightshade is the source of atropine

Knowledge of drugs increased in parallel with knowledge of body function (anatomy, physiology, and biochemistry) and chemistry. 1628 William Harvey 1785 William Withering

Mordern drug development depends on academia and industry working together.

Biotechnology Originally, this was the production of drugs or other useful products by biological means (e.g. antibiotic production from microorganisms or production of monoclonal antibodies).

基因工程药物过程示意图 ① ③ ④ ⑥ ①从细胞中分离出DNA ②限制酶截取DNA片断 ③分离大肠杆菌中的质粒 ④ DNA重组 ⑤用重组质粒转化大肠杆菌 ⑥ ⑥培养大肠杆菌克隆大量基因

Pharmacogenetics This is the study of genetic influences on responses to drugs. Originally, pharmacogenetics focused on familial idiosyncratic drug reactions, where affected individuals show an abnormal-usually adverse-response to a class of drug It now covers broader variations in drug response, where the genetic basis is more complex.

Pharmacogenomics This recent term overlaps with pharmacogenetics, describing the use of genetic information to guide the choice of drug therapy on an individual basis. The underlying principle is that differences between individuals in their response to therapeutic drugs can be predicted from their genetic make-up.

So far, they mainly involve genetic polymorphism of drug-metabolising enzymes or receptors Ultimately, linking specific gene variations with variations in therapeutic or unwanted effects of a particular drug should enable the tailoring of therapeutic choices on the basis of an individual's genotype. The consequences for therapeutics will be far-reaching.

Pharmacoepidemiology This is the study of drug effects at the population level It is concerned with the variability of drug effects between individuals in a population, and between populations.

药物流行病学pharmacoepidemiology Pharmacology: 研究药物与人体相互作用的规律和机理，主要任务是评价药物在人体内的安全有效性。 Epidemiology: 研究疾病和健康在人群中的分布及其影响因素的一门科学，药物则是影响疾病和健康分布的重要因素之一。 应用流行病学知识、方法和推理研究人群中药物的应用及效果药物流行病学(Porta & Hartzema，1987).

主要用途（1） 1. 补充上市前研究中未获得的信息——量化已知ADR发生率或是有效效益的频率 (1)精确度更高； (2)了解药物对特殊的人群组的作用； (3)研究并发疾病和合并用药的影响； (4)比较并评价新药是否更优于其它常用药物。

主要用途（2） 2. 获得上市前研究不可能得到的新信息 (1)发现罕见的或迟发的不良反应，并用流行病 3. 总体贡献 (1)确保用药安全 学的方法和推理加以验证； (2)了解人群中药物利用的情况； (3)卫生经济学评价。 3. 总体贡献 (1)确保用药安全 (2)履行伦理和法律的义务

Pharmacoeconomics This branch of health economics aims to quantify in economic terms the cost and benefit of drugs used therapeutically.

It arose from the concern of many governments to provide for healthcare from tax revenues, raising questions of what therapeutic procedures represent the best value for money.

“反应停”致海豹肢畸形儿事件 1953年，瑞士Ciba药厂（现瑞士诺华的前身之一）首次合成了一种名为thalidomide(沙利多胺，“反应停”）的药物。 This drug was marketed by the Germany firm Chemie Grünenthal as a safe alternative to barbiturate hypnotics, especially for pregnant women on October 1st,1957.

反应停便成了“孕妇的理想选择”（当时的广告用语），在欧洲、亚洲、非洲、澳洲和南美洲被医生大量处方给孕妇以治疗妊娠呕吐。 到1959年，仅在联邦德国就有近100万人服用过反应停，反应停的每月销量达到了1吨的水平。在联邦德国的某些州，患者甚至不需要医生处方就能购买到反应停。

但是在美国，因为有报道称，猴子在怀孕的第23到31天内服用反应停会导致胎儿的出生缺陷，美国食品和药品管理局（FDA）的评审专家(Dr Frances Kelsey)极力反对将反应停引入美国市场。最终，FDA没有批准此种药物在美国的临床使用，而是要求研究人员对其进行更深入的临床研究（后来的事实证明，这是一项多么明智的决定！）。

副作用逐渐浮出水面 1956年12月25日，世界上第一例因母亲在怀孕期间服用反应停而导致耳朵畸形的婴儿就出生了，但当时并未引起人们足够的注意）。 1960年，在德国卡塞尔举行的一次全国小儿科会议上，有人报道了两例奇怪的新生儿畸形病例，但没人加以注意。

