Transcript Principles_of_pharmacology

药理学
Pharmacology
By
Dechang Zhang
Department of Pharmacology, School of Basic
Medicine, Peking Union Medical College
General Principles
绪论 Introduction
药物基因组学Pharmacogenetics
药物流行病学Pharmacoepidemiology
药物代谢动力学Pharmacokinetics
药物效应动力学Pharmacodynamics
What is Pharmacology?
Pharmacology is the study of how
drugs exert their effects on living
systems.
What is Drug
Drugs can be defined as chemical agents that
interact with specific target molecules,
thereby producing a biological effect.
A drug can be defined as a chemical
substance of known structure, other than a
nutrient or an essential dietary ingredient,
which, when administered to a living
organism, produces a biological effect.
Drugs may be synthetic
chemicals obtained from
plants or animals, or
products of genetic
engineering.
What is Medicine
A medicine is a chemical preparation, which
usually but not necessarily contains one or
more drugs, administered with the intention of
producing a therapeutic effect.
Medicines usually contain other substances
(excipients, stabilisers, solvents, etc.) besides
the active drug, to make them more
convenient to use.
To count as a drug, the substance
must be administered as such,
rather than released by
physiological mechanisms.
Many substances, such as insulin
or thyroxine, are endogenous
hormones but are also drugs when
they are administered intentionally.
In everyday parlance, the word drug
is often associated with addictive,
narcotic or mind-altering substances
- an unfortunate negative
connotation that tends to bias
opinion against any form of chemical
therapy.
Main factors for classifying
drugs
Pharmacotherapeutic actions (may be
multiple)
Pharmacologic actions (may be multiple)
Molecular actions (both site and mechanism)
Other factors (source and chemistry, etc.)
The origins of
pharmacology:
religion,animals and
plants (Sheep,
mandrake flowers and
opium poppy head).
(Frieze from the Palace
of King Sargon II in
Kharasabad,
Mesopotamia , 800BC)
神农本草经记载
了365种药物和
许多方剂。很多
仍然为现在所用。
阿片作为麻醉剂，
大黄作为泻药，
苦艾驱虫，萝芙
木镇静，高岭土
治疗腹泻，麻黄
治疗哮喘。
Most drugs in
antiquity came
from plants and
animal pars of
fluids.
Foxglove is the
plant source of
digoxin
Nightshade
is the
source of
atropine
Knowledge of drugs increased
in parallel with knowledge of
body function (anatomy,
physiology, and biochemistry)
and chemistry.
1628 William Harvey
1785 William Withering
Mordern drug development
depends on academia and
industry working together.
Biotechnology
Originally, this was the production of
drugs or other useful products by
biological means (e.g. antibiotic
production from microorganisms or
production of monoclonal antibodies).
基因工程药物过程示意图
①从细胞中分
离出DNA
①
③
④
②限制酶截取
DNA片断
③分离大肠杆
菌中的质粒
④ DNA重组
⑥
⑤用重组质粒
转化大肠杆菌
⑥培养大肠杆菌
克隆大量基因
Pharmacogenetics
This is the study of genetic influences on
responses to drugs.
Originally, pharmacogenetics focused on
familial idiosyncratic drug reactions, where
affected individuals show an abnormalusually adverse-response to a class of drug
It now covers broader variations in drug
response, where the genetic basis is more
complex.
Pharmacogenomics
This recent term overlaps with
pharmacogenetics, describing the use of
genetic information to guide the choice of
drug therapy on an individual basis.
The underlying principle is that differences
between individuals in their response to
therapeutic drugs can be predicted from their
genetic make-up.
So far, they mainly involve genetic
polymorphism of drug-metabolising
enzymes or receptors
Ultimately, linking specific gene variations
with variations in therapeutic or unwanted
effects of a particular drug should enable
the tailoring of therapeutic choices on the
basis of an individual's genotype. The
consequences for therapeutics will be farreaching.
Pharmacoepidemiology
This is the study of drug effects at the
population level
It is concerned with the variability of
drug effects between individuals in a
population, and between populations.
