兽医药理学基础知识（中英文）

1、Reasons for study pharmacologycompulsory for veterinary medicine major students;R&D of pharmaceuticals;common sense, e.g. using aspirin to prevent artery clotting;introductionDefinition of a drugorigins of drugsdosage formobjectives of studenthistory of pharmacology(一)药物的概念（definition of a drug）药物（A

2、 Drug）is a substance used to diagnose, prevent or treat disease (用于诊断、预防或治疗疾病的物质). 兽药还包括能促进动物生长繁殖和提高生产性能的物质。毒物（poison）: 对动物机体能产生损害作用的物质。药物超过一定的剂量也能产生毒害作用，因此药物和毒物的区别仅在于剂量的差别。药物长期使用或剂量过大有可能成为毒物。(二）药物的来源1. 天然药物：Plant (botanical): the active components of plants that are useful as drugs include alkaloid

3、s（生物碱）, glycoside（糖苷）, gums（树胶）, resins（树脂）, and oils.生物碱的英文名以-ine结尾， 糖苷以-in结尾。例如， 生物碱有：atropine (阿托品), caffeine, nicotine；糖苷有digitoxin (洋地黄毒苷)， digoxin（地高辛）。2) 矿物质（mineral）：include the electrolytes (sodium chloride), iron, selenium, and others3) 动物：insects,4) 微生物发酵产物： Fermentation products of bacte

4、ria and molds, including many antibiotics（抗生素）and anthelmintics（抗蠕虫药）， such as penicillins, ivermectins.2. 合成药物：人工合成的化学药物、抗菌药物等. Aspirin, enrofloxacin3生物技术药物： using recombinant DNA technology to produce animal and human products, such as interferon, insulin, and so on. Nuclear acids( dsDNA)(三) 药物剂型将

5、药物的原料加工制成安全、稳定和便于应用的形式，这种药物的形式称之为药物剂型（dosage form）, 简称剂型，如pills、片剂（tablets)、粉剂(powders)、注射剂(injection solutions)等。剂型是一个集合名词，任何一种具体的剂型如安定片、葡萄糖氯化钠注射液，则称为制剂（preparation）。药剂学（pharmaceutics）主要是研究药物合适的制剂的科学。合理的制剂有利于药物的储存、运输和使用，提高药物的生物利用度，降低不良反应，发挥最大的疗效。4.新型制剂的进展长效制剂（缓释制剂）(long-released preparations)喷雾剂（兽用

6、疫苗） 浇泼剂靶向制剂(target delivery) 单抗、磁疗制剂（四）兽医药理学的性质和任务Scope of pharmacology. Pharmacology is an experiment science dealing with the properties of drugs and their effects on living systems. 任务（目标）：通过药理学的学习，熟悉和掌握各类药物的基本作用原理，主要适用症（indication）和禁忌症（contraindication），从而能正确的选药、合理用药。也为将来开发新药和新制剂打下基础。（五）兽医药理学的发展

7、简史1. Human employed drugs for treating disease and for social and religious purpose. Discovery of drugs were through the process of trials and errors. 2700BC, Chinese Emperor Shen Nung Pen tsao 1550BC Ebers papyrus recorded 829 prescriptions for medicaments empoyed in Egyptian medicineGreek civiliza

8、tion: Hippocrates (460-375BC), Hippocratic school promoted the use of inorganic salts as medicineGalen (131-201), Gelenic medicine consists of preparation of plants by soaking or boilingRenaissance: due to the development of printing, the 1st pharmacopeia was compiled by Valerius Cordus (1514-1544).

9、 1540 opium was introduced into clinical use2. The 17th and 18th Centuries: Drugs such as cinchona (quinine), coffee, tea, cocoa, curare, digitalis were discovered3.the 19th century : Friedrich Serturner (1783-1841), a German pharmacist, isolated the specific narcotic substance from opium and named

10、it Morphine after Morpheus, the Roman god of sleep. strychine, atropine and many other chemicals were isolated from medicinal plants.The first laboratory of study of pharmacology was established in Estonia(1820-1879). Since then, pharmacology gradually separately from pharmacy.4. 20世纪：药理学分支Molecular

11、 pharmacologyBiochemical pharmacologygenetical pharmacologyImmuno-pharmacologypharmacodanamicspharmacokineticsChapter 1 General pharmacology第一节 药物对机体的作用-药效学Pharmacodynamics 第二节 机体对药物的作用-药动学pharmacokinetics第三节 影响药物作用的因素及合理用药第一节 药物对机体的作用Pharmacodynamics Pharmacodynamics is the study of Physiological &

