Pharmacodynamics Pharmacodynamics

Department of pharmacology

Yang Fangju( 杨芳矩）

2010.3

1. 1. Drug action and pharmacological effectsDrug action and pharmacological effects(1) pharmacological action(1) pharmacological action: The action of the : The action of the drug does the body. That is original action drug does the body. That is original action between the drug and the cells of the body. The between the drug and the cells of the body. The action of the drug does the body. That is action of the drug does the body. That is original action between the drug and the cells original action between the drug and the cells of the body.of the body.

(2) pharmacological effects:

The functional change of the organs or tissue in the body that is produced by the original drug action.

(3) excitation and exciter (4) inhibition and inhibitor (5) selectivity of pharmacological effect

drugs are only selective--rather than specific--in their actions, because they bind to one or a few types of receptor more tightly than to others and because these receptors control discrete processes that result in distinct effects.

In drug development and in clinical medicine, selectivity is usually considered by separating effects into two categgries: beneficial or therapeutic effects versus toxic effects.

It is only because of their selectivity that drugs are useful in clinical medicine. Thus, it is important, both in the management of patients and in the development and evaluation of new drugs, to analyze ways in which beneficial and toxic effects of drugs may be related, in order to increase selectivity and usefulness of drug therapy.

Therapeutic Effects and Adverse Therapeutic Effects and Adverse Drug Reaction Drug Reaction

1. Therapeutic effectThe action is accord with using drug aim

and propitious to prevention or treatment disease.

(1) etiological treatment (2) symptomatic treatment (3) supplement therapy

2. Adverse Drug Reaction (ADR)The action is not accord with using drug aim

and bring ailment or harm to the patients.(1) side reaction This term is used to describe therapeutically

undesirable but unavoidable effects of drugs.Characteristics: it occurs in the treatment ①

dose, the symptoms are light, it can be ② ③predicated, and it is avoidable or lighten ④by combing with other drugs, but unavoidable when using alone.

(2) toxic reaction: These may be arise from a single large

dose or by accumulation after repeated dose and are usually shown as an exaggerated form of the pharmacological actions typical of the drugs.

Characteristics: it occurs in ①overdosage, the symptoms are ②severe, it can be predicated, and it is ③ ④avoidable.

Toxic effects of drugs may be classified as pharmacological, pathological change, or special toxicity (alteration of DNA, such as carcinogenesis, mutagenesis and teratogenesis).

Toxic effects of drugs may also be classified as acute and chronic toxic effects.

The acute toxicity mainly affects the circulation system, CNS, or blood system.

The chronic toxicity mainly induces pathological change of tissue or special toxicity of cells.

(3) Allergic Reactions: These are mediated by an antigen-antibody

reaction and usually involve previous exposure and sensitization to the drugs.

Characteristics: ① the occurrence of the symptoms is not

concerned with dose, ② the symptoms can be light or serve, ③ it can not be predicated, ④ and it is unavoidable in a tiny minority

condition.

(4) Residual (after) Effect: the residual biological effects when the

drug concentration in blood is decreased under the minimum effective concentration (threshold concentration).

(5) Withdrawal Reaction: it is induced after withdrawal drug

administration.

(6) Idiosyncrasy: it is used to describe a qualitatively

abnormal reaction to a drug. An example is the hemolytic anemia that occurs in some patients after taking the antimalarial drug primaquine

dose effect relationship dose effect relationship

Dose effect relationship: the regular variation between the dose

and the effects that the effects increase following the dose increase in some range.

1.Dose effect curve: the curve is obtained from intensity of

effect for the ordinate and dose or concentration for the abscissa.

(1) Quantitative dose response curve: the quantity for the ordinate expresses

the intensity of effects. Such as heart rate, blood pressure, volume of Na+ excretion .

(2) Qualitative dose response curve: A cumulative frequency distribution of individuals

achieving the defined effect as a function of drug concentration is qualitative dose response curve.

( the concentration-percent curve or the quantal concentration effect curve).

the effect of a drug is recorded as an “ all or none event ” ( positive, negative response) for the ordinate of effects, e.g. death or survival, convulsion or unconvulsion, anaesthetization or unanaethetization.

This curve resemble the sigmoid shape of the graded concentration-effect curve.

Both above curves are plotted rectangular hyperbolic relationship.

these curves become symmetrical S-shaped(sigmoidal) if a ogarithmic dose axis is used.

2. Dose effects relationship (1) dose: the share of drug administered. ① minimal effective dose( minimal effective concentration),

it is also called threshold dose or concentration. ② maximum effective dose ③ treatment dose ④ median effective dose ( ED50):the dose of drug that

produces 50 percent effectivity in a group of animals. ⑤ median lethal dose(LD50): the dose of drug that produces

50 percent mortality in a group of animals.

Acted intensity

min

imal effective

do

se

Min

imal toxic d

ose

Minim

al fatal dose

Lethal dose

Tolerance dose

Effective dose

ineffective dose

Toxic dose

effective

inaction

toxic action

lethal effect

(2) Effect ① maximal effect( efficacy, Emax)The maximal effect can be produced by a

drug. It is determined principally by the properties of the drug and its receptor-effecter system and is reflected in the plateau of the concentration-effect curve.

② potency

The location of the concentration-effect curve along the concentration axis is an expression of the potency of a drug.

Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug's maximal effect.

0.l 0.3 1 3 10 30 100 300 1000

dose （ mg ）

volume of N

a+ excretion .

（mmol ）

200

150

100

50

?

戊 ?? cyclopenthiazide

????

? 堵米

furosemide

???

The potency and Emax Comparison of Various diuretics

(3) assessment of drug safety ① therapeutic index: the ratio which is the ratio of the dose

which kills 50 percent of a group of animals, the median lethal dose(LD50),

and which produces a desired pharmacological effect in 50 percent of a group of animals, the median effective dose(ED50).

Therapeutic index = ② margin of safety: the ratio of the dose which kills 5 percent of a

group of animals(LD5), and the dose which produces a desired pharmacological effect in 95 percent in a group animals(ED95).

Margin safety =

59

5

ED

LD

③ reliable safety coefficient: the ratio of the dose which kills 1 percent of

a group of animals(LD1), and the dose which produces a desired pharmacological effect in 99 percent in a group animals(ED99).

reliable safety coefficient = LD1 /ED99

(4) individual variability The concentration of a drug that produces a special

effect in a single patient is termed the individual effective concentration.

This is quantal response, since the defined effect is either present or absent.

Individual effective concentration usually are lognormally distributed, which means that a normal variation curve is the result of plotting the logarithms of the concentration against the frequency of patients achieving the defined effect.

mechanisms of drug action mechanisms of drug action

1 enzyme 2 ion channel 3 nucleic acid 4 carrier 5 immunity system 6 gene therapy and gene engineering drug 7 others: receptor action of drugs; physic and chemical

action; complementarity action.

receptorsreceptors

1.concept of receptorsDrug receptors are proteins that serve as receptors

for endogenous regulatory ligands. Many drugs act on such physiological

receptors and are often particularly selective.

2. interaction theory of drug and receptor (1) occupation theory(2) rate theory(3) two model theory3. response dynamics of receptor and

drug(1) basic formula of response kinetics of

receptor and drug

A + R AR EA: drug, R: receptor, AR: complex of receptor and drug; E: effectKD =k2/k1 = ( K① D: ionized constant), [AR] = ①∵RT=[ R]+[ AR] , ② (RT is total amount of receptor) [R]=RT - [AR] [AR]=RT - [R]

][

]][[

AR

RA][

][

AK

Ar

D

DK

RA ]][[

From to :② ① KD = KD[AR] =[A]([RT]-[AR])=[A][RT]-[A][AR]

KD[AR]+[A][AR]=[A][RT]

[AR](KD+[A])=[A][RT]

∴

][

][

][

][

AK

A

R

AR

DT

][

][][][

][][

][][][

AR

ARRTA

RR

ARRA

T

T

When binding ratio of receptor and drug arrives 100%, the effect arrives 100%.

∴

If: (r is binding percent of drugs and receptor) the binding receptor holds in r of total receptors, the

effect arrives in corresponding fraction E/Emax, then r =

When r increase far off exceed KD, r→1, that arrives in Emax.

][

][

][

][

max AK

A

R

AR

E

E

DT

rR

AR

][

][

][

][

][

][

max AK

A

R

AR

E

E

DT

∵ ,

Transposition:

∴

When r→1,

][

][

AK

Ar

D

r

AAKD

][][

r

rAA

r

AKD

)1]([][

][

DKr

rA

1][

01

)11]([

A

KD

When r=50%,

That is drug dose when Emax arrives in the

half (it means 50% of receptors hold).

PD2: -logKD of KD. That is direct ratio with

affinity of A and R.

AK

AAA

K

D

D

][1][5.0

)5.01]([

3. agonist and antagonist (1) agonist ① affinity: The binding ability of the drug with receptor. ② intrinsic activity: The ability of the drug excites

receptor. It can be expressed asа. ③ full agonist: it has intense affinity and intrinsic

activity(а= 1) ④ partial agonist: it has intense affinity, but weak

intrinsic activity(а< 1) ⑤ inverse agonist or negative antagonist ligand.

(2) antagonist: it has intense affinity, but has no intrinsic

activity(а= 0) ① competitive antagonist affinity of competitive antagonist expresses as

PA2. It is negative logarithmicvalue of mol concentration of competitive

antagonist added in reacted system of agonist that makes the effect of agonist in 2 times concentration equal to the effect of agonist in 1 time concentration.

② non-competitive antagonistaffinity parameter of non-competitive

antagonist expresses as PA2’. It points

negative logarithmic value of mol concentration of non-competitive antagonist during it makes Emax of agonist

descend to half.

transmembrane signaling and intracellular transmembrane signaling and intracellular messenger messenger

1. classification of drug receptors according to mechanism of transmembrane signaling

(1) G protein-coupled receptor (2) ligand gate ion channel receptor (3) Tyrosine kinases receptor (4) cell nuclear hormone receptor (5) cytokine receptor (6) other enzyme receptor

2. intracellular signal transductant (1)   first messengers: hormones, neurotransmitters,

cytokines(interleukins, growth factor ). (2) Second messengers ① cAMP ② cGMP ③ phosphatidylinositol ， DG, IP3

④ calcium ion, it participates in protein medium, such as PKC, calomodulin, etc.

3. signal transduced system of receptor and intracellular