联邦德国汉堡大学的遗传学家兰兹博士根据自己的临床观察于1961年11月16日通过电话向Chemie　Gruenenthal公司提出警告，提醒他们反应停可能具有致畸胎性。 最后，因为发现越来越多类似的临床报告，Chemie　Gruenenthal公司不得不于1961年11月底将反应停从联邦德国市场上召回。

但此举为时已晚，人们此后陆续发现了1万到1·2万名因母亲服用反应停而导致出生缺陷的婴儿！ 据估计前西德有10000多名病例 英国有8000余例 日本有1000余例 加拿大200多例

Phocomelia (海豹肢) A deformity in which the limbs are rudimentary stumps with malformed digits

1961年年底，联邦德国亚琛市地方法院受理了全球第一例控告反应停生产厂家Chemie　Gruenenthal公司的案件。 前面提到的兰兹博士在作为控方证人提供证言时，将自己的观察结果和其他学者的病例报告汇总后如实提供给了法庭。 1969年10月10日，法庭经过近8年的审理，决定不采纳兰兹博士的证言。原因是辩方律师找到了各种理由来证明兰兹博士在作证时不能保持客观公正的态度。

1970年4月10日，案件的控辩双方于法庭外达成了和解，Chemie　Gruenenthal公司同意向控方支付总额1·1亿德国马克的赔偿金。 1970年12月18日，法庭作出终审判决，撤消了对Chemie　Gruenenthal公司的诉讼，但法庭同时承认，反应停确实具有致畸胎性，并提醒制药企业，在药品研发过程中，应以此为鉴。

1971年12月17日，联邦德国卫生部利用Chemie　Gruenenthal公司赔偿的款项专门为反应停受害者设立了一项基金，并邀请兰兹博士作为此项基金的监管人之一。 此后数年间，在兰兹博士的努力下，联邦德国有2866名反应停受害者得到了应有的赔偿。 此外，兰兹博士还接受日本同行的邀请，为帮助日本的反应停受害者进行了大量的工作。 兰兹博士因其为反应停受害者作出的巨大贡献而受到全球反应停受害者的深深敬仰。

生态学研究

ecological fallacy 生态学谬误 生态学研究中，我们并不知道每个个体的暴露与疾病状况，也无法控制可能的混杂因素，因此，这种方法只是粗线条的描述性研究，在结果解说时必须慎重。 生态学上某疾病与因素分布一致，可能是该因素与疾病之间确有联系，但也可能在个体水平二者毫无联系，此即所谓的生态学谬误。 例如，美国在70年代早期，随着口服避孕药的使用增加，同期育龄妇女中冠心病的死亡率下降，生态学分析提示口服避孕药与致死性冠心病之间有负的联系。但大量以个体资料为基础的分析性研究否定了这个结论。由此可见，生态学研究只是为病因分析提供线索，因果关系的确定必须采用分析性研究和实验性研究方法。

然而早在1965年，一位以色列医生在尝试把反应停当作安眠药治疗6名患麻风性皮肤结节红斑（为患麻风病后生长于患者皮肤的一种疼痛剧烈的结节，是机体对麻风杆菌产生的一种过度的免疫反应）而长期失眠的麻风病患者时意外地发现，反应停可以有效地减轻患者的皮肤症状。而在此之前，医学界虽然找到了可以有效地杀灭麻风杆菌的药物，但一直没有找到缓解麻风患者此种过度的免疫反应的方法。

这位以色列医生将自己的发现公之于众，并同时提醒医学界人士，在对反应停的副作用保持高度警惕的同时，也应该想到反应停可能对其他由免疫反应异常引起的疾病也有治疗效果。为此，在此后的数十年间，世界各地的科学家们一直没有放弃对反应停的临床研究。

经过大量谨慎而客观的临床实验观察，科学家们逐渐发现，反应停对结核、红斑狼疮、艾滋病导致的极度虚弱和卡波济肉瘤、骨髓移植时发生的移植物抗宿主病以及多发性骨髓瘤等多种疾病都有一定的疗效。人们对反应停的认识开始发生了变化。

1991年，美国洛克菲勒大学的科学家们在研究中发现，发生过度免疫反应的麻风病患者的血液中一种免疫调节因子（TNF-α）的含量很高，他们便推测反应停对此种反应的良好疗效就是因其对TNF -α有作用。1992年，他们终于证实反应停确实能够减低机体合成这种免疫调节因子的能力。

