Pharmacology – (Greek Pharmacon - medicine) a science that studies the interaction of chemical compounds of biological and non-biological origin with the human and animal body.

The main task of pharmacology: search, development and study of new drugs for the prevention, treatment and diagnosis of various diseases and pathological conditions.

The range of issues that pharmacology studies:

- drug classification;

- pharmacodynamics, incl. mechanism of action;

- pharmacokinetics;

- indications and contraindications for use;

- drug side effects and complications;

- interaction of drugs when administered in combination;

- providing assistance in case of drug poisoning.

Pharmacology is divided into general and specific.

General pharmacology studies the general patterns of interaction of drugs with the body, i.e. pharmacodynamics and pharmacokinetics.

Private pharmacology studies the pharmacological properties of specific pharmacological groups and individual drugs.

Sections of pharmacology:

1. Pediatric pharmacology – studies the characteristics of the effects of drugs on the children's body.

2. Perinatal pharmacology - studies the effect of drugs on the fetus (from 24 weeks before birth) and the body of the newborn (in the first 4 weeks of life).

3. Geriatric pharmacology – studies the characteristics of the action and use of drugs in elderly and senile people.

4. Pharmacogenetics - studies the role of genetic factors in the body's sensitivity to drugs.

5. Chronopharmacology – studies the dependence of the pharmacological effects of substances on daily and seasonal rhythms.

6. Clinical pharmacology – studies the effect of drugs on the body of a sick person.

7. Medicinal toxicology - studies the effects of toxic, lethal doses of drugs and methods of neutralizing the body in case of drug poisoning.

Pharmacodynamics.

Pharmacodynamics – a branch of pharmacology that studies the totality of effects caused by drugs, including mechanisms of their action.

The therapeutic and prophylactic effect of any drug is manifested by enhancing or inhibiting physiological or biochemical processes in the body. This is achieved as follows:

- By interaction of the drug with the receptor (drug + R).

- Through the action of drugs on enzyme activity (ds + enzyme).

- Through the action of drugs on biomembranes (drugs + biomembrane).

- Through the interaction of some drugs with other drugs or with endogenous substances.

1. Interaction of the drug with receptors.

Receptor is a protein or glycoprotein that has high sensitivity and affinity for a specific chemical compound, including drugs.

Agonist –A drug that, when interacting with receptors, causes a pharmacological effect.

Antagonist– A drug that reduces or completely eliminates the effect of another drug.

Antidotes– Drugs that eliminate the effect of other drugs that cause poisoning.

There are two types of antagonism:

- competitive (direct);

- non-competitive (indirect).

Competitive antagonism is carried out by the competition of different drugs for binding sites on the same receptor, which leads to a decrease in the effects of one drug by another. Noncompetitive antagonism is associated with various receptors.

Synergism –mutual enhancement of the pharmacological effect of one drug by another.

Summation– the total effect of two or more simultaneously used drugs, which is equal to the arithmetic sum of the effects of each of these drugs.

Potentiation- this is when the total effect of the combined drugs is greater than the arithmetic sum of their pharmacological effects.

2. The effect of drugs on enzyme activity.

Some drugs are capable of increasing or decreasing the activity of enzymes, thus exerting their pharmacotherapeutic effect. For example, aspirin exhibits analgesic, anti-inflammatory and antipyretic effects due to the ability to selectively inhibit the enzyme cyclooxygenase.

3. Interaction with biomembranes.

A number of drugs are capable of changing the physicochemical properties of cellular and subcellular membranes, thus changing the transmembrane current of ions (Ca 2+, Na+ , K+). This principle underlies the mechanism of action of antiarrhythmic crises of local anesthetics, calcium channel blockers and some other drugs.

4. Drug-drug interaction.

Based on the principle of action of antidotes. (see above)

Types of action of drugs.

Main –This is the effect of the medicine that the doctor expects when using it.

Undesirable:- side;

Allergic;

Toxic.

Side effect - This is an adverse reaction of the body caused by the pharmacological properties of the drug, and is observed when it is used in doses recommended for treatment. They occur simultaneously with the main therapeutic effect. These reactions are not life-threatening, and are sometimes used as the main action. For example, the side (hypnotic) effect of the antiallergic drug diphenhydramine is often used as the main one.

Relative overdose - these are toxic reactions that can occur when even moderate therapeutic doses enter the body if the patient’s functions of drug-metabolizing and excreting organs are impaired.

Teratogenic effect (tetas - freak) is an undesirable effect of a drug on the fetus, which leads to the birth of a child with anomalies or deformities.

Embryotoxic effect – this is the toxic effect of drugs on the fetus up to 12 weeks of pregnancy.

Fetotoxic effect – this is a toxic effect on the fetus after 12 weeks of pregnancy.

Mutagenic effect – the ability of drugs to disrupt the genetic apparatus of germ cells, changing the genotype of the offspring.

Carcinogenic effect – the ability of substances to cause the formation of malignant tumors.

Local action of drugs – this is a manifestation of the therapeutic and prophylactic effect of a drug at the site of application (application) of the drug.

Resorptive effect of drugs – manifestation of the pharmacotherapeutic effect of a drug after absorption of the drug into the systemic circulation.

Types of doses.

Threshold – This is the minimum dose of a drug that causes any biological effect.

Medium therapeutic – the dose of the drug that causes the optimal therapeutic effect.

Higher therapeutic – the dose that causes the greatest pharmacological effect.

Breadth of therapeutic action – this is the interval between the threshold and highest therapeutic doses.

Toxic- the dose at which symptoms of poisoning occur.

deadly- a dose that causes death.

one-time– pro dosi – dose per dose.

Percussion- a dose prescribed at the beginning of treatment, which exceeds the average therapeutic dose by 2-3 times and is prescribed to quickly achieve the required concentration of the drug in the blood or other biological media.

supportive- the dose prescribed after the shock dose, and it usually corresponds to the average therapeutic dose.

The effect of drugs when they are reintroduced into the body.

With repeated use, the effectiveness of drugs may change both upward and downward. Undesirable effects occur.

The increase in pharmacological effect is associated with its ability to cumulate. Cumulation ( cumulation ) is an increase in the effect of drugs when they are reintroduced into the body.

There are two types of cumulation: material (physical) and functional.

Material cumulation– is realized when an increase in the therapeutic effect occurs due to the accumulation of drugs in the body.

Functional cumulation– this is when the increase in the therapeutic effect and the appearance of overdose symptoms occurs faster than the accumulation of the drug itself in the body.

addictive– this is a decrease in the pharmacological activity of the drug when it is reintroduced into the body.

Cross habituation – this is an addiction to drugs of a similar (close) chemical structure.

Lecture No. 2.

GENERAL PHARMACOLOGY (continued).

Pharmacokinetics – This is a branch of pharmacology that studies the various stages of a drug’s passage in the body: absorption (absorption), biotransport (binding with serum proteins), distribution to organs and tissues, biotransformation (metabolism), excretion of drugs from the body.

Ways of introducing drugs into the body.

The route of administration of the drug into the body depends on:

- speed and completeness of drug delivery to the site of the disease;

- effectiveness and safety of drug use, i.e. without complications of pharmacotherapy.

1. Enteral route of administration – the route of entry of drugs into the body through the gastrointestinal tract.

The advantages of the enteral route of administration:

- ease of use;

- safety of use;

- manifestation of local and resorptive effects.

The enteral route includes:

- oral (per os ) – through the mouth (intragastric);

- sublingual (Sub linqva) - under the tongue;

- intraduodenal ( Intra duodenum ) – into the duodenum.

- rectal (per rectum ) – through the rectum.

2. Parenteral route of administration – this is the entry of drugs into the body, bypassing the gastrointestinal tract.

The advantages of the parenteral route include:

- achieving precise dosage;

- quick implementation of the drug effect.

The parenteral route includes:

- intravenous administration;

- intra-arterial administration;

- intramuscular administration;

- subcutaneous administration;

- intratracheal administration;

- intravaginal administration;

- intraosseous injection.

Characteristics of individual stages of pharmacokinetics.

1. Absorption (absorption) - the process of drug entry from the site of its administration into the systemic circulation during extravascular administration.

The rate of drug absorption depends on:

- dosage form of the drug;

- degree of solubility of drugs in fats or water;

- dose or concentration of drugs;

- routes of administration;

- intensity of blood supply to organs and tissues.

The rate of absorption during oral administration of drugs depends on:

- pH of the environment in various parts of the gastrointestinal tract;

- the nature and volume of stomach contents;

- microbial contamination of the intestines;

- activity of food enzymes;

- state of gastrointestinal motility;

- interval between taking medication and food.

The process of drug absorption is characterized by the following pharmacokinetic parameters:

- Bioavailability (f) – the relative amount of the drug that enters the blood from the injection site (%).

- Suction rate constant (K 01) – a parameter that characterizes the rate of entry of drugs from the injection site into the blood (h -1, min -1).

- Half-absorption period ( t ½ α ) – time required for absorption of ½ of the administered dose from the injection site into the blood (hours, minutes).

- Time to reach maximum concentration ( tmax) – this is the time during which the maximum concentration of the drug in the blood is reached (h, min).

The intensity of drug absorption processes in children reaches the level of adults only by the age of three. Up to three years of life, drug absorption is reduced, mainly due to insufficient microbial contamination of the intestine, as well as due to lack of bile formation. In people over 55 years of age, absorption is also reduced. Therefore, children and the elderly need to dose medications taking into account the age-related anatomical and physiological characteristics of the body.

2. Biotransport – reversible interactions of drugs with transport proteins of blood plasma and erythrocyte membranes.

The vast majority of drugs (90%) interact reversibly with human serum albumin. In addition, drugs form reversible complexes with globulins, lipoproteins, and glycoproteins. The concentration of the protein-bound fraction corresponds to the free fraction, i.e. fraction not bound to the protein: [C bound] = [C free].

Only the free (not bound to protein) fraction has pharmacological activity, and the bound fraction is a kind of reserve of the drug in the blood.

The bound part of the drug with the transport protein determines:

- the strength of the pharmacological action of the drug;

Biotransformation occurs in 2 phases.

Reactions Iphases (biotransformation) – this is hydroxylation, oxidation, reduction, deamination, dealkylation, etc. During the reactions I phase, the structure of the L molecule changes C , such that it becomes more hydrophilic. This ensures easier excretion of metabolites from the body in urine.

Reactions I phases are carried out with the help of enzymes of the endoplasmic reticulum (microsomal enzymes or enzymes of the monooxygenase system), the main of which is cytochrome P - 450. Medicines can either increase or decrease the activity of this enzyme. PMs who have passed I phase, structurally prepared for reactions II biotransformation phases.

In progress reactions IIphasesconjugates or paired compounds of the drug are formed with one of the endogenous substances (for example, with glucuronic acid, glutathione, glycine sulfuric acid). The formation of conjugates occurs during the catalytic activity of one of the enzymes of the same name. For example, the conjugate drug + glucuronic acid is formed using the enzyme glucuronide transferase. The resulting conjugates are pharmacologically inactive substances and are easily excreted from the body with one of the excrements. However, not all of the administered drug dose undergoes biotransformation; part of it is excreted unchanged. - Elimination constant (K el ) – characterizes the rate of disappearance of the drug from the body through excretion and biotransformation (h -1, min -1).

- Half-life (t 1/2 ) is the time of disappearance of the drug from the body through biotransformation and excretion of ½ of the administered or received and absorbed dose (h, min.).

LOCAL The effect of drugs develops at the site of their use. For example, the analgesic effect of local anesthetics, etc.

RESORPTIVE the effect of the drugs develops after absorption into the blood and penetration to the target organ through histohematic barriers (for example: cardiac glycosides:, etc., exert their main positive inotropic effect on the heart muscle as a result of a resorptive effect).

1. DIRECT and INDIRECT(in some cases a reflex action).

The direct effect of drugs develops directly in the target organ. This action can be local, for example: a local anesthetic has a local analgesic effect, and resorptive, for example, a local anesthetic is used as an antiarrhythmic drug; in order to have a therapeutic effect in ventricular tachyarrhythmias of the heart, lidocaine must be absorbed into the blood and undergo histohematic barriers to the source of arrhythmia in the heart tissue.

Indirect action can be considered using the example of the action of cardiac glycosides (digoxin, strophanthin, etc.). has a stimulating effect on the contractility of the heart muscle, resulting in an increase in cardiac output. The speed of blood flow increases and perfusion (blood flow) in the kidneys increases. This leads to an increase in diuresis (the amount of urine increases). Thus, it indirectly increases diuresis through stimulation of myocardial contractility.

reflex the effect of drugs develops when in one place of the body the drug changes the activity of receptors, and as a result of this effect, the function of an organ changes in another place of the body (for example: ammonia, stimulating the receptors of the nasal mucosa leads to stimulation of the cells of the respiratory center of the brain, As a result, the frequency and depth of breathing increases).

1. SELECTIVE and NON-SELECTIVE.

Selective (elective) action of drugs

drugs are carried out by influencing certain receptors (for example: prazosin blocks predominantly L1|-adrenergic receptors) or drugs can accumulate in a certain organ and have an inherent effect (for example: iodine selectively accumulates in the thyroid gland, and there changes the function of this organ). In clinical practice, it is believed that the higher the selectivity of the action of a drug, the less toxicity and severity of negative side reactions.

Non-selective action of drugs, a term opposite to the selective effect (for example: the anesthetic drug fluorotane indiscriminately blocks almost all types of receptor formations in the body, mainly in the nervous system, which leads to an unconscious state, that is, anesthesia).

1. REVERSIBLE and IRREVERSIBLE.

The reversible effect of a drug is due to the fragility of chemical interactions with receptor formations or enzymes (hydrogen bonds, etc.; for example: an anticholinesterase drug of a reversible type of action -).

An irreversible effect occurs when the drug binds tightly to receptors or enzymes (covalent bonds; for example: an anticholinesterase drug of an irreversible type of action - Armin).

1. MAIN and SIDE.

The main effect of a drug is the effect of the drug aimed at treating the underlying disease (for example: doxazosin - an alpha-1 adrenergic blocker used to treat hypertension). Side effects are the effects of a drug that are not aimed at treating the underlying disease.

Side effects may be POSITIVE(for example: doxazosin, during a course of treatment of hypertension, inhibits the growth of the prostate gland and normalizes the tone of the sphincter of the bladder, and, therefore, can be used for prostate adenoma and urination disorders) and NEGATIVE(eg: doxazosin may cause transient tachycardia when treating hypertension, and withdrawal symptoms are often reported).

AGONISTS– drugs that excite receptor formations. For example: orciprinaline sulfate (asmopent) stimulates p 2 -adrenergic receptors of the bronchi and leads to expansion of the lumen of the bronchi.

ANTAGONISTS- medications that block receptor stimulation (metoprolol blocks beta-1 adrenergic receptors in the heart muscle and reduces the force of heart contraction).

AGONIST-ANTAGONIST– drugs that have the properties of both stimulating and inhibiting receptor formations. For example: pindolol (Wisken) blocks beta-1 and beta-2 adrenergic receptors. However, pindolol has so-called “intrinsic sympathomimetic activity,” that is, the drug, by blocking beta-adrenergic receptors and preventing the effect of the mediator on these receptors for a certain time, also has some stimulating effect on the same beta-adrenergic receptors.

Doses of medicines

1. one-time– amount of drug per dose;
2. Daily– the amount of the drug used during the day;
3. coursework — the amount of the drug used during the course of treatment of a specific disease (for example, for the treatment of stage 1 hypertension, it is used for 1.5-2 months);
4. percussion(as a rule, the initial single dose is 2 times higher than subsequent ones, most typical when prescribing sulfonamide drugs and cardiac glycosides);
5. Minimum(threshold) – the dose of the drug at which the therapeutic (medicinal) effect begins to appear;
6. Average therapeutic dose- the dose of a drug that is most often used in the treatment of a specific disease by a specific doctor at a specific time period. For example, the average therapeutic dose in the mid-70s of the 20th century was 100 thousand units per injection, and currently a minimum of 500 thousand units per injection is used;
7. Maximum– a dose of a drug that exhibits therapeutic activity, but when prescribed, a toxic effect does not yet appear;
8. toxic– a dose of a drug, when administered, a toxic effect is detected.
9. Lethal dose- a dose of a drug that causes death when administered. Finding the lethal dose is used in experimental pharmacology to determine the toxicity of drugs. Usually, to determine toxicity, LD is determined - 50, the dose of the drug that causes the death of 50% of animals (mice, rats, etc.).

Medicines are dosed:

• In weight units. (g, mg, mcg per 1 kg; per 1 m2);
• In volume units (ml, drops, etc.);
  • In activity units (ME - international units, ICE - frog action units).

Concentration– the amount of drugs in a certain volume.

