Gastrointestinal System PR2152
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Questions and Answers

Which statement about digoxin is accurate?

  • Digoxin is highly acidic.
  • Digoxin binds extensively to plasma proteins.
  • Digoxin is neutral in charge. (correct)
  • Digoxin acts as both an acid and a base.

    • Which of the following drugs can function as both an acid and a base?

  • Amphotericin B (correct)
  • Digoxin
  • Ibuprofen
  • Aspirin

    • What does the unbound fraction $f_u$ represent?

  • The drug that is eliminated from the body.
  • The concentration of free drug in the plasma. (correct)
  • The total amount of drug in the body.
  • The drug that is bound to tissues.

    • Which factor does NOT affect the extent of drug distribution?

    <p>Body hydration levels.</p> Signup and view all the answers

    What is a key consideration regarding drug distribution between blood and tissue compartments?

    <p>Both bound and unbound fractions must be considered.</p> Signup and view all the answers

    Which of the following accurately describes protein binding of drugs?

    <p>Binding affects the distribution and efficacy of drugs.</p> Signup and view all the answers

    Which component is NOT a factor that affects tissue protein binding?

    <p>Physical state of the drug.</p> Signup and view all the answers

    What is the relationship between bound and unbound fractions in the context of drug distribution?

    <p>Changes in equilibrium affect the availability of the drug to exert its effects.</p> Signup and view all the answers

    What does the equation at distribution equilibrium represent?

    <p>The relationship between amount in body, plasma, and outside plasma</p> Signup and view all the answers

    How is total concentration (CT) calculated at distribution equilibrium?

    <p>CT is equal to the sum of concentrations in plasma and tissue</p> Signup and view all the answers

    What do V and VP represent in the drug distribution model?

    <p>V is the volume in organs and VP is plasma volume</p> Signup and view all the answers

    At distribution equilibrium, which equation correctly represents the relationship between volumes and concentrations?

    <p>$V = VP + VT$</p> Signup and view all the answers

    What does the term fu represent in the given equations?

    <p>The fraction of the unbound drug concentration</p> Signup and view all the answers

    Which relationship is defined by equation (3) in the context of drug distribution?

    <p>$C_T = C_u$ when equilibrium is reached</p> Signup and view all the answers

    What is the purpose of substituting equation (3) into equation (2)?

    <p>To determine the effect of drug binding on distribution</p> Signup and view all the answers

    Which of the following factors can affect the fraction of unbound drug (fu)?

    <p>The presence of other competing drugs</p> Signup and view all the answers

    Which factors primarily affect the extent of drug distribution?

    <p>Protein binding and tissue distribution models</p> Signup and view all the answers

    Which statement is true regarding drugs that do not distribute instantaneously to all tissues?

    <p>Their disposition involves multi-compartmental models</p> Signup and view all the answers

    What is the significance of understanding drugs that follow multi-compartmental distribution models?

    <p>It provides insight into their pharmacokinetic behavior</p> Signup and view all the answers

    How do basic compounds differ from acidic compounds regarding their volume of distribution?

    <p>Basic compounds tend to have a larger volume of distribution</p> Signup and view all the answers

    What characteristic of protein drugs impacts their volume of distribution?

    <p>They are unable to cross cell membranes effectively</p> Signup and view all the answers

    Which PK parameter can be derived from analyzing a two-compartment model after an IV bolus dose?

    <p>Distribution half-life</p> Signup and view all the answers

    What is a common misconception about drug distribution in pharmacokinetics?

    <p>All drugs distribute instantly across all tissues</p> Signup and view all the answers

    Which factor does NOT influence the rate of drug distribution?

    <p>Patient's metabolic rate</p> Signup and view all the answers

    What best describes the volume of distribution (V) of a drug?

    <p>The total amount of drug in the body divided by the plasma concentration</p> Signup and view all the answers

    How does one calculate the apparent volume of distribution for drugs that follow a two-compartment model?

