Impact of Hemodynamics and Blood Supply
The most critical condition determining the delivery of pharmacological agents to tissues is the hemodynamic factor. The rate of organ saturation is directly proportional to the intensity of its regional blood flow.
Drugs reach well-vascularized organs first. These include the heart (cor), lungs (pulmones), liver (hepar), kidneys (renes), and brain (cerebrum). Therapeutic concentrations are established here most rapidly.
Conversely, tissues with relatively poor blood supply become saturated slowly. This group includes subcutaneous tissue, adipose tissue, and bone tissue. Additionally, the route of administration significantly affects the rate at which a substance enters the systemic circulation and its initial concentration in the body.
Mechanisms of Transcapillary Exchange
Upon leaving the systemic circulation, molecules pass from plasma into interstitial fluid. This process is enabled by the anatomical features of the capillary network: a massive total endothelial surface area and low linear blood flow velocity. The mechanism of penetration is dictated by the physicochemical properties of the drug, specifically its lipophilicity or hydrophilicity.
- Hydrophilic (polar) substances cross the barrier through intercellular clefts (gaps) in the endothelium via filtration driven by hydrostatic pressure. Because hydrophilic molecules cross cell membranes poorly, their distribution in the body is uneven: they remain primarily in the extracellular space (plasma and interstitium).
- Lipophilic (non-polar) substances cross endothelial cell membranes transcellularly via passive diffusion along a concentration gradient. Due to their lipid solubility, they easily enter both extracellular and intracellular fluids, distributing relatively evenly.
Effect of pH and the "Ion Trapping" Phenomenon
For weak electrolytes, the degree of ionization is a crucial parameter. Biological membranes are permeable mainly to unionized (lipophilic) forms. Because extracellular fluid has a pH of approximately 7.4, while intracellular fluid is more acidic (pH around 7.0), distribution depends on the acid-base properties of the substance.
- Weak acids (with a $pK_a$ below 8.0) ionize more strongly at a physiological pH of 7.4, making them less able to cross membranes and causing them to be retained outside cells.
- Weak bases (with a $pK_a$ above 6.0) retain a sufficient fraction of their unionized form at pH 7.4, allowing them to penetrate the intracellular space.
A clear clinical example is the local anesthetic lidocaine, which is a weak base ($pK_a = 7.8$). In its unionized form, it penetrates the axon membrane. Upon entering the more acidic cytoplasm, the molecule partially ionizes, converting into a cation. The charged form can no longer leave the cell. This creates an "ion trap", causing the drug to accumulate intracellularly and reliably block sodium channels.
Plasma Protein Binding
While in the vascular bed, drug molecules form reversible complexes with plasma proteins. Albumins (albumina) serve this role most frequently.
Formation of the drug-protein complex temporarily strips the drug of its activity. This pharmacological inertness occurs because the bound fraction cannot interact with receptors. Furthermore, the large size of the protein molecule imposes strict limitations on transport: the complex cannot cross the capillary endothelium, bypass blood-tissue barriers, or leave the vascular bed. For the same reason, bound substances do not undergo glomerular filtration in the renal glomeruli.