Transcript Dose

Chapter 2
Pharmacodynamics
What the drug does to the body
Action and Effect of drug
Effect: Response resulting from interactions
between drugs and molecules in body. It is a
result of the drug action.
Such as ：Noradrenaline
↓
Blood pressure raise
↓
Vascular smooth muscle contract
↓
Vasoconstriction
Action: Initial response of leading
to the drug’s observed effects.
It is fashion processes which
drug brings about the molecules
response in organism(body).
Such as: interaction between adrenaline and
receptor
Noradrenaline
↓
α-receptor
↓
vasoconstriction
↓
blood pressure raise
↓
heart rate decrease
(Reflex response to blood pressure changes)
Analysis of drug effect
Basic expression of drug effect
• Excitation: increasing or raising of function
Adrenaline: blood pressure ↑
• Inhibition: decreasing of function
Insulin: blood glucose ↓
Benzodiazepines: Sedative-Hypnotic
action
• Same drug may produce different effects on
various tissues and organs
Selectivity
Selectivity is relative
• High selectivity: high pharmacological activity
• Low selectivity: wide pharmacological activity,
may be more side reaction
Such as
Morphine: distribution in kidney, but target
organ is CNS
Atropine: low selectivity , wide action, more
side reaction
Specificity
Sensitive
Drugs
Selectivity
Range
Question:
If a drug has high specificity, can we say the drug has
good selectivity?
Therapeutic effect
• 对因治疗（etiological treatment）
• 对症治疗（symptomatic treatment）
急则治其标，缓则治其本；
标本兼治，是其道也。
不良反应（Adverse reaction）
• Concept：all the reactions that can bring out the
uncomfortable or painful reaction, and have no
relationship with the aim of administration, are called
adverse reaction.
– 副作用（side reaction）: is the inherent property
of drugs, it appears at the clinical dosage
because of the selectivity of the drugs.
– 毒性反应（toxic reaction）：When dosage was
excessive or drugs are concentrated in certain
tissue, there will be harmful responses which are
serious and can be avoid.
– 后遗效应（residual effect，after effect）：when
the administration ceased, the concentration of
drug in the plasma would decrease below the
threshold concentration, but there still would
resist some residual pharmacological effect
– 停药反应（withdrawal reaction）： when the
administration ceased ，the symptoms of
original disease would be aggravated ,又称回跃
反应（rebound reaction）。
– 变态反应（allergic reaction）：又称过敏反应
（hypersensitive reaction）。
•immunoreaction ，半抗原(hapton)
characters： •Having no relationship with dosage
•Having no relationship with inherent effect
•Pharmacological antagonist having no efficacy on it when
poisoning
– 特异质反应(idiocyncrasy)：
特点： 非免疫反应
高敏体质
•与剂量有关
•症状与药物固有作用基本一致
•药理性拮抗药有效
Dose-effect relationship
(Dose-response relationship)
Dose effect relationship
• effect of the drug increases or
decreases followed by the change of
the drug dose or concentration
Dose-response (dose-effect) curve
Dose response curve…...
• According to the properties of effect：
–量反应（graded response）
•The effect was changed continuously, could be expressed by
concrete number or maximal ratio, eg. Bp，HR
•Dose-effect relationship：effect intensity for y-axis,
– Dose/concentration for x-axis：rectangle hyperbola
– Log Dose/concentration for x-axis ：symmetrical ”s” curve
– 质反应（quantal response/all-or-none response）：pharmacological effect was
not followed by continuous dosage changes, but expressed by quantitative
change.
• Positive or negative，all or none
• Dose-effect relationship：
– Frequency for y-axis，dose for x-axis：normal distribution curve
– Cumulative positive ratio for y-axis， dose for x-axis ：long tai “s” curve
– Cumulative positive ratio for y-axis， logD for x-axis ：symmetrical “s” curve
Dose-response (dose-effect) curve
Pharmacological effects
• 最小有效量（minimal effective dose）：the
dosage could elicit the minimal effect, also
could be called threshold dose
• 最大效应（maximal effect，Emax）：也称效能
（efficacy）
• EC50：the concentration could elicit 50
percentage of maximal effect
• 效价强度（potency）：the relative
concentration or dose could elicit equivalent
effect (50% Emax), smaller the value is, more
intensive the potency is。
• 斜率（slope）：variation of drug。
Drug efficacy, Emax
• The ability of a drug to elicit a
maximal response
– Also called intrinsic activity of a drug
(receptor theory)
Graded Dose-Response
Slope A
Slope B
Drug potency
% of animal population tested
• A measure of the amount of drug required to
obtain a particular response
50
10 mg
20 mg
% of population tested
Dose-response curves
ED50: Median effective dose
• ED50 (median effective dose):
– The dose of a drug that produces a
specified, desired effect in 50% of
the animal population tested
LD50: Median lethal dose
• LD50 (median lethal dose):
– The dose of a drug that produces
death in 50% of the animal
population tested
NO DRUG IS RISK-FREE
• All drugs are associated with
undesirable or harmful effects at
some dose or plasma concentration
Drug
plasma
concentration
Toxic levels
Therapeutic levels
Subtherapeutic levels
Therapeutic index (TI)
TI = LD 50
ED50
• The ratio of the dose producing a lethal
effect in 50% of the test population (LD50)
to the dose producing a specified desired
effect in 50% of the test population (ED50)
Narrow therapeutic index
10 mg
ED50
25 mg
LD50
Certain safety factor
LD1
ED99
• The ratio of the dose producing a lethal
effect in 1% of the test population (LD1)
to the dose produced a specified desired
effect in 99% of the test population (ED99)
Overlap between effective and toxic drug
plasma levels
ED99
LD1
safety margin
LD5~ED95
• The distance of the dose producing a
lethal effect in 5% of the test population
(LD5) to the dose produced a specified
desired effect in 95% of the test
population (ED95)
TI compared with Safety Margin
% of animal population tested
ED95
LD5
Dose (units)
ED50
LD50
20
60
Drug v.s. Receptor
Receptor
• 受体（receptor）： is
a macromolecular
substance that may be
a protein or an enzyme
which is located on cell
membrane or in cell
plasma. It could
recognize the minim
chemical substances
and bound with them.
