Transcript Introduction-1

WELCOME TO PHARMACOLOGY
PHARMACOLOGY
药 理 学
张岫美
Zhang Xiu-mei
山东大学医学院
药理学研究所
教学八楼8325
Tel: 83146
Email: [email protected]
CHAPTER 1
INTRODUCTION
1. The Nature and Duties of Pharmacology
Pharmacology（药理学）
To study the principles of interactions
between drug and living system which
includes human body, tumor cells and
microorganisms and its mechanisms.
Drug (药物，medicine, pharmakon,
remedy, materia medica）
Chemical substances (exogenous or
endogenous substances e.g., synthetic
drugs, hormones, antibiotics, peptides,
and DNA fragments etc.) used to treat,
prevent and diagnosis diseases.
Even including family planning
chemicals and rat poisons.
Poison （毒物）
Chemical substances to harm or injure
human health in small dose.
Some times poison can be used as a drug in
suitable dose, such as toxins from plant or
animals(snake venom). Drug may be a
poison when use overdose or long term use.
Barbiturates usually as sleeping drug, when
use over dose it may cause intoxication.
Poison
Sometimes, the differences between drug
and poison is dose.
 The dose makes the poison.
 If something is not a poison，
it is not a drug.
Sources of drugs
Plant - alkaloids, glycoside
Animal – insulin
Microorganisms – antibiotics
Synthetic chemicals
Genetic engineering drugs
Preparations（制剂）
The Main Parts of Pharmacology
a. Pharmacodynamics
(药物效应动力学，药效学)
Drug ≒ Body
b. Pharmacokinetics
(药物代谢动力学，药动学)
Pharmacodynamics
药效动力学
To explain the biochemical or physical
actions of drugs on the body. Include
action, mechanisms, indications,
adverse reactions, contraindications of
the drug.
Pharmacokinetics
药代动力学
To reveal the principles of dynamic
changes of drug in the body.
What drugs do on the body.
The Processes of Drug in the Body
receptor
B
tissue
free
F
bound
circula
Free
absorp
excret
metabolites
Bound
drug
metaboli
Pharmacokinetics
药代动力学
Mainly dealing with the change of drug
concentration in the human or animal
body following administration, i.e., the
changes of concentration in the
dynamic system of liberation,
absorption, distribution, metabolism
and excretion (ADME).
The Duties of Pharmacology
a. To explain the action and its mechanisms
of the drug, to provide the theoretical basis
for clinic, enhancing the drug efficacy and
reducing adverse drug reaction.
b. To develop new drug and new indications of
drug.
c. To explore the pathway of physio-,
biochemi- and pathology of the cells.
The Roles of Pharmacology
Key subject of basic medical sciences.
Part of pharmacy.
Bridges桥梁学科: Basic and clinic, medical
and pharmacy.
The Aims for Pharmacology Learning
Exactly important for a physician to treat
patients by drugs.
The Roles of Pharmacology
If you have learned Pharmacology,
you can become a half of physician.
2. History and Development
of Pharmacology
Materia Medica in China: long history
Pen Tsao（本草） by Shennong, 100 B.C.
Pen Tsao Gang Mu （本草纲目）by Li Shizhen (1596), 52 vols, 1 900 000 characters,
1 892 drugs, 1 160 figures, 11 000
prescriptions.
Pharmacology in the World
Chemistry, biochemistry,
physiology development
Germany chemist
F.W. Serturner(1783-1841)
-- morphine（吗啡,1803）
strychnine(1819), caffeine(1819)
quinine(1820), atropine(1831)
Pharmacology in the World
P. Ehrlich(German,1906):
新胂凡纳明, 606
R. Buchhneim(1820-1879): First
pharmacol. lab, first pharmacol.
textbook, first pharmacol. professor
in the World.
Pharmacology in the World
O.Schmiedeberg(1838-1921):
Experimental pharmacology
– Organic pharmacology
P. Ehrlich et J. N. Langley:
Receptor theory.
