pharmacologic principles chapter 3 pharmacodynamics ( drug acts on body )
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PHARMACOLOGIC PRINCIPLES CHAPTER 3 Pharmacodynamics ( drug Acts on body ). Pharmacodynamics. Basic Action. Ⅰ. Basic Action of Drug. 1. Excitation and Inhibition. The intrinsic functions of the body are altered by drugs: - PowerPoint PPT PresentationTRANSCRIPT
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.
PharmacodynamicsBasic Action
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 *
PharmacodynamicsBasic Action
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
PharmacodynamicsA type of ADR
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
PharmacodynamicsA type of ADR
starvationthirsty
abstinence syndrome
happyfood
amusesports
success
sex
drug
miseryachepain
disappointed
failure go blind
misshometown
good friend
lover
drugfamily
PharmacodynamicsA type of ADR
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
B type of ADR Pharmacodynamics
3) teratogenesis Drug affects fetation forming
teratism, especially early embryo.
Thalidomide happening ( 1961 )seal abnormity
pregnancy reaction gestation reaction
B type of ADR Pharmacodynamics
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.
PharmacodynamicsGraded response
: 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
PharmacodynamicsGraded response
E
B
A C
logD (C)potency :efficacy :threshold dose :slope :
A>B>CB> C >A
C>B>AA=B>C
PharmacodynamicsGraded response
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)
PharmacodynamicsQuantal 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
PharmacodynamicsQuantal response
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
PharmacodynamicsQuantal response
(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.
PharmacodynamicsQuantal response
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
PharmacodynamicsQuantal response
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
Competitive antagonism
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
Competitive antagonism
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
drugbody
Drug . StructurePolar, pKa
SolubilityDosage formProduct No
Administration
DosageRouteTime, IntervalDrug interactionRepeat useWithdraw
Physical sex age weightMentalityIllnessHeredityliving customIndividual variation
PD
PK
Impact factor