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    Pharmacodynamics 1

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    Anisa Wahyuniarti
    The document discusses pharmacodynamics and mechanisms of drug action. It describes how drugs can act through non-specific effects, transport systems, enzymes, and receptors. It provides details on receptor types, drug-receptor interactions, and transmembrane signaling pathways involving ion channels, G proteins, and second messengers. It also discusses the differences between agonists and antagonists.

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    Pharmacodynamics 1

    Uploaded by

    Anisa Wahyuniarti
    150 views49 pages
    The document discusses pharmacodynamics and mechanisms of drug action. It describes how drugs can act through non-specific effects, transport systems, enzymes, and receptors. It provides details on receptor types, drug-receptor interactions, and transmembrane signaling pathways involving ion channels, G proteins, and second messengers. It also discusses the differences between agonists and antagonists.

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    The document discusses pharmacodynamics and mechanisms of drug action. It describes how drugs can act through non-specific effects, transport systems, enzymes, and receptors. It provides details on receptor types, drug-receptor interactions, and transmembrane signaling pathways involving ion channels, G proteins, and second messengers. It also discusses the differences between agonists and antagonists.

    Copyright:

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    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    150 views49 pages

    Pharmacodynamics 1

    Uploaded by

    Anisa Wahyuniarti
    The document discusses pharmacodynamics and mechanisms of drug action. It describes how drugs can act through non-specific effects, transport systems, enzymes, and receptors. It provides details on receptor types, drug-receptor interactions, and transmembrane signaling pathways involving ion channels, G proteins, and second messengers. It also discusses the differences between agonists and antagonists.

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    Pharmacodynamics

    What the Drug Does to the Body

    Setyawati S Karyono Laboratorium Farmakologi Fakultas Kedokteran Unibraw

    Basic Pharmacological Concepts

    Pharmacology = The study of the interaction between chemicals and a biological system.
    Pharmacodynamics = study of the biochemical and physiological effects of drugs and their mechanisms of action (the effects of the drug on the body) Pharmacokinetics = deals with absorption, distribution, biotransformation and excretion of drugs (the way the body affects the drug with time)

    LOCUS OF ACTION RECEPTORS

    TISSUE RESERVOIRS

    Bound

    Free

    Free

    Bound

    ABSORPTION

    Free Drug Bound Drug


    SYSTEMIC CIRCULATION

    EXCRETION

    BIOTRANSFORMATION

    Pharmacodynamics
    Mechanisms of drug action

    Non-specific drug action general anaesthetics, osmotic diuretics, antacids Alter transport systems Ca antagonists, local anaesthetics, cardiac glycosides Alter enzyme function COX inhibitors, MAO inhibitors, AChE inhibitors Act on receptors Synaptic transmitter substances, hormones

    Langley (1905)
    Nicotin

    Receptive substance
    Electrical stimulation

    (-) CURARE
    Skeltal muscl. contraction Skeltal muscl. contraction

    Ehrlich (1913)

    specificity of the chemical structure receptor structure corpora non agunt nisi fixata

    Site of Drug Action

    The part of the body (organ, tissue, cell type) where a drug acts to initiate the chain of events leading to an effect. Example: systemic morphine induces pupillary miosis, but not due to direct action on iris muscle. Also, drugs may have different effects in the same tissue...

    Receptor

    The macromolecular (protein) complex with which drugs interact to elicit their characteristic biological effects. Drug receptors for endogenous ligands (hormones, neurotransmitters) Drug actions receptor-selectivity & tissue-specificity Structure-Activity Relationship: the relationship between the chemical structure of a drug and its biological effect.

    Classical Receptors

    Span the membrane. Amphipathic (polar and nonpolar regions). alpha-helices form the nonpolar transmembrane regions.

    Polar

    Nonpolar

    Polar

    Characteristics of DrugReceptor Interactions


    Chemical Bond: covalent, ionic, hydrogen, hydrophobic, and Van der Waals. Competitive, agonist-antagonist Specific and Selective Structure-activity relationships Transduction mechanisms

    DRUG RECEPTOR INTERACTIONS


    Intermolecular forces

    Covalent bonds - two atoms share an electron


    -

    (40-110kcal/mol) - long lasting

    - desirable?

    e.g. Alkylating agents (e.g. anticancer nitrogen mustards)

    Ionic bonds - electrostatic attraction between


    oppositely charged ions
    -

    much weaker than covalent bonds (10 kcal/mol) reversible

    Hydrogen bonds - electrostatic attraction between


    hydrogen atom and electronegative atom
    -

    relatively stable (1-7 kcal/mol)

    - reversible

    Van der Waals bond

    - weak bond (0.5 - 1 kcal/mol)

    Drug-receptor interaction

    Classification Receptor
    Transduction Mechanisms
    1. 2.

    3.

    4.

