Pharmacology: Drug Distribution Process

Drug Distribution

• Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues.
• The delivery of a drug from the plasma to the interstitium primarily depends on:
  • Blood flow
  • Capillary permeability
  • The degree of drug binding to plasma proteins
  • The relative hydrophobicity of the drug

Factors Affecting Drug Distribution

• Blood flow:
  • The rate of blood flow to tissues varies widely due to the unequal distribution of cardiac output to the various organs.
  • Blood flow to the brain, liver, and kidney is greater than that to the skeletal muscles, most viscera, skin, and fat.
• Capillary permeability:
  • Capillary structure varies widely in different tissues.
  • In the brain, the capillary structure is continuous, and there are no slit junctions.
  • In the liver and spleen capillaries, a large part of the basement membrane is exposed due to large fenestrations that allow drugs to exchange freely between blood and interstitium.
• Drug binding to plasma proteins:
  • Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows their transfer out of the vascular compartment.
  • Plasma albumin is the major drug-binding protein and may act as a drug reservoir.

Redistribution

• The process by which a drug is rapidly distributed to highly perfused tissues and then slowly redistributed to less perfused tissues, resulting in a decrease in plasma concentration.

Volume of Distribution

• The volume of distribution is a hypothetical volume of fluid into which a drug is dispersed.
• Water compartments in the body:
  • Plasma compartment (6% of the body weight)
  • Extracellular fluid (20% of the body weight)
  • Total body water (60% of body weight)
  • Other sites (e.g. fetus in pregnancy, lipid-soluble drugs)

Half-Life (t1/2)

• The time required to change the amount of drug in the body by one-half.
• The time it takes for the concentration of a drug in the plasma to drop by half from the peak concentration.

Steady State

• A state at which drug intake equals drug clearance.
• Reached after 4-5 half-lives of a drug.

Dosage Regimen

• A dosage regimen must be designed to reach a steady state, such that the plasma and tissue levels remain constant in the case of IV administration and fluctuate around a mean in the case of oral fixed dosage.
• Generally, a drug will reach the steady state in about 4 half-lives.

Maintenance Dose

• The dosage regimen that maintains a steady-state concentration.
• Takes four to five half-lives of a drug.

The process of drug distribution from the bloodstream to interstitium and cells, factors affecting it, and its relevance to pharmacology.