Drug absorption and distribution
In order to produce an effect, a drug must reach its target site in adequate concentration. This involves several processes, embraced by the general term pharmacokinetics.In general, the following processes are involved: (1) administration of the drug; (2) absorption from the site of administration into the bloodstream; (3) distribution to other parts of the body, including the target site; (4) metabolic alteration of the drug; and (5) excretion of the drug or its metabolites.
An important step in all of these processes is the movement of drug molecules through cellular barriers (e.g., the intestinal wall, the walls of blood vessels, the barrier between the bloodstream and the brain, and the walls of the kidney tubule), which constitute the main restriction to the free dissemination of drug molecules through the body. To cross most of these barriers, the drug must be able to move through the lipid layer of the cell membrane. Drugs that are highly lipid–soluble do this readily, hence they are rapidly metabolized and inactivated. They can also cross the renal tubule easily and thus tend to be reabsorbed into the bloodstream rather than being excreted in the urine.
Non–lipid–soluble drugs (e.g., neuromuscular blocking drugs) behave differently because they cannot easily enter the cells. Therefore, they are not absorbed from the intestine and they do not enter the brain. Because they may escape metabolic degradation in the liver, they are excreted unchanged in the urine. Certain of these drugs cross cell membranes, particularly in the liver and kidney, with the help of special transport systems, which can be important factors in determining the rate at which the drugs are metabolized and excreted.
The bloodstream carries drugs from the site of absorption to the target site and also to sites of metabolism and excretion, such as the liver, kidneys, and, in some cases, the lungs. Drugs distribute rapidly intissues with high blood flow, and more slowly to tissues with low blood flow.
Drugs rapidly cross capillary membranes in the tissues due to passive diffusion and hydrostatic pressure. Permeability of capillary membranes for the drugs varies. Thus, drugs easily cross the capillaries of the glomerulus of the kidney and the sinusoids of the liver. The capillaries of the brain are surrounded by the glial cells that create a blood–brain barrier that act as a thick lipid membrane. Polar and ionic hydrophylic drugs cross this barrier slowly.
Drugs may accumulate in the tissues as a result of their physicochemical characteristics or special affinity of the tissues for the drug. Lipid–soluble drugs may accumulate in the adipose (fat) tissues because of partitioning of the drug. Tetracycline may accumulate in the bones because complexes with calcium are formed.
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Plasma protein binding of drugs affects distribution. Many drugs are bound to plasma proteins, and in some cases more than 90% of the drug present in the plasma is bound in this way. This bound fraction is inert. A drug bound to a protein forms a complex that is too large to cross cell membranes. Protein binding reduces the overall potency of thedrug and provides a reservoir to maintain the level of the active drug in the blood plasma. The effects of the drug, therefore, are reduced but prolonged by binding.
As the drug is infused intravenously, the plasma drug concentration increases to a steady–state concentration(Css).Understeady–state conditions, the fraction of the drug absorbed equals the fraction of drug eliminated from the body. A loading doseis given as an initial intravenous bolus dose to produce the Сss as rapidly as possible.
Intermittent intravenous infusions are those in which the drug is infused for short periods to prevent accumulation and toxicity. Intermittent intravenous infusions are used for a few drugs, such as the aminoglycosides. For example, gentamicin may be given as a 1–hour infusion every 12 hours. In this case, steady–state drug concentrations are not achieved.
II.4. Ответьте на следующие вопросы по содержанию текста А.
1. Name the processes involved in the drug pharmacokinetics (in their logical order).
2. What constitutes a restriction to the free distribution of the drug through the body?
3. Which drugs can easily cross the cellular barrier?
4. Why is it difficult for non–lipid–soluble drugs to enter the cells?
5. What helps the drugs to distribute rapidly in tissues?
6. What helps the drugs to cross capillary membranes?
7. What is the blood–brain barrier?
8. What and how interferes with drug distribution?
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9. What is meant by steady–state plasma drug concentration?
10. What is the difference between bolus infusion and intermittent infusion?
II.5. Найдите в тексте А эквиваленты для следующих слов и словосочетаний:
распределение, метаболит, проникать в клетку, орган–мишень, клеточный барьер, реабсорбироваться в кровоток, глиальные клетки, гематоэнцефалический барьер, скорость метаболизма и экскреции, пассивная диффузия, связывание с белком, проходить сквозь барьер, активная транспортная система.
II.6. Ознакомьтесь со словами к тексту В.
