Pharmacology Lecture 3: Pharmacodynamics
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Questions and Answers

What is the primary function of second messenger molecules in signal transduction?

  • To open ion channels in the cell membrane
  • To activate G proteins
  • To amplify and transmit signals within the cell (correct)
  • To bind directly to receptors

    • What is the typical duration of response triggered by transmembrane G protein–coupled receptors?

  • Days to weeks
  • Seconds to minutes (correct)
  • Milliseconds
  • Hours to days

    • Which type of receptor undergoes conformational changes when activated by a ligand?

  • Transmembrane ligand-gated ion channels
  • Transmembrane G protein–coupled receptors
  • Enzyme-linked receptors (correct)
  • Intracellular receptors

    • What is the primary function of transmembrane ligand-gated ion channels?

    <p>To open or close ion channels in the cell membrane</p> Signup and view all the answers

    Which of the following receptors is an example of a transmembrane G protein–coupled receptor?

    <p>α adrenoceptor</p> Signup and view all the answers

    What is the effect of agonist binding on transmembrane ligand-gated ion channels?

    <p>The channel is opened for a few milliseconds</p> Signup and view all the answers

    Which type of receptor possesses tyrosine kinase activity?

    <p>Enzyme-linked receptors</p> Signup and view all the answers

    What is the effect of acetylcholine on cholinergic nicotinic receptors?

    <p>It opens a channel that allows sodium influx and potassium outflux</p> Signup and view all the answers

    What is the characteristic of a drug that determines the amount of drug necessary to produce an effect?

    <p>Potency</p> Signup and view all the answers

    What is the maximum effect of a drug achieved when all receptors are occupied?

    <p>Emax</p> Signup and view all the answers

    What is the concentration of drug producing 50% of the maximum effect?

    <p>EC50</p> Signup and view all the answers

    What is an example of chemical interaction outside the cell?

    <p>Chelating agents</p> Signup and view all the answers

    What determines the magnitude of response a drug causes when it interacts with a receptor?

    <p>Efficacy</p> Signup and view all the answers

    What is the effect of a competitive antagonist on two responses of an agonist?

    <p>Inhibit both responses</p> Signup and view all the answers

    Which of the following characteristics is more clinically useful?

    <p>Efficacy</p> Signup and view all the answers

    What is the primary mechanism of signaling for intracellular receptors?

    <p>Transmembrane diffusion of drug to bind to an intracellular receptor</p> Signup and view all the answers

    What is the result of stereoselectivity in drug molecules?

    <p>Biological activity is different for each configuration</p> Signup and view all the answers

    What is the reason for upregulation of receptors?

    <p>Due to long-term administration of an antagonist</p> Signup and view all the answers

    What is the result of an antagonist occupying 100% of the receptor sites?

    <p>No receptor activation</p> Signup and view all the answers

    What is the primary function of Janus Kinases (JAKs) in signal transduction?

    <p>To phosphorylate and activate STAT molecules</p> Signup and view all the answers

    What is the result of desensitization and tachyphylaxis?

    <p>Decrease in responsiveness to a drug</p> Signup and view all the answers

    What is the difference between full and partial agonists?

    <p>Maximal efficacy</p> Signup and view all the answers

    What is the defining characteristic of an agonist?

    <p>It has both affinity and intrinsic activity</p> Signup and view all the answers

    What is the duration of time for tolerance to develop?

    <p>Days or weeks</p> Signup and view all the answers

    What is the primary mechanism of signaling for transmembrane receptors that activate separate mobile protein tyrosine kinase molecules?

    <p>Transmembrane receptors that activate separate mobile protein tyrosine kinase molecules</p> Signup and view all the answers

    What is the relationship between the concentration of a drug and its pharmacologic effect?

    <p>Gradual</p> Signup and view all the answers

    What is the result of receptor downregulation?

    <p>Decrease in responsiveness to a drug</p> Signup and view all the answers

    What is the primary function of receptor phosphorylation?

    <p>To regulate the activity of other proteins</p> Signup and view all the answers

    What is the primary mechanism of signaling for G-Protein coupled receptors?

    <p>G-Protein coupled receptors, which utilize a coupling protein to activate a separate effector molecule</p> Signup and view all the answers

    What is the reason for quantitative variation in drug response?