Penicillin的发现(Fleming)
1928年的一天，英国细菌学家弗莱明在他的实验
室里研究葡萄球菌。他发现培养细菌用的琼脂上
附了一层青霉菌。这是从楼上研究青霉菌的窗口
飘落进来的。使弗莱明感到惊讶的是，在青霉菌
的近旁，葡萄球菌却不见了。这个偶然的现象吸
引了他，他设法培养这种霉菌进行多次试验，证
明青霉菌产生的物质可以在几小时内将葡萄球菌
全部杀死。这种物质就是弗莱明发明的葡萄球菌
的克星—青霉素。
弗莱明在实验室中
弗洛里（Florey)
造福人类的抗生素
美国制药企业1942年开始批量生产青霉素。青
霉素在世界反法西斯战争中挽救了大量伤病员。
为了表彰他们对人类健康的巨大贡献，弗莱明、
钱恩、弗洛里于1945年共同获得诺贝尔医学和
生理学奖。
Wonderful—阿司匹林
Aspirin
阿司匹林具有悠久的历史。1853年夏尔.弗雷德
里克.热拉尔（Gerhardt）用水杨酸与醋酐合成
了乙酰水杨酸，但没能引起人们的重视；1898年
德国化学家菲.霍夫曼（Felit Hoffmann）重新
进行合成，并为他父亲治疗风湿性关节炎，取得
巨大成功；1899年由德莱塞（Dreser）介绍到
临床，并取名为阿司匹林（Aspirin）。
阿司匹林
1999年3月6日德国拜尔（Bayer）公司在全世
界范围内庆祝阿司匹林的百岁生日。100年全
世界的人们大约服用了数十亿片阿司匹林，
主要用于解热、镇痛、抗炎抗风湿，近年又
在防治心脑血管疾病方面大显身手。阿司匹
林的百年历史是二十世纪发明史中的辉煌篇
章。
Pharmacology in Recent Years
Calcium channel blockers
Angiotensin I converting enzyme inhibitors
Satins
AT receptor antagonist
Pharmacology in China
陈克恢(K K Chen): ephedrine(1923)
“The Father of American Pharmacology”
(TIMES, 1988)
“The Father of Chinese Pharmacology”
(金荫昌, 1999)
张昌绍，邹冈：Analgesic site of
morphine(1963).
Qinghaosu(artemisinin，1970‘)
金国章：rotundine
秦伯益：dihydroetorphine
The Main Branches of Pharmacology
临床药理学：Clinical pharmacology
生化药理学：Biochemical pharmacology
分子药理学：Molecular pharmacology
免疫药理学：Immunopharmacology
心血管药理学：Cardiovascular pharmacology
神经药理学：Neuropharmacology
遗传药理学：Pharmacogenetics
化学治疗学：Chemotherapy
3. Pharmacology in New Drug
Research and Development
New drugs(新药)：Drugs without marketing
in China defined as new drug by Sino Food
and Drug Administration(SFDA,在中国未上
市销售的药物)
Western medicines
Traditional Chinese medicines
Biochemicals
Stages of Drug Development
Preclinical
__X13
Clinical
Marketing
The Steps for Drug Research
and Development(R&D)
Preclinical Research: 临床前研究
Pharmaceutical studies药学研究
Pharmacological studies药理学研究
Preclinical Research
Pharmaceutical studies
Physical and chemical properties:
Structure, technology, standard, quality，
stability and preparation studies.
Preclinical Research
Pharmacological studies
General pharmacology一般药理学
Pharmacodynamics药效学
Pharmacokinetics药动学
Toxicology毒理学
Approved Clinical Pharmacology
Phase Ⅰ: normal 20-30subjects
Phase Ⅱ: more than 100 patients
Phase Ⅲ: more than 300 patients
multiple-center trial.
Approved to manufacture by SFDA
Phase Ⅳ(postmarketing surveillance)
Attrition Rate
Synthesis
1000
Toxicology
30
Decision
Animal Experiments
100
Decision
Clinical Trials
3
Decision
Risk/benefit ratio that we must
not forget about...
In the past...
Y
Today...
Z
X
ETC.
Efficacy
Safety
The Organizations and Regulation for
New Drug Research and Development
Food and Drug Administration (FDA, USA)
Sino Food Drug Administration
(SFDA, China)
The Center for New Drug Evaluation.
