浙江大学医学院基础医学系 汤慧芳 Section Ⅵ. Section Ⅵ. Pharmacological Basis of...

浙江大学医学院基础医学系 • 汤慧芳

Section Ⅵ. Section Ⅵ. Pharmacological Pharmacological

Basis of Basis of TherapeuticsTherapeutics

药物治疗学基础药物治疗学基础

Chapter 1. Chapter 1. PharmacodynamicsPharmacodynamics

Chapter 2. PharmacokineticsChapter 2. PharmacokineticsChapter 3. Factors influencing effChapter 3. Factors influencing eff

ect of drugect of drugChapter 4. Anti-neoplastic drugsChapter 4. Anti-neoplastic drugs

Basic Concept of Pharmacology

Basic Concept of Pharmacology

版权所有 , 1997 (c) Dale Carnegie & Associates, Inc.

DrugsDrugs

BiologicBiologicalal

organisorganismsms

1. 1. What is pharmacology ?What is pharmacology ?

PharmacokineticsPharmacokinetics(( 药物代谢动力学药物代谢动力学 , , 药动学药动学

))

PharmacodynamicPharmacodynamicss

(( 药物效应动力学药物效应动力学 , , 药效学药效学 ))

Basic Concept of Pharmacology

(( 药物代谢动力学药物代谢动力学 , , 药动学药动学 ))

(( 药物效应动力学药物效应动力学 , , 药效学药效学 ))

Pharmacodynamics: Drug action; Mechanisms of drug action Pharmacokinetics:Pharmacokinetics: Absorption(Absorption( 吸收吸收 ),), Distribution(Distribution( 分布分布 ),), Biotransformation(Biotransformation( 生物转化生物转化 ),), Excretion(Excretion( 排泄排泄 )) Influence factorsInfluence factors

(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.

(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

● 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

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

(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:

The object of research: Human being

The contents of research: Therapeutic effect Adverse reaction Pharmacokinetics

(2)Clinical pharmacology

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

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 .

Part 1. Basic action of drug

●● Excitation:Excitation: function of organs or function of organs or systemssystems

● ● Inhibition:Inhibition: function of organs or systemsfunction of organs or systems

(2)Basic expression of drug action

● Definition of selectivity ● Selectivity is relative ● Clinical significance

(3)Selectivity of drug effect

(1)Therapeutic effect:● Etiological(对因 ) treatment● Symptomatic(对症 ) treatment● Supplement therapy(补充治疗 )

2. Therapeutic effect and adverse drug reaction

●Side reaction(副作用 )

● ●Toxic reaction(Toxic reaction( 毒性反应毒性反应 )) ▲▲ Acute toxicity; Acute toxicity; ▲▲ Chronic Chronic

toxicitytoxicity

●●After effect(After effect( 后遗效应后遗效应 ))

▲▲ Special toxicity:Special toxicity: Mutagenesis(Mutagenesis( 致突变致突变 ),),

Carcinogenesis(Carcinogenesis( 致癌致癌 ),), Teratogenesis( Teratogenesis( 致畸致畸 ).).

● ●Allergic reaction(Allergic reaction( 变态反应变态反应 )) ●● Idiosyncrasy(Idiosyncrasy( 特异质反应特异质反应 )) ●● Drug-induced diseaseDrug-induced disease(( 药源性疾药源性疾

病病 ))

(2)Adverse drug reaction(ADR)

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 )

①Graded response(量反应 ) ②Quantal response(质反应 )

(2)Types of effect(response)

(3)Dose effect curve ①Dose-effect curve (D, C) E (%)

100 E

max

50

0 ED50 D (C)

②Dose-effect curve (log D, log

C) E (%)

100 Emax

50

0 ED50 (pD2) log D (log C)

Dose effect curve

③Dose-effect curve (log D, log C)

E 100% Emax

84%

slope(斜率 )

50%

16%

0 ED50 (pD2) log D (log C)

● Dose-effect relationships

ED50: 50% effective dose

LDLD5050:: 50% lethal dose50% lethal dose

●● Concentration-effect Concentration-effect relationshipsrelationships

ECEC5050:: 50%50% effectiveeffective

concentrationconcentration

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 )