药物流行病学
pharmacoepidemiology
Pharmacology: 研究药物与人体相互作用的规律和机理，
主要任务是评价药物在人体内的安全有效性。
Epidemiology: 研究疾病和健康在人群中的分布及其影
响因素的一门科学，药物则是影响疾病和健康分布的重
要因素之一。
应用流行病学知识、方法和推理研究人群中药物的应用
及效果药物流行病学(Porta & Hartzema，1987).
主要用途（1）
1. 补充上市前研究中未获得的信息——量化已
知ADR发生率或是有效效益的频率
(1)精确度更高；
(2)了解药物对特殊的人群组的作用；
(3)研究并发疾病和合并用药的影响；
(4)比较并评价新药是否更优于其它常用药物。
主要用途（2）
2. 获得上市前研究不可能得到的新信息
(1)发现罕见的或迟发的不良反应，并用流行病
学的方法和推理加以验证；
(2)了解人群中药物利用的情况；
(3)卫生经济学评价。
3. 总体贡献
(1)确保用药安全
(2)履行伦理和法律的义务
Pharmacoeconomics
This branch of health
economics aims to quantify
in economic terms the cost
and benefit of drugs used
therapeutically.
It arose from the concern of
many governments to provide
for healthcare from tax
revenues, raising questions of
what therapeutic procedures
represent the best value for
money.
“反应停”致海豹肢畸形儿事件
1953年，瑞士Ciba药厂（现瑞士诺华的前身之
一）首次合成了一种名为thalidomide(沙利多
胺，“反应停”）的药物。
This drug was marketed by the Germany
firm Chemie Grünenthal as a safe
alternative to barbiturate hypnotics,
especially for pregnant women on October
1st,1957.
反应停便成了“孕妇的理想选择”（当
时的广告用语），在欧洲、亚洲、非洲、
澳洲和南美洲被医生大量处方给孕妇以
治疗妊娠呕吐。
到1959年，仅在联邦德国就有近100万人
服用过反应停，反应停的每月销量达到
了1吨的水平。在联邦德国的某些州，患
者甚至不需要医生处方就能购买到反应
停。
但是在美国，因为有报道称，猴子在怀孕的第23
到31天内服用反应停会导致胎儿的出生缺陷，美
国食品和药品管理局（FDA）的评审专家(Dr
Frances Kelsey)极力反对将反应停引入美国
市场。最终，FDA没有批准此种药物在美国的临
床使用，而是要求研究人员对其进行更深入的临
床研究（后来的事实证明，这是一项多么明智的
决定！）。
副作用逐渐浮出水面
1956年12月25日，世界上第一例因母亲在怀
孕期间服用反应停而导致耳朵畸形的婴儿就出
生了，但当时并未引起人们足够的注意）。
1960年，在德国卡塞尔举行的一次全国小儿
科会议上，有人报道了两例奇怪的新生儿畸形
病例，但没人加以注意。
联邦德国汉堡大学的遗传学家兰兹博士根
据自己的临床观察于1961年11月16日通过
电话向Chemie Gruenenthal公司提出警
告，提醒他们反应停可能具有致畸胎性。
最后，因为发现越来越多类似的临床报告，
Chemie Gruenenthal公司不得不于
1961年11月底将反应停从联邦德国市场上
召回。
但此举为时已晚，人们此后陆续发现了1万到
1·2万名因母亲服用反应停而导致出生缺陷的
婴儿！
据估计前西德有10000多名病例
英国有8000余例
日本有1000余例
加拿大200多例
Phocomelia
(海豹肢)
A deformity in which
the limbs are
rudimentary stumps
with malformed
digits
1961年年底，联邦德国亚琛市地方法院受理了
全球第一例控告反应停生产厂家Chemie
Gruenenthal公司的案件。
前面提到的兰兹博士在作为控方证人提供证言时，
将自己的观察结果和其他学者的病例报告汇总后如
实提供给了法庭。
1969年10月10日，法庭经过近8年的审理，决
定不采纳兰兹博士的证言。原因是辩方律师找到了
各种理由来证明兰兹博士在作证时不能保持客观公
正的态度。
1970年4月10日，案件的控辩双方于法庭
外达成了和解，Chemie Gruenenthal公司
同意向控方支付总额1·1亿德国马克的赔偿金。
1970年12月18日，法庭作出终审判决，撤
消了对Chemie Gruenenthal公司的诉讼，
但法庭同时承认，反应停确实具有致畸胎性，