GLP(good laboratory practice), GCP(G.
clinical P.), GMP(G manufacture P)
4. How to Learn Pharmacology
Dr. AJ Lehman, Chairman, Department
of Pharmacology, FDA, USA
“You too can learn pharmacology, in
only three lessons: each of them lasting
ten years(学习药理学也许仅需3节课，但
每节课却需要10年时间）” 。
How to Learn Pharmacology
a. Lectures 72 hours
b. Textbook
药理学，杨宝峰主编，第六版；2003
Basic and Clinical Pharmacology, Nineth
edition, 2004 ，B. G. Katzung. McGraw Hill
Co.
c. Experiments
药理学（六版）
主
编：哈尔滨医科大学
副主编：上海第二军医大学
杨宝峰 教授
苏定冯 教授
编委
中南大学湘雅医学院
周宏灏教授
天津医科大学
娄建石教授
北京大学
李学军教授
复旦大学医学院
姚明辉教授
中山大学
颜光美教授
河北医科大学
任雷鸣教授
华中科技大学同济医学院
陈建国教授
山东大学医学院
张岫美教授
第三军医大学
李晓辉教授
南京医科大学
胡
刚教授
浙江大学
方理本教授
合肥医科大学
李
俊教授
中国医科大学
李
吉林大学
杨世杰教授
上海第二医科大学
陈红专教授
哈尔滨医科大学
王
智教授
玲教授
d. References
(1) Goodman ﹠ Gilman’s The Pharmacological
Basis of Therapeutics J.G.Hardman et al,
Tenth ed 2001.
(2) Acta Pharmacol Sin , 中国药理学报
(3) Pharmacological Review
(4)药理学 杨世杰主编，人民卫生出版社，2001年
e. Exam
We will have two times exam, the first exam
is in the end of autonomic drugs; the
second exam in the end of endocrine drugs.
The type of exam is mainly choice
questions and somewhat the
pharmacological terms or answer question.
The Faculty Members
for Pharmacology Teaching
张岫美教授
总论、中枢药理
刘慧青讲师（博士）心血管系统药（组长）
娄海燕讲师（博士）化学治疗药
王姿颖讲师 （博士生）自主神经药
张 斌讲师（博士生）中枢神经药
安 杰讲师（博士生）内脏、内分泌药
陈 琳 薛慧艳
硕士研究生
附：Appendices
一、处方药与非处方药
处方药（prescription-only medicines, ethical drugs,
legend drugs）
（1）疾病必须由医生或试验室确诊，使用药物
需医师处方，并在医生指导下使用，如治疗心血
管疾病的药物。
（2）可产生依赖性的药物：吗啡类、中枢药物等。
（3）药物本身毒性较大：如抗肿瘤药。
（4） 刚上市的新药：对其活性、副作用还要进一步观
察。
非处方药
（nonprescription drugs, over the counter
drugs, home remedies, proprietary
nonprescription drugs, OTC ）
中国2000年1月1日开始施行
遴选原则： 应用安全 疗效确切
质量稳定 使用方便
至今SFDA公布非处方药4109个药品制剂，其中甲类3017
种，乙类1143种。
处方药与非处方药的区别

处方药
非处方药
疾病类型 较重、需医师确诊
较轻
诊断者
医师
患者自我认识和辨别、自我选择
取药凭据 医师处方
无需处方
取药地点 医院药房、药店
药店（甲类）超市（乙类）
剂量
较大
较小，有限定
疗程 长，医嘱指导
短，有限定
保护 新药保护、专利保护
品牌
宣传对象 医师
消费者
广告
不可上广告
批准后，可上大众媒体或广告
二、国家基本药物
（essential drugs, basic drugs）
遴选原则：
临床必需、安全有效、价格合理、使用方便
综合评价突出、中西药并重、稳定提高。
1994年完成中药遴选，1998进行调整，
176个病种，4441个症，1333个品种。
1992～1995年分四批完成西药遴选，
1997年进行调整，共27类740个品种。
三、药品名称
1 中文名 采用中国药品通用名称（药典名称）
2 英文名 采用国际非专利药名（International
nonproprietary names for pharmaceutical
substances, INM）
3 商品名（trade mark name）
普萘洛尔
Propranolol
心得安，恩得来，萘心安
inderal, angilol, cardinol
CHAPTER 3
PHARMCODYNAMICS
药物效应动力学
SECTION 1
Basic Actions of Drug
1. Drug Actions and Effects of
Pharmacological on the body作用与效应
Action（作用） referred to the initial or
primary interaction between drug
molecule with receptors on the cells.
