Transport of drugs by the blood system. Transport systems of drugs. Removal of drugs. biotransformation

General pharmacology. Pharmacokinetics. Ways and methods of introducing medicinal substances 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.

Subject of clinical pharmacology is a medicine in clinical practice.

Pharmacokinetics– changes in the concentration of medicinal substances in the environments of the body of a healthy and sick person, as well as the mechanisms by which these changes are carried out.

Pharmacokinetics - absorption, distribution, deposition, transformations

and excretion of drugs.

All routes of drug administration into the body can be divided into enteral and parenteral. Enteral routes of administration ( enteros– intestines) ensure the introduction of the drug into the body through the mucous membranes of the gastrointestinal tract. Enteral routes of administration include:

· Oral administration (orally, per os)– introduction of medicine into the body by ingestion. In this case, the medicine first enters the stomach and intestines, where it is absorbed into the portal vein system within 30-40 minutes. Next, through the bloodstream, the medicine enters the liver, then the inferior vena cava, the right side of the heart and, finally, the pulmonary circulation. Solid and liquid dosage forms (tablets, dragees, capsules, solutions, lozenges, etc.) are most often administered this way.

· Rectal route (>per rectum)- administration of the drug through the anus into the ampulla of the rectum. This way, soft dosage forms (suppositories, ointments) or solutions (using microenemas) are administered. The substance is absorbed into the hemorrhoidal vein system. 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) administration. In this way, solid dosage forms (tablets, powders), some 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 side of the heart and the pulmonary circulation. After this, the medicine is delivered to the left side of the heart and travels with arterial blood to the target organs.

Parenteral administration is a route of administration of a drug in which it enters the body bypassing the mucous membranes of the gastrointestinal tract.

· Injection administration. 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 tissue is damaged. They are carried out using a syringe and needle.

· Intravenous administration. With this method of administration, the syringe needle pierces the skin, hypodermis, and vein wall, and the medicine is directly injected into the systemic bloodstream (inferior or superior vena cava). The medicine can be administered slowly or quickly (bolus), as well as by drip.

· Intramuscular administration. All types of liquid dosage forms and powder solutions are administered this way. The needle of a syringe pierces the skin, hypodermis, muscle fascia and then its thickness, where the medicine is injected. The effect develops after 10-15 minutes. The volume of the injected solution should not exceed 10 ml. When administered intramuscularly, the drug is absorbed less completely than when administered intravenously, but better than when administered orally.

Inhalation administration- administration of a medicinal substance by inhalation of its vapors or tiny particles.

Transdermal administration– application of a medicinal substance to the skin to ensure its systemic action.

Local application. Includes application of the medicine to the skin, mucous membranes of the eyes (conjunctiva), nose, and larynx.

Mechanisms of drug absorption.

Suction- This is the process of drug entry from the injection site into the blood. The absorption of a drug substance depends on the route of administration into the body, the dosage form, physicochemical properties (lipid solubility or hydrophilicity of the substance), as well as on the intensity of blood flow at the injection site.

Drugs taken orally are absorbed, passing through the mucous membrane of the gastrointestinal tract, which is determined by their solubility in lipids and the 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 occurs without energy consumption along a concentration gradient.

Facilitated diffusion is the transport of drugs across biological membranes with the participation of specific transporter molecules. In this case, drug transfer also occurs along a concentration gradient, but the transfer rate is much higher. For example, cyanocobalamin is absorbed in this way. A specific protein, gastromucoprotein (internal Castle factor), which is formed in the stomach, is involved in its diffusion. If the production of this compound is impaired, then the absorption of cyanocobalamin is reduced and, as a consequence, pernicious anemia develops.

Filtration is carried out through the pores of cell membranes. This mechanism of passive absorption occurs without energy consumption and occurs along a concentration gradient. Characteristic of 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 occur against a concentration gradient. In this case, several substances can compete for the same transport mechanism. Active transport methods are highly specific, since they were formed during the long evolution of the body to meet its physiological needs. These mechanisms are the main ones for the delivery of nutrients into cells and the removal of metabolic products.

Pinocytosis (corpuscular absorption or pensorption) is also a type of absorption with energy expenditure, which can be carried out against a concentration gradient. In this case, the drug is captured and the cell membrane is invaginated to form a vacuole, which is directed to the opposite side of the cell, where exocytosis occurs and the drug is released.

