2. 浙江大学医学院基础医学系 汤慧芳 Section Ⅵ. Section Ⅵ. Pharmacological Basis of Therapeutics Pharmacological Basis of Therapeutics 药物治疗学基础

3. Chapter 1. Pharmacodynamics Chapter 2. Pharmacokinetics Chapter 3. Factors influencing effect of drug Chapter 4. Anti-neoplastic drugs Basic Concept of Pharmacology

4. 版权所有, 1997 (c) Dale Carnegie & Associates, Inc. Drugs Biological Biological organisms organisms 1. What is pharmacology ? Pharmacokinetics ( 药物代谢动力学, 药动学 ) Pharmacodynamics ( 药物效应动力学, 药效学 )

5. Basic Concept of Pharmacology ( 药物代谢动力学, 药动学 ) ( 药物效应动力学, 药效学 )

6. Pharmacodynamics: Drug action; Mechanisms of drug action Pharmacokinetics: Pharmacokinetics: Absorption( 吸收 ), Absorption( 吸收 ), Distribution( 分布 ), Distribution( 分布 ), Biotransformation( 生物转化 ), Biotransformation( 生物转化 ), Excretion( 排泄 ) Excretion( 排泄 ) Influence factors Influence factors

7. (1)To explain the drug action and the mechanisms of drug action, to direct clinical administration; (2)Research and development of new drugs; (3)To explore the secrets of the life.

8. ( 1)Source of new drugs ● Nature components of plant or others; ● Synthetic and semi-synthetic chemicals; ● Genetic recombination. 4. Research and development of new drugs

9. ● Preclinical study( 临床前研究 ) Pharmacodynamics; Pharmacokinetics; Toxicology. ● Clinical study( 临床研究 ) Clinical trials( 临床试验 ) Bioequivalent test( 等效性试验 ) (2)Process of new drug study

11. The development and testing process required to bring a drug to market in the USA.

13. (1) Preclinical pharmacology Research object: animal Experimental pharmacology in vivo & in vitro Experimental therapeutics animal model of disease Pharmacokinetics Toxicology 5. The research methods of pharmacology:

14. The object of research: Human being The contents of research: Therapeutic effect Adverse reaction Pharmacokinetics (2)Clinical pharmacology

16. Chapter 1. Pharmacodynamics Part 1. Basic action of drug Part 2. Dose-effect relationship Part 3. Mechanism of drug action Part 4. Drug and Receptor

17. 1. Action and effect of drug (1)Concept of action and effect Action: Noradrenaline(NA) stimulating  receptor of blood vessel. Effect: ① Vasoconstriction and BP  ② After BP , reflex heart rate . Part 1. Basic action of drug

18. ● Excitation:  function of organs or systems ● Excitation:  function of organs or systems ● Inhibition:  function of organs or systems ● Inhibition:  function of organs or systems (2)Basic expression of drug action

19. ● Definition of selectivity ● Selectivity is relative ● Clinical significance (3)Selectivity of drug effect

20. (1)Therapeutic effect: ● Etiological( 对因 ) treatment ● Symptomatic( 对症 ) treatment ● Supplement therapy( 补充治疗 ) 2. Therapeutic effect and adverse drug reaction

21. ● Side reaction( 副作用 ) ● Toxic reaction( 毒性反应 ) ● Toxic reaction( 毒性反应 ) ▲ Acute toxicity; ▲ Chronic toxicity ▲ Acute toxicity; ▲ Chronic toxicity ● After effect( 后遗效应 ) ● After effect( 后遗效应 ) ▲ Special toxicity: ▲ Special toxicity: Mutagenesis( 致突变 ), Carcinogenesis( 致癌 ), Teratogenesis( 致畸 ). Mutagenesis( 致突变 ), Carcinogenesis( 致癌 ), Teratogenesis( 致畸 ). ● Allergic reaction( 变态反应 ) ● Allergic reaction( 变态反应 ) ● Idiosyncrasy( 特异质反应 ) ● Idiosyncrasy( 特异质反应 ) ● Drug-induced disease( 药源性疾病 ) ● Drug-induced disease( 药源性疾病 ) (2)Adverse drug reaction(ADR)