Adrenaline（肾上腺素） stimulate
βreceptors on the myocardial cell to
stimulate the heart.
Effects（效应）
Pharmacological effect: physical
effects secondary to initial drug action.
Adrenaline act on β receptors called
action of adrenaline, stimulating heart
called effects of adrenaline.
Effects
Excitation(stimulation，兴奋): the body
function increase or potentiated by the drug.
Adrenaline accelerate the heart rate and
output. Acetylcholine contracts the gastrointestinal smooth muscle. These effects are
called stimulation. With the dose increase of
the drug it may induce augmentation（亢进）.
For example, overdose of adrenaline may
cause heart failure.
Effects
Inhibition（抑制）: the body function
decrease or suppressed by the drug.
If dose increase largely it may produce
paralysis（麻痹） or failure（衰竭）.
For instances, diazepam安定 induce
sedation and hypnosis. Aspirin lowers
the elevated body temperature.
Selectivity or specificity of
drug action
Selectivity or specificity（选择性，特异性）
Ideally, specificity means that a drug only
binds to one single type of receptor and
cause one single effect. Selectivity means
that a drug binds to one or a few types of
receptors with higher affinity than to other
receptors.
2. Therapeutic Effects of Drugs治疗效果
Therapeutic Effects治疗作用
The effects produced by the drug are the
purposes for the drug use, i.e., the beneficial
effects of the drug. Therapeutic effects are
useful to prevent or treat diseases.
Therapeutic Effects of Drugs
Etiological treatment
对因治疗(治本)
Symptomatical treatments
对症治疗(治标)
(1)Etiological treatment对因治疗
Elimination of the etiological factors by
using drug to cure diseases
a. Therapy by killing pathogens
If an inflammation is caused by the invasion
of pathogens, the application of suitable
antibiotics is preferred. Antibiotics
selectively kill bacteria without harming the
body. Gene therapy, immunotherapy.
b. Supplementary (replacement)
therapy
Lack of endogenous substance may cause many
kinds of diseases. For example, lack of vitamin A
may cause night blindness; lack of thyroid
hormones congenitally may cause cretinism. In
these cases, supplement of the corresponding
substances is an effective way to restore the body to
normal function. The supplement of vitamins,
hormones and other necessary substances of the
body is called replacement therapy.
(2) Symptomatic treatment对症治疗
The disease symptom improvement without
eliminating the cause of the disease.
For instance, pain relieved by aspirin;
hypertension lowered by anti-hypertensive
drugs.
3.Adverse Drug Reactions(ADR)
药物不良反应
The World Health Organization(WHO)
defined the drug adverse reaction:
“Any response to drug that is noxious
and unintended and that occurs at dose
used in man for prophylaxis, diagnosis
or therapy of a disease, or for the
modification of physiological function”.
(1) Side effects副反应
In the range of therapeutic doses, the drug
effects, which are not related to the current
therapeutic purpose, are called side effects.
The pharmacological basis of the presence of
side effects is low selectivity of the drug.
Side effects副反应
For instance, if a muscarine receptor
antagonist, atropine is used to prevent
airway secretion caused by anesthetics,
all other effects of atropine, such as
mydriasis, dry mouth, belong to the side
effects; however, if it is used in
ophthalmology (eye), all other effects
such as, dry mouth, accelerate cardiac
rate etc., belong to the side effects.
(2) Toxic reaction毒性反应
All drugs are capable of producing toxic
reactions if the dose is high enough or drugs
long term used.
A. According to on-speed of drug toxicity:
if toxicity caused by short term use of a
drug, it is called acute toxicity, and if
caused by long term use, called chronic
toxicity.
Toxic reaction毒性反应
B. According to the distribution of drug
toxicity: drug toxicity may be classified
local or systemic toxicity.
C. According to the extent of drug toxicity:
Pharmacological toxicity(most cases are
reversible) and pathological toxicity(part
of cases irreversible)
Toxic reaction毒性反应
Special toxications特殊毒性:
Carcinogenesis致癌: some drug may cause cancer.
Teratogenesis致畸: in few cases some drug may
induce teratogenesis, such as thalidomide.
Mutagenesis 致 突 变 : some special drug can
induce DNA change, resulting in carcinogenesis
or teratogenesis.