For example, 5 and 40% glucose solutions have different effects on the body. 5% glucose solution – saline solution; 40% glucose solution is hypertonic and has a pronounced diuretic effect.

There are currently several ways to calculate doses for patients, especially children:

1. By body weight; Initially, it is believed that the average therapeutic dose is designed for a person weighing 70 kg. Knowing the child’s weight, you can calculate its single or course dose. For example: the average single therapeutic dose of nootropil for an adult is 700 mg. Knowing that the child’s weight is 10 kg, we calculate its single dose, making up the proportion: For 70 kg of body weight of an adult, 700 mg of the drug is prescribed, and for 10 kg of body weight of a child, 100 mg is prescribed.
2. According to the age: The average dose of the drug is considered to be prescribed for a person aged 24 years. Knowing the child's age, you can calculate its dose. For example: a person in

At the age of 24 years, a dose of 500 mg is prescribed, and for a child aged 12 years, it is recommended to prescribe 250 mg.

1. The literature describes the calculation of doses, which is widely used in pediatric practice in countries such as England and France:

If CHILD'S WEIGHT less than 30 kg:

DOSE = (MASS X 2)% ADULT DOSE;

For example: a child’s weight is 25 kg, then the dose of the drug will be 50% of the adult dose.

If the child weighs more than 30kg:

DOSE = (MASS + 30)% ADULT DOSE.

For example: a child’s weight is 50 kg, then the dose will be 80% of an adult. If the child’s weight exceeds 70 kg, a dose of the drug is prescribed that is recommended for adults.

With repeated administration of drugs, the following may be observed:

1. INCREASED EFFECT (cumulation);
2. REDUCTION OF EFFECT (addiction);
3. THE EFFECT DOES NOT CHANGE.

CUMULATION – accumulation (increase) EFFECT drug WHEN USING REPEATED.

Cumulation can be:

• MATERIAL
• FUNCTIONAL

1) Material cumulation – accumulation of drugs in the body; typical for long-acting drugs (cordarone, digoxin, etc.), and may cause negative toxic effects during accumulation. To reduce the negative effect of the drug, gradually reduce the dose or increase the intervals between drug doses.

2) Functional cumulation – the effect accumulates, not the substance. Functional cumulation is most characteristic of ethyl alcohol in chronic alcoholism and for some.

tolerance, resistance develops with long-term use of drugs (promedol, phenobarbital, galazolin, etc.).

Habituation may be due to:

1. With a decrease in drug absorption;
2. Increased metabolism;
3. Increasing the intensity of excretion;
4. Decreased sensitivity of receptor formations;
5. Reducing the density of receptors in tissues.

Cross addiction to drugs that interact with the same receptors ( substrates). For example, the emergence of resistance of microorganisms when using penicillins And cephalosporins.

PHARMACOLOGY (from the Greek pharmakon - medicine, poison and logos - word, teaching), the science of the action of medicinal substances on a living organism. The word F. first appeared in the 17th century; in 1693 Dale entitled his work on pharmacognosy “Pharmacologia, s. manuductio ad materiam medicam." Only almost a hundred years later, Gren published (in 1790) a manual on medicinal substances with the doctrine of their therapy. and physiol. action under the title Handbuch der Pharmacologie. Experimental physiology developed at first thanks to the works of physiologists (Claude Bernard, Stannius, Schiff, and others); The first school of pharmacologists arose led by Bukhheim, who created the first pharmacol in 1847. laboratory at Dorpat University. An experimental method for examining the effect of medicinal substances consists of studying the effect on healthy animals, on their systems and individual organs; research is often also carried out on single-celled organisms, such as ciliates, fungi, bacteria; Plants are often used as experimental material. After studying pharmacodynamics in healthy animals, the study of drugs continues on sick animals, since the susceptibility of healthy and sick organisms is often different. With this type of research it is often possible to outline the basis for therapy. use of the drug, thereby further clarifying the suitability, value and possible uses of the studied substance in the patient. The last stage of the experimental study of the substance takes place in clinics, where the therapy is determined. the effect of a medicinal substance with all its features and side effects. According to the same plan, medicinal substances that have been used for a long time are studied, since it is necessary to establish the mechanism of their action, fate in the body, location in it, routes of excretion, cumulative or synergistic effect, etc., subject to the diseased state of the body. The subject of pharmacology. studies may also include substances that are not used in therapy, but deserve attention, for example. due to its toxicity. According to its content, f. is divided into so-called. general physiology and particular physiology. The content of general physiology serves, in addition to defining the subject and tasks of physiology, setting the boundaries of physiology in a number of disciplines that study the various properties of medicinal substances, clarifying the essence of local and general, resp. resorptive, action of medicinal or toxic substances on the body, reflex, selective or specific, clarification of the various phases of action and various conditions on the part of the body and on the part of the medicinal substance that affect the manifestation of the action of drugs or poisons, taking into account the nature of their action, routes of administration, distribution in the body and the routes of elimination from the body, as well as those changes that the drugs or poisons themselves undergo in the body. That. in the department of general physiology, questions of general toxicology also find a place. - Partial physiology studies individual medicinal substances in relation to their effect on the whole organism and on its systems, on animal organs in situ, on isolated organs, on metabolism substances, at t°; studies all the questions specified in the general F., but in relation to each medicinal (resp. poisonous) substance. Pharmacol. the study captures the life of an animal under conditions of 1) the initial effect of the drug-physiol. action; further 2) the developed action of the drug, but still within the limits of b. or m. a healthy state of the body; such an effect approaches the effect of a medicine used in the so-called. middle therapists doses; in both cases, phenomena resulting from the influence of a medicinal substance are characterized by their reversibility; finally, the drug is studied under conditions where its action disturbs the normal state of equilibrium and signs of toxic action appear; the reaction may still be reversible in these cases, but not always; 3) when the body dies from changes that occur under the influence of an administered substance (lethal doses) - the reaction is irreversible. Measures to help a patient poisoned by a medicine are also developed by F. Private F. establishes the principles of indications for therapy. prescription of a medicinal substance, as well as contraindications under certain conditions on the part of the drug, and is in close connection with physiology and physiol. chemistry, using their methods and all the results and conclusions. F. studies the effect of drugs on a sick organism, therefore F.’s connection with Pat. Physiology also seems quite natural, especially since medications can also cause a wide variety of pathologies. phenomena in the body. In turn, F. contributes to the success and development of these disciplines, serving them with his data on medicinal and toxic substances used to study various physiol. and Pat. functions and processes. Bacteriology and microbiology, in addition to their contact with F. on problems of a general biological nature, work together on issues of the pharmacodynamic properties of medicinal serums, the action of toxins and endotoxins, protective serums, antiseptic and disinfectant substances, etc. Moral foul. honey. sciences, led by a microscope, anatomy also mutually £29 with F. serve each other's needs; the former provide F. with a material substrate, the effect of drugs and poisons on which is studied by her, and the latter, with her research, comes to the aid of the former not only in determining the dynamic significance of the devices being studied, but also their morphology. structures (Lavrentiev). Physics also owes its development and success to chemistry and physics, with which its connection is growing stronger and is the foundation for further progress in pharmacology. knowledge. Physics teaching and colloid chemistry most fundamentally influences the solution of pharmacol problems. character about the intimate side of the action of medicinal substances on the cell and on the body as a whole, about the distribution of medicinal substances in the body and about the points of application of the action of poisons, about the conditions of action of drugs in the body, about changes in the blood and tissues, etc. Development of chemistry and in In particular, pharmaceutical chemistry with its methods for the synthetic production of medicinal substances helped resolve the issue, outlined by Bukhheim, about the dependence of the effects of drugs and poisons on their physical and chemical properties. properties and made it possible to establish the principle of similarity pharmacol. actions in chemically related bodies. The varied, centuries-old use of medicines for therapeutic purposes has connected F. with all types of therapy. F., serving clinics, in turn strives to carry out all the latest means, as well as new information about the substances used, through wedge analysis. The connection between F. and the judicial medicine is established through the department of toxicology. This latter has gained great importance in modern times, especially in the USSR, where the task of eliminating hazards affecting the health and productivity of workers was put in full swing. Therefore, sanitation and hygiene with all its subdepartments , in particular, professional hygiene and food hygiene, closely engaged in the study of the pharmacodynamics of many substances, the effects of which can adversely affect the health of workers under certain conditions of production or nutrition, or the use of prepared items, work hand in hand with F. In especially close F. is in contact with pharmaceutical chemistry, with pharmaceutical formulations and, through the latter, with the technology of medicinal products and forms; data from these disciplines are largely developed by pharmacology. Modern physiology concentrates its attention on the following tasks: 1) find and combine into one the most important laws that will make it possible to determine the nature and direction of the action of drugs on the body; 2) to study the transformation of drugs in the body of animals, in particular in humans, the place of distribution in the body, the route of excretion and the action of both the administered substance and its products of transformation in the body, in connection with the study of the environment in which the drug acts. The most important particular problems in this aspect are the following: 1) the problem of the action of heavy metals in connection with electrolytic. dissociation of their compounds; 2) question about pharmacol. irritants in connection with issues of isoionicity and isotonicity of the environment surrounding the cell; 3) the problem of anesthesia in connection with work on means for inhalation, intravenous and rectal anesthesia; 4) question about sleeping pills; 5) poisons of the autonomic nervous system with sympathicotropic and parasympathicotropic effects; 6) study of foxglove. ergot and other herbal preparations; 7) the synergistic effect of substances and the relationship in action between simple mixtures and compounds; 8) phenomena of habituation to certain drugs or poisons; 9) question about potential poisons; 10) study of the strength, speed and duration of action of drugs; 11) development of the problem of the relationship between the chemical structure and pharmacological action of medicinal and toxic substances; 12) study of natural (obtained from various plants) and synthetic camphor; 13) the problem of penetration and circulation of iodine in the body and its effect on metabolism, nutrition and tissue structure; 14) the problem of using drugs for preventive purposes; 15) studying the effect of drugs introduced into the body in minimal quantities; 16) the effect of drugs substances depending on their dosage form; 17) problems of hormone therapy, organotherapy, lysate therapy, protein therapy; 18) problem of studying traditional medicine. Methods. Physics, as a science adjacent to the cycle of biological disciplines, uses all the methods of experimental physiology, analytical , biological and colloid chemistry, microchemistry, the method of biological analysis, in many cases adapting and specializing them so much that essentially one or another method is strengthened by F. The method of isolated organs in relation to the liver, kidneys and heart, introduced by physiologists, worked out by Kravkov and his students on the heart, liver, ear and other parts of the body, is generally considered to be F., since the technique is used to study medicinal and toxic substances. Having determined the quality and intensity of the pharmacological action of the medicinal agent, it is then subjected to wedge testing and application. - History of pharmacology. experimental method is also known by the so-called. therapist methods, which include: 1) ancient therapy. the method is empirical, roughly experimental, and has provided enormous material about medicines, but not illuminated by scientific theory; 2) statistical method; applied with all the rigor of scientific criticism, it becomes a necessary and strict judge of modern experimental methods of laboratory and wedge, drug research; 3) symptomatic method, which consists in recording observations of the elimination or relief with the help of medications of specific painful symptoms of diseases, but the main cause and essence of the disease remains without attention; 4) the method of suggestion, when the effect of a medicine is looked at not as a result of the influence of certain material forces, but as a means of influencing the patient’s psyche; Therefore, the taste of the medicine, its smell, especially the novelty of the drug and the novelty of the method of administration are highly valued by the method of suggestion. While the experimental method of studying medicinal substances since the 40s of the 19th century. especially began to be cultivated in Germany, French scientists concentrated the study of medicinal substances in clinics, using mainly therapy for this. methods. This is how two main pharmacological schools were created; The French one was joined by specialists in England and Italy, and the German one was joined by scientists from other European countries, in particular Russians, who usually received and supplemented their special education in Germany. The development of pharmacodynamics in laboratories was so successful that the German school of pharmacologists transferred the entire study of the action of medicinal substances to the laboratory, concentrating the study of medicinal products only on animals; in the 60s of the 19th century. German pharmacologists even expressed the opinion that F. does not care whether the substance being studied will be used in clinics, the only important thing is which physiol. the effect the substance under study has on the body. This is the view of pharmacophysiologists. Current scientific philosophy is far from such a view. In the present, time and French pharmacol. the school under the leadership of Tiffeneau, Fourneau and Florence significantly deepened its research on medicinal substances by studying them using the experimental laboratory method on animals, while at the same time conducting conventional therapies on the same drugs. study methods. There was a shift towards the clip and examination of medicines in the German school in the 70s of the 19th century, when Schmiedeberg “together with the clinician Naunin organized pharmacol. a magazine that gives space to articles with a wedge, analysis of the effect of drugs; In the second decade of the present century, in the person of G. Meyer (Vienna), the German school raised the question of the need to join wedges, departments to pharmacological institutes to study the pharmacodynamic properties of medicinal substances in all the diversity of their actions in humans. After that Heutmer (Göttingen, Berlin) organized joint teaching with a therapist at the university on certain studies of the effects of drugs. Bornstein (Hamburg) systematically studied the effects of drugs in parallel in the laboratory on animals and in the clinic on humans. In Russia, Bogoslovsky (Moscow ) back in the 90s of the 19th century, he arranged the teaching of Physics in such a way that students saw the effect of drugs not only on animals, but also on patients in the clinic. Kravkov followed the same path in his research. Department of Pharmacology 1 MMI ( Nikolaev) raised the question of the need to reform the teaching of medicine in the direction of parallel study by students of medicinal substances in the laboratory on animals and in the clinic on humans. The latest medicinal substances produced by Soviet pharmaceutical companies. industry, are studied experimentally in pharmakol. laboratories and clinics on used and - only after such a test are recommended for medical use. The most prominent therapists (Pletnev) speak out for the timeliness of experimental study of drugs in humans, and not just in animals. In Italy, where previously the direction of the French school dominated in F., later under the influence of the German school, which educated a large number of modern Italian pharmacologists (Baldoni, Cervello), the doctrine of the action of drugs strongly deviated towards laboratory research. In England, Cuslmy combined experimental and therapeutic studies of medicinal substances. methods and managed to turn English F. onto this combined path. The Japanese school of pharmacologists, headed by Morishima and Hayashi, students of the German experimental school, works using both experimental laboratory and clinical therapeutic methods. American pharmacologists also work in the same direction. In the USSR, Kravkov created a prominent Leningrad school of pharmacologists, now headed by Likhachev. The Kazan (Dogel), Tomsk (Burzhinsky), Moscow (Chervinsky) schools are not rich in students; the first and last are experimental and physiological in nature, the second is experimental with a wedge, a bias^ F. is studied in the crust, time in Western Europe in special pharmakol. in-tah with high boots. Pharmakol is perfectly arranged and equipped. institutes in Freiburg (Baden), Munich, Bonn, Dusseldorf. Some occupy separate buildings of 3-4 floors. The institutes have departments: experimental vivisection, chemical, and in some places bacteriological; library, museum, material, darkroom; auditorium, separate rooms for the work of professors, assistants and medical specialists; Some institutes have rooms for practical training for students, a room for experimental animals, and a room with a low temperature. The vivarium is set up at the institute in a special room with sections for various animals; ranarium; glacier, basement. In Italy there is Pharmakol. experimental institutes, but there are institutes of a mixed type - institutes of F. with toxicology and institutes of pharmacology with pharmacognostic ones (Materia medica). In America - Pharmacol. departments, laboratories, departments of Materia medica and Therapeutics. Japan has special pharmacol in all high fur boots. Institute of German type. In the USSR Pharmacol. institutes are located in the same building with institutes from other departments. Institutes and laboratories have demonstration collections of Pharmakol. and pharmacognostic material, drawings and tables prepared in accordance with the course being taught. Older institutes and laboratories have their own libraries. In the USSR, pharmacologists are not united into a separate society, but are members of the Union Society of Physiologists, Biochemists, Pharmacologists and Histologists, in which they take part in congresses, forming a separate section. Pharmacologists of the USSR also take part in regional congresses of physiologists, pharmacologists and biologists, convened in Povolya and very regularly in the south in the republics of Transcaucasia and the Caucasus; the last congress was in Erivan in October 1934. Soviet pharmacologists do not have a separate publication; in physiol. USSR magazine named after. Sechenov pharmacology has its own department. The teaching of medicine developed in most countries under the predominant influence of the German school and consists of a lecture course accompanied by a demonstration of the effect of drugs on animals (Austria, Switzerland, Poland, Czechoslovakia, Norway, the Baltic states, partly Italy, Japan); in other countries the French system of wedge, the study of medicines, is practiced; England, Italy and America switched to a mixed system of laboratory-clinical method. The USSR follows the model of the German school. The teaching of experimental medicine began in the sixties with Sokolovsky’s course in Kazan. Before that, medicinal science was taught at the department of “Medical substance science, pharmacy and medical literature" in accordance with pharmacognostics, the content of collections on Materia medica and consisted of describing drugs from the pharmacognostic side and indicating their therapeutic use. According to the university charter of 1863, two departments were created at the medical faculties instead of one: one - "Pharmacognosy and Pharmacy", the other - "Theoretical and Experimental Pharmacology". Since 1884, the F. department was obliged to teach not only "pharmacology", but also "formulation, toxicology and the study of mineral waters"; pharmacy and pharmacognosy were taught at In the 2nd year, 6 hours a week for two semesters, and in the 3rd year, 6 hours a week, also for two semesters. They taught using the lecture method with demonstrations of experiments and preparations during the lecture. Practical classes in Physics were organized in exceptional cases (Likhachev, Boldyrev, Nikolaev). During the reorganization of all teaching in the USSR, the Department of Pharmacy and Pharmacognosy in 1923 was transferred to honey. faculties was liquidated, and the department of Physics was entrusted with the responsibility to include information on pharmacognosy and pharmaceuticals in the Physics course with recipes. chemistry necessary for the assimilation of medicines and the skillful administration of medicines. F. was given 5 hours a week to teach in both semesters of the 3rd year. Mandatory practical classes were introduced in 1926. Since the fall of 1934, 150 hours have been allocated for F. in the 3rd year in two semesters; According to the new plan, another 22 hours have been added, which should be considered sufficient for teaching F. By introducing mandatory practical classes for students in Physics, its teaching here compares favorably with that abroad. Lit.: B about l dbfp ev V., A short guide for practical classes in pharmacology, Kazan, 1913; Vershinin N., Pharmacology as the basis of therapy, Tomsk, 1933; Garkavi-Dandau D., A short guide to experimental pharmacology, Baku, 1927; Tsramepitsky M., General pharmacology, L.-M., 1931; about n e, Textbook of pharmacology, L.-M., 1935; K e sh n and A., Guide to pharmacology, vol. I-II, M., 1930-31; Kravkov N., Modern problems of pharmacology and materialism, St. Petersburg, 1903; aka, Fundamentals of Pharmacology, parts 1-2, D.-M., 1933; Lavrov D., Fundamentals of pharmacology and toxicology, Odessa, 1923; Lubu Shin A., Skvortsov V., Sobolev M. and Shishov I., A manual for practical classes in pharmacology with toxicology, M., 1933; Muller F., Theoretical and clinical pharmacology, Berlin, 1921; Pravdiv N., Experimental introduction to the study of pharmacology, M., 1926; Skvortsov V., Textbook of Pharmacology, M.-L., 1933; Soshestvensky N., Course of pharmacology and pharmacotherapy of domestic animals, parts 1-2, M.-L., 1930-31; Tif-no M., Pharmacological reviews, collection. 1-Pharmacology for 1928-29, M., 1932; Frobner E., Guide to pharmacology, M., 1934; Handbuch der experimentellen Pharmakologie, hrsg. v. A. Heffter u. W. Heubner, B. I-III, V., 1923-29 (lit.); H a n d o u 8 k u R., Pharmakologie in ihrer modernen Problemstellungen, Dresden-Jjpz., 1931; Magnus It., Einfaches pharmakologisches Praktikum f. Medizlner, V., 1921; Meyer H. u. G o t-t li e b R., Experimented Pharmakologie, V. - Wien, 1925 (Russian publishing house - St. Petersburg, 1913); Poulsson E., Lehrbuch der Pharmakologie, Lpz., 1920; Tap peiner H. u. Schmie-deberg 0., Grundriss der Pharmakologie, Lpz., 1909. Periodicals, Russian Physiological Journal named after. Sechenova, L., since 1917; Archives internationa-les de pharmacodynamie, P., since 1898; Archiv fur experi-mcntelle Pathologie und Pharmakologie, Lpz., since 1873; Bericnte iiber die gesamte Physiologie und experimentelle Pharmakologie, V., since 1920; Japanese journal ol medical sciences, Tokyo, since 1922; Journal of pharmacology and experimental therapeutics, Baltimore, since 1909. See also lit. to Art. Physiology. V. Nikolaev.

