Pharmacodynamic2-UNMUL 2007

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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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    11/37[D]

    (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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    12/37[D](concentration units)

    %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/