12、 biochemical effects of drugs and how these effects relate to a drugs Mechanisms of actionIt focuses on: Action and effects of drugs in bodyPharmacodynamics characterizes: what a drugs does to the patientPharmacokinetics: what the patients body does to a drug Pharmacodynamics一、pharmacodynamic terms二

13、、 structure-response relationship and dose-response relationship(药物的构效关系和量效关系)三、药物作用机理( mechanisms of action)一、pharmacodynamic terms 1. Drug action: drug molecules combine with components of cell membrane to initiate reactions2.Pharmacological effect: the results of drug actionse.g. 药物心肌细胞膜受体心肌细胞收缩增

14、加（drug action)心输出量和外周组织血流量增加patient with congestive heart failure 的症状改善（药理效应）3. Stimulants: enhance the activity of cells, tissues, organs of body e.g. caffeine4. Depressants: diazapine5. local function(局部作用) 6. absorptive action（吸收作用）, also called general or systemic action（全身作用）7. direct action or

15、 primary action:digitoxin加强心肌收缩力8.Indirect action or secondary action:digitoxin使水肿减轻9. Selectivity：preferentially produce a particular effect in a certain tissuee.g. clenbuterol: high selectivity for 2 receptor in airways, less selectivity in cardiac1原因：组织亲和力（affinity) 药物在组织的代谢率10. therapeutic actio

16、n（治疗作用）:对防治疾病有利的作用 etiological treatment (对因治疗)： symptomatic treatment (对症治疗)11. adverse reaction：an undesirable response to a drug; it may vary in severity from mild to fatal(与用药目的无关作用，称为不良反应）。side effect (副作用)：在治疗剂量时产生的与治疗无关的作用或危害不大的不良作用。如Atropine麻醉前给药时对胃肠道平滑肌的抑制作用toxic effect (毒性反应)：用药剂量过大或用药时间过长

17、引起的不良反应。 少数药物 在常用剂量时也能产生毒性反应，如chloramphenicol , aminoglycosides.(3) Allergy (变态反应)：青霉素(4）Second reaction(继发反应): 由治疗作用引起的不良后果。如二重感染。(5）Residual effect (后遗效应)：停药后的残存药理效应二、structure-response relationship and dose-response relationship(一) structure-response relationship(二) dose-response relationship(一)

18、structure-response relationshipstructure-response relationship: 药物的药理作用与特定的化学结构的关系结构相似的化合物：相似或相反的反应。光学异构体影响药理作用：多数药物的左旋体有药理活性，右旋体无活性，如左旋氯霉素、左旋咪唑。研究构效关系的意义：了解药物的作用机理、寻找和合成新药(二) dose-response relationshipestablishing and maintaining for a certain time an effective concentration of the drug in the imme

19、diate vicinity of action site.dose-response relationship: 定量分析与阐明药物的剂量与效应之间的变化规律称为量效关系。It is the fundamental principle of pharmacology. 1. Dose-response relationship curve（量效曲线）A: Dose-response relationship curveB: log dose-response curve: the concentration of the drug is expressed on a logarithmic

20、scale as showed in fig1.b. The slope (斜率) indicates the range of dosageEfficacy(效能) ：the maximal response a drug can produce; once the efficacy level of a drug is reached, increasing the dose does not improve the effect (Y 轴）. Potency（强度） ： a measure of the dose that is required to produce a respons

21、e（X轴）在临床上药物的效能比强度重要For example: drug A produces 100% response （ 10 mg）. Drug B produces 100% response （20 mg）. Drug C can produce the 60% response （ 50mg. ）2.graded response and quantal response(1) Graded response (量反应) the intensity of the response is consecutive(连续的)， 如心率、血压、体温。(2) Quantal respons

22、e (质反应) as the dose in increased, the number or proportion of animals exhibiting a particular, stated response is greater，（如死亡、睡眠等），all or none responseY轴用阳性反应频率表示时，则质反应量效曲线呈常态分布（normal distribution）;当Y轴为累积频率(cumulative frequency)时，则为累积分布曲线（cumulative distribution curve）。累积曲线表示动物对某一剂量和其以下的所有剂量的有反应的动

23、物百分率，其斜率表示群体中的药效学差异。质反应与量反应： digoxin（地高辛）治疗狗心脏病： 如果采纳的标准是心室收缩率，那么我们可以根据心电图上的连续数字来测定心率，因此这是一个量反应。 对一群狗用digoxin来治疗，规定心率降低到140 beats per minute(bpm)为阳性, 那么每个狗对某一剂量的digoxin的反应将是全或无的反应（all or none response）。3.therapeutic index&margin of safety1）半数有效量（median effect dose , ED50）is the dose required to prod