1. The concept of treatment as a targeted correction of physiological disorders in the body. Benefits and risks of using medications. Reasons for their use. Safety assessment.

Pharmacology– theoretical basis of pharmacotherapy.

Reasons for using medications:

1) to correct and eliminate the cause of the disease

2) in case of insufficient prophylactic agents

3) for health reasons

4) obvious need based on level of knowledge and experience

5) desire to improve the quality of life

Benefits when prescribing medications:

1) correction or elimination of the cause of the disease

2) relief of symptoms of the disease if it is impossible to treat it

3) replacement of natural biologically active substances with medicinal substances that are not produced by organisms in sufficient quantities

4) implementation of disease prevention (vaccines, etc.)

Risk– the likelihood that the exposure will result in harm or damage; is equal to the ratio of the number of unfavorable (aversive) events to the size of the risk group.

A) unacceptable (harm > benefit)

B) acceptable (benefit > harm)

B) minor (105 – safety level)

D) conscious

Drug safety assessment begins at the level of chemical laboratories synthesizing drugs. A preclinical assessment of the safety of a drug is carried out by the Ministry of Health, the FDA, etc. If the drug successfully passes this stage, its clinical evaluation begins, consisting of four phases: Phase I - assessment of tolerability on healthy volunteers 20-25 years old, Phase II - on sick volunteers of less than 100 people suffering from a certain disease, phase III - multicenter clinical trials on large groups of people (up to 1000 people), phase IV - monitoring of the drug for 5 years after its official approval. If a drug successfully passes all these phases, it is considered safe.

2. The essence of pharmacology as a science. Sections and areas of modern pharmacology. Basic terms and concepts of pharmacology - pharmacological activity, action, effectiveness of chemicals.

Pharmacology– the science of medicines in all aspects – the theoretical basis of therapy:

A) the science of the interaction of chemicals with living systems

B) the science of controlling the vital processes of the body with the help of chemicals.

Sections of modern pharmacology:

1) Pharmacodynamics– studies a) the effect of drugs on the human body, b) the interaction of various drugs in the body when prescribed simultaneously, c) the influence of age and various diseases on the effect of drugs

2) Pharmacokinetics– studies the absorption, distribution, metabolism and excretion of drugs (i.e. how the patient’s body reacts to drugs)

3) Pharmacogenetics– studies the role of genetic factors in the formation of the body’s pharmacological response to drugs

4) Pharmacoeconomics– evaluates the results of use and the cost of drugs to make a decision on their subsequent practical use

5) Pharmacoepidemiology– studies the use of drugs and their effects at the level of populations or large groups of people to ensure the use of the most effective and safe drugs

Pharmacological (biological) activity– the property of a substance to cause changes in the biosystem (human body). Pharmacological substances = biologically active substances (BAS)

pharmachologic effect– influence of drugs on the object and its targets

Pharmacological effect– the result of the action of a substance in the body (modification of physiological, biochemical processes, morphological structures) – a quantitative, but not qualitative change in the state of biosystems (cells, tissues, organs).

Drug effectiveness– the ability of a drug to cause certain pharmacological effects necessary in this case in the body. Judged on the basis of "substantial evidence" - adequate, well-controlled studies and clinical trials conducted by experts with appropriate scientific training and experience in the study of drugs of this type (FDA)

3. Chemical nature of drugs. Factors that provide the therapeutic effect of drugs are pharmacological action and placebo effects.

Medicines are 1) plant 2) animal 3) microbial 4) mineral 5) synthetic

Synthetic drugs are represented by almost all classes of chemical compounds.

pharmachologic effect– the influence of drugs on the object and its targets.

placebo- any component of therapy that does not have any specific biological effect on the disease being treated.

It is used for the purpose of control when assessing the effect of drugs and in order to benefit the patient without any pharmacological agents as a result of only psychological effects (i.e. Placebo effect).

All types of treatment have a psychological component, either satisfying ( Placebo effect), or causing concern ( Nocebo effect). An example of a placebo effect: rapid improvement in a patient with a viral infection when using antibiotics that do not affect viruses.

The beneficial effect of the placebo effect is associated with the psychological impact on the patient. It will be maximum only when you use it In combination with treatment methods, having a pronounced specific effect. Expensive substances as a placebo also help achieve greater response.

Indications for use of placebo:

1) mild mental disorders

2) psychological support for a patient with an incurable chronic disease or with suspected severe diagnosis

4. Sources and stages of drug creation. Definition of the concepts of medicinal substance, medicinal product, medicinal product and dosage form. The name of the drugs.

Sources for creating drugs:

A) natural raw materials: plants, animals, minerals, etc. (cardiac glycosides, pork insulin)

B) modified natural biologically active substances

B) synthetic compounds

D) genetic engineering products (recombinant insulin, interferons)

Stages of creating LS:

1. Synthesis of drugs in a chemical laboratory

2. Preclinical assessment of the activity and undesirable effects of drugs of the Ministry of Health and other organisms

3. Clinical trials of drugs (for more details, see section 1)

Medicine– any substance or product used to modify or study physiological systems or pathological conditions for the benefit of the recipient (according to WHO, 1966); individual substances, mixtures of substances or compositions of unknown composition that have proven medicinal properties.

medicinal substance– an individual chemical compound used as a medicine.

Dosage form– a form convenient for practical use, given to a medicinal product to obtain the necessary therapeutic or prophylactic effect.

medicinal product– a medicinal product in a specific dosage form approved by a government agency.

5. Routes of administration of drugs into the body and their characteristics. Presystemic drug elimination.

1. For systemic action

A. Enteral route of administration: orally, sublingually, buccally, rectally, via tube

B. Parenteral route of administration: intravenous, subcutaneous, intramuscular, inhalation, subarachnoid, transdermal

2. For local effects: cutaneously (epicutary), on mucous membranes, in the cavity (abdominal, pleural, articular), in tissue (infiltration)

Route of drug administration	Advantages	Flaws
Orally - through the mouth	1. Convenient and simple for the patient 2. Sterility of drugs is not required	1. The absorption of many drugs depends on food intake, the functional state of the gastrointestinal tract and other factors that are difficult to take into account in practice 2. Not all drugs are well absorbed from the gastrointestinal tract 3. Some drugs are destroyed in the stomach (insulin, penicillin) 4. Some drugs cause adverse effects on the gastrointestinal mucosa (NSAIDs – mucosal ulcers, antacids – suppress motility) 5. Not applicable in patients who are unconscious and have difficulty swallowing
Sublingual and buccal	1. Convenient and quick administration 2. Rapid absorption of drugs 3. The drug is not subject to presystemic elimination 4. The effect of the drug can be quickly interrupted	1. Inconvenience caused by frequent, regular use of tablets 2. Irritation of the oral mucosa, excessive secretion of saliva, which promotes swallowing of the drug and reduces its effectiveness 3. Bad taste
Rectally	1. Half of the drugs do not undergo first-pass metabolism 2. The gastrointestinal mucosa is not irritated 3. Convenient when other routes of administration are unacceptable (vomiting, motion sickness, infants) 4. Local action	1. Unpleasant psychological moments for the patient 2. Drug absorption slows down significantly when the rectum is not emptied.
Intravascular (usually intravenous	1. Rapid entry into the blood (emergency conditions) 2. Quick creation of high system concentration and the ability to manage it 3. Allows the administration of drugs that are destroyed in the gastrointestinal tract	1. Technical difficulties of intravascular access 2. Risk of infection at the injection site 3. Vein thrombosis at the site of drug administration (erythromycin) and pain (potassium chloride) 4. Some drugs are adsorbed on the walls of droppers (insulin)
Intramuscularly	Sufficiently rapid absorption of the drug into the blood (10-30 min)	Risk of local complications
subcutaneously	1. The patient can inject himself after training. 2. Long-term effect of drugs	1. Slow absorption and manifestation of the drug effect 2. Atrophy of adipose tissue at the injection site and a decrease in the rate of drug absorption
Inhalation	1. Rapid onset of action and high concentration at the injection site in the treatment of respiratory diseases. ways 2. Good controllability of action 3. Reduce toxic systemic effects	1. The need for a special device (inhaler) 2. Pressurized aerosols may be difficult to use for some patients.
Local LS	1. High active concentration of the drug at the injection site 2. Undesirable systemic effects of this drug are avoided	If the integrity of the skin is damaged, the drug can enter the systemic bloodstream - a manifestation of undesirable systemic effects.

Presystemic drug elimination (first pass effect)– the process of biotransformation of a drug before the drug enters the systemic circulation. Enzymatic systems of the intestine, portal vein blood and hepatocytes participate in presystemic elimination during oral administration of the drug.

When administered intravenously, there is no presystemic elimination.

In order for an orally taken drug to have a beneficial effect, its dose must be increased to compensate for losses.

6. Transfer of drugs through biological barriers and its varieties. The main factors influencing the transport of drugs in the body.

Methods of absorption (transport) of drugs through biological membranes:

1) Filtration (water diffusion) - passive movement of substance molecules along a concentration gradient through water-filled pores in the membrane of each cell and between neighboring cells, typical for water, some ions, small hydrophilic molecules (urea).

2) Passive diffusion (lipid diffusion) is the main mechanism of drug transfer, the process of drug dissolution in membrane lipids and movement through them.

3) Transport using specific carriers - transfer of drugs using carriers (usually proteins) built into the membrane, typical for hydrophilic polar molecules, a number of inorganic ions, sugars, amino acids, pyrimidines:

a) facilitated diffusion - carried out along a concentration gradient without the consumption of ATP

b) active transport - against the concentration gradient with ATP consumption

Saturable process - i.e., the rate of absorption increases only until the number of drug molecules is equal to the number of carriers.

4) Endocytosis and pinocytosis - the drug binds to a special recognition component of the cell membrane, invagination of the membrane occurs and a vesicle containing drug molecules is formed. Subsequently, the drug is released from the vesicle into the cell or transported out of the cell. Characteristic of high molecular weight polypeptides.

Factors influencing the transport of drugs in the body:

1) physical and chemical properties of the substance (hydro- and lipophilicity, ionization, polarizability, molecular size, concentration)

2) structure of transfer barriers

3) blood flow

7. Transfer of drugs through membranes with variable ionization (Henderson-Hasselbalch ionization equation). Principles of transfer management.

All drugs are weak acids or weak bases, having their own ionization constant (pK) values. If the pH value of the medium is equal to the pK value of the drug, then 50% of its molecules will be in the ionized and 50% in the non-ionized state and the medium for the drug will be neutral.

In an acidic environment (pH less than pK), where there is an excess of protons, the weak acid will be in an undissociated form (R-COOH), i.e. it will be associated with a proton - protonated. This form of the acid is uncharged and highly soluble in lipids. If the pH shifts to the alkaline side (i.e., the pH becomes greater than pK), then the acid will begin to dissociate and lose a proton, turning into an unprotonated form, which has a charge and is poorly soluble in lipids.

In an alkaline environment, where there is a deficiency of protons, the weak base will be in an undissociated form (R-NH2), i.e., it will be unprotonated and lacking a charge. This form of the base is highly soluble in lipids and is quickly absorbed. In an acidic environment, there is an excess of protons and a weak base will begin to dissociate, thereby binding protons and forming a protonated, charged form of the base. This form is poorly lipid soluble and poorly absorbed.

Hence, Absorption of weak acids occurs predominantly in an acidic environment, and of weak bases in an alkaline environment.

Features of the metabolism of weak acids (SA):

1) stomach: SA in the acidic contents of the stomach is non-ionized, but in the alkaline environment of the small intestine it will dissociate and the SA molecules will acquire a charge. Therefore, absorption of weak acids will be most intense in the stomach.

2) the environment in the blood is sufficiently alkaline and the absorbed SA molecules will transform into an ionized form. The glomerular filter of the kidneys allows both ionized and non-ionized molecules to pass through, therefore, despite the charge of the molecule, SCs will be excreted into the primary urine

3) if the urine is alkaline, then the acid will remain in ionized form, will not be able to be reabsorbed back into the bloodstream and will be excreted in the urine; If the urine is acidic, the medicine will turn into a non-ionized form, which is easily reabsorbed back into the blood.

Features of the metabolism of weak bases: opposite to CK (absorption is better in the intestine; reabsorption occurs in alkaline urine)

That., To speed up the removal of a weak acid from the body, urine must be alkalized, and to speed up the removal of a weak base, it must be acidified. (detoxification according to Popov).

The quantitative dependence of the process of drug ionization at different pH of the medium allows us to obtain the equation Henderson– Hasselbach:

Where pKa corresponds to the pH value at which the concentrations of the ionized and non-ionized forms are in equilibrium .

The Henderson-Hasselbach equation allows one to estimate the degree of ionization of a drug at a given pH value and predict the probability of its penetration through the cell membrane.

