Chapter II Drug receptors &

Pharmacodynamics

DURGE RAJ GHALAN

ghalan_raj@hotmail.com
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?
 drugaction
 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

 Tobe 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?

100 100
% maximal responses

% maximal responses
50 50

0 0
EC50 C EC50 log C

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?

Efficacy
Intensity of effect

pe variability
S lo

Potency

Concentration of drug
Fig.2-2 The log dose-effect relationship. Representative log dose-effect curve,
illustrating its four characterizing variables
What is guantal dose-response curve ?

Slope
ED50
LD50

Fig.2-3 The frequency curve and cumulative frequency curve of a drug action
in a quantal-effect experiment
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?

200
uric Na+ excretion

ide
e
(mmol/ L / day)

de

zid
azi

sem
150

hia

ide
thi

rot
en

az
Fur
100
hlo
lop

thi
oc
cyc

lor
dr
50

ch
hy

o
0.1 0.3 1 3 10 30 100 300 1000
dose(mg)

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)

 100 o ooo
△ □ 100 oo □□ Fig. 2-4 Comparison of therapeutic index
o △ □ o □
effect (%)

o △ □ o □
(TD50∕ED50) and margin of
△
△ safety(LD5 ～ ED95). For therapeutic
o o △
□
50 △
□ 50 △
index (TI): drug A= C>B, and for
o △
△
□ △
margin of safety: drug A >B>C. When
□
△ o △
(A) o
o
□
□
△ (B) o o □
□ △ drug A reaches Emax , it causes no toxic
logC
100
logC
o o □
reaction. However, in the cases of drug B
□
o or drug C, the dosage of Emax may cause
effect (%)

□
o △
over 50% individual toxic reactions.
△ □
△
50 △
□
In the figure:
△
o □ o for effective dose-response curves;
△
(C) o □
o o □
□ △ △ □ for toxic-response curves; and
logC
△ = o% － □ %.
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 Bonds
Occupancy theory

D+R DR E

[D][R]
KD =
[DR]
[RT]=[R]+[DR]
代入
[D] （ [RT]- [DR] ）
KD =
[DR]
 E [DR] [D]
= =
E max [RT] KD+ [D]

[D] = 0 E=0
[D]>>> KD E=E max
[DR]
=50%
[RT]
KD = [D]
 100 100
% maximal responses

% maximal responses
50 50

0 0
EC50 C EC50 log C

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 : the equilibrium dissociation constant

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.
Affinity ( 亲和力 )
Intrinsic Activity ( 内在活 性 )

intrinsic activity: α
E [DR]
=α
E max [RT]

0 ≤ α≤ 1
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