Transcript 药理概论1

Section XIII
Introduction of
Pharmacology
- 药理学概论 -
Chapter 1
General Concepts
Human disease: prevention and treatment
Drug therapy
Surgery
Radiotherapy
Physical therapy
Psychological therapy
药理学是药物治疗学的基础理论
Pharmacology can be defined as the study of substances that
interact with living systems through chemical processes,
especially by binding to regulatory molecules and activating or
inhibiting normal body processes.
Medical Pharmacology is often defined as the science of
substances used to prevent, diagnose, and treat disease.
－ Katzung BG (Ed). Basic & Clinical Pharmacology (11th Edition). New
York:McGraw-Hill, 2010.
药理学是研究药物与机体（包括病原体）相互作用的规律及其
原理，是一门为临床合理用药防治疾病提供基本理论的医学基
础学科。
What is Pharmacology studied?
Pharmacodynamics: the actions of the drug on the
body and the mechanisms
Pharmacokinetics: the actions of the body on the
drugs
Influencing factors on the processes of
pharmacodynamics and pharmacokinetics
Drugs
Pharmacodynamics
Human
Body
Action and mechanism
Pharmacokinetics
Absorption, distribution,
metabolism, excretion (ADME),
and drug concentration in the body
Interaction between drug and human body
Drug
Pathogens
Human
Interactions between drug , human body,
and pathogens
药剂学过程
崩解，溶出，与
其他药物相互作
用
药动学过程
ADME
药效学过程
Targets；
疗效，不良反应
The Goals of Pharmacology
Pharmacy
Pharmacology
Therapeutics
Clinical
Pharmacology
Basic
Research
Life Science
Drugs
New
Drug
Screening
and
Evaluation
药物和药品的概念
药物：影响机体生理、生化功能，能够用于诊断、预防
和治疗疾病的物质。
药品：指用于预防、治疗、诊断人的疾病，有目的地调
节人的生理机能并规定有适应证、用法和用量的物质，包
括中药材、中药饮片、中成药、化学原料药及其制剂、抗生素、生化
药品、放射性药品、血清疫苗、血液制品和诊断药品等。
Drug resources and preparation
Nature
sources
Dose
Forms
Synthesis
Human
Bioengineering
Pharmacy
Pharmacology
Research and Development (R&D)
of New Drugs
 新药定义：未曾在中国境内上市销售的药品。
已生产的药品改变剂型、改变给药途径、增加新的适
应证或制成新的复方制剂，亦按新药管理。
 旧定义：我国尚未生产过的药品。
4 Steps of New Drug R&D
1. Preclinical testing（临床前研究）
2. Approval for clinical testing（申请临床研究）
3.
Clinical testing (clinical pharmacology)
（临床研究）
4.
Approval for production and marketing
（申请生产）
1. Preclinical testing
Efficacy (screening and evaluation by pharmacological methods)
Safety (evaluation by toxicological methods)
Quantity (pharmacy)
good laboratory practice（GLP）
2. Clinical testing
Efficacy (therapeutic effects)
Safety (adverse effects)
Pharmacokinetics (PK parameter or bioavaibility)
good clinical practice (GCP)
The phases of drug development
Chapter 2
General Considerations
of Pharmacology
Part 1
Pharmacodynamics
药物效应动力学
Pharmacological Action - Overview
 1.1 Action and effect of drug
 Action
 Specifically primary action between drug
and cells or molecules
 Effect
 Apparent functional and morphological
changes induced by drug directly and/or
indirectly
 1.2 Direct and indirect effects of drugs
 Direct effects:
 Effects resulted from the action of drug on
the target organ(s) or tissue(s)
 Indirect effects:
 Effects resulted from functional integration
of target system(s) and modulation system(s)
Action on
vascular 1
receptors
Action
BP ↑
direct
HR ↓
indirect
Neuroendocrine
modulation
Effect
 1.3 Selectivity of drug effect
 Selectivity: Organs / Tissues
 Specificity: Biomolecules
 Reasons of selectivity
 Drug distribution
 Biological properties of tissues or organs
bronchodilation
Salbutamol
heart rate↑
BP ↑
Epinephrine
bronchodilation
Selective effects of βreceptor agonists on the
treatment of bronchial asthma
 1.4 Basic effects of drugs
 Excitation or Inhibition of the functions of the body
 Kill or suppress the pathogens
1.5 Therapeutic effect and adverse reaction
(desirable and undesirable effects)
Balance the ratio of benefits / risk !!
 1) Therapeutic effects (efficacy)

