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Learning Objectives
To understand dose (concentration)-effect relationships.
To be familiar the major classes of physiological
receptors and their mechanisms of signal transduction.
To understand receptor theory.
I drug action & pharmacological effect
drug action: the interactions between a drug and components of a cell or organism, initiates the chain of biochemical events.
pharmacological effect: drug action leading to the drug’s observed effects.
drug action
Adrenaline(AD) activating α-adrenergic receptors on vascular smooth muscle cells
vascular smooth muscles contract
blood pressure increase
Pharmacological effect
How do drugs acts?
drug action mechanism of drug action or signal transduction pharmacological effect
In most circumstance drug action=pharmacological effect
Type of pharmacological effect
Excitation & Inhibition
directly effect & indirectly effect
Type of pharmacological effect
Excitation:
e.g. adrenaline blood pressure increase
Inhibition:
e.g. propranolol heart beat slow down
sedative-hypnotics cause sedation or
facilitate sleep
Selectivity of pharmacological effect
Selectivity------the ability of a drug to affect one cell type
and not others
The higher the selectivity of pharmacological effect, the
narrower the range of drug action.
In contrast,
The lower the selectivity of pharmacological effect, the
broader the range of drug action.
For example:
Antibiotics can be divided into two groups,
narrow antibiotics and broad antibiotics.
Specificity of drug action
Specificity------the ability of a drug to manifest only one
kind of action
Selectivity of ===== Specificity of
pharmacological effect drug action
For example:
Atropine ------muscarinic acetylcholine receptor antagonist, has higher specificity of drug action, but its selectivity of pharmacological effect is lower, because of the broad distribution of muscarinic acetylcholine receptor in the body (gland, eyes, smooth muscle, heart, blood vessels, and CNS) .
Atropine has higher specificity, lower selectivity, broader drug effects, and more side effects.
How do we choose a drug?
In clinic, we often choose a drug with higher selectivity to decrease side effects of the drug.
II Therapeutic effect & Adverse drug reaction
Therapeutic effect consists of the following three aspects:
etiological treatment symptomatic treatment supplement treatment (therapy)
Adverse drug reaction
Side effect Toxic reaction After effect Withdrawal reaction Allergic reaction Idiosyncrasy
A. Side effect: under the dose, lower selectivity of the drug,
usually is non-deleterious
e.g. Atropine
B. Toxic reaction: over the dose, long term accumulation,
or high sensitivity of an individual to a drug like digoxin. acute toxicity: respiratory system, circulation system, and CNS
chronic toxicity: liver, kidney, the blood and hematopoietic system
specific toxicity: carcinogenesis, teratogenesis, mutagenesis
C. after effect
D. withdrawl reaction or rebound reaction
E. Allergic reaction Such reactions are mediated by the immune system. e.g. Penicillin-induced shock
F. Idiosyncratic reaction Idiosyncratic is defined as genetically determined abnormal reactivity to a chemical. e.g. Black males, Hemolytic anemia, by primaquine because of deficiency of G-6-PD.
III Dose-effect relationship
Learning Objective
To understand the ways in which drugs may affect receptor function and the use of dose-effect curves to provide clues to mechanism of drug action.
Learning Objective
To be familiar with, and be able to use in problem
solving, such terms and concepts as ED50 , LD50 ,
Affinity, Potency, Efficacy, Therapeutics Index,
Standardized Safety Margin, etc., as related to
dose-effect curves and their interpretation.
What is dose-effect relationship?
The relation between concentration of a drug or dose of a drug and its pharmacological effect is called dose-effect relationship.
What is dose-effect curve?%
max
imal
res
pons
es
100
50
0C
100
50
0log C
% m
axim
al r
espo
nses
EC50 EC50
% m
axim
al r
espo
nses
100
50
0C
100
50
0log C
% m
axim
al r
espo
nses
EC50 EC50
Fig.2-1 The dose-effect curve of drug action. The EC50 is the concentration at which a drug reaches to the half-maximal effect. When plotted semi-logarithmically, the hyperbolic shape of the curve (figure on the left ), is switched into a sigmodial one (figure on the right). However, it is approximately linear between 20% ～ 80% of the maximal effect, a range commonly observed for drugs used at therapeutic doses.
What is graded dose-response curve?
Concentration of drug
Inte
nsit
y o
f e
ffec
t
Potency
Efficacy
Slop
e variability
Fig.2-2 The log dose-effect relationship. Representative log dose-effect curve,
illustrating its four characterizing variables
What is guantal dose-response curve ?
Fig.2-3 The frequency curve and cumulative frequency curve of a drug action
in a quantal-effect experiment
Slope
ED50
LD50
Maximal Efficacy and potency
1. Maximun Efficacy ( or Efficacy, Emax )
The maximal effect that can be produced by a drug is its maximal efficacy.
