What is pharmacology. General pharmacology. International educational institutions in pharmacology

Pharmacology is divided into general and specific. General Pharmacology examines the mechanisms of action of medicinal substances (primary pharmacological reactions, effects on enzymes, biological membranes, electrical potentials, receptor mechanisms); studies the general patterns of their action on the body, depending on the nature of distribution, biotransformation (oxidation, reduction, hydrolysis, deamination, acetylation, etc.), routes of administration (oral, subcutaneous, intravenous, inhalation, etc.), excretion (by the kidneys , intestines).

In addition, it characterizes the principles of action of medicinal substances (local, reflex, resorptive); conditions that determine their action in the body (chemical structure, physicochemical properties, doses and concentrations, exposure time, repeated use of drugs; gender, age, weight, genetic characteristics, functional state of the body); principles of combined drug therapy, issues of standardization, classification, research of medicinal substances, etc.

Sections of general pharmacology

principles of production of medicines, their composition and properties.
metabolism - pharmacokinetics and pharmacodynamics,

Pharmacodynamics - the actual doctrine of the effect of medicinal substances on the body; pharmacokinetics - the doctrine of their absorption, distribution and biotransformation in the body.

Basic Pharmacokinetic Issues

Absorption (absorption) - how does the substance enter the body (through the skin, gastrointestinal tract, oral mucosa)?
Distribution - how is the substance distributed through the tissues?
Metabolism (metabolic transformations) - into which substances it can be chemically converted in the body, their activity and toxicity.
Excretion (excretion) - how is the substance excreted from the body (with bile, urine, through the respiratory system, skin)?

Molecular pharmacology is the study of the biochemical mechanisms of action of medicinal substances.

The study of drugs in clinical practice and their final approbation are the subject of clinical pharmacology.

History

New time

The beginning of modern experimental pharmacology was laid by R. Buchheim (Dorpat) in the middle of the 19th century. Its development was promoted by O. Schmideberg, G. Meyer, V. Straub, P. Trendelenburg, K. Schmidt (Germany), A. Keschny, A. Clarke (Great Britain), D. Bove (France), K. Geimans (Belgium) , O. Levy (Austria), etc.

In Russia in the 16-18 centuries. already existed "pharmaceutical gardens", and information about medicinal plants was recorded in the "herbalists" and "zeleiniki". The first Russian pharmacopoeia, Pharmacopoea Rossica, was published in 1778.

XX century

Experimental pharmacology of the late XIX - early XX century (V. I, Dybkovsky, A. A. Sokolovsky, I. P. Pavlov, N. P. Kravkov, etc.) gave a new impetus to domestic science.

Leading scientific institutions in the CIS

Scientific research in pharmacology is carried out at the Institute of Pharmacology of the Academy of Medical Sciences and the Ukrainian National Pharmaceutical University (formerly Kharkov Chemical-Pharmaceutical Institute), at the Research Chemical-Pharmaceutical Institute. S. Ordzhonikidze (Moscow), and others, at the departments of medical and pharmaceutical universities. Pharmacology is taught in medical and pharmaceutical institutes and schools.

Major research centers abroad

Institutes of Pharmacology in Krakow, Prague, Berlin; pharmacological laboratories of the medical center in Bethesda (USA), at the Mill Hill Institute (London), at the Higher Institute of Sanitation (Rome), the Max Planck Institute (Frankfurt am Main), the Karolinska Institute (Stockholm). Pharmacology is taught at the relevant departments of the medical faculties of universities.

Pharmacological trends of the XXI century

Recently, a field of knowledge has been developed that originated from the combination of pharmacology and epidemiology - pharmacoepidemiology. The latter science is the theoretical and methodological basis of pharmacovigilance carried out in the Russian Federation, in the EU and the USA, as well as around the world. Biopharmacology is undergoing rapid development.