Absorption is the transfer of a drug from the site of administration into the systemic circulation. Naturally, with the enteral route of administration, the drug released from the dosage form enters the blood through the epithelial cells of the gastrointestinal tract and is then distributed throughout the body. However, even with parenteral routes of administration, in order to get to the site of implementation of its pharmacological effect, it must, at a minimum, pass through the vascular endothelium, i.e., with any method of administration, in order to reach the target organ, the drug must penetrate through various biological membranes of epithelial and ( or) endothelial cells.

The membrane is represented by a bilayer of lipids (phospholipids) permeated with proteins. Each phospholipid has 2 hydrophobic tails facing inward and a hydrophilic head.

There are several options for the passage of a drug through biological membranes:

Passive diffusion.

Filtration through pores.

Active transport.

Pinocytosis.

Passive diffusion - the main mechanism of drug absorption. The transfer of drugs occurs through the lipid membrane along a concentration gradient (from an area of ​​higher concentration to an area of ​​lower concentration). In this case, the size of the molecules is not as significant as with filtration (Fig. 2).

Rice. 2. Passive diffusion

Factors affecting the rate of passive diffusion:

Suction surface(the main site of absorption of most drugs is the proximal part of the small intestine).

blood flow at the site of absorption (in the small intestine it is larger than in the stomach, therefore the absorption is greater).

Contact time Drugs with an absorption surface (with increased intestinal peristalsis, drug absorption decreases, and with weakened peristalsis, it increases).

Solubility degree Drugs in lipids (since the membrane contains lipids, lipophilic (non-polar) substances are better absorbed).

Degree of ionization PM. If a drug, at pH values ​​characteristic of body environments, is mainly in a non-ionized form, it is better soluble in lipids and penetrates well through biological membranes. If a substance is ionized, it penetrates membranes poorly, but has better water solubility.

Concentration gradient.

Membrane thickness.

Body fluids under physiological conditions have a pH of 7.3–7.4. The contents of the stomach and intestines, urine, inflamed tissues and tissues in a state of hypoxia have a different pH. The pH of the medium determines the degree of ionization of molecules of weak acids and weak bases (there are more weak bases among drugs than weak acids) according to the Henderson-Hasselbach formula.

For weak acids:

for weak bases:

Knowing the pH of the medium and the pKa of the substance (tabular data), it is possible to determine the degree of ionization of the drug, and therefore the degree of its absorption from the gastrointestinal tract, reabsorption or excretion by the kidneys at different urine pH values.

It follows that there are significantly fewer non-ionized forms of atropine in the acidic environment of the stomach than ionized ones (for 1 non-ionized form there are 10 7,7 ionized), which means that it will practically not be absorbed in the stomach.

Example 2.

Determine whether phenobarbital (pKa 7.4) will be reabsorbed in “acidic” urine (pH 6.4). Phenobarbital is a weak base.

It follows that under these conditions there are 10 times fewer non-ionized phenobarbital molecules than ionized ones, therefore, it will be poorly reabsorbed in “acidic” urine and excreted well.

In case of phenobarbital overdose, urine acidification is one of the methods of combating intoxication.

Filtration carried out through the pores existing between the epidermal cells of the gastrointestinal mucosa, cornea, capillary endothelium, and so on (most brain capillaries do not have such pores (Fig. 3)). Epithelial cells are separated by very narrow gaps through which only small water-soluble molecules (urea, aspirin, some ions) pass.

Rice. 3. Filtration

Active transport is the transport of drugs against a concentration gradient. This type of transport requires energy costs and the presence of a specific transfer system (Fig. 4). The mechanisms of active transport are highly specific; they were formed during the evolution of the organism and are necessary to fulfill its physiological needs. Because of this, drugs that penetrate cell membranes through active transport are close in their chemical structure to substances natural to the body (for example, some cytostatics are analogues of purines and pyrimidines).

Rice. 4. Active transport

Pinocytosis . Its essence is that the transported substance comes into contact with a certain area of ​​the membrane surface and this area bends inward, the edges of the recess close, and a bubble with the transported substance is formed. It is detached from the outer surface of the membrane and transferred into the cell (reminiscent of phagocytosis of microbes by macrophages). Drugs with a molecular weight greater than 1000 can enter the cell only through pinocytosis. In this way, fatty acids, protein fragments, and vitamin B12 are transferred. Pinocytosis plays a minor role in drug absorption (Fig. 5) .

