Transcript Introduction-2

PHARMACOLOGY
 WELCOME !
药 理 学
PHARMACOLOGY
张岫美
山东大学医学院
药理学研究所
Tel: 88383146
Email: [email protected]
CHAPTER 2
PHARMACOKINETICS
药物代谢动力学
Pharmacokinetics
药代动力学
The Processes of Drug in the Body
体内过程
PHARMACOKINETICS
To reveal the principles of dynamic
changes of drug in the body, mainly
explained the changes of blood
concentration of drug with time in
the body.
The Processes of Drug in the Body
receptor
B
tissue
F
free
bound
circula
Free drug
absorp
excret
metabolites
Bound
drug
metaboli
The Drug Processes in the Body
The Classifications
Absorption吸收
Distribution分布
Metabolism代谢
Excretion排泄
Disposition处置:转运与转化
Elimination消除:代谢与排泄
SECTION 1
Transportation of Drug Molecules
1. Modes of transportation转运方式
(1) Filtration滤过
(2) Simple diffusion简单扩散 (down hill)
Passive transport被动转运
No need for energy, carrier.
No saturation limited.
No competitive inhibition.
Passive Transport by Factors
Affected by properties, areas of
membrane, concentration between
memb., and properties of drug:
molecular size, lipid solubility,
polarity.
Ion trapping离子障
Transports of weak acidic and weak basic
drug by Handerson-Hasselbalch Equation
Weak acidic drug
weak basic drug
HA ≒ H+ + ABH+ ≒ H+ + B
Ka = H+A-/HA
Ka = H+B/BH+
pKa = A-/HA
pKa = H+B/BH+
pKa = pH - logA-/HA pKa=pH-logB/BH+
pH–pKa=logA-/HA pK –pH=logBH+/B
when pH = pKa, A- = HA B = BH+
Transports of weak acidic and weak basic
drug by Handerson-Hasselbalch Equation
pH–pKa=logA-/HA
pK – pH=logBH+/B
[HA]/[A-] = 10pka-pH
BH+/B = 10pka-pH
[A-]/[HA] = 10pH-pka
(3) Carrier transport
载体转运
Need carrier
Selectivity
Saturation limited
Competitive inhibition
a. Active Transport
主动转运 (up hill)
Need energy, carrier
Has saturation limited
With competitive inhibition
b. Facilitated diffusion易化扩散
No energy need, with carrier, belong to
passive transport.
SECTION 2
The Drug Processes in the Body
1. Absorption吸收
The movement of a drug from its site of
administration into the blood circulation.
The pathways of absorption
Gastroentestinal pathway
Gastroentestinal pathway
(1)Oral administration口服给药 (per os)
Advantages
Safety, convenience and economy.
It is most frequently used route in clinic.
Disadvantages
Absorption and onset low, some drugs
have first-pass elimination.
First-pass elimination首关消除
Drugs are absorbed by the gastrointestinal
tract, first enter the liver via portal vein along
with blood flow and then enter into the
systemic circulation. Some drugs are
metabolized in the gastrointestinal tract and
liver before entering the systemic circulation.
The process, called first-pass elimination, this
process decreases actual quantity of drug
entering the systemic circulation.
Bioavailability
Bioavailability生物利用度 (F):
The fraction of unchanged drug
reaching systemic circulation following
administration by any route.
F = A/D x 100%
The Pathways of Absorption
(2)Inhalation吸入给药
(3)Topical uses
Sublingual舌下含服
Transdermal经皮给药
Per rectum直肠给药
Adoption of sublingual and rectal
administration without passing the portal vein
can avoid the first pass elimination of the
liver.
(4)Injection administration注射给药
Injection also is one of the most common
clinical routes of administration, through
which drugs directly reach the systemic
blood circulation without the process of
absorption after intravenous administration.
Following intramuscular and subcutaneous
injection, drugs entering into the blood
circulation via capillary vessels.
Injection administration注射给药
Intravenous injection静脉注射(iv)
Intravenous infusion静脉滴注(ivd)
Intramuscular injection肌内注射 (im)
Subcutaneous injection皮下注射(sc)
Intra-arterial injection动脉注射 (ia)
The rate of absorption by different routes
iv (ia) inhalation sublingual per
rectum  im sc per os transdermal
2. Distribution
Conception
The process by which a drug leaves the
blood circulation to enter the
extracellular fluids and the tissues of
the body.
