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?

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?%

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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

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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?

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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)

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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:

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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