Chapter 1 Pharmacodynamics 药物效应动力学

1. Chapter 1Pharmacodynamics药物效应动力学 • Pharmacological action - Overview • Dose-effect relationship • Mechanisms of drug actions • Drug receptors

2. 1-Pharmacological Action - Overview • 1.1 Action and effect of drug • Action 作用 • Specifically primary action between drug and cells or molecules • Effect 效应 • Apparent functional and morphological changes induced by drug directly and/or indirectly

3. 1-Pharmacological Action - Overview • 1.2 Direct and indirect effects of drugs • Direct effects（直接效应）: • Effects resulted from the action of drug on the target organ(s) or tissue(s) • Indirect effects（间接效应）: • Effects resulted from functional integration of target system(s) and modulation system(s)

4. BP ↑ direct Action on vascular 1receptors HR ↓ indirect Neuroendocrine modulation Action 作用 Effect 效应

5. 1-Pharmacological Action - Overview • 1.3 Selectivity（选择性）of drug effect • Selectivity 选择性: Organs / Tissues • Specificity 特异性:Biomolecules • Reasons of selectivity • Drug distribution • Biological properties of tissues or organs

6. bronchodilation 支气管扩张 Salbutamol 沙丁胺醇 heart rate↑ BP ↑ bronchodilation 支气管扩张 Epinephrine 肾上腺素 Selective effects ofβreceptor agonists on the treatment of bronchial asthma

7. 1-Pharmacological Action - Overview • 1.4 Basic effects（基本作用）of drugs • Excitation（兴奋）orInhibition（抑制）of the functions of the body • Kill or suppress the pathogens

8. 1-Pharmacological Action - Overview 1.5 Therapeutic effect and adverse reaction (desirable and undesirable effects) 治疗作用和不良反应

9. Balance the ratio of benefits / risk !! 平衡用药的利弊！！

10. 1-Pharmacological Action - Overview • 1) Therapeutic effects 治疗作用(Efficacy疗效) • (1) Etiological treatment（对因治疗） • (2) Symptomatic treatment（对症治疗） • (3) Supplement therapy（补充治疗）

11. 1-Pharmacological Action - Overview • 2) Adverse drug reactions (Adverse effects) • 不符合用药目的，并对病人带来不适或痛苦的反应（广义） Box 1 现在，我国将不良反应定义为上市药品在正常用法用量情况下出现的与用药目的无关的有害反应。以区别于药物过量（overdose），在本课程中将两者合称为“不良反应”。

12. 1-Pharmacological Action - Overview • (1) Side effectundesirable effects of that drug for that therapeutic indication at usual doses, usually are non-deleterious. （治疗剂量时出现的与治疗目的无关的药物作用） GI ↓ Constipation Gland ↓ Dry mouth Atropine Mydriasis Blurring vision Bladder↓ Urine retention HR ↑ Palpitation

13. 1-Pharmacological Action - Overview • (2) Toxic effectFunctional or morphological damages produced by larger doses of longer terms of drug uses. （剂量过大或用药时间过长体内蓄积过多时发生的危害性反应） • Local & system toxicity • Reversible & irreversible toxic reactions • Acute & delayed/chronic toxicity • Teratogenic / carcinogenic effects

14. 1-Pharmacological Action - Overview • Box 2药源性疾病(drug-induced diseases) • 严重的不良反应可以引起疾病，这种由药物不良反应引起的疾病称为药源性疾病，它主要是不合理用药造成的。药源性疾病实际上是药物不良反应在一定条件下产生的后果，一般来说，药源性疾病不包括因使用药物超过极量所引起的急性中毒。

15. 1-Pharmacological Action - Overview • (3) After effect • Effects after drug concentration in the body is lower than threshold level. • (停药后血药浓度已降至阈浓度之下时残存的药理效应) • Short-lasting：e.g.Barbiturates • Long-lasting：e.g.Glucocorticoids