    <p>Considering both plasma concentration and total body drug amount over time</p> Signup and view all the answers

    What does the variable $K_P$ represent in the context of drug binding?

    <p>The relative binding of a drug between plasma and tissue</p> Signup and view all the answers

    Which of the following is used to experimentally determine physiological volumes?

    <p>Equilibrium dialysis</p> Signup and view all the answers

    What is the equation $V = V_P + V_T$ used to represent?

    <p>Distribution of drug between plasma and tissue</p> Signup and view all the answers

    What does the free drug fraction $f_u$ indicate?

    <p>The portion of drug not bound to proteins</p> Signup and view all the answers

    How is the free drug fraction $f_u$ calculated?

    <p>$f_u = 1/(1 + K_a*PT)$</p> Signup and view all the answers

    What does the variable $C_{u}$ stand for in the context of drug binding?

    <p>The concentration of unbound drug</p> Signup and view all the answers

    What can affect the value of the association constant $K_a$?

    <p>Protein concentration and drug characteristics</p> Signup and view all the answers

    What does the term 'apparentness' of volume of distribution (V) refer to?

    <p>Relationship between drug binding and distribution</p> Signup and view all the answers

    What is the purpose of estimating $f_uT$ in drug distribution studies?

    <p>To determine average binding across all tissues</p> Signup and view all the answers

    What role does $K_d$ play in the context of drug binding equations?

    <p>It is the concentration of unbound drug over the bound drug</p> Signup and view all the answers

    What is the effect of changing the fu on the volume V for drugs with a large volume of distribution (V > 1 L/kg)?

    <p>Changes in fu result in a proportional change in V.</p> Signup and view all the answers

    What happens to the new fu' if PT is altered accordingly to the provided formula?

    <p>fu' increases by a proportionate value based on PT changes.</p> Signup and view all the answers

    How does a change in fu affect the clearance rate CL for drugs with a small volume of distribution (V ~ 0.7)?

    <p>It has a minimal impact on clearance.</p> Signup and view all the answers

    What is the role of PT in the equation for determining the new fu'?

    <p>PT determines the proportionate relationship with fu.</p> Signup and view all the answers

    For drugs with low extraction ratio (EH), what is the expected effect on clearance when fu changes?

    <p>Clearance remains relatively stable.</p> Signup and view all the answers

    What is indicated by a high protein binding (>90%) for a drug like Propranolol?

    <p>It correlates with a low fraction unbound (fu).</p> Signup and view all the answers

    In the approximation equation, what does Kaa represent?

    <p>It indicates the drug's affinity for binding sites.</p> Signup and view all the answers

    What is the significance of multi-compartmental models in pharmacokinetics?

    <p>They allow for the understanding of varying distribution rates.</p> Signup and view all the answers

    What is the main goal of therapeutic drug monitoring (TDM)?

    <p>To minimize the number of blood samples needed</p> Signup and view all the answers

    Why is the timing of sampling critical for drugs following a two-compartment model?

    <p>Incorrect timing may distort the elimination half-life</p> Signup and view all the answers

    What could result from using a one-compartment model for pharmacokinetic calculations?

    <p>It may provide an inaccurate prediction of drug concentrations</p> Signup and view all the answers

    How might the onset of action for some drugs be affected by their distribution model?

    <p>It may be slower if the target is in the peripheral compartment</p> Signup and view all the answers

    What should be considered when determining the distribution of drugs?

    <p>Both plasma and tissue protein binding factors</p> Signup and view all the answers

    What is one characteristic of drugs that do not conform to instant distribution assumptions?

    <p>Their disposition is complex and may be multi-compartmental</p> Signup and view all the answers

    What role do mathematical equations play in pharmacokinetics within the context of research?

    <p>They are essential for accurately characterizing drug pharmacokinetics</p> Signup and view all the answers

    Which of the following is NOT a factor influencing drug distribution?