(3) After effect (residual effect)
后遗效应
After withdrawal of the drug, the drug
concentration is below the threshold, the
effect still exists, such as after taking
barbiturates, the second morning, the
patient feels hangover, drowsiness, and fatigue.
After effect后遗效应
For instance, stop administration of
hydrocortisone after its long-term use
will cause hypoadrenocorticism which
need several months to recover.
(4)Withdrawal reaction (rebound)
停药反应
Rapid withdrawal when long-term use
some drug may lead to accelerate the
symptoms of ordinary disease, such as
when stop use propranolol for its longterm use in angina patients, which can
provoke angina attacks, arrhythmias, or
myocardial infarction, even more severe
than before.
(5) Allergic reaction变态反应
Hypersensitive reaction: drug allergy is an
altered response to a drug resulting from a
previous sensitizing exposure and an
immunological mechanism.
It is also a pathological allergic reaction of a
drug.
Allergic reaction变态反应
Drug induced allergy have been
reported for almost every drug in
extensively clinical use. Some agents,
such as streptokinase, penicillin,
iodides, phenytoin, and sulfonamides
are truly allergic in nature.
（过敏反应, hypersensitivity）
Allergic reaction变态反应
The drug allergies are manifested as
skin eruption, edema, anaphylactoid
reactions, eosinophilia, immune
complex disorders and contact
dermatitis, and may be most severe
allergic shock in some cases, such as
penicillin caused allergic shock.
(6)Idiosyncrasy特异质反应
Drug idiosyncrasy refers to an abnormal
response to a drug by an individual.
It is quite likely that idiosyncrasy are
genetically abnormalities of enzymes
and receptors. Therefore, these
abnormal response are often referred to
as phamacogenetic disorders.
Idiosyncrasy特异质反应
For example, hemolytic anemia elicited
by primaquine in patients whose red
blood cells are deficient in glucose-6phosphate dehydrogenase; apnea
caused by succinylcholine in patients
with abnormal serum ACh esterase
which is incapable of destroying
succinylcholine as usual.
SECTION 2
Drug Dose and Dose-Effect Relationship
Drug dose(dosage): Amount of drug used
in the prevention or treatment of diseases.
Dose-Effect Relationship
Concentration-effect relationship(CER)
In a certain range of doses, the pharmacological
response is increased with the increase in doses
without evident toxic effects(usually log
concentration is used), the relationship between
dose(or concentration) called CER. The curve of
this relationship called dose-effect curve.
Drug Dose and Dose-Effect Relationship
Concentration-effect
relationship(CER)
Dose-effectc urve
S–shape
Dose-effect
relationship(DER)
1. Graded Dose Response量反应
Graded dose response means the
pharmacological effects of the drugs
expressed in quantity or number, such as the
heart rate by beat, blood pressure by mmHg,
also the contract of ileum in height effected
by the drugs.
Graded Dose Response量反应
(1)Minimum effective dose最小有效量
(最小有效浓度，minimum effective
concentration, threshold concentration,
阈浓度, Cmin)
Cmin means in that minimum dose can cause
the pharmacological effect, indicate the least
amount of drug needed to exert therapeutic
effects.
Graded Dose Response
(2)Maximum efficacy(最大效应，效能,
efficacy, Emax)
Emax means the drug is capable of exerting
maximal effect. The term describes the
maximal biological response produced by a
drug. Efficacy of a drug depends on the
receptor density or the number of active
receptors.
Graded Dose Response
(3)Concentration for 50% of maximum
effect(半最大效应浓度， EC50)
The concentration of a drug that gives rise to
to one-half of the maximum response
(continuous effect)is called median effective
concentration.
Graded Dose Response
(4)Potency效价强度
The term describes the comparative
expression of a drug activity measured in
term of dose required to produce a
particular effect of given intensity
related to a given standard reference.
引起等效反应的相对浓度或剂量。
Potency效价
ED50 is often used to compare potency of drugs.
A drug with low ED50, is more potent than that
with large ED50.
(5)Slope(斜率)
2. Quantal Response质反应
(all-or-non-response)
Quantal Response(all-or-non-response) That
is the pharmacological effects are expressed
in positive or negative, indicating that a
given dose of a drug has or has not evoked a
certain effect in the various subject under
investigation. For example, to test either
presence or absence of hypnosis for a
sedative.