24、uce the effect in 50% of individuals . LD50 is the dose which can cause 50% lethality in treated group.therapeutic index=LD50 / ED50To assess the drug safety, margin of safety(LD5/ED95) is better than therapeutic index三、药物作用机制 （mechanisms of drug action） （一）受体机制（二）非受体机制（一）受体机制 A drug receptor : macr

25、omolecular component of body tissue with which a drug interacts to initiate its action (能与药物结合、相互作用并产生药理作用的生物大分子物质，可以是 proteins, enzymes, nucleic acids, and other cellular components ).A Ligand (配体)：对受体具有选择结合能力的生物活性物质。内源性配体神经递质noradrenaline, or norepipherine, acetylcholine，激素、活性肽等； 药物等是外源性的配体。2.受体-配

26、体反应的特性：饱和性（saturability）特异性（specificity）可逆性（reversibility）3.受体类型（1）G蛋白偶联受体（7次转膜受体） 神经递质受体、自体活性物质受体、神经肽受体和趋化因子受体等。（2）离子通道受体(配体门控离子通道)，如氯离子通道受体（3）激酶受体 由单一肽链组成，细胞外的部分为识别部位，胞内部分具有酶活性或与激酶偶联。配体结合受体后，能启动细胞内级联蛋白磷酸化反应，调节细胞内的型号转导。如胰岛素受体细胞因子受体等（4）核内受体 位于细胞浆或细胞核内，如甾类激素受体、二恶英受体等 4受体的作用方式配体结合膜受体并激活受体构型改变激活下游的蛋白质产

27、生第二信使物质（second messenger)信号级联反应。例如去甲肾上腺素与血管内皮细胞等细胞膜上的受体结合激活与受体偶联的GTP酶激活腺苷酸环化酶使GTP分解为cAMP激活一系列的下游蛋白激酶使糖原分解、血管收缩等。5. 受体学说占领学说(occupation theory)：药物效应与被占领的受体数量成正比。Affinity describes the tendency of a drug to combine with particular kind of receptor.An agonist (激动剂) is a drug that possesses affinity for

28、 a particular receptor and cause a change in the receptor that results in an observable effect. Full agonist ： producing a maximal response by occupying all or a fraction of receptors; partial agonist, producing less than maximal response even occupying all of the receptors. An antagonist (拮抗剂) : ca

29、n interact with receptor, but devoid of intrinsic activity. competitive antagonist: completely reversible; an increase in the concentration of the agonist in the immediate vicinity of its sites will overcome the effect of antagonist. atropine (antimuscarinic agent), dephenhydr-amine (苯海拉明)（H1recepto

30、r blocker）, propranolol (-adrenergic block). noncompetitve antagonis: the agonist has no influence on the degree of antagonism or its reversibility. 有机磷中毒(二）药物作用的非受体机制（自学）第二节 pharmacokinetics Pharmacokinetics: study and characterization of the time course of drug absorption, distribution, metabolism

31、(代谢） and excretion （排泄）absorption and distribution : influence the concentration attained in the immediate vicinity of its receptor sites biotransformation and excretion : responsible for eliminating action of the drug一、drugs cross biological membraneBy passive transfer or by active participation of

32、 the membrane 1被动转运(passive transfer) The membrane behaves as an inert lipoid-pore boundary.药物通过生物膜由高浓度向低浓度转运包括简单扩散和滤过. (1) 简单扩散(simple diffusion) 又称被动扩散(passive diffusion) nonpolar lipid-soluble compounds， polar water-soluble substance that possess sufficient lipid solubilityratio of diffusion ：con

33、centration gradient across the membrane, lipid-water partition coefficient of the drug. Characteristics of passive diffusion: movement of drug molecules down a concentration gradient without the cellular expenditure of energy. Most drugs (weak organic acids or bases): exist in solution as both nonio

34、nized and ionized forms. The degree of ionization of an organic electrolyte depends on its pKa value and pH of the environment The pka value, the negative logarithm of acidic ionization (or dissociation )constantFor acid drug(青霉素、磺胺药、水杨酸盐）解离浓度/非解离浓度=10 pH-pKapH=pKa, 50%药物解离；pH-pKa=1， 91%药物解离pH-pKa=2

