Transcript Document

PHARMACOLOGIC PRINCIPLES
CHAPTER 3
Pharmacodynamics
（drug Acts on body）
Basic Action
Pharmacodynamics
Ⅰ. Basic Action of Drug
1. Excitation and Inhibition
The intrinsic functions of the body are altered
by drugs:
1) Excitation or stimulation：the functions are
increased by drugs. ( heart rate↑, BP↑,
contraction, unstable …)
2) Inhibition：the functions are decreased by
drugs. (heart rate↓, Bp↓, relaxation, stable or
sedation …)
Basic Action
Pharmacodynamics
2. Local action and general action
1) Local action：action on the locale
before absorption of administered drugs.
2) General action (absorptive action,
systemic action)：action of drugs on
general system after absorption.
Pharmacodynamics
Basic Action
Local action and general action
For example, magnesium sulfate (orally)
→80% no absorption →intestinal osmotic
pressure↑→ volume ↑→catharsis (purgation)
↘cholagogic action
For example, magnesium sulfate (injection)
→circulation → General action site
↗vasodilation → BP↓ ----------↘central inhibition→sedation
Treatment of eclampsia gravidarum
Basic Action
Pharmacodynamics
3. Specificity: Singularity of action on drug target;
Selectivity: Singularity of effect on organ or tissue .
1) Interaction of drug —target
high specificity→ high selectivity →high
clinic pertinency →less side reaction
 low specificity→low selectivity→ low
pertinency → more side reaction and wide
clinical use

2) high concentration of drug in the organ or
tissue →high selectivity
iodine→intaked by thyroid gland →high concentration
→action on thyroid
Pharmacodynamics
Basic Action
α-adrenoceptors blockor
Α1,α2-blockor
(phentolamine)
α1-blockor
(prazosin)
α1↓→vasodilation→BP↓ ----↘
α2↓→NA release↑→β↑→heart ↑ ↑
α1D,α1B ↓→ vasodilation→BP↓
α1A↓→smooth muscle of prostate↓
α1A-blockor → α1A↓→smooth muscle of prostate↓
(tamsulosin)
(uroschesis of prostatic hyperplasia)
Pharmacodynamics
Basic Action
4. therapeutic effect
Therapeutic effect can be difined as the drug
effects that are consistent with therapeutic
purposes.
etiological treatment
Eliminate cause of a
disease. (Chemotherapy…)
symptomatic treatment
Remission of symptoms or
suffering of a disease. (analgesia, sedation…)
Basic Action
Pharmacodynamics
5. adverse drug reaction，ADR *
ADR can be defined as the drug effects that
are not consistent with therapeutic purposes
and induce harm to patients in normal use and
dose for a qualified drug.
-- WHO- 5-10% of patients in hospital are because of
ADR. 10-20% of patients in hospital suffer ADR.
--WHO--
106,000 patients in USA lost life from ADR in
2002. The cause of death was fourth mortality in
USA.
Basic Action- adverse drug reaction
Pharmacodynamics
A type of ADR (augmented)
The augmented
effects of drug are too strong to induce harm
following increasing dose (normal dosage).
A type of ADR
(character)
• dose–dependent
• forecastable
• high incidence rate
• less serious and
low mortality.
*side reaction, *toxic effect, after effect,
*dependence
Basic Action- adverse drug reaction
Pharmacodynamics
B type of ADR (bizarre) The bizarre effects of
drug are independent of pharmacological action.
B type of ADR
(character)
• not dose-dependent
• difficult to forecast and find
• low incidence rate
• serious and high mortality
allergy, idiosyncratic reaction, teratogenesis,
carcinogenesis
Pharmacodynamics
A type of ADR
A type of ADR (augmented)
1) Side reaction
The 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.
therapeutic
action
therapeutic purpose
side
reaction
A type of ADR
Pharmacodynamics
2) Toxic effect Pharmacological responses
are too strong and induce organic and
functional injury in some patients when drug
administration in normal dose and period
because of hypersensitivity induced by
individual variation, pathological state and
interaction of drugs.
