Download 药理概论2

Part 2
Pharmacokinetics
药物代谢动力学
Kinetics
Models
Parameters
 2. Transport of Drug in the Body
A. aqueous
B. lipid cell
channels in the membranes
intercellular
junctions
C. carriers
(transporters)
(into or out of
cells)
D. endocytosis
exocytosis
Mechanisms of drug permeation across cell membrane
 2.1 Transmembrane Transport of Drugs
 (1) Non-carrier Transport


Simple diffusion（简单扩散/单纯扩散）
Filtration（滤过）
 (2) Carrier-mediated Transport







a. Active transport
Characteristics of active transport
Involving specific carrier (transporter)
Energy-dependent
Saturability
Competition at same carrier
Moving against concentration gradient (up-hill)
 b. Facilitated diffusion（易化扩散）

(transporter-mediated diffusion)





Involving specific carriers (transporter)
Energy-independent
Saturability
Competition with other drugs
Concentration gradient (down-hill)
 (3) Endocytosis/exocytosis（入胞/出胞）
 Another classification
 Passive transport
 Simple diffusion（简单扩散/单纯扩散）
 Filtration（滤过）
 Facilitated diffusion（易化扩散）
 Active transport
 Active transport (主动转运)
 Pinocytosis/exocytosis（入胞/出胞）
 A. Simple diffusion
Most drugs are weak
acids or bases.
Their diffusion
passing through cell
membrane depends
the lipid-soluble state
(un-ionized form)
 Determinants of simple diffusion

For most drugs of small molecules (usually
are weak acids or weak bases):

Lipid-soluble or un-ionized forms

pKa of the drug and pH of the body fluid

The pKa is the pH at which the concentrations of
the ionized and un-ionized forms are equal.
 Henderson-Hasselbalch equation
 Weak acid drugs:
 pH - pKa = log ( [A-] / [HA] )
 pKa - pH = log ( [HA] / [A-] )
 Weak base drugs:
 pKa - pH = log ( [BH+] / [B] )
 pH - pKa = log ( [B] / [BH+] )
pH
pKa
Weak
acids
And / or
Weak
bases
And / or
And / or
And / or
un-ionized
form
lipidsoluble
Simple
diffusion
B. Carrier (transporter)-mediated
transport
Three types of functional membrane proteins.
Models of transmembrane transport across the lipid bilayer
 2.2 Free and Bound Forms

Plasma protein binding

Tissue / organ affinity
 3. Fate of the drug in the body






Absorption
Distribution
Metabolism
(Biotransformation)
Excretion
－ ADME
ADME
 3.1 Absorption
 Absorption is the transfer of a drug from its site of
administration to the blood stream.




Gastrointestinal tract
Parenteral injection - i.m., s.c.
Inhalation
Transdermal
 (1) Gastrointestinal tract
 Route:



Oral
Sublingual
Rectal
 Absorption sites:




Oral
Gastric
Intestinal
Rectal
 Factors influencing absorption:





blood flow to the absorption site
total surface area available for absorption
contact time at the absorption surface
physic-chemical properties of the drug
first-pass elimination
 (2) Parenteral injection


intramuscular injection ( i.m. )
subcutaneous injection ( s.c. )


Determinants
Local blood flow; Solubility of the drug
 (3) Others


Inhalation; Intranasal;
Transdermal; Topical
 3.2 Distribution
 Drug distribution is the process by which a drug
reversibly leaves the blood stream and enters the
interstitium (extracellular fluid) and / or the
cells of the tissues.



