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浙江大学医学院 基础医学系 • 汤慧芳

Section Ⅵ. Pharmacological Basis of Therapeutics. 浙江大学医学院 基础医学系 • 汤慧芳. 药物治疗学基础. Basic Concept of Pharmacology. Chapter 1. Pharmacodynamics Chapter 2. Pharmacokinetics Chapter 3. Factors influencing effect of drug Chapter 4. Anti-neoplastic drugs. Basic Concept of Pharmacology.

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浙江大学医学院 基础医学系 • 汤慧芳

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

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

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

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

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

  6. (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.

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

  8. (2)Process of new drug study ● 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)

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

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

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

  12. 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

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

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

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

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

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

  18. 1. Dose effect relationships (1)Basic concept of dose Minimal effective doseMinimal lethal dose (threshold dose)Minimal toxic dose Therapeutic dose 0Dose Invalid doseEffective doseToxic doseLethal dose Maximal dose(极量)

  19. (2)Types of effect(response) ①Gradedresponse(量反应) ②Quantal response(质反应)

  20. (3)Dose effect curve ①Dose-effect curve (D, C) E(%) 100 Emax 50 0 ED50D (C)

  21. ②Dose-effect curve (logD, logC) E(%) 100 Emax 50 0 ED50 (pD2)logD(logC)

  22. Dose effect curve

  23. ③Dose-effect curve (log D, log C) E 100% Emax 84% slope(斜率) 50% 16% 0 ED50 (pD2)logD (logC)

  24. ●Dose-effect relationships ED50:50% effective dose LD50:50% lethal dose ●Concentration-effect relationships EC50:50%effectiveconcentration

  25. 2. Efficacy(效能) and Potency(效应强度) 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).

  26. 3. Individual variability (个体差异)EMean (平均值)0D • • Standard difference (标准差, SD) • • •

  27. 4. Safety evaluation(安全性评价) Therapeutic index(TI) = LD50 / ED50 Margin of safety:ED95~LD5or ED99~LD1 E A B A’B’ 0log D ED50ED50LD50LD50 95 % 50 % 5 %

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

  29. Let’s take a rest !

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

  31. 2. Occupation theory(占领学说) 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 E

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

  33. Relations between drug concentration and drug effect (A) or receptor-bound drug (B). The drug concentrations at whicheffect or receptor occupancy is half-maximal are denoted by EC50 and Kd, respectively.

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

  35. Langmuir fomula: [LR] [L] = [RT] KD+[L] Let: [LR] =r (表示药物受体结合%) [RT] r [L] = KD 1 – r Ifr = 50 %, ∴ KD = [L], pD2=-logKD=-log[L] (50% Emax)

  36. pD2:表示激动药与受体亲和力的大小. 其含义为引起50% Emax所需激动药摩尔浓度的负对数. pD2= –log[L] E 100% Emax 50% 0pD2 log C

  37. 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.

  38. (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

  39. (3)Competitive and non-competitive antagonist

  40. Competitive antagonistNon-competitive antagonist 100Emax Emax Emax 50 0log C 0log C Agonist (A) Agonist (A’)

  41. Competitive antagonism(竞争性拮抗) ①Antagonist combined with receptor reversiblely; ②it’s action can be completely overcome by increasing the dose of agonist; ③It 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).

  42. Non-competitive antagonism(非竞争性拮抗) ①Antagonist combinewithreceptorirreversiblely; ②it’s action can not be completely over-come by increasing the dose of agonist; ③It 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).

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

  44. 2. Classification of receptors: (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, NN, NM DA receptor: D1, D2 Histamine receptor: H1, H2 Opioid receptor: μ, ,  GABA receptor, et al.

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

  46. 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+

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