(1)For dilute acid, A,

HA ↔ H+ + A – , where HA is the concentration of the non-ionized (protonated) form of the acid and A – is the concentration of the ionized (non-protonated) form.

(2) For weak base, B,

BH+ ↔ H+ + B, where BH+ is the concentration of the protonated form of the base, B is the concentration of the unprotonated form

Knowing the pH of the medium and the pKa of the substance, it is possible, using the calculated logarithm, 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, etc.

8. Transfer of drugs in the body. Water diffusion and diffusion in lipids (Fick's law). Active transport.

The transfer of drugs in the body can be carried out by water and lipid diffusion, active transport, endo- and pinocytosis.

Features of drug transfer in the body by water diffusion:

1. Epithelial covers (gastrointestinal mucosa, oral cavity, etc.) - water diffusion of only very small molecules (methanol, lithium ions, etc.)

2. Capillaries (except brain capillaries) – filtration of substances with a molecular weight of up to 20-30 thousand Yes.

3. Brain capillaries - generally do not have water pores, with the exception of the areas of the pituitary gland, pineal gland, zone of the IV ventricle, choroid plexus, median eminence

4. Placenta - does not have water pores (although the issue is controversial).

5. The binding of drugs to blood proteins prevents their exit from the bloodstream, and therefore water diffusion

6. Diffusion in water depends on the size of drug molecules and water pores

Features of lipid diffusion:

1. The main mechanism of drug transfer through cell membranes

2. Determined by the lipophilicity of the diffusing substance (i.e., the oil/water distribution coefficient) and the concentration gradient; it can be limited by the very low solubility of the substance in water (which prevents the penetration of the drug into the aqueous phase of membranes)

3. Nonpolar compounds diffuse easily, ions diffuse difficultly.

Any diffusion (both aqueous and in lipids) obeys Fick’s diffusion law:

Diffusion rate is the number of drug molecules transferred per unit time; C1 is the concentration of the substance outside the membrane; C2 is the concentration of the substance from inside the membrane.

Corollary from Fick's law:

1) filtration of a drug is higher, the greater its concentration at the site of administration (the absorbed surface area in the intestine is greater than in the stomach, therefore the absorption of drugs into the intestine is faster)

2) the higher the drug concentration at the injection site, the higher the drug filtration

3) the higher the thickness of the biological membrane being overcome, the higher the filtration of drugs (the thickness of the barrier in the alveoli of the lungs is much less than that of the skin, so the absorption rate is higher in the lungs)

Active transport– transfer of drugs, regardless of the concentration gradient using ATP energy, is typical for hydrophilic polar molecules, a number of inorganic ions, sugars, amino acids, pyrimidines. Characterized by: a) selectivity to certain compounds b) the possibility of competition between two substances for one transport mechanism c) saturability at high concentrations of the substance d) the possibility of transport against a concentration gradient e) energy consumption.

9. The central postulate of pharmacokinetics is the concentration of a drug in the blood - the main parameter for controlling the therapeutic effect. Problems solved on the basis of knowledge of this postulate.

The central postulate (dogma) of pharmacokinetics: the concentration of drugs in the blood plasma determines (quantifies) the pharmacological effect.

In most cases, the rate of absorption, distribution, metabolism and excretion of drugs is proportional to their concentration in the blood plasma (subject to the law of mass action), therefore knowing it it is possible:

1) determine the half-life period (for drugs with first-order kinetics)

2) explain the duration of some toxic effects of drugs (for drugs in high doses with saturation kinetics)

10. Bioavailability of drugs - definition, essence, quantitative expression, determinants. The concept of bioavailability

Bioavailability (F) - characterizes the completeness and rate of absorption of a drug through extra-systemic routes of administration - reflects the amount of unchanged substance that reached the systemic bloodstream, relative to the initial dose of the drug.

F is 100% for drugs that are administered intravenously. When administered by other routes, F is usually less due to incomplete absorption and partial metabolism in peripheral tissues. F is equal to 0 if the drug is not absorbed from the lumen of the gastrointestinal tract.

To estimate F, a curve of the dependence of the drug concentration in the blood on time after its intravenous administration, as well as after administration by the studied route, is constructed. This is the so-called. pharmacokinetic time-concentration curves. By integration, the values ​​of the area under the pharmacokinetic curve are found and F is calculated as the ratio:

≤ 1, where AUC is the area under the pharmacokinetic curve (Area Under Curve)

Bioavailability > 70% is considered high, below 30% is considered low.

Bioavailability Determinants:

1) suction speed

2) completeness of absorption - insufficient absorption of the drug due to its very high hydrophilicity or lipophilicity, metabolism by intestinal bacteria during enteral administration, etc.

3) presystemic elimination - with high biotransformation in the liver of F drugs is low (nitroglycerin when administered orally).

4) dosage form - sublingual tablets and rectal suppositories help drugs avoid presystemic elimination.

11. Distribution of drugs in the body. Compartments, ligands. Main determinants of distribution.

Distribution Drugs are the process of distribution of drugs through organs and tissues after they enter the systemic circulation.

Distribution compartments:

1. Extracellular space (plasma, intercellular fluid)

2. Cells (cytoplasm, organelle membrane)

3. Fat and bone tissue (drug deposition)

In a person weighing 70 kg, the volumes of liquid media are 42 liters in total, then if:

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

[ Vd = 4-14 l, then all the medicine is distributed in the extracellular fluid;

[ Vd = 14-42 l, then all the medicine is approximately evenly distributed in the body;

[Vd>42 l, then all the medicine is located mainly in the extracellular space.

Molecular ligands of drugs:

A) specific and nonspecific receptors

B) blood proteins (albumin, glycoprotein) and tissues

B) connective tissue polysaccharides

D) nucleoproteins (DNA, RNA)

Distribution determinants:

· Nature of drugs– the smaller the molecule size and the more lipophilic the drug, the faster and more uniform its distribution.

· Organ size– the larger the size of the organ, the more drug can enter it without a significant change in the concentration gradient

· Blood flow in the organ– in well-perfused tissues (brain, heart, kidneys) the therapeutic concentration of the substance is created much earlier than in poorly perfused tissues (fat, bone)

· The presence of histohematic barriers– Drugs easily penetrate into tissues with poorly expressed HGB

· Plasma protein binding of the drug– the larger the bound fraction of a drug, the worse its distribution in the tissue, since only free molecules can leave the capillary.

· Deposition of drugs in tissues– binding of the drug to tissue proteins promotes its accumulation in them, since 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 (Vd).

Apparent volume of distributionVd- this is the hypothetical volume of liquid in which the entire administered dose of the drug can be distributed to create a concentration equal to the concentration in the blood plasma.

Vd is equal to the ratio of the administered dose (the total amount of drug in the body) to its concentration in the blood plasma:

.

The greater the apparent volume of distribution, the more of the drug is distributed into the tissue.

12. Elimination constant, its essence, dimension, relationship with other pharmacokinetic parameters.

Elimination rate constant(kel, min-1) – shows what part of the drug is eliminated from the body per unit of time Þ Kel = Avyd/Atot, where Avyd is the amount of drugs released per unit. time, Atot – the total amount of drugs in the body.

The kel value is usually found by solving a pharmacokinetic equation that describes the process of drug elimination from the blood, which is why kel is called a model kinetics indicator. kel is not directly related to dosage regimen planning, but its value is used to calculate other pharmacokinetic parameters.

The elimination constant is directly proportional to clearance and inversely proportional to the volume of distribution (from the definition of clearance): Kel=CL/Vd; = hour-1/min-1=fraction per hour.

13. Half-life of drugs, its essence, dimension, relationship with other pharmacokinetic parameters.

Half-life(t½, min) is the time required to reduce the concentration of a drug in the blood by exactly half. It does not matter how the concentration reduction is achieved - through biotransformation, excretion, or through a combination of both processes.

The half-life period is determined by the formula:

The half-life is the most important pharmacokinetic parameter, allowing:

B) determine the time of complete elimination of the drug

C) predict the concentration of a drug at any time (for drugs with first-order kinetics)

14. Clearance as the main pharmacokinetic parameter for controlling the dosage regimen. Its essence, dimension and relationship with other pharmacokinetic indicators.

Clearance(Cl, ml/min) – the volume of blood that is cleared of drugs per unit of time.

Since plasma (blood) is the “visible” part of the volume of distribution, clearance is the fraction of the volume of distribution from which the drug is released per unit time. If we denote the total amount of drug in the body by Total, and the amount released through Avyd, That:

On the other hand, from the definition of volume of distribution it follows that the total amount of drug in the body is Atotal=Vd´ CTer/plasma. Substituting this value into the clearance formula, we get:

.

Thus, clearance is the ratio of the rate of elimination of a drug to its concentration in the blood plasma.

In this form, the clearance formula is used to calculate the maintenance dose of the drug ( DP), that is, the dose of the drug that should compensate for the loss of the drug and maintain its level at a constant level:

Rate of infusion = rate of withdrawal =Cl´ CTer(dose/min)

DP= injection rate´ T (T- the interval between taking the medicine)

Ground clearance is additive, i.e. elimination of a substance from the body can occur with the participation of processes occurring in the kidneys, lungs, liver and other organs: Clsystemic = Clrenal. + Cl liver + Cl others.

Clearance bound With the half-life of drugs and the volume of distribution: t1/2=0.7*Vd/Cl.

15. Dose. Types of doses. Units of dosing of medicines. Targets of dosing drugs, methods and options for administration, interval of administration.

The effect of drugs on the body is largely determined by their dose.

Dose- the amount of the substance introduced into the body at one time; expressed in weight, volume or conditional (biological) units.

Types of doses:

A) single dose - the amount of a substance at one time

B) daily dose - the amount of drug prescribed per day in one or more doses

C) course dose - the total amount of the drug for the course of treatment

D) therapeutic doses - doses in which the drug is used for therapeutic or prophylactic purposes (threshold, or minimum effective, average therapeutic and highest therapeutic doses).

E) toxic and lethal doses - doses of drugs at which they begin to have pronounced toxic effects or cause death of the body.

E) loading (introductory) dose - the amount of administered drug that fills the entire volume of distribution of the body in the effective (therapeutic) concentration: VD = (Css * Vd)/F

G) maintenance dose - a systematically administered amount of drugs that compensates for the loss of drugs with clearance: PD = (Css * Cl * DT)/F

Dosing units of drugs:

1) in grams or fractions of a gram of medicine

2) the number of drugs per 1 Kg body weight (for example, 1 mg/kg) or per unit surface area of ​​the body (for example, 1 Mg/m2)

The goals of drug dosing:

1) determine the amount of drugs required to cause the desired therapeutic effect with a certain duration

2) avoid intoxication and side effects when administering drugs

Methods of drug administration: 1) enterally 2) parenterally (see section 5)

Options for the introduction of drugs:

A) continuous (by long-term intravascular infusions of drugs by drip or through automatic dispensers). With continuous administration of a drug, its concentration in the body changes smoothly and is not subject to significant fluctuations

B) intermittent administration (injection or non-injection methods) - administration of the drug at certain intervals (dosing intervals). With intermittent administration of a drug, its concentration in the body continuously fluctuates. After taking a certain dose, it first increases and then gradually decreases, reaching minimum values ​​before the next administration of the drug. The greater the dose of medication administered and the interval between administrations, the greater the fluctuations in concentration.

Injection interval– the interval between administered doses, ensuring the maintenance of a therapeutic concentration of the substance in the blood.

16. Administration of drugs at a constant rate. Kinetics of drug concentration in the blood. The steady-state concentration of the drug in the blood ( Css), the time of its achievement, its calculation and management.

The peculiarity of administering a drug at a constant speed is a smooth change in its concentration in the blood during administration, while:

1) the time to reach a steady-state concentration of the drug is 4-5t½ and does not depend on the infusion rate (the size of the administered dose)

2) with an increase in the infusion rate (administered dose), the CSS value also increases a proportional number of times

3) elimination of the drug from the body after stopping the infusion takes 4-5t½.

WITHSs– equilibrium stationary concentration– drug concentration achieved when the rate of administration is equal to the rate of elimination, therefore:

(from the definition of clearance)

For each subsequent half-life, the drug concentration increases by half of the remaining concentration. All drugs subject to the first-order elimination law will reachCssafter 4-5 half-lives.

Approaches to Level C ManagementSs: change the administered drug dose or administration interval

17. Intermittent administration of drugs. Kinetics of drug concentration in the blood, therapeutic and toxic range of concentrations. Calculation of steady-state concentration ( CSs), the boundaries of its fluctuations and its control. Adequate interval for administering discrete doses.

Fluctuations in the concentration of drugs in the blood plasma: 1 – with constant intravenous drip administration; 2 - with fractional administration of the same daily dose with an interval of 8 hours; 3 - with the introduction of a daily dose with an interval of 24 hours.

Intermittent administration of drugs- administration of a certain amount of drugs at certain intervals.

The steady-state equilibrium concentration is achieved after 4-5 half-elimination periods, the time to achieve it does not depend on the dose (at the beginning, when the drug concentration level is low, the rate of its elimination is also low; as the amount of the substance in the body increases, the rate of its elimination also increases, so early or the moment will come late when the increased rate of elimination will balance the administered dose of the drug and further increase in concentration will stop)

Css is directly proportional to the dose of the drug and inversely proportional to the interval of administration and clearance of the drug.

Css fluctuation limits: ; Cssmin = Cssmax × (1 – el. fr.). Fluctuations in drug concentration are proportional to T/t1/2.

Therapeutic range (safety corridor, therapeutic window)– this is the range of concentrations from the minimum therapeutic to those causing the first signs of side effects.

Toxic range– concentration range from the highest therapeutic to lethal.

Adequate regimen of discrete doses: a mode of administration in which the fluctuation of drug concentration in the blood falls within the therapeutic range. To determine an adequate drug administration regimen, it is necessary to calculate. The difference between Cssmax and Cssmin should not exceed 2Css.

Oscillation controlCss:

Oscillation rangeCssis directly proportional to the dose of the drug and inversely proportional to the interval of its administration.

1. Change the drug dose: with increasing drug dose, the range of fluctuations of its Css increases proportionally

2. Change the drug administration interval: with increasing interval of drug administration, the range of fluctuations of its Css proportionally decreases

3. Change the dose and dosing interval at the same time

18. Introductory (loading) dose. Therapeutic meaning, calculation of pharmacokinetic parameters, conditions and limitations of its use.

Introductory (loading) dose- a dose administered at one time and filling the entire volume of distribution in the current therapeutic concentration. VD=(Css*Vd)/F ; =mg/l, =l/kg

Therapeutic meaning: the introductory dose quickly provides the effective therapeutic concentration of the drug in the blood, which allows, for example, to quickly stop an attack of asthma, arrhythmias, etc.

The induction dose can be administered at a time only when The process of substance distribution is ignored

Restriction on the use of VD: if drug distribution occurs Significantly slower than its entry into the blood, administration of the entire loading dose at once (especially intravenously) will create a concentration significantly higher than the therapeutic one and will cause toxic effects. Conditions for using VD: therefore, the introduction of loading doses Should always be slow or fractional.

19. Maintenance doses, their therapeutic meaning and calculation for the optimal dosage regimen.

Maintenance dose– a dose of drug administered systematically, which fills the clearance volume, i.e. that fragment Vd that is cleared of drugs during the DT interval: PD = (Css*Cl*DT)/F.

Therapeutic meaning: PD compensates for losses in clearance during the interval between drug administrations.

Calculation for optimal dosing of drugs (for quick relief of an attack):

1. Calculate VD: VD=(Css*Vd)/F

2. Select the DT administration interval (usually most drugs are prescribed at an interval close to t1/2) and calculate the DP: DP = (Css*Cl*DT)/F

3. We check whether drug fluctuations in the blood are outside the therapeutic range by calculating Cssmax and Cssmin: ; Cssmin = Cssmax × (1 – el. fr.). The difference between Cssmax and Cssmin should not exceed two Css.

The eliminated fraction is found according to the graph (see clause 16) or according to the formula:

4. If, at the drug administration interval we have chosen, its fluctuations fall outside the therapeutic range, change DT and repeat the calculation (point 2 - point 4)

NB! If the drug is not intended to relieve emergency conditions or is taken in tablets, the VD is not calculated.

20. Individual, age and sex differences in the pharmacokinetics of drugs. Adjustments for calculating individual drug volume of distribution values.

1. Age-related differences in the pharmacokinetics of drugs.

1. The stratum corneum of the skin is thinner, so when applied cutaneously, drugs are absorbed better. Absorption of drugs when administered rectally is also better. 2. The volume of fluid in the body of children is 70-80%, while in adults it is only »60%, so they have more Vd of hydrophilic drugs and require higher doses. 3. In a newborn, the level of albumin in plasma is lower than in adults, so the binding of drugs to protein is less intense. 4. Newborns have low intensity of cytochrome P450 systems and conjugating enzymes, but high activity of methylation systems. 5. The glomerular filtration rate in the kidneys of children under 6 months is 30-40% of the rate of adults, therefore the renal excretion of drugs is reduced.

