FFP1 Pharmacokinetics Drug Distribution, Metabolism and Elimination 2024

Drug Distribution

  • Definition: The process by which a drug reversibly leaves the bloodstream and enters the extracellular fluid and/or cells of the tissue (intracellular fluid).

Extent of Distribution of a Drug

  • Importance:

    • Determines the relationship between plasma concentration and total amount of drug in the body.

    • Influences the dosing needed to achieve a specific plasma concentration, necessitating the use of a loading dose for certain drugs (e.g., digoxin).

  • Descriptive Parameter: Apparent volume of distribution (Vd).

Volume of Distribution (Vd)

  • Definition: A theoretical volume representing how much fluid a drug would occupy if the total amount of drug in the body was at the same concentration as in the plasma.

  • Characteristics:

    • Not a real physical volume; rather, it reflects the ratio of drug in extravascular space to plasma space.

    • Provides a measure of the tendency of a drug to move out of plasma to other sites.

Calculation of Volume of Distribution

  • Formula: Vd = Total amount of drug in the body / Plasma concentration.

  • Example Calculation:

    • If a 30mg dose of an analgesic gives a plasma concentration of 0.5ug/ml:Vd = 30mg / 0.5ug/ml = 60,000ml = 60 litres.

  • Note: 1mg = 1000ug

Clinical Usefulness of Volume of Distribution

  • Indications:

    • Reflects the size of distribution space.

    • Drugs with Large Vd need higher doses to reach therapeutic concentrations.

    • Drugs with Small Vd need lower doses to achieve the same.

  • Loading Dose Calculation:

    • Formula: LD = Vd x Desired plasma concentration.

Drug Elimination

  • The irreversible loss of a drug from the body, occurs through:

    1. Metabolism: Converts lipid-soluble drugs to water-soluble forms.

      • Phase 1: Oxidation, reduction, hydrolysis.

      • Phase 2: Conjugation.

    2. Excretion: Through fluids (urine, bile, sweat), solids (faeces), and gases (expired air).

Major Routes of Drug Excretion

  1. Renal: Includes glomerular filtration, active tubular secretion, and reabsorption (works with low molecular weight)

  2. Biliary/Gastrointestinal: Hepatic uptake, metabolised and excreted into bile (works if high molecular weight).

    1. Joining with Glucuronide often increases molecular weight sufficiently for bile excretion

  3. Pulmonary: Excretion via the lungs and breath. Good for volatile substances (e.g., anesthetics).

  4. Mammary: Milk concentration in mothers reflects free concentration in maternal blood(e.g., tetracyclines (discoloured mottled teeth) and chloramphenicol (bone marrow suppression)).

Drug Elimination Kinetics

  • First-Order Kinetics:

    • Elimination rate is directly proportional to serum drug concentration.

    • Constant fraction per time unit

  • Zero-Order Kinetics:

    • Elimination occurs at a fixed maximum rate (independent of drug concentration).

    • Constant quantity per time unit

Half-Life (t1/2)

  • The time taken for plasma concentration of a drug to fall by 50%.

Factors Determining Plasma Half-Life (t₁/₂) of a Drug

  1. Metabolizing Enzymes & Excretion Mechanisms (Clearance)

    • Faster clearance (efficient metabolism/excretion) = shorter t₁/₂.

    • Slower clearance = prolonged t₁/₂.

  2. Drug Distribution Between Blood and Tissues (Volume of Distribution, Vd)

    • High Vd (drug mainly stored in tissues) = extended t₁/₂.

    • Low Vd (drug mostly in bloodstream) = shorter t₁/₂.

  • Clinical Relevance: Used to determine dosing intervals and the time to reach steady-state drug levels.

  • General Rule: After 4 half-lives, the drug plasma concentration generally falls by ~94%.

Steady-State Concentration

  • Achieved when the rate of drug input equals the rate of elimination

  • reaching steady-state means that the drug’s concentration remains stable within the desired range, maximising therapeutic benefits while minimising side effects

Pharmacokinetics vs. Pharmacodynamics

  • Pharmacokinetics: Relates to the concentration of the drug over time.

  • Pharmacodynamics: Focuses on the drug's effect over time.

    • Illustrated using dose-response curves.