16. 1-Pharmacological Action - Overview • (4) Allergic reaction ( Hypersensitivity ) • Abnormal immunological reactions induced by drugs. • ( 接触药物后发生的异常免疫反应) • Types I, II, III, IV • Skin, fever, blood-forming organs, anaphylactic shock

17. 1-Pharmacological Action - Overview • (5) Idiosyncratic reactions • A genetically determined abnormal reactivity to a chemical. • (少数特异质病人对某些药物特别敏感，反应性质也可能与常人不同) • Genetic abnormality • Examples: • Deficiency of erythrocytic glucose-6-phosphate dehydrogenase • Hypersensitivity to scoline

18. 1-Pharmacological Action - Overview • (6) Others • Secondary reaction • Adverse reactions resulting from primary therapeutic effects of drugs. • (继发于药物治疗作用之后的不良反应) • Example: • Broad-spectrum antibiotics induce overgrowth of resistant bacteria (superinfection)

19. 1-Pharmacological Action - Overview • Withdrawal symptoms • Clinical syndrome appeared or worsened when the drug is terminated. • ( 突然停药后原有疾病复发或加剧) • Examples: • Propranolol－ CHD • Clonidine－ hypertension • Anti-epileptic drugs－ epilepsy

20. 1-Pharmacological Action - Overview • Dependence 依赖性 • An adaptive state that develops in response to repeated drug administration. • Psychologic dependence 精神依赖性is manifested by compulsive drug-seeking behavior. • Physiologic dependence 生理依赖性is present when withdrawal of drug produces symptoms and signs. • Drug addiction 药物成瘾is defined as the compulsive, out-of-control drug use, despite negative consequences. • Drug abuse 药物滥用:any use of a drug for non-medical purposes. • (a maladaptive pattern of drug use leading to clinically significant impairment or distress)

21. 1-Pharmacological Action - Overview • Box 3药物不良反应的分型 • 剂量关系密切型(甲型)：是药物固有药理作用的延续和增强，包括的副作用、毒性反应。具有剂量依赖性和可预测性的特点。 • 剂量关系不密切型(乙型)：与药物固有药理作用无关的异常反应，与变态反应或高敏体质有关。具有与剂量无关和难以预测的特点。 • 特殊型（丙型）：药物引起的癌症、畸胎、染色体畸变等。

22. 2-Dose-Effect Relationship • The observed effect of a drug as a function of its dose in the living system, usually drug results in a greater magnitude of effect as the dose increased. • 药理效应与剂量在一定范围内成比例，称为剂量-效应关系（量效关系） • In vitro studies:concentration-effect relationship

23. 2-Dose-Effect Relationship 2.1 Dose（concentration） Clinical：Threshold doses(阈剂量) Therapeutic (usual) doses(治疗量，常用量) Maximal doses(极量) Toxic doses(中毒量) Lethal doses(致死量) MIC and other concentrations Experimental： in vivo - ED50, TD50, LD50 , …… in vitro-IC50, EC50, ……

24. 2-Dose-Effect Relationship • 2.2 Responses (Effects) • （1）Graded responses （量反应）： • Response changes quantitatively • Measurable responses in an individual • （2）Quantal responses（质反应）： • All-or-none • Percentage of the population

25. 2-Dose-Effect Relationship • 2.3 Dose-effect curve or dose-response curve • ( 量效曲线) • （1）logD-E (logC-E):S-shaped curve • Gradedin vitro：pD2 , EC50 , IC50 , MIC …… • in vivo：PD100, ID30 , …… • Quantalmedian doses: ED50 , LD50 , ID50 …… • （用药个体的一半出现某种效应所需剂量，半数效量）

26. Concentration-effect curve (graded response)

27. Dose-effect curve (quantal response)

28. Individual variability ofdose-effect curve

29. 2-Dose-Effect Relationship • （2）Maximal effect and potency • Maximal effect (最大效应) or efficacy (效能):different maximal magnitudes of effects • Potency (效价强度):difference in doses that produce an effect at same level（等效剂量） • 药物作用强弱及敏感程度的比较