Rice. 5. Pinocytosis

The listed mechanisms “work”, as a rule, in parallel, but usually one of them makes the predominant contribution. Which one depends on the place of administration and the physicochemical properties of the drug. Thus, in the oral cavity and stomach, passive diffusion is mainly realized, and to a lesser extent, filtration. Other mechanisms are practically not involved. In the small intestine there are no obstacles to the implementation of all the above mechanisms of absorption. In the large intestine and rectum, the processes of passive diffusion and filtration predominate. They are also the main mechanisms of drug absorption through the skin.

Option 2. (inaccurate)

Inhalation The following dosage forms are administered:

aerosols (β-adrenergic agonists);

gaseous substances (volatile anesthetics);

fine powders (sodium cromoglycate).

This method of administration provides both local (adrenergic agonists) and systemic (anesthetics) effects. Inhalation of drugs is carried out using special equipment (from the simplest spray cans for self-administration by patients to stationary devices). Given the close contact of inhaled air with the blood, as well as the huge alveolar surface, the rate of drug resorption is very high. Do not inhale medications that have irritating properties. It must be remembered that during inhalation, substances immediately enter the left side of the heart through the pulmonary veins, which creates conditions for the manifestation of a cardiotoxic effect.

Advantages of the method:

rapid development of the effect;

possibility of precise dosing;

absence of presystemic elimination.

Disadvantages of this method:

the need to use complex technical devices (anesthesia machines);

fire hazard (oxygen).

Transport of drugs in the body, to the place of application of their action is carried out by liquid tissues of the body - blood and lymph. In the blood, the drug can be in a free state and in a state associated with proteins and blood cells. Pharmacologically active, i.e. able to penetrate from the blood into target tissues and cause an effect is the free fraction of the drug.

The bound fraction of the drug represents the inactive depot of the drug and ensures its longer existence in the body.

As a rule, basic drugs bind to acidic a 1 -glycoproteins in the blood plasma, and acidic drugs are transported on albumin. Some drugs (hormonal, vitamin or mediator substances) can be transported on specific carrier proteins (thyroxine-binding globulin, transteritin, sex globulin, etc.). Some drugs can bind and be transported to LDL or HDL.

Depending on their ability to bind to proteins, all drugs can be divided into 2 classes:

· Class I: Drugs that are administered in doses less than the number of protein binding sites. Such drugs in the blood are almost completely (90-95%) bound to protein and the proportion of their free fraction is small;

· Class II: Drugs that are administered in doses greater than the number of protein binding sites. Such drugs in the blood are predominantly in a free state and the proportion of their bound fraction does not exceed 20-30%.

If a patient taking a Class I drug that is 95% protein bound (eg, tolbutamide) is coadministered with another drug, it will compete for binding sites and displace some of the first drug. Even if we assume that the proportion of displaced drug is only 10%, the level of the free fraction of drug from class I will be 5 + 10 = 15%, i.e. will increase 3 times (!) and the risk of developing toxic effects in such a patient will be very high.

If a patient takes a drug from class II, which is 30% protein bound, then if 10% is displaced by prescribing another drug, the free fraction will be only 70 + 10 = 80% or will increase by 1.14 times.

Scheme 3. Binding of class I and class II drugs to albumin, when they are prescribed separately and together. A. Class I drugs. The dose of drug is less than the number of binding sites available. Most of the drug molecules are bound to albumin and the concentration of the free drug fraction is low.

B. II class of drugs. The dose is greater than the number of binding sites available. Most albumin molecules contain bound drug, but the concentration of the free fraction is still significant.

C. Co-prescription of class I and class II drugs. With simultaneous administration, a class I drug is displaced from its binding to the protein and the level of its free fraction increases.

Thus, drugs that are significantly bound to protein have a longer-lasting effect, but can cause the development of toxic reactions if, while taking them, the patient is prescribed an additional drug, without adjusting the dose of the first drug.

Some drugs are in the blood in a state associated with formed elements. For example, pentoxifylline is carried on erythrocytes, and amino acids and some macrolides are carried on leukocytes.

Distribution A drug is the process of its distribution through organs and tissues after it enters the systemic circulation. It is the distribution of the drug that ensures that it reaches the target cells. The distribution of drugs depends on the following factors:

· The nature of the drug substance - the smaller the molecular size and the more lipophilic the drug, the faster and more uniform its distribution.

