Pharmacokinetics-Distribution

Pharmacokinetics

Distribution

Definition of Drug Distribution

  • Drug distribution is defined as the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and tissues.

Plasma Protein Binding

  • Plasma Protein:
      -
    Vascular space (Volume = Vp):
      - Porous capillaries membrane

  • Tissue compartment consists of extracellular fluid and tissue.

  • Concentration relationships:
      - Cp=Cfree+CboundC_p = C_{free} + C_{bound} (where $C_p$ is the total plasma concentration)
      - fu,p=racCfreeCpf_{u,p} = rac{C_{free}}{C_p} (free fraction in plasma)
      - Total tissue concentration: CT=Cfree+CTboundC_T = C_{free} + C_{Tbound}
      - Cfree=CTfu,TC_{free} = C_T f_{u,T}

  • Total compartment volume:
      - V1imesCp=VpimesCp+V1imesCTV_1 imes C_p = V_p imes C_p + V_1 imes C_T
      - Where V1=Vp+VTV_1 = V_p + V_T
      - Resulting formula: Cp=CTfu,TC_p = C_T f_{u,T}
      - This results in $V_1 = V_p + V_T$

Factors Influencing Distribution
1. Blood Flow

  • The higher the blood flow, the better the ability for the medication to distribute to that tissue system/organ.

2. Capillary Permeability

  • Higher permeability allows for more drug to potentially pass through.

  • Capillary structure varies in exposed basement membrane areas through slit junctions between endothelial cells.

  • Capillary permeability is determined by both capillary structure and the chemical nature of the drug.

  • Specific examples:
      - Liver and Spleen: Large, discontinuous capillaries with significant basement membrane exposure.
      - Brain: Continuous capillary structure with no slit junctions; drugs must pass through endothelial cells or be actively transported, creating a blood-brain barrier.

Conclusion: Correct distribution across capillary structures is crucial for therapeutic efficacy.

Example of Drug Transport

  • Transporter: A specific transporter carries levodopa into the brain.

  • Lipid-soluble drugs: These drugs readily penetrate the central nervous system (CNS) as they dissolve in the endothelial cell membrane.

  • Ionized or Polar Drugs: Typically fail to enter the CNS as they cannot pass through endothelial cells due to tight junctions that comprise the blood-brain barrier.

3. Binding of Drugs

  • Binding to Plasma Proteins:
      - Reversible binding sequesters drugs in a nondiffusible form, slowing their transfer out of the vascular compartment.
      - Example of Albumin: May act as a drug reservoir, where as the concentration of free drug decreases due to elimination, the bound drug dissociates from the protein. This mechanism maintains the free drug concentration as a constant fraction of the total drug in plasma.

  • Binding to Tissue Proteins:
      - Many drugs accumulate in tissues, resulting in higher concentrations in tissues compared to extracellular fluid and blood.
      - Mechanisms include binding to lipids, proteins, nucleic acids, or active transport into tissues.
      - Example of Toxicity: Acrolein (metabolite of cyclophosphamide) accumulates in the bladder, leading to hemorrhagic cystitis.

Lipophilicity vs. Hydrophilicity

  • Lipophilic Drugs:
      - Move readily across biological membranes and dissolve in lipid membranes.
      - Key influencing factor for distribution: blood flow to the area.

  • Hydrophilic Drugs:
      - Do not easily penetrate cell membranes and must pass through slit junctions.

Apparent Volume of Distribution (V_D)

  • Definition:
      - The apparent volume of distribution, $V_D$, is defined as the fluid volume that is required to contain the entire drug in the body at the same concentration as measured in plasma.

  • Physical Basis:
      - While $V_D$ has no strict physiologic or physical basis, it serves as a useful comparative measure against volumes of the body's natural water compartments.

Water Compartmental Distribution

  • Key Compartments:
      - Plasma
      - Extracellular Fluid
      - Total Body Water

Drug Compartment Distribution Properties

  • Drugs rarely associate exclusively with a single water compartment.

  • Most drugs distribute into:
      - Several compartments: lipids (in adipocytes and cell membranes), proteins (in plasma and cells), nucleic acids (in cell nuclei).

  • Implication: The volume into which drugs distribute is called the apparent volume of distribution ($V_D$).

  • Utility: $V_D$ is useful for calculating a drug's loading dose.

Impact of Apparent Volume of Distribution

  • $V_D$ significantly impacts the half-life of a drug because:
      - Drug elimination relies on the quantity of drug delivered to organs responsible for metabolism (e.g., liver or kidney) per unit time.
      - Delivery depends on both blood flow and the fraction of the drug present in plasma.

  • If a drug exhibits a large $V_D$, it typically means most of the drug resides in the extravascular space, thus being unavailable for excretion by metabolic organs.

  • Conclusion: Any factor that increases $V_D$ can also increase the half-life and extend the duration of action of the drug.