Transport of drugs to the site of action. Transport and distribution of medicines
General pharmacology. Pharmacokinetics. Ways and means of introducing drugs into the body.
Subject and tasks of clinical pharmacology.
Clinical Pharmacology (CP)- a science that studies the principles and methods of effective and safe pharmacotherapy, methods for determining the clinical value and optimal use of drugs (PM).
The subject of clinical pharmacology is a drug in clinical practice.
Pharmacokinetics- changes in the concentration of medicinal substances in the body media of a healthy and sick person, as well as the mechanisms through which these changes are carried out.
Pharmacokinetics - absorption, distribution, deposition, transformations
and excretion of drugs.
All ways of introducing drugs into the body can be divided into enteral and parenteral. Enteral routes of administration ( enteros- intestines) provide the introduction of the drug into the body through the mucous membranes of the gastrointestinal tract. Enteral routes of administration include:
· Oral administration (inside, per os)- the introduction of drugs into the body by swallowing. In this case, the drug first enters the stomach and intestines, where it is absorbed into the portal vein system within 30-40 minutes. Further, with the blood flow, the drug enters the liver, then into the inferior vena cava, the right heart and, finally, the pulmonary circulation. In this way, solid and liquid dosage forms (tablets, dragees, capsules, solutions, lozenges, etc.) are most often administered.
· Rectal path (> per rectum)- the introduction of the drug through the anus into the ampoule of the rectum. This way, soft dosage forms (suppositories, ointments) or solutions (using microclysters) are administered. Absorption of the substance is carried out in the system of hemorrhoidal veins. The rectal route of administration is often used in children of the first three years of life.
· Sublingual (under the tongue) and subbucal (into the cavity between the gum and cheek) injection. In this way, solid dosage forms (tablets, powders), some of the liquid forms (solutions) and aerosols are administered. With these methods of administration, the drug is absorbed into the veins of the oral mucosa and then sequentially enters the superior vena cava, the right heart and the pulmonary circulation. After that, the drug is delivered to the left side of the heart and enters the target organs with arterial blood.
Parenteral administration is the route of administration of a drug, in which it enters the body bypassing the mucous membranes of the gastrointestinal tract.
· injection introduction. With this route of administration, the drug immediately enters the systemic circulation, bypassing the tributaries of the portal vein and the liver. Injection includes all methods in which the integrity of the integumentary tissues is damaged. They are carried out using a syringe and a needle.
· Intravenous administration. With this method of administration, the syringe needle pierces the skin, hypodermis, vein wall and the drug is directly injected into the systemic circulation (inferior or superior vena cava). The drug can be administered as a stream slowly or quickly (bolus), as well as drip.
· Intramuscular administration. In this way, all types of liquid dosage forms and solutions of powders are administered. The syringe needle pierces the skin, hypodermis, muscle fascia and then its thickness, where the medicine is injected. The effect develops in 10-15 minutes. The volume of the injected solution should not exceed 10 ml. With intramuscular injection, the drug is less completely absorbed than with intravenous administration, but better than with oral administration.
Inhalation administration- the introduction of a medicinal substance by inhalation of its vapors or the smallest particles.
Transdermal administration- application to the skin of a medicinal substance to ensure its systemic action.
Local application. Includes application of the drug to the skin, mucous membranes of the eyes (conjunctiva), nose, larynx.
Mechanisms of drug absorption.
Suction- is the process of receipt of drugs from the injection site into the blood. The absorption of a medicinal substance depends on the route of its introduction into the body, dosage form, physicochemical properties (solubility in lipids or hydrophilicity of the substance), as well as on the intensity of blood flow at the injection site.
Orally administered drugs undergo absorption through the mucosa of the gastrointestinal tract, which is determined by their lipid solubility and degree of ionization. There are 4 main mechanisms of absorption: diffusion, filtration, active transport, pinocytosis.
Passive diffusion occurs through the cell membrane. Absorption occurs until the concentration of the drug on both sides of the biomembrane is equal. Lipophilic substances (for example, barbiturates, benzodiazepines, metoprolol, etc.) are absorbed in a similar way, and the higher their lipophilicity, the more active their penetration through the cell membrane. Passive diffusion of substances proceeds without energy expenditure along the concentration gradient.
Facilitated diffusion is the transport of drugs through biological membranes involving molecules of specific carriers. In this case, the transfer of the drug is also carried out along the concentration gradient, but the transfer rate is much higher. For example, cyanocobalamin is absorbed in this way. In the implementation of its diffusion, a specific protein is involved - gastromucoprotein (internal Castle factor), which is formed in the stomach. If the production of this compound is impaired, then the absorption of cyanocobalamin decreases and, as a result, pernicious anemia develops.
Filtration is carried out through the pores of cell membranes. This mechanism of passive absorption proceeds without energy expenditure and is carried out along a concentration gradient. It is typical for hydrophilic substances (for example, atenolol, lisinopril, etc.), as well as ionized compounds.
Active transport is carried out with the participation of specific transport systems of cell membranes. Unlike passive diffusion and filtration, active transport is an energy-consuming process and can be carried out against a concentration gradient. In this case, several substances can compete for the same transport mechanism. The methods of active transport are highly specific, since they were formed in the course of a long evolution of the organism to meet its physiological needs. It is these mechanisms that are the main ones for the delivery of nutrients to cells and the removal of metabolic products.
Pinocytosis (corpuscular absorption or pensorption) is also a type of absorption with energy expenditure, the implementation of which is possible against a concentration gradient. In this case, the capture of the drug substance and invagination of the cell membrane with the formation of a vacuole occurs, which goes to the opposite side of the cell, where exocytosis occurs with the release of the drug compound.
medicinal antiarrhythmic contractile uterus
Mechanisms of drug absorption in the body.
Absorption is the process by which a drug enters the bloodstream from the injection site. Regardless of the route of administration, the absorption rate of the drug is determined by three factors:
- a) dosage form (tablets, suppositories, aerosols);
- b) solubility in tissues;
- c) blood flow at the injection site.
There are a number of successive stages in the absorption of drugs through biological barriers:
1) passive diffusion. In this way, drugs that are highly soluble in lipids penetrate. Diffusion occurs directly across cell membranes along a concentration gradient by dissolving in membrane lipids. This is the most significant mechanism, since most drugs are characterized by a significantly higher solubility in lipids than in water. Thus, in order to carry out absorption (absorption) along the second path of passive diffusion, the drug must be lipophilic, that is, it must be with a low degree of ionization. In other words, it should be little ionized, undissociated.
It has been established that if the drug substance at pH values typical of body media is mainly in a non-ionized form (that is, in a lipophilic form), it is better soluble in lipids than in water and penetrates well through biological membranes.
Conversely, if the substance is ionized, it does not penetrate well through cell membranes into various organs and tissues, but has better water solubility.
Thus, the rate and extent of absorption of drugs, for example, in the stomach and intestines, depends on whether the substance is predominantly water-soluble (ionized, dissociated) or fat-soluble (non-ionized), and this is largely determined by whether it (the drug) is a weak acid or weak base.
Knowing the physicochemical properties of drugs and the characteristics of the processes of xenobiotic penetration through various tissue barriers, it is possible to predict how a particular drug will be absorbed into the blood, distributed in organs and tissues, and excreted from the body.
Drugs with strong acid or alkali properties are in an ionized form at the pH of the blood and intestinal contents and are therefore poorly absorbed. For example, streptomycin, kanamycin are drugs that have the properties of strong alkalis, so their absorption from the gastrointestinal tract is insignificant and unstable. Hence the conclusion that such drugs should be administered only parenterally.
It is noticed that the absorption of drugs decreases, slows down with increased intestinal motility, as well as: diarrhea (diarrhea). Absorption also changes under the influence of agents that reduce the motor activity of the intestine, for example, under the influence of anticholinergic agents (drugs of the atropine group).
Inflammatory processes of the intestinal mucosa, its edema are also accompanied by inhibition of the absorption of drugs, for example, the absorption of hypothiazide is sharply reduced in patients with congestive heart failure.
Absorption is also affected by the chemical and physical structure of the drug substance. For example, some quaternary ammonium compounds (containing a tetravalent nitrogen atom N), which are curarepodal drugs (tubocurarine, anatruxonium, dithylin, etc.) - muscle relaxants, do not penetrate the lipid layer of cells at all, and therefore they must be administered only intravenously.
The size of its particles also affects the absorption of the drug. Tablets consisting of large aggregates of the active substance, even with a long stay in the gastrointestinal tract, do not break up well and therefore are poorly absorbed. Medicinal substances in dispersed form or emulsified are absorbed better.
2) active transport. In this case, the movement of substances through the membranes occurs with the help of transport systems contained in the membranes themselves;
Active transport assumes that absorption occurs with the help of special carriers (facilitated absorption) - carriers, that is, it involves the transfer of certain substances through cell membranes using the protein carriers present in them (enzyme proteins or transport proteins). This is how amino acids (sugars, pyrimidine bases) are transferred through the blood-brain barrier, placenta, weak acids - in the proximal tubules of the kidneys.
Active transport - is carried out by special carriers with energy consumption and can proceed against a concentration gradient; this mechanism is characterized by selectivity, competition of two substances for one carrier and "saturation", that is, the achievement of the maximum speed of the process, limited by the amount of carrier and not increasing with a further increase in the concentration of the absorbed substance; in this way, hydrophilic polar molecules, a number of inorganic ions, sugars, amino acids, etc. are absorbed;
It is important to remember that we practically cannot influence active transport.
- 3) Filtration(convection transport) - the passage of drug molecules through the pores of the membranes, which is of rather limited importance due to the small size of the pores (on average, up to 1 nm); in addition to the size of molecules, filtration depends on their hydrophilicity, ability to dissociate, the ratio of the charge of particles and pores, as well as on hydrostatic, osmotic and oncotic pressures; in this way water, some ions and small hydrophilic molecules are absorbed;
- 4) pinocytosis. Drugs with a molecular weight greater than 1000 daltons can enter the cell only through pinocytosis, that is, the absorption of extracellular material by membrane vesicles. This process is especially important for drugs with a polypeptide structure, as well as, apparently, a complex of cyanocobalamin (vitamin B-12) with internal factor Castle.
The listed mechanisms of absorption (absorption) "work", as a rule, in parallel, but the predominant contribution is usually made by one of them (passive diffusion, active transport, filtration, pinocytosis). So, in the oral cavity and in the stomach, passive diffusion is mainly realized, and filtration is to a lesser extent. Other mechanisms are practically not involved.
In the small intestine there are no obstacles to the implementation of all mechanisms of absorption; which one dominates depends on the drug.
Passive diffusion and filtration processes predominate in the large intestine and rectum. They are also the main mechanisms of drug absorption through the skin.
The use of any drug for therapeutic or prophylactic purposes begins with its introduction into the body or application to the surface of the body. The rate of development of the effect, its severity and duration depend on the routes of administration.
Distribution and transport of drugs in the body
After absorption, medicinal substances enter, as a rule, into the blood, and then they are carried to various organs and fabrics. The nature of the distribution of the drug is determined by many factors, depending on which the drug will be distributed in the body evenly or unevenly. It should be said that most drugs are distributed unevenly and only a small part is relatively evenly distributed (inhalation drugs for anesthesia). The most important factors influencing the distribution pattern of a drug are:
- 1) solubility in lipids,
- 2) the degree of binding to plasma proteins,
- 3) intensity of regional blood flow.