治疗作用（疗效）

(1) Etiological treatment

(2) Symptomatic treatment

(3) Supplement therapy
 2) Adverse drug reactions (adverse effects)
不良反应
 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”。
 (1) Side effect（副作用） undesirable 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）
 (2) Toxic effect （ 毒 性 反 应 ）
Functional 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）
 (3) After effect（后遗效应） 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)
 (4) Allergic reaction (Hypersensitivity)
（变态反应，药物过敏）Abnormal
immunological reactions induced by drugs.
( 接触药物后发生的异常免疫反应 )
 (5) Idiosyncratic reactions （ 特 异 质 反 应 ） 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 )
 (6) Others
 Secondary reaction （继发效应） 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 )
 Withdrawal symptoms （ 停 药 反 应 ） Clinical
syndrome appeared or worsened when the drug is
terminated. ( 突然停药后原有疾病复发或加剧 )
 Dependence （依赖性）
 An adaptive state that develops in response to
repeated drug administration.
 Psychologic dependence is manifested by compulsive drugseeking behavior.
 Physiologic dependence is present when withdrawal of drug
produces symptoms and signs.
 Drug addiction is defined as the compulsive, out-of-control
drug use, despite negative consequences.
 Drug abuse: any use of a drug for non-medical purposes.

(a maladaptive pattern of drug use leading to clinically
significant impairment or distress)
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）
Generally considered
Currently recognized
2.1 Dose (concentration)
Clinical or Experimental doses
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
 2.3 Dose-effect curve or dose-response curve

( 量效曲线 )
 （1）logD-E (logC-E): S-shaped curve
 Graded in vitro：pD2 , EC50 , IC50 , MIC ……

in vivo：PD100, ID30 , ……
 Quantal median 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）
Concentration-effect curve (graded response)
Dose-effect curve (quantal response)
 （2）Maximal effect and potency
 Maximal effect (最大效应) or efficacy
maximal magnitudes of effects
(效能):
different
 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
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
 1.4 Rask 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
Therapeutic index
Therapeutic index
Safety margin
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.
CH 2
CH
CH 3
O
Atropine
NCH3 CH
CH 2
CH
CH
CH
HO
CH
CH
CH
CH
CH
C6H5
Peripheral
& Central
CH2 OH
CH 3
O
C
O
CH
CH 3
CH 3
C6H5
Scopolamine
Central
CH 2 OH
CH 3
NCH3 CH
CH 2
CH
CH3
NCH3 CH
O
C
O
O
O
C
CH
CH 2 OH
Anisodamine
C6H5
Peripheral
HO
HO
CH
Norepinephrine
NH2
CH 2
 receptor
OH
HO
HO
CH
, 
CH 3
OH
HO
HO
Epinephrine
NH
CH 2
receptors
CH 3
CH
CH2
N
CH
CH 3
OH
Isoprenaline
 receptor
 3.2 Non-specific mechanisms (非特异性机制)
 （1）Physioc-chemical reactions