1. There is a decrease in the concentration of albumin in the blood plasma and the fraction of the drug associated with protein 2. The water content in the body decreases from 60% to 45%, therefore the accumulation of lipophilic drugs increases. 3. The glomerular filtration rate may fall to 50-60% of that in a mature patient, so renal elimination of drugs is severely limited.

2. Sex differences in the effects of drugs. Women are characterized by lower body weight than men, and therefore the dose of the drug for them should, as a rule, be at the lower limit of the range of therapeutic doses.

3. Pathological conditions of the body and the effect of drugs

A) liver diseases: F drugs due to the shutdown of first-pass metabolism, fraction of unbound drugs due to lack of albumin synthesis, the effects of drugs are prolonged due to their biotransformation.

B) kidney pathology: the elimination of drugs that are excreted through the kidneys slows down

4. Genetic factors– deficiency of certain enzymes of drug metabolism can help prolong their action (pseudocholinesterase, etc.)

Amendments for calculating individual values ​​of the volume of distribution of drugs:

A) in case of obesity, lipophobic drugs are insoluble in adipose tissue; it is necessary to calculate the ideal weight based on height (Brock’s formula: ideal weight = height (in cm) – 100) and recalculate Vd to ideal weight based on height.

B) for edema, you need to calculate the excess volume of water = excess weight - ideal, Vd should be increased by a liter for each excess kilogram of water.

Dependence of the main pharmacokinetic parameters on various factors:

1. Drug absorption: with age, the absorption of the drug, its metabolism during presystemic elimination, the bioavailability of the drug changes.

2. Volume of distribution Vd: with age and obesity, with edema

3. Half-life: changes with age and obesity (as Vd decreases)

4. Clearance: determined by the functional state of the kidneys and liver

21. Renal clearance of drugs, mechanisms, their quantitative and qualitative characteristics.

Renal clearance is a measure of the volume of blood plasma that is cleared of a drug per unit time by the kidneys: Cl (ml/min) = U × V/P, where U is the concentration of the drug in ml of urine, V is the volume of urine excreted per minute and P = drug concentration per ml of plasma.

Mechanisms of renal clearance and their characteristics:

1. Filtration: Drug released Only by filtering(insulin) will have a clearance equal to GFR (125-130 ml/min)

Determined by: renal blood flow, unbound drug fraction and filtration capacity of the kidneys.

Most drugs have low molecular weights and are therefore freely filtered from the plasma in the glomerulus.

2. active secretion: Drug released Filtration and complete secretion(para-aminohippuric acid), will have a clearance equal to renal plasma clearance (650 ml/min)

The renal tubule contains two transport systems, which can release drugs into the ultrafiltrate, one for organic acids and another for organic bases. These systems require energy for active transport against a concentration gradient; they are a place of competition for the transport of some medicinal substances with others.

Determined by: maximum secretion rate, urine volume

3. Reabsorption: clearance values ​​between 130 and 650 ml/min suggest that the drug Filtered, excreted, and partially reabsorbed

Reabsorption occurs throughout the entire renal canal and depends on the polarity of the drug; nonpolar and lipophilic drugs are reabsorbed.

Determined by: primary pH value and drug ionization

A number of indicators such as Age, concomitant use of multiple medications, illness significantly affect renal clearance:

A) renal failure ® decreased clearance of drugs ® high level of drugs in the blood

B) glomerulonephritis ® loss of serum protein, which was usually available and bound drugs ® increase in the level of the free fraction of drugs in plasma

22. Factors affecting renal clearance of drugs. Dependence of clearance on the physicochemical properties of drugs.

Factors affecting renalCl:

A) glomerular filtration

B) renal blood flow velocity

B) maximum secretion rate

D) volume of urine

D) unbound fraction in the blood

Dependence of renal clearance on the physicochemical properties of drugs:

General patterns: 1) polar drugs are not reabsorbed, non-polar drugs are reabsorbed 2) ionic drugs are secreted, non-ionic drugs are not secreted.

I. Non-polar nonionic substances: filtered only in unbound forms, not secreted, reabsorbed

Renal clearance is small and is determined by: a) the fraction of the drug unbound in the blood b) the volume of urine

II. Polar nonionic substances: filtered in unbound form, not secreted, not reabsorbed

Renal clearance is high, determined by: a) the fraction of drugs unbound in the blood b) the rate of glomerular filtration

III. Non-polar ionized in urine in non-ionic form: filtered, actively secreted, non-polar reabsorbed

Renal clearance is determined by: a) the fraction of the drug unbound in the blood b) the fraction of the drug ionized in the urine c) the volume of urine

IV. Ionized in urine, polar in non-ionized form: filtered, actively secreted, not reabsorbed

Renal clearance is determined by: a) renal blood flow and glomerular filtration rate b) maximum secretion rate

23. Hepatic clearance of drugs, its determinants and limitations. Enterohepatic cycle of drugs.

Mechanisms of hepatic clearance:

1) metabolism (biotransformation) by oxidation, reduction, alkylation, hydrolysis, conjugation, etc.

The main strategy for the metabolism of xenobiotics: non-polar substances ® polar (hydrophilic) metabolites excreted in the urine.

2) secretion (removal of untransformed substances into bile)

Only polar substances with an active molecular weight > 250 are transported into bile (organic acids, bases).

Determinants of hepatic clearance:

A) Blood flow rate in the liver

B) Maximum rate of excretion or metabolic transformations

B) Km – Michaelis constant

D) Fraction not bound to protein

Limitations of hepatic clearance:

1. If Vmax/Km is high → Cl liver = blood flow velocity in the liver

2. If Vmax/Km are average values ​​→ Cl = sum of all factors

3. If Vmax/Km is small → Cl is small, limited

Enterohepatic cycle of drugs – A number of drugs and their transformation products are excreted in significant quantities with bile into the intestines, from where they are partially excreted with excrement, and partially - Reabsorbed into the blood, again enters the liver and is excreted into the intestines.

Hepatic elimination of drugs may be significantly altered Liver disease, age, diet, genetics, duration of medication(for example, due to induction of liver enzymes), and other factors.

24. Factors that change the clearance of drugs.

1. Drug interactions at the level of: renal secretion, biochemical transformation, enzyme induction phenomena

2. Kidney diseases: blood flow disorders, acute and chronic kidney damage, outcomes of long-term kidney diseases

3. Liver diseases: alcoholic cirrhosis, primary cirrhosis, hepatitis, hepatomas

4. Diseases of the gastrointestinal tract and endocrine organs

5. Individual intolerance (lack of acetylation enzymes - aspirin intolerance)

25. Correction of drug therapy for liver and kidney diseases. General approaches. Correction of the dosage regimen under the control of the total clearance of the drug.

1. Stop medications that are not necessary

2. For kidney diseases, use drugs that are excreted by the liver and vice versa.

3. Reduce the dose or increase the interval between doses

4. Close monitoring for side effects and toxicities

5. In the absence of a pharmacological effect, the dose must be increased slowly and under the control of pharmacological and toxic effects

6. If possible, determine the concentration of the substance in plasma and adjust therapy according to the Cl of the drug individually

7. Use an indirect method for estimating Cl.

Correction of the dosage regimen under the control of the total clearance of the drug:

Dose adjustment : Dind.=Dtypical×Clind./Cltypical

With continuous intravenous administration of the drug: Individual administration rate = Typical administration rate × Cl ind. / Cl typical

With intermittent administration: 1) change the dose 2) change the interval 3) change both parameters. For example, if clearance decreases by 50%, you can reduce the dose by 50% and maintain the interval, or double the interval and maintain the dose. It is preferable to reduce the dose and maintain the dosage interval.

26. Correction of the dosage regimen under the control of residual renal function.

Creatinine clearance– the most important quantitative indicator of kidney function, on the basis of which the dosage regimen can be adjusted

We know:

A) residual renal function, determined by creatinine clearance in a given patient Clcr/patient

B) total clearance of a given drug (CL/total) and the share of renal clearance of the drug in the total clearance

B) normal creatinine clearance Clcr/normal according to the normogram

3) Css and F for this drug (from the directory)

Find: drug dose for a given patient

Clds/renal norm = Clds/total X proportion of renal clearance of drugs in total clearance

ClLS/renal of the patient = Clcr/patient / Clcr/norm * ClCL/renal norm

ClLS/non-renal norm = ClLS/total – ClLS/renal norm

ClLS/general patient = ClLS/renal patient + ClLS/non-renal norm

The oral dose of this drug with normal renal function is equal to: PDnorm = Css X Cl / F

The oral dose of this drug for our patient is equal to: PD of the patient = PDnorm X SlLS/total patient / SlLS/total

Answer: PD patient

27. Correction of drug therapy for liver damage and other pathological conditions.

Liver disease can reduce clearance and prolong the half-life of many drugs. However, some drugs that are eliminated by the liver do not change these parameters in case of liver dysfunction, therefore Liver diseases do not always affect intrinsic hepatic clearance. There is currently no reliable marker that can be used to predict hepatic clearance similar to creatinine clearance.

For correction of the dosage regimen for kidney disease, see above in paragraph 26, general principles of correction - in paragraph 25.

28. Strategy for individual drug therapy.

Recognition of the important role of concentration as a link between pharmacokinetics and pharmacodynamics contributes to the creation of a target concentration strategy - dose optimization for a given patient based on drug concentration measurements. It consists of the following stages:

1. Selection of target concentration

2. Calculation of Vd and Cl based on typical values ​​and adjustments taking into account factors such as body weight and kidney function.

3. Enter a loading dose or maintenance dose, calculated taking into account the values ​​of TC, Vd and Cl.

4. Registration of the patient’s reaction and determination of drug concentration

5. Revise Vd and Cl based on concentration measurements.

6. Repeat steps 3-6 in order to select the maintenance dose necessary for an optimal response to the drug.

29. Biotransformation of drugs, its biological meaning, main focus and influence on the activity of drugs. The main phases of metabolic transformations of drugs in the body.

Biotransformation of drugs– chemical transformations of drugs in the body.

Biological meaning of drug biotransformation: creation of a substrate convenient for subsequent utilization (as an energy or plastic material) or in accelerating the elimination of drugs from the body.

The main direction of metabolic transformations of drugs: non-polar drugs → polar (hydrophilic) metabolites excreted in the urine.

There are two phases of metabolic reactions of drugs:

1) Metabolic transformation (non-synthetic reactions, phase 1)– transformation of substances due to microsomal and extramicrosomal oxidation, reduction and hydrolysis

2) conjugation (synthetic reactions, phase 2)– 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 by a) formation of glucuronides b) glycerol esters c) sulfoesters d) acetylation e) methylation

The influence of biotransformation on the pharmacological activity of drugs:

1) most often, biotransformation metabolites do not have pharmacological activity or their activity is reduced compared to the original substance

2) in some cases, metabolites can remain active and even exceed the activity of the original substance (codeine is metabolized to the more pharmacologically active morphine)

3) sometimes toxic substances are formed during biotransformation (metabolites of isoniazid, lidocaine)

4) sometimes during biotransformation metabolites with opposite pharmacological properties are formed (metabolites of non-selective b2-adrenergic receptor agonists have the properties of blockers of these receptors)

5) a number of substances are prodrugs that initially do not produce pharmacological effects, but during biotransformation are converted into biologically active substances (inactive L-dopa, penetrating the BBB, is converted in the brain into active dopamine, while there are no systemic effects of dopamine).

30. Clinical significance of drug biotransformation. The influence of gender, age, body weight, environmental factors, smoking, alcohol on the biotransformation of drugs.

Clinical significance of drug biotransformation: Since the dose and frequency of administration required to achieve effective concentrations in the blood and tissues may vary in patients due to individual differences in the distribution, metabolic rate and elimination of drugs, it is important to take them into account in clinical practice.

The influence of various factors on the biotransformation of drugs:

A) Functional state of the liver: with its diseases, drug clearance usually decreases, and the half-life increases.

B) Influence of environmental factors: smoking promotes the induction of cytochrome P450, resulting in accelerated drug metabolism during microsomal oxidation

IN) For vegetarians biotransformation of drugs is slowed down

D) elderly and young patients are characterized by increased sensitivity to the pharmacological or toxic effects of drugs (in elderly people and in children under 6 months, the activity of microsomal oxidation is reduced)

D) in men, the metabolism of some drugs occurs faster than in women, because androgens stimulate the synthesis of microsomal liver enzymes (ethanol)

E) High protein content and intense physical activity: acceleration of drug metabolism.

AND) Alcohol and obesity slow down drug metabolism

31. Metabolic interaction of drugs. Diseases affecting their biotransformation.

Metabolic interaction of drugs:

1) induction of drug metabolism enzymes - an absolute increase in their quantity and activity due to the influence of certain drugs on them. Induction leads to an acceleration of drug metabolism and (usually, but not always) to a decrease in their pharmacological activity (rifampicin, barbiturates - inducers of cytochrome P450)

2) inhibition of drug metabolism enzymes - inhibition of the activity of metabolic enzymes under the influence of certain xenobiotics:

A) competitive metabolic interaction - drugs with high affinity for certain enzymes reduce the metabolism of drugs with lower affinity for these enzymes (verapamil)

B) binding to a gene that induces the synthesis of certain isoenzymes of cytochrome P450 (cymedine)

B) direct inactivation of cytochrome P450 isoenzymes (flavonoids)

Diseases affecting drug metabolism:

A) kidney disease (impaired renal blood flow, acute and chronic kidney disease, outcomes of long-term kidney disease)

B) liver diseases (primary and alcoholic cirrhosis, hepatitis, hepatomas)

C) diseases of the gastrointestinal tract and endocrine organs

C) individual intolerance to certain drugs (lack of acetylation enzymes - intolerance to aspirin)

32. Pathways and mechanisms for removing drugs from the body. Possibilities for controlling drug excretion.

Pathways and mechanisms of drug elimination: elimination of drugs by the liver and kidneys and some other organs:

A) kidneys through filtration, secretion, reabsorption

B) liver through biotransformation, excretion with bile

B) through the lungs, saliva, sweat, milk, etc. by secretion, evaporation

Possibilities for managing drug withdrawal processes:

1. pH management: in alkaline urine, the excretion of acidic compounds increases, in acidic urine, the excretion of basic compounds

2. use of choleretic drugs (cholenzym, allochol)

3. hemodialysis, peritoneal dialysis, hemosorption, lymphosorption

4. forced diuresis (in / in NaCl or glucose for water load + furosemide or mannitol)

5. gastric lavage, use of enemas

33. The concept of receptors in pharmacology, the molecular nature of receptors, signaling mechanisms of drug action (types of transmembrane signaling and second messengers).

Receptors – Molecular components of a cell or organism that interact with drugs and induce a series of biochemical events leading to the development of a pharmacological effect.

Concept of receptors in pharmacology:

1. Receptors determine the quantitative patterns of drug action

2. Receptors are responsible for the selectivity of drug action

3. Receptors mediate the action of pharmacological antagonists

The concept of receptors is the basis for the targeted use of drugs that affect regulatory, biochemical processes and communications.

Molecular nature of receptors:

1. regulatory proteins, mediators of the action of various chemical signals: neurotransmitters, hormones, autocoids

2. enzymes and transmembrane transporter proteins (Na+, K+ ATPase)

3. structural proteins (tubulin, cytoskeletal proteins, cell surface)

4. nuclear proteins and nucleic acids

Signaling mechanisms of drug action:

1) penetration of lipid-soluble ligands through the membrane and their action on intracellular receptors.

2) the signal molecule binds to the extracellular domain of the transmembrane protein and activates the enzymatic activity of its cytoplasmic domain.

3) a signaling molecule binds to the ion channel and regulates its opening.

4) the signal molecule binds to a receptor on the cell surface, which is coupled to the effector enzyme via a G-protein. The G protein activates the second messenger.

Types of transmembrane signaling:

A) through 1-TMS receptors with and without tyrosine kinase activity

B) through 7-TMS receptors coupled to G protein

C) through ion channels (ligand-dependent, voltage-dependent, gap junctions)

Secondary intermediaries: cAMP, Ca2+ ions, DAG, IP3.

34. Physico-chemical and chemical mechanisms of action of medicinal substances.

A) Physico-chemical interaction with biosubstrate– non-electrolyte action.

Main pharmacological effects: 1) narcotic 2) general depressive 3) paralyzing 4) locally irritating 5) membranolytic action.

Chemical nature of substances: chemically inert hydrocarbons, ethers, alcohols, aldehydes, barbiturates, gas drugs

The mechanism of action is reversible destruction of membranes.