The lipid solubility of a drug determines its ability to cross biological barriers. This is, first of all, the wall of capillaries and cell membranes, which are the main structures of various histohematic barriers, in particular, such as the blood-brain and placental barriers. Non-ionized fat-soluble drugs easily penetrate cell membranes and are distributed in all body fluids. The distribution of drugs that do not penetrate well through cell membranes (ionized drugs) is not so uniform.
The permeability of the BBB increases with an increase in the osmotic pressure of the blood plasma. Various diseases can change the distribution of drugs in the body. Thus, the development of acidosis can contribute to the penetration of drugs into tissues - weak acids, which are less dissociated under such conditions.
Sometimes the distribution of a medicinal substance depends on the affinity of the drug for certain tissues, which leads to their accumulation in individual organs and tissues. An example is the formation of a tissue depot in the case of the use of drugs containing iodine (J) in the tissues of the thyroid gland. When using tetracyclines, the latter can selectively accumulate in bone tissue, in particular, teeth. Teeth in this case, especially in children, may acquire a yellow color.
Such selectivity of action is due to the affinity of tetracyclines for biological substrates of bone tissue, namely the formation
tetracycline-calcium complexes by the type of chelates (hela - cancer claw). These facts are important to remember, especially for pediatricians and obstetrician-gynecologists.
Some drugs can accumulate in large quantities inside the cells, forming cellular depots (Acrichin). This happens due to the binding of the drug substance to intracellular proteins, nucleoproteins, phospholipids.
Some anesthetics, due to their lipophilicity, can form fat depots, which should also be taken into account.
Drugs are deposited, as a rule, due to reversible bonds, which, in principle, determines the duration of their stay in tissue depots. However, if persistent complexes are formed with blood proteins (sulfadimethoxine) or tissues (heavy metal salts), then the presence of these funds in the depot is significantly prolonged.
It should also be borne in mind that after absorption into the systemic circulation, most of the drug substance in the first minutes enters those organs and tissues that are most actively perfused by blood (heart, liver, kidneys). The saturation of the muscles, mucous membranes, skin and adipose tissue with the drug occurs more slowly. To achieve therapeutic concentrations of drugs in these tissues takes time from several minutes to several hours.
The route of administration of the drug largely determines whether it can get to the site of action (into the biophase) (for example, in the focus of inflammation) and have a therapeutic effect.
Passage of drugs through the digestive tract associated with their lipid solubility and ionization. It has been established that when medicinal substances are taken orally, the rate of their absorption in different parts of the gastrointestinal tract is not the same. After passing through the mucous membrane of the stomach and intestines, the substance enters the liver, where it undergoes significant changes under the action of liver enzymes. The process of drug absorption in the stomach and intestines is influenced by pH. So, in the stomach pH 1-3, which contributes to easier absorption of acids, and an increase in the small and large intestines pH up to 8 bases. At the same time, in the acidic environment of the stomach, some drugs can be destroyed, for example, benzylpenicillin. Enzymes of the gastrointestinal tract inactivate proteins and polypeptides, and bile salts can accelerate the absorption of drugs or slow down, forming insoluble compounds. The rate of absorption in the stomach is influenced by the composition of food, gastric motility, the time interval between meals and taking drugs. After introduction into the bloodstream, the drug is distributed throughout all tissues of the body, while its solubility in lipids, the quality of communication with blood plasma proteins, the intensity of regional blood flow, and other factors are important. A significant part of the drug in the first time after absorption enters the organs and tissues that are most actively supplied with blood (heart, liver, lungs, kidneys), and muscles, mucous membranes, adipose tissue and skin are slowly saturated with medicinal substances. Water-soluble drugs that are poorly absorbed in the digestive system are administered only parenterally (for example, streptomycin). Fat-soluble drugs (gaseous anesthetics) are quickly distributed throughout the body.
Key Issues for Discussion
Absorption of drugs from the site of administration into the blood. absorption mechanisms. Factors affecting the absorption process. Transport of medicinal substances with blood.
The value of binding drugs to plasma proteins.
distribution of drugs in the body. Factors affecting the distribution of drugs in the body. Histohematic barriers. 1 blood-brain and placental barriers. Circles of circulation of medicinal substances; Enterohepatic circle of circulation and its significance. Pharmacokinetic indicators characterizing the processes of absorption and distribution. Bioavailability of medicinal substances and methods for its calculation.
Determination of the baseline
Instructions: Choose one or more correct answers for the test questions below.
Option I
A. Absorption of medicinal substances. B. Distribution of medicinal substances in the body. B. Interaction with targets in the body. D Pharmacological effects. D. Metabolism. E. Removal.
2. The main mechanism of absorption of medicinal substances from FA "G" into the blood:
A. Filtration. B. Passive diffusion. B. Active transport. G. Pinocytosis.
3. With an increase in the ionization of weak electrolytes, their absorption "from FA" G into the blood:
A. Increases. B. Decreases. B. Does not change.
4. Absorption of medicinal substances by the mechanism of passive diffusion:
5. Medicinal substances associated with blood plasma proteins:
A. Pharmacologically active. B. Pharmacologically inactive. C. Slowly metabolized, D. Not excreted by the kidneys.
Option 2
1. The concept of "pharmacokinetics" includes:
A. Absorption of medicinal substances. B. Deposition of medicinal substances. B. Localization of action. D Biotransformation. D. Excretion.
2. It is easier to penetrate through the histohematic barriers:
A. Polar hydrophilic substances. B. Non-polar lipophilic substances.
3. The following are well absorbed from the CT into the blood:
A. Ionized molecules. B. Peionized molecules. B. Hydrophilic molecules. D. Lipophilic molecules.
4. Absorption of medicinal substances by the mechanism of active * to th transport:
A. Accompanied by the expenditure of metabolic energy. B. Not accompanied by the expenditure of metabolic energy.
5. Medicinal substances not associated with blood plasma proteins:
A. They have pharmacological effects. B. Do not have pharmacological effects. B. Excreted by the kidneys. G. Not excreted by the kidneys.
Independent work
Task I. Fill in the table:
Mechanisms of absorption of medicinal substances into the blood and their characteristics
Task 2. Fill in the table. Based on the data in the table, determine which of the drugs can be used as means:
A. For the relief of angina attacks. B. For the prevention and treatment of angina pectoris.
Task 3. Fill in the table.
Pharmacokinetic indicators
Based on the pharmacokinetic parameters, discuss with the teacher questions about:
Speed and completeness of absorption;
The speed of development of the maximum pharmacological effect;
The level of free and bound molecules in blood plasma;
Distribution in organs and tissues and the possibility of their use during pregnancy and lactation.
Task 4. Situational task.
Healthy volunteers were administered atorvastatin (liprimar) intravenously in 1 ml of a 1% solution and orally in tablets at a dose of 10 mg.
The area under the curve (A11C) "blood concentration - time" with intravenous administration was 44.5 μg/min/ml *\, and with oral administration - 43.2 μg/min/ml-1.
Calculate the bioavailability of atorvastatin (liprimar) tablets.
Experimental work
Experience 1. Two isolated rat stomachs are filled
0.2% solution of acetylsalicylic acid and 5% solution of analgin. The pH of the medium in the stomach, equal to 2, is set to 0.1 N. NS solution). Two isolated segments of the rat small intestine (5-8 cm long) are also filled with 0.2% acetylsalicylic acid solution and 5% analgin solution. The pH value of the medium in the intestine, equal to 8.0. set with 2% NaHCO solution. The stomachs and segments of the small intestine, filled with acetylsalicylic acid, are placed in chemical cups with 0.9% NaCl solution, where indicators FeClh are added. The stomachs and segments of the small intestine, filled with analgin solution, are placed in a glass with an indicator prepared earlier (5 ml of 95% ethyl alcohol + 0.5 ml of diluted HC1 + 5 ml of 0.1 N ED03 solution). The speed and completeness of the absorption of medicinal substances is judged by the time of appearance of staining and its intensity. The results are recorded in a table and a conclusion is drawn about the dependence of the absorption of medicinal substances from the stomach and intestines on their acid-base properties:
| doctor natural substance | Acid main properties | Ionization | The intensity of staining through | ||||||
| pH | pH | 5 min | 30 minutes | 60 min | |||||
| F | TO | F | TO | F | TO | ||||
| Analgin | |||||||||
| Acetyls licyl | |||||||||
Control of the assimilation of the topic (test tasks)
Instruction; select one or more correct answers for the test questions below, option /
/. What mechanism of absorption of medicinal substances is accompanied by the expenditure of metabolic energy T L. Pinocytosis. B. Ultrafiltration. B. Passive diffusion. D. Active transport.
2. Molecules of medicinal substances associated with 6 blood plasma cells:
A. Pharmacologically active. G>. Excreted by the kidneys.
B. Pharmacologically inactive. D. Not displayed at night. D. They create a depot of the drug in the blood.
3. With an increase in dissociated molecules of the drug substance, its absorption from the gastrointestinal tract:
L. Decreases. B. Increases.
4. Medicinal substances from the mother's body to the fetus pass through:
A. Blood-brain barrier. B. Placental barrier. B. Hematoophthalmic barrier.
5. Hydrophilic medicinal substances are distributed mainly in:
A. Intercellular fluid. B. Kidney. B. Fat depot.
6. The amount of unchanged drug that has reached the blood plasma, relative to the administered dose of the drug is called:
A. Suction. B. Excretion. B. Biotransformation. D. Bioavailability.
7. How will the effect of digoxin change when co-administered with diclofenac, if it is known that the latter displaces digoxin from the complex with plasma proteins?
A. Increase. B. Decrease. B. Has not changed.
8. What factors influence the distribution of drugs in the body *
A. Physical and chemical properties. B. The ability to penetrate through histohematic barriers. B. The speed of blood flow in organs and tissues. G. The ability to bind to plasma proteins. D. That's right.
9. Medicinal substances of the main nature, taken by peror, gno, are optimally absorbed in:
A. Stomach. B. Duodenum. B. Throughout the F CT.
Option 2
1. What absorption mechanism is characterized by protrusion of the cell membrane, capture of the smallest droplets of liquid or solid particles and their passage into the cell?
A. Passive diffusion. B. Active transport. B. Filtration. G. Pinocytosis.
2. Orally administered acidic drugs are optimally absorbed in:
A. Stomach. B. Duodenum. B. Rectum. D Throughout the gastrointestinal tract.
3. Medicinal substances from the blood to the brain cells passes through.
Details
General pharmacology. Pharmacokinetics
Pharmacokinetics- a section of pharmacology devoted to the study of the kinetic patterns of the distribution of medicinal substances. It studies the release of medicinal substances, absorption, distribution, deposition, transformation and release of medicinal substances.
Routes of drug administration
The rate of development of the effect, its severity and duration depend on the route of administration. In some cases, the route of administration determines the nature of the action of substances.
Distinguish:
1) enteral routes of administration (through the digestive tract)
With these routes of administration, substances are well absorbed, mainly by passive diffusion through the membrane. Therefore, lipophilic non-polar compounds are absorbed well and hydrophilic polar compounds are poorly absorbed.
Under the tongue (sublingual)
Absorption occurs very quickly, substances enter the bloodstream, bypassing the liver. However, the suction surface is small, and only highly active substances administered in small doses can be administered in this way.
Example: Nitroglycerin tablets containing 0.0005 g of nitroglycerin. The action occurs in 1-2 minutes.
Through the mouth (per os)
Medicinal substances are simply swallowed. Absorption occurs partly from the stomach, but for the most part from the small intestine (this is facilitated by the large absorptive surface of the intestine and its intensive blood supply). The main mechanism of absorption in the intestine is passive diffusion. Absorption from the small intestine is relatively slow. It depends on intestinal motility, pH, quantity and quality of intestinal contents.