1995年，美国的两家制药公司在联合研究反应停对一种名为“多型性成胶质细胞瘤”的脑瘤的治疗效果时发现，反应停还具有抗血管生成的作用，而已知丰富的血液供应是肿瘤细胞在体内存活的必备条件，所以，科学家们又推测反应停对某些肿瘤也有治疗作用可能就是缘于其抗血管生成作用，但迄今为止，这种推测还没有得到足够的理论支持。

美国FDA一直未批准反应停的临床应用。为此，各国科学家以及美国国内反应停生产厂家塞尔基因公司进行了不懈的努力。 终于，在1998年7月16日，美国FDA在医学界的强烈要求及大量临床实验的有力支持下，批准将反应停用于治疗麻风病的皮肤损害。

反应停目前在美国还没有被正式批准用于治疗癌症，但已经有很多医生在暗地里尝试将反应停用于治疗晚期癌症患者的极度衰弱。一些艾滋病患者也从黑市上购买反应停以治疗爱滋病导致的极度虚弱和卡波济肉瘤。据估计，在过去的3年里，已经有超过5万名美国人接受过反应停的治疗，其中绝大多数是癌症患者，而在用于治疗多发性骨髓瘤的病例中，也有30％-50％的患者病情都或多或少地得到了改善。

不久前，塞尔基因公司的发言人在接受媒体采访时说，目前医学界已经尝试将反应停用于治疗50多种疾病。但反应停销售总量中只有约1％是被用于治疗麻风病，将近92％则是被用于治疗癌症（虽然这并未得到官方机构的认可）。 现在，全球已经有将近150项有关反应停的临床实验正在进行之中。全球医学界人士都翘首以待，希望反应停能够将功补过，在不久的将来为人类健康作出更大的贡献。

药物代谢动力学（Pharmacokinetics） 药物效应动力学 （Pharmacodynamics） 药物代谢动力学（Pharmacokinetics） 作用、作用机制 吸收、分布、代谢、排泄

药物的吸收、分布与排除

Routes for administering drugs gastrointestinal tract：oral (first pass effect), sublingual, rectal injection：intravenous, intramuscular, subcutaneous other：inhalation, transdermal delivery, intrathecal or intravitreal administration, local administration, nasal mucosa

Drug molecules move around the body in two ways: bulk flow (i. e Drug molecules move around the body in two ways: bulk flow (i.e. in the bloodstream) diffusion (i.e. molecule by molecule, over short distances).

The chemical nature of a drug makes no difference to its transfer by bulk flow. In contrast, diffusional characteristics differ markedly between different drugs. In particular, ability to cross hydrophobic diffusion barriers is strongly influenced by lipid solubility.

There are four main ways by which small molecules cross cell membranes ● by diffusing directly through the lipid ● by diffusing through aqueous pores formed by special proteins (‘aquaporins’) that traverse the lipid ● by combination with a transmembrane carrier protein that binds a molecule on one side of the membrane then changes conformation and releases it on the other ● by pinocytosis (胞吞作用).

Of these routes, diffusion through lipid and carrier-mediated transport are particularly important in relation to pharmacokinetic mechanisms.

Diffusion through aquaporins (membrane glycoproteins that can be blocked by mercurial reagents such as para-chloromercurobenzene sulfonate) is probably important in the transfer of gases such as CO2, but the pores are too small in diameter (about 0.4 nm) to allow most drug molecules (which usually exceed 1 nm in diameter) to pass through.

Pinocytosis involves invagination of part of the cell membrane and the trapping within the cell of a small vesicle containing extracellular constituents. The vesicle contents can then be released within the cell, or extruded from its other side. This mechanism appears to be important for the transport of some macromolecules (e.g. insulin, which crosses the blood-brain barrier by this process), but not for small molecules.

Active and passive transport of drugs across biomembrane 被动扩散 孔道转运 载体主动转运

The importance of lipid solubility in membrane permeation The importance of lipid solubility in membrane permeation. Figures show the concentration profile in a lipid membrane separating two aqueous compartments. A lipid-soluble drug (A) is subject to a much larger transmembrane concentration gradient (ΔCm) than a lipid-insoluble drug (B). It therefore diffuses more rapidly, even though the aqueous concentration gradient (C1-C2) is the same in both cases.