    <p>Drug formulation type</p> Signup and view all the answers

    Study Notes

    Gastrointestinal System Lecture Notes

    • The lecture covers PK concepts for distribution.
    • The course is PR2152.
    • The semester is AY2024/25 Sem 1.
    • The instructor is Chng Hui Ting, PhD.
    • Email: [email protected]

    Overview of Distribution Lectures

    • Part 1: Factors affecting drug distribution
      • What factors influence drug distribution?
      • Not all drugs distribute instantaneously. How do we describe the disposition of drugs that don't distribute instantly?
      • What is the clinical relevance of understanding multi-compartmental models for drug disposition?
    • Part 2: PK parameters from two-compartment models
      • What PK parameters can be derived from a drug's profile following IV bolus administration in a two-compartment model?
      • What factors affect the rate of drug distribution?

    Learning Outcomes (Part 1)

    • Students will be able to explain the factors affecting drug distribution using protein binding equations and tissue distribution models.
    • Students will be able to relate the fundamental concepts of drug distribution to their clinical relevance.
    • Students will be able to describe PK processes and different apparent volume of distributions associated with drugs following a two-compartment model.

    Body Water and Compartments

    • Total body water (70 kg person): 42L
    • Intracellular water (VR) = 27L
    • Extracellular water
      • Intravascular (plasma) = 3L
      • Extravascular (interstitial) = 12L

    Primary PK Parameter - Apparent Volume of Distribution

    • Big idea: The apparent volume of distribution (V) represents the fluid volume in which a drug distributes to account for its concentration in plasma.
    • V relates the amount of drug in the body to the plasma concentration.
    • V may be defined with respect to blood, plasma, or water, depending on the specific concentration used in the calculation.

    Clinical Application of V

    • Protein drugs often have V values similar to plasma volume due to their large size, hindering their ability to cross cell membranes.
    • Basic compounds tend to have larger Vs than acidic compounds.
    • Digoxin is neutral, while Amphotericin B is both an acid and a base.

    Plasma and Tissue Protein Binding

    • Concept: Unbound fraction (fu)
      • Blood/Plasma: fu = Cu / Cp
      • Tissues: fur = CuT / Cr
    • There are several equilibria to consider, including:
      • The bound-unbound equilibrium in plasma/blood
      • The bound-unbound equilibrium in tissues
      • The equilibrium between blood and tissue compartments.
    • Examples of plasma proteins binding to drugs?

    Factors Affecting the Extent of Drug Distribution

    • Factors affecting plasma protein binding (e.g., fu)
    • Factors affecting tissue protein binding
    • Factors affecting tissue volume

    Acidic vs. Basic Drugs

    • Acidic: Tend to have a smaller volume of distribution (<1 L/kg) due to high affinity for plasma albumin and low affinity for tissues. Drugs like Tolbutamide have V = 0.15 L/kg and f₁ = 5–10%.
    • Basic: Typically have a larger volume of distribution (>1 L/kg). Propranolol, for example, has V = 4L/kg and f₁ = 5–10%.

    Tissue-to-Plasma Equilibrium Ratio

    • Kp is the tissue-to-plasma equilibrium distribution ratio, which varies from one tissue to another.
    • Equilibrium is reached when the net flux of free drug movement is zero (CuT = Cp).

    Model of Tissue Distribution

    • Amount in body = Amount in plasma + Amount outside plasma
    • VC = VpCp + VTCT (1)
    • V = Vp + VT* (f u T / f u )

    Model of Tissue Distribution (Continued)

    • At distribution equilibrium: Amount in body = Amount in plasma + Amount outside plasma VC = Vp * Cp + VT * CT (1) V = Vp + VT * (CT/Cp) (2)

    Model of Tissue Distribution (Continued)

    • Since, fu = Cu/Cp and fur = CuT/CT (3)
    • Substitute (3) into (2): V = Vp + VT*fuT/fu (4)

    Model of Tissue Distribution (Continued)

    • This equation relates the apparent volume of distribution (V) to the volume of plasma (Vp) and the total volume of other tissues (VT). This is important in assessing how a drug distributes throughout a body.