· Organ size - the larger the organ size, the more drug can enter it without significantly changing the concentration gradient. For example, the volume of skeletal muscle is very large, so the concentration of drug in it remains low even after a significant amount of drug has been absorbed. On the contrary, the volume of the brain is limited and the entry of even a small amount of drug into it is accompanied by a sharp increase in its concentration in the central nervous system tissue and the disappearance of the gradient.

· Blood flow in the organ. In well-perfused tissues (brain, heart, kidneys), a therapeutic concentration of the substance is created much earlier than in poorly perfused tissues (fat, bone). If a drug is rapidly degraded, its concentration may never increase in poorly perfused tissues.

· Presence of histohematic barriers (HB). The HGB is the collection of biological membranes between the capillary wall and the tissue it supplies. If the tissue has a poorly defined HGB, then the drug easily penetrates through it. This situation occurs in the liver, spleen, and red bone marrow, where there are sinusoidal type capillaries (i.e., capillaries with holes in the wall - fenestrae). On the contrary, in tissue with dense HGBs, the distribution of drugs occurs very poorly and is possible only for highly lipophilic compounds. The most powerful HGBs in the human body are:

[The blood-brain barrier is a barrier between blood capillaries and brain tissue. Covers all brain tissue with the exception of the pituitary gland and the bottom of the fourth ventricle. During inflammation, the permeability of the barrier increases sharply.

[ Blood-ophthalmic barrier - a barrier between capillaries and tissues of the eyeball;

[ Blood-thyroid barrier – barrier between capillaries and follicles of the thyroid gland;

[ Blood-placental barrier - separates the blood circulation of the mother and fetus. One of the most powerful barriers. Practically does not allow drug substances with Mr>600 Yes to pass through, regardless of their lipophilicity. The permeability of the barrier increases from 32-35 weeks of pregnancy. This is due to its thinning.

[The blood-testicular barrier is a barrier that separates the blood vessels and testicular tissue.

· Binding of the drug to plasma proteins. The larger the bound fraction of the drug, the worse its distribution in the tissue. This is due to the fact that only free molecules can leave the capillary.

· Deposition of the drug in tissues. Binding of the drug to tissue proteins promotes its accumulation in them, because The concentration of free drug in the perivascular space decreases and a high concentration gradient between the blood and tissues is constantly maintained.

A quantitative characteristic of drug distribution is the apparent volume of distribution (V d). The apparent volume of distribution is the hypothetical volume of fluid into which the entire administered dose of the drug can be distributed to create a concentration equal to the concentration in the blood plasma. That. V d is equal to the ratio of the administered dose (the total amount of drug in the body) to its concentration in the blood plasma:

.

Let's consider two hypothetical situations (see diagram 4). A certain substance A practically does not bind to macromolecules (thick, winding lines in the diagram) in both the vascular and extravascular compartments of the hypothetical organism. Therefore, substance A diffuses freely between these two compartments. When 20 units of a substance are introduced into the body, a state of stable equilibrium occurs when the concentration of substance A in the blood is 2 units/l and the volume of distribution, accordingly, is 10 l. Substance B, on the contrary, binds tightly to blood proteins, and the diffusion of the substance is significantly limited. When equilibrium is established, only 2 units of the total amount of substance B diffuse into the extravascular volume, and the remaining 18 units remain in the blood and the volume of distribution is 1.1 l. In each case, the total amount of drug in the body is the same (20 units), but the calculated volumes of distribution, as can be easily seen, are very different.

Scheme 4. Effect of binding of substances by tissues on the volume of their distribution. Explanations in the text.

Thus, the larger the apparent volume of distribution, the more of the drug is distributed into the tissue. For a person weighing 70 kg, the volume of liquid media is a total of 42 liters (see diagram 5). Then if:

[V d =3-4 l, then all the medicine is distributed in the blood;

[ V d<14 л, то все лекарство распределено во внеклеточной жидкости;

[V d =14-48 l, then all the medicine is approximately evenly distributed in the body;

[ V d >48 l, then all the medicine is located predominantly in the extracellular space.

Scheme 5. Relative magnitude of various volumes of body fluids where the distribution of drugs occurs in a person weighing 70 kg.

Apparent volume of distribution is often used when planning dosing regimens to calculate loading doses ( D n) and their corrections. A loading dose is a dose of medication that allows you to completely saturate the body with the drug and ensure its therapeutic concentration in the blood:

DRUG ELIMINATION

Elimination of drugs ( lat. elimino- take beyond the threshold) - is a set of metabolic and excretory processes that help remove the active form of a drug from the body and reduce its concentration in the blood plasma. Elimination includes 2 processes: biotransformation (metabolism) and excretion of drugs. The main organs of elimination are the liver and kidneys. In the liver, elimination occurs through biotransformation, and in the kidneys through excretion.

