Transcript 酸枣仁油软胶囊的新药开发研究

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Pharmacology
Pharmacology
1. General Principles
2. Peripheral Nervous Drugs
3. Central Nervous Drugs
4. Cardiovascular and Blood Drugs
5. Splanchnic Drugs
6. Endocrine Drugs
7. Chemotherapeutic Drugs
(7 sections )
PART 1
GENERAL PRINCIPLES OF
PHARMACOLOGY
1. Introduction of Pharmacology
2. Pharmacodynamics
3. Pharmacokinetics
4. Impact factors
Yuan Bing-Xiang (袁秉祥)
Department of Pharmacology,Medical School,
Xi’an Jiaotong University,
Tel: 82657724, Email: [email protected]
PHARMACOLOGIC PRINCIPLES
CHAPTER 1
Introduction of Pharmacology
GENERAL PRINCIPLES
Pharmacology
Pharmacodynamics, PD
drugs
Impact factors
organisms
Pharmacokinetics, PK
Pharmacology can be defined as the
science or course studying interaction
between drugs and organisms (bodies) .
Pharmacology
GENERAL PRINCIPLES
human being
drugs
Bodies
animals
pathogens
pathogenic
microorganisms
parasites
bacteria
virus
fungus
tumor cells
Peripheral Nervous drugs
Central Nervous drugs
Cardiovascular and Blood rugs
Splanchnic drugs
Endocrine drugs
drugs act
to systems
Chemotherapeutic drugs ― drugs act to
pathogens
drugs
bodies
GENERAL PRINCIPLES
Pharmacology
Drugs are the substances or compounds
administered beneficially altering biochemical
and physiological states of the body, applied to
prevent, treat or diagnose diseases.
Poisons are the substances or compounds
inducing the undesirable or toxic reactions on
body in smaller dose.
no strict limit between drugs and poisons
GENERAL PRINCIPLES
Pharmacology
Pharmacodynamics (drug acts on body)
Drug
action
effects
Primary acting
on the target
Secondary Inducing
effects in the organ
cell signal
transduction
(mechanism of effect)
drug-protein（receptors;
ion channels; enzymes;
transporter…
E
KD
therapeutic effects
adverse reaction
dose-effect
curves →PD parameters
(KD, EMAX…)
Dose
Pharmacology
GENERAL PRINCIPLES
Pharmacokinetics (body acts on drug)
Undergoing of
drug in body
absorption
transportation
 distribution
 excretion
 biotransformation

C-T curves
PK parameters are from C-T curves
(drug blood Concentration-Time curves)
t1/2, Ka, Ke, F, Vd…
C
C-T curves
T
PHARMACOLOGIC PRINCIPLES
CHAPTER 2
Pharmacodynamics
（drug Acts on body）
Basic Action
Pharmacodynamics
Ⅰ. Basic actions or effects of drug
1. Excitation and Inhibition
The intrinsic functions of body are
altered by drugs:
1) Excitation or stimulation：The functions are
increased by drugs. (contraction, heart rate↑, BP↑,
unstable or restlessness …)
2) Inhibition：The functions are decreased by
drugs. (relaxation, heart rate↓, Bp↓, tranquilize
and sedation …)
Basic Action
Pharmacodynamics
2. Local effects and general effects
1) Local effects are the effects of drug induced
in administered locale before absorption.
2) General effects (absorptive effects, systemic
effects) are the effects of circulated drugs
induced in general system (injection or after
absorption).
Basic Action
Pharmacodynamics
For example: magnesium sulfate (MgSO4)
Orally →80% no absorption → Local effects →
intestinal osmotic pressure↑( volume ↑) →
catharsis (purgation) → elimination of toxin
cholagogic effect (for cholecystitis)
Orally →20% absorption
Injection →to circulation →general effects →
vasodilation →BP↓
-------------------
central inhibition → anticonvulsion
treatment of eclampsia
Gravida With hypertension and convulsion
Basic Action
Pharmacodynamics
3. Specificity: Singularity of actions on target
Selectivity: Singularity of effects in organ or sys.
drug-target→specificity → selectivity

Drug-subtype of receptor →higher specificity
→higher selectivity┌→tight clinic indication
└→less side reaction

