How distribution occurs
The distribution of a drug substance throughout the body directly depends on its ability to cross biological membranes and histohematic barriers. The physicochemical properties of the molecule play a major role in this:
- Lipophilicity (ability to dissolve in fats). Lipophilic non-polar compounds are distributed most widely, penetrating all aqueous compartments (intracellular, extracellular, and transcellular fluids).
- Hydrophilicity (water solubility).
The pattern of distribution is also influenced by the structural and biochemical features of the tissue barriers themselves.
Mechanisms of deposition
During distribution, drugs may be retained and accumulate—they undergo deposition. Biochemically, this is explained by the reversible binding of drug molecules to cellular proteins (proteinae), phospholipids, and nucleoproteins.
The choice of "storage site" depends on the nature of the substance:
- Connective tissue — accumulates polar compounds.
- Adipose tissue (textus adiposus) — a depot for lipophilic substances (e.g., the general anesthetic sodium thiopental).
- Target organs — some 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 type of deposition within the vascular bed. 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 — for 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 pass through the vascular endothelium to target cells, therefore the bound fraction is pharmacologically inactive. Only the free molecule is active. When the concentration of the free substance in plasma drops, the complex dissociates, releasing new portions of the drug.
Clinical significance: effects and toxicity
Deposition affects the pharmacodynamics and pharmacokinetics of drugs, creating various clinical scenarios.
Therapeutic effect: Selective accumulation can be beneficial. Iodine (Iodum) concentrates in the thyroid gland (glandula thyroidea) for hormone synthesis, while fluorine (Fluorum) concentrates in bones and teeth.
Prolongation and after-effect: The substance is slowly released from the depot into the blood, prolonging the duration of action. For example, sodium 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 prenatal development) and dental impairment in children, which is why they are contraindicated in pregnant women and children under 8 years of age.
Drug interactions: Protein binding is often non-specific. If two drugs competing for the same protein binding sites are administered simultaneously, the drug with higher affinity will displace the other. This sharply increases the fraction of the free (active) displaced drug, which can lead to intoxication. For example, sulfonamides (Sulfanilamida) displace the anticoagulant warfarin (Warfarinum), drastically increasing the risk of massive hemorrhages due to reduced blood clotting.
Briefly: answers to topical questions
What are the main histohematic barriers through which drug substances penetrate?
The main histohematic barriers mentioned in the sources include the endothelial barrier and specialized barriers.
- Endothelial barrier — the wall of peripheral tissue vessels; there are large gaps between endothelial cells.
- Blood-brain barrier (barriera haematoencephalica) — the barrier of cerebral blood vessels, formed by endothelial cells with tight junctions.
- Blood-placental barrier — a selective transport system separating the maternal and fetal blood supplies.
- Blood-ocular barrier — restricts the penetration of hydrophilic polar substances into ocular tissues.
- Blood-testicular barrier — restricts the penetration of hydrophilic polar substances into the gonads.
- Blood-air barrier — the barrier of lung tissue.
What physicochemical properties of a molecule, besides lipophilicity and hydrophilicity, determine its permeability across biological membranes?
In addition to lipophilicity and hydrophilicity, a molecule's permeability across biological membranes is determined by its size and degree of ionization.
- Degree of ionization — determines the ability to cross membranes, as the non-ionized form easily passes through them, while the ionized form does not. This parameter depends on the acid dissociation constant and the pH of the medium.
- Molecular size — high-molecular-weight compounds and large complexes (e.g., a drug-protein complex) cannot cross cell membranes and intercellular clefts because their size exceeds the pore diameter.
Class and exam questions
Why does the plasma protein-bound fraction of a drug have no pharmacological effect?
The drug-protein complex is a large molecule incapable of penetrating intercellular endothelial clefts and cell membranes. Therefore, it does not reach receptors and remains inactive.
How does deposition affect drug elimination?
The drug-protein complex cannot penetrate hepatocytes for biotransformation and is not filtered in the renal glomeruli. This slows down metabolism and excretion, prolonging the drug's action.
In what cases is the displacement of a drug from protein binding clinically insignificant?
It is insignificant if the original drug is bound to proteins by less than 90%, if the displacement process is slow (the body has time to eliminate excess), or if tissues actively uptake the free substance, acting as a buffer.
What else to study on this topic
- Mechanisms of penetration across the blood-brain and placental barriers
- Features of the distribution of hydrophilic polar compounds
- Factors affecting plasma protein concentrations in pathological states
- Mathematical modeling of pharmacokinetic compartments
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