B) Chemical(molecular-biochemical) mechanism of action of drugs.

Main types of chemical interaction with biosubstrate:

1. Weak (non-covalent, reversible interactions) (hydrogen, ionic, monodipole, hydrophobic).
2. Covalent bonds (alkylation).

The importance of non-covalent drug interactions: the effect is nonspecific, does not depend on the chemical structure of the substance.

The importance of covalent interactions of drugs: the action is specific, critically depends on the chemical structure, and is realized through its influence on receptors.

35. Terms and concepts of quantitative pharmacology: effect, effectiveness, activity, agonist (full, partial), antagonist. Clinical difference between the concepts of activity and effectiveness of drugs.

Effect (response)– quantitative yield of the reaction of interaction of a cell, organ, system or organism with a pharmacological agent.

Efficiency– a measure of reaction along the effect axis – the magnitude of the response of a biological system to a pharmacological effect; This is the ability of a drug to have the maximum effect possible for it.. That is, in fact, this is the maximum effect that can be achieved with the administration of this medicine. Numerically characterized by the value Emax. The higher the Emax, the higher the effectiveness of the drug

Activity– a measure of sensitivity to a drug along the concentration axis, characterizes the affinity (affinity of the ligand for the receptor), Shows what dose (concentration) of the drug is capable of causing the development of a standard effect equal to 50% of the maximum possible for this drug. Numerically characterized by the value of EC50 or ED50. The higher the activity of the drug, the lower its dose is required to reproduce the therapeutic effect.

Efficiency: 1=2>3

Activity: 1>3>2

In clinical work, it is more important to know the effectiveness rather than the activity, since we are more interested in the ability of a drug to cause a certain effect in the body.

Agonist– a ligand that binds to a receptor and causes a biological reaction, the activation of a physiological system. Full agonist– maximum response, Partial– cause a smaller reaction even when all receptors are occupied.

Antagonist– ligands that occupy receptors or change them in such a way that they lose the ability to interact with other ligands, but do not themselves cause a biological reaction (block the action of agonists).

Competitive antagonists– interact with receptors reversibly and thereby compete with agonists. Increasing the concentration of the agonist can completely eliminate the effect of the antagonist. A competitive antagonist shifts the dose-effect curve for the agonist, increases EC50, and does not affect Emax.

Non-competitive antagonists– irreversibly change the affinity of receptors for the agonist, binding often does not occur with the active site of the receptor, increasing the concentration of the agonist does not eliminate the effect of the antagonist. A non-competitive antagonist reduces Emax, does not change EC50, and the dose-effect curve is compressed relative to the vertical axis.

36. Quantitative patterns of drug action. The law of decreasing response of biological systems. Clark's model and its consequences. General view of the concentration-effect relationship in normal and lognormal coordinates.

Clark-Ariens model:

1. The interaction between the ligand (L) and the receptor (R) is reversible.

2. All receptors for a given ligand are equivalent and independent (their saturation does not affect other receptors).

3. The effect is directly proportional to the number of occupied receptors.

4. The ligand exists in two states: free and bound to the receptor.

A) , where Kd is the equilibrium constant, Ke is the internal activity.

B) Since when the number of ligands increases, at some point in time all receptors will be occupied, the maximum possible number of ligand-receptor complexes formed is described by the formula:

= [R] × (1)

The effect is determined by the probability of receptor activation upon binding to a ligand, i.e., its intrinsic activity (Ke), therefore E = Ke×. In this case, the effect is maximum at Ke=1 and minimal at Ke=0. Naturally, the maximum effect is described by the relation Emax = Ke×, where is the total number of receptors for a given ligand

The effect also depends on the concentration of the ligand on the receptors [C], therefore

E = Emax (2)

From the above relationships it follows that EC50=Kd

Emax is the maximum effect, Bmax is the maximum number of bound receptors, EC50 is the drug concentration at which an effect equal to half of the maximum occurs, Kd is the dissociation constant of the substance from the receptor, at which 50% of the receptors are bound.

Law of diminishing response corresponds to a parabolic dependence “concentration - efficiency”. The response to low doses of drugs usually increases in direct proportion to the dose. However, as the dose increases, the increase in response decreases and eventually a dose can be reached at which there is no further increase in response (due to the occupancy of all receptors for a given ligand).

37. Change in the effect of drugs. Gradual and quantum assessment of the effect, essence and clinical applications. Measures for quantitative assessment of the activity and effectiveness of drugs in experimental and clinical practice.

All pharmacological effects can be divided into two categories:

A) Gradual (continuous, integral) effects- such effects of drugs that can be measured quantitatively (the effect of antihypertensive drugs - by blood pressure level). They are described by a gradual “dose-effect curve” (see paragraph 36), on the basis of which one can evaluate: 1) individual sensitivity to the drug 2) the activity of the drug 3) the maximum effectiveness of the drug

B) Quantum effects– such effects of drugs that are a discrete value, a qualitative sign, i.e., they are described by only a few variants of conditions (a headache after taking an analgesic is either present or not). A quantum dose-effect curve is described, where the dependence of the manifestation of the effect in the population on the dose of the drug taken is noted. The dose-response graph has a dome-shaped appearance and is identical to the Gaussian normal distribution curve. Based on the quantum curve, you can: 1) assess the population sensitivity of the drug 2) note the presence of an effect at a given dose 3) select the average therapeutic dose.

Differences between gradual and quantum dose-response characteristics:

Quantitative assessment of the activity and effectiveness of drugs is carried out on the basis of constructing dose-effect curves and their subsequent evaluation (see clause 35)

38. Types of action of drugs. Changes in the effect of drugs upon repeated administration.

Types of action of drugs:

1. Local action- the effect of a substance that occurs at the site of its application (anesthetic - on the mucous membrane)

2. Resorptive (systemic) action- the action of a substance that develops after its absorption, entry into the general bloodstream, and then into the tissues. Depends on the route of administration of drugs and their ability to penetrate biological barriers.

With both local and resorptive effects, drugs can have either Direct, or reflex influence:

A) direct effect - direct contact with the target organ (adrenaline on the heart).

B) reflex – changing the function of organs or nerve centers by influencing extero- and interoreceptors (mustard plasters in pathologies of the respiratory system reflexively improve their trophism)

Changes in the action of drugs upon repeated administration:

1. Cumulation– increased effect due to the accumulation of drugs in the body:

a) material cumulation - accumulation of the active substance in the body (cardiac glycosides)

b) functional cumulation - increasing changes in the function of body systems (changes in the function of the central nervous system in chronic alcoholism).

2. Tolerance (addiction) – Reduced response of the body to repeated administration of drugs; in order to restore the response to a drug, it has to be administered in larger and larger doses (diazepam):

A) true tolerance - observed both with enteral and parenteral administration of a drug, and does not depend on the degree of its absorption into the bloodstream. It is based on pharmacodynamic mechanisms of addiction:

1) desensitization - a decrease in the sensitivity of the receptor to the drug (beta-adrenergic agonists with long-term use lead to phosphorylation of beta-adrenergic receptors, which are not able to respond to beta-adrenergic agonists)

2) Down-regulation - a decrease in the number of receptors for the drug (with repeated administration of narcotic analgesics, the number of opioid receptors decreases and larger and larger doses of the drug are required to cause the desired response). If a drug blocks receptors, then the mechanism of tolerance to it may be associated with up-regulation - an increase in the number of receptors for the drug (b-blockers)

3) inclusion of compensatory regulatory mechanisms (with repeated administration of antihypertensive drugs, collapse occurs much less frequently than with the first administration due to adaptation of baroreceptors)

B) relative tolerance (pseudotolerance) - develops only when the drug is administered orally and is associated with a decrease in the rate and completeness of drug absorption

3. Tachyphylaxis– a condition in which frequent administration of a drug causes the development of tolerance within a few hours, but with sufficiently rare administration of the drug its effect is fully preserved. The development of tolerance is usually associated with depletion of effector systems.

4. drug addiction– an irresistible desire to take a previously administered substance. There are mental (cocaine) and physical (morphine) drug addictions.

5. Hypersensitivity– an allergic or other immunological reaction to the drug upon repeated administration.

39. Dependence of the effect of drugs on age, gender and individual characteristics of the body. The value of circadian rhythms.

A) From age: in children and the elderly, sensitivity to drugs is increased (because in children there is a deficiency of many enzymes, kidney function, increased permeability of the blood-brain barrier, in old age the absorption of drugs is slower, metabolism is less efficient, the rate of drug excretion by the kidneys is reduced):

1. In newborns, sensitivity to cardiac glycosides is reduced, because they have more Na+/K+-ATPases (targets of glycoside action) per unit area of ​​the cardiomyocyte. 2. Children have lower sensitivity to succinylcholine and atracurium, but increased sensitivity to all other muscle relaxants. 3. Psychotropic drugs can cause abnormal reactions in children: psychostimulants can increase concentration and reduce motor hyperactivity, tranquilizers, on the contrary, can cause the so-called. atypical excitement.

1. Sensitivity to cardiac glycosides sharply increases due to a decrease in the number of Na+/K+-ATPases. 2. Sensitivity to beta-blockers decreases. 3. Sensitivity to calcium channel blockers increases, as the baroreflex is weakened. 4. There is an atypical reaction to psychotropic drugs, similar to the reaction of children.

B) From the floor:

1) antihypertensive drugs - clonidine, b-blockers, diuretics can cause sexual dysfunction in men, but do not affect the functioning of the reproductive system of women.

2) anabolic steroids cause a greater effect in the body of women than in the body of men.

IN) From the individual characteristics of the body: deficiency or excess of certain enzymes of drug metabolism leads to an increase or decrease in their action (deficiency of blood pseudocholinesterase - abnormally prolonged muscle relaxation when using succinylcholine)

G) From circadian rhythms: change in the effect of a drug on the body quantitatively and qualitatively depending on the time of day (maximum effect at maximum activity).

40. Variability and variability of drug effects. Hypo- and hyperreactivity, tolerance and tachyphylaxis, hypersensitivity and idiosyncrasy. Reasons for variability in drug action and rational treatment strategy.

Variability reflects differences between individuals in response to a given drug.

Reasons for variability in drug action:

1) change in the concentration of a substance in the receptor area - due to differences in the rate of absorption, its distribution, metabolism, elimination

2) variations in the concentration of the endogenous receptor ligand - propranolol (a β-blocker) slows heart rate in people with elevated levels of catecholamines in the blood, but does not affect the background heart rate in athletes.

3) change in receptor density or function.

4) changes in reaction components located distal to the receptor.

Rational therapy strategy: prescription and dosage of drugs, taking into account the above reasons for the variability of drug action.

Hyporesponsiveness– a decrease in the effect of a given dose of a drug compared to the effect that is observed in most patients. Hyper-reactivity– an increase in the effect of a given dose of a drug compared to the effect that is observed in most patients.

Tolerance, tachyphylaxis, hypersensitivity – see section 38

Idiosyncrasy– a perverted reaction of the body to a given drug, associated with the genetic characteristics of drug metabolism or with individual immunological reactivity, including allergic reactions.

41. Assessing drug safety. Therapeutic index and standard safety margins.

Safety assessment is carried out at two levels:

A) preclinical (obtaining information about the toxicity of drugs, effects on reproductive functions, embryotoxicity and teratogenicity, long-term effects)

B) clinical (further assessment of the effectiveness and safety of drugs)

If, after the effect plateau is reached, the dose of the drug continues to increase, then after a certain period of time its toxic effect will begin to appear. The dependence of the toxic effect on the dose (concentration) of a drug is of the same nature as its beneficial effect and can be described by gradual or quantum curves. On these curves the value can also be determined T.D.50 or TC50– a toxic dose (concentration) of a drug that causes a toxic effect equal to 50% of the maximum (for a quantum curve – a toxic effect in 50% of individuals in the population). Sometimes, instead of TD50, they use the indicator LD50 – lethal dose, which causes the death of 50% of objects in the population.

The safety assessment of drugs is characterized on the basis of graded or quantum dose-effect curves and the following indicators:

A) Therapeutic index– this is the ratio between the toxic and effective doses of the drug that cause the half-maximal effect: TI=TD50/ED50. The higher the therapeutic index value, the safer the medicine is.

B) Therapeutic latitude (therapeutic window)– this is the dose range between the minimum therapeutic and minimum toxic doses of a drug. It is a more correct indicator of drug safety, since it allows one to take into account the degree of increase in undesirable effects on the dose-effect curve.

IN) Reliable Security Factor– this is the ratio of the minimum toxic dose to the maximum effective dose (FNB = TD1/ED99), shows how many times the therapeutic dose of a drug can be exceeded without the risk of developing intoxication (undesirable effects).

G) Therapy corridor is the range of effective concentrations of a drug in the blood that must be created and maintained in the body to ensure the desired therapeutic effect is achieved.

42.46. Drug interactions. Incompatibility of drugs (since the issues are interrelated, choose according to the circumstances)

Drug interaction– this is a change in the severity and nature of effects with the simultaneous or preliminary use of several drugs.

Reasons for unwanted interactions:

1) polypharmacy – 6 or more drugs give 7 times more side effects than if the drug is less than 6.

2) doctors’ mistakes

3) violation of the dosage regimen

Rationale for combination therapy:

1. Monotherapy is not effective enough.

2. The absence of etiotropic therapy for most diseases; the need for medicinal effects on different parts of pathogenesis

3. Polymorbidity - the older a person is, the more diseases he has that occur simultaneously

4. The need to correct undesirable effects of drugs

5. Reducing the number of appointments and administration of drugs (convenience for the patient, saving labor for health workers)

Types of interaction:

I. Pharmaceutical interaction – A type of interaction associated with a physicochemical reaction between drugs during the manufacturing process of a medicinal product, even before the introduction of these drugs into the human body

A) typical mistakes leading to pharmaceutical incompatibility: writing complex prescriptions, improper storage, not taking into account the possibility of drug adsorption on the surface of plastic (organic nitrates)

B) problems with infusion therapy: mixing soluble salts, derivatives of insoluble weak acids or bases leads to their precipitation; in liquid dosage forms, cardiac glycosides and alkaloids are hydrolyzed and ABs are destroyed; pH of the environment (in an alkaline environment alkaloids precipitate)

C) recommendations: 1) It is better to prepare all mixtures ex tempore 2) The most reliable solution is with one drug 3) All solutions must be checked for the presence of suspensions before use 4) Interaction can occur without visible changes in solutions 5) Drugs should not be added to blood and AA solutions 6) In the absence of special instructions, drugs should be dissolved in 5% glucose solution (pH 3.5-6.5), isotonic NaCl solution (pH 4.5-7.0).

Glucose solution stabilized with HCl is incompatible with adrenaline, benzylpenicillin, apomorphine, kanamycin, vitamin C, oleandomycin, and cardiac glycosides. Cardiac glycosides are incompatible with atropine, papaverine, and platyphylline. ABs are incompatible with heparin and hydrocortisone. Vitamins of group B are incompatible with each other, with vitamins PP, C. Vitamin PP and C are also incompatible with each other.

Do not mix with any other drugs: phenothiazide, chlorpromazine, barbiturates, vitamin C preparations, amphotericin B, furosemide, sulfadiazine, aminophylline, adrenergic agonists.

II. Pharmacological– drug interaction, which manifests itself only in the human body after their combined use

A) pharmacokinetic

1) at the suction stage.

When insertedPer Osinteraction is determined by:

1. acidity of the environment

2. direct interaction in the gastrointestinal tract

Tetracyclines interact with calcium, aluminum, iron, magnesium to form chelate complexes. Cholestyramine interferes with the absorption of acid derivatives, calcium preparations, barvarin, digoxin, digitoxin, fat-soluble vitamins, trimethoprim, clindamycin, cephalexin, tetracycline. Iron preparations are better absorbed with vitamin C. Iron preparations with carbonates and tetracyclines are poorly absorbed.

3. gastrointestinal motility

Slow down peristalsis: some antidepressants, antihistamines, phenothiazine antipsychotics, narcotic drugs, increase the absorption of digoxin, corticosteroids, anticoagulants, reduce the absorption of levodopa. Strengthen peristalsis and increase gastrointestinal evacuation: metoclopramide, laxatives. They reduce the absorption of drugs: phenobarbital - griseofulvin, aspirin - indomethacin and diclofenac, PAS - rifampicin.

Methods to control absorption during parenteral administration: local anesthetics + adrenaline + phenylephrine – absorption of local anesthetics is reduced

4. intestinal flora

5. change in suction mechanism

2) upon distribution and deposit:

1. direct interaction in blood plasma: gentamicin + ampicillin or carbenicillin - reduce the activity of gentamicin

2. competitive displacement from the connection with albumin in the blood plasma: indomethacin, digitoxin, warfarin are bound to blood proteins by 90-98%, therefore, a doubling of the free fraction of drugs means a sharp increase in toxic effects; NSAIDs are being replaced by: warfarin, phenytoin, methotrexate.