Absorption mechanisms (mechanisms of transport of medicinal substances) are presented in Fig. 2.3.

The most common mechanism of drug transport is passive diffusion through the membranes of intestinal wall cells (enterocytes). The rate of absorption in this case is proportional to the concentration gradient of substances and significantly depends on their solubility in the membrane (they are most easily absorbed by passive diffusion lipophilic nonpolar substances ).

Rice. 2.3.

A – diffusion; IN - filtration; WITH – active transport; D – pinocytosis

As a rule, electrolytes that are in a non-dissociated state undergo diffusion. The solubility and degree of ionization of a drug is determined by the pH of the contents of the stomach and intestines. It must be emphasized that drugs are well absorbed by passive diffusion in the rectum, which serves as the basis for administering drugs rectally. Types of passive transport are presented in Fig. 2.4.

Rice. 2.4.

Water, electrolytes and small hydrophilic molecules (for example, urea) are transported into the blood by another mechanism - filtration through pores in the intestinal epithelium. Filtration through pores is important for the absorption of drugs with a molecular weight of less than 100 Da and occurs along a concentration gradient.

Uses specialized mechanisms in cell membranes to expend energy to transport specific ions or molecules against a concentration gradient. It is characterized by selectivity and saturation. During active transport, there is competition between substances for the general transport mechanism (for example, during the absorption of certain vitamins and minerals). The degree of absorption depends on the dose of the drug, since the phenomenon of “carrier protein saturation” is possible. Features of active transport are presented in Fig. 2.5.

Main suction mechanism xenobiotics (synthesized medicinal substances) – passive diffusion. For substances of natural origin, such as amino acids, vitamins, essential microelements, etc., the body has specialized active transport mechanisms. In this case, the main route of absorption is active transport, and passive diffusion begins to play a role only at very high concentrations.

Drugs with large molecules or complexes of a drug with a large transport molecule are absorbed by pinocytosis. In this case, invagination of the intestinal epithelial cell membrane occurs and the formation of a vesicle (vacuole) filled with trapped fluid along with the drug. The vacuole migrates through the cytoplasm of the cell to the opposite side and releases its contents into the internal environment of the body. However, pinocytosis is not essential for the absorption of drugs and is used only

in rare cases (for example, when absorbing a complex of cyanocobalamin with protein - internal Castle factor).

Rice. 2.5.

Modern controlled release technologies in the production of drugs use such technological techniques as:

• use of excipients;
• granulation;
• microencapsulation;
• use of special pressing;
• coating with shells, etc.

With their help, you can change the disintegration time of the tablet, the rate of dissolution or release of the drug, the location of release and the duration of stay in a certain zone of the gastrointestinal tract (above the absorption window). And this, in turn, determines the speed and completeness of absorption, the dynamics of the concentration of the drug in the blood, i.e. bioavailability of the drug. For some drugs, tablets are created from microparticles with adhesive properties that “stick” to the mucous membrane, or tablets that swell in the stomach so much that they float on the surface and (or) cannot pass through the pyloric sphincter into the intestine. The rate at which tablets disintegrate in the stomach is affected by the way they are produced. Thus, regular (compressed) tablets are stronger than triturated (molded) tablets. The rate of disintegration also depends on the excipients used to impart the necessary properties to the tablet mixture (flowability, plasticity, compressibility, moisture content, etc.).

