Influence of hemodynamics and blood supply
The most critical condition upon which the delivery of pharmacological agents to tissues depends is the hemodynamic factor. The rate of organ saturation is directly proportional to the intensity of its regional blood flow.
First, the drug reaches the so-called well-vascularized organs. These include the heart (cor), lungs (pulmones), liver (hepar), kidneys (renes), and brain (cerebrum). Therapeutic concentrations are established here as quickly as possible.
Conversely, tissues with a relatively poor blood supply become saturated slowly. This group includes subcutaneous tissue, adipose tissue, and bone tissue. In addition, the chosen 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
Leaving the systemic circulation, molecules pass from plasma into interstitial fluid. This process is made possible by the anatomical features of the capillary network: a huge total endothelial surface area and a 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) of the endothelium. The process occurs via filtration driven by hydrostatic pressure. Because hydrophilic molecules poorly penetrate inside cells, their distribution in the body is uneven: they remain predominantly in the extracellular space (in plasma and interstitium).
- Lipophilic (non-polar) substances cross endothelial cell membranes transcellularly. They move via passive diffusion along a concentration gradient. Due to their lipid solubility, they easily enter both extracellular and intracellular fluid, distributing relatively evenly.
Effect of pH and the "ion trap" phenomenon
For weak electrolytes, the most critical parameter is the degree of their ionization. Biological membranes are permeable mainly to non-ionized (lipophilic) forms. Since extracellular fluid has a pH of about 7.4 and intracellular fluid has a more acidic environment (pH of about 7.0), distribution depends on the acid-base properties of the substance.
- Weak acids (with a pKa below 8.0) are ionized more strongly at physiological pH 7.4, which causes them to penetrate membranes worse and remain outside cells.
- Weak bases (with a pKa above 6.0) retain a sufficient proportion of the non-ionized form at pH 7.4, allowing them to penetrate the intracellular space.
A striking clinical example is the local anesthetic lidocaine, which is a weak base (pKa = 7.8). In its non-ionized form, it penetrates the axon membrane. Upon entering the more acidic cytoplasm, the molecule is partially ionized, turning into a cation. The charged form can no longer leave the cell. An "ion trap" is created, causing the drug to accumulate inside and reliably block sodium channels.
Plasma protein binding
While in the vascular bed, drug molecules form reversible complexes with plasma proteins. Albumins (albumina) most frequently play this role.
The formation of the drug-protein complex temporarily deprives the drug of activity. Such pharmacological inertness is explained by the fact that the bound fraction is unable to interact with receptors. Moreover, the large size of the protein molecule imposes strict limitations on transport: the complex does not pass through the capillary endothelium, does not cross histhematic barriers, and does not leave the vascular bed. For the same reason, bound substances do not undergo glomerular filtration in the renal glomeruli.
Briefly: answers to topical questions
Which blood plasma proteins are involved in the binding and transport of drug substances?
Albumin is predominantly involved in the binding and transport of drug substances.
- Albumins (albumina) are the main transport proteins of blood plasma, forming reversible complexes with drug substances.
The protein-bound fraction of the drug is pharmacologically inert: it does not interact with receptors, produces no effect, does not leave the vascular bed, and is not filtered in the renal glomeruli due to the large size of the protein molecule.
What histhematic barriers exist along the pathway of drug distribution?
The following histhematic barriers exist along the pathway of drug distribution:
- Blood-brain barrier (barriera haematoencephalica) — prevents the penetration of hydrophilic polar substances into the brain due to tight junctions between endothelial cells.
- 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.
- Placental barrier — limits the penetration of hydrophilic polar substances to the fetus.
Which pharmacokinetic parameters are used to quantitatively assess drug distribution?
The apparent volume of distribution ($V_d$) is used to quantitatively assess the distribution of drug substances.
- Apparent volume of distribution ($V_d$) is a hypothetical value reflecting the volume of fluid required to dissolve the entire amount of the drug in the body to a concentration equal to that in blood plasma.
What pathological conditions or factors can alter the degree of drug binding to plasma proteins?
The degree of drug binding to plasma proteins can change in hypoalbuminemia and competitive drug interactions.
A decrease in albumin level leading to impaired binding is observed in:
- Inflammatory processes;
- Liver lesions (cirrhotic type with impaired synthetic function);
- Kidney lesions (nephrotic syndrome with urinary protein loss).
Binding is also disrupted during concurrent administration of multiple drugs due to competition for binding sites on plasma proteins, when one substance displaces another, increasing the concentration of its free fraction.
Remember the rule of protein binding: "Bound means locked." As long as a drug molecule is bound to plasma albumin, it is pharmacologically inactive, does not interact with receptors, and cannot be filtered in the kidneys.
Class and exam questions
How do hydrophilic drugs penetrate the capillary wall?
They pass through intercellular endothelial clefts via filtration driven by hydrostatic pressure. At the same time, they penetrate poorly into cells.
What is the essence of the "ion trap" effect?
This is a process in which a non-ionized molecule enters a compartment with a different pH (e.g., a more acidic intracellular environment), becomes ionized there, and loses the ability to pass back through the lipid membrane, accumulating inside.
Does a drug bound to a plasma protein produce a pharmacological effect?
No, the protein-bound fraction of a drug substance is pharmacologically inert. It does not bind to receptors and cannot leave the bloodstream due to the large size of the complex.
What else to study on this topic
- The concept of the partition coefficient and its effect on pharmacokinetics.
- Physiological mechanisms of renal glomerular filtration of drugs.
- Structure and permeability of specific histhematic barriers.
- Patterns of passive diffusion along a concentration gradient.
- Effect of the route of administration on the initial concentration of a substance in the blood.
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