Determinants that determine the clinical significance of this interaction:

ü Vd value (large – no problem, small – possible)

ü the influence of one drug substance on the activity of transport mechanisms through the mechanisms of other drugs: the transport of drugs – insulin, ACTH, angiotensin, kinins, etc. – increases dose-dependently; insulin increases the concentration of isoniazid only in the lungs, and the concentration of clopromazine only in the SMC.

3. displacement from binding with tissue proteins: quinidine displaces digoxin + reduces excretion by the kidneys, therefore increasing the risk of digoxin toxicity

3) in the process of metabolism

Drugs can increase or decrease the activity of cytochrome P450 and its enzymes (ethanol increases the activity of certain cytochrome isoenzymes)

Frequently interacting enzyme inhibitors:

1. AB: ciprofloxacin, erythromycin, isoniazid, metronidazole

2. Cardiovascular drugs: amiodarone, diltiazem, quinidine, verapamil

3. Antidepressants: fluoxetine, sertralene

4. Antisecretory drugs: cimetidine, omeprazole

5. Antirheumatic drugs: allopurinol

6. Fungicides: fluconazole, intracanazole, ketoconazole, miconazole

7. Antiviral: indinavir, retonavir, saquinavir

8. Others: disulfiram, sodium valproate

Drugs that produce toxic effects when inhibiting MAO: adrenomimetics, sympathomimetics, antiparkinsonian, narcotic analgesics, phenothiazines, sedatives, antihypertensive diuretics, hypoglycemic drugs

4) In the process of breeding– more than 90% of drugs are excreted in the urine.

Effect on urine pH and the degree of ionization of drugs, their lipophilicity and their reabsorption

1. interaction during passive diffusion: part of the drug is excreted unchanged, part of the drug is ionized at a urine pH of 4.6-8.2. Alkalinization of urine is clinically important: poisoning with acetylsalicylic acid or phenobarbital, when taking sulfonamides (reducing the risk of crystalluria), taking quinidine. Increased acidity of urine: increased excretion of amphetamine (of practical importance for identifying this drug in athletes)

2. interaction during the period of active transport: probenecid + penicillin increases the duration of movement of penicillin, probenecid + salicylates - eliminates the uricosuric effect of probenecid, penicillin + SA - reduces the excretion of penicillin

The influence of urine composition on the excretion of drugs:

Increased sugar in urine - increased excretion of: vitamin C, chloramphenicol, morphine, isoniazid, glutathione and their metabolites.

B) pharmacodynamic – this is the interaction of drugs associated with a change in the pharmacodynamics of one of them under the influence of the other (under the influence of thyroid hormones, the synthesis of b-adrenergic receptors in the myocardium increases and the effect of adrenaline on the myocardium increases).

Examples of clinically significant adverse synergistic interactions:

NSAIDs + Varvarin – increased risk of bleeding

Alcohol + benzodiazepines – potentiation of sedative effect

ACE inhibitors + K+-sparing diuretics – increased risk of hyperkalemia

Verapamil + b-blockers – bradycardia and asystole

Alcohol is a strong inducer of microsomal enzymes, leads to the development of tolerance to drugs (especially anesthetics and hypnotics), and increases the risk of developing drug dependence.

43. Drug interactions. Antagonism, synergism, their types. The nature of changes in the effect of drugs (activity, effectiveness) depending on the type of antagonism.

When drugs interact, the following conditions may develop: a) increased effects of a combination of drugs b) weakened effects of a combination of drugs c) drug incompatibility

Strengthening the effects of a drug combination is implemented in three options:

1) Summation of effects or additive interaction– a type of drug interaction in which the effect of the combination is equal to the simple sum of the effects of each drug separately. That is 1+1=2 . Characteristic of drugs from the same pharmacological group that have a common target of action (the acid-neutralizing activity of the combination of aluminum and magnesium hydroxide is equal to the sum of their acid-neutralizing abilities separately)

2) synergism - a type of interaction in which the effect of the combination exceeds the sum of the effects of each of the substances taken separately. That is 1+1=3 . Synergism can relate to both desired (therapeutic) and undesirable effects of drugs. The combined administration of the thiazide diuretic dichlorothiazide and the ACE inhibitor enalapril leads to an increase in the hypotensive effect of each drug, which is used in the treatment of hypertension. However, the simultaneous administration of aminoglycoside antibiotics (gentamicin) and the loop diuretic furosemide causes a sharp increase in the risk of ototoxicity and the development of deafness.

3) potentiation - a type of drug interaction in which one of the drugs, which by itself does not have this effect, can lead to a sharp increase in the effect of another drug. That is 1+0=3 (clavulanic acid does not have an antimicrobial effect, but can enhance the effect of the b-lactam antibiotic amoxicillin due to the fact that it blocks b-lactamase; adrenaline does not have a local anesthetic effect, but when added to the ultracaine solution, it sharply prolongs its anesthetic effect by slowing down absorption anesthetic from the injection site).

Reducing Effects Drugs when used together are called antagonism:

1) Chemical antagonism or antidotism– chemical interaction of substances with each other with the formation of inactive products (chemical antagonist of iron ions deferoxamine, which binds them into inactive complexes; protamine sulfate, the molecule of which has an excess positive charge - chemical antagonist of heparin, the molecule of which has an excess negative charge). Chemical antagonism underlies the action of antidotes (antidotes).

2) Pharmacological (direct) antagonism- antagonism caused by the multidirectional action of 2 drugs on the same receptors in tissues. Pharmacological antagonism can be competitive (reversible) or non-competitive (irreversible):

A) competitive antagonism: a competitive antagonist reversibly binds to the active center of the receptor, i.e., shields it from the action of the agonist. Since the degree of binding of a substance to the receptor is proportional to the concentration of this substance, the effect of a competitive antagonist can be overcome by increasing the concentration of the agonist. It will displace the antagonist from the active center of the receptor and cause a full tissue response. That. a competitive antagonist does not change the maximum effect of the agonist, but a higher concentration of the agonist is required for the interaction of the agonist with the receptor. Competitive antagonist Shifts the dose-response curve for the agonist to the right relative to the initial values ​​and increases the EC50 for the agonist without affecting the E value Max.

In medical practice, competitive antagonism is often used. Since the effect of a competitive antagonist can be overcome if its concentration falls below the level of the agonist, during treatment with competitive antagonists it is necessary to constantly maintain its level sufficiently high. In other words, the clinical effect of a competitive antagonist will depend on its half-life and the concentration of the full agonist.

B) non-competitive antagonism: a non-competitive antagonist binds almost irreversibly to the active center of the receptor or generally interacts with its allosteric center. Therefore, no matter how much the concentration of the agonist increases, it is not able to displace the antagonist from its connection with the receptor. Since some of the receptors that are associated with a non-competitive antagonist are no longer able to activate , E valueMax decreases, but the affinity of the receptor for the agonist does not change, so the EC50 value remains the same. On a dose-response curve, the effect of a non-competitive antagonist appears as a compression of the curve relative to the vertical axis without shifting it to the right.

Scheme 9. Types of antagonism.

A – a competitive antagonist shifts the dose-effect curve to the right, i.e., it reduces the sensitivity of the tissue to the agonist without changing its effect. B – a non-competitive antagonist reduces the magnitude of the tissue response (effect), but does not affect its sensitivity to the agonist. C – option of using a partial agonist against the background of a full agonist. As the concentration increases, the partial agonist displaces the full one from the receptors and, as a result, the tissue response decreases from the maximum response to the full agonist to the maximum response to the partial agonist.

Non-competitive antagonists are used less frequently in medical practice. On the one hand, they have an undoubted advantage, because their effect cannot be overcome after binding to the receptor, and therefore does not depend either on the half-life of the antagonist or on the level of the agonist in the body. The effect of a non-competitive antagonist will be determined only by the rate of synthesis of new receptors. But on the other hand, if an overdose of this medicine occurs, it will be extremely difficult to eliminate its effect.

Competitive antagonist	Non-competitive antagonist
Similar in structure to an agonist	It differs in structure from the agonist
Binds to the active site of the receptor	Binds to the allosteric site of the receptor
Shifts the dose-response curve to the right	Shifts the dose-response curve vertically
The antagonist reduces tissue sensitivity to the agonist (EC50), but does not affect the maximum effect (Emax) that can be achieved at a higher concentration.	The antagonist does not change the sensitivity of the tissue to the agonist (EC50), but reduces the internal activity of the agonist and the maximum tissue response to it (Emax).
The antagonist effect can be reversed by a high dose of the agonist	The effects of the antagonist cannot be reversed by a high dose of the agonist.
The effect of the antagonist depends on the ratio of doses of agonist and antagonist	The effect of an antagonist depends only on its dose.

Losartan is a competitive antagonist for angiotensin AT1 receptors; it disrupts the interaction of angiotensin II with receptors and helps lower blood pressure. The effect of losartan can be overcome by administering a high dose of angiotensin II. Valsartan is a non-competitive antagonist for these same AT1 receptors. Its effect cannot be overcome even with the administration of high doses of angiotensin II.

Of interest is the interaction that takes place between full and partial receptor agonists. If the concentration of the full agonist exceeds the level of the partial agonist, then a maximum response is observed in the tissue. If the level of a partial agonist begins to increase, it displaces the full agonist from binding to the receptor and the tissue response begins to decrease from the maximum for the full agonist to the maximum for the partial agonist (i.e., the level at which it occupies all receptors).

3) Physiological (indirect) antagonism– antagonism associated with the influence of 2 drugs on various receptors (targets) in tissues, which leads to a mutual weakening of their effect. For example, physiological antagonism is observed between insulin and adrenaline. Insulin activates insulin receptors, as a result of which the transport of glucose into the cell increases and the glycemic level decreases. Adrenaline activates b2-adrenergic receptors in the liver and skeletal muscles and stimulates the breakdown of glycogen, which ultimately leads to an increase in glucose levels. This type of antagonism is often used in emergency care of patients with an insulin overdose that has led to hypoglycemic coma.

44. Side and toxic effects of drugs. Teratogenic, embryotoxic, mutagenic effects of drugs.

Side effects– those effects that occur when using substances in therapeutic doses and constitute the spectrum of their pharmacological action (the analgesic morphine in therapeutic doses causes euphoria) can be primary and secondary:

A) primary side effects - as a direct consequence of the influence of this drug on a specific substrate (hyposalivation when using atropine to eliminate bradyarrhythmia)

B) secondary side effects - indirectly occurring adverse effects (ABs, suppressing normal microflora, can lead to superinfection)

Toxic effects– undesirable effects that appear in a given drug when it leaves the therapeutic range (drug overdose)

The selectivity of the action of a drug depends on its dose. The higher the dose of the drug, the less selective it becomes.

Teratogenic effect– the ability of a drug, when prescribed to a pregnant woman, to cause anatomical abnormalities of fetal development (thalidomide: phocomelia, anti-blastoma drugs: multiple defects)

Embryotoxic effect– adverse effects not associated with impaired organogenesis in the first three months of pregnancy. It appears at a later date Fetotoxic effect.

Mutagenic effect of drugs– damage to the germ cell and its genetic apparatus by drugs, which is manifested by a change in the genotype of the offspring (adrenaline, cytostatics).

Carcinogenic effect of drugs– the ability of some drugs to induce carcinogenesis.

45. Medical and social aspects of the fight against drug addiction, drug addiction and alcoholism. The concept of substance abuse.

« It is unlikely that humanity as a whole will ever manage without an artificial paradise. Most men and women lead such a painful life, which at best is so monotonous, miserable and limited, that the desire to “get away” from it, to disconnect at least for a few moments, is and has always been one of the main Zhela Niy soul"(Huxley, work "The Doors of Perception")

1) drug addiction– a mental and/or physical condition that is a consequence of the effects of drugs on the body and is characterized by specific behavioral reactions, a difficult to overcome desire to repeatedly take drugs in order to achieve a special mental effect or to avoid discomfort in the absence of drugs in the body. Drug dependence is characterized by:

A) Psychological dependence– development of emotional distress when stopping taking drugs. A person feels empty, plunges into depression, experiences a feeling of fear, anxiety, and his behavior becomes aggressive. All these psychopathological symptoms arise against the background of thoughts about the need to inject oneself with drugs that have caused addiction. The desire to take drugs can range from a simple desire to a passionate thirst for taking drugs, which absorbs all other needs and turns into the meaning of a person’s life. It is believed that psychological dependence develops when a person becomes aware that he can achieve optimal well-being solely through the administration of drugs. The basis of psychological dependence is a person’s belief in the effect of the medicine (cases of the development of psychological dependence to placebo are described in the literature).

B) Physical dependence– a violation of the normal physiological state of the body, which requires the constant presence of drugs in it to maintain a state of physiological balance. Stopping the medication causes the development of a specific symptom complex - withdrawal syndrome - a complex of mental and neurovegetative disorders in the form of dysfunction in the direction opposite to that which is characteristic of the action (morphine eliminates pain, depresses the respiratory center, constricts the pupils, causes constipation; during abstinence the patient experiences excruciating pain, frequent noisy breathing, dilated pupils and persistent diarrhea develops)

IN) Tolerance. Tolerance to drugs that cause drug dependence is often of a cross nature, i.e., it occurs not only to a given chemical compound, but also to all structurally similar compounds. For example, in patients with drug dependence on morphine, tolerance develops not only to it, but also to other opioid analgesics.

For the development of drug addiction, the presence of all 3 criteria is not a necessary condition; Table 3 presents the main types of drug addiction and its components.

Opioids, barbiturates, and alcohol cause strong physical and psychological dependence and tolerance. Anxiolytics (diazepam, alprazolam) mainly cause psychological dependence.

2) Drug addiction (drug addiction)– this is an extremely severe form of drug addiction, compulsive use of drugs, characterized by an ever-increasing, irresistible attraction to the administration of this drug, increasing its dose. Compulsivity of drive means that the need to administer medication dominates the patient over all other (even vital) needs. From the standpoint of this definition, craving for morphine is a drug addiction, while craving for nicotine is drug addiction.

3) Addiction to medicine– characterizes a less intense craving for taking medications, when refusal of the medication causes only a feeling of mild discomfort, without the development of physical dependence or a full picture of psychological dependence. That. addiction covers that part of drug dependence that does not fall under the definition of drug addiction. For example, the drug addiction to nicotine mentioned above is a form of addiction.

4) Drug abuse– unauthorized use of drugs in doses and in ways that differ from accepted medical or social standards in a given culture and time. That. drug abuse covers only the social aspects of drug use. An example of abuse is the use of anabolic steroids in sports or for physique enhancement by young men.

5) Alcoholism– chronic abuse of alcohol (ethyl alcohol), which over time leads to damage to a number of organs (liver, gastrointestinal tract, central nervous system, cardiovascular system, immune system) and is accompanied by mental and physical dependence.

6) Substance abuse– chronic abuse of various drugs (including drugs, alcohol, hallucinogens), manifested by a variety of mental and somatic disorders, behavioral disorders, and social degradation.

Drug addiction treatment a difficult and thankless task. Until now, no effective technique has been created that would ensure treatment success in more than 30-40% of patients. Achieving any noticeable results is possible only with the full cooperation of the efforts of the patient, the doctor and the social environment in which the sick person is located (the principle of voluntariness and individuality). Modern methods are based on the following principles:

ü psychotherapeutic and occupational therapy methods;

ü group treatment and rehabilitation (societies of anonymous alcoholics, drug addicts)

ü gradual or abrupt withdrawal of the drug during detoxification therapy

ü carrying out substitution therapy (replacement of drugs with slow and long-acting analogues with their subsequent abolition; for example, the so-called methadone substitution therapy program for heroin addicts)

ü treatment with specific antagonists (naloxone and naltrexone) or sensitizing agents (teturam)

ü neurosurgical methods of cryodestruction of the cingulate gyrus and hippocampus

47. Types of pharmacotherapy. Deontological problems of pharmacotherapy.

Pharmacotherapy (PT) – a set of treatment methods based on the use of drugs. Main types of TF:

1. etiotropic PT – correction and elimination of the cause of the disease (AB for infectious diseases)

2. pathogenetic FT – impact on the mechanism of disease development (ACE inhibitors for hypertension)

3. symptomatic PT – elimination of symptoms of a disease when it is impossible to influence its cause or pathogenesis (NSAIDs for influenza)

4. replacement PT – use of drugs for insufficiency of natural biologically active substances (insulin for diabetes)

5. preventive PT (vaccines, serums, acetylsalicylic acid for ischemic heart disease)

Society’s attitude towards drugs at the present stage 1) desire to receive benefits without risk 2) hope for a miracle, super expectations 3) lack of understanding of the risk of using drugs 4) indignation and “righteous indignation”, hasty assessments of drugs 5) desire to obtain new drugs

Doctor's attitude towards drugs: therapeutic optimism (hope for drugs as a powerful component of therapy), therapeutic nihilism (denial of new drugs, adherence to certain drugs, distrust of new drugs)

Compliance (adherence) of the patient to treatment: 1) understanding the doctor’s instructions and treatment goals 2) the desire to strictly follow the doctor’s instructions.