Ligand
• 配体（Ligand）：is
the substance that
can specially bind to
receptor 。
a) Endogenous :
transmitter,
hormone,
b) Exogenous
• Properties of receptor：
– sensitivity：
– specificity：
– saturability：
– reversibility：
– Multiple-variation：
Classical theory——
occupation theory
Only if drugs bound
with receptor, the
drugs could be
activated which
intensity was
proportional with the
number of occupative
receptors. When all
receptors were
occupied, the effects
were the maximal
Interaction between receptor with drug
– 亲和力（affinity）：is the capabilities that drug
could bind with receptors, and can be expressed
by the concentration at which reach 50% Emax
– 1954，modified
– the effect that drugs could bind with receptors and
be activated not only need affinity, but also need
intrinsic activity.
– 内在活性（intrinsic activity，α）：is the
information encoded in a drug’s chemical structure
causes the receptor to change accordingly when
the drug is bound.
D+R
DR
E
[RT]=[R]+[DR]
代入
KD =
KD =
[D][R]
[DR]
KD：平衡解离常数，
表示药物与受体亲
和力，KD越大,药物
与受体亲和力越小
(反比)
[D]（ [RT]- [DR]）
[DR]
E
Emax
=
[D] = 0
[D]>>> KD
[DR]
[RT]
[DR]
[RT]
E=0
E=Emax
=50%
=
[D]
KD+ [D]
KD：单位mol/L，引
起最大效应一半
(50%受体被占领)时
所需的药物浓度
KD = [D]
• KD
– KD represents the concentration of free drug at which
half-maximal binding is observed.
– The KD is the drug concentration for 50% saturation of
the receptors.
– The KD is the dose of 50% for the maximal effect.
– The KD is inversely proportionate to the affinity of the
drug .
•
pD2
affinity index
pD2 = -㏒KD
KD ↓， pD2 ↑，affinity ↑；
KD ↑, pD2 ↓，affinity↓
Intrinsic activity
E
Emax
=
[DR]
[RT]
0 ≤ ≤ 1
If affinity is equal, Emax depends on intrinsic activity
If intrinsic activity is equal, affinity depends on potency of drug
Classification of drugs
Endogenous ligand
(e.g. endorphin on opoid receptor)
Agonist
(e.g. morphine on opoid receptor)
Antagonist
(e.g. naloxone on opoid receptor)
Classification of drugs
• 激动药 agonist
–Full agonist
•Strong affinity
•Strong intrinsic activity（α＝1）
–Partial agonist
•Strong affinity
•Weak intrinsic activity
（ 0 <α< 1 ）
• 拮抗药 antagonist
antagonist：
• Full antagonist：
– Strong affinity
– No intrisic activity（α= 0）
• Partial antagonist：
– Strong affinity
– Weak intrisic activity（0 <α< 1）
Competitive
antagonist
Agonist
Competitive antagonist:
Because antagonism is
competitive, the presence of
antagonist increases , the
agonist concentration required
for a given degree of response,
and so the agonist
concentration-effect curve
shifts to the right.
The presence of different
concentration of antagonist
may paralleling shift
concentration-effect curve of
agonist to the right, Emax is
not changed.
Antagonism index, pA2：
– The intensity of antagonism
– When agonist was combined with antagonist, if
the effects that doule agonist joined up with
antagonist coud elicit were equal to the effect that
only agonist without antagonist could elicit, the
negative logarithm mol concentration of
antagonist was pA2
– pA2↑，antagonism↑
Noncompetitive
antagonist
Agonist
Irreversible antagonist
• Affinity&intrisic
activity↓
• Emax↓
• concentrationeffect curve shifts
to the right.（ not
parallel）
Two State Receptor Model
Resting
Restingstate
stateR(Ri)
actviated
Activated
state
state
(Ra)
R*
Full effect
partial
effect
no effect
Reverse
effect
Reverse Agonist
•Spare receptor:
•Not occupied receptors. Maximal effect can be
elicited by a agonist at a concentration that not
result in occupancy of the full complement of
available receptor.
•Available receptor and spare receptor are not
hidden or unavailable and when they are occupied
they can be coupled to response.
受体类型
1.
2.
3.
4.
5.
Ligand-Gated Channels
G Protein coupled receptor
Receptor Tyrosine Kinase
Cytosolic Recptors
other
受体调节
•受 体 脱 敏 （ receptor
desensitization
）
：
receptor-mediated
responses to drugs and
hormonal agonists often
desensitize with time. After
reaching an initial high
level,
the
response
gradually diminishes over
seconds or minutes, even
in the continued presence
of
the
agonist.
This
desensitization is usually
reversible.
•受体增敏： 长期应用拮抗药
造成的。
Factors affecting drug response
• Drug factor
– Drug properties:
• Preparation
• Physiochemical properties
• Administration
• Drug in combination
• Physiological factors
– Age
– Weight
– Sex
– hyposensitivity
• Psychological factors:
– 安慰剂（placebo）：was made of the
neural substances that had no special
pharmacological activity, which shape was
the same as real drug.
– Placebo effect：often caused by
psychological factors
– Pathological factors:
• Heart disease
• Hepatic disease
• Renal disease
• Innutrition
• Balance of base or acid disordered
• Electrolytes disordered
• Genetic factors
• Time
• Living habits and environments