Drug-type of receptor (all subtypes of receptor)
→lower specificity →lower selectivity
┌→wide clinic indication
└→ more side reaction
Pharmacodynamics
Basic Action
For example
α-adrenoceptors blocker
α
α1
α1A
α1B
α1D
α 2 (presynaptic)
α1↓→vasodilation→BP↓ ↘（reflect)
α1 α2-blocker
(phentolamine) α ↓→NA release↑→β↑→heart ↑ ↑
2
cardiopalmus, arhythmia
α1-blocker
(prazosin)
α1D α1B ↓→ vasodilation→BP↓
α1A↓→smooth muscle of prostate↓
α1A-blocker
(tamsulosin) → α1A↓→smooth muscle of prostate↓
(relieving of uroschesis of prostatic hyperplasia)
Basic Action
Pharmacodynamics
4. therapeutic effects are the effects that
are consistent with therapeutic purposes.
(in normal dose and in almost patients)
Etiological treatment
eliminating causes of
disease. (for instance, chemotherapy…)
Symptomatic treatment remission of symptoms
or suffering of disease. (for instance, analgesia,
sedation…)
Basic Action
Pharmacodynamics
5. adverse drug reactions，ADRs *
ADRs can be defined as the drug effects that
are not consistent with therapeutic purposes and
induce harms to patients.
10-20% of patients in hospital suffer ADR. --WHO-106,000 patients in USA lost life from ADRs every
year.
First killer：cardiac disease, 743,000
The cause Second killer：cancer, 529,000
of death
Third killer：stroke, 150,000
Fourth killer：ADRs, 106,000
Fifth killer：drug abuse, 80,000
Vietnam war (10
AIDS≈road accident, 41,000
years)：56,000
Pharmacodynamics
ADR
1) Side reaction
The light reactions without
relationship to therapeutic purpose of a drug
administrated in normal dose are induced in
almost patients, because of low selectivity of the
drug. The lower selectivity, the wider clinic
indication and more side reaction.
therapeutic
purpose
therapeutic
effects
Atropine
→M↓
side
reactions
A: smooth muscle ↓→spasmolysis……intestinal tympanites
（stomachache）
B: gland ↓→bronchus secrete↓……… dry mouth
（preanesthetic medication）
C: mydriasis→intraocular tension↑……eyeground check
ADR
Pharmacodynamics
2) Toxic effect Pharmacological effects are
too strong and induce organic and functional
injury in some patients when high dose and long
drug administration.
aminoglycosides→injury
of auditory nerve→deaf dumbness
Pharmacodynamics
ADR
3) After effects Effects remain when drug
blood concentration is
reduced below threshold
concentration.
C
TC
T
Transient
Phenobarbital ┌ drowsiness in early morning
└ nightmare in next night
duration
Cortine (long administration）→stop→
persistent hypofunction of adrenal cortex
Pharmacodynamics
ADR
4) Dependence
The physical and psychic
dependent states are induced following repeated
drug administration, displaying compulsive,
continual hunt to drugs (or narcotics).
First drug
administration
Diamorphine（heroin）
Dependence
Pleasant
feeling
discontinue
discontinue Mental desire
Ice,benzedrinum
（lifetime）
Repeated drug
administration
Abstinence syndromes
(5～7days)
Grave social
problem
Vicious cycle
Addict: lost of personality, responsibility and shame→crime rate↑
ADR
Pharmacodynamics
Physical dependence: Addiction induced following
repeated administration. The vital activity depends on
drugs, the serious abstinence syndromes could be
induced after discontinue.
Psychic dependence: Psychic desire and pleasant
feeling are induced following the repeat. The mental
state depends on drugs without abstinence syndromes
after discontiune.
Ice,benzedrinum
Pharmacodynamics