Quantal Response质反应 (all-or-non-response)
Quantal Response
(1) Median effective dose(半数有效量，
ED50): For all-or-none response, the
dose of a drug that gives rise to a
positive response in 50% of the subject.
The more potent the drug, the lower its
ED50.
Quantal Response
(2) Lethal dose致死量
The dose of a drug can cause the
experimental animal to death.
(3) Median lethal dose(半数致死量，LD50)
A dose of a drug that gives rise to the death
of 50% of experimental animals is called LD50.
Quantal Response
(4) Minimum toxic dose(最小中毒量)
(5)Median toxic dose(TD50)
A dose of a drug that cause a toxic
effect in 50% of experimental animal is
called TD50.
3. The Safety of Drug药物的安全性
(1)Maximum dose（极量）
The largest dose of drug is permeated in
clinical use by Pharmacopoeias, if a doctor
uses a dose beyond the maximum
dose, it is over the law. If some thing
happened inducing some harm or injure on
the patient, the doctor prescribed drug is
responsible for this.
The Safety of Drug
(2) Therapeutic index (TI)
＝ LD50/ED50
TI describes the safety of a drug. The larger
value of the TI is, the wider margin between
effective dose and toxic dose is safe.
安全范围
(3) Margin of safety
Margin of safety of the drug is also described
as.
ED99 ～ LD1 or ED95 ～ LD5
SECTION 3
DRUG AND RECEPTORS
Drugs can do two things to recepters:
(1) bind to them (affinity) and
(2) possibly change their behavior
toward the host cell system (efficacy).
1. Mechanisms of Drug Action
The Types of Mechanism of Drug Action:
(1) Physical and chemical reaction
Some drugs are used to treat diseases by physical and
chemical reaction in the body. Such as antacids
neutralizing gastric acid are used to treat ulcer and
osmotic diuretic dextran increasing osmolarity of
plasma, is used to treat edema; and metal chelating
agents combine to toxic metals.
(2)Joining or interfering with
cell metabolism
Vitamins, iron preparations and some
anticancer drugs whose chemical structure
resemble purine or pyrimidine are called
counterfeit incorporation or antimetabolite.
The effects of these substances are through
joining or interfering with cell metabolism.
(3) Affecting transportation of
physical substances
The actions of ephedrine and aramine
induce partly the release of norepinephrine
from noradrenergic nerve endings. And
reserpine, a hypotensive agent, affect the
uptake of norepinephrine.
(4) Affecting enzyme activity
Many drugs produce their effects by selectively
interacting with corresponding enzymes, for
example, neostigmine exerts its cholinergic effect
by inhibiting activity of AChE; digitalis enhance
the cardiac contraction by inhibiting Na/K-ATPase
activity on myocardial membrane; sulfonamides
produce bacteriostatic effects by inhibiting the
activity of dihydrofolate synthase of bacteria.
(5) Affecting ion channels on the
cell membrane
Calcium, sodium and potassium ion channels
may be affected by drugs and then to exert
its pharmacological effects.
Calcium and sodium channel blockers, and
potassium channel openers used in the
treatment of cardiovascular diseases because
of the affection to these ion channels.
(6) Affecting immunology function
The immunosuppressive and immunomodulating agents result in efficiency
by influencing body immunity function.
(7)Affecting nucleotide metabolism
The DNA and RNA are vital substances
which control DNA reproduce protein
synthesis and cell split, many
anticancer drugs exert effective action
on cancer cells by interrupting DNA and
RNA metabolism of cancer cells.
(8) Drugs and receptors
A (specific) receptor can be defined as many
biologic target macromolecule in cells that
interacts specifically with extracellular
signal, e.g., a drug and converts it into
intracellular effects. Receptor determine the
maximum effect of a drug, i.e., the response
extent is proportional to the number of drugreceptor interaction.
2. Drug and Receptors
(1) Development of Receptor
theory
a. Langley(1878): Intercounter
of atropine with pilocarpine in
salivary excretion.
Development of Receptors therory
b. Langley(1906): Intercounter
tubocurarine with nicotine in
skeletal muscle – “receptive
substance”
c. Ehrlich(1908): “lock and key
(receptor)”
Receptor Theory:
the Pride of Pharmacologists！
d. Clark(1926-33): Acetylcholine on
heart contraction.
e. Dale, Ahlquist, Gaddum, Schild,
Sutherland, et al.