Antacids, mannitol, dextran, ……
 （2）Membrane-stablizing

Anesthetics, ethanol, ……
 （3）Disinfectants
 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)
Specific mechanisms：Actions on cell functions
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 antitumor drugs
Drugs acting on ion channels
Furosemide inhibits
Na+-K+-2Cl--transporter
Neurotransmitter transporter
inhibitors
Drugs acting on transporters
Targets of drug
4- Drug receptors
Key events in the discovery and establishment of the
concept of 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 binding with a specific ligand;
signal transduction
 Structure: a protein with ligand-binding domain and
effector (transducer) domain
 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)
 4.2 Receptor classification
 (1) G protein-coupled receptors
7TM受体)
(G蛋白偶联受体, GPCR,
 (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)
Another classification
(1) Cytosolic [or nuclear] receptors
(2) Receptors as enzymes
酪氨酸激酶活性[或偶联]受体
(3) Receptors coupled by enzymes
(4) Ligand-gated ion channel receptors
(5) G protein-coupled receptors
Black box and
mechanistic approaches
to pharmacology
Examples:
M cholinoceptor
Adrenoceptors
5-HT receptors
DA receptors
Opioid receptors
ect.
G protein-coupled receptors (GPCR)
GPCR signal
transduction
PKA
IP3-Ca2+ / PKC
cAMP-PKA
Examples:
N cholinoceptor
GABAA receptor
5-HT3 receptor
NMDA receptor
Ligand-gated ion channel receptors
Receptors as
enzymes
Growth factor
receptors
Receptors
coupled by
enzymes
Cytokine
receptors
Cytosolic
receptors
Steroid receptors as
transcript factors
Nuclear receptors: thyroid receptor as a transcript factor
 4.3 Interactions of drug and receptor
D＋R
DR
E
 Occupation theory: Drug binds to its
receptor, then produce physiological effects
 Binding properties
 Binding assay（radioactive tests）
 KD＝[D][R] / [DR]
 Bioassay（biological effect tests）
 E/Emax＝[DR] / [RT]＝[D] / {KD+[D]}
 （1） Affinity（亲和力）

ability of drug to bind to the receptor
 Ligand binding tests：KD；KB
 In vitro effect test：pD2（negative log molar
concentration of the agonist which produces
50％ of the maximal effect）
 （2） Intrinsic activity（内在活性）

Ability of drug to produce effects after
binding to the receptor

E/Emax＝α·[DR] / [RT]
Intrinsic
activity
Affinity
Concentration-effect curve：different affinity
same intrinsic activity
Intrinsic activity
Affinity
Concentration-effect curve：same affinity
different intrinsic activity
 4.4 Agonists and antagonists
 Drugs that act on receptors can be classified
into three types based on their affinity,
intrinsic activity and produced physiological
effect ：



Full agonist (激动药)
Partial agonist (部分激动药)
Antagonist (拮抗药)
 Classification of drugs that acting on receptors






Affinity
Agonist
Yes
Antagonist Yes
Partial
agonist
Yes
Intrinsic activity
Yes（100％）
None（ 0％）
Effects
Yes
None，
blocking agonist
Weak（0～100％） Weak ,
blocking agonist
Box
Recently，there are new classes of drugs
that act on the receptors：
inverse agonist (反向激动剂) or negative
antagonist （负拮抗剂）
具有拮抗剂特点，本身又产生与激动剂相反的效应。
co-agonist (协同激动剂)
与其它激动剂共同发挥效应。
4.5 Competitive and non-competitive antagonism
（竞争性和非竞争性拮抗）
Antagonist
none
lower
Antagonist
higher
none
lower
higher
agonist
agonist
A：Effect of a competitive antagonist on agonist concentration- response
curve (affinity – pA2)
B： Effect of a non-competitive antagonist on agonist concentrationresponse curve
Co-agonist
Possible mechanisms of
antagonisms
 4.6 Regulation of receptors
 (1) Desensitization （脱敏）


Receptor phosphorylation
Internalization or Endocytosis
Reversible
同种脱敏
异种脱敏
Receptor phosphorylation and internalization
 (2) Changes of receptor numbers

Down-regulation （向下调节，下调）

Up-regulation（向上调节，上调）