PHARMACOLOGIC PRINCIPLES CHAPTER 3 Pharmacodynamics （ drug Acts on body ）

PHARMACOLOGIC PRINCIPLES

CHAPTER 3

Pharmacodynamics

（ drug Acts on body ）

The intrinsic functions of the body are altered by drugs:

1) Excitation or stimulation ： the functions are increased by drugs. ( heart rate↑, BP↑, contraction, unstable …)

2) Inhibition ： the functions are decreased by drugs. (heart rate↓, Bp↓, relaxation, stable or sedation …)

Ⅰ. Basic Action of Drug

1. Excitation and Inhibition

PharmacodynamicsBasic Action

2. Local action and general action

1) Local action ： action on the locale before absorption of administered drugs. 2) General action (absorptive action, systemic action) ： action of drugs on general system after absorption.


Pharmacodynamics

For example, magnesium sulfate (orally) →80

% no absorption →intestinal osmotic pressur

e↑→ volume ↑→catharsis (purgation)

↘cholagogic action

Basic Action

For example, magnesium sulfate (injection)

→circulation → General action site

↗vasodilation → BP↓ -----------

↘central inhibition→sedation

Local action and general action

Treatment of eclampsia gravidarum

3. Specificity: Singularity of action on drug target; Selectivity: Singularity of effect on organ or tissue .

Pharmacodynamics

high specificity→ high selectivity →high clinic pertinency →less side reaction

low specificity→low selectivity→ low pertinency → more side reaction and wide clinical use

1) Interaction of drug —target

2) high concentration of drug in the organ or tissue →high selectivity

iodine→intaked by thyroid gland →high concentration →action on thyroid

Basic Action

Pharmacodynamics

α-adrenoceptors blockor

Α1,α2-blockor (phentolamine)

α1-blockor (prazosin)

α1↓→vasodilation→BP↓ ----↘

α2↓→NA release↑→β↑→heart ↑ ↑

α1D,α1B ↓→ vasodilation→BP↓

α1A↓→smooth muscle of prostate↓

α1A↓→smooth muscle of prostate↓

(uroschesis of prostatic hyperplasia)

Basic Action

α1A-blockor (tamsulosin)

→

4. therapeutic effect

Eliminate cause of a disease. (Chemotherapy…)

etiological treatment

Pharmacodynamics

Remission of symptoms or suffering of a disease. (analgesia, sedation…)

symptomatic treatment

Basic Action

Therapeutic effect can be difined as the drug effects that are consistent with therapeutic purposes.

5. adverse drug reaction ， ADR *


ADR can be defined as the drug effects that are not consistent with therapeutic purposes and induce harm to patients in normal use and dose for a qualified drug. -- WHO--

5-10% of patients in hospital are because of ADR. 10-20% of patients in hospital suffer ADR.

--WHO--

106,000 patients in USA lost life from ADR in 2002. The cause of death was fourth mortality in USA.

The augmented effects of drug are too strong to induce harm following increasing dose (normal dosage).

A type of ADR (augmented)

*side reaction, *toxic effect, after effect, *dependence

Basic Action- adverse drug reaction Pharmacodynamics

A type of ADR(character)

• dose–dependent• forecastable• high incidence rate• less serious and low mortality.

B type of ADR (bizarre) The bizarre effects of drug are independent of pharmacological action.

allergy, idiosyncratic reaction, teratogenesis, carcinogenesis

Basic Action- adverse drug reaction Pharmacodynamics

• not dose-dependent• difficult to forecast and find• low incidence rate• serious and high mortality

B type of ADR(character)

The reactions without relationship to therapeutic purpose of a drug administrated in normal dose are induced in almost patients, because of low selectivity of the drug.

therapeutic purposetherapeutic action

side reaction

1) Side reaction

Pharmacodynamics

A type of ADR (augmented)

A type of ADR

Pharmacological responses

are too strong and induce organic and functional

injury in some patients when drug

administration in normal dose and period

because of hypersensitivity induced by

individual variation, pathological state and

interaction of drugs.

2) Toxic effect

PharmacodynamicsA type of ADR

Effects remain when drug blood concentration is

reduced below threshold

concentration.

following repeated administration of some drugs.

3) After effect

TC

4) Dependence New balance induced


C

T

Addiction induced following repeat administration. The vital activity of body depends on drugs, the serious abstinence syndrome is induced after discontinue.

Psychic desire and pleasant feeling are induced following the repeat. The mental state depends on drugs without abstinence after discontiune.

Physical dependence

psychic dependence


starvationthirsty

abstinence syndrome

happyfood

amusesports

success

sex

drug

miseryachepain

disappointed

failure go blind

misshometown

good friend

lover

drugfamily


A drug as an antigen or

semi- antigen produces exceptional immunoreaction in

minority of allergic patients without relationship to ph

armacological action and dose.