A type of ADR
Pharmacodynamics
3) After effect
Effects remain when drug
blood concentration is
C
reduced below threshold
TC
concentration.
T
4) Dependence
New balance induced
following repeated administration of
some drugs.
A type of ADR
Pharmacodynamics
Physical dependence Addiction induced
following repeat administration. The vital
activity of body depends on drugs, the
serious abstinence syndrome is induced after
discontinue.
psychic dependence
Psychic desire and
pleasant feeling are induced following the
repeat. The mental state depends on drugs
without abstinence after discontiune.
Pharmacodynamics
A type of 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
B type of ADR
B type of ADR (augmented)
1) allergic reaction
A drug as an antigen or
semi- antigen produces exceptional immunoreaction in
minority of allergic patients without relationship to
pharmacological action and dose.
(penicillin→ allergic shock)
2) idiosyncratic reaction
A
drug
produces
exceptional reaction in minority of gene defect patients
without relationship to pharmacological action.
Pharmacodynamics
B type of ADR
Glucose
ATP
G-6-P
G-6-PD↓
glucose-6-phosphate
Dehydrogenase, G-6-PD
ADP
NADP
NADPH↓
6-PG Acid
Absence of + Oxidizing
G-6-PD
agent
GSSG
H2O2 ↑↑
GSH↓
H2O↓
Hemolytic anemia
sulfonamides
vitamin K
primaquine
anminopyrine
broad beans
B type of ADR
Pharmacodynamics
3) teratogenesis
Drug affects fetation forming
teratism, especially early embryo.
Thalidomide happening（1961）
seal abnormity
pregnancy reaction
gestation reaction
Pharmacodynamics
B type of ADR
4) carcinogenesis
Long osculation of
chemical substances including drugs could
induce malignancy or cancer, about 80%～85%
of human cancers would be induced by chemical
substances..
5) mutagenesis
Drug induce damnification
of germ plasm (DNA).
mutagenesis
carcinogenesis
teratogenesis
Dose-response relationship
Pharmacodynamics
Ⅱ、Dose-response relationship
Graded
BP
mmHg
• Continuous scale
• Measured in a single biologic unit
• Relates dose to intensity of effect
• Mean ± standard difference (x ± s)
( t test )
Dose
Quantal • All-or-none pharmacologic effect
rate
(%)
• Population studies (χ2 test)
• Relates dose to frequency of effect
Dose
Pharmacodynamics
Dose-response relationship
The antihypertensive effect of a new drug to blood
pressure (mmHg) was researched in hypertensives
Graded data
control
-21 -17 -22 -25 -18 -29 -20
-31 -25 -18
-22.6±4.8
test
-25 -31 -28 -27 -18 -35 -28
-28 -35 -28
-28.3±4.9
Statistics (T test)
Significant
P<0.05
Quantal data
control
+
-
+
+
-
+
+
+
+
-
7/10 70%
test
+
+
+
+
-
+
+
+
+
+
9/10 90%
Statistics (χ2 test)
Not significant
P>0.05
Graded response
Pharmacodynamics
1. Graded response
rectangular
hyperbola
Ordinate Effects
[D]/E
Abscissa arithmetic
symmetry
S curves
(dose)
Straight line
E
logarithm
[D]
E
E
[D]
Lg[D]
[D]
Graded response
Pharmacodynamics
effect
Emax
E
Kd
logD (C)
D (C)
Threshold
maximal minimal
dose
dose
Toxic dose
↓
↓
↙
├─┴┴─────┴─╂─┴───┴── D (C)↑
common
minimal
dose
lethal dose
Graded response
Pharmacodynamics
① Threshold dose ：Minimum effective dose
② Efficacy (Emax) ：Maximum effect of a drug
or the limit of the drug response.
③Potency ：Dose inducing given effect, or a
dose (KD) inducing 50% Emax.
Dose or KD↑→
Potency↓
Efficacy
is
usually
more
important
potency in selecting drugs for clinical use.
than
Graded response
Pharmacodynamics
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
logD (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)
An all-or-none response to a drug and relates
to the frequency with which a specific dose of a
drug produces a specific response in a
population.