Currently, there are about 100,000 drugs in the world, more than 4,000 are registered in the Republic of Belarus, of which about 300 are vital drugs. Studying pharmacology helps you avoid drowning in a sea of ​​drugs.

48. Basic principles of treatment and prevention of drug poisoning. Antidote therapy.

Classification of toxic substances (OS):

1. By belonging to certain classes of chemical compounds: barbiturates, benzodiazepines, cyanides.

2. By origin: non-biological nature (acids, alkalis, salts of heavy metals), toxic waste products of some microbes (botulinum toxin), plant origin (alkoloids, glycosides), animal origin (venoms of snakes, bees)

3. By degree of toxicity: a) extremely toxic (DL50< 1 мг/кг) б) высоко токсические (1-50) в) сильно токсические (50-500) г) умеренно токсические (500-5000) д) мало токсические (5000-15000) е) практически нетоксические (> 15.000)

4. According to the toxicological effect: a) nerve-paralytic (bronchospasm, suffocation) b) skin-resorptive c) general toxic (hypoxic convulsions, coma, paralysis) d) suffocating e) tear and irritant f) psychotropic (impaired mental activity, consciousness)

5. Depending on the area of ​​primary use: industrial poisons, pesticides, household poisons, chemical warfare agents, medicinal substances.

6. Depending on the toxicity of the drug: List A - drugs, the prescription, use, dosage and storage of which, due to their high toxicity, must be carried out with great care. This list also includes drugs that cause drug addiction; List B - drugs, the prescription, use, dosing and storage of which must be carried out with caution due to possible complications when used without medical supervision.

Selectively toxic effect of drugs.

A) cardiotoxic: cardiac glycosides, potassium preparations, antidepressants

B) neurotoxic: psychopharmacological agents, hydroxyquinolines, aminoglycosides

C) hepatotoxic: tetracyclines, chloramphenicol, erythromycin, paracetamol

D) nephrotoxic: vancomycin, aminoglycosides, sulfonamides

D) gastroenterotoxic: steroidal anti-inflammatory drugs, NSAIDs, reserpine

E) hematotoxic: cytostatics, chloramphenicol, sulfonamides, nitrates, nitrites

G) pneumotoxic

Toxicokinetics – studies the absorption, distribution, metabolism and excretion of drugs taken in toxic doses.

The entry of toxic substances into the body is possible a) enterally b) parenterally. The speed and completeness of absorption reflects the speed of development of the toxic effect and its severity.

Distribution in the body: Vd=D/Cmax – the actual volume in which the toxic substance is distributed in the body. Vd > 5-10 l/kg – OM is difficult to remove (antidepressants, phenothiazines). Vd< 1 л/кг – ОВ легче удалить из организма (теофиллин, салицилаты, фенобарбитал).

Overdose– changes in pharmacokinetic processes: solubility, binding with proteins, metabolism ® significant increase in the free fraction of drugs ® toxic effect.

With increasing drug concentration, first-order kinetics transforms into zero-order kinetics.

The toxigenic stage is detoxification therapy, the somatogenic stage is symptomatic therapy.

Toxicodynamics . Main mechanisms of toxic action:

A) mediator: direct (type of competitive blockade - FOS, psychomimetics) and indirect (enzyme activators or inhibitors)

B) interaction with biomolecules and intracellular structures (hemolytic substances)

B) metabolism according to the type of lethal synthesis (ethyl alcohol, thiophos)

D) enzymatic (snake venoms, etc.)

Types of action: local, reflex, resorptive.

Classification of poisonings:

1. Etiopathogenetic:

a) accidental (self-medication, erroneous intake)

b) intentional (for the purpose of suicide, murder, development of a helpless state in the victim)

2. Clinical:

a) depending on the rate of development of poisoning: acute (administration of a toxic dose of a substance once or with a short time interval), subacute (slow development of the clinical picture after a single dose), chronic

b) depending on the manifestation of the main syndrome: damage to the CVS, damage to the DS, etc.

c) depending on the severity of the patient’s condition: mild, moderate, severe, extremely severe

3. Nosological: takes into account the name of the drug, the name of the group of substances

General mechanism of death due to poisoning:

A) defeat of the cardiovascular system:

1) decreased blood pressure, peripheral vascular hypovolemia, collapse, brady or tachycardia (tricyclic antidepressants, beta blockers, calcium channel blockers)

2) arrhythmias (ventricular tachycardia, fibrillation - tricyclic antidepressants, theophylline, amphetamine)

B) damage to the central nervous system: stupor, coma ® respiratory depression (drugs, barbiturates, alcohol, hypno-sedative drugs)

B) cramps, muscle hyperreactivity and rigidity ® hyperthermia, myoglobinuria, renal failure, hyperkalemia

Toxicological triad:

1) duration of use, dose and substance ® anamnesis.

2) assessment of the state of consciousness based on symptoms: breathing, blood pressure, body temperature

3) laboratory data

Basic principles of treatment:

I. First aid: artificial respiration, cardiac massage, anti-shock therapy, monitoring water and electrolyte balance

II. Delayed absorption and removal of unabsorbed substances from the body:

Goal: stop contact with the agent

1. Parenteral route:

a) through the lungs:

1) stop inhalation

2) irritants (ammonium alcohol, formaldehyde) ® strengthen active movements, warm, give oxygen and defoamers (ammonia alcohol has the antifoam vinegar, and formaldehyde has a diluted solution of ammonia)

b) through the skin: wash off with plenty of warm water with soap or detergent, specific antidotes, neutralization and cessation of exposure to chemical agents on the skin (FOS: washed with water, removed with 10-15% ammonia or 5-6% sodium bicarbonate solution with water; phenolcresol: vegetable oil or ethylene glycol, but not petroleum jelly, KMNO4: 0.5-1% solution of ascorbic acid or equal volumes of 3% hydrogen peroxide and 3% acetic acid solution, CCl4, turpentine, gasoline: warm soapy water )

c) when injecting into a limb: tourniquet above the injection site

d) in case of contact with the eyes: rinse with warm saline or milk for 10-20 minutes, instill a local anesthetic; If exposed to acids or alkalis, it cannot be neutralized. Consultation with an ophthalmologist is required.

2. Enteral route: free the stomach from OM, speed up passage

a) removal of agent:

1) pre-drink water. You should not take milk (exception – caustic toxic substances) and ethanol (exception – methanol).

2) vomiting - indicated mainly for poisoning with large tablets or capsules that cannot pass through the tube. Can be provoked reflexively or with emetics (NaCl: 1 tablespoon per 1 glass of water; ipecac syrup: adults 2 tablespoons, children 2 teaspoons; mustard: 1-2 teaspoons per glass of water; apomorphine: 5-10 mg/kg subcutaneously , except for children under 5 years old). Do not induce vomiting after taking: organic solvents - danger of inhalation, detergents - foaming, convulsive agents - danger of aspiration, caustic substances - damage to the esophagus)

3) tube gastric lavage is an emergency and mandatory measure. The stomach is washed if no more than 4-6 hours have passed since the poisoning, sometimes up to 10 hours; in case of poisoning with acetylsalicylic acid - after 24 hours. The patient is preliminarily intubated with a tube with an inflatable cuff: in a comatose state in the absence of a cough and laryngeal reflex. The stomach is washed with water or saline solution at 30° C, the procedure takes 4 hours or more. At the end of washing - activated carbon and sodium sulfate.

b) reducing absorption from the gastrointestinal tract: activated carbon orally after gastric emptying + sodium or magnesium sulfate. Features of measures to reduce absorption:

1) organic solvents: do not induce vomiting, gastric lavage after intubation, activated charcoal + petroleum jelly

2) detergents: do not induce vomiting and rinse the stomach, you must give a lot of water + defoamers (simethicone)

3) acids and alkalis: you cannot induce vomiting; gastric lavage through a tube lubricated with vegetable oil after administration of a narcotic analgesic is the only indication for giving milk. For acid poisoning - antacids, for alkali poisoning - citric or acetic acid.

III. Removal of absorbed chemical agents from the body

a) forced diuresis (conditions: sufficient renal blood flow and glomerular filtration; pour in and out 20-25 liters in 24 hours)

b) peritoneal hemodialysis

c) hemosorption

d) exchange blood transfusion

e) forced hyperventilation

IV. Symptomatic treatment of functional disorders.

Antidotes: 1) toxicotropic - binding, neutralizing and preventing the absorption of agents: acting on the principle of activated carbon, acting on a chemical principle (unithiol, penicillamine, pentacin)

2) toxicokinetic – accelerate the biotransformation of chemical agents (trimedoxime bromide, sodium thiosulfate, ethanol, AO)

3) pharmacological – atropine, naloxone

4) immunological antidotes

Unithiol, succimer – binds heavy metals, metalloids, cardiac glycosides. Esmolol binds theophylline and caffeine. Calcium trisodium pentotate – forms complexes with divalent and trivalent metals.

49. Recipe and its structure. General rules for writing a prescription. State regulation of the rules for prescribing and dispensing drugs.

Recipe- this is a written request from a doctor to a pharmacist with a request to dispense a medicine in a certain form and dosage, indicating the method of its use.

The recipe has the following parts:

1. Inscriptio – title, inscription. The date of issue of the prescription, the surname, initials and age of the patient, the surname and initials of the doctor are written here.

2. Invocatio - contacting a pharmacist. Expressed by the word “Recipe” (take) or the abbreviation (Rp.)

3. Designatio materiarum – designation or name of medications indicating their doses. In a complex prescription, the listing of medicinal substances is done in a certain sequence. The main medicinal substance (basis) is indicated first. Then they write adjuvans. After that, ingredients are indicated that correct the taste, smell, color of the medicine (corrigens). The substances that give the drug a specific dosage form (constituens) are written last.

4. Subscriptio – prescription (instruction) to the pharmacist. Here the dosage form is indicated, the pharmaceutical operations necessary for its manufacture, the number of dispensed doses of the drug.

5. Signatura - instructions to the patient on how to use the medicine.

6. Subscriptio medici – signature of the doctor who wrote the prescription, his personal seal.

The doctor's address to the pharmacist, the name of the drugs included in the prescription, the name of the dosage form and the nature of the pharmaceutical operations are written in Latin. The names of medicines and botanical names of plants are written with a capital letter. The prescription to the patient is written in Russian or national languages.

General rules for writing a prescription:

1. The prescription is written on a special form, depending on the drug being prescribed, in clear handwriting, ink or a ballpoint pen without corrections.

2. The prescription shall indicate the day, month, year, surname, first name, patronymic and age of the patient, surname, first name and patronymic of the doctor. Then comes the text of the recipe, which lists the names of the substances included in the recipe in the genitive case, indicating their quantity.

3. The unit of mass in recipes is gram or ED.

4. If the maximum dose of toxic and potent substances is exceeded, it is confirmed in words

5. The prescription is confirmed by the signature and personal seal of the doctor

In the Republic of Belarus there is a State regulation of the rules for prescribing and dispensing drugs.

50. Rules for prescribing poisonous, narcotic and potent drugs.

List A includes drugs, the prescription, use, dosing and storage of which, due to their high toxicity, must be carried out with great care. This list also includes drugs that cause drug addiction.

List B includes drugs whose prescription, use, dosing and storage must be carried out with caution due to possible complications when used without medical supervision.

For toxic and potent drugs, maximum single and daily doses have been established. These doses are intended for adults over 25 years of age. When recalculating doses for people over 60 years of age, age sensitivity to different groups of drugs is taken into account. Doses of drugs that depress the central nervous system, as well as cardiac glycosides and diuretics, are reduced by 50%, doses of other toxic and potent drugs are reduced to 2/3 of the adult dose. Doses of antibiotics, sulfonamides, and vitamins are usually the same for all age groups, starting at age 25.

1. Narcotic drugs (list A) are written out on a prescription form 2. One form - one medicine. Must be: the signature and seal of the attending physician, the signature of the head physician of the health facility, the round seal of the health facility.

2. Poisonous drugs (List A), potent drugs (List B) are written out on a prescription form 1. There must be a signature and personal seal of the doctor, the seal of the health facility.

51. Controlled drugs. Medicines prohibited for prescription.

Under control are narcotic, poisonous and potent drugs (see c. 20)

A) Medicines not registered in the Republic of Belarus and not approved for official use

B) drugs at the request of patients and their relatives without examining the patient and establishing a diagnosis

C) prescriptions for narcotic drugs for injection, anesthetic ether, chloroethyl, pentamin, fluorotane, sodium hydroxybutyrate in ampoules, lithium hydroxybutyrate, barium sulfate for fluoroscopy.

52. Pharmacokinetic models (single-chamber and two-chamber), quantitative laws of absorption and elimination of drugs.

Single chamber model.

The entire body is a single homogeneous container. Assumptions:

1) a rapid dynamic development is established between the content of the drug in the bloodstream and its concentration in extravascular tissues

2) The drug is quickly and evenly distributed throughout the entire blood volume

3) The elimination of the drug is subject to first-order kinetics: the rate of decrease in the content of the drug in the blood is proportional to its concentration

If the mechanisms for drug elimination (hepatic biotransformation, renal secretion) are not saturated at a therapeutic dose, a log-normal plot of plasma concentration over time will be linear.

Incline lognormal axis – Kel, where Kel is the elimination rate constant and has the dimension time-1. The C0 value is obtained by extrapolating the graph to the intersection with the y-axis. Plasma drug concentration(Ct) at any time t after introduction into the body is:

Ln Ct = Ln C0 – kt. The elimination constant Kel, Vd, and total clearance (CL) are related by: CL = k × Vd

Two-chamber model.

Often, after a drug enters the body, it is not possible to quickly achieve equilibrium between the content of the drug in the blood and its concentration in the extravascular fluid. Then it is believed that in the totality of tissues and biological fluids of the body, two chambers can be distinguished, which differ in the degree of accessibility for the penetration of drugs. The central chamber includes blood (often with intensively perfused organs - liver, kidneys), the peripheral chamber includes the interstitial fluid of internal organs and tissues.

The resulting graph shows the initial Distribution phase ( The time required for the drug to reach an equilibrium state between the central and peripheral chambers and the following slow Elimination phase First order.

The value of C0 is obtained by extrapolation Elimination phases until it intersects with the ordinate axis. C0 is used to calculate the volume of distribution and the elimination constant. The formulas for calculating Ct and Cl given for the single-compartment model also apply during the elimination phase for drugs that meet the conditions of the two-compartment model.

53. Selectivity and specificity of drug action. Therapeutic, side and toxic effects of drugs, their nature from the perspective of the concept of receptors. Therapeutic strategy to combat the side and toxic effects of drugs.

Specificity- this is when a drug binds to a strictly specific type of receptor.

Selectivity- this is when a drug is able to bind to one or more types of receptors more accurately than others.

It is more preferable to use the term selectivity because it is unlikely that any drug molecule can bind to only one type of receptor molecule, since the number of potential receptors in each patient is astronomical.

Therapeutic effect- the main desired pharmacological effect expected from a given pharmacological drug.

Side effects– those effects that occur when substances are used in therapeutic doses and constitute the spectrum of their pharmacological action.

Toxic effects– undesirable effects that appear in a given drug when it leaves the therapeutic range.

Relationships between the therapeutic and toxic effects of drugs based on the analysis of receptor-effector mechanisms:

1) therapeutic and toxic effects mediated by the same receptor-effector mechanism (prazosin acts as an alpha-selective antagonist on vascular SMC receptors and has a hypotensive effect in essential hypertension, but with a large dose the patient may experience postural hypotension)

2) therapeutic and toxic effects mediated by identical receptors, but different tissues or different effector pathways (cardiac glycosides are used to increase myocardial contractility, at the same time they disrupt the function of the gastrointestinal tract and vision due to blockade of the Na+/K+-ATPase of the cell membrane)

3) therapeutic and toxic effects mediated by different types of receptors (for example, norepinephrine has a hypertensive effect through a1-Ar, but at the same time causes tachycardia through b1-Ar)

Therapeutic strategy to combat therapeutic and side effects of drugs:

1. Drugs should always be administered in the lowest dose that produces an acceptable therapeutic effect

2. Reducing the dose of one drug by prescribing another drug with a similar effect, but through different receptors and with a different toxicity profile.

3. The selectivity of the action of drugs can be increased by controlling the concentration of drugs in the area of ​​​​receptors of various parts of the body (local use of drugs - inhaled use of salbutamol for bronchial asthma)