Blood flow-dependent phase of distribution
Selective distribution
Tissue-plasma balance: importance of measuring
plasma concentration
 (1) Binding of drug to plasma proteins





Bound drug:
can not distribute / inactive temporally
reversible (storage form) / percentage of binding
plasma protein capacity
competitive displacement
(2) Physic-chemical properties of the drug
(3) Blood flow and re-distribution
(4) Affinity to organs or tissues
(5) Barriers
Blood-brain barrier (BBB)
Placental barrier
Blood-eye barrier
Blood-brain barrier (BBB)
Able to pass through
Unable to pass through
Small molecules
Large molecules
Lipid-soluble
Water-soluble
Transporter-mediation
Amount of drug passing through BBB
Increases when inflammation or larger doses used
Placental barrier:
More permeable
Drugs for pregnant
women:
A, B – relatively safe
C - caution
D, X - toxic
 3.3 Metabolism (biotransformation)
 Drug metabolism is the process transforming lipophilic drug
into more hydrophilic metabolites, which is essential for the
elimination of these compounds from the body and termination
of their biological activity.
 (1) Metabolism sites

Liver: for most of the drugs

Other organs/tissues: intestine, kidney, lung,
plasma, etc.
 (2) Phases of metabolism



Phase I: Oxidation, reduction, hydrolysis
most drugs are inactivated
few (prodrugs) is activated


Phase II: Conjugation
inactivated

Metabolites: more water-soluble easier to excrete
 (3) Enzymes in drug metabolism



Enzymes in Phase I:
cytochrome-P450, such as CYP2A6, CYP3A4
many other enzymes




Enzymes in Phase II:
acetylase
glucuronosyltransferase
etc.
 Induction of hepatic enzymes by drugs


example:
phenytoin－steroids, nifedipine
 Inhibition of hepatic enzymes by drugs


example:
verapamil－diazepam
 3.4 Excretion
 Removal of a drug from the body via a
number of routes.
 Elimination of drugs from the body
 Action on excretory organs
 3.4 Excretion
 (1) Excretion routes






Kidney -renal excretion
Bile (hepato-enteral circulation)
Lung
GI tract
Milk
Secretion glands
 3.5 Elimination and Accumulation
 Elimination（消除）



Metabolism
Excretion
Distribution (stored in fat, hair, etc)
 Accumulation（蓄积）

Dosing rate > elimination rate
Kinetic Processes
Kinetics
Models
Parameters




1.
2.
3.
4.
Drug concentration-time curve (C-T curve)
Kinetic rate processes
Pharmacokinetic models
Pharmacokinetic parameters and their implications
Kinetic Processes
 1. Drug concentration-time curve (C-T curve)

Maximal (peak) concentration: Cmax or Cp


Time to maximal concentration (Peak time ) :
Tmax or Tp

Area under the curve: AUC


Multiple dosing (steady state):
Css max, Css min, Css
C
←
i.v.
i.m.
← Cmax
← Cp
s.c.
Oral
↑
↑
↑
Tmax, Tp
←
t
C
←Cmax
AUC
↑
Tmax
t
Tmax, Cmax and AUC
C-T curve after multiple dosing (same dose and interval)
在临床治疗中多数药物通过重复给药以期达到有效治疗血药浓度，并维持
在一定水平，此时给药速率与消除速率达到平衡，其血药浓度称为稳态浓
度，用Css表示
 2. Kinetic rate processes

dC / dt ＝ －KCn
 2.1 Zero order kinetics







n＝0
dC / dt ＝ －K
Ct ＝ C0－K t
C0－Ct ＝ K t
when Ct＝1/2 C0, t = t1/2
then, 0.5 C0 ＝K t1/2
t1/2＝0.5 C0 / K
 Zero order kinetics
 A. same amounts of drug are

eliminated per unit time
 B. t1/2 is not a constant
 C. C-T curve is linear
 D. no Css theoretically
Kinetic properties of C-T curves after single bolus
injection of drug
 2.2 First order kinetics
 n＝1
 dC / dt ＝ －KC
 Ct ＝ C0e－Kt
 lnCt ＝ lnC0－Kt
 Kt＝lnC0－lnCt＝ln(C0 / Ct)
 when Ct＝1/2C0，t＝t1/2， then
 t1/2＝ln2/K＝0.693/K
 First order kinetics
 A. eliminated at same rate per unit time
 B. t1/2 is a constant
 C. logC-T curve is linear
 D. steady state (Css) after 4-5 t1/2
Kinetic properties of C-T curves after single bolus
injection of drug
 2.3 Non-linear kinetics
 Higher concentration (or larger dose):