ADR
food
drug
success
happy
amuse
sports
sex
starvation
thirsty failure
go blind
abstinence
syndrome
misery
ache disappointed
pain
hometown family
drug
miss
good
friend
lover
Pharmacodynamics
ADR
5) allergic reaction
The exceptional
immunoreaction is produced by a drug as an
antigen or semi-antigen in minority of allergic
patients without relationship to pharmacological
action and dose (in any dose).
• penicillin→allergic shock (Ⅰtype) (immediate allergy)
• qunine→hemolytic anemia (Ⅱtype)
(cytolytic type hypersensitivity)
• sulfa→drug fever or eruption (Ⅳ type) (delayed allergy)
• Ⅲ type（immune complex type）is seldom seen
Pharmacodynamics
ADR
6) idiosyncratic reaction
The exceptional
reaction produced by a drug in minority of
gene defect patients without relationship to
pharmacological action.
sulfonamides
vitamin K
primaquine
broad beans
Absence of
G-6-PD
Oxidizing
Hemolytic
Anemia &
jaundice
glucose-6-phosphate
Dehydrogenase, G-6-PD
Pharmacodynamics
Dose-response relationship
Ⅱ、Dose-response relationship
The effects of a hypotensive drug on BP
hypertensives
graded response
BP↓(MMHg)
quantal response
10 mmHg↓=effective
1
2
3
4
5
6
7
8
9
10
statistics
15
20
8
12
6
16
25
9
22
19 15.2±6.4
+
+
-
+
-
+
+
-
+
+
70%
（millimeters of mercury）
graded response: measured effects indicated in biologic unit (mmHg)
quantal response: all-or-none effect indicated in frequency (population) or rate.
x  S（mean±standard deviation）
Dose-response relationship
Pharmacodynamics
1. Graded response
(Quantitative response)
Graded response is the quantitative
relationship between dose and measured
effects indicated in biologic unit and
continuous scale.
BP(mmHg), RBC(1012/L), cholesterol (mmol/L) ……
Graded response
Pharmacodynamics
Dose-effect curve of graded response
Project
纵坐标Y-axis
横坐标X-axis
E Emax
hyperbola
Kd
E
Symmetry
S curve
Log D (C)
Threshold
maximal minimal
dose
dose
Toxic dose
↓
↓
↙
├─┴┴─────┴─╂─┴───┴── D (C)↑
common
minimal
dose
lethal dose
D (C)
Graded response
Pharmacodynamics
① Threshold dose ：Minimum effective dose
② Efficacy (Emax) ：Maximum effect or the limit of the
drug response.
③ Potency ：Dose inducing given effect, or a dose (KD)
inducing 50% Emax. Dose or KD↑→ Potency↓
④ Slope： Slope at 50% Emax (slope↑→range of common
dose↓→less safety）
⑤ Maximal
dose:
The
limit
of
dose
permitted
in
pharmacopeia for some drugs.
⑥ Common dose：The effective dose in most of patients.
maximal dose＞common dose＞threshold dose
Graded response
Pharmacodynamics
E
B
A
C
log D (C)
potency：Ａ＞Ｂ＞Ｃ
efficacy：Ｂ＞C ＞Ａ
threshold dose：Ｃ＞Ｂ＞Ａ
slope：Ａ＝Ｂ＞Ｃ
Quantal response
Pharmacodynamics
2. Quantal response
(Qualitative Response)
The qualitative relationship between dose
and all-or-none effect is indicated by the
frequency (population) or rate.
(e.g., the death rate or population among
mice in a pre-clinical study or effective rate
or population among the patients in a clinical
trial.
Quantal response
Pharmacodynamics
D (mg)
1
1.1
1.2 1.3
F
distribution
0
2
4
6
10
8
6
5
4
3
2
cumulative
0
2
6
12
22
30
36
41
45
48
50
%
distribution
0
4
8
12
20
16
12
10
8
6
4
cumulative
0
4
12
24
44
60
72
82
90
96
100
percentage
E
1.4
1.5 1.6 1.7 1.8 1.9
F
cumulative
distribution
D
supersensitivity tolerance
%
50 100- cumulative
40 8030 6020
40-
10
20-
0
0
distribution
lgD
distribution curve→Individual variation (sensitivity).
 cumulative curve→qualitative parameters (LD50, ED50)