    <p>Normal biological variation</p> Signup and view all the answers

    What is the primary difference between intracellular receptors and other receptor families?

    <p>Intracellular receptors are entirely intracellular, while others are not</p> Signup and view all the answers

    What is the primary function of STAT molecules in signal transduction?

    <p>To regulate transcription</p> Signup and view all the answers

    What is the primary mechanism by which drugs exert their effects on the body?

    <p>By interacting with specialized target macromolecules called receptors</p> Signup and view all the answers

    What is the term for the process by which a drug molecule binds to a receptor and initiates a series of reactions that ultimately result in a specific intracellular response?

    <p>Signal transduction</p> Signup and view all the answers

    Which of the following is an example of a drug that exerts its effect through activation?

    <p>Caffeine</p> Signup and view all the answers

    What is the term for a drug that binds to a site on a receptor protein and activates it to initiate a series of reactions?

    <p>Agonist</p> Signup and view all the answers

    Which of the following is an example of a drug that exerts its effect through neutralization?

    <p>Antacids</p> Signup and view all the answers

    What is the term for the process by which a drug molecule makes a complex with the target site, thereby making it inactive by sequestration?

    <p>Complexation</p> Signup and view all the answers

    Which of the following is an example of a drug that exerts its effect through inhibition?

    <p>Aspirin</p> Signup and view all the answers

    What is the primary characteristic of a partial agonist?

    <p>Very low intrinsic activity</p> Signup and view all the answers

    What is the consequence of long-term administration of an antagonist on the receptor activity?

    <p>Upregulation of receptors</p> Signup and view all the answers

    What is the result of the combined use of two drugs with additive action?

    <p>Synergism</p> Signup and view all the answers

    What determines the range of effective doses and toxic doses of a drug?

    <p>Therapeutic index</p> Signup and view all the answers

    Which of the following is a mechanism of quantitative variation in drug response?

    <p>Tolerance</p> Signup and view all the answers

    What is the primary mechanism of action of drugs that interact with cell membrane ion channels?

    <p>Physico-chemical interaction</p> Signup and view all the answers

    What is the result of desensitization and tachyphylaxis?

    <p>All of the above</p> Signup and view all the answers

    What is the characteristic of a drug that determines the amount of drug necessary to produce an effect?

    <p>Potency</p> Signup and view all the answers

    What is the characteristic of a drug molecule that leads to different biological activities?

    <p>Stereo selectivity</p> Signup and view all the answers

    Which of the following is an example of a physical mechanism that occurs outside the cell?

    <p>Osmotic diuretics</p> Signup and view all the answers

    What is the result of the interaction of an inverse agonist with a receptor?

    <p>Opposite action to that of an agonist</p> Signup and view all the answers

    What is the consequence of a competitive antagonist on two responses of an agonist?

    <p>Inhibition of both responses</p> Signup and view all the answers

    What is the primary mechanism of action of drugs that interact with intracellular constituents?

    <p>Action on cytosolic or nuclear receptors</p> Signup and view all the answers

    What is the term for the range of doses between the minimum effective dose and the maximum effective dose of a drug?

    <p>Range of effective doses</p> Signup and view all the answers

    What is the reason for quantitative variation in drug response from one individual to another?

    <p>Normal biological variation</p> Signup and view all the answers

    What is the result of receptor downregulation?

    <p>Decreased receptor activity</p> Signup and view all the answers

    What is the primary characteristic of a receptor that is entirely intracellular?

    <p>It has sufficient lipid solubility to diffuse into the cell</p> Signup and view all the answers

    What is the primary function of Janus Kinases (JAKs) in signal transduction?

    <p>To phosphorylate STAT molecules</p> Signup and view all the answers

    What is the primary mechanism of signaling for transmembrane receptors that activate separate mobile protein tyrosine kinase molecules?

    <p>Activation of JAKs and phosphorylation of STAT molecules</p> Signup and view all the answers

    What is the primary characteristic of an agonist?

    <p>It has both affinity and intrinsic activity</p> Signup and view all the answers

    What is the primary mechanism of signaling for G-protein coupled receptors?

    <p>Utilization of a coupling protein to activate a separate effector molecule</p> Signup and view all the answers

    What is the primary difference between intracellular receptors and other receptor families?

    <p>Intracellular receptors are entirely intracellular</p> Signup and view all the answers

    What is the result of receptor-occupancy?