Basic concepts and terms

Active ingredient - a substance in the composition of a medicinal product, with the physiological effect of which on the body is associated with the desired effect of this medicinal product

Educational establishments

Some well-known educational institutions in the field of pharmacology:

St. Petersburg State Chemical-Pharmaceutical Academy
Pyatigorsk State Pharmaceutical Academy

International educational institutions in pharmacology

Duke University
Massachusetts College of Pharmacy and Health Sciences
Purdue University
SUNY Buffalo
University of California, Santa Barbara
University of Michigan
University of the Sciences in Philadelphia
University of Wisconsin-Madison
Kharkiv National Pharmaceutical University

Literature

// Encyclopedic Dictionary of Brockhaus and Efron: In 86 volumes (82 volumes and 4 additional). - SPb. , 1890-1907.
Anichkov S.V., Belenky M.L., Textbook of pharmacology, 3rd ed., L., 1969;
Albert E., Selective toxicity, M., 1971;
Mashkovsky M.D., Medicines. Pharmacotherapy manual for doctors, 9th ed., Parts 1-2, M., 1987;
Goodman L. S., Oilman A., The pharmacological basis of therapeutics, 3rd ed., N. Y., 1965;
Drill V. A., Pharmacology in medicine, 4th ed., N. Y., 1971;
Drug Design, ed. by E. J. Ariens, v. 1 = 3.5, N. Y. = L., 1971 = 75.

Periodicals

"Pharmacology and Toxicology" (M., since 1938)
Acta pharmacologica et toxicologica (Cph., Since 1945)
"Archives internationales de pharmacodynamie et detherapie" (P., from 1894)
"Arzneimittej = Forschung" (Aulendorf. From 1951)
Biochemical Pharmacology (Oxf., Since 1958)
British Journal of Pharmacology and Chemotherapy (L., since 1946);
Helvetica physiologica et pharmacologica acta (Basel, since 1943);
Journal of Pharmacology and Experimental Therapeutics (Baltimore, since 1909)
"Naunyn - Schmiedebergs Archiv fur experimentelle Pathologie und Pharmacologie" (Lpz., 1925) (in 1873-1925 - "Archiv fur experimentelle Pathologie und Pharmakologie")

Links

Pharmacology- an article from the Great Soviet Encyclopedia.
Basic concepts of the sections of Pharmacology.
Generally Popular Articles on Pharmacology.

Wikimedia Foundation. 2010.

Synonyms:

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

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

DIRECT and INDIRECT(in some cases, reflex action).

The direct action of drugs develops directly in the target organ. This action can be local, for example: a local anesthetic has a local anesthetic 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 histological barriers to the focus of arrhythmia in the heart tissue.

The indirect action can be considered on the example of the action of cardiac glycosides (digoxin, strophanthin, etc.). has a stimulating effect on the contractility of the heart muscle, resulting in increased cardiac output. The blood flow rate increases and the perfusion (blood flow) in the kidneys increases. This leads to an increase in the level of urine output (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 the organ changes in another place of the body (for example: ammonia, exciting the receptors of the nasal mucosa, leads to the excitation of the cells of the respiratory center of the brain, as a result, the frequency and depth of breathing increases).

ELECTORAL and NON-ELECTIVE.

Selective (elective) action of medicinal

funds are carried out by influencing certain receptors (for example: prazosin blocks mainly L1 | -adrenergic receptors) or drugs can accumulate in a certain organ and have their 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 drug action, the less toxicity and the severity of negative side reactions.

The indiscriminate action of drugs, the term opposite to the selective effect (for example: the anesthetic agent fluorotan indiscriminately blocks almost all types of receptor formations in the body, mainly in the nervous system, which leads to unconsciousness, that is, anesthesia).

Reversible and irreversible.

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

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

MAIN and SIDE.

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

Side effect can be POSITIVE(for example: doxazosin in the course of treatment of hypertension inhibits the growth of the prostate gland and normalizes the tone of the urinary bladder sphincter, and, therefore, can be used for prostate adenoma and urinary disorders) and NEGATIVE(for example: doxazosin can cause transient tachycardia in the treatment of hypertension, and withdrawal symptoms are often reported).