(penicillin→ allergic shock)

1) allergic reaction

Pharmacodynamics

B type of ADR (augmented)

B type of ADR

2) idiosyncratic reaction A drug produces

exceptional reaction in minority of gene defect patients

without relationship to pharmacological action.

Glucose

G-6-P

ATP

ADP

6-PG Acid

G-6-PD↓NADP

NADPH↓

GSSG

GSH↓

H2O2 ↑↑

H2O↓

Hemolytic anemia

Oxidizing agent

Absence of G-6-PD

sulfonamides vitamin K primaquine anminopyrine broad beans

+

glucose-6-phosphate Dehydrogenase, G-6-PD

B type of ADR Pharmacodynamics


3) teratogenesis Drug affects fetation forming

teratism, especially early embryo.

Thalidomide happening （ 1961 ）seal abnormity

pregnancy reaction gestation reaction


4) carcinogenesis

5) mutagenesis

Long osculation of chemical substances including drugs could induce malignancy or cancer, about 80% ～ 85% of human cancers would be induced by chemical substances..

Drug induce damnification of germ plasm (DNA).

mutagenesis carcinogenesis

teratogenesis

Ⅱ、 Dose-response relationship

GradedGraded

QuantalQuantal

•• Measured in a single biologic unitMeasured in a single biologic unit•• Relates dose to intensity of effectRelates dose to intensity of effect• Mean Mean ± ± standard differencestandard difference (x ± s) (x ± s) ( t test )( t test )

•• All-or-none pharmacologic effectAll-or-none pharmacologic effect

•• Population sPopulation studtudies (ies (χ2 test)

•• Relates dose to frequency of effectRelates dose to frequency of effect

• • Continuous scaleContinuous scale

Dose

BP mmHg

Dose

rate(%)

PharmacodynamicsDose-response relationship

Dose-response relationship Pharmacodynamics

control -21 -17 -22 -25 -18 -29 -20 -31 -25 -18 -22.6±4.8

test -25 -31 -28 -27 -18 -35 -28 -28 -35 -28 -28.3±4.9

Statistics (T test) Significant P<0.05

The antihypertensive effect of a new drug to blood pressure (mmHg) was researched in hypertensives

control + - + + - + + + + - 7/10 70%

test + + + + - + + + + + 9/10 90%

Statistics (χ2 test) Not significant P>0.05

Graded dataGraded data

QuantalQuantal datadata

Ordinate Effects

[D]/E

Abscissa arithmetic

logarithm

E

[D]

rectangular hyperbola

symmetry S curves

1. Graded response

(dose) Straight line

[D]E

[D]Lg[D]

E

PharmacodynamicsGraded response

logD (C)

effect

Emax

E

Kd

↓ ↓ ↙ ├─┴┴─────┴─ ─┴───┴── ╂ D (C)

Threshold dose

maximal dose

minimal Toxic dose

minimal lethal dose

↑common dose

Pharmacodynamics

D (C)

Graded response

① Threshold dose ： Minimum effective dose

② Efficacy (Emax) ： Maximum effect of a dru

g or the limit of the drug response.

③Potency ： Dose inducing given effect, or a d

ose (KD) inducing 50% Emax. Dose or KD↑→ Pote

ncy↓

Efficacy is usually more important than potenc

y in selecting drugs for clinical use.


： Slope at 50% Emax (slope↑→range of c

ommon dose↓→less safety）

: The limit of dose permitted in

pharmacopeia for some drugs.

： The effective dose in most of p

atients.

maximal dose＞ common dose＞ threshold d

ose

④ Slope

⑤ Maximal dose

⑥ Common dose


E

B

A C

logD (C)potency ：efficacy ：threshold dose ：slope ：

Ａ＞Ｂ＞ＣＢ＞ C ＞Ａ

Ｃ＞Ｂ＞ＡＡ＝Ｂ＞Ｃ


An all-or-none response to a drug and relates to the frequency with which a specific dose of a drug produces a specific response in a population.

(e.g., death among the mice in a pre-clinical study or effective among the patients in a clinical trial.