Factors Affecting Drug Distribution
a. Plasma protein binding血浆蛋白结合
Acidic drug-albumin, basic drugalbumin, lipoptrotein, and 1 acidic
glycoprotein.
D ≒ D + P ≒ DP
Free drug
bound drug
Plasma Protein Binding Rate(PPBR)
The fraction of drug binding to
plasma protein to amount of drug in
the body:
The extent of combination of drugs with
plasma protein differs, which is usually
expressed by the ratio of the
concentration of bound drug over total
drug in the body, i.e., PPBR.
Plasma Protein Binding
Reversibility
Inactivation
Molecule bigger
Unmetabolized
No transmembrane
Capacity-limited protein binding
Replacement
Plasma Protein Binding
Replacement
Anticoagulant warfarin with PPBR of
99%, an anti-inflammatory agent,
phenylbutazone with PPBR of 98%,
when the two drugs are used at the
same time, the replacement may occur,
and eventually bleeding tendency due
to the high free warfarin.
b. Organ blood flow
The more blood flow of tissue and organ,
the more drugs go to these tissues or
organs. Such as liver, brain, kidney and
lung.
Organ blood flow
Some higher lipid-solubility drug first go to
the abundant blood flow tissue or organ and
then go to the much poor blood flow tissue or
organ, such as thiopental first go to brain,
and then go to muscle or other lipid tissue to
form new equilibrium called redistribution.
c. Binding to tissue cells
Some tissue or organs have affinity to
some drugs, then the concentration of
these drug are higher in these tissue or
organ than others. Such as iodide in
thyroid gland, tetracycline in bone
tissue, chloroquine concentrated in liver
and red blood cells.
d.The properties of drug and physical pH
The pH of body fluid may influence the
extent of dissociation of drugs and thus
affect the distribution and transport of
drugs in the body.
The properties of drug and physical pH
The pH of cellular fluid is 7.0 and that
of extracellular fluid is 7.4 under
physiological circumstances, so the
concentration of weak acidic drugs in
extracellular fluid is higher than that in
cellular fluid.
The properties of drug and physical pH
Reducing the pH of the blood can transfer
weak acidic drugs into cells, while decreasing
the pH of the blood can cause right-about
transfer of acidic drugs. The situation for
weak basic drugs is opposite.
The properties of drug and physical pH
Pentobarbital is a weak acidic drug,
when it is used overdose and
intoxication, the sodium bicarbonate
may used to base the blood and urine to
increase the excretion of pentobarbital
and to anti-toxicant.
e. Cell membrane barriers
Blood-brain barrier血脑屏障 (BBB):
Blood-brain cells
Blood-cerebrospinal fluid (CSF)
CSF-brain
Placental barrier胎盘屏障: Fetus and
maternal tissue胎盘绒毛-子宫血窦
Blood-eye barrier血眼屏障
3. Metabolism
(Biotransformation)
Concept
The process in which drugs result in chemical
changes, that may lead to the termination or
alternation of biological activity. it is also
called biotransformation of drug in the body.
The metabolism and excretion of drugs are
generally called elimination.
Roles of drug metabolism
Action of drug metabolism the polarity of
drugs increases after metabolism in the body,
which is helpful to the excretion of drugs.
However, the alternation of pharmacological
activities after metabolism of drugs are
complex. Most of metabolic products are
often inactivated, some is active, some is
toxic.
Roles of drug metabolism
For instance, procainamide is metabolized to
acetyl procaninamide in the body both of
which have antiarrhythmic activity, and the
activities are similar with the only change of
pharmacokinetic behavior.
Roles of drug metabolism
If a drug without any pharmacological
activities is metabolized to be active,
the maternal drug is called pro-drug,
such as cyclophosphamide which is
metabolized to be aldophosphamide in
liver.
The sites of drug metabolism
Most drugs are metabolized in liver. So
liver is the most important organ for
drug metabolism.
Metabolism
Action of drug metabolism: help to
excretion or inactivation, active,
toxicity.
Pro-drug.
