Interaction of drugs in the distribution in the body

After absorption of drugs are a long way, before reaching the site of action. Entered into the bloodstream, they are distributed between the tissues of the body.

The distribution of drugs estimated pharmacokinetic methods mainly on the extracellular fluid, including blood plasma, CSF, intraocular fluid and the fluid contents of the gastrointestinal tract. The normal extracellular fluid volume in man weight 70 kg is assumed equal 15 l in a total amount of body water around 40 l. The total volume of extracellular fluid increases with effusion in the abdominal and thoracic cavities, edema, etc.. P., which could affect the distribution of drugs in the body.

Drug distribution in the body is typically occurs unevenly, which is due:

• differences binding substances with the tissues;
• unequal pH values ​​last;
• varying permeability of cell membranes.

Arrival rate of drugs in tissue depends on the local flow, fabric weight and characteristics of their distribution between the tissue and blood. The balance between the rate of income and absorption materials in a well-vascularized tissue is reached more quickly, than in tissues with a less developed system of blood supply. Patients with heart failure reduces blood flow in the liver and kidneys, whereby efficiency may decrease diuretics. With the normalization of hemodynamic effects increases saluretics.

Increased penetration of many drugs in the organs and tissues with impaired circulation while improving blood rheology. Saluretiki, reducing blood viscosity and platelet aggregation, significantly improve the microcirculation of acetylsalicylic acid, xanthinol nicotine, pentoxifylline, etamzilata, dipyridamole, and others., thereby improving the distribution of drugs in parts of, previously inaccessible due to violation of the microcirculation. The penetration of drugs into the tissue, eg, beclomethasone dipropionate or cromolyn sodium, It can be facilitated via β₂-adrenomimetikov (salbutamol, Terbutaline sulfate and others.).

The concentration of the substance in the extracellular fluid may change in the conditions of hypo- or overhydration. Therefore, diuretics, reducing the volume of extracellular fluid, can significantly increase therein drug concentration.

Each drug has the structure of the molecule and the characteristic arrangement reactive functional radicals in space, which causes the peculiarities of its distribution in the body. Some substances act in the adipose tissue, others remain in the interstitial fluid, others bind to certain tissues. The pattern of distribution of drugs in tissues depends on binding to proteins of blood and tissue components. Acidic compounds are generally better bind to plasma albumin, and most importantly - with α₁-glycoproteins and / or lipoproteins.

Medicinal substances carried by the blood or dissolved (free) form, or in combination with various components - proteins or blood cells. Passive diffusion of substances into the extravascular space or tissue, where he performed the pharmacological action, it is only possible for an unrelated (free) shape. Therefore, plasma protein binding affects the drug distribution in the body and the relationship between the total of its concentration in the blood and pharmacological activity.

In other words, the degree of binding agent with the blood determines the nature and extent of its therapeutic action. So, By strophanthin, while in large quantities in the form of unbound plasma proteins (It binds in an amount 2-3%), provides fast therapeutic effect - on the one hand, and on the other - is rapidly excreted from the body. Digitoxine, conversely, Associated with the blood of more than 90% of the administered dose, therefore, its action is slow (during 10-14 hours) and as he slowly removed from the body (I. B. Maksimovic, A. I. Gaidenko, 1988). A similar pattern is typical for many other drugs: the greater the number is in the free state, the faster and stronger action.

Established, that the combined use of drugs is often observed competition between them for binding to the protein components of blood. For Example, phenylbutazone, acetylsalicylic acid, Antimicrobial sulfonamides and certain other compounds have higher affinity to blood proteins, than anticoagulants. When combined with their use of anticoagulants are associated to a lesser extent, than usual, so their effectiveness is more pronounced, that may cause bleeding. Anticoagulants in combination with sulfonylureas bind strongly to blood proteins and enhance the effect of the past. This phenomenon deserves special attention due to the frequency of diabetic angiopathy and a violation of blood coagulation for patients with diabetes.

The practical significance of the results of the competition binding protein drugs are then, when they bind to 85% and more.

So, decrease in the content of protein-bound digitoxin in combination with clofibrate (from 98 to 96%) It leads to increased free digitoxin in blood, that can lead to side effects. Digoxin binding protein of blood does not exceed 50%, therefore an increase in the concentration of its free 10-15% It has no practical significance.

Sometimes the interaction of drugs with the blood has a complex mediated. For Example, Heparin enhances the activity of lipoprotein lipase, which enables the formation of free fatty acid triglycerides. Latest, in turn, displace from its association with protein lidocaine, propranolol, yerapamïl, digitoxine, quinidine, phenytoin.

Aspirin displace anticoagulant from albumin complexes – anticoagulants, which increases their concentration in the serum and, Consequently, bleeding. However, this risk occurs most often chronic administration of maximum doses of drugs.

We also know the specific binding of drugs Some fabrics. So, readily soluble in lipid substances, eg, barbiturates, deposited in adipose tissue. Upon exiting the anesthesia or during dialysis over barbiturate poisoning phenomenon manifests the so-called secondary sleep, developing from the mobilization of these substances from fat depots. Another example of a specific deposition of drugs in humans is the accumulation of tetracycline into growing bone and dentin of the teeth.

The most important binding site are drugs specific receptors. In the specific receptor concentration of drug is much greater than its concentration in a biological fluid environment, but due to the relatively small size of the receptor binding is usually virtually no impact on the overall picture of its distribution in the body.

After, as the free form of the drug leaves the bloodstream, in the blood is bound to proteins form. It serves as a depot, from which the drug is released as a result of the elimination of its distribution in the body, metabolism and excretion of.

The accumulation of the drug in a particular tissue, acting as a depot, may prolong or significantly change the picture of his actions. So, eg, thiopental very soluble in lipids and after a single intravenous injection of rapidly penetrates into the brain, providing anesthetic effect. A few minutes after the start of accumulation in brain tissues, its concentration in the tissues decreases simultaneously reduce plasma concentration, and at least in the compartments of the distribution, where specific blood flow below, anesthetic effect quickly disappears. But, if we trace his fate for a long time, then found the third phase distribution, during thiopental which is slowly released from adipose tissue. Repeated administration of thiopental it accumulates in large amounts in the adipose tissue, forming a depot, provides long-term anesthetic effect.

Some drugs, eg, antimalarials, They can accumulate in cells at higher concentrations, than in the extracellular fluid by protein binding, phospholipids and nucleic acids. So, chloroquine in ocular cells and hepatic tissue may be present in concentrations, a thousand times greater than the concentration in the blood plasma. The drug substance in the blood enters as elimination. However, the rate of release from the depot is often too low and does not provide the level of concentration in the blood, necessary for the manifestation of the therapeutic effect. In other words, Depot is not effective, because they do not provide prolonged systemic effect.