Once a drug has entered the bloodstream after absorption, the distribution of drug to various fluid compartments such as:
b. Interstitial fluid compartment (extracellular fluid space).
c. Transcellular fluid compartment, e.g. fluid in the gastrointestinal tract, bronchi, CSF.
d. Cellular fluid compartment (intracellular fluid compartment).
Every drug is distributed throughout the tissues of the body that initially has no drug. At this stage, concentration gradient is in the direction of plasma to tissues. The extent of distribution of drug depends on many factors such as:
• Lipid solubility.
• Ionization at physiological pH.
• Extent of binding to plasma and tissue proteins.
• Difference in regional blood flow.
Finally equilibrium is reached between unbound drug in plasma and tissue fluids and distribution of drug is stopped. Some drugs pass into the cell, some remain on the cell membrane and some may be distributed extracellularly. Lipid insoluble drugs do not enter cells. Drugs extensively bound to plasma proteins are largely restricted to the vascular compartments.
When highly lipid soluble drugs are given intravenously or by inhalation, they initially get distributed to organs with rich blood supply such as brain, heart, kidney, etc. Later on less vascular but more bulky tissues (muscle, fat) take up the drug and plasma concentration falls. Due to this, drug is withdrawn from these organs with high blood flow thus letting the distribution of drug take place.
If the site of action of the drug is in one of the highly perfused organs, redistribution results in termination of drug action (e.g. thiopentone). However, on repeated or continuous administration of drug for the proper distribution of drug, the low perfusion high capacity sites get progressively saturated and the drug becomes longer acting.
Volume of distribution of drug
Distribution of drug in tissues determines the biological activity. The extent of distribution of drug can be assessed by a convenient mathematical concept, assuming that the drug is homogenously distributed throughout the body.
More precise multiple compartment models for distribution of drug have been worked out, but the single compartment model, described above, is simple and fairly accurate.
Blood-brain and blood-CSF barrier: The endothelial cells of the capillaries of the brain and the cerebrospinal axis has tight interendothelial junctions and do not have intercellular pores or gaps. Also a sheet of glial cells lines these capillaries. So water soluble drugs cannot filter into CSF or brain. Drugs can either be transported into these areas by diffusion or by carrier mediated transport.
Hence they allow the entry of lipoidal drugs while a large number of non-lipoid soluble drugs do not cross these barriers and have no central effect. However, this barrier is absent in hypothalamus, pineal gland, and the area postrema. So the distribution of drug takes place when all circulating drugs come in contact with the vomiting centre and CTZ (chemoreceptor trigger zone) and may then initiate centrally mediating vomiting.
Placental barrier: A layer of trophoblastic cells in the chorionic villi separate the maternal and fetal bloodstreams. This lipid barrier allows the passage of lipid soluble drugs into fetal circulation by diffusion while water soluble drugs or essential nutrients cross the placental barrier by carrier mediated transport system. Placental transfer depends on:
• Properties of the drug.
• Evolving properties of the placenta.
• Altered maternal blood levels which are controlled by changing pharmacokinetics of pregnancy.
The knowledge of passage of drugs through placental barrier is important in a pregnant woman, because some drugs may have teratogenic properties and so are contra-indicated during pregnancy. Further, one has to be careful in administering drugs to the mother at the lime of delivery because they may have adverse effect on the physiology of the newborn.
Plasma protein binding: After absorption, the distribution of drug takes place when drug circulates in the blood either in the free form or bound to plasma proteins. Drugs may reversibly bind to nonspecific non-functional sites on plasma proteins which serve no biological effect. Affinity of most drugs for plasma proteins depends on their physico-chemical properties as well as on the concentration of binding protein in the plasma.
Thus, in pregnancy, the protein bound fraction of substances such as thyroxine increases due to a rise in the concentration of the specific binding protein in plasma. Conversely, free fraction of the drug is increased due to low plasma proteins in a patient of hypoproteinaemia for distribution of drug. Acidic and neutral drugs bind to albumin fraction, e.g. salicyhtes, diazepam, phenytoin, warfarin.
Basic drugs bind to orsomucoid (alfa-2-acid glycoprotein), lipoprotein, and beta-globulin. Examples of such drugs are lidocaine, propranolol and quinidine. Usual figures of percentage binding refer to the usual therapeutic plasma concentration of a drug.
Clinical significance of plasma protein binding:
• Binding of drugs to plasma proteins assists absorption.
• Protein binding acts as temporary ‘store’ of a drug. It, therefore, prevents large fluctuations in concentration of unbound drug in the body fluids.
• Protein binding reduces diffusion of the drug into the cell. So it delays its metabolic degradation and excretion.
• Highly plasma protein bound drugs are largely restricted to the vascular compartment. So it will have lower volume of distribution of drug.
• Figures of plasma concentrations of the drug refer to bound as well as free drug. Bound fraction is not available for action. While prescribing any new drug such as an antibacterial agent claimed to have higher and longer plasma concentration than a previously available drug, one should ascertain the degree of protein binding. With extensively protein bound drugs, the therapeutic activity may be low.
• Various drugs get bound to the same binding sites on plasma proteins. This may lead to displacement interactions among drugs bound to the same site. Due to this sudden increase in the free concentration of one of them may occur to a dangerous toxic level.
Drug storage: After administration of a single dose of a drug, the distribution of drug may not be proper and it may accumulate in specific organ or get bound to specific tissue constituents even when its plasma concentration is reduced to low or undetectable levels. For example, digoxin is accumulated in skeletal muscle, heart, liver and kidney.
Many lipid soluble drugs are stored in the body fat depots such as thiopentone, DDT, ether, etc. Although the effect of a drug is mainly terminated by bio transformation and excretion, it may also result from re distribution of drug from its site of action into other tissues or sites.
[Source: Principles of Pharmacology for Dental Students]