Enteric tablets are prepared by coating them with a gastro-resistant coating or by compressing granules or microcapsules previously coated with such coatings. If necessary, the shells can provide a longer dissolution delay than the 1 hour that the tablet spends in the stomach. The coating can be quite thick, for example a sugar coating, which sometimes has a greater mass than the tablet core containing the drug substance. Thin film shells (less than 10% of the tablet weight) can be made from cellulose, polyethylene glycols, gelatin, gum arabic, etc. By selecting the shell and introducing additional substances, it is possible to slow down the increase in the concentration of the active substance in the blood, which is important to reduce the risk of developing an undesirable reaction, and (or) shift the time to reach the maximum by several hours, if you want to prolong the effect of the drug and thereby reduce the frequency of administration in order to increasing compliance. Extended-release tablets (retard), for example, are usually prepared by compressing microgranules of the drug in a biopolymer shell or distributing it in a biopolymer matrix. With the gradual (layer-by-layer) dissolution of the base or shell, successive portions of the medicinal substance are released. Modern high-tech delivery methods make it possible to achieve a gradual, uniform release of the drug, for example, by creating osmotic pressure inside the capsule with the active substance. Based on this principle, new dosage forms of the well-known drugs nifedipine (Corinfar Uno), indapamide (Indapamide retard-Teva), piribedil (Pronoran®), tamsulosin (Omnic Okas), glipizide (Glibenez retard), trazodone (Trittiko) have been created. Controlled release can be achieved by using microcapsules with a drug substance coated with a special polymer in tablets. After the outer layer dissolves, liquid begins to flow into the capsule and as the core dissolves, the drug gradually releases and diffuses through the capsule membrane. The main factor limiting the production and use of such dosage forms remains the requirement for the release of all the active principle during the passage of the tablet through the main sites of drug absorption in the gastrointestinal tract - 4-5 hours.

In recent years, nanoparticle systems have been used for drug delivery. Lipid nanoparticles (liposomes) have obvious advantages due to their high degree of biocompatibility and versatility. These systems allow the creation of pharmaceuticals for local, oral, inhalation or parenteral routes of administration. The proven safety and efficacy of liposome-based drugs have made them attractive candidates for pharmaceuticals, as well as vaccines, diagnostics and nutraceuticals. A liposome in a cell is shown in Fig. 2.6. Liposomes are similar to vesicles that are composed of many, few, or only one phospholipid bilayer. The polar nature of the core allows for improved delivery of polar drug molecules that need to be encapsulated. The drug encapsulated in a liposome is shown in Fig. 2.7. Amphiphilic and lipophilic molecules dissolve in the phospholipid bilayer according to their affinity for phospholipids. The formation of bilayer niosomes is possible with the participation of nonionic surfactants instead of phospholipids.

Rice. 2.6.

Rice. 2.7.

Combination preparations containing several active substances that require different conditions for optimal absorption pose special technological problems for developers. Of course, if the requirements for the place and time of absorption are the same for the components, you can simply tablet the mixture or, if necessary (for example, to limit contact between the components during storage), pre-granulate and encapsulate the components. If the components require different parts of the gastrointestinal tract for optimal absorption, then the tablets are pressed from granules with different dissolution rates. In this case, it is also possible to use multilayer tabletting or controlled release technologies. Typically, the composition of a combined medicinal product does not include components that negatively affect the safety, absorption or pharmacological action of each other.

If the components of a complex drug must be absorbed at different times (but in the same place in the gastrointestinal tract), then there is no alternative to separate administration.

Sublingual administration used for nitroglycerin, because the drug immediately enters the general bloodstream, bypassing the intestinal wall and liver. However, most medications cannot be taken this way because they are less active or irritating.

Rectal administration used in cases where the patient cannot take the medicine by mouth due to nausea, inability to swallow, or if he cannot eat (for example, after surgery). In a rectal suppository, the drug is mixed with a low-melting substance that dissolves after insertion into the rectum. The thin mucous membrane of the rectum is well supplied with blood, so the drug is absorbed quickly, bypassing the liver on the first pass.

Injection route ( parenteral administration ) includes subcutaneous, intramuscular and intravenous methods of drug administration. In contrast to oral administration, drugs administered parenterally enter the bloodstream, bypassing the intestinal wall and liver, so such administration is accompanied by a faster and more reproducible response. Parenteral administration is used for the following situations: the patient cannot take drugs orally, the drug must enter the body quickly and in a certain dose, and it is also poorly or unpredictably absorbed.

At subcutaneous injections the needle is inserted under the skin, and the drug enters the capillaries and is then carried away by the bloodstream. Subcutaneous administration is used for many protein drugs, such as insulin, which, when taken orally, are digested in the gastrointestinal tract. Medicines for such injections can be suspensions or relatively insoluble complexes: this is necessary to slow down their entry into the blood (from several hours to several days or longer) and reduce the frequency of administration.

If you need to administer a large volume of drugs, intramuscular injections preferable to subcutaneous injections. For such injections, a longer needle is used.

At intravenous injections the needle is inserted directly into the vein. This is technically more difficult to perform compared to other methods of administration, especially in people with thin, mobile or sclerotic veins. The intravenous route of administration, a single injection or continuous drip, is the best way to deliver the drug to its intended destination quickly and in an accurate dose.