zero order kinetics
 Lower concentration (or smaller dose):

first order kinetics
 Because of limits in elimination capacity
 Examples: aspirin, phenytoin, ethanol
 Confirmation: different t1/2 when given different doses
 Michaelis-Menten kinetics




dC / dt = Vmax  C / (Km + C)
if Km >> C
dC / dt = Vmax  C / Km
Vmax / Km = Ke


if C >> Km
dC / dt = Vmax  C / C

dC / dt = -Vmax
－ First order
－ Zero order
Kinetic properties of C-T curves after single bolus
injection of drug
Kinetic properties of C-T curves after
single dose of aspirin
 3. Pharmacokinetic models
 One-compartment model
logC
iv
t
 3.2 Two-compartment model
2
1
First, enter the central
compartment
2, 3
Then, distributed to peripheral
compartment, and eliminated
Distribution
Elimination


t1/2 
logC
t1/2 
iv


t
logC-T curve
4. Pharmacokinetic parameters and
their implications
4.1 Bioavailability ( F )
Bioavailability is the fraction of administered
drug (oral) that reaches the systemic circulation
Absolute bioavailability（绝对生物利用度）
F = AUC(po, sc, im) / AUC (iv)
Relative bioavailability （相对生物利用度）
F = AUC(tested) / AUC(standard)
Implication: Evaluation for absorption and drug
quality control
Influence: Absorption rate; First-pass elimination
AUC (iv)
C
AUC (po)
t
Absolute bioavailability: F = AUC(po) / AUC (iv)
4.2 Apparent volume of distribution (Vd)
The volume of distribution (Vd) relates the amount of
drug in the body (D) to the concentration of drug (C) in
the blood or plasma.
i.v. Vd = D / C
p.o. Vd = FD / C
4.3 Half-life (t1/2) / elimination constant (Ke)
The half-life (t1/2) is the time takes for the plasma
concentration or the amount of drug in the body
reduced by 50%.
t1/2 = 0.693 / Ke＝ Vd / Cl
(First-order kinetics, for most cases)
Ke: A constant fraction of drug in the body is eliminated per unit
of time (first-order kinetics).
Implications of t1/2
Elimination rate
Estimating the times of fully elimination and
reaching steady state
Classifying short- and long-acting drugs
Adjusting dosage regimens for patients with
hepatic or renal failures
4.4 Clearance (CL)
The drug in a constant volume of body fluid
[usually plasma] is eliminated per unit of time.
(First-order kinetics)
CLs = Ke  Vd = FD/AUC
There are also hepatic [CLH] and renal
clearances [CLR].
First order kinetics
lnCt = lnC0－ Ke t
One compartment model
slope = - Ke
Intravenous administration
lnC0
t1/2 = 0.693 / Ke
Vd = D / C0
lnCt
CL = Vd × Ke
slope = - Ke
t (min)
Part 3
Factors Influencing Drug
Effects
影响药物作用的因素
Patient
Drug
Dosage regimen
drugs, doses,
intervals, duration
Adjustment
efficacy/adverse effects
drug concentrations
Doctor
A. Drug Factors
 1. Physic-chemical properties of drugs
 2. Dose forms
 3. Administration
 4. Multiple-drug therapy
 5. Long-term drug therapy
 1. Physic-chemical properties of drugs




Stability
Molecular size
Lipid- and water-soluble
……
 2. Dose forms




slow release formulation
controlled release formulation
transdermal patch
inhalation
 3. Administration








Doses
Routes
oral
intramuscular injection
subcutaneous injection
intravenous injection or infusion
Administration time
Dosing intervals
Dosing duration
 4. Multiple-drug therapy (drug combination)
 Drug-drug interactions



pharmacy
pharmacokinetics
pharmacodynamics
 Drug effects in combination


synergism: potentiation / addition
antagonism
Efficacy: ↓,↑
Toxicity: ↓,↑
B. Patient Factors
 1. Physiological Factors
 1.1 Age
 Children