From the small intestine, the substance enters the liver through the portal vein system of the liver and only then into the general circulation.
The absorption of substances is also regulated by a special membrane transporter - P-glycoprotein. It promotes the excretion of substances into the intestinal lumen and prevents their absorption. Known inhibitors of this substance are cyclosporine A, quinidine, verapamil, itraknazol, etc.
It should be remembered that some medicinal substances are not advisable to be administered orally, as they are destroyed in the gastrointestinal tract by the action of gastric juice and enzymes. In this case (or if the drug has an irritating effect on the gastric mucosa), it is prescribed in capsules or dragees, which dissolve only in the small intestine.
Rectally (per rectum)
A significant part of the substance (about 50%) enters the bloodstream, bypassing the liver. In addition, with this route of administration, the substance is not exposed to gastrointestinal enzymes. Absorption occurs by simple diffusion. Rectal substances are prescribed in the form of suppositories or enemas.
Medicinal substances having the structure of proteins, fats and polysaccharides are not absorbed in the large intestine.
A similar route of administration is also used for local exposure.
2) parenteral routes of administration
The introduction of substances bypassing the digestive tract.
Subcutaneous
Substances can be absorbed by passive diffusion and filtration through intercellular spaces. With this orbase, both lipophilic non-polar and hydrophilic polar substances can be injected under the skin.
Usually solutions of medicinal substances are administered subcutaneously. Sometimes - oil solutions or suspensions.
Intramuscular
Substances are absorbed in the same way as with subcutaneous administration, but more quickly, since the vascularization of skeletal muscles is more pronounced compared to subcutaneous fat.
Hypertonic solutions, irritating substances should not be injected into the muscles.
At the same time, oil solutions, suspensions are injected into the muscles in order to create a depot of the drug, in which the drug can be absorbed into the blood for a long time.
Intravenously
The medicinal substance immediately enters the bloodstream, so its action develops very quickly - in 1-2 minutes. In order not to create too high a concentration of the substance in the blood, it is usually diluted in 10-20 ml of isotonic sodium chloride solution and injected slowly over several minutes.
Oil solutions should not be injected into a vein, suspensions due to the risk of blockage of blood vessels!
Intra-arterial
Allows you to create in the area that is supplied with blood by this artery, a high concentration of the substance. Anticancer drugs are sometimes administered in this way. To reduce the general toxic effect, the outflow of blood can be artificially hindered by applying a tourniquet.
intrasternal
Usually used when the technical impossibility of intravenous administration. The drug is injected into the spongy substance of the sternum. The method is used for children and the elderly.
intraperitoneal
Rarely used, usually in operations. The action comes very quickly, since most drugs are well absorbed through the sheets of the peritoneum.
Inhalation
Administration of drugs by inhalation. This is how gaseous substances, vapors of volatile liquids, aerosols are introduced.
The lungs are well supplied with blood, so absorption occurs very quickly.
transdermally
If you need long-term action of highly lipophilic drugs that easily penetrate through intact skin.
intranasally
For introduction into the nasal cavity in the form of drops or spray, based on local or resorptive action.
The penetration of drugs through the membrane. Lipophilic non-polar substances. Hydrophilic polar substances.
The main modes of penetration are passive diffusion, active transport, facilitated diffusion, and pinocytosis.
The plasma membrane consists mainly of lipids, which means that only lipophilic non-polar substances can penetrate through the membrane by passive diffusion. On the contrary, hydrophilic polar substances (HPV) practically do not penetrate the membrane in this way.
Many medicinal substances are weak electrolytes. In solution, some of these substances are in a non-ionized form, i.e. in non-polar, and part - in the form of ions carrying electric charges.
By passive diffusion, the non-ionized part of the weak electrolyte penetrates the membrane
To evaluate the ionization, the pK a value is used - the negative logarithm of the ionization constant. Numerically, pK a is equal to the pH at which half of the molecules of the compound are ionized.
To determine the degree of ionization, the Henderson-Hasselbach formula is used:
pH = pKa+ - for bases
Ionization of bases occurs by their protonation
The degree of ionization is determined as follows
pH \u003d pK a + - for acids
The ionization of acids occurs by their protonation.
ON \u003d H + + A -
For acetylsalicylic acid pKa = 3.5. At pH = 4.5:
Therefore, at pH = 4.5, acetylsalicylic acid will be almost completely dissociated.
Absorption mechanisms
Drugs can enter the cell by:
passive diffusion
There are aquaporins in the membrane through which water enters the cell and can pass by passive diffusion along the concentration gradient hydrophilic polar substances with very small molecular sizes dissolved in water (these aquaporins are very narrow). However, this type of drug entry into the cell is very rare, since the size of most drug molecules exceeds the diameter of aquaporins.
Also, lipophilic non-polar substances penetrate by simple diffusion.
active transport
Transport of a hydrophilic polar drug across a membrane against a concentration gradient using a special carrier. Such transport is selective, saturable and requires energy.
A drug that has an affinity for a transport protein binds to the binding sites of this transporter on one side of the membrane, then a conformational change of the transporter occurs, and finally the substance is released on the other side of the membrane.
Facilitated diffusion
Transport of a hydrophilic polar substance across the membrane by a special transport system along a concentration gradient, without energy consumption.
Pinocytosis
Invaginations of the cell membrane that surround the molecules of a substance and form vesicles that pass through the cytoplasm of the cell and release the substance from the other side of the cell.
Filtration
through the pores of the membranes.
Also matters filtration of drugs through intercellular spaces.
Filtration of HPV through intercellular spaces is important for absorption, distribution and excretion and depends on:
a) the size of the intercellular spaces
b) the size of the molecules of substances
1) through the gaps between the endothelial cells in the capillaries of the renal glomeruli, most of the drugs in the blood plasma easily pass by filtration if they are not associated with plasma proteins.
2) in the capillaries and venules of the subcutaneous fat, skeletal muscles, the gaps between the endothelial cells are sufficient for the passage of most drugs. Therefore, when injected under the skin or into muscles, both lipophilic non-polar substances (by passive diffusion in the lipid phase) and hydrophilic polar substances (by filtration and passive diffusion in the aqueous phase through the gaps between endothelial cells) are well absorbed and penetrate into the blood.
3) when HPV is introduced into the blood, substances quickly penetrate into most tissues through the gaps between capillary endotheliocytes. Exceptions are substances for which there are active transport systems (the antiparkinsonian drug levadopa) and tissues separated from the blood by histohematogenous barriers. Hydrophilic polar substances can penetrate such barriers only in some places where the barrier is poorly expressed (in the area postrema of the medulla oblongata, HPV penetrates into the trigger zone of the vomiting center).
Lipophilic non-polar substances easily penetrate into the central nervous system through the blood-brain barrier by passive diffusion.
4) In the epithelium of the gastrointestinal tract, the intercellular spaces are small, so HPV is poorly absorbed in it. Thus, the hydrophilic polar substance neostigmine is prescribed under the skin at a dose of 0.0005 g, and to obtain a similar effect when administered orally, a dose of 0.015 g is required.
Lipophilic non-polar substances are easily absorbed in the gastrointestinal tract by passive diffusion.
Bioavailability. Presystemic elimination.
Due to the fact that the systemic action of a substance develops only when it enters the bloodstream, from where it enters the tissues, the term "bioavailability" has been proposed.
In the liver, many substances undergo biotransformation. Partially, the substance can be excreted into the intestine with bile. That is why only a part of the injected substance can enter the blood, the rest is exposed elimination during the first passage through the liver.
Elimination– biotransformation + excretion
In addition, drugs may not be completely absorbed in the intestine, be metabolized in the intestinal wall, and partially excreted from it. All this, together with elimination during the first passage through the liver, is called first elimination.
Bioavailability- the amount of unchanged substance that entered the general circulation, as a percentage of the amount administered.
As a rule, the reference books indicate the values \u200b\u200bof bioavailability when administered orally. For example, the bioavailability of propranolol is 30%. This means that when administered orally at a dose of 0.01 (10 mg), only 0.003 (3 mg) of unchanged propranolol enters the bloodstream.
To determine the bioavailability, the drug is injected into a vein (with an intravenous route of administration, the bioavailability of the substance is 100%). At certain time intervals, the concentrations of the substance in the blood plasma are determined, then a curve of the change in the concentration of the substance over time is plotted. Then the same dose of the substance is administered orally, the concentration of the substance in the blood is determined and a curve is also built. Measure the area under the curves - AUC. Bioavailability - F - is defined as the ratio of AUC when administered orally to AUC when administered intravenously and is indicated as a percentage.
Bioequivalence
With the same bioavailability of two substances, the rate of their entry into the general circulation can be different! Accordingly, the following will be different:
Time to reach peak concentration
Maximum plasma concentration
The magnitude of the pharmacological effect
That is why the concept of bioequivalence is introduced.
Bioequivalence - means similar bioavailability, peak action, nature and magnitude of the pharmacological effect.
Distribution of medicinal substances.
When released into the bloodstream, lipophilic substances, as a rule, are distributed relatively evenly in the body, while hydrophilic polar substances are unevenly distributed.
A significant influence on the nature of the distribution of substances is exerted by biological barriers that they encounter on their way: capillary walls, cell and plasma membranes, blood-brain and placental barriers (it is appropriate to see the section "Filtration through intercellular spaces").
The endothelium of the capillaries of the brain has no pores, there is practically no pinocytosis. Astroglia also play a role, which increase the barrier strength.
Hematoophthalmic barrier
Prevents the penetration of hydrophilic polar substances from the blood into the tissue of the eye.
Placental
Prevents the penetration of hydrophilic polar substances from the mother's body into the fetus's body.
To characterize the distribution of a drug substance in the system of a single-chamber pharmacokinetic model (the body is conventionally represented as a single space filled with liquid. When administered, the drug substance is instantly and evenly distributed), such an indicator as the apparent volume of distribution is used - V d
Apparent volume of distribution reflects the estimated volume of liquid in which the substance is distributed.
If for a medicinal substance V d \u003d 3 l (blood plasma volume), then this means that the substance is in the blood plasma, does not penetrate into the blood cells and does not leave the bloodstream. Perhaps this is a high molecular weight substance (V d for heparin = 4 l).
V d \u003d 15 l means that the substance is in the blood plasma (3 l), in the intercellular fluid (12 l) and does not penetrate into tissue cells. It is probably a hydrophilic polar substance.
V d \u003d 400 - 600 - 1000l means that the substance is deposited in peripheral tissues and its concentration in the blood is low. For example, for imipramine - a tricyclic antidepressant - V d \u003d 23 l / kg, that is, approximately 1600 l. This means that the concentration of imipramine in the blood is very low and in case of poisoning with imipramine, hemodialysis is ineffective.
Deposit
During the distribution of the drug substance in the body, a part can be retained (deposited) in various tissues. From the depot, the substance is released into the blood and has a pharmacological effect.
1) Lipophilic substances can be deposited in adipose tissue. The anesthetic agent sodium thiopental causes anesthesia lasting 15-20 minutes, since 90% of sodium thiopental is deposited in adipose tissue. After the cessation of anesthesia, post-anesthetic sleep occurs for 2-3 hours due to the release of sodium thiopental.
2) Tetracyclines are deposited in bone tissue for a long time. Therefore, it is not prescribed for children under 8 years of age, as it can disrupt bone development.
3) Deposition associated with blood plasma. In combination with plasma proteins, the substances do not show pharmacological activity.