Transdermal administration used for drugs that can be introduced into the body using a patch applied to the skin. Such drugs, sometimes mixed with chemicals to facilitate penetration through the skin, enter the bloodstream slowly and continuously over hours, days, or even weeks without injection. However, some people experience irritation on the skin at the site of contact with the patch. In addition, with this administration, the medicine may not be delivered through the skin quickly enough. Only drugs prescribed in relatively small daily doses, such as nitroglycerin (for angina), nicotine (for smoking cessation), and fentanyl (for pain relief), are administered transdermally.

Some medications, such as general anesthetic gases and aerosolized asthma treatments, can be administered into the body by inhalation (inhalation). They enter the lungs and from there enter the bloodstream. Relatively few drugs are taken this way.

Absorption rate constant (TO a) characterizes the rate of entry from the injection site into the blood.

The pharmacokinetics diagram of drugs is presented in Fig. 2.8.

Rice. 2.8. Pharmacokinetics of drugs(scheme)

Distribution, metabolism, excretion of drugs

The distribution changes with an increase in the permeability of the blood-brain barrier (meningitis, encephalitis, head injury, shock, caffeine intake, aminophylline) and a decrease in the permeability of the blood-brain barrier (prednisolone, insulin).

Hydrophilic compounds penetrate the blood-brain barrier less well (lower incidence of side effects on the central nervous system).

Distribution changes when the drug accumulates excessively in tissues (lipophilic compounds) in cases of obesity. Volume of distribution of the drug ( V d) characterizes the degree of its uptake by tissues from blood plasma (serum). V d ( V d = D/C 0) – the conditional volume of liquid in which the entire dose of the drug that enters the body must be dissolved ( D ) to serum mv (C0). The distribution changes with hypoproteinemia (hepatitis, fasting, glomerulonephritis, old age), hyperproteinemia (Crohn's disease, rheumatoid arthritis), hyperbilirubinemia.

The phases of drug biotransformation are shown in Fig. 2.9. The metabolism of lipophilic drugs changes with liver pathology (it is necessary to reduce the dose of drugs or the frequency of doses), and the simultaneous administration of several drugs. Many vitamins, particularly vitamin B6, are cofactors for drug-metabolizing enzymes. Thus, foods rich in vitamin B6 increase the rate of breakdown of levodopa. This reduces the concentration of dopamine in the blood. The severity of the effects of antiparkinsonian drugs is reduced. On the other hand, vitamin B6 deficiency can reduce the rate of metabolism of drugs such as isoniazid and others.

Total drug clearance (C1 t) characterizes the rate of cleansing of the drug from the body. There are renal (Clr) and extrarenal ( Cl er) clearances, which reflect the excretion of the drug through urine and other routes (primarily bile). Total clearance is the sum of renal and extrarenal clearance. Half-life ( T 1/2) – the time required to halve the concentration of the drug in the blood depends on the elimination rate constant ( T 1/2 = 0,693/K el) . Elimination rate constants (TO el) and excretion (TO ate) characterize, respectively, the rate of disappearance of the drug from the body through biotransformation and excretion, the rate of excretion in urine, feces, saliva, etc. Elimination of hydrophobic drugs changes with liver pathology (it is necessary to reduce the dose of drugs or the frequency of doses), heart failure.

The elimination of drugs changes with the simultaneous administration of drugs that inhibit the activity of microsomal liver enzymes (cimetidine). The excretion of hydrophilic drugs changes with changes in urine pH, a decrease in active tubular secretion (hypoxia, infection, intoxication). Reabsorption and secretion of electrolytes and non-electrolytes in the nephron are shown in Fig. 2.10.

• Kuznetsova N.V. Clinical pharmacology. M., 2013.
• Katzung B. G. Basic and clinical pharmacology. M.: Binom, 1998.

Key Discussion Questions

Absorption of drugs from the injection site into the blood. Suction mechanisms. Factors influencing the absorption process. Transport of medicinal substances in the blood.

The significance of the binding of drugs to plasma proteins.

Distribution of drugs in the body. Factors influencing the distribution of drugs in the body. Histohematonic barriers. 1 blood-brain and placental barriers. Circulation circles of medicinal substances; enterohepatic 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 initial level

Instructions: Select one or more correct answers for the test questions below.

Option I

A. Absorption of drugs. B. Distribution of drugs in the body. B. Interaction with targets in the body. D Pharmacological effects. D. Metabolism. E. Excretion.