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

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

AGONISTS-ANTAGONISTS- drugs that have properties to both excite and inhibit receptor formations. For example: pindolol (wisken) blocks beta-1 and beta-2-adrenergic receptors. However, pindolol has the so-called “internal sympathomimetic activity,” that is, the drug, blocking beta-adrenergic receptors and preventing the mediator from acting on these receptors for a certain time, also has some stimulating effect on the same beta-adrenergic receptors.

Doses of medicines

One-time- the amount of the drug per dose;
Daily- the amount of the drug used during the day;
Coursework - the amount of the drug used during the course of treatment of a certain disease (for example, for the treatment of hypertension stage 1 for 1.5-2 months, it is used);
Shock(as a rule, the initial single dose is 2 times higher than the subsequent ones, most typical for the appointment of sulfa drugs and cardiac glycosides);
Minimum(threshold) - the dose of the drug at which the therapeutic (therapeutic) effect begins to manifest;
Average therapeutic dose- the dose of the drug that is most often used in the treatment of a specific disease by a specific doctor in a specific period of time. For example, the average therapeutic dose in the mid-70s of the 20th century was 100 thousand units per injection, and at present, at least 500 thousand units are used per injection;
Maximum- a dose of a drug that exhibits therapeutic activity, but when administered, the toxic effect is not yet manifested;
Toxic- the dose of the drug, when prescribed, the toxic effect is revealed.
Lethal dose- the dose of the drug, the appointment of which leads to a fatal outcome. Finding the lethal dose is used in experimental pharmacology to determine the toxicity of drugs. Usually, to determine toxicity, LD-50 is determined, the dose of the drug that causes the death of 50% of animals (mice, rats, etc.).

Medicines are dosed:

In weight units. (g, mg, μg per 1 kg; per 1 sq. m);
In bulk units. (ml, drops, etc.);
- In units of activity (ME - international units, ICE - frog units of action).

Concentration- the number of drugs in a certain amount.

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

Currently, there are several ways to calculate doses for patients, especially children:

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

at the age of 24 years is prescribed in a dose of 500 mg, and a child at the age of 12 is recommended to appoint 250 mg.

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

If CHILD WEIGHT less than 30 kg:

DOSE = (MASS X 2)% ADULT DOSE;

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

If the child's weight is over 30kg:

DOSE = (MASS + 30)% ADULT DOSE.

For example: the weight of a child 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, which is recommended for adults.

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

INCREASE EFFECT (cumulation);
REDUCED EFFECT (addictive);
EFFECT DOES NOT CHANGE.

CUMULATION - accumulation (increase) EFFECT drug ON RE-USE.

Cumulation can be:

MATERIAL
FUNCTIONAL

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

2) Functional cumulation - the effect is accumulating, not the substance. Functional cumulation is most typical for ethyl alcohol in chronic alcoholism and for some.

tolerance, resistance develops with prolonged use of drugs (promedol, phenobarbital, galazolin, etc.).

Addiction can be associated with:

With a decrease in the absorption of drugs;
Increased metabolism;
By increasing the intensity of excretion;
Decreased sensitivity of receptor formations;
A decrease in the density of receptors in tissues.

Cross addictive to drugs that interact with the same receptors ( substrates). For example, the emergence of resistance of microorganisms when applied penicillins and cephalosporins.

1. The concept of treatment as directed correction of physiological disorders in the body. The benefits and risks of using medications. The grounds for their application. Safety assessment.

Pharmacology- the theoretical basis of pharmacotherapy.