    Ion channel linked receptors e.g. Ach nicotinic (Na+) and GABA (Cl-) Second messenger generation, adenylate cyclase stimulation or inhibition - cAMP, guanylate cyclase - cGMP, phospholipase C IP3,DAG Some receptors are themselves protein kinases Intracellular receptors (e.g. corticosteroids, thyroid hormone)

    Transmembrane Signaling Mechanisms


    = drug

    Out In

    G X Y

    gene

    Transmembrane Actions

    Drugs acting at the cell membrane produce transmembrane signals by regulating one or more of the following: Ligand-gated ion channels.
    G proteins and second messengers. Transmembrane enzymes

    1: Ligand-gated Ion Channels

    Neurotransmitters GABA (A-type), ACh (nic), 5-HT (5-HT3), and EAAs (e.g., glu) bind in part to ligand-gated channels.

    Increased membrane conductance occurs by the opening of gated channels for specific ions (Na+, K+, Ca2+), which then follow their electrochemical gradients.
    Examples: cartoon illustrations.

    GABAA Receptor: chloride channel

    Channel pore

    2: Membrane Receptors Associated With


    G Proteins, an Effector, and Diffusible Second Messengers: GPCRs.

    G proteins are inactive when GDP is bound and active when GTP is bound. G proteins consist of an a, a b, and a g subunit. The a subunit interacts with the activated receptor, with GDP/GTP, and with the effector enzyme (or channel). Types of G proteins: Gs, Gi, Go, Gq

    Schematic of a G Protein-Linked Receptor

    extracellular
    NH2 Ligand binds here

    7 transmembrane segments

    Plasma Membrane

    intracellular

    binds here: 3rd Intracellular loop

    Gs

    COOH

    AC / cAMP System

    Receptor

    The chemical message is transduced across the cell membrane in four stages.
    1)

    Binding of drug (i.e., ligand) to receptor. Receptor activation of a G protein. G protein regulation of an enzyme or ion channel.

    2) 3)

    4)

    Change in the concentration of a second messenger.

    Binding of drug to receptor

    receptors

    Change in the Receptor activation cons.of second messenger of a G protein

    Inactivation mechanism

    G prot regulation of an enzyme or ion channel

    Stage 1

    Stage 2

    Stage 3

    Stage 4

    Mechanism of beta-1 receptor activation in cardiac muscle

    Effect of beta-2 receptor activation on smooth muscle

    The Major Effectors and Intracellular Second Messengers in GPCR Systems


    2nd messenger

    Effector

    adenylyl cyclase
    phospholipase C

    cyclic AMP (cAMP)


    calcium, DAG, and
    phosphoinositide (IP3)

    Calcium-Phosphoinositide Second Messenger System


    G protein-linked. Activation of phospholipase C results in hydrolysis of phosphotidylinositol-4,5bisphosphate (PIP2) into two second messengers, diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3). DAG activates protein kinase C. IP3 mobilizes stored intracellular calcium.

    The Ca2+-Phosphoinositide Signaling Pathway

    Rec

    PLC

    PIP2

    DAG + PKC
    ATP ADP

    membrane

    cytoplasm Ca2+

    IP3
    CaM CaM-E*
    Substrate

    Sub-P

    Response

    Mechanism of alpha-1 receptor activation of smooth muscle contraction

    3: Ligand-regulated Transmembrane Enzymes (tyr Kinases)


    Drug or hormone binds extracellular domain. Allosteric effect autophosphorylation of intracellular domain. Phosphorylated form phosphorylates substrate proteins. Agonists: insulin, EGF, other growth factors

    1) 2)

    3)

    Linked directly to tyrosine kinase

    Receptor acts as an enzyme

    receptors

    EGF Receptor
    Active dimer

    Inactive monomer form

    4: Intracellular Actions: Regulation of Gene Transcription


    Cytosolic receptors. Steroid hormones cross the cell
    membrane and bind cytosolic receptors. The complex is transported to the nucleus and binds DNA sequences near the gene whose expression is to be regulated.

    Nuclear receptors.

    Thyroid hormone enters the cell and passively enters nucleus to bind its receptor (part of chromatin).

    Intracellular Mechanism: Steroid


    Nucleus
    XXXXXXXXXXXXX

    Effects Protein RNA mRNA

    drug

    Plasma

    Nuclear receptors that regulate gene transcription

    receptors

    Speed of responses

    DRUG - Agonis - Antagonis

    Agonists

    Agonists: produce effects similar to those produced by naturally occurring hormones, neurotransmitters and other substances Example: beta agonists stimulate beta cells (B2) in the lungs causing relaxation of the bronchial smooth muscles. (Albuterol, Alupent inhalers)

    Antagonists

    Antagonists: inhibit cell functions by occupying receptor sites. Prevent natural body substances or other drugs from occupying receptor sites and activating cell functions Example: beta antagonists (beta blockers) occupy beta sites throughout the body causing slowing of the pulse, decrease blood pressure and decreased cardiac output. (Atenolol, Timolol)

    Agonist vs antagonist
    K+1
    Ag

    K-1

    Ag

    Response

    K+1 Ant

    R K-1

    Ant

    Agonist & Antagonist

    Agonist & Antagonist

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