并提醒制药企业，在药品研发过程中，应以此
为鉴。
1971年12月17日，联邦德国卫生部利用
Chemie Gruenenthal公司赔偿的款项专门
为反应停受害者设立了一项基金，并邀请兰兹
博士作为此项基金的监管人之一。
此后数年间，在兰兹博士的努力下，联邦德
国有2866名反应停受害者得到了应有的赔偿。
此外，兰兹博士还接受日本同行的邀请，为
帮助日本的反应停受害者进行了大量的工作。
兰兹博士因其为反应停受害者作出的巨大贡
献而受到全球反应停受害者的深深敬仰。
生态学研究
ecological fallacy
生态学谬误
生态学研究中，我们并不知道每个个体的暴露
与疾病状况，也无法控制可能的混杂因素，因
此，这种方法只是粗线条的描述性研究，在结
果解说时必须慎重。
生态学上某疾病与因素分布一致，可能是该因
素与疾病之间确有联系，但也可能在个体水平
二者毫无联系，此即所谓的生态学谬误。
然而早在1965年，一位以色列医生在尝试
把反应停当作安眠药治疗6名患麻风性皮
肤结节红斑（为患麻风病后生长于患者皮肤的一
种疼痛剧烈的结节，是机体对麻风杆菌产生的一种过
度的免疫反应）而长期失眠的麻风病患者时
意外地发现，反应停可以有效地减轻患者
的皮肤症状。而在此之前，医学界虽然找
到了可以有效地杀灭麻风杆菌的药物，但
一直没有找到缓解麻风患者此种过度的免
疫反应的方法。
这位以色列医生将自己的发现公
之于众，并同时提醒医学界人士，在
对反应停的副作用保持高度警惕的同
时，也应该想到反应停可能对其他由
免疫反应异常引起的疾病也有治疗效
果。为此，在此后的数十年间，世界
各地的科学家们一直没有放弃对反应
停的临床研究。
经过大量谨慎而客观的临床实验
观察，科学家们逐渐发现，反应停对
结核、红斑狼疮、艾滋病导致的极度
虚弱和卡波济肉瘤、骨髓移植时发生
的移植物抗宿主病以及多发性骨髓瘤
等多种疾病都有一定的疗效。人们对
反应停的认识开始发生了变化。
1991年，美国洛克菲勒大学的科学
家们在研究中发现，发生过度免疫反应
的麻风病患者的血液中一种免疫调节因
子（TNF-α）的含量很高，他们便推测反
应停对此种反应的良好疗效就是因其对
TNF -α有作用。1992年，他们终于证实
反应停确实能够减低机体合成这种免疫
调节因子的能力。
1995年，美国的两家制药公司在联合
研究反应停对一种名为“多型性成胶质细
胞瘤”的脑瘤的治疗效果时发现，反应停
还具有抗血管生成的作用，而已知丰富
的血液供应是肿瘤细胞在体内存活的必备
条件，所以，科学家们又推测反应停对某
些肿瘤也有治疗作用可能就是缘于其抗血
管生成作用，但迄今为止，这种推测还没
有得到足够的理论支持。
美国FDA一直未批准反应停的临床
应用。为此，各国科学家以及美国国
内反应停生产厂家塞尔基因公司进行
了不懈的努力。
终于，在1998年7月16日，美国
FDA在医学界的强烈要求及大量临床
实验的有力支持下，批准将反应停用
于治疗麻风病的皮肤损害。
反应停目前在美国还没有被正式批准用于
治疗癌症，但已经有很多医生在暗地里尝试将
反应停用于治疗晚期癌症患者的极度衰弱。一
些艾滋病患者也从黑市上购买反应停以治疗爱
滋病导致的极度虚弱和卡波济肉瘤。据估计，
在过去的3年里，已经有超过5万名美国人接受
过反应停的治疗，其中绝大多数是癌症患者，
而在用于治疗多发性骨髓瘤的病例中，也有30
％-50％的患者病情都或多或少地得到了改善。
不久前，塞尔基因公司的发言人在接受媒
体采访时说，目前医学界已经尝试将反应停用
于治疗50多种疾病。但反应停销售总量中只有
约1％是被用于治疗麻风病，将近92％则是被
用于治疗癌症（虽然这并未得到官方机构的认
可）。
现在，全球已经有将近150项有关反应停
的临床实验正在进行之中。全球医学界人士都
翘首以待，希望反应停能够将功补过，在不久
的将来为人类健康作出更大的贡献。
药物效应动力学
（Pharmacodynamics）
作用、作用机制
吸收、分布、代谢、排泄
药物代谢动力学
（Pharmacokinetics）
药物的吸收、
分布与排除
Routes for
administering drugs
gastrointestinal tract：
oral (first pass effect),
sublingual, rectal
injection：intravenous,
intramuscular,
subcutaneous
other：inhalation,
transdermal delivery,
intrathecal or intravitreal
administration, local
administration, nasal
mucosa
Drug molecules move around
the body in two ways:
bulk flow (i.e. in the bloodstream)
diffusion (i.e. molecule by
molecule, over short distances).