2. Quantal response

PharmacodynamicsQuantal response

（ response frequency or rate (%), χ2 test ）

(Qualitative Response)


D (mg/kg) 1 1.2 1.4 1.6 1.9 2.3 2.7 3.1 3.7 4.3 5.1

distribution 0 2 4 6 10 8 6 5 4 3 2

cumulative 0 2 6 12 22 30 36 41 45 48 50

distribution 0 4 8 12 20 16 12 10 8 6 4

cumulative 0 4 12 24 44 60 72 82 90 96 100

F

%

E

D

distribution

cumulative

F

D

F p

lgD lgD

Pharmacodynamics

1) Cumulative curve

long tail S curves

symmetry S curves

Ordinate(effects)

Abscissa

(dose) straight line

cumulative frequency or rate

arithmetic dose

probit unit （ p ）

logarithm dose

Quantal response

F

D

F

logD


2) Distribution curve

Cumulative(effects)

Abscissa

(dose)

normal distributio

n

skew distributio

n

distribution frequency or rate

arithmetic dose

logarithm dose

logD

E

D

Pharmacodynamics

Individual variation: There is variation of sensitivity to a drug among population (patients or animals). Supersensitivity or tolerance to a drug are produced in a few population, most of them are middle sensitivity.

Quantal response

Therapeutic index (TI) ＝ LD50 ／ ED50

Safety index (SI) ＝ LD5/ED95

100% 95%

5%

toxicity or deatheffective

50%

ED50 ED95 LD5 LD50

dose

ED95


(Median effective dose) ： The dose at wh

ich 50% of individuals (experimental animals) exhi

bits specified effect.

（ Median lethal dose ）： The dose re

quied to produce death in 50% of animals.

ED50

TI ＝ LD50 ／ ED50

LD50

Therapeutic index (TI): The index used forjudging drug's safety.


The TI may be misleading if the dose-

responses curves for effectiveness and toxicity

have different slopes (i.e., not parallel).

Therefore, the Safety index (SI) may be more

useful.

Safety index (SI)

SI ＝ LD5/ED95


Ⅲ. Mechanism of action of drugs

1) Alteration of chemical or physical condition of locale administered to: osmotic diuretics; antacid; osmotic laxatives.

2) Participate in nutrition and metabolism of cells ： Vitamin, ferrous sulfate 、 glucose.Calcium…

Pharmacodynamics

1. Unspecific action

Mechanism of action of drugs

1) Influence on activity of enzymes ： Insulin→oxygenase of glucose↑→blood sugar↓;

Neostigmine→cholinesterase↓→ACh↑

2) Action on ion-channel of ： Antiarrhythmics

3) Action on release of transmiters or hormones ： Ephedrine→release of noradrenaline↑

　 Iodide→release of thyroxine↓

4) Drug-receptor *

Pharmacodynamics

2. Specific action: drug-receptors; drug-ion channels; drug-enzymes;

Mechanism of action of drugs

The receptive substances of a cell or

an organism that specifically interacts with their

ligands (corresponding drugs, transmitter or ho

rmone) and initiates the chain of biochemical an

d physiological changes.

ligand ： A corresponding drug, transmitter or hormone binding to a receptor.

Ⅳ. Drug receptor

Receptor

1. Drug-receptor concept

PharmacodynamicsDrug receptor

2. Characters of drug-receptor interaction

PharmacodynamicsDrug receptorDrug receptor

1) Saturation: Because of finitude of number of re

ceptor molecule for unlimited drug molicular →E

max

2) Specific binding

3) Reversible binding: ionic bond, hydrogen bond,

molecular attraction covalend bond.

Therefore, there is competitive binding

between 2 drugs binding to same receptor.

3. Drug-receptor binding Theory

1) Receptor occupancy theory: It is

assumed that response emanates from

the receptor occupied by a drug.

The greater response observed, the

more receptor occupation.

PharmacodynamicsDrug-receptor binding Theory

In general, the effect (E) is a equation of the quantity of the drug -receptor complex [DR], and can be expressed as:

Once all receptors are saturated, the maximum effect (Emax) is achieved. If the 50% of receptors were occupied, 50% Emax is produced.

Pharmacodynamics

α[D]+[R] [DR]┄→E

KD

KD: dissociation constant

E

CKD

Emax (α)

E = α[DR]

Drug-receptor binding Theory

The effect associates not only with binding rat

e (k1), but also with dissociation rate (k2).

k2↑→the effect↑→Emax↑

2) Rate theory ：

Pharmacodynamics

3) two state theory

[D]+[R] [DR]k1

K2

Active receptor inactive receptor

agonist partial agonist antagonist

Drug-receptor binding Theory

The ability of a drug's binding to recepto

r. A drug's affinity for binding its receptor d

etermines the concentration of drug requir

ed to occupy 50% its receptor or elicits 50

% Emax.

The greater concentration required, the

weaker affinity of a drug.

4. Parameter of receptor-specific interaction

1) Affinity (or potency)

PharmacodynamicsParameter of drug-receptor

Pharmacodynamics

pD2 is the parameter of agonist's affinity and th

e negative logarithm of molarity (mol) concentrati

on (KD) of a drug binding 50% receptor or inducin

g 50% Emax. pD2 = -log KD

The more KD, the low agonist's affinity; The more pD2, the more agonist's affinity.