Biotransformation
Only highly hydrophilic ionized compounds, agents for inhalation anesthesia, are released unchanged.
Biotransformation of most substances occurs in the liver, where high concentrations of substances are usually created. In addition, biotransformation can occur in the lungs, kidneys, intestinal wall, skin, etc.
Distinguish two main types biotransformations:
1) metabolic transformation
The transformation of substances through oxidation, reduction and hydrolysis. Oxidation occurs mainly due to microsomal oxidases of mixed action with the participation of NADP, oxygen, and cytochrome P-450. Restoration occurs under the influence of the system of nitro- and azoreductases, etc. They usually hydrolyze esterases, carboxylesterases, amidases, phosphatases, etc.
Metabolites are usually less active than the parent substances, but sometimes more active than them. For example: enalapril is metabolized to enaprilat, which has a pronounced hypotensive effect. However, it is poorly absorbed in the gastrointestinal tract, so they try to administer intravenously.
Metabolites may be more toxic than the parent substances. The metabolite of paracetamol, N-acetyl-para-benzoquinone imine, causes liver necrosis in case of overdose.
2) conjugation
A biosynthetic process accompanied by the addition of a number of chemical groups or molecules of endogenous compounds to a medicinal substance or its metabolites.
Processes go either one after another, or proceed separately!
There are also:
-specific biotransformation
A single enzyme acts on one or more compounds, while exhibiting high substrate activity. Example: methyl alcohol is oxidized by alcohol dehydrogenase with the formation of formaldehyde and formic acid. Ethyl alcohol is also oxidized by aclogold dehydrogenase, but the affinity of ethanol for the enzyme is much higher than that of methanol. Therefore, ethanol can slow down the biotransformation of methanol and reduce its toxicity.
- non-specific biotransformation
Under the influence of microsomal liver enzymes (mainly mixed-function oxidases) localized in the smooth surface areas of the endoplasmic reticulum of liver cells.
As a result of biotransformation, lipophilic uncharged substances are usually converted into hydrophilic charged substances, therefore, they are easily excreted from the body.
Withdrawal (excretion)
Medicinal substances, metabolites and conjugates, are mainly excreted in the urine and bile.
-with urine
In the kidneys, low molecular weight compounds dissolved in plasma (not associated with proteins) are filtered through the membranes of the capillaries of the glomeruli and capsules.
Also active secretion of substances in the proximal tubule with the participation of transport systems plays an active role. Organic acids, salicylates, penicillins are released in this way.
Substances can slow down the excretion of each other.
Lipophilic uncharged substances are reabsorbed by passive diffusion. Hydrophilic polar are not reabsorbed and are excreted in the urine.
pH matters a lot. For the accelerated removal of acidic compounds, the urine reaction should be changed to the alkaline side, and to remove the bases - to the acidic side.
- with bile
This is how tetracyclines, penicillins, colchicine, etc. are excreted. These drugs are significantly excreted in the bile, then partially excreted in the feces, or reabsorbed ( intestinal-hepatic recycling).
- with the secrets of different glands
Particular attention should be paid to the fact that during lactation, the mammary glands secrete many substances that a nursing mother receives.
Elimination
Biotransformation + excretion
To quantify the process, a number of parameters are used: elimination rate constant (K elim), half-life (t 1/2), total clearance (Cl T).
Elimination rate constant - K elim- reflects the rate of removal of a substance from the body.
Elimination half-life - t 1/2- reflects the time required to reduce the concentration of a substance in plasma by 50%
Example: Substance A is injected into a vein at a dose of 10 mg. Elimination rate constant = 0.1/h. After an hour, 9 mg will remain in the plasma, after two hours - 8.1 mg.
Clearance - Cl T- the amount of blood plasma cleared of a substance per unit time.
There are renal, hepatic and total clearance.
At a constant concentration of a substance in the blood plasma, renal clearance - Cl r is determined as follows:
Cl \u003d (V u x C u) / C p [ml / min]
Where C u and C p are the concentration of the substance in urine and blood plasma, respectively.
V u - the rate of urination.
General ground clearance Cl T is determined by the formula: Cl T = V d x K el
The total clearance shows what part of the volume of distribution is released from the substance per unit time.
PHARMACOKINETICS
Pharmacokinetic processes - absorption, distribution, deposition, biotransformation and excretion - are associated with the penetration of drugs through biological membranes (mainly through the cytoplasmic membranes of cells). There are the following methods of penetration of substances through biological membranes: passive diffusion, filtration, active transport, facilitated diffusion, pinocytosis (Fig. 1.1).
^ passive diffusion. By passive diffusion, substances penetrate the membrane along a concentration gradient (if the concentration of a substance on one side of the membrane is higher than on the other, the substance moves through the membrane from a higher concentration to a lower one). This process does not require energy. Since biological membranes are mainly composed of lipids, substances that are soluble in lipids and do not have a charge easily penetrate through them in this way, i.e. l and -philic non-polar substances. Conversely, hydrophilic polar compounds practically do not penetrate directly through membrane lipids.
If LV are weak electrolytes - weak acids or weak bases, then the penetration of such substances through the membranes depends on the degree of their ionization, since only non-ionized (uncharged) molecules of the substance easily pass through the double lipid layer of the membrane by passive diffusion.
The degree of ionization of weak acids and weak bases is determined by:
pH values of the medium;
ionization constant (K a) of substances.
ON ^ H + + A~
Alkaline environment
Ionization of weak bases
BH + ^ B + H +
The ionization constant characterizes the ability of a substance to ionize at a certain pH value of the medium. In practice, to characterize the ability of substances to ionization, the pK a index is used, which is the negative logarithm of K a (-lg K a). The pKa index is numerically equal to the pH value of the medium at which half of the molecules of a given substance are ionized. The pKa values of weak acids, as well as weak bases, vary widely. The lower the pKa of a weak acid, the easier it is to ionize even at relatively low pH values. Thus, acetylsalicylic acid (рКа = 3.5) at pH 4.5 is ionized by more than 90%, while the degree of ionization of ascorbic acid (рКа = 11.5) at the same pH value is fractions of % (Fig. .1.2). For weak bases, there is inverse relationship. The higher the pKa of a weak base, the more it is ionized even at relatively high pH values.
The degree of ionization of a weak acid or weak base can be calculated using the Henderson-Hasselbalch formula:
This formula allows you to determine what will be the degree of penetration of drugs (weak acids or weak bases) through membranes that separate body media with different pH values, for example, when absorption of drugs from the stomach (pH 2) into blood plasma (pH 7.4).
Passive diffusion of hydrophilic polar substances is possible through water pores (see Fig. 1.1). These are protein molecules in the cell membrane, permeable to water and substances dissolved in it. However, the diameter of the water pores is small (about 0.4 nm) and only small hydrophilic molecules (for example, urea) can penetrate through them. The majority of hydrophilic drugs with a molecular diameter of more than 1 nm do not pass through the water pores in the cell membrane. Therefore, most hydrophilic drugs do not penetrate into cells.
Filtration- this term is used both in relation to the penetration of hydrophilic substances through water pores in the cell membrane, and in relation to their penetration through intercellular spaces. Filtration of hydrophilic substances through intercellular spaces occurs under hydrostatic or osmotic pressure. This process is essential for the absorption, distribution and excretion of hydrophilic drugs and depends on the size of the intercellular spaces.
Since the intercellular gaps in different tissues are not the same in size, hydrophilic drugs are absorbed to an unequal degree with different routes of administration and are distributed unevenly in the body. For example, pro-
The gaps between the epithelial cells of the intestinal mucosa are small, which makes it difficult for the absorption of hydrophilic LB from the intestine into the blood.
The gaps between the endothelial cells of the vessels of peripheral tissues (skeletal muscles, subcutaneous tissue, internal organs) are quite large (about 2 nm) and allow most hydrophilic drugs to pass through, which ensures a fairly rapid penetration of drugs from tissues into the blood and from the blood into tissues. At the same time, there are no intercellular gaps in the endothelium of cerebral vessels. Endothelial cells tightly adhere to each other, forming a barrier (blood-brain barrier) that prevents the penetration of hydrophilic polar substances from the blood into the brain (Fig. 1.3).
^ active transport carried out with the help of special transport systems. Usually these are protein molecules that penetrate the cell membrane (see Fig. 1.1). The substance binds to the carrier protein on the outside of the membrane. Under the influence of ATP energy, the conformation of the protein molecule changes, which leads to a decrease in the binding force between the carrier and the transported substance and the release of the substance from the inside of the membrane. Thus, some hydrophilic polar substances can enter the cell.
Active transport of substances across the membrane has the following characteristics: specificity (transport proteins selectively bind and
Only certain substances are carried through the membrane), saturation (when all carrier proteins are bound, the amount of the substance transported through the membrane does not increase), occurs against the concentration gradient, requires energy (therefore, it is inhibited by metabolic poisons).
Active transport is involved in the transfer through cell membranes of substances necessary for the life of cells, such as amino acids, sugars, pyrimidine and purine bases, iron, and vitamins. Some hydrophilic drugs cross cell membranes by active transport. These LVs bind to the same transport systems that transport the above compounds through the membranes.
^ Facilitated diffusion - the transfer of substances through membranes using transport systems, which is carried out along a concentration gradient and does not require energy. Like active transport, facilitated diffusion is a substance-specific and saturable process. This transport facilitates the entry of hydrophilic polar substances into the cell. Thus, glucose can be transported across the cell membrane.
In addition to carrier proteins that carry out transmembrane transport of substances into the cell, many cell membranes contain transport proteins - P-glycoproteins, contributing to the removal of foreign compounds from cells. The P-glycoprotein pump is found in intestinal epithelial cells, in endothelial cells of brain vessels that form the blood-brain barrier, in the placenta, liver, kidneys, and other tissues. These transport proteins prevent the absorption of certain substances, their penetration through histohematological barriers, and affect the excretion of substances from the body.
pinocytosis(from Greek. pino - drink). Large molecules or aggregates of molecules come into contact with the outer surface of the membrane and are surrounded by it with the formation of a bubble (vacuole), which is separated from the membrane and immersed inside the cell. Further, the contents of the vesicle can be released inside the cell or from the other side of the cell to the outside by exocytosis.
^ 1.1. DRUG ABSORPTION
Suction(absorption, from lat. absorbeo - absorb) - the process by which a substance enters the blood and / or lymphatic system from the site of administration. Absorption of LB begins immediately after the introduction of LB into the body. The way the drug is introduced into the body depends on the rate and extent of its absorption, and ultimately the speed of the onset of the effect, its magnitude and duration.
^ Routes of drug administration
Distinguish enteral(through the digestive tract) and parenteral(bypassing the digestive tract) routes of drug administration.
A. Enteral routes of administration
To enteral (from the Greek. ento - inside and enteron - intestine) routes of administration include:
sublingual (under the tongue);
transbuccal (for the cheek);
oral (by mouth, per os)\
rectal (through the rectum, per rectum).
Sublingual and buccal routes of administration have a number of positive features:
they are simple and convenient for the patient;
substances administered sublingually or buccally are not affected by hydrochloric acid;
substances enter the general circulation, bypassing the liver, which prevents their premature destruction and excretion with bile, i.e., the so-called effect of the first passage through the liver is eliminated (see page 32);
due to good blood supply to the oral mucosa, the absorption of LB occurs quite quickly, which ensures fast development effect. This allows the use of such routes of administration in emergency conditions.
