Saturday, April 09, 2005

The extent of the distribution of drugs into tissues depends on binding to plasma proteins and tissue components.

This article has been published by the International Biopharmaceutical Association www.ibpassociation.org

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After a drug enters the general circulation, it distributes throughout the body's tissues. Distribution is generally uneven because of differences in binding in tissues, regional variations in pH, and differences in the permeability of cellular membranes.
Binding Components
The extent of the distribution of drugs into tissues depends on binding to plasma proteins and tissue components.
Plasma protein binding: Drugs are transported in the bloodstream partly in solution (as free drug) and partly bound to various blood components ( plasma proteins and blood cells). Many plasma proteins can interact with drugs. Albumin, alpha1-acid glycoprotein, and lipoproteins are the most important ones. Acidic drugs are generally bound more extensively to albumin, while basic drugs often are more extensively bound to either one or both of the latter 2 proteins.
Because only the unbound form is available for passive diffusion to the extravascular or tissue sites where pharmacologic effects occur, plasma protein binding influences the distribution and apparent relationship between pharmacologic activity and plasma (total) drug concentration.
The fraction unbound (Fu) is often more useful than the fraction bound.
Tissue Binding
The substances to which drugs bind in tissue are highly varied. Often these substances are not proteins. Furthermore, they may be very specific, as is the case for the binding of chloroquine to nucleic acids. Tissue binding usually involves an association of drug with a macromolecule within an aqueous environment. Another kind of association that results in apparent tissue binding is partitioning of drug into body fat.
Drug reservoir: Accumulation of drugs in tissues or body compartments can prolong drug action because the tissues serve as depots.
Some drugs accumulate in cells in higher concentrations than those in Extra Cellular Fluid (ECF). Such accumulation most commonly involves binding of drugs with protein, phospholipids, or nucleic acids.
Passage of drugs into the Central Nervous System (CNS) takes place in the capillary circulation and the Cerebro Spinal Fluid (CSF). Although the brain receives a large proportion of the cardiac output (about 1/6), distribution of drugs to brain tissue is restricted. While some lipid-soluble drugs (e.g., thiopental) do enter and exert their pharmacologic effects rapidly, many drugs, particularly the more water-soluble agents, enter the brain slowly. Another important barrier to water-soluble substances is the close approximation of the glial connective tissue cells (astrocytes) to the basement membrane of the capillary endothelium. The capillary endothelium and the astrocytic sheath together are referred to as the blood-brain barrier.
DRUG ELIMINATION
The sum of the processes of drug loss from the body. Removal of drugs from the body occurs by metabolism and excretion.
METABOLISM
The process of chemical alteration of drugs in the body. The liver is the principal, but not the sole, site of drug metabolism. Some metabolites are pharmacologically active. When the substance administered is inactive and an active metabolite is produced, the administered compound is called a pro-drug.
Changes with Age
Neonates have partially developed liver microsomal enzyme systems and, consequently, have difficulty with the metabolism of many drugs. Elderly patients often show a reduced ability to metabolize drugs. The reduction varies depending on the drug and is not as severe as that in neonates.
Individual Variation
Variability among individuals makes it difficult to predict the clinical response to a given dose of a drug. Some patients may metabolize a drug so rapidly that therapeutically effective blood and tissue levels are not achieved; in others, metabolism may be so slow that toxic effects result with usual doses. Concurrent disease states, particularly chronic liver disease, drug interactions, especially those involving induction or inhibition of metabolism, and other factors also contribute.


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