受体学说：药理学的灵魂
如果把受体学说从医学中抽掉，医学将
不再是医学，就像临床医学专业中没有
药理学科一样。
Drug-Receptor Interactions
Drug
Ligand-binding
domain
Effector domain
Drug-Receptor
Complex
k1
k2
Receptor
Effect
Maximal effect • [Drug]
Effect =
KD + [Drug]
3. The Concept and Properties
of Receptors
(1)Concept
A specific receptor can be defined as any
biological component of cells that specifically
with a endogenous ligand or with a
exogenous drug, and induce pharmacological
effects.
Receptors
Endogenous ligand or drug or autacoid
(prostaglans, serotonin): first messenger.
cAMP, cGMP, Ca2+, IP3 and DAG and so on:
Second messenger.
(2) Properties性质
a. Senitivity 灵敏性
b. Specificity 特异性
c. Saturability饱和性
d. Reversibility可逆性
〔R〕+ 〔L〕≒ 〔RL〕→ Effect
〔E〕+ 〔S〕≒ 〔ES〕≒〔ES〕’
→ E + Metabolites
e. Multiple-variation多样性
4. Interaction between Receptor and
Drug (receptor theory)
Binding force for receptor and ligand:
Van der Walls force, ion, hydrogen,
convalent band.
(1)Occupation theory (Clark,1926)
①药物作用强度与药物占领受体的数量成正
比,药物与受体的相互作用是可逆的
[D] + [R] = [DR] →→ E
Occupation theory
②药物浓度与效应服从质量作用定律;药物
占领受体的数量取决于受体周围的药物浓
度、单位面积或单位容积内受体总数。
③被占领的受体数目增多时,药物效应
增强, 当全部受体被占领时,药物效
应达Emax.
(2) Kinetics of Receptor and Drug
[D] + [R] = [DR] →→ E
KD = [D][R]/[ DR]
KD: dissociation constant
Because [RT] = [R] + [ DR]
(RT: total receptors)
[DR]/[RT] = [D]/KD + [D]
Kinetics of Receptor and Drug
Because only DR is effective,
E/Emax = [DR]/[RT] = [D]/ KD + [D]
When [D] = 0, E = 0
When [D] >> KD,
[DR]/[RT] = 100%, Emax
[DR]max = [RT]
When [DR]/[RT] = 50%, EC50,
KD = [D]
Kinetics of Receptor and Drug
KD = [D]
KD express affinity (mole) of D to R.
The more the KD, the little the affinity.
Affinity means the measure of the
propensity of a drug to bind with a given
receptor.
Affinity
If pD2 = -log KD
pD2 is the affinity index, the larger the
pD2 , the higher the affinity of the drug
to the receptors.
Intrinsic activity
Intrinsic activity proposed by Ariens (1954):
Intrinsic activity (α，内在活性) is the
biological response induced by drug-receptor
interaction. The efficacy of a drug is
decided by its intrinsic activity.
0 <α≤100%
E/Emax = α[DR]/[RT]
Other Theories
(2) Two-model Theory二态模型学说
4. Drugs on the Receptors
(1)Agonist激动药
Affinity with intrinsic activity.
Full agonist完全激动药 : α= 1
Partial agonist (部分激动药, mixed
agonist) Affinity with weak intrinsic
activity: α< 1
Reverse agonist(反向激动药)
Drugs on the Receptors
(2) Antagonist拮抗药
Affinity without intrinsic activity.
α= 0
Antagonist拮抗药
A. Competitive antagonist
竞争性拮抗药
Ligand (L)
Inhibitor(I)
[RT] = [R] + [LR] + [IR]
[LR]/[RT] = [L]/KD + [L]
[LR]/[RT] = [L]/[L] + KD(1 + [I]/KI)
Competitive Antagonist
药物的作用取决于 [I]/KI，
[I]浓度愈高或KI愈小,激动药的效应低，
拮抗作用强。
如果[LR]/[RT]→100%, 激动药的量效
反应曲线可以被竞争性拮抗药平行右移。
如果增加竞争性激动药浓度，仍可达到
Emax.