The chemical nature of a drug makes
no difference to its transfer by bulk
flow.
In contrast, diffusional
characteristics differ markedly
between different drugs. In
particular, ability to cross
hydrophobic diffusion barriers is
strongly influenced by lipid solubility.
There are four main ways by which small
molecules cross cell membranes
● by diffusing directly through the lipid
● by diffusing through aqueous pores formed
by special proteins (‘aquaporins’) that traverse
the lipid
● by combination with a transmembrane carrier
protein that binds a molecule on one side of the
membrane then changes conformation and
releases it on the other
● by pinocytosis (胞吞作用).
Of these routes, diffusion
through lipid and carriermediated transport are
particularly important in
relation to pharmacokinetic
mechanisms.
Diffusion through aquaporins (membrane
glycoproteins that can be blocked by
mercurial reagents such as parachloromercurobenzene sulfonate) is
probably important in the transfer of
gases such as CO2, but the pores are too
small in diameter (about 0.4 nm) to allow
most drug molecules (which usually exceed
1 nm in diameter) to pass through.
Pinocytosis involves invagination of part
of the cell membrane and the trapping
within the cell of a small vesicle
containing extracellular constituents.
The vesicle contents can then be
released within the cell, or extruded
from its other side. This mechanism
appears to be important for the
transport of some macromolecules (e.g.
insulin, which crosses the blood-brain
barrier by this process), but not for
small molecules.
Active and
passive transport
of drugs across
biomembrane
被动扩散
孔道转运
载体主动转运
The importance of lipid
solubility in membrane
permeation. Figures show
the concentration profile in
a lipid membrane separating
two aqueous compartments.
A lipid-soluble drug (A) is
subject to a much larger
transmembrane
concentration gradient (ΔCm)
than a lipid-insoluble drug
(B). It therefore diffuses
more rapidly, even though
the aqueous concentration
gradient (C1-C2) is the same
in both cases.
Effect of pH and ionisation
BH+
Ka
B+
+
H
+
[BH ]
pKa = pH + log10
[B]
Ka
- + H+
A
AH
[AH+]
pKa = pH + log10
[A-]
Ionisation affects not only the
rate at which drugs permeate
membranes but also the steadystate distribution of drug
molecules between aqueous
compartments, if a pH
difference exists between them.
Weak acid
permeates
lipid membrane
非解离型的HA易
于扩散通过生物膜，
带电荷的解离部分
不易通过。
Weak base
permeates lipid
membrane
药物解离型与非解离性的比例取决于两个因素
药物的pKa和环境的pH
HA=A-或HB=B –时， pH = pKa ， pKa是药
物的固有性质。
pKa values for some acidic
and basic drugs
一些酸性很弱的药物,如苯妥英及
巴比妥类药物,其pKa≥7.5，在pH为
1~8之间的环境中，主要以非解离型
存在，其吸收不受pH影响。
而pKa在2.5～7.5之间的药物，
其解离受环境pH影响较大，pH的改
变直接影响药物吸收速度。
膜两侧的pH不同会改变药物的
转运方向
When a weak acid (pKa=4.4) is
dissolved in the gastric juice
(pH=2.4) , its concentration
difference of ionized drug between
both sides of lipid mucosal barrier is
100,000 times because the pH value
of plasma is 7.4. Acidic drugs are well
absorbed in the acidic medium of the
stomach.