    <p>A variety of responses depending on the nature of the drug molecule</p> Signup and view all the answers

    What is the primary function of receptor phosphorylation?

    <p>To phosphorylate tyrosine residues on itself and other specific proteins</p> Signup and view all the answers

    What is the term used to describe the phenomenon where a drug becomes less effective over time due to physiological adaptation?

    <p>Pharmacokinetic tolerance</p> Signup and view all the answers

    What is the primary focus of drug resistance in the field of chemotherapy?

    <p>Antimicrobial therapy</p> Signup and view all the answers

    What is the term used to describe the effects of a drug on reproduction, including teratogenicity?

    <p>Reproductive toxicity</p> Signup and view all the answers

    What is the term used to describe an adverse drug reaction that occurs due to an excess of normal, predictable, dose-related pharmacodynamic effects?

    <p>Side effects</p> Signup and view all the answers

    What is the term used to describe a drug-induced disease, such as Parkinson's syndrome during therapy with phenothiazine?

    <p>Iatrogenic diseases</p> Signup and view all the answers

    What is the term used to describe a low threshold to pharmacological action of a drug?

    <p>Intolerance</p> Signup and view all the answers

    What is the primary focus of pre-clinical toxicity testing?

    <p>Acute toxicity, subacute and chronic toxicity, and reproductive toxicity</p> Signup and view all the answers

    What is the term used to describe the quantitative variation in drug response due to genetic differences?

    <p>Pharmaco-genetic variation</p> Signup and view all the answers

    What is the primary factor that determines the potency of a drug?

    <p>The concentration of drug producing 50% of the maximum effect</p> Signup and view all the answers

    What is the primary characteristic of an antagonist?

    <p>It occupies 100% of the receptor sites but does not activate the receptor</p> Signup and view all the answers

    What is the difference between the maximal response of a full agonist and a partial agonist?

    <p>Full agonists have a higher maximal response than partial agonists</p> Signup and view all the answers

    What is the clinically more useful characteristic of a drug?

    <p>Its efficacy</p> Signup and view all the answers

    What is the relationship between the concentration of a drug and its pharmacologic effect?

    <p>The effect of a drug increases as the concentration increases</p> Signup and view all the answers

    What is the significance of EC50 in dose-response relationships?

    <p>It is the concentration of drug producing 50% of the maximum effect</p> Signup and view all the answers

    What is the primary factor that determines the efficacy of a drug?

    <p>The intrinsic activity of the drug</p> Signup and view all the answers

    What is the effect of an antagonist on the efficacy of an agonist?

    <p>It decreases the efficacy of the agonist</p> Signup and view all the answers

    Study Notes

    Pharmacodynamics

    • Describes the actions of a drug on the body, which is achieved by interacting with specialized target macromolecules called receptors.
    • The drug-receptor complex initiates alterations in biochemical and/or molecular activity of a cell through a process called signal transduction.

    Fundamentals of Drug Action

    • Activation: a drug molecule stimulates a process or selectively accelerates it, e.g. caffeine causes CNS stimulation and increased alertness.
    • Inhibition: a drug molecule inhibits a process or selectively deaccelerates it, e.g. aspirin inhibits cyclooxygenase, thereby inhibiting the formation of prostaglandins.
    • Complexation: a drug molecule makes a complex with the target site, making it inactive by sequestration, e.g. deferoxamine chelates iron.
    • Neutralization: a drug molecule binds to the target site and neutralizes the action of the existing molecule directly through a chemical reaction or physical interaction, e.g. antacids (sodium bicarbonate, magnesium hydroxide) or physical interaction (polyvalent anti-snake venom).

    Signal Transduction

    • Drugs act as signals, and receptors act as signal detectors.
    • A drug is termed an "agonist" if it binds to a site on a receptor protein and activates it to initiate a series of reactions that ultimately result in a specific intracellular response.
    • "Second messenger" or effector molecules are part of the cascade of events that translates agonist binding into a cellular response.

