第一章 药理学总论 蚌埠医学院 药学系药理教研室 2005.9
General principles of pharmacology Chapter 1. General principles of pharmacology Introduction
Bengbu Medical College Faculty of pharmacy Department of Pharmacology Zhu xiaoguang
? drug 薬 葯
1 drug alter prevent Chamical substance diagnose Cure Physiology and pathology Chamical substance prevent diagnose Cure
2 sources of drugs (来源) 天然: plants (植物) animals (动物) minerals(矿物)
合成: 3)Genetic engineering drugs (基因工程药物) 2)semi-synthetic drug (半合成) 1) full-synthetic drug (全合成) 2)semi-synthetic drug (半合成) 3)Genetic engineering drugs (基因工程药物)
Drug & poison 罂粟
药物
3 pharmacology ?
is the study of interaction between drug and body Pharmacology is the study of interaction between drug and body and the laws of drug actions.
pharmacology 药效学 drugs body 抑制或杀灭 药动学 抵抗力 抗药性 致病作用 microbes
4 药动学 Pharmacokinetics disposes drug body
1)absorption A. 吸收、 2)distribution D. 分布、 3)metabolism M. 代谢、 4)excretion E. 排泄
5、药效学 Pharmacodynamics acts on body drugs responds to responds to
1)action (作用)、 2)mechanism (作用机制)、 3)use (应用、用途)、 4)Adverse reaction (不良反应)
Why do you study pharmacology? characters of subject ?
? 1、桥梁学科 特点 2、基础学科 3、实验学科
药理学 基础课 临床课 解剖 生理 生化 病理 内科 外科 妇科 儿科 实验学科
? tasks : of drug drug research tool for other vital science. 1、direct rational usage of drug 2、Research and develop new drug 3、Provide scientific basis and research tool for other vital science.
二、Historical development of pharmacology 古代:药物学《神农本草经》 《本草纲目》 现代:药理学 化学:提供纯品、单体 生理学:提供实验方法 生物化学:器官细胞分子水平
实验方法 1、实验药理学方法 2、实验治疗学方法 3、临床药理学方法
三、Development and research of new drugs 1)preclinical research 3)post-marketing surveilance
新药开发与研究 药物化学 1、临床前研究 2、临床研究 3、上市后药物检测—售后调研 药理学 Ⅰ期临床 Ⅱ期临床 Ⅲ期临床 Ⅳ期临床
Chapter 2 Pharmacokinetics
药动学 qualitative research quantitative research (定性研究) A、D、M、E及过程 (定量研究) 用数学的方法研究体内药浓变化的规律,(药动学参parameter)
transportation (转运) transformation (转化) 药物 位置变化。 (A、D、E、) 药物 化学结构变化。 药物 位置变化。 (A、D、E、) transformation (转化) 药物 化学结构变化。 (M) 体内 体内
Researching content
drug ? transport Transmembrane
§1 transmembrane transportation of drugs 脂质双分子层
Manners of transport ① non carrier mediated transport (非载体转运} (载体转运}
一、 passive diffusion Mode of transmembrane transportation (被动扩散) 1、filtration (滤过) 2、simple diffusion (简单扩散) (lipid diffusion ,脂溶扩散 )
药物通过细胞膜的方式
non carrier transport 2)Simple diffusion(简单扩散) Ion trapping 1)filtrtion 滤过 2)Simple diffusion(简单扩散) Ion trapping
(被动扩散) passive diffusion simple diffusion 1、大多数药物的转运方式 (most common and important mode) 2、顺浓差(along the concentration gradient) 3、不耗能(does not expend energy) 4、不需载体(does not need carrier) 5、 没有饱和现象和竞争抑制 (has not saturation &competitive inhibition)
? transmembrane transportation 1)膜两侧药浓差 2)药物脂溶性 易跨膜 脂溶性 解离度小 极性低
weak acid (弱酸) Handerson-Hasselbalch equation HA = H+ + A- Ka = [H+] [A-] / [HA] (解离常数) pKa: Ka 的负对数 pH:[H+]浓度负对数 10 pH-pKa = [A-] / [HA] pH–pKa= log [A-] / [HA]
weak base (弱碱) BH =H+ + B Ka =[H+][B]/[BH] pKa-pH=log[BH]/[B] 10 pKa-pH=[BH+]/[B]
100 100 Free% 80 80 50 50 20 20 3 -3 -2 -1 1 2
口诀 酸酸碱碱促吸收, 酸碱碱酸促排泄
盐 ? 酸性药 Penicillin G 青霉素 + 钾(钠) (酸) (碱)
? 碱性药 Morphine 盐酸+吗啡 盐酸吗啡 (酸)(碱) (盐)
苯巴比妥钠 PH 7.0 PH 7.4 cell ?
Carrier mediated transport (载体转运) 1)Active transport (主动转运) 2)Facilitated diffusion (易化扩散)
Carrier mediated transport ? / Characteristics
1)Selectivity (选择性) 2)Saturation ( 饱和性) 3)Competition(竞争性) Competitive inhibition (竞争性抑制)
drug transmembrane transportation ? Factors affecting
Permeable amount 1、 (通透量) 膜面积×通透系数 (C1 C2) 膜厚度 2 、 Blood flow
? §2 Course of drug in the body 一、Absorption ♥
drug cellular membrane barrier circulation
1、 Per os(口服) velocity of disintegration、 dissolution Administration of drug (给药途径) 1、 Per os(口服) Molecular weight, velocity of disintegration、 dissolution
1)first pass elimination (首关消除) Orally administered drugs the portal vein the liver ,small intestine the drugs may be metabolized less drugs reach the systemic circulation first-pass elimination or first-pass metabolism.