    Gibaldi and McNamara Model

    • Looking at the equation V=Vp + VT *(fuT / fu ), the term fuT/fu is a measure of the relative binding of a drug between plasma and tissues.
    • Aids in interpreting data on V, enabling estimation of fut, which is the average value across all tissues into which the drug distributes

    Plasma Protein Binding

    • Free drug fraction (fu): fu =(1+KafupPT)⁻¹
      • Ka=association constant
      • Cup =concentration of unbound drug
      • PT=concentration of total binding protein.
    • Factors affecting free drug fraction (fu) include alterations to total protein and diseases.

    Factors Affecting Free Drug Fraction (fu)

    • Diseases
    • Genetic variants of albumin, or a₁-AGP .
    • Drug-drug interactions.

    Calculating Changes in fu

    • fu = 1 / (1 + Ka * fup * Pr)
    • For drugs with low fu, we can approximate fu =1 / (Ka * fup * Pr)
    • If the total protein (Pr) changes, a new fu can be calculated using the same equation.

    Impact of Change in fu on V

    • For drugs with large V, changes in fu lead to a proportional change in V.
    • For drugs with small V, changes in fu have minimal impact on V.

    Impact of Change in fu on CL

    • For drugs with high extraction ratio ( > 0.7), changes in fu have minimal impact on CL.
    • For drugs with low extraction ratio ( <0.3 ), changes in fu result in changes in CL.

    Factors Affecting fu, fut, and V₁

    • Plasma Protein Binding (fu): Disease, genetic variations, drug interactions.
    • Tissue Protein Binding (fut): Genetic variations, drug interactions.
    • Tissue Water (Vt): Altered physiology (e.g., pediatrics, geriatrics, pregnancy), pathology (e.g., liver or kidney disease).

    Impact of Change in fut on V

    • V = Vp + VT *(fut / fu)
    • fut represents the average value across all tissues into which the drug distributes.

    Clinical Relevance of Multi-compartmental models

    • Minimizing the need to draw too many blood samples during therapeutic drug monitoring (TDM).
    • Correct timing of sampling is critical especially for drugs that exhibit a two-compartment model, for example, aminoglycosides, digoxin, and lithium.
    • Avoid erroneous determination of elimination half-life which would result in improper dose adjustments

    Two-compartment Model

    • Assumptions:
      • Drug distributes instantaneously throughout the central compartment.
      • Drug in tissues of the peripheral compartment reaches equilibrium with the central compartment after some time.

    Two-compartment Model - PK Processes

    • I: End of Injection: Central compartment is quickly filled, some drug may transfer to the peripheral compartment.
    • II: Distribution Predominates: Central compound elimination & initial rate of drug transfer between central and peripheral compartment.
    • III: Distribution equilibrium: Rapid transfer between central and peripheral compartments, resulting in equilibration.
    • IV: Elimination predominates: The central compartment elimination becomes dominant.

    Different Apparent Volumes of Distribution

    • Vc: Volume of central compartment
    • Vs: Volume at steady-state.

    Two-, Three-, Four- etc Compartment Model

    • Compartmental models are useful for describing how drug concentration changes over time in the body.
    • The number of compartments (e.g., one, two, three) needed depends on how many exponential terms are required to model the data.

    Trend of Decline of Drug Concentration

    • A one-compartment model predicts a single exponential decline in plasma drug concentration over time.
    • A two-compartment model predicts a bi-exponential decline in plasma drug concentration over time.

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    IC06 Gastrointestinal System PK Concepts for Distribution, AY2024/25 PDF

    Description

    This quiz covers the key pharmacokinetic (PK) concepts related to drug distribution as part of the Gastrointestinal System course (PR2152). Students will explore various factors influencing distribution, the relevance of multi-compartmental models, and the parameters derived from two-compartment models. Understanding these concepts is essential for effective drug administration and therapy.

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