Reasons for using drugs:

1) to correct and eliminate the cause of the disease

2) in case of insufficient preventive measures

3) for health reasons

4) obvious need based on level of knowledge and experience

5) striving to improve the quality of life

Benefits in 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) substitution of medicinal substances for natural biologically active substances, not produced by organisms in sufficient quantities

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

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

A) unacceptable (harm> benefit)

B) acceptable (benefit> harm)

B) insignificant (105 - security level)

D) conscious

Drug safety assessment begins at the level of chemical laboratories that synthesize drugs. The preclinical assessment of drug safety is carried out by the Ministry of Health, FDA, etc. If the drug successfully passes this stage, its clinical assessment begins, consisting of four phases: Phase I - assessment of tolerance on healthy volunteers 20-25 years old, Phase II - on sick volunteers numbering 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 - drug monitoring for 5 years after its official approval. If a drug successfully passes all of these phases, it is considered safe.

2. The essence of pharmacology as a science. Sections and fields of modern pharmacology. The main terms and concepts of pharmacology are 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 managing 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 while prescribing them, c) the effect 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 for making 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- the 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).

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

3. The chemical nature of drugs. Factors providing the therapeutic effect of drugs are pharmacological action and placebo effects.

There are drugs 1) vegetable 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 the object of treatment.

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

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

The benefit of the placebo effect is related to the psychological impact on the patient. It will be maximum only when using it. Combined with therapies that have a pronounced specific effect. Expensive substances as a placebo also help to achieve a greater response.

Placebo indications:

1) weak mental disorders

2) psychological support for a patient with an incurable chronic disease or suspected of having a difficult 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 of drug creation:

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 drug creation:

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 investigate 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 with proven medicinal properties.

Medicinal substance- an individual chemical compound used as a medicine.

Dosage form- a convenient form for practical use, given to a drug to obtain the required therapeutic or prophylactic effect.

Medicinal product- a medicinal product in a specific dosage form, approved by a government authority.

5. Ways of introducing drugs into the body and their characteristics. Presystemic elimination of drugs.

1. For systemic action

A. Enteral route of administration: oral, sublingual, buccal, rectal, tube

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

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

Route of drug administration	Dignity	disadvantages
Orally - by mouth	1. Convenient and easy 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 hardly taken into account in practice 2. Not all drugs are well absorbed in the digestive tract 3. Some drugs are destroyed in the stomach (insulin, penicillin) 4. Part of the drug has NLR on the gastrointestinal mucosa (NSAIDs - mucosal manifestations, antacids - suppress motor skills) 5. Not applicable for patients in an unconscious state and with impaired swallowing
Sublingual and buccal	1. Convenient and quick introduction 2. Fast absorption of drugs 3. Medicines are not subject to presystemic elimination 4. The action of the drug can be quickly interrupted	1. Inconvenience caused by frequent regular use of pills 2. Irritation of the oral mucosa, excessive salivation, contributing to the swallowing of drugs and a decrease in its effectiveness 3. Bad taste
Rectally	1. Half of the drugs are not subject to presystemic 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. The absorption of drugs is significantly slowed down when the rectum is not emptied.
Intravascular (usually intravenous	1. Rapid entry into the bloodstream (emergency conditions) 2. Rapid creation of high systemic concentration and the ability to manage it 3. Allows the introduction 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 injection site of drugs (erythromycin) and pain (potassium chloride) 4. Some drugs are adsorbed on the walls of droppers (insulin)
Intramuscularly	Sufficiently fast absorption of the drug into the blood (10-30 min)	Risk of local complications
Subcutaneously	1. The patient can inject independently 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 absorption of drugs
Inhalation	1. Rapid onset of action and high concentration at the injection site in the treatment of respiratory diseases. ways 2. Good controllability of the action 3. Reduction of toxic systemic effects	1. The need for a special device (inhaler) 2. Difficulty using pressurized aerosols for some patients
Local PM	1. High effective concentration of drugs at the injection site 2. Undesirable systemic effects of this drug are avoided	If the integrity of the skin is violated, the drug can enter the systemic circulation - a manifestation of undesirable systemic effects.

Presystemic elimination of drugs (first pass effect)- the process of biotransformation of the drug before the drug enters the systemic circulation. Enzymatic systems of the intestine, portal vein blood and hepatocytes are involved in presystemic elimination with oral administration of the drug.