(e.g., death among the mice in a pre-clinical
study or effective among the patients in a
clinical trial.
（response frequency or rate (%), χ2 test）
Quantal response
F
%
Pharmacodynamics
D (mg/kg)
1
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
E
1.2 1.4 1.6
1.9
2.3 2.7 3.1 3.7 4.3
cumulative
distribution
D
5.1
Quantal response
Pharmacodynamics
1) Cumulative curve
Ordinate
(effects)
Abscissa
(dose)
F
long tail
S curves
cumulative
frequency or rate
probit unit（p）
symmetry
S curves
arithmetic dose
straight line
logarithm dose
F
D
p
lgD
lgD
Quantal response
Pharmacodynamics
2) Distribution curve
Cumulative
(effects)
Abscissa
(dose)
distribution
frequency or rate
skew
distribution
arithmetic dose
normal
distribution
logarithm dose
F
F
D
logD
Quantal response
Pharmacodynamics
Individual variation: There is variation of sensitivity to a
drug among population (patients or animals).
 Supersensitivity or tolerance to a drug are produced in
a few population, most of them are middle sensitivity.

E
D
logD
Quantal response
Pharmacodynamics
effective
toxicity
or death
100%
95%
50%
ED95
5%
ED50
ED95 LD5 LD50
Therapeutic index (TI) ＝ LD50／ED50
Safety index (SI)＝LD5/ED95
dose
Quantal response
Pharmacodynamics
Therapeutic index (TI): The index used for
judging drug's safety.
TI＝LD50／ED50
ED50
(Median effective dose)：The dose at
which 50% of individuals (experimental animals)
exhibits specified effect.
LD50（Median lethal dose）：The dose
requied to produce death in 50% of animals.
Quantal response
Pharmacodynamics
Safety index (SI)
The TI may be misleading if
the
dose-
responses curves for effectiveness and toxicity
have
different
slopes
(i.e.,
not
parallel).
Therefore, the Safety index (SI) may be more
useful.
SI＝LD5/ED95
Mechanism of action of drugs
Pharmacodynamics
Ⅲ. Mechanism of action of drugs
1. Unspecific action
1) Alteration of chemical or physical condition
of locale administered to: osmotic diuretics;
antacid; osmotic laxatives.
2) Participate in nutrition and metabolism of
cells：Vitamin, ferrous sulfate、glucose.
Calcium…
Mechanism of action of drugs
Pharmacodynamics
2. Specific action: drug-receptors; drugion channels; drug-enzymes;
1) Influence on activity of enzymes：
Insulin→oxygenase of glucose↑→blood sugar↓;
Neostigmine→cholinesterase↓→ACh↑
2) Action on ion-channel of：Antiarrhythmics
3) Action on release of transmiters or hormones：
Ephedrine→release of noradrenaline↑
Iodide→release of thyroxine↓
4) Drug-receptor *
Drug receptor
Pharmacodynamics
Ⅳ. Drug receptor
1. Drug-receptor concept
Receptor The receptive substances of a cell or
an organism that specifically interacts with their
ligands (corresponding drugs, transmitter or
hormone) and initiates the chain of biochemical
and physiological changes.
ligand：A corresponding drug, transmitter or
hormone binding to a receptor.
Drug receptor
Drug receptor
Pharmacodynamics
2. Characters of drug-receptor interaction
1) Saturation: Because of finitude of number of
receptor molecule for unlimited drug molicular
→Emax
2) Specific binding
3) Reversible binding: ionic bond, hydrogen bond,
molecular attraction covalend bond.
Therefore, there is competitive binding
between 2 drugs binding to same receptor.
Drug-receptor binding Theory
Pharmacodynamics
3. Drug-receptor binding Theory
1) Receptor occupancy theory: It is
assumed that response emanates from
the receptor occupied by a drug.
The greater response observed, the
more receptor occupation.
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)
KD
C
KD: dissociation constant
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.
