pharmacodynamic2-unmul 2007
TRANSCRIPT
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Pharmacodynamics
(continued)
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Model of simple
occupancy theory
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Receptor Binding
The dose-response relationship (from C.D. Klaassen, Casarett and Doulls Toxicology, 5th ed., New York: McGraw-Hill, 1996).
%Bound
Concentration of Ligand
Kd
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Dose-Effect and Log Dose-Effect Curves
Dose Log Dose
Effect
ED50
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k1
D + R DRk2
EFFECT
HUBUNGAN DOSIS DENGANINTENSITAS EFEK
menurut teori pendudukan reseptor (receptor
occupancy), intensitas efek obat berbanding lurus
dengan fraksi reseptor yang diduduki atau
diikatnya, dan intensitas efek mencapai maksimal
bila seluruh reseptor diduduki oleh obat.Dan oleh karena interaksi obat reseptor ini analog
dengan interaksi substrat enzim, maka disini
berlaku persamaan Michaelis-Menten:
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Emax [D]
Kd + [D]=E
Persamaan Michaelis-Menten:
Dimana :
E = Intensitas efek obat
Emax = efek maksimal
[D] = kadar obat bebasKD = K2/K1 = konstanta disosiasi
kompleks obat-reseptor
Bila KD = [D], maka:
E =Emax [D]
[D] +[D]= .Emax
Ini berarti 50% reseptor diduduki oleh obat
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From Ross EM and Gilman AG. Pharmacodynamics: mechanisms of drug action and the relationship between drug
concentration and effect.. in Goodman and Gilmans The Pharmacological Basis of Therapeutics. 7th edition, 1985, Pages 35-48.Macmillan Publishing Company.
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Drugs are described based on the
magnitude of two properties:
1)Affinity for the receptor. Affinity is related topotency.
2) Efficacy once bound to the receptor.
Efficacy refers to the maximal effect the drug
can elicit.
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(concentration units)
[DR]/R
T
0.01 0.10 1.00 10.00 100.000.00
0.25
0.50
0.75
1.00
Kd=1
kd=5
Kd=0.5
Compounds Have Different Affinities for the Same Receptor
Compare the ED50s
equal efficacies
Differ In Potency
RT = total # of receptors
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%M
aximalEffect
0.01 0.10 1.00 10.00 100.00 1000.000.0
0.2
0.4
0.6
0.8
1.0
Partial agonist
Full Agonist
Partial agonist
PARTIAL AGONISTSEven though drugs may occupy the same # of receptors, the
magnitude of their effects may differ.
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Agonists and Antagonists
AGONIST - Has affinity for receptor and efficacy.
(efficacy intrinsic actinvity)ANTAGONIST - Has affinity but no efficacy.
Competitive Antagonist
Noncompetitive Antagonist
Partial Agonist or Partial Antagonist - Has affinity butlowerefficacy than full agonist.
Examples of typical curves...
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70000
000000o
0000
200000
000
70
20
7127
2000
700
200
70
20
127
Kontraksi otot polos
akb. pemberian :
A. AgonisB. Agonis + Antagonis
11 2 3
2
5
4
3
6
5
4
A B
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Competitive Noncompetitive
Types of Receptor Antagonists
From Taylor, P and Insel PA. Molecular Basis of Pharmacological Selectivity, in Principles of Drug Action, W Pratt and P Taylor, editors, p1-103,1990, Churchill Livingstone
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Competitive Antagonism Shifts The
Agonist D-R Curve( Potency)
Drug Concentration (log scale)
AG + ANTAG alone
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Noncompetitive Antagonism (NC ANT)
Decreases AgonistEfficacy
Log Drug Concentration
%
Maxresponse
AG alone
AG + NC ANT
AG + higher dose
NC ANT
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Agonist + AntagonisAgonist +
Antagonist Non Compt
Efek antagonis Efek antagonis
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GRADED DOSE-
RESPONSE CURVEED50
ED50
From Nierenberg W and Melmon KL. Introduction to Clinical Pharmacology in Clinical Pharmacology: Basic Principles inTherapeutics, Third edition, 1992, Melmon KL et al., editors, p 1-51, McGraw Hill.
intensity
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QUANTAL DOSE-
RESPONSE CURVE
Frequency
Distribution
Cumulative
FrequencyDistribution
From Ross EM and
Gilman AG.