2. The main mechanism of absorption of medicinal substances from FA 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 fatty acids” into the blood:

A. Intensifies. B. Decreasing. B. Does not change.

4. Absorption of drugs by the mechanism of passive diffusion:

5. Drugs bound to blood plasma proteins:

A. Pharmacologically active. B. Pharmacologically inactive. B. Slowly metabolized, D. Not excreted by the kidneys.

Option 2

1. The concept of “pharmacokinetics” includes:

A. Absorption of drugs. B. Deposition of medicinal substances. B. Localization of action. D Biotransformation. D. Excretion.

2. It is easier to penetrate through histohematic barriers:

A. Polar hydrophilic substances. B. Non-polar lipophilic substances.

3. The following are well absorbed from GCT into the blood:

A. Ionized molecules. B. Peionized molecules. B. Hydrophilic molecules. D. Lipophilic molecules.

4. Absorption of medicinal substances via the active transport mechanism:

A. Accompanied by the expenditure of metabolic energy. B. Not accompanied by the expenditure of metabolic energy.

5. Medicinal substances not bound to blood plasma proteins:

A. They have pharmacological effects. B. They do not have pharmacological effects. B. Excreted by the kidneys. D. Not excreted by the kidneys.

Independent work

Task I. Fill out the table:

Mechanisms of absorption of drugs into the blood and their characteristics

Task 2. Fill out the table. Based on the data in the table, determine which of the drugs can be used as means:

A. To relieve attacks of angina. B. For the prevention and treatment of angina pectoris.

Task 3. Fill out the table.

Pharmacokinetic parameters

Based on pharmacokinetic parameters, discuss with your teacher questions about:

Speed ​​and completeness of absorption;

The speed of development of the maximum pharmacological effect;

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 a 1 ml 1% solution and orally in tablets at a dose of 10 mg.

The area under the curve (A11C) “concentration in blood - 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

Experiment 1. Two isolated rat stomachs are filled with

0.2% acetylsalicylic acid solution and 5% analgin solution. The pH of the environment in the stomach, equal to 2, is set to 0.1 N. NS solution). Two isolated sections of the small intestine of a rat (5-8 cm long) are also filled with a 0.2% solution of acetylsalicylic acid and a 5% solution of analgin. The pH value of the intestinal environment is 8.0. set with a 2% solution of NaHCO. Stomachs and sections of the small intestine filled with acetylsalicylic acid are placed in chemical cups with a 0.9% NaCl solution, to which PeClH indicators are added. Stomachs and sections of the small intestine filled with analgin solution are placed in a glass with a previously prepared indicator (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 absorption of medicinal substances is judged by the time the color appears 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:

Control of mastery of the topic (test tasks)

Instructions; select one or more correct answers for the test questions below, option /

/. What mechanism of drug absorption 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 proteins in blood plasma:

A. Pharmacologically active. G>. Excreted by the kidneys.

B. Pharmacologically inactive. D. They do not hatch at night. D. Create a drug depot in the blood.

3. With an increase in dissociated molecules of the drug, its absorption from the gastrointestinal tract:

L. Decreases. B. Increases.

4. Medicinal substances pass from the mother’s body to the fetus’s body through:

A. Blood-brain barrier. B. Placental barrier. B. Blood-ophthalmic barrier.

5. Hydrophilic medicinal substances are distributed predominantly in:

A. Intercellular fluid. B. Kidneys. V. 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 administered simultaneously with diclofenac, if it is known that the latter displaces digoxin from the complex with plasma proteins?

A. Will increase. B. Will decrease. V. Has not changed.

8. What factors influence the distribution of drugs in the body*

A. Physico-chemical properties. B. Ability to penetrate histohematic barriers. B. The speed of blood flow in organs and tissues. D. The ability to bind to blood plasma proteins. D. That's right.

9. Basic medicinal substances taken orally and gno are optimally absorbed into:

A. Stomach. B. Duodenum. B. Throughout the entire length of the gastrointestinal CT scan.

Option 2

1. Which absorption mechanism is characterized by protrusion of the cell membrane, capture of tiny droplets of liquid or solid particles and their passage into the cell?

A. Passive diffusion. B. Active transport. B. Filtration. G. Pinocytosis.

2. Medicinal substances of an acidic nature taken orally are optimally absorbed into:

A. Stomach. B. Duodenum. B. Rectum. D Throughout the gastrointestinal tract.

3. Medicinal substances pass from the blood to the brain cells through.