2. Potency
The location of the concentration-effect curve along the concentration axis is an expression of the potency of a drug.
How to evaluate drugs with dose-effect curve?
uri
c N
a+ex
cret
ion
(mm
ol/ L
/ d
ay)
0.1
dose(mg)0.3 3 3010 300100
o1000
150
100
200cy
clop
enth
iazi
de
chlo
rthi
azid
e
Fu
rose
mid
e
hydr
ochl
orot
hiaz
ide
0.1 0.3 1 3010 300100o
50uri
c N
a+ex
cret
ion
(mm
ol/ L
/ d
ay)
0.1
dose(mg)0.3 3 3010 300100
o1000
150
100
200cy
clop
enth
iazi
de
chlo
rthi
azid
e
Fu
rose
mid
e
hydr
ochl
orot
hiaz
ide
0.1 0.3 1 3010 300100o
50
Fig.2-4 Comparison of the efficacy and potency of the different diuretics
Evaluation of drug safety
1. Therapeutic Index, TI
TI=LD50/ED50
2. Margin of safety (LD5 ~ ED95)
o
100
50
o
100
50
(A)
effe
ct (
%)
logC
o
o
ooo
o
o
o
o
oo o
oo
o
oo
oo
oo
o
o
△
□
△
△ △
△
△
△△
△
△
△
o
100
50
logC
logC
△△
△
△
△
△
△
△
△
△△
△
△
(B)
(C)
□
□□
□
□
□
□□
□□
□□□
□
□
□
□
□
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□
□
□
Fig. 2-4 Comparison of therapeutic index (TD50∕ ED50) and margin of safety(LD5 ～ ED95). For therapeutic index (TI): drug A= C>B, and for margin of safety: drug A >B>C. When drug A reaches Emax , it causes no toxic reaction. However, in the cases of drug B or drug C, the dosage of Emax may cause over 50% individual toxic reactions.
In the figure:
o for effective dose-response curves; □ for toxic-response curves; and △ = o% － □ %.
effe
ct (
%)
o
100
50
o
100
50
o
100
50
o
100
50
o
100
50
o
100
50
o
100
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o
100
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(A)
effe
ct (
%)
logC
o
o
ooo
o
o
o
o
oo o
oo
o
oo
oo
oo
o
o
△
□
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△△
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o
100
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logC
logC
△△
△
△
△
△
△
△
△
△△
△
△
(B)
(C)
□
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□
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□□
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Fig. 2-4 Comparison of therapeutic index (TD50∕ ED50) and margin of safety(LD5 ～ ED95). For therapeutic index (TI): drug A= C>B, and for margin of safety: drug A >B>C. When drug A reaches Emax , it causes no toxic reaction. However, in the cases of drug B or drug C, the dosage of Emax may cause over 50% individual toxic reactions.
In the figure:
o for effective dose-response curves; □ for toxic-response curves; and △ = o% － □ %.
effe
ct (
%)
Evaluation of drug safety
3. penicillin-induced allergic shock
4. The event of thalidomide in 1959
Summary
1. Maximal efficacy: the plateau of longitudinal axis (y axis)
2. Potency: an expression of abscissa axis (x axis)
3. Slope and variability
In graded dose-effect curve ： steep slope, which means small
change of drug dose can cause big change of drug effect.
In quantal dose-effect curve: steep slope, which means there is small individual variability in this experiment.
In dose-effect curve, points on the plot represent average and standard deviation.
Question?
How to evaluate the effective intensity of a drug
and choose a rational drug in clinic?
IV Drug action and Receptors
How do drugs act?
1. for some drugs, effect on body is a consequence of
bulk chemical properties
(1) Acidity/alkalinity (e.g. antacids)
(2) Bulk laxatives------absorb water
2. For most drugs, effects are not obviously related
to bulk properties.
1) Small changes in molecular structure can greatly
affect pharmacological activity.
2) Sometimes a molecular and its mirror image
stereoisomer have different effects, despite
identical bulk chemical properties.
3. Receptor hypothesis
To explain the fact that drugs can have dramatically different effects on different cells, Ehrlich & Langley proposed that drugs act by combining with a specific component of a cell, known as a receptor.
Drug + Receptor Drug-receptor Effect
What is receptor?
Receptor: the component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drug’s observed effects.
Most receptors are proteins : regulatory proteins and other classes of proteins, e.g.enzymes, transport proteins, and structural proteins.
Families of physiological receptors
A. Ligand-gated ion channels
1. Nicotinic acetylcholine receptors a. Pentameric doughnut structure
b. Central ion channel
c. Four membrane-spanning
regions per subunit
Excitatory ---Transport Na+, depolarizing
membrane, making it easier for membrane to
reach threshold for action potential generation.