Pharmacodynamics:
mechanisms of drug action
and the relationship
between drug
concentration and effect..
in Goodman and Gilmans
The Pharmacological Basisof Therapeutics. 7th edition,
1985, Pages 35-48.Macmillan Publishing
Company.
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Morphine
Aspirin
From Nierenberg W and Melmon KL. Introduction to Clinical Pharmacology in Clinical Pharmacology: Basic Principles in
Therapeutics, Third edition, 1992, Melmon KL et al., editors, p 1-51, McGraw Hill.
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Therapeutic and Toxic Effects are
Dose-Related: Phenobarbital
Sleep Death
Dose of Phenobarbital
ED50 LD50
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Therapeutic Index (TI)
LD50
ED50
LD50
ED50
= > 1Obat Ideal :
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Factors Affecting Drug Response
Resistance: used in context of antimicrobialdrugs.
Tolerance: a decrease in drug responseduring repeated administration.
Tachyphylaxis: acute development oftolerance due to rapid repeated admin. ofsome drugs.
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Receptor Regulation
Supersensitization or Up-regulation
1. Prolonged/continuous use of receptor blocker
2. Inhibition of synthesis or release ofhormone/neurotransmitter - Denervation
Desensitization or Down-regulation
1. Prolonged/continuous use of agonist
2. Inhibition of degradation or uptake of agonist
Homologous vs. Heterologous
DYNAMICS OF RESEPTOR
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DYNAMICS OF RESEPTOR
RESEPTOR REGULATION
REGULATION HOMEOSTASIS
*DESENSITIZATION
*DOWN REGULATION
*SUPERSENSITIZATION
*UP REGULATION
SIFAT REGULASI HOMOLOG
HETEROLOG CROSS-TALK
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Mekanisme terjadinya desensitisasi adrenoseptor
REGULASI HOMOLOG
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REGULASI HOMOLOG
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Desensitization
Homologous: affecting responses
elicited only by the stimulated receptor.
Heterologous: acting on several
receptors or on a pathway common to
many receptors.
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MECHANISM
DESENSITISATION PHOSPHORILATION
SEKUESTRATIONBARK, ARRESTIN, PKA
DOWN REGULATION c-AMP
mRNA receptor
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REGULASI HETEROLOG
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From Taylor, P and Insel PA. Molecular Basis of Drug Action, in Principles of Drug Action, 3rd edition, W Pratt and P Taylor,editors, p 103-200, 1990, Churchill Livingstone
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The anticoagulant heparin and its antagonist,
protamine.
Chelating agents EDTA, penicillamine, and
dimercaprol bind toxic metals (lead, copper, and
mercury).
Antacids act by neutralizing gastric acid
Incorporation into a macromolecule (e.g. some
anticancer agents - purine and pyrimidine analogues)
Nonspecific effects (e.g. membrane perturbation
by general anesthetics)
Non-receptor Mediated Effects
Mana yang lebih efficacy ?
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Mana yang lebih efficacy ?
Mana yang lebih potent ?
C I
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Case I
Jika anda sebagai dokter mendapat informasi daripabrik obat untuk pengobatan astma sepertipada gambar A & B.
Data apa yang didapat untuk potensi obat &efficacy pada gambar A & B ?
CASE II
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CASE II
Jika anda sebagaidokter akanmemilih obatdengan profil
seperti gambar A& B.
Obat mana yanglebih aman
menurut anda (A atau B) &alasannya ?
http://animat%28%27chart06%27%29/