Competitive Antagonist(A)
激动药的量效反应曲线被竞争性拮抗药平行右移,
如果增加竞争性激动药浓度，仍可达到Emax。
Competitive Antagonist(A)
激动药的量效反应曲线被竞争性拮抗药平行右移,
如果增加竞争性激动药浓度，仍可达到Emax。
Competitive Antagonist
pA2 is the antagonism parameter
pA2 = -log[I] = -logKI
pA2 Express the extent of antagonism of a given
antagonist, when the agonist and antagonist are
used in same preparation, two times concentration
(X2) of agonist(A2) only produce ordinary
concentration of that agonist effect, in that time the
negative log concentration of antagonist is called as
pA2 .
B. Noncompetitive antagonist
非竞争性拮抗药
Spare receptors ( by Stephenson 1956)
储备受体
Uncompetitive Antagonist(B)
激动药的量效反应曲线不能被非竞争性拮抗药平行右移,如果
增加激动药浓度，不能达到Emax。
5. The Types of Receptors
According to protein structure,
transmembrane signaling mechanisms,
effect properties and sites of receptors,
the classifications of receptors as
follows:
The Types of Receptors
(1) G protein coupling receptors
(G-蛋白偶联受体)
Gs, Gi, Gt(transducin), Go
α,β, D, 5-HT, M, Opioid, Purine, PG 受体
Types of Receptors
(2) Ligand-gated ion channel receptors
(配体门控离子通道受体, receptors
containing ion channel)
N, GABA receptors
Ach + N2 receptor → Na+ channel open
→ depolarization → skeletal muscle
contraction.
Types of Receptors
(3) Tyrosine protein kinase receptors
(酪氨酸激酶活性受体)
Insulin(胰岛素)
Epidermal growth factor(上皮生长因子, EGF)
Platelet-derived growth factor
(血小板衍生的生长因子, PDGF)
Transforming growth factor-β
(转化生长因子β, TGF-β)
Insulin-like growth factor(胰岛素样生长因子)
Types of Receptors
(4) Intracellular receptors
(细胞内受体)
Corticosteroids甾体激素
Mineralocorticoids
Sex steroids
Vitamin A, D
Thyroid hormone甲状腺激素
Retinoic acid维甲酸
R R
R R
R
R
B
Genomic mechanism of steroid hormone action
Types of Receptors
(5) Cytokin receptors (细胞因子受体)
Interleukins白细胞介素
Erythropoietin红细胞生成素
Granulocyte macrophage colony
stimulating factors粒细胞巨噬细胞集落刺
激因子(GM-CSF)
Types of Receptors
Granulocyte colony stimulating factors
粒细胞集落刺激因子(G-CSF)
Prolactin催乳素
Lymphokines淋巴因子
See You !
6. Intracellular Signal Transduction
and the Second Messengers
(1) Cyclic adenosine-3’,5’monophosphate (cAMP)
β, D1, H2 → Gs → cAMP↑
α, D2, M, opioid → GI → cAMP↓
(2)Cyclic guanosine-3’,5’monophosphate (cGMP)
肾上腺素受体的作用机制
b1
a2
Gs
Gi
乙酰胆碱M受体
ATP
Adenylyl
cyclase
a1
Gp
Phaspholi
paseC
cAMP
DG+IP3
AC腺苷酸环化酶， PIP2二磷酸肌醇磷脂， IP3三磷酸肌醇（增加胞内钙），
DG甘油二脂（增加胞外钙内流）
PIP2
Intracellular Signal Transduction
and the Second Messengers
(3)Phosphatidyl inositol: IP3, DAG
α1, H1, 5-HT1, M1, M3.
(4)Calcium ion
Ca2+ intracellular less than 1μmole/L.
7. The Regulation of Receptors
(1) Receptor desensitization
受体脱敏
Agonist-specific desensitization
Agonist-nonspecific desensitization
Down-regulation 向下调节
Isoprenaline 异丙肾上腺素
Tolerance 耐受性
The Regulation of Receptors
(2) Receptor hypersensitivity
受体超敏
Up-regulation 向上调节
rebound 反跳
Propranolol普萘洛尔
Thank You !
Welcome to Pharmacology ！
张岫美
山东大学医学院
药理学研究所
Welcome to Pharmacology