膜两侧的pH不同会改变药物的
转运方向
Basic compounds exist primarily in their
un-ionized form in the blood (pH 7.4),
they readily diffuse from the blood into
the gastric juice. Once in contact with
the gastric contents (pH 1-2), they will
ionize rapidly, which restricts their
diffusibility.
The concentration gradients
produced by ion trapping can
theoretically be very large if there
is a large pH difference between
compartments. Thus aspirin would be
concentrated more than four fold
with respect to plasma in an alkaline
renal tubule, and about 6000-fold in
plasma with respect to the acidic
gastric contents.
Such large gradients are, however,
unlikely to be achieved in reality for
two main reasons:
First, the attribution of total impermeability to
the charged species is not realistic, and even a
small permeability will considerably attenuate the
concentration difference that can be reached.
Second, body compartments rarely approach
equilibrium. Neither the gastric contents nor the
renal tubular fluid stands still, and the resulting
flux of drug molecules reduces the concentration
gradients well below the theoretical equilibrium
conditions.
pH partition is not the main
determinant of the site of
absorption of drugs from the
gastrointestinal tract.
This is because the enormous
absorptive surface area of the villi
and microvilli in the ileum
compared with the much smaller
surface area in the stomach is of
overriding importance.
Drug Absorption
Gastrointestinal absorption
Most drug absorption occurs in the
proximal jejunum (first 1-2 m in human)
胆盐与维生素B12在回肠吸收
药物在小肠停留3～4h，大肠10～12h
（缓释药物释放时间)
Drug Absorption
Gastrointestinal absorption
Weak acidic and weak basic drugs
Molecular weight, ionization, lipid solubility
Carrier for special substances (amino acid,
derivatives of purine or pyrimidine, LDOPA).
Drug Absorption
Factors affecting rate of
gastraintestinal absorption
Drugs & formulation factors (release, dissolve,
transmembrane)
Gastric emptying time (increased, decreased)
Food
intestinal motility
Drug interactions
First-pass
effect
After absorption from
the stomach or small
intestine, a drug must
pass through the liver
before reaching the
general circulation and
its target site. If the
capacity of liver
metabolic enzymes to
inactivate the drug is
great, only limited
amounts of active drug
will escape the process.
Routes for
administering drugs
gastrointestinal tract：
oral (first pass effect),
sublingual, rectal
injection：intravenous,
intramuscular,
subcutaneous
other：inhalation,
transdermal delivery,
intrathecal or intravitreal
administration, local
administration, nasal
mucosa
Absorption
of drugs
from the
intestine, as
a function
of pKa ,for
acids and
bases
Variation in oral absorption among
different formulations of digoxin
药物在其他部位的吸收
口腔粘膜 被动扩散 不经过肝脏
直肠粘膜 经过肝脏
透皮吸收
肺吸收
快，局部，毒物
眼部吸收 剂量损失，稀释
鼻粘膜吸收 不经过肝脏
肌肉吸收 血流速率
皮下吸收 缓慢
The main body
fluid
compartments,
expressed as a
percentage of
body weight.
only the free
drug is able to
move between
the
compartments.
Bioavailability
(生物利用度)
is the fraction of
drug that reaches
the bloodstream
unaltered.
