Once a drug has entered the general circulation, it is distributed in the body tissues. The distribution is uneven in general, since differences in the blood flow, tissue binding exist (eg. As a result of the fat content), the local pH and the permeability of the cell membranes.
(See also Overview pharmacokinetics.) Once a drug has entered the general circulation, it is distributed in the body tissues. The distribution is uneven in general, since differences in the blood flow, tissue binding exist (eg. As a result of the fat content), the local pH and the permeability of the cell membranes. The rate of entry of the drug into a tissue depends on the rate of blood flow to tissue, the tissue mass and the distribution characteristics between blood and tissues. At vascularized places the partition equilibrium between blood and tissue (if the entry and exit rates are equal) reached more quickly, unless the diffusion across cell membranes is the rate-limiting factor. Once equilibrium is established, the plasma concentration reflects the drug concentrations reflected in tissues and extracellular fluids. Metabolism and excretion occur simultaneously, which makes the process dynamic and complex. When a substance has entered in the tissue, the distribution rate in the interstitial fluid is determined primarily by blood circulation. In poorly perfused tissues (eg. As muscle, adipose tissue), the distribution very slowly, particularly if the fabric has a high affinity to the drug. The volume of distribution apparent volume of distribution is the theoretical volume of liquid in which the total amount of drug administered should be solved in order to achieve the plasma concentration. For example, if 1000 mg of a drug is added and the plasma concentration then determined is 10 mg / l, 1000 mg in 100 l seem to be dissolved (dose / volume = concentration of 1000 mg / xl = 10 mg / l, thus x = valid 1000 mg / 10 mg / l = 100 l). The volume of distribution has nothing to do with the actual volume of the body or its liquid compartments, but rather refers to the distribution of the drug within the body. With a pharmaceutical drug which is highly tissue-bound, comparatively little drug portion remaining in the circuit, therefore, the plasma concentration is low and volume of distribution high. Medicines that remain in circulation, tend to have a low volume of distribution. The volume of distribution provides a comparison value for the expected plasma concentration at a particular dose, but provides little information about the specific distribution pattern. Each drug is distributed individually in the body. Some medicines are distributed mainly in fat, others remain in the extracellular fluid and other bind extensively to certain tissues. Many acidic drugs (eg. As warfarin, aspirin [acetylsalicylic acid]) are highly protein bound and therefore have a low apparent volume of distribution. Many basic drugs (eg. B. amphetamine, meperidine [corresponding pethidine]) are absorbed by the tissue to a large extent and therefore have an apparent volume of distribution, which is greater than the volume of the entire body. Binding The extent of drug distribution in certain tissues depends on the degree of plasma protein and tissue binding. In the bloodstream, drugs are partially dissolved as a free (unbound) drug and partially reversibly bound to blood components (eg., Plasma proteins, blood cells) transported. Of the many plasma proteins that may interact with the drug, the main albumin, alpha-1-acid glycoprotein, and lipoproteins. Acidic drugs are usually tied to a greater extent to albumin. Basic drugs are usually bound more extensively to alpha-1-acid glycoprotein, lipoproteins, or both. Only the unbound drug is available for the passive diffusion at extravascular locations such tissue or available where carried out pharmacological reactions of the drug. Therefore, the concentration of unbound drug in the systemic circulation typically determines the drug concentration at the site of action and thus the efficacy. At high drug concentrations, the amount of the bound drug reaches an upper limit, which is determined by the number of available binding sites. A saturation of the binding sites is the base for displacement interactions among drugs (see Fig. Drug-receptor interactions). Drugs bind to numerous substances that are not proteins. Binding occurs usually when a drug in an aqueous environment associated with a macromolecule, but can also occur when the drug is stored in body fat. Since fat is poor circulation, is the length of time until an equilibrium is established, long, especially when the drug is highly lipophilic. An accumulation of the drug in tissues or body compartments can prolong drug action as fabrics release the stored drug, as soon as the plasma concentration decreases. This effect ends within a few minutes, because the drug is redistributed to low-perfused adipose tissue. For example, thiopental is highly fat-soluble, occurs after a single i.v. Injection quickly to the brain and has a significant and rapid anesthetic effect. Thiopental is then slowly released from the fat stores and remains on a subanesthetic plasma levels. These mirrors can be significant if more Thiopentaldosen be given, resulting in large amounts, which are stored in fat. Thus, the storage in fat initially shortens the efficacy of the drug, they extended but then. Some drugs accumulate in the cells as they form bonds with proteins, phospholipids or nucleic acids. For example, the concentration of chloroquine in the white blood cells and liver cells may be higher than in the plasma is several thousand times. The drug in the cells is in equilibrium with the drug in plasma and goes into the plasma as soon as the drug is eliminated from the body. Blood-brain barrier medicines reaching the CNS via brain capillaries and the cerebrospinal fluid. Although the brain receives about one-sixth of the cardiac output, the absorption of drugs is limited due to the permeability of the brain. Although some fat-soluble drugs (eg. As thiopental) readily pass into the brain, this is not the case for polar compounds. The reason is the blood-brain barrier, which consists of the endothelium of the brain capillaries and the Astrozytenscheide. The brain capillary endothelial cells, which appear to be more closely connected than those of most capillaries, slowing down the diffusion of water-soluble drugs. The Astrozytenscheide consists of a layer of connective tissue cells, glia (astrocytes) near the basement membrane of the capillary endothelium. With age, the blood-brain barrier may be less effective and thus enable increased transfer of connections in the brain. Drugs can enter the ventricular cerebrospinal fluid and then diffuse from the cerebrospinal fluid passively into brain tissue directly over the choroid plexus. and organic acids (eg., penicillin) of the cerebrospinal fluid in the choroid plexus also be actively transported into the bloodstream. The rate on contact of the drug in the cerebrospinal fluid, is determined similar to other tissue cells mainly by the extent of protein binding, the degree of ionization, and lipid-water partition coefficient of the drug. The rate for the passage into the brain is highly protein-bound drug for low, for the ionized form of weak acids or bases almost non-existent. Since the central nervous system is well supplied with blood, the distribution rate is determined primarily by the permeability.