Sensitivity to drugs
Pharmacokinetic properties
 Elderly


Sensitivity to drugs
Pharmacokinetic properties
Age-related factors
influencing
pharmacokinetic
processes
 1.2 Sex
 Women
 Pregnancy
 - malformation and dysfunction of the
fetuses
 Lactation
 - milk: effects on infants
 2. Psychological Factors


Placebo effects
Placebo effects commonly are manifested as
alteration of mood, other subjective effects,
and objective effects that are under autonomic
or voluntary control.
安慰剂（placebo）是指没有药理活性的物质（如乳
糖、淀粉等），被制成与试验药外观、气味相同的
制剂，作为临床对照试验中的阴性对照物。
Pharmacological
effects
Overall
responses
Non-specific drug
effects
Non-specific
medication effects
Natural recovery
Absolute placebo
effects
No treatment
Components underlying drug effects
Placebo
effects
 3. Pathological Factors






Heart diseases
Hepatic diseases
Renal diseases
Gastrointestinal diseases
Malnutrition
Imbalances of acid-base or electrolytes
 4. Genetic Factors

Pharmacogenetics


abnormality of drug responses
example: tolerance of warfarin


abnormality of pharmacokinetic properties
example: fast or slow acetylation
 5. Individual variation (个体差异)
 (1) Sensitivity to drugs


Hypersensitivity
Hyposensitivity (tolerance)
 (2) Abnormal responses to drugs


Idiosyncracy (genetic abnormality)
Allergy (immunological abnormality)
One goal in the post-genomic medicine:
Individualized Medicine
 6. Changed responses after long-term
drug use
(长期用药后机体对药物反应的变化)

(1) Tolerance and tachyphylaxis (human body)

(2) Resistance to chemotherapy (pathogens)

(3) Drug dependence - an adaptive state that develops
in response to repeated drug administration.
药理学基本概念
药剂学过程
药动学过程
药学特点；用药程序
跨膜转运；
影响因素
ADME及其影响因素；
药物：理化特点，
血药浓度及动力学参数
剂型，给药方式，
联合应用
基本作用特点；
药效学过程
治疗作用与不良反应；
量效关系；
与靶分子相互作用：如受体
机体：生理、精
神、病理、遗传
因素，长期用药
后的改变
药理学基本概念
药动学过程
跨膜转运：主动转运；被动转运（含简单扩散）
ADME及其影响因素：
A：GI吸收/首过消除； D：血浆蛋白结合，药物理化特点，BBB
M：肝药酶；
E：肾排泄；胆汁排泄/肝肠循环
血药浓度及动力学参数：
C-T曲线：Cmax，Tmax，AUC，Css； 房室模型：一室，二室；
速率过程：一级，零级/非线性;
药动学参数：生物利用度F，
表观分布容积Vd，半衰期t1/2，消除速率常数Ke，清除率Cl
药理学基本概念
药效学过程
基本作用特点：作用与效应；选择性
治疗作用与不良反应：
治疗作用：对因，对症，补充
不良反应：副反应，毒性反应，变态反应，后遗效应，特异质反应等
量效关系：效能，效价强度，治疗指数 ( TI = LD50 / ED50 )
与靶分子相互作用（特异性作用机制）：
受体：亲和力，内在活性，激动药，拮抗药，部分激动药
药理学基本概念
影响因素
药物因素：理化特点，剂型，给药方式；
联合应用：协同、拮抗，有利、有害
机体因素：
生理：年龄、性别等
精神：安慰剂效应等
病理：肝、肾、胃肠道功能，疾病状态等
遗传：药物代谢、效应的个体差异
长期用药后的改变：耐受/快速耐受，耐药，依赖性/成瘾
思考题
一个催眠药口服后，从给药后到作用发挥和作用消除，
在体内经历哪些过程？
你认为药物作用基本规律主要有哪些方面？
为什么血浆白蛋白及体内各种酶不能称为药物受体？
怎么理解药动学基本过程（ADME）和药动学参数的关
系？
药物血浆消除半衰期（t1/2）在临床应用中有何意义？