2.0
Quantal response
Pharmacodynamics
1) Cumulative curve
F
F
(%)
P
(probit)
(%)
D
long tail S curves
logD
symmetry S curves
logD
straight line
2) Distribution curve
F
F
D
skew distribution
logD
normal distribution
Quantal response
E(%)
100%
95%
Pharmacodynamics
toxicity
or death
effective
50%
cardiac glycoside
ED95
5%
ED50
ED95 LD5 LD50
Therapeutic index (TI) ＝ LD50／ED50
Safety index (SI)＝LD5/ED95
dose
Quantal response
Pharmacodynamics
Therapeutic index (TI) and safety index (SI) are
used for judging drug's safety.
TI＝LD50／ED50
SI＝LD5 ／ ED95
ED50 (Median effective dose)：the dose required
to produce specified effect in 50% individuals
(experimental animals).
LD50 (Median lethal dose）：The dose required to
produce death in 50% of animals.
Drug receptor
Pharmacodynamics
Ⅲ. Drug receptor
1. Drug-receptor concept
Receptor The receptive substances (proteins)
of cell (membrane) specifically interact with
their ligands (corresponding drugs, transmitter,
hormone, autacoids) and initiate the chain of
signal transduction and biochemical and
physiological changes.
ligands: corresponding drugs, transmitters,
hormones or autacoids binding to their special
receptor.
Drug receptor
Pharmacodynamics
2. Characters of drug-receptor interaction
1) Saturation: Because of finitude of number of
receptor molecules or unlimited drug molecules,
the drug-receptor binding is limited. →Emax
2) Specific binding (lock-key)
3) Reversible binding
4) High potency (affinity) →low KD (dose)
5) Competitive binding 2 drugs binding to
same receptor.
a antagonist is competitive
with an endogenous agonist
Drug-receptor binding Theory
Pharmacodynamics
3. Drug-receptor binding theory
1) Receptor occupancy theory: It is
assumed that drug responses could be
initiated from the receptor occupied by a
drug.
The greater response observed, the more
receptor occupied.
Drug-receptor binding Theory
Pharmacodynamics
In general, the effect (E) is a equation of the
quantity of the drug-receptor complex [DR], and
can be expressed as:
[D]+[R]
E
α
KD
[DR]┄→E
Emax (α)
E
Log[D]
KD
[D]
E = α[DR]
Once all receptors are saturated,
the maximum effect (Emax) is
achieved. If the 50% of receptors
were occupied, 50% Emax is
produced.
KD
(dissociation
constant) is drug concentration
occupying 50% of receptors.
Drug-receptor binding Theory
2) Rate theory：
Pharmacodynamics
[D]+[R]
k1
[DR]
K2
The effect associates not only with binding
rate (k1), but also with dissociation rate (k2).
k2↑→the effect↑→Emax↑
3) two state theory
agonist partial agonist
Positive
effect
active
receptor
antagonist
inactive
receptor
Negative
effect
Inverse agonist
Parameter of drug-receptor
Pharmacodynamics
4. Parameter of drug-receptor interaction
1) Affinity (or potency) is the ability of a
drug binding to its receptor.
Affinity is the concentration of drug required
to occupy 50% its receptor or elicits 50% Emax.
The greater concentration (KD) required, the
lower affinity of a drug.
Parameter of drug-receptor
Pharmacodynamics
pD2 is the parameter of agonist's affinity and
the negative logarithm of molarity (mol)
concentration (KD) of a drug binding 50%
receptor or inducing 50% Emax.
pD = -log K
2
E
Emax
50%
E
Emax
50%
KD
pD2
[D]
-log [D]
The more KD, the low agonist's affinity;
The more pD2, the more agonist's affinity.
D
Parameter of drug-receptor
2) Intrinsic activity (or efficacy)
Pharmacodynamics
The ability of
a drug inducing effect after binding to receptor.
The faster dissociation rate (k2), the greater
Emax, and the greater intrinsic activity.
Classification of drugs
Pharmacodynamics
3) Classification of drugs binding to receptor
Classification
occupancy
affinity Intrinsic activity
rate
k1
k2
agonist
antagonist
＋
＋＋
＋
＋＋
＋
－
＋
－
partial agonist
＋
＋
＋
＋
Inverse agonist
＋
＋ (opposite effect)
＋
＋
agonist
partial agonist
antagonist
Inverse agonist
Drug-receptor binding Theory
Pharmacodynamics
4）straight formula of hyperbola
KD
E
[D]+[R]
hyperbola
[D]
α
[DR]┄→E
D