    Major Receptor Families

    • Transmembrane ligand-gated ion channels: the channel is usually closed until the receptor is activated by an agonist, which opens the channel for a few milliseconds, e.g. cholinergic nicotinic receptor is stimulated by acetylcholine.
    • Transmembrane G protein–coupled receptors: the extracellular portion of this receptor contains the ligand-binding site, and the intracellular portion interacts with a G protein when activated, e.g. α and β adrenoceptors.
    • Enzyme-linked receptors: this family of receptors undergoes conformational changes when activated by a ligand, resulting in increased intracellular enzyme activity, e.g. growth factors and insulin receptors possess tyrosine kinase activity.
    • Intracellular receptors: the receptor is entirely intracellular, and the ligand (e.g. steroid hormones) must have sufficient lipid solubility to diffuse into the cell to interact with the receptor.

    Signaling Mechanisms for Drug Effect

    • Transmembrane diffusion of drug to bind to an intracellular receptor.
    • Transmembrane enzyme receptor, whose outer domain provides the receptor function and inner domain provides the effector mechanism.
    • Transmembrane receptors that, after activation by an appropriate ligand, activate separate mobile protein tyrosine kinase molecules (Janus Kinases or JAKs), which phosphorylate (signal transducer and activators of transcription or STAT) molecules that regulate transcription.
    • Transmembrane channels that are gated open or closed by the binding of a drug to the receptor site.
    • G-Protein coupled receptors, which utilize a coupling protein to activate a separate effector molecule.

    Response of Drug-Receptor Interaction

    • If a drug has affinity for the receptor, and if it is in close proximity of the receptor site, receptor-occupancy takes place.
    • This drug-receptor coupling leads to a variety of responses depending upon the nature of the drug molecule.
    • Agonist: a drug that resembles the natural transmitter or hormone, may activate the concerned receptor and result in response, so an agonist has “affinity” as well as “intrinsic activity”.
    • Antagonist: a drug that binds to the receptor but does not activate it.
    • Partial agonist: a drug that binds to the receptor and activates it, but not to the same extent as the natural transmitter or hormone.
    • Inverse agonist: a drug that binds to the receptor and reduces its activity.

    Structure-Activity and Receptor Classes

    • Structure-activity relationship: the same receptor type may mediate two effects, a competitive antagonist will inhibit both responses of the agonist.
    • Stereoselectivity: drug molecules have more than one 3-dimensional configuration, and biological activity for each is different.
    • Receptor classes: there are multiple receptor subtypes for each endogenous ligand, e.g. Ach(5), NA(5), H(3), 5-HT(4).

    Quantitative Variation in Drug Response

    • Response to drugs vary from animal to animal, human to human due to normal biological variation.
    • Response may change quantitatively in the same individual during the course of therapy.
    • Up and down regulation of receptors: upregulation (i.e., increase in the number) of receptors occurs when the activity of the receptor is lower than usual, e.g. administration of beta-blockers upregulates β-adrenoreceptors.
    • Desensitization and tachyphylaxis: change in receptors, loss of receptors, or exhaustion of mediators.
    • Tolerance: a gradual decrease in responsiveness (in vivo) to a drug, taking days or weeks to develop.
    • Factors influencing drug response: age, sex, pregnancy, diseases (e.g. hepatic or renal dysfunction), and genetic factors.

    Dose-Response Relationships

    • Graded dose–response relations: as the concentration of a drug increases, its pharmacologic effect also gradually increases until all the receptors are occupied (the maximum effect).
    • Potency: a measure of the amount of drug necessary to produce an effect, measured by the concentration of drug producing 50% of the maximum effect (EC50).
    • Efficacy: the magnitude of response a drug causes when it interacts with a receptor, dependent on the number of drug–receptor complexes formed and the intrinsic activity of the drug.
    • Maximal efficacy of a drug (Emax) assumes that the drug occupies all receptors, and no increase in response is observed in response to higher concentrations of drug.

    Signal Transduction

    • When activated, a receptor phosphorylates tyrosine residues on itself and other specific proteins.

    Major Receptor Families

    • Intracellular receptors: differ from other three families in that the receptor is entirely intracellular, and the ligand (e.g., steroid hormones) must have sufficient lipid solubility to diffuse into the cell to interact with the receptor.

    Signaling Mechanisms for Drug Effect

    • Five major signaling mechanisms are recognized:
      • Transmembrane diffusion of drug to bind to an intracellular receptor.
      • Transmembrane enzyme receptor, whose outer domain provides the receptor function and inner domain provides the effector mechanism.
      • Transmembrane receptors that, after activation by an appropriate ligand, activate separate mobile protein tyrosine kinase molecules (Janus Kinases or JAKs), which phosphorylate (signal transducer and activators of transcription or STAT) molecules that regulate transcription.
      • Transmembrane channels that are gated open or closed by the binding of a drug to the receptor site.
      • G-Protein coupled receptors, which utilize a coupling protein to activate a separate effector molecule.