Oral administration. When drugs are administered orally, the main mechanism of drug absorption is passive diffusion - thus non-polar substances are easily absorbed. The absorption of hydrophilic polar substances is limited due to the small size of the intercellular spaces in the epithelium of the gastrointestinal tract. Few hydrophilic LB (levodopa, pyrimidine derivative - fluorouracil) are absorbed in the intestine by active transport.
The absorption of weakly acidic compounds (acetylsalicylic acid, barbiturates, etc.) begins already in the stomach, in the acidic environment of which most of the substance is non-ionized. But basically the absorption of all drugs, including weak acids, occurs in the intestine. This is facilitated by a large suction surface of the intestinal mucosa (200 m 2) and its intensive blood supply. Weak bases are absorbed in the intestine better than weak acids, since in the alkaline environment of the intestine, weak bases are mainly in a non-ionized form, which facilitates their penetration through the membranes of epithelial cells.
The absorption of medicinal substances is also influenced by their ability to dissolve in water (to reach the site of absorption, the substances must dissolve in the contents of the intestine), the particle size of the substance and the dosage form in which it is prescribed. When using solid dosage forms (tablets, capsules), the speed with which they disintegrate in the intestine is of great importance. The rapid disintegration of tablets (or capsules) helps to achieve a higher concentration of the substance at the site of absorption. To slow down the absorption and create a more constant concentration of drugs, dosage forms with a delayed (controlled) release of drugs are used. In this way, drugs of the so-called prolonged action can be obtained, which, unlike conventional drugs, last much longer
(calcium channel blocker nifedipine in conventional dosage forms is prescribed 3 times a day, and its prolonged forms 1-2 times a day).
Ingested medicinal substances are exposed to hydrochloric acid and digestive enzymes of the gastrointestinal tract. So, for example, benzylpenicillin is destroyed by hydrochloric acid of gastric juice, and insulin and other substances of the polypeptide structure are destroyed by proteolytic enzymes. To avoid destruction of some substances under the action of hydrochloric acid of gastric juice, they are prescribed in special dosage forms, namely in the form of tablets or capsules with an acid-resistant coating. Such dosage forms pass through the stomach without change and disintegrate only in the small intestine (intestinal dosage forms).
Absorption of LB in the gastrointestinal tract can be influenced by other factors. In particular, it depends on the motility of the gastrointestinal tract. Thus, the absorption of many drugs, especially weak bases (propranolol, codeine, etc.), which are predominantly in a non-ionized form in the alkaline environment of the intestine, occurs more intensively when gastric emptying is accelerated (for example, when using the gastrokinetic metoclopramide). The opposite effect is observed with the introduction of substances that delay gastric emptying, such as M-cholinoblockers (for example, atropine). At the same time, an increase in intestinal motility and, consequently, an acceleration of the movement of contents through the intestines can disrupt the absorption of slowly absorbed substances.
The quantity and qualitative composition of the intestinal contents also affect the absorption of drugs in the gastrointestinal tract. The constituent components of food can interfere with the absorption of drugs. For example, the calcium contained in in large numbers in dairy products, forms poorly absorbed complexes with tetracycline antibiotics. Tannin contained in tea forms insoluble tannates with iron preparations. Some drugs significantly affect the absorption of other drugs administered at the same time. So, wheel-tyramine (used in atherosclerosis to reduce the level of atherogenic lipoproteins) binds bile acids in the intestine and thus prevents the absorption of fat-soluble compounds, in particular vitamins K, A, E, D. In addition, it prevents the absorption of thyroxine, warfarin and some other LVs.
From the small intestine, substances are absorbed into the portal (portal) vein and with the blood flow first enter the liver and only then into the systemic circulation (Fig. 1.4). In the liver, most drugs are partially biotransformed (and inactivated at the same time) and/or excreted in the bile, so only a part of the absorbed substance enters the systemic circulation. This process is called the liver first pass effect or liver first pass elimination (elimination includes biotransformation and excretion).
Due to the fact that medicinal substances have a resorptive effect only after they have reached the systemic circulation (and then distributed over organs and tissues), the concept bioavailability.
Bioavailability- part of the administered dose of the medicinal substance, which, unchanged, reached the systemic circulation. Bioavailability is usually expressed as a percentage. The bioavailability of a substance when administered intravenously is assumed to be 100%. When administered orally, bioavailability is generally less. In the reference literature, bioavailability values of drugs for oral administration are usually given.
When administered orally, the bioavailability of drugs can be reduced for various reasons. Some substances are partially destroyed by hydrochloric acid and / or digestive enzymes of the gastrointestinal tract. Some drugs are not well absorbed in the intestine (for example, hydrophilic polar compounds) or are not completely released from tablet dosage forms, which may also be the reason for their low bioavailability. Known substances that are metabolized in the intestinal wall.
In addition, many substances, before entering the systemic circulation, undergo very intensive elimination during the first passage through the liver and, for this reason, have low bioavailability. Accordingly, doses of such drugs when administered orally usually exceed the doses required to achieve the same effect when administered parenterally or sublingually. So, nitroglycerin, which is almost completely absorbed from the intestine, but is eliminated by more than 90% during the first passage through the liver, is prescribed sublingually at a dose of 0.5 mg, and orally at a dose of 6.4 mg.
For comparative characteristics of drugs, in particular, drugs produced by different pharmaceutical companies and containing the same substance in the same dose, use the concept "bioequivalence". Two drugs are considered bioequivalent if they have the same
Bioavailability and absorption rate constant (characterizes the rate of drug entry into the systemic circulation from the injection site). At the same time, bioequivalent drugs should provide the same rate of reaching the maximum concentration of a substance in the blood.
The oral route of administration, as well as the sublingual route, has some advantages over parenteral routes of administration, namely, it is the simplest and most convenient for the patient, does not require the sterility of preparations and specially trained personnel. However, only those substances that are not destroyed in the gastrointestinal tract can be administered orally, in addition, the degree of absorption is influenced by the relative lipophilicity of the drug. The disadvantages of this route of administration include the dependence of the absorption of medicinal substances on the state of the mucous membrane and intestinal motility on the pH of the environment and the composition of the intestinal contents, in particular, on interaction with food components and other drugs. A significant disadvantage is that many drugs are partially are destroyed during the first passage through the liver.
In addition, the drugs themselves can affect the process of digestion and absorption of nutrients, including the absorption of vitamins. So, for example, osmotic laxatives impede the absorption of nutrients from the intestines, and antacids, by neutralizing the hydrochloric acid of gastric juice, disrupt the process of protein digestion.
The use of the oral route of administration is sometimes simply not available in some patients (if the patient refuses to take medication, in violation of the act of swallowing, persistent vomiting, in an unconscious state, in early childhood). In these cases, drugs can be administered through a small gastric tube through the nasal passages or through the mouth into the stomach and/or duodenum.
Rectal administration. The introduction of drugs into rectum(rectal) is used in cases where the oral route of administration is not possible (for example, with vomiting) or the medicinal substance has an unpleasant taste and smell and is destroyed in the stomach and upper intestines. Very often, the rectal route of administration is used in pediatric practice.
Rectally, medicinal substances are prescribed in the form of suppositories or in medicinal enemas with a volume of 50 ml. When administered in this way, substances that irritate the rectal mucosa are pre-mixed with mucus and heated to body temperature for better absorption.
Medicinal substances are rapidly absorbed from the rectum and enter the general circulation, bypassing the liver by 50%. The rectal route is not used for the introduction of high-molecular drugs of protein, fat and polysaccharide structure, since these substances are not absorbed from the large intestine. Some substances are administered rectally for local action on the rectal mucosa, for example, suppositories with benzocaine (anesthesin).
B. Parenteral routes of administration
Parenteral routes of administration include:
intravenous;
intra-arterial;
intrasternal;
intramuscular;
subcutaneous;
intraperitoneal;
under the membranes of the brain; and some others.
Aqueous solutions of medicinal substances are injected into the vein. The introduction into the vein of most drugs should be done slowly (often after preliminary dilution of the drug with a solution of sodium chloride or glucose).
However, if you need to quickly create a high concentration of a medicinal substance in the blood, it is administered quickly, in a stream. Intravenous administration of solutions of large volumes is carried out by the drip (infusion) method. In these cases, special systems with droppers are used to control the rate of administration. The latter is usually 20-60 drops per minute, which corresponds to about 1-3 ml of solution.
In small quantities, hypertonic solutions can be administered intravenously (for example, 10-20 ml of a 40% glucose solution). Due to the risk of blockage of blood vessels (embolism), intravenous administration of oil solutions, suspensions, aqueous solutions with gas bubbles is unacceptable. The introduction of irritants into the vein can lead to the development of thrombosis.
The intravenous route of administration is usually used in emergency medical care, but can be used on a planned basis and for course treatment in a hospital and outpatient setting.
Intra-arterial administration. The introduction of a medicinal substance into an artery supplying a certain organ makes it possible to create a high concentration of the active substance in it. X-ray contrast and antitumor drugs are administered intra-arterially. In some cases, intra-arterial antibiotics are administered.
Intrasternal administration (introduction to the sternum). This route of administration is used when intravenous administration is not possible, for example, in children, elderly people.
Intramuscular administration. Medicinal substances are usually injected into the upper-outer region of the gluteal muscle. Both lipophilic and hydrophilic drugs are administered intramuscularly. Absorption of hydrophilic LB when administered intramuscularly occurs mainly by filtration through intercellular spaces in the endothelium of skeletal muscle vessels. Lipophilic drugs are absorbed into the blood by passive diffusion. The muscle tissue has a good blood supply and therefore the absorption of drugs into the blood occurs quite quickly, which allows creating a sufficiently high concentration of the drug in the blood in 5-10 minutes.
Aqueous solutions (up to 10 ml) are injected intramuscularly, and oil solutions and suspensions are used to ensure a long-term effect, which delays the absorption of the substance from the injection site into the blood (Fig. 1.5). Hypertonic solutions and irritants should not be administered intramuscularly.
Subcutaneous administration. When administered under the skin, medicinal substances (lipophilic and hydrophilic) are absorbed in the same ways (ie, by passive diffusion and filtration) as with intramuscular injection. However, from the subcutaneous tissue, medicinal substances are absorbed somewhat more slowly than from muscle tissue, since the blood supply to the subcutaneous tissue is less intense than the blood supply to the skeletal muscles.
Aqueous solutions are injected subcutaneously, and oily solutions and suspensions are used with caution (see Fig. 1.5). Silicone containers are implanted into the subcutaneous tissue; tableted sterile solid dosage forms are implanted in the interscapular region. Subcutaneously it is impossible to enter substances with an irritant effect and hypertonic solutions.
Intraperitoneal administration. Substances are injected into the peritoneal cavity between its parietal and visceral sheets. This route is used, for example, to administer antibiotics during abdominal surgery.
Introduction under the membranes of the brain. Drugs can be administered sub-arachnoid or subdurally. Thus, in infectious tissue lesions and membranes of the brain are injected with antibiotics that poorly penetrate the blood-brain barrier. Subarachnoid administration of local anesthetics is used for spinal anesthesia.
Intravenous, intra-arterial, intrasternal, intramuscular, subcutaneous, and submenopausal administration require sterile dosage forms and are performed by qualified medical personnel.
Inhalation administration (from lat. inhalare - inhale). Gaseous substances, vapors of easily evaporating liquids, aerosols and air suspensions of fine solids are administered by inhalation. The absorption of drugs into the blood from a large surface of the lungs occurs very quickly. Thus, funds for inhalation anesthesia are administered.