[ DR ]

[ RT ] K D   D 
Clark equation
Scott
method
 DY =
[D]
E
E
straight line
[D]
k2  D  R 
KD 

k1
 DR 
D

E

Emax K D   D 
dose-effect formula
1b x + KaD
 D 
Emax
Emax
Scott straight formula
b =1/Emax，a=KD/Emax，
Emax=1/b，KD=a/b，
pD2
Pharmacodynamics
ACh (mol/L)
E (mm)
E
E
10-9
3×10-9
10-8
3×10-8
10-7
3×10-7
10-6
0
7
20
40
62
73
73
 D E
max
K D   D
Emax
50%
KD
 D 
KD
1
XD + a
Y
=
b
E
Emax
Emax
[D]/E
a: intercept
[D]
[D]
linear regression: Emax=1/b=80.5mm,
KD=a/b=3.055×10-8 mol/L，pD2＝-logKD =7.515.
Competitive antagonism
Pharmacodynamics
4. Competitive antagonism
1) agonist-antagonist: In the presence of a fixed
concentration of antagonist, dose-effect curves of
the agonist would be shifted to the right :
a. Threshold concentrations are increased;
b. Curves is shifted to the right in equal slope;
（parallel）
c. Emax is unchanged.
Competitive antagonism
Pharmacodynamics
pA2 is the parameter of Blocker (antagonist)
affinity, or the negative logarithm of molarity (mol)
of a Blocker in double KD of Agonist.
fictitious
E
Emax
A
A+BF A+B1 A+B2 A+B3
fictitious
KDF / KD0 = 2
50%
pA2=-log[BR]
KD0 KDF KD1 KD2 KD3
[D] (agonist)
[A]＋[R] ＝ [RA]─→E
log(R-1)
[B]＋[R] ＝ [RB]
.
.
.
[RT]＝[R]＋[RA]＋[RB]
.
Y =b X
+ a
log(R-1)＝-(-log[B])＋(-logK
B)
R= KDx / KD0 (R1, R2, R3…)
linear regression: x= -log[B], y= log(R-1)
according to the concept of pA2,
R=2, y=0, pA2 (-logKB)= -log[B]
pA2
-log[B]
ACh [D] (mol/L)
3×10-9
10-8
3×10-8
10-7
3×10-7
10-6
3×10-6
Atropine [B] 0
7
20
40
62
73
10-8 (mol/L)
0
8
18
44
58
72
3×10-8 (mol/L)
0
0
5
16
47
64
74
10-7 (mol/L)
0
0
0
9
27
45
65
10-6
73
energy
transducer
pre-amplifier
E
fictitious
K DF
2
KD0
KDF
KD0 KD1
KD2 KD3
[D]
R= KDx / KD0
(R1= KD1 / KD0, R2= KD2 / KD0, R3= KD3 / KD0 …)
linear regression
Y =b X
+ a )
log(R-1)＝-(-log[B])＋(-logK
B
R=2 or y=0, pA2= 8.05
log(R-1)
pA2
-log[B]
Competitive antagonism
Pharmacodynamics
2) agonist-partial agonist: In the presence of a
fixed concentration of partial agonist, dose-
effect curves of the agonist would be altered
following increasing concentration of agonist.
a. Threshold concentrations↓
b. Emax is unchanged;
c. Curves is shifted to the left at low
concentration of agonist (partial
agonist would like agonist).
d. Curves is shifted to the right at
high concentration of agonist
(like antagonist).
E
A A+P' A+P''
logC
Competitive antagonism
E
Pharmacodynamics
A A+P' A+P''
logC
A
A
low concentration of agonist
B high concentration of agonist
Noncompetitive antagonism
Pharmacodynamics
6. Noncompetitive antagonism
After administration of a noncompetitive
antagonist
(phenoxybenzamine),
high
concentrations of agonist cannot completely
overcome the antagonism and Emax can be
reduced. Dose-effect curves of agonist are
altered as that:
a. Threshold concentrations are unchanged;
b. Emax is decreased;
c. KD is unchanged theoretically.
Noncompetitive antagonism
E
Emax
Pharmacodynamics
A
A+N1
1/2EmaxA+N
2
A+N3
KD
fictitious
pD2′= -log[N2]
C (agonist)
pD2′: The parameter of noncompetitive
antagonist affinity. The negative mol of a
noncompetitive antagonist required to
decrease Emax by 50%.
Pharmacodynamics
The End of
pharmacodynamics