Metabolism
(Biotransformation)
Steps of drug metabolism
a. phase 1: oxygenation,
reduction, hydrolysis
b. phase 2: conjugation
(glucuronic acid, glycine or sulfate,
acetylation and methylation)
Biotransformation
The enzymes of drug metabolism
Cytochrome P450 monooxidase system,
Hepatic microsomal mixed function
oxidase system, hepatic microsomal
enzymes(肝药酶):
P450
P450
Cytochrome P450 （CYP450）is
superfamily of aheme-thiolate
proteins(亚铁血红素-硫醇盐蛋白), it
metabolize the endogenous
and exogenous substances including
drugs, and environmental chemicals.
The properties of cytochrome P450
P450 with low selectivity to its substrates,
and it can metabolize various drugs with
different chemical structures.
Variability with the nutrition,
pathological state.
Activity changed by other factors
Cytochrome P450 (P450)
Enzyme induction
Enzyme inhibition
Enzyme inducer: phenobarbital,
rifampin, carbamazepine, phenytoin
sodium, dexamethasone
Enzyme inhibitor: chloramphenicol
ketoconazole, citemidine
Enzyme inducers and its affected drugs
inducers
affected drugs
barbiturates barbiturates, chloramphenicol
chlorpromazine, cortisone,
dicumarol, digoxin, phenytoin
griseofulvin
warfarin
phenylbutazone cortisone, digoxin
phenytoin
cortison, dexamethason
rifampin
dicumarol, digoxin, cortison
oral contraceptives
Enzyme inhibitors and its affected drugs
inhibitors
affected drugs
chloramphenicol dicumarol
isoniazid
diazepam
cimetidin
warfarin
dicumarol
phenytoin
phenylbutazone
phenytoin
Metabolism
 Non-microsomal enzymes
4. Excretion of Drug
The process in which of their prototype
and their metabolites transferred from
the internal to the external environment
of body.
The pathways of excretion includes: renal
peptic, respiratory and milk excretion.
The pathways of excretion
a. Kidney肾脏
Glomerular filtration
Active tubular secretion:
Probenecid丙磺舒 – penicillin青霉素
Passive tubular reabsorption
phenobarbital – sodium bicarbonate
b. Peptic excretion-bile excretion
Some drugs can be excreted from bile into
duodenum by means of simple diffusion or
active transport, and then excreted along with
excrement. Drugs excreted into duodenum by
bile can be partially reabsorbed in the
intestine, which forms enterohepatic
circulation. Digitoxin 26%, t1/2 7days, digoxin
7%, t1/2 36 hours，blocked by cholestyamine.
Excretion of drug
c. Other routes
Respiratory tract: ethanol
Milk: low pH, morphine
Sweat
Salivary
Section 3 Compartment Models
One-compartment open model
一室开放模型
Two-compartment open model
二室开放模型
Central compartment中央室:
plasma, liver, heart, brain, lung.
Peripheral compartment周边室:
bone, adipose tissue, muscle.
SECTION 4
The Elimination Kinetics of Drug
The elimination of drug means the
duration of drug concentration
reduction in plasma due to distribution,
metabolism and excretion.
The Elimination Kinetics of Drug
Kinetic Types
dC/dt = -kCn
C: drug concentration,
t: time
K: constant
n = 0, zero-order kinetics
n = 1, first-order kinetics
1. First-order Elimination Kinetics
一级消除动力学
The character of first-order kinetics is that the
rate of elimination is directly proportional to
the drug dose (linear relationship), here the
half-life time keeps constant and has nothing
to do with the amount of drug in the body.
Most drug are eliminated with this kind of
kinetics in their metabolism capacity.
First-order Elimination Kinetics
一级消除动力学
dc/dt = -keC1 = -keC
Ct = C0e-ket
logCt = logC0 – ke/2.303 x t
t = logC0/Ct x 2.303/ke
when Ct = 1/2C0,
t is half life(t1/2),
t1/2 = log2 x 2.303/ke
= 0.301 x 2.303/ke = 0.693/ke
2. Zero-order Elimination Kinetics
零级消除动力学
The character of zero-order kinetics is that
the rate of elimination is constant, i.e.,
independent of drug doses, and that the halflife time is positively relates to the drug doses.
When the concentration of drug exceeds the
capacity of the metabolism of the body, the
drug is eliminated with zero-order kinetics.
And then turn to the first-order kinetics
elimination.