35、， 99%药物解离在碱性体液中解离浓度高。For a base drug (安定、红霉素、土霉素）非解离浓度/解离浓度=10 pH-pKa在酸性体液中解离浓度高。The nonionized form is more lipid-soluble and readily diffuse across membrane,the ionized moiety is low lipid soluble, can not cross membraneIon-trapping mechanism:转运达到平衡时，在解离度较高的一侧有较高的药物浓度。Question: how to choose drugs

36、?(1) treat mastitis (pH=6.5)（红霉素、土霉素）(2) urethra inflammation （马、牛、羊尿液pH7.28.0）（磺胺药）(2) Filtration : common mechanism for transfer of many small, water-soluble, polar, and nonpolar substance.diameter of membrane channels :channels in the capillary endothelial membranes are large (4-8nm), 0.4nm in th

37、e intestinal epithelium and most cell membranes. Drug permeation through aqueous channels is important in renal excretion (renal glomerular filtration), removal of drugs from the cerebrospinal fluid. 2主动转运(active transport) 载体介导(carrier-mediated)的逆浓度或逆电化学梯度的转运过程。选择性、饱和性、竞争性，竞争性抑制是载体转运的特征。 主动转运：耗能，逆浓

38、度梯度转运，导致药物的不均匀分布和肾脏的排泄3易化扩散(facilitated diffusion) 也是载体介导的转运，故也具有饱和性和竞争性的特征。但是易化扩散是顺浓度梯度转运，不需要消耗能量，这是它跟主动转运的区别。氨基酸(如L-多巴)、葡萄糖进入红细胞、维生素B12从肠道吸收等是易化扩散转运的例子。 4胞饮吞噬作用(pinocytosisphagocytosis) 由于生物膜具有一定的流动性和可塑性，因此细胞膜可以主动变型而将某些物质摄人细胞内或从细胞内释放到细胞外，这种过程称胞饮或胞吐作用，摄取固体颗粒时称为吞噬作用大分子量超过900的药物进入细胞或穿过组织屏障一般是以胞饮或吞噬的方

39、式其他物质包括：蛋白质、破伤风毒素、肉毒梭菌毒素、抗原、脂溶性维生素等。 5离子对转运(ion pair transport) 有些高度解离的化合物，如磺胺类和某些季铵盐化合物能从胃肠道吸收，很难用上述机制解释。现认为这些高度亲水性的药物，在胃肠道内可与某些内源性化合物结合，如与有机阴离子黏蛋白(mucin)结合，形成中性离子对复合物，既有亲脂性，又具水溶性，可通过被动扩散穿过脂质膜。这种方式称为离子对转运。二、药物的体内过程AbsorptionDistributionBiotransformationexcretion（一） absorption:药物从用药部位进入血液的过程。给药途径、剂型

40、等影响吸收过程。1.Oral Administration:Common oral dosage forms include tablets, capsules, boluses, powders, granules, syrups, solutions, suspensions, and pastes. Other specialized delivery systems ：enteric-coated tablets and sustained-action （controlled-release）preparations.Drugs administered PO are exposed

41、 to low pH ranges, digestive enzymes, intestinal microflora, and ingesta that vary greatly among species.the “first-pass” effect ： a drug absorbed from the GI tractthe portal circulation passes through the liver before reaching the systemic circulation. A high degree of metabolic transformation may

42、occur.2.Parenteral Administration:The most common parenteral dosage form is a stable aqueous solution. Less frequently, the active components may be dissolved in an inert vegetable oil, which delays absorption. Several novel approaches for the parenteral delivery of drugs :microspheres, microcapsule

43、s, liposomes, microsponges, resealed carrier erythrocytes, and projectile biodegradable missiles, monoclonal antibodies . The most frequently used parenteral routes: intravenous (IV), intramuscular (IM), and subcutaneous (SC).less frequently used routes include epidural, intradermal, intratracheal,

44、and intraperitoneal (IP). In all cases, solutions for injection must be sterile, techniques aseptic, the dose accurate. For IV, aqueous solutions are preferable, which lead immediately to predictably high blood levels with a rapid onset of action. The duration of drug action: SC IM IV3. Inhalation (

45、Pulmonary Route):Gases, volatile agents, and fine particles usually are rapidly absorbed from the airways and alveoli into the pulmonary circulation. Delivery is done by standard anesthetic machines, or by vaporization for the local delivery of bronchodilators anti-infective agents. Drugs in the gas

46、eous state readily reach the alveolar surfaces particles 2 m reach the terminal ducts and alveoli. Particles 5 m may reach the respiratory bronchioles, and those 5-10 m in size may reach the upper respiratory tract and larger airways. 4.Topical Administration Several drugs are deliberately applied t