    Response of Drug-Receptor Interaction

    • If a drug has affinity for the receptor, and if it is in close proximity of the receptor site, receptor-occupancy takes place, leading to a variety of responses depending on the nature of the drug molecule.
    • Types of drug responses:
      • Agonist: a drug that resembles the natural transmitter or hormone, may activate the concerned receptor and result in a response, so an agonist has both affinity and intrinsic activity.
      • Antagonist: a drug that has affinity to receptors without intrinsic activity.
      • Partial agonist: a drug that has affinity but very low intrinsic activity.
      • Inverse agonist: a drug that produces actions specifically opposite to those of an agonist.

    Combined Use of Drugs

    • Synergism: occurs when two drugs have similar actions and are additive, or when one drug increases the action of another.
    • Antagonism: occurs when two drugs have opposite actions, resulting in reduced biological activity.

    Therapeutic Index (Safety Margin)

    • The therapeutic index is a measure of the range of effective doses (up to ED max) and the range of toxic doses (from minimal toxic dose upward) in humans.
    • A wide margin of safety indicates a high therapeutic index, while a narrow margin of safety indicates a low therapeutic index.

    Mechanism of Drug Action

    • Mechanisms of drug action include:
      • On cell membrane: action of receptors of agonists and antagonists, action on enzymes and pumps, action on ion channels, and physico-chemical interaction.
      • On intracellular constituents: action on cytosolic or nuclear receptors, enzymes, DNA or RNA, and transport carrier molecules.
      • Outside the cell: chemical interaction, physical mechanisms, and antimicrobial action.

    Structure Activity and Receptor Classes

    • Structure-activity relationship: the same receptor type may mediate two effects, a competitive antagonist will inhibit both responses of the agonist.
    • Stereoselectivity: drug molecules have more than one 3-dimensional configuration, with biological activity for each being different.
    • Receptor classes: multiple receptor subtypes exist for each endogenous ligand.

    Quantitative Variation in Drug Response

    • Response to drugs varies from animal to animal, human to human due to normal biological variation, and may change quantitatively in the same individual during the course of therapy.
    • Factors contributing to quantitative variation in drug response:
      • Up and down regulation of receptors.
      • Desensitization and tachyphylaxis.
      • Tolerance: a gradual decrease in responsiveness to a drug, requiring either raising the dose or substituting a different drug.
      • Drug resistance: used in the field of chemotherapy during antimicrobial therapy or chemotherapy of malignancy.

    Adverse Drug Reactions (Toxicity)

    • Measurement of pre-clinical toxicity: extensive toxicity testing is done in various animal species to determine acute toxicity, subacute and chronic toxicity, effects on reproduction, carcinogenicity, and mutagenicity.
    • Definitions of commonly used terms:
      • Side effects: some reaction due to excess of normal, predictable, dose-related, pharmacodynamic effects seen in therapeutic doses.
      • Secondary effects: super infection or vitamin deficiency during chemotherapy.
      • Intolerance: low threshold to pharmacological action of a drug, inability to tolerate the adverse effects of a medication.
      • Iatrogenic diseases: drug-induced diseases.

    Adverse Drug Reactions ADR (Toxicity)

    • Factors influencing ADR:
      • Drugs.
      • Patients: age, sex, pregnancy, and other factors.
      • Diseases: hepatic dysfunction, renal dysfunction, and others.
      • Genetic factors.

    Dose-Response Relationships

    • Graded dose-response relations:
      • As the concentration of a drug increases, its pharmacologic effect also gradually increases until all the receptors are occupied (the maximum effect).
      • Potency: a measure of the amount of drug necessary to produce an effect, determined by the concentration of drug producing 50% of the maximum effect (EC50).
      • Efficacy: the magnitude of response a drug causes when it interacts with a receptor, dependent on the number of drug-receptor complexes formed and the intrinsic activity of the drug.

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    Description

    This quiz covers the principles of pharmacodynamics, including the actions of drugs on the body and their interactions with receptors to initiate biochemical and molecular changes.

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