Inhalation administration (usually in the form of aerosols) is also used to affect the mucous membrane and smooth muscles of the respiratory tract. This is one of the most common ways of administering bronchodilators and glucocorticoid preparations in bronchial asthma. In this case, the absorption of substances into the blood is undesirable, as it leads to the appearance of systemic side effects.
Intranasal administration. Substances are injected into the nasal cavity in the form of drops or special intranasal sprays. Absorption occurs from the mucous membrane of the nasal cavity. In this way, preparations of some peptide hormones are administered, which are prescribed in small doses. For example, desmopressin, an analogue of the antidiuretic hormone of the posterior pituitary gland, is used intranasally for diabetes insipidus at a dose of 10-20 mcg.
Transdermal administration. Some lipophilic medicinal substances in the form of metered ointments or patches (transdermal therapeutic systems) are applied to the skin, absorbed from its surface into the blood (in this case, the substances enter the systemic circulation, bypassing the liver) and have a resorptive effect. V Lately this route is used to administer nitroglycerin. With the help of transdermal dosage forms, it is possible to maintain a constant therapeutic concentration of the drug substance in the blood for a long time and thus ensure a long-term therapeutic effect. Thus, patches containing nitroglycerin have an antianginal effect (therapeutic effect in angina pectoris) for 12 hours.
It is possible to introduce ionized medicinal substances using iontophoresis (iontophoretic administration). The absorption of such substances after applying them to the skin or mucous membranes occurs under the influence of a weak electric field.
In addition, medicinal substances are applied to the skin or mucous membranes to obtain a local effect. In such cases, special dosage forms for external use are used (ointments, creams, solutions for external use, etc.). In this case, the absorption of drugs into the blood is undesirable.
Medicinal substances can also be injected into the pleural cavity (anti-tuberculosis drugs), into the cavity of the articular sac (administration of hydrocortisone for rheumatoid arthritis), into the body and into the lumen of the organ (for example, the introduction of oxyt-F-cine into the cervix and body of the uterus to stop postpartum hemorrhage).
^ 1.2. DISTRIBUTION OF MEDICINAL SUBSTANCES IN THE BODY
After entering the systemic circulation, drugs are distributed to various organs and tissues. The nature of the distribution of drugs is largely determined by their ability to dissolve in water or lipids (i.e., their relative hydrophilicity or lipophilicity), as well as the intensity of regional blood flow.
Hydrophilic polar substances are distributed unevenly in the body. Most hydrophilic drugs do not penetrate into cells and are distributed mainly in blood plasma and interstitial fluid. They enter the interstitial fluid through intercellular spaces in the vascular endothelium. There are no intercellular gaps in the endothelium of the capillaries of the brain - the endothelial cells are tightly adjacent to each other (there are so-called tight junctions between the cells). Such a continuous layer of endothelial cells forms the blood-brain barrier (BBB), which prevents the distribution of hydrophilic polar substances (including ionized molecules) in the brain tissue (see Fig. 1.3). Apparently, glial cells also perform a certain barrier function. Few hydrophilic drugs (for example, levodopa) penetrate this barrier only with the help of active transport.
However, there are areas of the brain that are not protected by the blood-brain barrier. The trigger zone of the vomiting center is accessible to substances that do not penetrate the BBB, such as the dopamine receptor antagonist domperidone. This allows the use of domperidone as an antiemetic that does not affect other brain structures. In addition, with inflammation of the meninges, the blood-brain barrier becomes more permeable to hydrophilic LB (this allows intravenous administration of benzylpenicillin sodium salt for the treatment of bacterial meningitis).
In addition to the BBB, there are other histohematic barriers in the body (i.e., barriers separating blood from tissues), which are an obstacle to the distribution of hydrophilic LB. and placental barriers. The placental barrier during pregnancy prevents the penetration of some hydrophilic polar drugs from the mother's body into the fetus's body.
Lipophilic non-polar substances are relatively evenly distributed in the body. They penetrate by passive diffusion through cell membranes and are distributed both in extracellular and intracellular body fluids. Lipophilic drugs pass through all histohematic barriers, in particular, they diffuse directly through the membranes of capillary endothelial cells into the brain tissue. Lipophilic LB easily pass through the placental barrier. Many drugs can have an undesirable effect on the fetus and therefore the use of drugs by pregnant women should be under strict medical supervision.
The distribution of drugs is also influenced by the intensity of blood supply to organs and tissues. Drugs are distributed faster to well-perfused organs, i.e. organs with an intensive blood supply, such as the heart, liver, kidneys, and rather slowly - in tissues with a relatively poor blood supply - subcutaneous tissue, adipose and bone tissue.
^ 1.3. DEPOSIT OF MEDICINAL SUBSTANCES IN THE BODY
D When distributed in the body, some LB can partially linger and accumulate in various tissues. This happens mainly due to the reversible binding of drugs to proteins, phospholipids and nucleoproteins of cells. This process is called depositing. The concentration of the substance at the place of its deposition (in the depot) can be quite high. From the depot, the substance is gradually released into the blood and distributed to other organs and tissues, including reaching the site of its action. Deposition can lead to a prolongation (prolongation) of the action of the drug or the appearance of an aftereffect. This happens with the introduction of an agent for intravenous anesthesia, sodium thiopental, a highly lipophilic compound that accumulates in adipose tissue. The drug causes a short anesthesia (about 15 minutes), after the termination of which comes post-anesthetic sleep (within 2-3 hours), associated with the release of thiopental from the depot.
The deposition of drugs in some tissues can lead to the development of side effects. For example, tetracyclines bind to calcium and accumulate in bone tissue. However, they can disrupt the development of the skeleton in young children. For the same reason, these drugs should not be given to pregnant women.
Many LVs bind to plasma proteins. Weakly acidic compounds (non-steroidal anti-inflammatory drugs, sulfonamides) bind mainly to albumins (the largest fraction of plasma proteins), and weak bases to α1-acid glycoprotein and some other plasma proteins. Binding of drugs to plasma proteins - reversible process, which can be represented as follows:
LP + protein complex LP-protein.
Substance-protein complexes do not penetrate through cell membranes and through intercellular spaces in the vascular endothelium (they are not filtered in the capillaries of the renal glomeruli either) and therefore are a kind of reservoir or depot of this substance in the blood.
Protein-bound drug does not show pharmacological activity. But since this binding is reversible, part of the substance is constantly released from the complex with the protein (this happens when the concentration of the free substance in the blood plasma decreases) and has a pharmacological effect.
The binding of LV to plasma proteins is not specific. Different drugs can bind to the same proteins with a sufficiently high affinity, while they compete for binding sites on protein molecules and can displace each other. In this case, the degree of binding of substances to proteins at their therapeutic concentrations in the blood is of great importance. So, for example, tolbutamide (a hypoglycemic agent used in diabetes mellitus) is approximately 96% bound to blood plasma proteins (while only about 5% of the substance is in the free, and, therefore, active state in the blood). With the simultaneous administration of sulfonamides, which at therapeutic concentrations bind to a significant fraction of plasma proteins, tolbutamide is rapidly displaced from the binding sites. This leads to an increase in the concentration of free tolbutamide tfc in the blood. The result, as a rule, is an excessive hypoglycemic effect of the drug, as well as a more rapid cessation of its effect, since at the same time biotransformation and excretion of a substance not bound to proteins from the body is accelerated. Of particular danger is the simultaneous administration of sulfonamides and the anticoagulant warfarin, which binds to plasma proteins by 99%. A rapid increase in the concentration of free warfarin (a drug with a small breadth of therapeutic action) leads to a sharp decrease in blood clotting and bleeding.
^ 1.4. BIOTRANSFORMATION OF DRUGS
Biotransformation (metabolism)- change in the chemical structure of medicinal substances and their physico-chemical properties under the action of body enzymes. The main focus of this process is the conversion of lipophilic substances, which are easily reabsorbed in the renal tubules, into hydrophilic polar compounds, which are rapidly excreted by the kidneys (not reabsorbed in the renal tubules). In the process of biotransformation, as a rule, there is a decrease in the activity (toxicity) of the starting substances.
Biotransformation of lipophilic drugs mainly occurs under the influence of liver enzymes localized in the membrane of the endoplasmic reticulum of hepatocytes. These enzymes are called microsomal because
They are associated with small subcellular fragments of the smooth endoplasmic reticulum (microsomes), which are formed during homogenization of the liver tissue or tissues of other organs and can be isolated by centrifugation (precipitated in the so-called "microsomal" fraction).
In blood plasma, as well as in the liver, intestines, lungs, skin, mucous membranes and other tissues, there are non-microsomal enzymes localized in the cytosol or mitochondria. These enzymes may be involved in the metabolism of hydrophilic substances.
There are two main types of drug metabolism:
non-synthetic reactions (metabolic transformation);
synthetic reactions (conjugation).
Metabolic transformation includes the following reactions: oxidation, reduction, hydrolysis. Many lipophilic compounds are oxidized in the liver by a microsomal system of enzymes known as mixed function oxidases, or monooxygenases. The main components of this system are cytochrome P-450 reductase and cytochrome P-450, a hemoprotein that binds drug molecules and oxygen in its active center. The reaction proceeds with the participation of NADPH. As a result, one oxygen atom is attached to the substrate (drug) with the formation of a hydroxyl group (hydroxylation reaction).
RH + 0 2 + NADPH + H + -> ROH + H 2 0 + NADP +, where RH is a drug substance, and ROH is a metabolite.
Oxidases of mixed functions have low substrate specificity. There are many known isoforms of cytochrome P-450 (Cytochrome P-450, CYP), each of which can metabolize several drugs. Thus, the CYP2C9 iso-form is involved in the metabolism of warfarin, phenytoin, ibuprofen, CYP2D6 metabolizes imipramine, haloperidol, propranolol, and CYP3A4 - carbamazepine, cyclosporine, erythromycin, nifedipine, verapamil and some other substances. The oxidation of some medicinal substances occurs under the influence of non-microsomal enzymes that are localized in the cytosol or mitochondria. These enzymes are characterized by substrate specificity, for example, monoamine oxidase A metabolizes norepinephrine, adrenaline, serotonin, alcohol dehydrogenase metabolizes ethyl alcohol to acetaldehyde.
Restoration of medicinal substances can occur with the participation of microsomal (chloramphenicol) and non-microsomal enzymes (chloral hydrate, naloxone).
Hydrolysis of medicinal substances is carried out mainly by non-microsomal enzymes (esterases, amidases, phosphatases) in blood plasma and tissues. In this case, due to the addition of water, ester, amide and phosphate bonds break in the molecules of medicinal substances. Esters undergo hydrolysis - acetylcholine, suxamethonium (hydrolyzed with the participation of cholinesterases), amides (procainamide), acetylsalicylic acid (see Table 1.1).
