Pharmacology2( Drug Receptors & Pharmacodynamics)

Chapter II Drug receptors & Pharmacodynamics

DURGE RAJ GHALAN [email protected]

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 ===== pharmacological effect

Specificity of 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  To

Objective

understand the ways in which drugs may affect receptor function and the use of doseeffect 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.

100

100 % maximal responses

% maximal responses

What is dose-effect curve?

50

0

EC50

C

50

0

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.

pe

Efficacy

S lo

Intensity of effect

What is graded dose-response curve?

variability 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.

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3

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Fur o

rot hlo dr oc

o 0.1 0.3

sem ide

azi de

hy

50

en thi

100

lop

150

hia zid e

200

cyc

uric Na+ excretion (mmol/ L / day)

How to evaluate drugs with dose-effect curve?

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)

effect (%)

100

o o

o ooo △ △

□

100

□

o o

△ □

△

o

50

(A) o

□

o

(B) o o

△

logC

100 effect (%)

o o

o

o

□

□

△ △ △

□ □

o

□□

△ □

△

□

□

△

△

△ △

□

o

50

△ □

o

oo

logC □

□

□

△

△

□ △

50

△

□

o (C)

o

o

o □

□ □

□

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:

△ △ △

△

logC

o for effective dose-response curves; □ for toxic-response curves; and △ = 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 KD =

[RT]=[R]+[DR] 代入 KD =

E [D][R] [DR]

[D] （ [RT]- [DR] ） [DR]

E

[DR] =

E max

[D] =

[RT]

KD+ [D]

[D] = 0 E=0 [D]>>> KD E=E max [DR] [RT]

=50%

KD = [D]

100 % maximal responses

% maximal responses

100

50

0

EC50

C

50

0

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 semilogarithmically, 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 E max

=α

0 ≤ α≤ 1

[DR] [RT]

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 doseresponse curves. For fig. (A): drugs’ affinity: XB>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