When administered intravenously, there is no presystemic elimination.

In order for an orally administered drug to have a beneficial effect, it is necessary to increase its dose to compensate for losses.

6. Transport of drugs across biological barriers and its varieties. The main factors affecting the transport of drugs in the body.

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

1) Filtration (water diffusion) - passive movement of molecules of a substance along a concentration gradient through pores filled with water 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 by means of specific carriers - drug transfer by means of carriers built into the membrane (usually proteins) is characteristic of hydrophilic polar molecules, a number of inorganic ions, sugars, amino acids, pyrimidines:

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

b) active transport - against the concentration gradient with the costs of ATP

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

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

Factors affecting 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. Transport through membranes of medicinal substances with variable ionization (Henderson-Hasselbalch ionization equation). Transfer control principles.

All drugs are weak acids or weak bases, which have their own values of the ionization constant (pK). 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 state and 50% in the non-ionized state, and the medium for the drug will be neutral.

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

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

Hence, The absorption of weak acids takes place mainly in an acidic medium, and of weak bases in an alkaline medium.

Features of the metabolism of weak acids (SC):

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

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

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

Features of the metabolism of weak bases: opposite to SC (absorption is better in the intestine; in alkaline urine they are reabsorbed)

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

The quantitative dependence of the drug ionization process at different pH of the medium allows one 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 makes it possible to estimate the degree of drug ionization at a given pH value and to 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 non-protonated form

Knowing the pH of the medium and the pKa of the substance, it is possible, from the calculated logarithm, to determine the degree of drug ionization, and hence the degree of its absorption from the gastrointestinal tract, reabsorption or excretion by the kidneys at different pH values of urine, 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 the transfer of drugs in the body by water diffusion:

1. Epithelial integuments (mucous membranes of the gastrointestinal tract, oral cavity, etc.) - water diffusion of only very small molecules (methanol, lithium ions, etc.)

2. Capillaries (except for cerebral ones) - filtration of substances with a molecular weight of up to 20-30 thousand. Yes.

3. Capillaries of the brain - basically do not have water pores, except for the areas of the pituitary gland, pineal gland, zone IV ventricle, choroid plexus, median eminence

4. Placenta - has no water pores (although a controversial issue).

5. Binding of drugs to blood proteins prevents their release from the bloodstream, and hence 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 across cell membranes

2. Determined by the lipophilicity of the diffused substance (ie, 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 drug from penetrating into the aqueous phase of membranes)

3. Non-polar compounds diffuse easily, ions are difficult to diffuse.

Any diffusion (both water and lipids) obeys Fick's law of diffusion:

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

Corollary from Fick's law:

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

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

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

Active transport- transfer of drugs, regardless of the concentration gradient using the energy of ATP, is characteristic of hydrophilic polar molecules, a number of inorganic ions, sugars, amino acids, pyrimidines. Characterized by: a) selectivity for certain compounds b) the possibility of competition of two substances for one transport mechanism c) saturation at high concentrations of the substance d) the possibility of transport against the 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 blood plasma determines (quantitatively determines) the pharmacological effect.

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

1) determine the half-life (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. Bioavailability

Bioavailability (F) - characterizes the completeness and rate of absorption of drugs with extra-systemic routes of administration - reflects the amount of unchanged substance that has reached the systemic circulation, 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 0 if the drug is not absorbed from the lumen of the gastrointestinal tract.

To estimate F, a curve is plotted as a function of the drug concentration in the blood versus time after its intravenous administration, as well as after administration by the investigated route. This is the so-called. pharmacokinetic curves of the relationship "time-concentration". 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 Curve

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

Determinants of bioavailability:

1) suction speed

2) completeness of absorption - insufficient absorption of drugs due to its very high hydrophilicity or lipophilicity, metabolism by intestinal bacteria when administered enterally, etc.