30. Potency:B > A > C > D Efficacy:A = C = D > B Slope:D > A, B, C Efficacy:loop diuretics > thiazide diuretics;morphine > aspirin Potency:difference in the effective doses of same type drugs

31. 2-Dose-Effect Relationship • 1.4 Risk and its assessment (安全性评价) • （1）Therapeutic index（治疗指数, TI） • TI＝LD50/ED50， • （2）Safety margin:LD5～ED95 • or LD1～ED99

32. Therapeutic index Therapeutic index Safety margin 安全范围

33. 3- Mechanisms of Drug Actions • 3.1 Structure-Activity Relationship • (构效关系) • Both the affinity of a drug and its functional activity are determined by its chemical structure. • Relatively minor modifications in the drug molecule may result in major changes in pharmacological properties.

34. Atropine 阿托品 Peripheral & Central 中枢/外周 Scopolamine东莨菪碱Central 中枢 Anisodamine 山莨菪碱 Peripheral 外周

35. Norepinephrine去甲肾上腺素  receptor Epinephrine 肾上腺素 ,  receptors Isoprenaline 异丙肾上腺素  receptor

36. 3- Mechanisms of Drug Actions • 3.2 Non-specific mechanisms (非特异性机制) • （1）Physioc-chemical reactions • Antacids, mannitol, dextran, …… • （2）Membrane-stablizing • General anesthetics, ethanol, …… • （3）Disinfectants

37. 3- Mechanisms of Drug Actions • 3.3 Specific mechanisms (特异性机制) (1)Receptor(受体) (2) Enzyme(酶) (3) Ion channel(离子通道) (4) Transporter(转运体) (5) Immune system(免疫系统) (6) Gene therapy (基因治疗)& genetic engineering drugs (基因工程药物) (7) Others (其他)

38. Specific mechanisms：Actions on cell functions

39. Enzyme-targeting drugs Acetylcholinesterase inhibitor Cyclo-oxygenase inhibitor Angiotensin converting enzyme inhibitor Na+-K+-ATPase inhinitor H+-K+-ATPase inhinitor HMG-CoA reductase inhibitors Most of antibiotics and anti-tumor drugs

40. Drugs acting on ion channels

41. Neurotransmitter transporter inhibitors Furosemide inhibits Na+-K+-2Cl--transporter

42. Targets of drug

43. 4- Drug receptors Key events in the discovery and establishment of the concept of receptors

44. 4- Drug receptors • 4.1 Concept of receptors • Receptor:the component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drug’s observed effects. • （受体：细胞膜或细胞质的特异性蛋白质，具有识别、结合配体，并发生信号转导的作用） • Function:recognizing and bindingwith a specific ligand;signal transduction • Structure:a protein withligand-bingdingdomain andeffector (transducer) domain

45. 4- Drug receptors • Ligand:Chemicals that can bind to receptors, including endogenous or exogenous agonists and antagonists • (配体：能与受体特异性结合的物质，分为激动剂和拮抗剂；根据来源分为内源性和外源性两类)

46. 4- Drug receptors Characteristics of receptor （interaction between drug and receptor) a) Sensitivity (灵敏性) b) Specificity (特异性) c) Saturability (饱和性) d) Reversibility (可逆性) e) Multiple-variation (多样性)

47. 4- Drug receptors • 4.2 Receptor classification • (1) G protein-coupled receptors(G蛋白偶联受体, GPCR, 7TM受体) • (2) Ligand-gated ion channel receptors(含离子通道的受体，配体门控离子通道受体) • (3) Receptors as enzymes or coupled by enzymes • (具有酪氨酸激酶活性[或偶联］受体, 1TM受体) • (4) Cytosolic [or nuclear] receptors(细胞内受体, • 核内受体)

49. Another classification (1) Cytosolic [or nuclear] receptors (2) Receptors as enzymes (3) Receptors coupled by enzymes (4) Ligand-gated ion channel receptors (5) G protein-coupled receptors

50. Examples: M cholinoceptor Adrenoceptors 5-HT receptors DA receptors Opioid receptors ect. G protein-coupled receptors (GPCR)