Zero-order Elimination Kinetics
零级消除动力学
When n = 0
-dC/dt = KC0 = -KC0 = -K
Ct = C0 – Kt
C0 is initial drug concentration，
Ct is drug concentration at t time
1/2C0 = C0 - Kt1/2
t1/2 = 0.5 x C0/K
SECTION 5
The Drug Concentration –Time
in the Body
1. AUC of drug concentration-time in
single dose
(1)The time-concentration curve of drug
Time–concentration relationship
时量关系
Time–response relationship
时效关系
Time–Concentration (effect) Curve
时–量（效）曲线
Three periods in the curve
Latent period潜伏期: the period from
administration to the time when the drug
concentration in plasma reached the
minimum effective plasma concentration.
The length of this period depends on the rate
of absorption and distribution of the drug.
Peak Concentration(峰浓度，Cmax)
Peak Time(达峰时间, tmax, tpeak)
Peak concentration(Cmax)
Peak concentration(Cmax )
The highest concentration of the drug
achieved in the plasma following extravascular administration.
Peak time (tmax, tpeak)
The time of the peak concentration is the
period of time required to achieve the peak
concentration of drug.
Elimination half-life time消除半衰期(t1/2)
Minimum effective concentration最低有效浓度(MEC)
Elimination half-life time(t1/2)
Minimum effective concentration (MEC)
Elimination half-life time(t1/2): The time
required for any given drug
concentration in plasma to decrease
by half.
Minimum effective concentration (MEC)
The concentration inducing the minimal effect.
Effective period: duration of MEC效应持续时间
Persistent period (duration of MEC)
Referring to period during which the drug
concentration in the plasma exceeds the
minimum effective plasma concentration.
The length is mainly determined by the rate
of absorption and elimination of drug.
Residual period残效期
The drug concentration in the plasma in
residual period is below the minimum
effective plasma concentration. So residual
period is defined as the period from the
minimum effective plasma concentration
point to the time when the drug is completely
eliminated from the body. The length of the
period depends on the rate of elimination of
drug.
Area Under the Curve
(曲线下面积，AUC)
AUC = C0/ke (g.h.L-1)
Area Under the Curve (AUC)
AUC indicates the area under the timeconcentration curve which can be calculated
by trapezoid area method.
AUC = C0/ke (g.h.L-1)
AUC is an important index to appraise the
extent of absorption of drugs and is usually
applied in the quality evaluation of
preparation.
Minimum toxic concentration最低中毒浓度(MTC)
Minimum toxic concentration
(MTC)
The concentration of drug inducing the
minimal toxic effect.
MTC represents the toxicity of a drug, the
higher the MTC, the lower the toxicity of the
drug.
2. Css in Multiple-dose
一级消除动力学药物在体内消除量及累积量
t1/2数
1
2
3
4
5
6
7
体内剩余量 消除总量 反复用药累积量
50%A0
50%A0
50%A0
25%A0
75%A0
75%A0
12.5%A0
87.5%A0 87.5%A0
6.25%A0
93.8%A0 93.8%A0
3.13%A0
96.9%A0 96.9%A0
1.56%A0
98.4%A0 98.4%A0
0.78%A0
99.2%A0 99.2%A0
Css in Multiple-dose
(1)Steady state concentration
Css（稳态浓度）
Css is defined as a time of not net change in
the amount of drug when rate of input equals
rate of output.
Css = R x t1/2/Vd x 0.693
R: rate of intravenous infusion
Css in Multiple-dose
(2)the maximum steady state
concentration，Css-max （峰浓度）and
the minimum steady state concentration，
Css-min（谷浓度, trough concentration）
Css-max = A/Vd x (1/1- e-kt)
Css-min = A/Vd x (1/1- e-kt) x e-kt
= C(ss)max x e-kt
Multiple-dose Kinetics
Multiple-dose Kinetics
2.The average concentration of Css
(平均峰浓度, Css)
Css = A/Vd x K x  = A/CL x 
The Average Concentration of Css
When in steady state,
RA = RE = Css x CL= Css x Vd x Ke
RA: absorption rate
RE: elimination rate
Therefore,
Css = RA/CL = RA/Vd x Ke
= RA/Vd x 0.693/t1/2= RA x 1.44 x t1/2/Vd
Section 6
Pharmacokinetic Parameters
1. Half life半衰期, t1/2
The time required for any given drug
concentration in plasma to decrease
by half.血浆药物浓度下降一半所需要的时
间。
t1/2 = 0.693/ke = 0.693 x Vd/CL
Significance of Half-life
Using a single dose, during 5 t1/2 is to
3.13% of total drug in the body;
Using multiple doses, during 5 t1/2 reach
to 96.9% of steady state concentration
(Css).