Table 1.1. The main pathways of metabolism (biotransformation) of medicinal substances
| Processes Biotransformations Enzymes
| chemical reactions | medicinal substances |
metabolic reactions
| Oxidation Hydroxylases Demethylase N-oxidase S-oxidase
| Hydroxylation Deamination N-oxidation S-oxidation | Phenobarbital, codeine, cyclosporine, phenytoin, propranolol, warfarin. Diazepam, amphetamine, ephedrine. Morphine, quinidine, acetaminophen. Phenothiazines, omeprazole, cimetidine |
| Recovery Reductases
| Recovery | Chloral hydrate, metronidazole, nitrofurans |
| Hydrolysis Esterases Amidases
| Hydrolysis of esters Hydrolysis of amides | Procaine, acetylsalicylic acid, enalapril, cocaine. Novocainamide, lidocaine, indomethacin |
Biosynthetic reactions
| ^ Conjugation with Sulfuric Acid Residue | ||
| Sulfotransferases | sulfate formation | Acetaminophen, steroids, methyldopa, estrone |
| ^ Conjugation with a glucuronic acid residue |
||
| Glucuronyl transfer-fold | Formation of esters, thio-esters or amides of glucuronic acid | Acetaminophen, chloramphenicol, diazepam, morphine, digoxin |
| ^ Conjugation with a-amino acid residues (glycycin, glutamine) | Amidation | Nicotinic acid, salicylic acid |
| Methylation |
||
| Methyltransferases | Joining a metal group | dopamine, epinephrine, histamine |
| Acetylation |
||
| N-acetyl transfers | Formation of amides of acetic acid | Sulfonamides, isoniazid |
Metabolites that are formed as a result of non-synthetic reactions may, in some cases, have a higher activity than the parent compounds. An example of increasing the activity of drugs in the process of metabolism is the use of drug precursors (prodrugs). Prodrugs are pharmacologically inactive, but they are converted into active substances in the body. For example, salazopyridazine, a drug for the treatment of ulcerative colitis, is converted by the intestinal azoreductase enzyme into sulfapyridazine and 5-aminosalicylic acid.
Acid with antibacterial and anti-inflammatory action. Many antihypertensive agents, such as angiotensin-converting enzyme inhibitors (enalapril), are hydrolyzed in the body to form active compounds. Prodrugs have a number of advantages. Very often, with their help, problems with the delivery of a medicinal substance to the site of its action are solved. For example, levodopa is a precursor of dopamine, but unlike dopamine, it penetrates the blood-brain barrier into the central nervous system, where, under the action of DOPA decarboxylase, it is converted into the active substance, dopamine.
Sometimes metabolic transformation products turn out to be more toxic than the parent compounds. Thus, the toxic effects of drugs containing nitro groups (metronidazole, nitrofurantoin) are determined by the intermediate products of the metabolic reduction of NO 2 -rpynn.
In the process of biosynthetic reactions (conjugation), residues of endogenous compounds (glucuronic acid, glutathione, glycine, sulfates, etc.) or highly polar chemical groups (acetyl, methyl groups) are attached to the functional groups of molecules of medicinal substances or their metabolites. These reactions proceed with the participation of enzymes (mainly transferases) of the liver, as well as enzymes of other tissues (lungs, kidneys). Enzymes are localized in microsomes or in the cytosolic fraction (see Table 1.1).
Most general reaction is conjugation with glucuronic acid. Attachment of glucuronic acid residues (formation of glucuronides) occurs with the participation of the microsomal enzyme UDP-glucuronyl transferase, which has a low substrate specificity, as a result of which many medicinal substances (as well as some exogenous compounds, such as corticosteroids and bilirubin) enter into a conjugation reaction with glucuronic acid . In the process of conjugation, highly polar hydrophilic compounds are formed, which are rapidly excreted by the kidneys (many metabolites also undergo conjugation). Conjugates are generally less active and toxic than the parent drugs.
The rate of biotransformation of medicinal substances depends on many factors. In particular, the activity of enzymes that metabolize medicinal substances depends on gender, age, body condition, and the simultaneous administration of other drugs. In men, the activity of microsomal enzymes is higher than in women, since the synthesis of these enzymes is stimulated by male sex hormones. Therefore, some substances are metabolized faster in men than in women.
In the embryonic period, most enzymes of the metabolism of medicinal substances are absent; in newborns in the first month of life, the activity of these enzymes is reduced and reaches a sufficient level only after 1-6 months. Therefore, in the first weeks of life, it is not recommended to prescribe such medicinal substances as chloramphenicol (due to insufficient activity of enzymes, its conjugation processes are slowed down and toxic effects appear).
The activity of liver enzymes decreases in old age, as a result of which the metabolic rate of many drugs decreases (for people over 60 years of age, such drugs are prescribed in smaller doses). In liver diseases, the activity of microsomal enzymes decreases, the biotransformation of certain medicinal substances slows down, and their action is strengthened and lengthened. In tired and debilitated patients, the neutralization of medicinal substances is slower.
Under the influence of certain drugs (phenobarbital, rifampicin, carbamazepine, griseofulvin), induction (increase in the rate of synthesis) of microsomal liver enzymes can occur. As a result, with simultaneous administration of other drugs (for example, glucocorticoids, oral contraceptives) with inducers of microsomal enzymes, the metabolic rate of the latter increases and their effect decreases. In some cases, the metabolic rate of the inductor itself may increase, as a result of which its pharmacological effects (carbamazepine) decrease.
Some medicinal substances (cimetidine, chloramphenicol, ketoconazole, ethanol) reduce the activity of metabolizing enzymes. For example, cimetidine is an inhibitor of microsomal oxidation and, by slowing down the metabolism of warfarin, may increase its anticoagulant effect and provoke bleeding. Known substances (furanocoumarins) contained in grapefruit juice that inhibit the metabolism of drugs such as cyclosporine, midazolam, alprazolam and, therefore, increase their action. With the simultaneous use of medicinal substances with inducers or inhibitors of metabolism, it is necessary to adjust the prescribed doses of these substances.
The metabolic rate of some drugs is determined by genetic factors. There was a section of pharmacology - pharmacogenetics, one of the tasks of which is to study the pathology of drug metabolism enzymes. A change in the activity of enzymes is often the result of a mutation in the gene that controls the synthesis of this enzyme. Violation of the structure and function of the enzyme is called enzymopathy (enzymopathy). With enzymopathies, the activity of the enzyme can be increased, and in this case, the process of metabolism of medicinal substances is accelerated and their effect is reduced. Conversely, the activity of enzymes can be reduced, as a result of which the destruction of medicinal substances will occur more slowly and their action will increase up to the appearance of toxic effects. Features of the action of medicinal substances in persons with genetically modified enzyme activity are given in Table. 1.2.
Table 1.2. Special reactions of the body to medicinal substances with genetic deficiency of certain enzymes
| enzyme deficiency | Special reactions | medicinal substances | Distribution in the population |
| Glucose-6-phosphate dehydrogenase of erythrocytes | Hemolysis of erythrocytes due to the formation of quinone. Hemolytic anemia | Quinine, quinidine, sulfonamides, acetylsalicylic acid, chloramphenicol | Tropical and subtropical countries; up to 100 million people |
| Liver N-acetyltransferase | More frequent adverse reactions due to slow acetylation of substances | Isoniazid, sulfonamides, procainamide | Caucasians (up to 50%) |
| catalase | No effect due to slow formation of atomic oxygen | Hydrogen peroxide | In Japan, Switzerland (up to 1%) |
| Plasma pseudocholinesterase | Prolonged relaxation of skeletal muscles (6-8 hours instead of 5-7 minutes) due to slow hydrolysis of the substance | Succinylcholine (ditylin) | Caucasians (0.04%), Eskimos (1%) |
^ 1.5. REMOVAL OF MEDICINAL SUBSTANCES FROM THE BODY
Medicinal substances and their metabolites are excreted (excreted) from the body mainly with urine (renal excretion), as well as with bile into the intestinal lumen.
renal excretion. Excretion of drugs and their metabolites by the kidneys occurs with the participation of three main processes: glomerular filtration, active secretion in the proximal tubules and tubular reabsorption.
Glomerular filtration. Medicinal substances dissolved in blood plasma (with the exception of substances associated with plasma proteins and macromolecular compounds) are filtered under hydrostatic pressure through intercellular spaces in the endothelium of the capillaries of the renal glomeruli and enter the lumen of the tubules. If these substances are not reabsorbed in the renal tubules, they are excreted in the urine.
active secretion. By active secretion, most of the substances excreted by the kidneys are released into the lumen of the tubules. Substances are secreted in the proximal tubules using special transport systems against a concentration gradient (this process requires energy). There are separate transport systems for organic acids (penicillins, salicylates, sulfonamides, thiazide diuretics, furosemide, etc.) and organic bases (morphine, quinine, dopamine, serotonin, amiloride, and a number of other substances). In the process of excretion, organic acids (as well as organic bases) can competitively displace each other from their association with transport proteins, as a result of which the excretion of the displaced substance decreases.
Reabsorption (reabsorption). Through the membranes of the renal tubules, drugs are reabsorbed by passive diffusion along a concentration gradient. Thus, lipophilic non-polar compounds are reabsorbed, since they easily penetrate the membranes of the epithelial cells of the renal tubules. Hydrophilic polar substances (including ionized compounds) are practically not reabsorbed and excreted from the body. Thus, the excretion of weak acids and weak bases by the kidneys is directly proportional to the degree of their ionization and, therefore, largely depends on the pH of the urine.
/Acid urine reaction promotes the excretion of weak bases (for example, alkaloids of nicotine, atropine, quinine) and makes it difficult to excrete weak acids (barbiturates, acetylsalicylic acid). To speed up the excretion of weak bases by the kidneys, you should change the reaction of urine v acid side (lower urine pH). Usually in such cases appoint ammonium chloride. Conversely, if it is necessary to increase the excretion of weak acids, sodium bicarbonate and other compounds are prescribed that shift the urine reaction to the alkaline side (increase the pH of the urine). Intravenous administration of sodium bicarbonate, in particular, is used to accelerate the excretion of barbiturates or acetylsalicylic acid in case of their overdose.
Reabsorption of some endogenous substances (amino acids, glucose, uric acid) is carried out by active transport.
Excretion through the gastrointestinal tract. Many medicinal substances (digoxin, tetracyclines, penicillins, rifampicin, etc.) are excreted in the bile into the intestinal lumen (in unchanged form or in the form of metabolites and conjugates) and are partially excreted from the body with excrement. However, some of the substances can be reabsorbed and, when passing through the liver, again
Excreted with bile into the intestinal lumen, etc. This cyclic process is called enterohepatic (enterohepatic) circulation. Some substances (morphine, chloramphenicol) are excreted in the bile in the form of conjugates with glucuronic acid (glucuronides), which are hydrolyzed in the intestine to form active substances, which are reabsorbed again. Thus, enterohepatic circulation contributes to the prolongation of the action of drugs. Some medicinal substances are poorly absorbed from the gastrointestinal tract and are completely excreted from the body through the intestines. Such substances are mainly used for the treatment or prevention of intestinal infections and dysbacteriosis (neomycin, nystatin).
Gaseous and volatile substances are excreted by the lungs. Thus, funds for inhalation anesthesia are removed. Some substances can be secreted by sweat, salivary glands (penicillins, iodides), stomach glands (quinine) and intestines (weak organic acids), lacrimal glands (rifampicin), mammary glands during lactation (hypnotics, ethyl alcohol, nicotine, etc. .). During feeding, medicinal substances that are secreted by the mammary glands can enter the baby's body with milk. Therefore, nursing mothers are contraindicated in the appointment of drugs (cytostatics, narcotic analgesics, chloramphenicol a, isoniazid, diazepam, antithyroid drugs, etc.), which can cause serious developmental disorders and adversely affect the child.
To characterize the totality of processes, as a result of which the active drug substance is removed from the body, the concept is introduced elimination, which combines two processes: biotransformation and excretion. Quantitatively, the elimination process is characterized by a number of pharmacokinetic parameters (see section " Mathematical modeling pharmacokinetic processes).
