Distribution Of Drugs

Distribution in pharmacokinetics refers to the reversible movement of a medication from one part of the body to another. A medication needs to be dispersed into intracellular and interstitial fluids after it is directly administered or absorbed and goes into systemic circulation. Once a medication enters the bloodstream, it is dispersed to tissues that were not previously receiving it; this is known as the concentration gradient, which indicates the direction of plasma distribution to tissues.

Table of Contents

A drug’s distribution pattern and extent are determined by its:
Solubility in lipids, the degree of binding to tissue proteins and plasma, the ionization at physiological pH (a function of its pKa), the existence of tissue-specific transporters and variations in local blood flow.

Apparent volume of distribution (V) = dose administered i.v. / plasma concentration.

Distribution involves dilution, binding, and sequestration. The drug can be given in different doses to each organ or tissue, and it can stay in each organ or tissue for a different length of time. Vascular permeability, local blood flow, cardiac output, tissue perfusion rate, drug ability to bind tissue and plasma proteins, and drug lipid solubility all affect how a drug is distributed among tissues.

The pH partition is also very important. Organs with high perfusion, such as the liver, heart, and kidney, readily absorb the medication. Smaller amounts of it are found in less perfused tissues like muscle, fat, and peripheral organs.

Factors affecting drug distribution

Redistribution

Redistribution is the term used to describe the process by which highly lipid-soluble medications lose their ability to function. These medications are first distributed to organs with high blood flow, such as the kidney, heart, and brain, when administered intravenously or by inhalation. Drug action is terminated by redistribution if the drug’s site of action was in an organ with high blood flow.

Subsequently, the medication is taken up by bulkier, less vascular tissues (fat, muscles), which causes the drug’s plasma concentration to drop and its removal from these areas. Greater the lipid solubility of drug, faster is its redistribution.

Penetration into brain and CSF

The brain’s capillary endothelial cells lack wide paracellular gaps and have tight junctions. Moreover, the capillaries are covered in neural tissue. They collectively make up the so-called blood-brain barrier (BBB). In the choroid plexus, where capillaries are lined with choroidal epithelium with tight junctions, there is a similar blood-CSF barrier. These two lipoidal barriers prevent nonlipid soluble medications from entering.

Only lipid-soluble drugs, therefore, are able to penetrate and have action on the central nervous system. Dopamine does not enter in the brain but, levodopa, the precursor of dopamine, enters the brain and is used in parkinsonism. However, drug exit from the CSF and brain is rather unrestricted and is not dependent on lipid-solubility.

Tissue storage

Drugs can accumulate in specific organs through active transport or be bound to specific tissue constituents.

Passage across placenta

Placental membranes are lipoidal in nature and allow free passage of lipophilic drugs while restricting hydrophilic drugs to cross placental membranes. Drug metabolism occurs in the placenta as well, which may reduce or alter the amount of the drug that is given to the foetus. On the other hand, a limited quantity of nonlipid-soluble medications can enter the foetus when they are in the mother’s bloodstream for extended periods of time or in high concentrations.

Placenta is an incomplete barrier because of some influx transporters also operate at the placenta and almost any drug taken by the mother can affect the foetus or the newborn.

Plasma Protein Binding

The majority of medications have a physicochemical affinity for plasma proteins and form reversible bonds with them. Generally, basic drugs bind to α1 acid glycoprotein, while acidic drugs bind to plasma albumin. Binding to albumin is quantitatively more important. Drugs can progressively saturate the binding sites at higher concentrations; when high doses of the drug are administered, fractional binding may be reduced. The generally expressed percentage binding refers to the usual therapeutic plasma concentrations of a drug.

The following are the clinically relevant effects of plasma protein binding-

Highly plasma protein bound drugs cannot cross membranes because they are primarily limited to the vascular compartment.

There is nothing that can be done with the bound fraction. On the other hand, it is in balance with the free drug in plasma and separates when the latter’s concentration drops as a result of elimination. Thus, plasma protein binding relates to the drug being temporarily stored.

Drugs with high protein binding typically have a longer half-life as the bound fraction cannot be metabolized or excreted unless actively extracted by the liver or kidney tubules.

A drug can bind to multiple sites on the albumin molecule. Alternatively, multiple drugs can bind to the same site. Drugs bound to the same site may interact, causing displacement. Drugs with higher affinity will displace those with lower affinity.

Summary

Drug distribution is the process by which drugs move from the bloodstream to various tissues in the body, especially those where their actions are needed. After absorption into the systemic circulation, drug molecules equilibrate between the vascular compartment and other body compartments, including interstitial and intracellular spaces. Factors influencing drug distribution affect the rate and delivery of drugs to different organs. Rapid distribution often occurs, and it significantly impacts the extent of a drug’s action. Maintaining an optimal concentration in the plasma is essential for therapeutic effectiveness, while excessively high levels may lead to toxic effects.

Distribution of Drugs