一级消除动力学药物在体内消除量及累积量
t1/2数
1
2
3
4
5
6
7
体内剩余量 消除总量 反复用药累积量
50%A0
50%A0
50%A0
25%A0
75%A0
75%A0
12.5%A0
87.5%A0 87.5%A0
6.25%A0
93.8%A0 93.8%A0
3.13%A0
96.9%A0 96.9%A0
1.56%A0
98.4%A0 98.4%A0
0.78%A0
99.2%A0 99.2%A0
Time–Concentration (effect) Curve
Multiple-dose Kinetics
Parameters of Kinetics
2. Clearance(CL, 清除率，L/h ):
The volume of body fluid containing a
drug that can be eliminated by the body
in unit time. 单位时间内有多少毫升血浆中所含
的药物被机体清除。
CL = rate of elmination(RE)/Cp
= Vd x ke (L.h-1)
Parameters of kinetics
3. Apparent volume of distribution (表观分布容
积, Vd)
Vd means that the ratio of in vivo drug
quantity verses concentration in plasma when
the drug reaches the dynamic equilibrium in
the body.
Vd = A/C0 = A/AUC x Ke(L)
Apparent volume of distribution
For instance, if the Vd of a drug is about 3-5L,
this drug may mainly distribute in the blood.
If the Vd of a drug is about 10-20L, the drug
chiefly distributing in plasma and extacellular
fluid. And if a drug has the Vd of 40L, the
drug could distribute in extra-cellular and
intracellular fluids, indicating its widespread
distribution in whole body.
Importances of Vd
Vd: 5L(plasma), 10~20L(systemic fluid),
> 40L(tissue and organs),
>100L(concentrate in some organ or
large area of tissue)
a 70kg male, blood volume is 5.5L,
plasma 3L , extracellular fluid is 12L,
total body fluids about 42L, Vd of aspirin
is 11L, diazepam 80L, morphine 230L.
Pharmacokinetic Parameters
4. Bioavailability生物利用度 (F)
Concept: The fraction of unchanged
drug reaching systemic circulation
following administration by any route.
经任何给药途径给予一定剂量的药物后到达
全身血循环内药物的百分率。
Bioavailabilty
Oral bioavailability
F = A/D x 100%
F absolute = AUC(oral)/AUC(iv) x 100%
F relative = AUCtest/AUCstandard x 100%
Bioequivalence生物等效性
Parameters of Kinetics
5. Elimination rate constant
(消除速率常数，Ke)
Ke = 0.693/t1/2(h-1)
The percentage elimination of drug in a
moment.体内药物瞬间消除的百分率。
Parameters of Kinetics
6. Rate of elimination(清除速率，RE)
Drug amount eliminated by body
within unit time.单位时间内被机体消除的
药量。
RE = CL x Cp
Section 7 Design and
Optimization of Dosage Regimens
1. The maintenance dose维持剂量, Am
Am = CL x TC x  x F
TC: target concentration
: dose internal
F: bioavailabilty
if TC = Css,
Am = Css x K x 
Or = (MTC-MEC) x Vd
Multiple-dose kinetics
2. The loading dose负荷量, Dl
Dl = Css x Vd = RA/Ke = 1.44t1/2RA
When  is t1/2 ,
Dl = Dm/1-e-0.693 = D/0.5 = 2Dm
3. Amount of drug in the body
药物在体内的总量 A
A = C x Vd
How cute it is ?