22. 1. Dose effect relationships (1)Basic concept of dose Minimal effective dose Minimal lethal dose (threshold dose) Minimal toxic dose Therapeutic dose 0 Dose Invalid dose Effective dose Toxic dose Lethal dose Maximal dose( 极量 )

23. ① Graded response( 量反应 ) ② Quantal response( 质反应 ) (2)Types of effect(response)

24. (3)Dose effect curve ① Dose-effect curve (D, C) E (%) 100 E max 50 0 ED 50 D (C)

25. ② Dose-effect curve (log D, log C) E (%) 100 E max 50 0 ED 50 (pD 2 ) log D (log C)

26. Dose effect curve

27. ③ Dose-effect curve (log D, log C) E 100% Emax 84% slope( 斜率 ) 50% 16% 0 ED 50 (pD 2 ) log D (log C)

28. ● Dose-effect relationships ED 50 : 50% effective dose LD 50 : 50% lethal dose LD 50 : 50% lethal dose ● Concentration-effect relationships EC 50 : 50% effective concentration EC 50 : 50% effective concentration

29. Efficacy 反映 药物的内在活 性 (Intrinsic activity); Potency 反 映药物与受体 的亲和力 (affinity). 2. Efficacy( 效能 ) and Potency( 效应强度 )

30. 3. Individual variability ( 个体差异 ) E Mean ( 平均值 ) 0 D Standard difference ( 标准差, SD)

31. 4. Safety evaluation( 安全性评价 ) Therapeutic index(TI) = LD 50 / ED 50 Margin of safety: ED 95 ~LD 5 or ED 99 ~LD 1 E A B A ’ B ’ 0 log D ED 50 ED 50 LD 50 LD 50 5 % 95 % 50 %

33. Part 3. Mechanism of Drug action 1. Action on receptor( 作用受体 ) 2. Interfering cell metabolism 2. Interfering cell metabolism 3. Influencing transport of substance 3. Influencing transport of substance 4. Action on enzyme( 酶 ) 4. Action on enzyme( 酶 ) 5. Action on ion channel( 离子通道 ) 5. Action on ion channel( 离子通道 ) 6. Action on nucleic acid( 核酸 ) 6. Action on nucleic acid( 核酸 ) 7. Influencing immune system 7. Influencing immune system 8. Non-special action( 非特异性作用 ) 8. Non-special action( 非特异性作用 ) 9. Physicochemical reaction 9. Physicochemical reaction

34. Let’s take a rest !

35. Part 4. Drug and Receptor 1. Concept of receptor (1)Receptor( 受体 ) and Ligand( 配体 ) (1)Receptor( 受体 ) and Ligand( 配体 ) (2)Characteristics of receptor (2)Characteristics of receptor ① Sensitivity( 灵敏性 ) ① Sensitivity( 灵敏性 ) ② Specificity( 特异性 ) ② Specificity( 特异性 ) ③ Saturability( 饱和性 ) ③ Saturability( 饱和性 ) ④ Reversibility( 可逆性 ) ④ Reversibility( 可逆性 ) ⑤ Multiple-variation( 多样性 ) ⑤ Multiple-variation( 多样性 )

36. Affinity( 亲和力 ) Intrinsic activity( 内在活性 ) Agonist( 激动药 ): 有亲和力和内在活性 Antagonist( 拮抗药 ): 有亲和力, 无内在活性 L + R LR L + R LR E 2. Occupation theory( 占领学说 )

37. 3. Dynamics of receptor ( 受体动力学 ) (1)Basic formula [L][R] [L][R] K D = K D = [LR] [LR] K D 为解离常数 K D 为解离常数 L + R LR E L + R LR E

38. Relations between drug concentration and drug effect (A) or receptor- bound drug (B). The drug concentrations at which effect or receptor occupancy is half-maximal are denoted by EC 50 and Kd, respectively.