Effect of pH and ionisation

Ionisation affects not only the rate at which drugs permeate membranes but also the steady-state distribution of drug molecules between aqueous compartments, if a pH difference exists between them.

Weak acid permeates lipid membrane 非解离型的HA易于扩散通过生物膜，带电荷的解离部分不易通过。

Weak base permeates lipid membrane

药物解离型与非解离性的比例取决于两个因素 药物的pKa和环境的pH HA=A-或HB=B –时， pH = pKa ， pKa是药物的固有性质。

pKa values for some acidic and basic drugs

一些酸性很弱的药物,如苯妥英及巴比妥类药物,其pKa≥7 一些酸性很弱的药物,如苯妥英及巴比妥类药物,其pKa≥7.5，在pH为1~8之间的环境中，主要以非解离型存在，其吸收不受pH影响。 而pKa在2.5～7.5之间的药物，其解离受环境pH影响较大，pH的改变直接影响药物吸收速度。

膜两侧的pH不同会改变药物的转运方向 When a weak acid (pKa=4.4) is dissolved in the gastric juice (pH=2.4) , its concentration difference of ionized drug between both sides of lipid mucosal barrier is 100,000 times because the pH value of plasma is 7.4. Acidic drugs are well absorbed in the acidic medium of the stomach.

膜两侧的pH不同会改变药物的转运方向 Basic compounds exist primarily in their un-ionized form in the blood (pH 7.4), they readily diffuse from the blood into the gastric juice. Once in contact with the gastric contents (pH 1-2), they will ionize rapidly, which restricts their diffusibility.

The concentration gradients produced by ion trapping can theoretically be very large if there is a large pH difference between compartments. Thus aspirin would be concentrated more than four fold with respect to plasma in an alkaline renal tubule, and about 6000-fold in plasma with respect to the acidic gastric contents.

Such large gradients are, however, unlikely to be achieved in reality for two main reasons: First, the attribution of total impermeability to the charged species is not realistic, and even a small permeability will considerably attenuate the concentration difference that can be reached. Second, body compartments rarely approach equilibrium. Neither the gastric contents nor the renal tubular fluid stands still, and the resulting flux of drug molecules reduces the concentration gradients well below the theoretical equilibrium conditions.

pH partition is not the main determinant of the site of absorption of drugs from the gastrointestinal tract. This is because the enormous absorptive surface area of the villi and microvilli in the ileum compared with the much smaller surface area in the stomach is of overriding importance.

Drug Absorption Gastrointestinal absorption Most drug absorption occurs in the proximal jejunum (first 1-2 m in human) 胆盐与维生素B12在回肠吸收 药物在小肠停留3～4h，大肠10～12h（缓释药物释放时间)

Drug Absorption Gastrointestinal absorption Weak acidic and weak basic drugs Molecular weight, ionization, lipid solubility Carrier for special substances (amino acid, derivatives of purine or pyrimidine, L-DOPA).

Drug Absorption Factors affecting rate of gastraintestinal absorption Drugs & formulation factors (release, dissolve, transmembrane) Gastric emptying time (increased, decreased) Food intestinal motility Drug interactions

First-pass effect After absorption from the stomach or small intestine, a drug must pass through the liver before reaching the general circulation and its target site. If the capacity of liver metabolic enzymes to inactivate the drug is great, only limited amounts of active drug will escape the process.

Routes for administering drugs gastrointestinal tract：oral (first pass effect), sublingual, rectal injection：intravenous, intramuscular, subcutaneous other：inhalation, transdermal delivery, intrathecal or intravitreal administration, local administration, nasal mucosa

Absorption of drugs from the intestine, as a function of pKa ,for acids and bases

different formulations of digoxin Variation in oral absorption among different formulations of digoxin

药物在其他部位的吸收 口腔粘膜 被动扩散 不经过肝脏 直肠粘膜 经过肝脏 透皮吸收 肺吸收 快，局部，毒物 眼部吸收 剂量损失，稀释 口腔粘膜 被动扩散 不经过肝脏 直肠粘膜 经过肝脏 透皮吸收 肺吸收 快，局部，毒物 眼部吸收 剂量损失，稀释 鼻粘膜吸收 不经过肝脏 肌肉吸收 血流速率 皮下吸收 缓慢

The main body fluid compartments, expressed as a percentage of body weight. only the free drug is able to move between the compartments.