^ 1.6. MATHEMATICAL MODELING OF PHARMACOKINETIC PROCESSES
The magnitude and duration of the pharmacological effect is largely determined by the concentration of the drug substance (PM) in those organs or tissues where it has its effect. Therefore, it is very important to maintain a certain (therapeutic) concentration of the drug at the site of its action. However, in
in most cases, the concentration of a substance in tissues can be determined practically
impossible, therefore, in pharmacokinetic studies, the con
concentration of drugs in blood plasma, which for most substances correlate with
their concentrations in target organs.
As a result of absorption, distribution, deposition and elimination (biotransformation and excretion) of the drug, its concentration in the blood plasma changes. These changes can be displayed graphically. To do this, the concentration of the drug substance is measured in the blood plasma immediately and at certain intervals after its administration, and on the basis of the data obtained, a curve of changes in the concentration of the drug over time, or the so-called pharmacokinetic curve, is built (Fig. 1.6).
In order to quantify the effect of absorption, distribution of deposition and elimination on the concentration of drugs in the blood, mathematical pharmacokinetic models are used. There are single-chamber, two-chamber and multi-chamber pharmacokinetic models.
Time
intravenous administration
oral administration (per os)
In the single-chamber model, the body is conventionally represented as a chamber filled with liquid. The substance may enter the chamber gradually, as with oral administration (or other extravascular routes), or instantaneously, as with: rapid intravenous administration (Fig. 1.7).
After the substance enters the chamber in the amount D, it is distributed instantly and evenly and occupies the volume of the chamber, while the concentration of the substance that is created in the chamber is designated as the initial concentration - C 0 . The volume of distribution of the substance in the chamber is V d (volume of distribution) = D/C 0 .
In clinical practice, a parameter is used, which is called apparent volume of distribution(apparent volume of distribution, V d).
The apparent volume of distribution is the hypothetical volume of body fluid in which the drug substance is evenly distributed and at the same time is at a concentration equal to the concentration of this substance in the blood plasma (C). Accordingly, the apparent volume of distribution V d \u003d Q / C where Q is the amount of a substance in the body at a concentration in blood plasma of C.
If we assume that the substance after intravenous administration at a dose D was instantly and evenly distributed in the body, then the apparent volume of distribution is V d = D/C 0 , where C 0 is the initial concentration of the substance in the blood plasma.
The apparent volume of distribution makes it possible to judge the ratio in which the substance is distributed between body fluids (blood plasma, interstitial, intracellular fluids). So, if the value of V d of any substance has a value approximately equal to 3 liters (average plasma volume
blood), which means that this substance is mainly found in the blood plasma. Such a volume of distribution is typical for large molecular compounds that practically do not penetrate into blood cells and through the vascular endothelium (do not go beyond the vascular bed), for example, for heparin (V d - about 4 l).
If V d is equal to 15 l (the sum of the average volumes of blood plasma and interstitial fluid), the substance is predominantly in the blood plasma and interstitial fluid (extracellular fluid), i.e. does not penetrate into cells. Presumably this is a hydrophilic compound that does not pass through cell membranes. These substances include aminoglycoside antibiotics (gentamicin, tobramycin). Therefore, these antibiotics have practically no effect on microorganisms inside the cells, i.e. ineffective against intracellular infections.
Some medicinal substances have a volume of distribution of the order of 40 liters (the average volume of all body fluids). This means that they are found both in the extracellular and intracellular fluids of the body, i.e. penetrate through cell membranes. Basically, this is how lipophilic non-polar compounds are distributed in the body.
If the value of V d of the drug significantly exceeds the volume of body fluids, this substance is most likely deposited in peripheral tissues, and its concentration in blood plasma is extremely low. Large values of the volume of distribution are characteristic of tricyclic antidepressants imipramine and amitriptyline (V d - about 1600 l). Such drugs cannot be effectively removed from the body by hemodialysis.
After instantaneous and uniform distribution of the substance in the volume of the chamber and reaching the concentration C 0, the concentration of the substance in the chamber gradually decreases with the participation of two processes - biotransformation and excretion (see Fig. 1.7). Both of these processes are combined by the term elimination.
For most drugs, the elimination rate depends on the concentration of the substance (the lower the concentration of the substance, the lower the elimination rate). In this case, the curve of change in the concentration of a substance over time has an exponential character (Fig. 1.8). Such elimination corresponds to the kinetics of the 1st order (in a unit of time, certain part substances^.
The main parameters characterizing the elimination process are elimination rate constant(k el , k e) and half-life(t 1/2).
48
The rate constant of elimination of the 1st order shows what part of the substance is eliminated from the body per unit time (dimension min -1 , h -1). For example, if the k eI of any substance that was administered intravenously at a dose of 100 mg is 0.1 h ~ ", then after 1 h the amount of the substance in the blood will be 90 mg, and after 2 h - 81 mg, etc. .
Few drugs (ethanol, phenytoin) are eliminated according to zero order kinetics. The rate of such elimination does not depend on the concentration of the substance and is a constant value, i.e. eliminated per unit of time a certain amount of substances (for example, 10 g of pure ethanol is eliminated in 1 hour). This is due to the fact that at therapeutic concentrations of these substances in the blood, the enzymes that metabolize these substances are saturated. Therefore, with an increase in the concentration of such substances in the blood, the rate of their elimination does not increase.
The half-life (t I / 2, half-life) is the time during which the concentration of a substance in the blood plasma decreases by 50% (Fig. 1.9). For most drugs (for those whose elimination is subject to the kinetics of the 1st order), the elimination half-life is a constant value within certain limits and does not depend on the drug dose. Therefore, if 50% of the intravenously administered drug is removed from the blood plasma in one half-life period, then 75% is removed in 2 periods, and 90% in 3.3 periods (this parameter is used to select the intervals between injections of a substance necessary to maintain its constant blood concentration).
The half-life is related to the elimination rate constant by the following relationship:
T 1/2 \u003d ln2 / k eI \u003d 0.693 / k el.
If, immediately after intravenous administration of a substance, its concentration in blood plasma is measured at short intervals, then a two-phase pattern of changes in the concentration of a substance in the blood can be obtained (see Fig. 1.11).
The same character of the curve can be obtained using a two-chamber pharmacokinetic model (Fig. 1.10). In this model, the body is represented as two interconnected chambers. One of the chambers of this model is called central and represents blood plasma and well-perfused organs (heart, liver, kidneys, lungs), and the other, called peripheral, represents
poorly perfused tissues (skin, adipose, muscle tissue). The substance is introduced into the central chamber, where it is instantly and evenly distributed and from there it then penetrates into the peripheral chamber. This period is referred to as the distribution phase, or α-phase. Then the substance is redistributed from the peripheral chamber to the central one and is removed from it due to elimination. This phase (the elimination phase) is referred to as the β-phase. The α-phase is characterized by a parameter called the half-distribution period - t 1/2 (X, and the characteristic of the β-phase is the half-life itself, denoted as t 1/2 g (Fig. 1.11). The half-life is usually less than the half-life , since the substance is distributed from the central chamber to the peripheral one faster than it is eliminated.
Clearance is a pharmacokinetic parameter that characterizes the rate of release of the body from the drug.
Since the release of the body from drugs occurs due to the processes of biotransformation (metabolism) and excretion, metabolic and excretory clearance are distinguished. Metabolic clearance (Cl met) and excretory clearance (C excr) in total amount to systemic (total) clearance (Cl t, total clearance):
Cl met + C excr = Cl t
Systemic clearance is numerically equal to the volume of distribution that is released from the substance per unit time (the dimension is the volume per unit time, for example, ml / min, l / h, sometimes taking into account body weight, for example, ml / kg / min):
CL t = V d k el
Clearance values are directly proportional to the rate of elimination of the substance and inversely proportional to its concentration in the biological fluid (blood, plasma, serum):
Where C is the concentration of the substance.
Depending on the routes of elimination of LB, renal clearance (C1 hep), hepatic clearance (Cl hep), as well as clearance carried out by other organs (lungs, salivary, sweat and mammary glands, extrahepatic metabolism) are distinguished. The most important components of systemic clearance are renal and hepatic clearance.
Renal clearance is numerically equal to the volume of blood plasma that is released from the drug per unit time and depends on the intensity of the processes of glomerular filtration, tubular secretion and reabsorption. Renal clearance can be determined at a constant concentration of the substance in the blood plasma:
Where C u is the concentration of the substance in the urine, C is the concentration of the substance in the blood plasma and V u is the rate of urination.
Hepatic clearance depends on the processes of drug biotransformation and excretion of unchanged drug in the bile. The values of renal and hepatic clearance should be taken into account when prescribing drugs to patients with renal or hepatic insufficiency, respectively.
^ Optimization of drug dosing
To achieve the optimal therapeutic effect of a drug, it is necessary to constantly maintain its therapeutic concentration in the blood. A constantly maintained level of a substance in the blood plasma is denoted as stationary concentration(C ss , C steady-state). Stationary concentration is established when an equilibrium is reached between the process of entry of a substance into the systemic circulation and the process of its elimination (when the rate of entry is equal to the rate of elimination). The easiest way to achieve stationary concentration is intravenous drip (Fig. 1.12). With intravenous drip, the value of C ss depends on the rate of administration of the substance, which can be determined by the formula D / T = C CI.
The drug must be administered at such a rate as to maintain its therapeutic concentration in the blood. There is a range of therapeutic concentrations (Fig. 1.13). The lower limit of this range is the minimum effective concentration (C ™ p, below this concentration the substance does not have the necessary effect), the upper limit is the maximum safe concentration (C ™ \\ above which the area of toxic concentrations is located). Usually maintain the average concentration of this range, ie. mean therapeutic concentration of a substance in the blood. The values of the average therapeutic concentrations of medicinal substances are given in the reference literature.
The time to reach a stationary therapeutic concentration of a substance in the blood depends on its half-life. Through the period of elimination, 50% is reached, after 2 periods of elimination - 75% and after 3.3 periods - 90% of the stationary level of the substance in the blood. Therefore, if it is necessary to obtain a rapid therapeutic effect, especially if the substance has a sufficiently long half-life, a large loading dose of the drug is first administered (to achieve a stationary therapeutic concentration), and then the substance is administered by infusion at a certain rate to maintain a stationary concentration. However, most often the substances are prescribed in separate doses at certain intervals of time (most often the substances are administered orally). In such cases, the concentration of a substance in the blood does not remain constant, but varies relative to a stationary level, and these fluctuations should not go beyond the range of therapeutic concentrations. Therefore, after the appointment of a loading dose, which ensures the rapid achievement of a stationary therapeutic concentration, smaller maintenance doses are administered, which should provide only small fluctuations in the concentration of a substance in the blood relative to its stationary therapeutic level (Fig. 1.14). Loading and maintenance doses of drugs for each individual patient can be calculated using formulas that use the pharmacokinetic parameters presented in this section: volume of distribution, half-life, etc. When administered orally, the degree of drug absorption from the gastrointestinal tract, which is characterized by such parameter like bioavailability(part of the administered dose of a substance that reached the systemic circulation unchanged).
The bioavailability of substances when administered orally depends on many factors (see page 33) and is determined as follows. The substance is administered to the patient internally
rivenno and measure its concentration in the blood at regular intervals. Based on the data obtained, a curve is drawn for changing the concentration of the substance over time with intravenous administration. Then, to the same patient, this substance is administered orally in the same dose and its concentration in the blood is determined at certain time intervals. Based on the results of the measurement, a curve is built for changing the concentration of a substance over time when administered orally (Fig. 1.15).
Then measure the area under the curves concentration - time (AUC, Area Under the Curve). The bioavailability of a substance is determined by the formula:
Where F is bioavailability (Fraction); AUC - area under the concentration-time curve (Area Under the Curve).