2. GABAA receptors Structure similar to nicotinic acetylcholine receptor 3. Glycine receptors Structure similar to nicotinic acetylcholine receptor their function: Inhibitory---Transport Cl-,
Decreases membrane resistance, making it harder for membrane potential to reach threshold; reduces firing of postsynaptic neuron
4. Glutamate receptors 1) NMDA receptors 2) non-NMDA receptors Different structural family from other ligand-gated ion
channels (3 transmembrane regions, one re-entrant loop) Excitatory ---Transport positive ions(Na+, K+, and/or Ca2+ ), depolarizing membrane, making it easier for membrane to reach threshold for action potential generation.
B. G-protein-coupled receptors(GPCRs)
1. Examples
a. Muscarinic acetylcholine receptor
b. GABAB receptor
c. Metabotropic glutamate receptor
d. Catecholamine receptors
e. Odorant receptors
f. Neuropeptide receptors
2. Structure
a. Single macromolecular
b. Integral membrane protein
c. Seven membrane-spanning segments
d. Interacts with separate guaanine nucleotide binding effector complex, which regulates activity of various cellular enzymes and ion channels
3. function
C. Intracellular hormone receptors
1. found in nucleous or cytoplasm
2. Interact with DNA to control gene expression
3. Examples
a. steroid receptors
b. thyroid hormone receptor
D. Growth factor and cytokine receptors 1. One or two subunits
2. Single transmembrane region
3. Regulate intracellular enzyme activity, typically tyrosine protein kinase or guanylyl cyclase
4. May have enzymatic activity associated with intracellular domain, or may recruit mobile protein tyrosine kinase
5. Examples: a. Epidermal growth factor receptor
b. Insulin receptor
Other sites of drug action
A. Enzymes
a. Digitalis inhibits Na/K ATPase(pump)
b. Antibiotics inhibit crucial enzymes of microorganisms
B. Membrane ion channels
Local anesthetics inhibit voltage-gated Na channels of nerve
C. Structural proteins
Colchicine binds to and diassembles microtubules
D. Nucleic acids
Target of some chemotherapeutic agents used in treatment
of cancer
V Receptor Theory
A. Occupancy theory(Clark, 1933)
First quantitative theory of drug action effect is due
to occupation of “receptors” by agonist molecules.
Agonist: substance capable of inducing
a physiological effect.
Drug-Receptor BondsDrug-Receptor Bonds
Occupancy theory
D+R DR E
[RT]=[R]+[DR]
代入
KD = [D][R]
[DR]
KD =[D] （ [RT]- [DR] ）
[DR]
[D] = 0 E = 0
[D]>>> KD E=E max
KD = [D]
E=
[DR]=
[D]
E max [RT] KD+ [D]
[DR]=50%
[RT]
% m
axim
al re
spon
ses
100
50
0C
100
50
0log C
% m
axim
al re
spon
ses
EC50 EC50
% m
axim
al re
spon
ses
100
50
0C
100
50
0log C
% m
axim
al re
spon
ses
EC50 EC50
Fig.2-1 The dose-effect curve of drug action. The EC50 is the concentration at which a drug reaches to the half-maximal effect. When plotted semi-logarithmically, the hyperbolic shape of the curve (figure on the left ), is switched into a sigmodial one (figure on the right). However, it is approximately linear between 20% ～ 80% of the maximal effect, a range commonly observed for drugs used at therapeutic doses.
KD: 1) when [DR]=1/2[RT] or E=1/2Emax, KD = [D], it represent the concentration of free drug at which half-maximal binding is observed.
2) this constant characterizes the receptor’s affinity for binding the drug in a reciprocal fashion. If the KD
is low, binding affinity is high, and vice versa. pD2 : pD2 = - ㏒ KD If pD2 is large, binding affinity is high, and vice versa.
KD : the equilibrium dissociation constant
Affinity (亲和力 )
intrinsic activity:
0 ≤ ≤ 1
E=
[DR]
E max [RT]
Intrinsic Activity (内在活性 )
1. Agonist
full agonist α=1
partial agonist 0< α<1
2. Antagonist α=0
competitive antagonist
noncompetitive antagonist
pA2
pA2’
Fig. 2-5 Comparison of drugs’ affinity and intrinsic activity in dose-
response curves.
For fig. (A): drugs’ affinity: X<Y<Z, and intrinsic activity ： X=Y=Z.
For fig. (B): drugs’ affinity: A=B=C, and intrinsic activity ： A>B>C.
Fig. 2-6 Dose-response curves for agonist in the presence of increasing concentrations of competitive (A) and noncompetitive (B) antagonists. Furthermore, in the cases of (C) and (D), the antagonists display different intrinsic activities.
B. Rate theory (Paton, 1961)
C. Two-or three-state model theory