Sublingual Per os hapatic per rectum
2、Inhalation (吸入给药) 3、topical application(局部用药) 4、Sublingual (舌下给药) per rectum (直肠给药)
5、injection intravenous injection,iv or infusion (静脉注射或输液) intramucular injection,im(肌内注射) subcutaneous injection ,sc(皮下注射) intra-arterial ,ia(动脉注射) Transdermal (鞘内注射)
factors affecting drug absorption physicochemical properties & preparations药物的理化性质和制剂特点 、 administration routes &absorption environment 给药途径和吸收环境 、 pH of the environment 环境pH
? 二、 Distribution drug circulation all organs
Factor affecting distribution: 1)binding to Plasma protein 2 )Blood flow of organs 3 )Tissue binding 4 ) pKa and pH 5 ) Barrier
binding to plasma protein D+P DP 暂失活性 DP 暂时贮存 难以跨膜转运 不易排泄 有竟争置换作用
redistribution--- Blood flow distribution blood brain blood fat drug blood brain blood fat all organs
Competitive inhibition Plasma protein binding Saturable Competitive inhibition 1) Protein + drug A 90% Free - drug A 10% 2) drug B binding 90% drug A 10% Free - drug A 90%
T issue binding: 1)Iodin(碘) thyroid gland 2)chloroquine liver, red cell infected (氯喹) by plasmodium 3)gentamicin hair, skin, nail (庆大霉素) 4)thisodium fat (redistribution) (硫喷妥钠)
Barrier (屏障) Blood-brain barrier (血脑屏障) 2) Placenta barrier (胎盘屏障) Blood – eye barrier (血眼屏障)
? 三、Transformation 1、(metabolism) by enzymatic system The structure of drug is altered by enzymatic system
2、Phases of biotransformation: Oxidation (氧化) Reduction (还原) Hydrolysis (水解) Phase 1 Phase 2: Conjugation(结合)
3、results of metabolism 1) effect↓,polar↑,excretion ↑ 2) effec↑,toxin↑ 3) metabolism activity 4) no metabolism in body
1) structure of drug 2) transformation 3) metabolic enzymes 4、Factor affecting metabolism 1) structure of drug 2) transformation 3) metabolic enzymes
Enzymes Hepatic microsomal drug-metabolizing enzyme system (肝微粒体药物代谢酶,肝药酶) 1)Cytochromes P-450 2)hepatic mixed-function oxydase system, (混合功能氧化酶系统)
hepatic mixed- function oxidase Characteristics 1) low specificity 2) represent a mixed-function oxidase system 3) have individual variation 4) inducible and inhibition
enzyme inducer (肝药酶诱导剂): 使肝药酶活性↑的药物,如苯巴比妥 1) increase the activity of cytochrome P450 2)increase their own metabolism as well as that of other drugs. enzyme inhibitor (肝药酶抑制剂): the activity of cytochrome P450
Results : Conjugation 5、 1) Most drugs become polarized molecule and secreted easily 2)Some drug become active metabolites,
? Excretion drugs are discharged out of the body
drug body Pharmcodynamic effect Pharmcokinetic process elimination (E) administration body Pharmcodynamic effect Pharmcokinetic process excretion out of (A. D. M) elimination (E)
Excretory routes: > > > > > > > Biliary excretion Renal excretion (肾脏) > (胆囊) > Gaistriintestinal (胃肠道) > Rispiratory (呼吸道) > > Sweat(汗) milk(乳汁) Saliva(唾液) Tears (泪) Sikin (皮肤) >
①Renal excretion ⓐ Filtration ⓑ Nonspecific secretion mechanisms: acidic (anion,阴离子) basic (cation,阳离子) competitive inhibition ⓒPassive reabsorption
② Biliary excretion hepato-enteral circulation Cardiac glycoside 强心苷
Questions: 1. How many factors affect the absorption,distribution? 2. What`s hepatoenteral circulation? What`s its importance?
Questions: 3. Do you can describe characteristics and importance of the hepatic biotransformation of drug.
三、Model of compartment 1、 Model of one opening compartment (po.) M. A. body Drug E. D.
中央室 E. 2、 Model of two opening compartment (po.) PO drug 周边室 A. M. D. 血供丰富组织 血供贫乏组织
4. Eliminationkinetics of drug zero-order kinetics (零级动力学) first-order kinetics (一级动力学)
1、first-order elimination kinetics Constant fraction (恒定比例) of drug is eliminated per unit time.
properties: 3. t1/2 is constant.(t1/2 =0.693 / ke) 1、the major pattern of elimination; 2、Amount of drug eliminated per unit time is in direct ratio with the plasma concentration 3. t1/2 is constant.(t1/2 =0.693 / ke)
Constant amount of drug is eliminated per unit time. 2、zero-order Elimination kinetics Constant amount of drug is eliminated per unit time. 单位时间内药物消除的量恒定。
propertie(特点) 1、the few pattrn of elimination; 2、Amount of drug eliminated per unit time is no relationship 3、t½ is not constant.
Mixed elimination kinetics 3、 Mixed elimination kinetics 混合动力学消除 properties : 1、the few pattrn of elimination: aspirin、phenytoin 2、high concentration--constant amount low concentration –constant fraction 。 3、t½ is constant.
quantitative lows of pharmacokinetics 药动学的 定量规律 一 、quantity—time relationship (一) time - concentration curve(时浓曲线)