47、o the skin with the anticipation of systemic effects after transdermal absorption, eg, ectoparasiticides available as “pour-on” formulations absorption into the systemic circulation occurs due to percutaneous drug absorption(二) Distribution of Drugs Compounds that permeate freely through cell membra

48、nes become distributed both extracellular and intracellular. Substances that pass readily through and between capillary endothelial cells, but do not penetrate other cell membranes, are distributed into the extracellular fluid space. redistribution : initial high levels are achieved in rich vascular

49、 supply tissues （brain） redistributed to other tissues with poor blood supplies :muscles, fat depots. Only the unbound or free fraction of a drug can diffuse out of capillaries into tissues. The most important binding of drugs in circulation is to plasma albuminThe extent of a drug bound to plasma p

50、roteins, depending on: (1)plasma pH, (2)concentration of plasma proteins, (3)concentration of the drug, (4) the presence of another agent with a greater affinity for the limited number of binding sites. clinical significance of plasma-protein binding :dicumarol （双香豆素) may be 98% bound, but if only 9

51、6% bound, then the concentration of the free active drug becomes available in the plasma is doubled, with potentially harmful consequences. overdose drug concentration exceed the binding capacity of the plasma protein lead to an excess of free drug diffuse into various target tissues and produce exa

52、ggerated effects. Importance of drugs dissociate from plasma proteins: Those tightly bound tend to have much longer elimination half-lives because they are released gradually from the plasma protein reservoir. eg. the long-acting sulfonamides “physiologic” (the blood-brain, placental, and mammary) b

53、arriers. A drug may gain access to the CNS by two distinct routesthe capillary circulation and the CSF. The placental barrier : The potential teratogenicity of any drugThe passage of drugs across the placenta is largely by lipid diffusion.(三) Biotransformation of DrugsBiotransformation increase wate

54、r-solubility of compounds which can be easily excreted。“elimination”（清除）:Metabolism or biotransformation and the subsequent excretion of drugs.Metabolism generally occurs in two phases(相）: Phase I, phase IIPhase I, induces a chemical change (oxidation,reduction，hydrolysis), introducing into the drug

55、s polar groups: OH，SH，COOH，NH2.Phase II conjugates with endogenous polar molecule:glucuronic acid, acetate, sulfate, amino acids (glutathione, glycine).consequences of the biochemical transformation of drugs: 1) inactivation, during which an active drug is converted to an inactive metabolite(s); 2)

56、activation, during which an inactive drug (or pro-drug) is converted to a active primary metabolite; 3) modification of activity after the conversion of an active drug to a metabolite that also has pharmacologic activity; 4) lethal synthesis (or intoxication), in which a drug is incorporated into a

57、normal cellular metabolic pathway that ultimately leads to failure of the reaction sequence .生物转化的酶系 : 主要是肝脏微粒体药物代谢酶系(liver microsomal drug metabolizing enzymes)，简称药酶，包括催化氧化、还原、水解和结合反应的酶系。其中最重要的是细胞色素P-450混合功能氧化酶系，又称单加氧酶(monoxygenase)。其次血浆、肾脏等组织的非微粒体酶系也可催化氧化和结合反应 。clinical significance of biotransfor

58、mation of drugs : microsomal enzyme induction and inhibition.microsomal enzyme induction :有些药物能兴奋肝微粒体酶系，促进其合成增加或活性增强，称为酶的诱导(enzyme induction)。如苯巴比妥等。药物耐受性(tolerance)：酶的诱导可使药物本身或其他药物的代谢速率提高，使药理效应减弱。 某些药物可使药酶的合成减少或酶的活性降低，称为酶的抑制(enzyme inhibition)。具有酶抑制作用的药物主要有：有机磷杀虫剂、氯霉素、乙酰苯胺、异烟肼、对氨水杨酸等。例如：应用氯霉素可使戊巴比妥

59、的代谢减慢，使血中戊巴比妥浓度升高，麻醉时间延长。 （四）Excretion of Drugs and Their Metabolitesprincipal organ of excretion ：kidneys liver, GI tract, and lungs may play important roles. Milk, saliva, and sweat are of less importance。1. Renal excretion :glomerular(肾小球) filtration, carrier-mediated secretion, re-absorption of

60、the tubular lumen(肾小管) (1)glomerular filtration : Only unbound molecules 66,000 daltons are readily filtered through the glomerular membranes into the tubular lumen. (2) re-absorption : Acidification or alkalinization of the urine(3) secretion : Competitive inhibition 如果同时给予两种利用同一载体转运的药物，则出现竞争性抑制，亲和