影响因素：
first-pass metablism
solubility
chemical stability
formulation
Bioequivalence (生物等效)：两种
相关药物有相同的生物利用度以
及相同的达峰时间。反之，则生
物不等效。
Treatment equivalence (治疗等
效)：两种药物有相同的疗效和安
全性。
生物等效未必治疗等效。
Distribution of drugs
体重70kg的个体体液组成：
总水42L：药物分子量小或疏水，
易于从细胞间隙进入组织间液,也
能跨细胞膜进入细胞。其分布体积
与总体液之和相近
细胞内液 28L
细胞外液 14L
组织间液 10L 药物分子量小或
亲水，易于从细胞间隙进入组织间
液 但不能跨细胞膜进入细胞。其
分布体积与血浆和组织间液之和相
近
血浆 4L：药物分子量很大或大
量与血浆蛋白结合，则主要分布在
血浆中。其分布体积基本与血浆相
同。
表观分布容积
Apparent volume of distriburion
Vd = D/C
D: Total amount of drug in the
body
C: Plasma concentration of drug
假定药物在体
内分布但并不
排出体外，一
次注射后血浆
中药物浓度的
时相变化
有药物排出体
外，一次注射
后药物分布及
血浆中药物浓
度的时相变化
单次注射后立即有
药物排出并且分布
排出过程很快
可以外推出C0,并据
此算出Vd。
药物在体内分布的不均匀性
组织血流量不均匀，药物与组织亲和力不同
药物与蛋白结合，屏蔽现象
表观分布容积并不意味着药物在体内
是均匀分布的，其意义在于反映药物
分布的广泛程度或与组织中大分子的
结合程度
The binding of drugs
to plasma proteins
结合的可逆性
结合的可饱和性
结合的亲和力
D + S
free binding
drug site
DS
complex
[ albumin] = 0.6 mmol/l, S = 1.2 mmol/l.
D <<< S.
[DS] ∝ [D].
[DS]/([D] + [DS]) is independent of
the drug concentration.
[sulfonamides] ≈ 50% [S]
[S-sulfonamides] / {[free
sulfonamides] + [S-sulfonamides] }
is dependent on [sulfonamides]
Doubling the dose of such a drug
can therefore more than double
the free (pharmacologically
active) concentration.
多种药物存在时，药
物与血浆蛋白结合的
竞争及其意义
PARTITION INTO BODY
FAT AND OTHER TISSUES
Morphine lipid:water partition coefficient =
0.4, quite lipid-soluble enough to cross the
blood-brain barrier.
Thiopental fat:water partition coefficient
=10, accumulates substantially in body fat.
This has important consequences that limit
its usefulness as an intravenous
anaesthetic to short-term initiation
('induction') of anaesthesia.
Drug Elimination and
Termination of Action
药物的消除 Elimitation
代谢 Metabolism
(生物转化 biotransformation)
+
药物的排泄 Excretion
Drug Metabolism
PHASE 1 reactions involve oxidation,
reduction, and hydrolysis, reactions that
provide a functional group to increase
the polarity of the drug.
PHASE 2 reactions involve conjugation
or synthetic reactions in which a large
chemical group is attached to the
molecule.
Biotransformation
药物剂量与
代谢速率的
关系
Pharmacokinetics
Pharmacokinetics
Pharmacokinetics is the description
of the time course of a drug in the
body, encompassing absorption,
distribution, metabolism, and
excretion.
Pharmacokinetics describes changes
in plasma drug concentration over
time.
Steady-state
(稳态)：Drug
input = Drug
output
Pharmacokinetics
of infusion dosing
Effect of
dose rate on
Css：A faster
rate of infusion
does not change
the time needed
to achieve
steady state;
only the Css
changes.
Css = R0/KeVd = R0/CLt
R0 = rate of infusion（mg/min)
Ke = elimination rate constant
Vd = apparent volume of distribution
CLt = clearance
Ke 、Vd 、CLt 对线性代谢药物是常
数，因此R0 与Css 成正比
Time required to achieve
Css
T 1/2 : The time it takes for half of
the drug to be eliminated from the
body.
A large loading dose may be needed
initially when the therapeutic
concentration of a drug in the
plasma must be achieved rapidly
Loding dose = Desired drugplasma ×
Vd
Pharmacokinetics
of single versus
mutiple dosing
Single
injection
kinetics
t ½ of drug does
not depend on size
of administered
dose
Multiple
injection
kinetics
To achieve Css
by various
means of
dosing
Oral administration
Dose-response
of drug action
Agonist,
Antagonist,
Partial Agonist
Therapeutic
index (TI)
TI = LD50/ED50
Therapeutic
index (TI)