Distribution refers to the reversible transfer of a drug from the bloodstream into the interstitial space and the cells of body tissues. Once a drug enters the systemic circulation, it is carried throughout the body and begins to move into various compartments. The extent and pattern of distribution determine which tissues are exposed to the drug and at what concentrations, directly influencing both therapeutic and adverse effects.
Apparent Volume of Distribution
The apparent volume of distribution (Vd) is a theoretical concept that relates the total amount of drug in the body to the concentration measured in plasma. It is not a real physiological volume but rather an indication of how extensively a drug distributes into tissues. A low Vd, typically below the volume of total body water (approximately 42 L in a 70 kg adult), suggests that the drug remains largely within the plasma or extracellular fluid. A high Vd, exceeding total body water, indicates extensive tissue binding and sequestration. For example, digoxin has a Vd of approximately 500 L, reflecting its extensive binding to cardiac and skeletal muscle tissue.
Plasma Protein Binding
Once in the bloodstream, many drugs bind reversibly to plasma proteins. Albumin is the most abundant plasma protein and binds primarily acidic drugs, while alpha-1-acid glycoprotein binds basic drugs. Only the unbound or free fraction of a drug can cross membranes and reach its site of action. Protein binding therefore acts as a reservoir: as free drug is eliminated, bound drug dissociates to maintain equilibrium. Changes in protein levels due to disease, pregnancy, or malnutrition can alter the free fraction and affect drug distribution and activity.
Tissue Binding and Redistribution
Drugs may accumulate in specific tissues through binding to intracellular proteins, nucleic acids, or lipids. Highly lipophilic drugs such as thiopental readily partition into adipose tissue, where they can be stored and slowly released. This phenomenon contributes to redistribution, where a drug initially distributes to highly perfused organs like the brain and heart, producing rapid onset of effect, and then redistributes to less perfused tissues like fat and muscle, terminating the effect. Redistribution is a key concept for understanding the duration of action of many anesthetic agents.
Barriers to Distribution
Several anatomical barriers restrict drug distribution to certain organs. The blood-brain barrier consists of tight junctions between capillary endothelial cells in the central nervous system, preventing the passage of polar and large-molecular-weight drugs. Only small, lipophilic molecules can cross the blood-brain barrier by passive diffusion, while others require active transport mechanisms. P-glycoprotein efflux transporters at the blood-brain barrier further restrict entry by pumping drugs back into the bloodstream.
The placental barrier separates maternal and fetal circulations. Most drugs cross the placenta by passive diffusion, and lipid solubility, molecular weight, and degree of ionization determine the extent of transfer. This has critical implications for drug therapy during pregnancy, as many drugs can reach the fetus and potentially cause harm.
Factors Affecting Distribution
Multiple factors influence how a drug distributes throughout the body. Perfusion rate determines how quickly a drug reaches different organs, with highly perfused tissues like the liver, kidneys, brain, and heart receiving drug rapidly. Capillary permeability varies between tissues and affects drug exit from the bloodstream. The physicochemical properties of the drug itself, including lipid solubility, molecular size, and ionization state at physiological pH, govern its ability to cross membranes. Binding to plasma proteins and tissue components further modifies distribution patterns. Age, body composition, pregnancy, and disease states all introduce variability that must be considered in clinical practice.
A thorough understanding of drug distribution allows clinicians to predict which tissues will be exposed, estimate the appropriate loading dose, and anticipate potential drug interactions arising from protein binding displacement.