3. Individual variability (个体差异 ) E Mean (平均值 )

0 D••••

••

••••

Standard Standard difference (difference ( 标准标准

差差 , , SD)SD)

4. Safety evaluation(安全性评价 )

Therapeutic index(TI) = LD50 / ED50

Margin of safety: ED95~LD5 or ED99~LD1

E A B A’ B’

0 log D

ED50 ED50 LD50 LD50

5 %5 %

95 %95 %

50 %50 %

Part 3. Mechanism of Drug action

1. Action on receptor(作用受体 ) 2. Interfering cell metabolism2. Interfering cell metabolism 3. Influencing3. Influencing transporttransport ofof

substancesubstance 4. Action on enzyme(4. Action on enzyme(酶酶 )) 5. Action on ion channel(5. Action on ion channel( 离子离子通通道道 ) ) 6. Action on nucleic acid(6. Action on nucleic acid( 核酸核酸 ))

7. 7. InfluencingInfluencing immune systemimmune system 8. Non-special action(8. Non-special action( 非非特异性作特异性作用用 )) 9. Physicochemical reaction9. Physicochemical reaction

Let’s take a rest !

Part 4. Drug and Receptor 1. Concept of receptor (1)Receptor((1)Receptor( 受受体体 ) and Ligand() and Ligand( 配配体体 )) (2)Characteristics of receptor(2)Characteristics of receptor

① ① Sensitivity(Sensitivity( 灵敏性灵敏性 )) ② ② Specificity(Specificity( 特异性特异性 )) ③ ③ Saturability(Saturability( 饱和性饱和性 )) ④ ④ Reversibility(Reversibility( 可逆性可逆性 )) ⑤ ⑤ Multiple-variation(Multiple-variation( 多样性多样性 ))

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 LRL + R LR

EE

2. Occupation theory( 占领学说 )

3. Dynamics of receptor(受体动力学 )

(1)(1)Basic formula Basic formula

[L][R][L][R] KKDD = = [LR][LR]

KKD D 为解离常数为解离常数

L + R LR L + R LR EE

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 EC50 and Kd, respectively.

[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 )

Langmuir fomula: [LR] [L] = [RT] KD+[L]

Let: [LR] = r (表示药物受体结合%) [RT] r [L] = KD 1 – r

If r = 50 %, ∴ KD = [L],

pD2=-logKD =-log[L] (50% Emax)

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%

0 pD2 log C

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 .

(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

(3)Competitive and non-competitive antagonist

Competitive antagonist Non-competitive antagonist

100 Emax Emax

Emax

50

0 log C 0

log C Agonist (A) Agonist (A’)

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).

Non-competitive antagonism(非竞争性拮抗 )

①Antagonist combine with receptor irreversiblely;

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 ).

(4)Two model theory(二态模型学说 )

R* R R*: activated state

R : resting state

(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.

2. Classification of receptors:

(2)According to mechanism of action ①①ligand gated ion channel ligand gated ion channel

receptor:receptor: e.g. e.g. N-receptor; GABA receptorN-receptor; GABA receptor②②G-protein coupled receptor: G-protein coupled receptor: e.g. Ad receptor; DA receptor; M receptor e.g. Ad receptor; DA receptor; M receptor ③③tyrosine kinase receptor: tyrosine kinase receptor: e.g. insulin receptore.g. insulin receptor④④cell nuclear hormone receptor:cell nuclear hormone receptor: e.g. corticoid receptore.g. corticoid receptor

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+

4. Regulation of receptor

Down-regulation(向下调节 ) Up-regulation(向上调节 )

Tolerance(Tolerance( 耐受性耐受性 ), ), ororRefractoriness(Refractoriness( 不应性不应性 )) Tachyphylaxis(Tachyphylaxis( 快速耐受性快速耐受性 ))Receptor desensitizition(Receptor desensitizition( 受体脱受体脱

敏敏 ))

Let's have a rest!