Pharmacology Drug Distribution

Drug distribution

• After uptake, drugs are distributed to different tissues and body fluids: Plasma, interstitial fluid, intracellular fluid.
• Four patterns of drug distribution:
  • Single compartment (intravascular):
    • Drug stays in the blood compartment.
    • Examples: Heparin, dextran.
    • These drugs bind to plasma protein.
  • Two compartments (intravascular + interstitial):
    • Drugs cross capillary walls but not cell membranes.
    • Localized in extracellular fluid.
    • Examples: Insulin, quaternary ammonium compounds, electrolytes.
  • Multi-compartment (extracellular + intracellular):
    • Drugs can pass through cell membranes, are lipid-soluble, and have low molecular weight.
    • Examples: Barbiturates, tertiary amines.
  • Tissue reservoirs:
    • Some drugs accumulate in specific tissues.
    • Examples:
      • Hair: Arsenic
      • Thyroid: Iodine
      • Bone: Calcium
      • Fat: Thiopental
      • Liver: Chloroquine

Apparent Volume of Distribution (Vd)

• Vd is a term used to quantify how a drug distributes between plasma and the rest of the body.
• It represents a hypothetical volume where the drug is distributed to reach the estimated concentration.
• Vd can be calculated: Vd = Total amount of drug in the body / Plasma concentration of the drug.
• The amount of drug in the body can be estimated: M = Vd x C
• Factors affecting Vd:
  • Increased Vd: Renal failure (fluid retention), liver failure (increased body fluid, decreased plasma protein binding).
  • Decreased Vd: Dehydration.
• Relationship between Vd and drug binding:
  • High plasma protein binding: Small Vd.
  • High tissue protein binding: High Vd.
  • Digoxin has a slow clearance and does not require dialysis due to its low Vd.

Drug Binding to Plasma Proteins

• Most drugs bind to plasma proteins reversibly.
• Albumin is the major binding protein.
• Bound fraction:
  • Pharmacologically inactive.
  • Not active.
  • Not filtered.
  • Not metabolized.
  • Not excreted.
  • Serves as a drug depot.
• Free fraction:
  • Active.
  • Filtered.
  • Metabolized.
  • Excreted.
• Examples of drugs extensively bound to plasma proteins:
  • Phenylbutazone.
  • Dicoumarol.
  • Tolbutamide.
  • Long-acting sulfonamides.
  • Thiopental.
  • Diazoxide.

Drug Interactions Related to Plasma Protein Binding

• Aspirin, phenytoin, sulfonamides can displace drugs from their protein binding sites, leading to:
  • Increased free drug concentration.
  • Increased risk of adverse effects.
  • Examples:
    • Oral anticoagulants (e.g., Warfarin): Hemorrhage.
    • Oral hypoglycemic agents (e.g., Tolbutamide): Hypoglycemia.
    • Bilirubin in newborns: Jaundice and kernicterus.

Passage of Drugs to the Central Nervous System (CNS)

• Blood-brain barrier (BBB) limits drug entry to the CNS.
• BBB is a lipid barrier composed of:
  • Brain capillary endothelium: Lacks water channels.
  • Adjacent glial tissue.
• Only lipid-soluble (non-ionized) drugs can pass the BBB along their concentration gradient.
• Inflammation (meningitis, encephalitis) increases BBB permeability, allowing agents like penicillin to enter the CNS.
• BBB characteristics:
  • Tight junctions: High electrical resistance, preventing ion passage.
  • No fenestrae (pores).
  • Minimal pinocytosis.
  • Only water, small lipophilic molecules, and actively transported substances can cross.
  • Brain capillary endothelial cells have 2-4 times more mitochondria than other endothelial cells to maintain electrochemical gradients and tight junctions.

Passage of Drugs to the Fetus

• Lipid-soluble (non-ionized) drugs can cross the placental barrier.
• Drugs that pass the placenta poorly:
  • Water-soluble drugs.
  • Drugs with high molecular weight.
  • Drugs actively transported out of the fetus.