Bioavailability (生物利用度) is the fraction of drug that reaches the bloodstream unaltered. 影响因素： first-pass metablism solubility chemical stability formulation

Bioequivalence (生物等效)：两种相关药物有相同的生物利用度以及相同的达峰时间。反之，则生物不等效。 Treatment equivalence (治疗等效)：两种药物有相同的疗效和安全性。 生物等效未必治疗等效。

Distribution of drugs

体重70kg的个体体液组成： 总水42L：药物分子量小或疏水，易于从细胞间隙进入组织间液,也能跨细胞膜进入细胞。其分布体积与总体液之和相近 细胞内液 28L 细胞外液 14L 组织间液 10L 药物分子量小或亲水，易于从细胞间隙进入组织间液 但不能跨细胞膜进入细胞。其分布体积与血浆和组织间液之和相近 血浆 4L：药物分子量很大或大量与血浆蛋白结合，则主要分布在血浆中。其分布体积基本与血浆相同。

表观分布容积 Apparent volume of distriburion Vd = D/C D: Total amount of drug in the body C: Plasma concentration of drug

假定药物在体内分布但并不排出体外，一次注射后血浆中药物浓度的时相变化

有药物排出体外，一次注射后药物分布及血浆中药物浓度的时相变化

单次注射后立即有药物排出并且分布排出过程很快 可以外推出C0,并据此算出Vd。

药物在体内分布的不均匀性 组织血流量不均匀，药物与组织亲和力不同 药物与蛋白结合，屏蔽现象 表观分布容积并不意味着药物在体内是均匀分布的，其意义在于反映药物分布的广泛程度或与组织中大分子的结合程度

The binding of drugs to plasma proteins 结合的可逆性 结合的可饱和性 结合的亲和力

[ albumin] = 0.6 mmol/l, S = 1.2 mmol/l. D <<< S. [DS] ∝ [D]. [DS]/([D] + [DS]) is independent of the drug concentration.

[sulfonamides] ≈ 50% [S] [S-sulfonamides] / {[free sulfonamides] + [S-sulfonamides] } is dependent on [sulfonamides] Doubling the dose of such a drug can therefore more than double the free (pharmacologically active) concentration.

多种药物存在时，药物与血浆蛋白结合的竞争及其意义

PARTITION INTO BODY FAT AND OTHER TISSUES Morphine lipid:water partition coefficient = 0.4, quite lipid-soluble enough to cross the blood-brain barrier. Thiopental fat:water partition coefficient =10, accumulates substantially in body fat. This has important consequences that limit its usefulness as an intravenous anaesthetic to short-term initiation ('induction') of anaesthesia.

Drug Elimination and Termination of Action

代谢 Metabolism (生物转化 biotransformation) + 药物的排泄 Excretion 药物的消除 Elimitation 代谢 Metabolism (生物转化 biotransformation) + 药物的排泄 Excretion

Drug Metabolism PHASE 1 reactions involve oxidation, reduction, and hydrolysis, reactions that provide a functional group to increase the polarity of the drug. PHASE 2 reactions involve conjugation or synthetic reactions in which a large chemical group is attached to the molecule.

Biotransformation

药物剂量与代谢速率的关系

Pharmacokinetics

Pharmacokinetics Pharmacokinetics is the description of the time course of a drug in the body, encompassing absorption, distribution, metabolism, and excretion. Pharmacokinetics describes changes in plasma drug concentration over time.

Steady-state (稳态)：Drug input = Drug output

Pharmacokinetics of infusion dosing

Effect of dose rate on Css：A faster rate of infusion does not change the time needed to achieve steady state; only the Css changes.

Css = R0/KeVd = R0/CLt R0 = rate of infusion（mg/min) Ke = elimination rate constant Vd = apparent volume of distribution CLt = clearance Ke 、Vd 、CLt 对线性代谢药物是常数，因此R0 与Css 成正比

Time required to achieve Css T 1/2 : The time it takes for half of the drug to be eliminated from the body. A large loading dose may be needed initially when the therapeutic concentration of a drug in the plasma must be achieved rapidly Loding dose = Desired drugplasma × Vd

Pharmacokinetics of single versus mutiple dosing

Single injection kinetics t ½ of drug does not depend on size of administered dose

Multiple injection kinetics To achieve Css by various means of dosing

Oral administration

Dose-response of drug action

Agonist, Antagonist, Partial Agonist

Therapeutic index (TI) TI = LD50/ED50

Therapeutic index (TI)