| to eliminate[I΄lImIneIt] | удалять, выводить из крови в ткани |
| to be catalyzed[΄k{t@laIzd] | ускоряться |
| enzymes[΄enzaIms] | ферменты, энзимы |
| intracellular[Intr@΄seljul@] | внутриклеточный |
| the endoplasmic reticulum [end@΄pl{zmIk rI΄tIkjul@m] | эндоплазматическая сеть |
| resultant[rI΄zölt@nt] | полученный в результате |
| the parent drug[΄pE@r@nt ΄drög] | исходное вещество |
| biotransformation pathways [baIou tr{nsf@΄meIS@n΄pa:Tweiz] | пути биотрансформации |
| intermediate[Int@΄mi:dIIt] | промежуточный |
| to retain[rI΄teIn] | сохранять |
| to a greater/smaller extent | в большей/ меньшей степени |
| to be converted to[k@n΄v@:tId] | превращаться в |
| prodrugs[΄proudrögs] | пролекарства |
| oxidation[OksI΄deIS@n] | окисление |
| reduction[rI΄dökS@n] | восстановление |
| removal of substituent chemical group[rI΄mu:v@l] | реакция замещения химической группы |
| splitting of bonds[΄splItIÎ @v΄bOndz] | разрыв связей (химических) |
| liable[΄laI@bl] | лабильный (химически неустойчивый) |
| substituents[söb΄stItju@nts] | заменители, заместители |
| normally[΄nO:m@lI] | обычно |
| to be detoxicated[dI΄tOksIkeItId] | обезвреживаться |
| consequently[΄kOns@kwentlI] | следовательно, впоследствии |
| the majority of[m@΄dZOrItI] | большинство |
| to encounter[In΄kaunt@] | встречать |
| constituent[k@n΄stItju@nt] | компонент, составляющая |
| hydrolysis[haId΄OlIsIs] | гидролиз |
| a conjugate[΄kOndZu:geIt] | конъюгат |
| conjugation[kOndZu΄geIS@n] | конъюгация |
| gender[΄dZend@] | пол, половая принадлежность |
| this is particularly true of | это касается особенно |
| to decline[dI΄klaIn] | приходить в упадок, снижать |
| to slow down[΄slou΄ daun] | замедляться |
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II.7. Прочтите текст В и переведите его.
Text В
Metabolism
In order to alter or stop a drug's biological activity and prepare it to be eliminated from the body, it must undergo one of the many different kinds of chemical transformations. One particularly important site for these actions is the liver. Metabolic reactions in the liver are catalyzed by enzymes located on a system of intracellular membranes known as the endoplasmic reticulum. In most cases, the resultant metabolites are less active than the parent drug. However, there are instances where the metabolite is as active as, or even more active than, the parent. In some cases, the toxic effects of drugs are produced by metabolites rather than the parent drug. Normally a drug undergoes a variety of biotransformation pathways, resulting in production of a mixture of intermediate metabolites. Rarely is only one metabolite produced from a single drug.
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Some metabolites are inactive, i.e., their pharmacologically active parent compounds become inactivated or detoxicated. Certain metabolites retain the pharmacologic activity of their parent compounds to a greater or lesser extent. Fоr example, codeine is demethylated to the more active analgesic, morphine. Some metabolites develop activity different from that of their parent drug. Thus, vitamin A is isomerised to isotretinoic acid. Some pharmacologically inactive parent compounds are converted to active forms within the body. These parent compounds are known as prodrugs. The antiparkinsonian levodopa is decarboxylated in the neuron to active dopamine.
Many different kinds of reactions are catalyzed by drug–metabolizing enzymes, including oxidation, reduction, removal of substituent chemical groups, splitting of liable (chemically unstable) bonds, and addition of new substituents. The product is often less–lipid soluble than the parent, and is consequently excreted in the urine more rapidly.
Phase I reactions are those in which polar functional groups are introduced into the molecule or unmasked by oxidation, reduction, or hydrolysis. Oxidation is the most common phase I biotransformation. The majority of oxidation reactions occur in the liver, however, extrahepatic tissues, such as the intestinal mucosa, lungs and kidney, can also serve as metabolic sites. Reduction is less commonly encountered than oxidation; however, the result is the same – polar functional groups are formed, which can be eliminated in the urine. Enzymatic hydrolysis, the addition of water across a bond, also results in polar metabolites.
Phase II reactions are those in which the functional groups of the parent drug (or metabolite formed in phase I reaction) are masked by a conjugation reaction. Most phase II conjugates are very polar, and promote a rapid elimination of the drug from the body. Conjugation reactions combine the parent drug (or its metabolites) with certain natural endogenous constituents, such as glucoronic acid, glycine, glutamine, or other similar agents. There are six conjugation pathways: glucoronidation, sulfate conjugation, amino acid conjugation, glutathione conjugation, methylation and acetylation.
The factors that influence drug metabolism include the chemical structure of the drug, physiological state of the organism, the drug dosage, nutritional status of the patient, the age and gender of the patient, and the route of drug administration. In infants and young children, metabolizing enzyme systems are not fully developed, so they need smallerdoses of drugs than adults to avoid toxic side effects. This is particularly true for the drugs that require glucoronide conjugation. In the elderly, metabolizing enzyme systems decline. The lowered level of enzyme activity slows down the rate of drug elimination, causing higher plasma drug levels per dose than in young adults.
II.8. Просмотрите текст еще раз и выберите утверждения, которые соответствуют содержанию текста.
1. Each parent drug produces one metabolite in the process of biotransformation.
2. The chief site of drug metabolism is the liver.
3. Enzymes in the liver promote excretion of metabolites in the urine by catalyzing the reactions.
4. There are three phases in metabolic reactions.
5. In elderly patients, the rate of drug elimination is increased, which lowers plasma drug levels per dose.
II.9. Задайте не менее 10 вопросов по содержанию текста В.
II.10. Назовите основные этапы биотрансформации лекарства в организме.
II.11. Составьте список ключевых слов, связанных с процессом биотрансформации лекарств.
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