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
Active receptor
agonist
inactive receptor
partial agonist
antagonist
Parameter of drug-receptor
Pharmacodynamics
4. Parameter of receptor-specific interaction
1) Affinity (or potency)
The ability of a drug's binding to receptor.
A drug's affinity for binding its receptor
determines the concentration of drug
required to occupy 50% its receptor or
elicits 50% Emax.
The greater concentration required, the
weaker 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
c
Emax
50%
c
Emax
50%
KD
pD2
C
-log c
The more KD, the low agonist's affinity;
The more pD2, the more agonist's affinity.
D
Parameter of drug-receptor
Pharmacodynamics
2) Intrinsic activity (or afficacy)
The ability of inducing effect of a drug after
binding to receptor.
The faster dissociation rate (k2), the greater
intrinsic activity, the greater Emax.
Classification of drugs
Pharmacodynamics
4. 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
Competitive antagonism
Pharmacodynamics
5. Competitive antagonism
1) antagonist-agonist: In the presence of a fixed
concentration of antagonist, dose-effect curves of
the agonist would be shifted following increasing
concentration of agonist:
a. Threshold concentrations are increased;
b. Curves is shifted to the right in equal slope;
c. Emax is unchanged.
Competitive antagonism
Pharmacodynamics
pA2: The parameter of Blocker’s affinity. The
negative logarithm of molarity (mol) of a blocker
required to inducing same effect (or 50% Emax) in
double concentrations of agonist.
A
E
A+B1
A+B2
KD1 / KD0 = 2
pA2=-log[B1]
1
KD0
2
KD1
3 C (agonist)
KD2
Competitive antagonism
Pharmacodynamics
2) partial agonist –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).
A A+P' A+P''
E
A
B
lgC
Competitive antagonism
A A+P' A+P''
E
A
A
A
Pharmacodynamics
B
low concentration of agonist
lgC
B high concentration of agonist
Noncompetitive antagonism
Pharmacodynamics
6. Noncompetitive antagonism
After administration of a noncompetitive
antagonist, high concentrations of agonist cannot
completely overcome the antagonism and Emax
can be reduced. Dose-effect curves of agonist are
altered:
a. Threshold concentrations are unchanged;
b. Shifted to the right ;
c. Emax is decreased.
Noncompetitive antagonism
E
Emax
Pharmacodynamics
A
A+N1
()
1/2EmaxA+N
2
pD2′= -log[N2]
A+N3
KD
C (agonist)
pD2′: The parameter of noncompetitive
antagonist affinity. The negative mol of a
noncompetitive antagonist required to
decrease Emax by 50%.
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
 D 
KD
1
XD + a
Y
=
b
E
Emax
Emax
[D]/E
50%
a: intercept
KD
[D]
[D]
linear regression: Emax=1/b=80.5mm, KD=a/b=3.055×10-8
mol/L，pD2＝-logKD =7.515.
Ach [D] (mol/L)
3×10-9
10-8
3×10-8
10-7
3×10-7
10-6
3×10-6
Atropine [A] 0
7
20
40
62
73
10-8
0
8
18
44
58
72
3×10-8
0
0
5
16
47
64
74
10-7
0
0
0
9
27
45
65
10-6
73
E
KD0 KD1 KD2 KD3
KDx / KD0=2
[D]
log(R-1)＝-(-log[A])＋(-logKA)
Y = b X + a
log(R-1)
pA2
-log[A]
log(R-1)＝-(-log[A])＋(-logKA)
R= KDx / KD0 (R1, R2, R3)
linear regression: R=2 or y=0, pA2= 8.05
Pharmacodynamics
The End of
pharmacodynamics
PHARMACOLOGIC PRINCIPLES
CHAPTER 4
Impact factor
to pharmacodynamics and
pharmacokinetics
Impact factor
Drug
.
Structure
Polar, pKa
Solubility
Dosage form
Product No
PK
drug
Administration
Dosage
Route
Time, Interval
Drug interaction
Repeat use
Withdraw
PD
Physical
sex
age
weight
Mentality
Illness
Heredity
living
custom
Individual
variation
body
The end of
PHARMACOLOGIC
PRINCIPLES