Distribution of drugs

Definition:

A reversible process of drug movement in which drug travels from the blood stream to enter the extracellular fluid and tissues is called distribution of drugs.

Factors effecting drug distribution:

Drug distribution occurs differently for different dosage forms. Administering a drug in IV formulation, distribution is not an important factor to consider as the drug rapidly moves from circulation into the tissues in the initial phase. Drug distribution is mainly effected by cardiac output, blood flow and permeability of the capillaries, degree of binding with proteins, and hydrophilic and lipophilic properties of drugs. Each of these factors is discussed below in detail:

Rate of Blood flow:                  

Various organs receive varying degree of blood depending upon their needs and the functions they perform. For instance, brain, liver and kidneys are more perfused organs of the blood as compared to skeletal muscles. Similarly, skin, adipose tissues and visceral organs receive much less amount of blood. The short hypnosis produced by IV bolus of propofol can be clearly explained by this variation in blood flow rates. The rapid anesthesia produced by propofol is due to its high lipophilicity which allows its quick distribution into the CNS. Comparatively, the drug distributes much slower in the skeletal muscles, lowering its plasma concentration. The slow diffusion of the drug outside the CNS down the concentration gradient allows the patient to regain consciousness.

Capillary permeability:

Capillary structure of the cells of different organs varies owing to the difference in capillary permeability to various molecules. In the liver, the slit junction of the basement membrane of capillaries is large and exposed, allowing bigger molecules to pass through. Whereas in the brain, the continuous capillary structure has no slit junctions. For entrance into the brain, passage of drug through the endothelial cells of the capillaries or active transport is required. Lipid insoluble drugs such as Levodopa are carried into the CNS through a carries whereas lipid soluble drugs penetrate the CNS by dissolving into the endothelial cell membrane. The inability of ionized or polar drugs to pass through endothelial cells prevents their entry into the CNS. The blood brain barrier is also formed by the close and tight juxtaposition of these endothelial cells.

Drug binding to plasma proteins and tissues:

Plasma protein binding:

If a drug binds reversibly to plasma proteins, it is converted into nondiffusible form and thus its transfer from the vessels slows down. Albumin is the major drug binding protein. It maintains a constant fraction of free drug concentration in the blood plasma.

Binding to tissue proteins: 

Many drugs tend to accumulate in the tissues which lead to their increased concentration in tissues as compared to blood and ECF. This accumulation may be due to binding with any biological molecule or active transport of drugs in the tissues. Tissues may become reservoirs of drug which prolongs their action and sometimes it may cause local toxicity.

Lipophilicity:

The ability of drugs to cross cell membranes is largely dependent on their chemical nature. Lipophilic drugs move readily across the membranes due to their ability to dissolve in the lipid bilayer. In contrast, hydrophilic drugs cannot penetrate the lipid bilayer and require entry through the slit junctions.

Volume of distribution:

The volume of fluid required to maintain the concentration of entire drug in the body same as the concentration of drug in the plasma is known as apparent volume of distribution. It is a useful  method to compare the rate of drug distribution with the volume of water compartments (i.e. plasma,ECF and total body water).