CHAPTER 4
FACTORS AFFECTING DRUG
EFFECTS AND PRINCIPALS FOR
RATIONAL DRUG USE
SECTION 1
Factors From the Drug
1. Preparations and administration route
Pharmaceutical equivalance
Bioequivalance
slow release formulation缓释制剂
controlled release formulation控释制剂
Factors From the Drug
extended release formulation
延迟释放剂
sustained release formulation
持续释放剂
transdermal patch透皮贴剂
2. Administration Methods
pathway
Administration methods
iv inhalation  sublingual  per rectum
 im  sc per os transdermal
2. Drug interaction
Drug Combination use
(1) Incompatibility（配伍禁忌）
两种或以上药物在体外配制时直接发生的理
化作用而影响药物疗效或产生毒性反应。
Drug interaction
(2) Drug interaction
两种或以上药物在体内发生的药效学或
药动学的作用而影响药物疗效或产生不
良反应。
Drug interaction
The results of drug combination use
Synergism协同
Addition相加：1 + 1 = 2
Potentiation增强：1 + 1 > 2
Antagonism拮抗
Subtraction(相减): 1 + 1 < 1
Counteraction(抵消): 1 + 1 = 0
Drug interaction
a. Pharmacokinetics
Absorption
Plasma protein binding
Biotransformation
Hepatomicrosomal drug metabolism
enzymes:
Induction and inhibition
Excretion: kidney
Drug interaction
b. Pharmacodynamics
Physical antagonism and synergism
Receptor synergism and antagonism
Interfering with transport of
neurotransmitters
SECTION 2
Factors From the Body
1. Age
Children
Elderly
2. Sex
3. Genetic Factors
Genetic pharmacology
(pharmacogenetics)
Genetic Pharmacology
Extensive(rapid)metabolizer(EM)
Poor(slow)metabolizer(PM)
Isoniazid
6-p-glucose-dehydroxygenase
(G6PD) difficiency: primaquine
Acetylcholinesterase inactivated:
succinylcholine
Factors From the Body
4. Idiosyncrasy
6-p-glucose-dehydroxygenase
(G6PD) difficiency: primaquine(伯氨喹)
Acetylcholinesterase inactivated:
Succinylcholine(琥珀胆碱)
Factors From the Body
5. Pathological States
Heart, Liver, kidney, gastro-intestinal,
nutrition, acidic-basic disorder.
6. Psychological Factors
Placebo and placebo effects
Factors From the Body
7.The Changes of Organism to Drug
Reaction in Long term Use
(1) Tolerance and drug resistance
Tachyphylaxis: ephedrine
Cross tolerance
Drug resistance
(2) Dependence, withdrawal
symptoms/syndrome
Dependence依赖性
WHO专家委员会的定义：“药物依赖性是
药物与机体相互作用所造成的一种精神状态，
有时也包括身体状态，它表现出一种强迫要
连续或定期用该药的行为和其他反应，为的
是要去感受它的精神效应，或是为了避免由
于断药所引起的不舒适。可以发生或不发生
耐受性。同一个人可以对一种以上药物产生
依赖性”
Dependence
a. Psychological dependence
用药后使人产生一种对药物欣快感的渴求，
这种精神上不能自制的强烈欲望驱使滥用者
周期性或连续地用药(WHO)。
some times habituation: nicotine,
alcohol
Dependence
b. Physical dependence
大多数具有依赖性特征的药物经过反复使用
所造成的一种适应状态，用药者一旦停药，
将发生一系列生理功能紊乱，称戒断症状。
Dependence
Euphoria: rush and high
Addiction
Drug abuse
Narcotics（麻醉药品): morphine,cocaine
Anaesthetics（麻醉药）
Papaver somniferum
Is it a beautiful flower or a poison ?
Beautiful flower
站在祖国西南边疆的国境线上极目远望，田野、山川、小溪构成了
一幅美丽的南国田园风光。田野里生长着许多植高花大，色彩艳丽
的花朵。有白色、红色，还有紫色等。一眼望去似牡丹又像芍药，
morphine
heroin-biacetylmorphine
 二乙酰吗啡—海洛因。海洛因呈白色粉状，俗称
白粉。人一旦吸上，就想再吸，连续数日即成瘾。
即使强行戒毒也很难脱瘾，因为心理上毒瘾如魔
鬼一般，使其经常复发。
Some International Airport Say
If you carry heroine, we
shall hang you !
Life is Most Important !
The World is so beautiful,
Please love yourself, love
your family and the society.
Never to touch the drugs !
Withdrawal symptoms/syndrome
Antihypertensive drugs
βadrenoceptor antagonists used in the
treatment of angina.
SECTION 3
The Principals For Drug Rational Use
1. Exact Diagnosis
2. Choosing Drug According to
Pharmacological theory
3. Understanding Factors Affecting Drug
Action - individualization
4. Both Etiological and Symptomatic
Treatments are Important
5. High Responsibility for Patients
Thank You !
How cute it is ?