50% 50%

Emax Emax

KD pD2

c c

-log cC

Parameter of drug-receptor

The ability of inducing effect of a drug after bi

nding to receptor.

The faster dissociation rate (k2), the greater in

trinsic activity, the greater Emax.

2) Intrinsic activity (or afficacy)

PharmacodynamicsParameter of drug-receptor

Pharmacodynamics

4. Classification of drugs binding to receptor

Classificationoccupancy rate

affinity Intrinsic activity k1 k2

agonist ＋＋＋＋＋＋

antagonist ＋－＋－

partial agonist ＋＋＋＋

Inverse agonist ＋＋ (opposite effect) ＋＋

agonistpartial agonist

antagonist

Inverse agonist

Classification of drugs

1) antagonist-agonist: In the presence of a fixed c

oncentration of antagonist, dose-effect curves of t

he agonist would be shifted following increasing c

oncentration of agonist:

a. Threshold concentrations are increased;

b. Curves is shifted to the right in equal slope;

c. Emax is unchanged.

Pharmacodynamics

5. Competitive antagonism

Competitive antagonism

pA2: The parameter of Blocker’s affinity. The neg

ative logarithm of molarity (mol) of a blocker requ

ired to inducing same effect (or 50% Emax) in dou

ble concentrations of agonist.

KD1 / KD0 = 2pA2=-log[B1]

Pharmacodynamics

A A+B1 A+B2

E

1 2 3 C (agonist)KD0 KD1 KD2


a. Threshold concentrations↓

b. Emax is unchanged;

c. Curves is shifted to the left at low

concentration of agonist (partial

agonist would like agonist).

d. Curves is shifted to the right at hi

gh concentration of agonist (like

antagonist).

2) partial agonist –agonist: In the presence of a fixed concentration of partial agonist, dose-effect curves of the agonist would be altered following increasing concentration of agonist.

PharmacodynamicsCompetitive antagonism

lgC

E A A+P' A+P''

A B

Pharmacodynamics

low concentration of agonist high concentration of agonistA

A B

lgC

E A A+P' A+P''

A B


After administration of a noncompetitive antagonist, high concentrations of agonist cannot completely overcome the antagonism and Emax can be reduced. Dose-effect curves of agonist are altered: a. Threshold concentrations are unchanged; b. Shifted to the right ; c. Emax is decreased.

6. Noncompetitive antagonism

PharmacodynamicsNoncompetitive antagonism

Pharmacodynamics

()

E

C (agonist)

A

A+N1

A+N2

A+N3

KD

Emax

1/2Emax pD2′= -log[N2]

pD2′: The parameter of noncompetitive antagonist affinity. The negative mol of a noncompetitive antagonist required to decrease Emax by 50%.

Noncompetitive antagonism

pD2 Pharmacodynamics

ACh (mol/L) 10-9 3×10-9 10-8 3×10-8 10-7 3×10-7 10-6

E (mm) 0 7 20 40 62 73 73

50%

Emax

KD

E [D]/E

[D][D]

max max

1 DD K

DE E E

maxD

DE E

K D

linear regression: Emax=1/b=80.5mm, KD=a/b=3.055×10-8 mol/L， pD2＝ -logKD =7.515.

Y = b X + a

a: intercept

b: slope

Ach [D] (mol/L) 3×10-9 10-8 3×10-8 10-7 3×10-7 10-6 3×10-6 10-6

Atropine [A] 0 7 20 40 62 73

10-8 0 8 18 44 58 72

3×10-8 0 0 5 16 47 64 74

10-7 0 0 0 9 27 45 65 73

E

KDx / KD0=2

log(R-1)＝ -(-log[A])＋ (-logKA)

KD0 KD1 KD2 KD3 [D]

Y = b X + a

log(R-1) ＝ -(-log[A]) ＋ (-logKA)

R= KDx / KD0 (R1, R2, R3)

linear regression: R=2 or y=0, pA2= 8.05

pA2 -log[A]

log(R-1)

b= -1

The End of pharmacodynamics

Pharmacodynamics

Impact factorto pharmacodynamics and p

harmacokinetics

PHARMACOLOGIC PRINCIPLES

CHAPTER 4

drugbody

Drug . StructurePolar, pKa

SolubilityDosage formProduct No

Administration

DosageRouteTime, IntervalDrug interactionRepeat useWithdraw

Physical sex age weightMentalityIllnessHeredityliving customIndividual variation

PD

PK

Impact factor

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PHARMACOLOGIC PRINCIPLES CHAPTER 3 Pharmacodynamics （ drug Acts on body ）