Principles of Drug Distribution
The distribution of a drug throughout the body depends directly on its ability to cross biological membranes and histohematic barriers. The primary determinants are the physicochemical properties of the molecule:
- Lipophilicity (lipid solubility): Lipophilic, nonpolar compounds distribute most widely, penetrating all body water compartments (intracellular, extracellular, and transcellular fluids).
- Hydrophilicity (water solubility).
The pattern of distribution is also influenced by the structural and biochemical characteristics of tissue barriers themselves.
Mechanisms of Sequestration
During distribution, drugs may be retained and accumulated—sequestered. Biochemically, this is explained by the reversible binding of drug molecules to cellular proteins (proteinae), phospholipids, and nucleoproteins.
The choice of "storage depot" depends on the nature of the substance:
- Connective tissue — accumulates polar compounds.
- Adipose tissue (textus adiposus) — a storage depot for lipophilic drugs (e.g., the general anesthetic thiopental).
- Target organs — certain drugs concentrate in specific organs. For example, chloroquine accumulates in the liver (hepar), reaching concentrations a thousand times higher than in plasma.
Plasma Protein Binding
This is the primary form of intravascular sequestration. Drugs form reversible complexes (via hydrogen and van der Waals bonds) with various carrier proteins:
- Albumins — bind weakly acidic drugs (NSAIDs, sulfonamides).
- $\alpha_1$-Acid glycoprotein — binds weak bases.
- Specific proteins — transcortin (for glucocorticoids), transferrin (for iron preparations — Ferrum).
The drug-protein complex acts as a reservoir. The complex molecule is too large to cross the vascular endothelium to target cells; therefore, the bound fraction is pharmacologically inactive. Only the free, unbound molecule is active. When the concentration of free drug in plasma drops, the complex dissociates, releasing new portions of the drug.
Clinical Significance: Effects and Toxicity
Sequestration affects pharmacodynamics and pharmacokinetics, leading to various clinical scenarios.
Therapeutic Action: Selective accumulation can be beneficial. Iodine (Iodum) concentrates in the thyroid gland (glandula thyroidea) for hormone synthesis, while fluoride (Fluorum) concentrates in bones and teeth.
Prolongation and Post-Effect: Drugs slowly exit storage depots into the blood, prolonging their duration of action. For example, thiopental rapidly induces anesthesia (by accumulating in the brain) and then redistributes into adipose tissue. Its slow return to the bloodstream causes post-anesthetic sleep and CNS depression.
Toxicity: Tetracyclines bind to calcium (Calcium) and accumulate in bones and teeth. This causes skeletal malformations in the fetus (during intrauterine development) and dental enamel hypoplasia/discoloration in children; thus, they are contraindicated in pregnant women and children under 8 years of age.
Drug Interactions: Protein binding is often nonspecific. If two drugs competing for the same protein binding sites are administered simultaneously, the drug with higher affinity displaces the other. This sharply increases the free (active) fraction of the displaced drug, risking severe toxicity. For example, sulfonamides (Sulfanilamida) displace the anticoagulant warfarin (Warfarinum), significantly increasing the risk of massive bleeding due to decreased blood clotting.