39. [L][R] ∵ R T = [R]+[LR], K D = [LR] [R]=[R T ] - [LR] [L] ([R T ] - [LR]) ∴ K D = [LR] [L][R T ] = - [L] [LR] [LR] [L] = [R T ] K D +[L] —— Langmuir fomula( 药物反应动力学的基本公式 )

40. Langmuir fomula: [LR] [L] = [R T ] K D +[L] Let: [LR] = r ( 表示药物受体结合 %) [R T ] r [L] = K D 1 – r If r = 50 %, ∴ K D = [L], pD 2 =-logK D =-log[L] (50% E max )

41. pD 2 : 表示激动药与受体亲和力的大小. 其含义为引起 50% E max 所需激动药摩尔浓 度的负对数. pD 2 = – log [L] E 100% E max 50% 0 p D 2 log C

42. A,B,C 三个药与受体的亲和力 (pD2) 不等, 但内在活性 (Emax) 相等 ; C,D,E 三个药与受体的亲和力 (pD2) 相等, 但内在活性 (Emax) 不等.

43. (2)Agonist( 激动药 ), Partial agonist( 部分激动药 ), and Antagonist( 拮抗药 )  : intrinsic activity; * : weak, partially antagonize the effect of agonist; **:antagonizing the effect of agonist. affinity  direct effect + 1 + agonist + 0~1 +* partial agonist + 0 – ** Antagonist

44. (3)Competitive and non-competitive antagonist

45. Competitive antagonist Non-competitive antagonist 100 E max E max E max 50 0 log C 0 log C Agonist (A) Agonist (A’)

46. Competitive antagonism ( 竞争性拮抗 ) ① Antagonist combined with receptor reversiblely; ② it’s action can be completely overcome by increasing the dose of agonist; ③ It has the Dose-Effect curve of agonist parallel shift to the right, and Emax of agonist is unchanged. pA2 is the affinity parameter of com- petitive antagonist ( 表示竞争性拮抗药与 受体亲和力的大小 ).

47. Non-competitive antagonism ( 非竞争性拮抗 ) ① Antagonist combine with receptor irreversiblely; ② it’s action can not be completely over- come by increasing the dose of agonist; ③ It has the Dose-Effect curve of agonist downward shift to the right, and Emax of agonist decreases. pA2’ is the affinity parameter of non- competitive antagonist ( 表示非竞争性拮抗 药与受体亲和力的大小 ).

48. (4)Two model theory( 二态模型学说 ) R* R R*: activated state R : resting state

49. (1) According to ligand: cell nuclear hormone receptor: e.g. corticoid receptor Ad receptor:  1,  2, β1, β2 Ach receptor: M1, M2, M3, M4, M5, N N, N M DA receptor: D1, D2 Histamine receptor: H1, H2 Opioid receptor: μ, ,  GABA receptor, et al. 2. Classification of receptors:

50. (2)According to mechanism of action ① ligand gated ion channel receptor: e.g. N-receptor; GABA receptor e.g. N-receptor; GABA receptor ② G-protein coupled receptor: e.g. Ad receptor; DA receptor; M receptor e.g. Ad receptor; DA receptor; M receptor ③ tyrosine kinase receptor: e.g. insulin receptor e.g. insulin receptor ④ cell nuclear hormone receptor: e.g. corticoid receptor e.g. corticoid receptor

51. 3. Second messenger( 第二信使 ) (1)First messenger: neurotransmitter, peptide hormone, cytokine (2)Second messenger: G-protein, cAMP, cGMP, DAG( 二酰基甘油 ), IP3( 三磷酸肌醇 ) Ca2+

52. 4. Regulation of receptor Down-regulation( 向下调节 ) Up-regulation( 向上调节 ) Tolerance( 耐受性 ), or Refractoriness( 不应性 ) Tachyphylaxis( 快速耐受性 ) Tachyphylaxis( 快速耐受性 ) Receptor desensitizition( 受体脱敏 )

53. Let's have a rest!