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

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

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

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

Distribution bays:

1. Extracellular space (plasma, intercellular fluid)

2. Cells (cytoplasm, membrane of organelles)

3. Adipose and bone tissue (deposition of drugs)

In a person weighing 70 kg, the volume of liquid media is 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 drug is distributed in the extracellular fluid;

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

[Vd> 42 L, then all the drug is located mainly in the extracellular space.

Molecular ligands of drugs:

A) specific and non-specific receptors

B) blood proteins (albumin, glycoprotein) and tissues

C) connective tissue polysaccharides

D) nucleoproteins (DNA, RNA)

Distribution determinants:

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

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

· Organ blood flow- in well perfused tissues (brain, heart, kidneys), the therapeutic concentration of the substance is created much earlier than in poorly perfused tissues (fatty, bone)

· The presence of histohematogenous barriers- drugs easily penetrate tissues with poorly expressed GHB

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

· Deposition of the drug in tissues- the binding of drugs to tissue proteins contributes to its accumulation in them, since the concentration of free drugs in the perivascular space decreases and a high concentration gradient between blood and tissues is constantly maintained.

A quantitative characteristic of drug distribution is the apparent volume of distribution (Vd).

Apparent volume of distributionVd Is a hypothetical volume of fluid in which the entire administered dose of the drug can be distributed in order to create a concentration equal to the concentration in the blood plasma.

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

The larger the apparent volume of distribution, the more drugs are 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 drugs is eliminated from the body per unit of time Þ Kel = Avid / Atot, where Avid is the amount of drugs excreted in units. time, Absh - the total amount of drugs in the body.

The kel value is usually found by solving a pharmacokinetic equation describing the process of drug elimination from the blood; therefore, kel is called a model kinetic index. Kel is not directly related to the planning of the dosage regimen, but its value is used to calculate other pharmacokinetic parameters.

The elimination constant is directly proportional to the 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. The half-life of drugs, its essence, dimension, relationship with other pharmacokinetic parameters.

Half-elimination period(t½, min) is the time required to reduce the concentration of drugs in the blood by exactly half. At the same time, it does not matter in what way a decrease in concentration is achieved - by means of biotransformation, excretion, or by a combination of both processes.

The half-life is determined by the formula:

The half-life is the most important pharmacokinetic parameter that allows:

B) determine the time of complete elimination of the drug

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

14. Clearance as the main pharmacokinetic parameter for dosing regimen management. Its essence, dimension and relationship with other pharmacokinetic parameters.

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

Since plasma (blood) is the "visible" part of the volume of distribution, the clearance is the fraction of the volume of distribution from which the drug is released per unit of time. If we denote the total amount of the drug in the body through General, and the amount that was allocated after Avyd, then:

On the other hand, it follows from the definition of the volume of distribution that the total amount of the drug in the body is Absh =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 blood plasma.

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

Injection rate = Excretion rate =Cl´ CTer(dose / min)

DNS= injection rate´ T (T- the interval between taking the medication)

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

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

15. Dose. Types of doses. Drug dosage units. Drug dosage goals, administration methods and options, administration interval.

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

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

Dose types:

A) single dose - the amount of substance per dose

B) daily dose - the amount of the 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 higher 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 number of injected drugs, which 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

Pharmaceutical dosage units:

1) in grams or fractions of a gram of drugs

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)

Drug dosing goals:

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

2) avoid the phenomena of intoxication and side effects with the introduction of drugs

Methods of drug administration: 1) enteral 2) parenteral (see section 5)

Drug administration options:

A) continuous (by long-term intravascular infusion of drugs by drop or through automatic dispensers). With continuous administration of drugs, its concentration in the body changes smoothly and does not undergo significant fluctuations.

B) intermittent administration (by injection or non-injection methods) - the introduction of a drug at regular intervals (dosing intervals). With intermittent administration of drugs, its concentration in the body constantly fluctuates. After taking a certain dose, it first rises, and then gradually decreases, reaching minimum values before the next administration of the drug. The concentration fluctuations are the more significant, the larger the administered dose of the drug and the interval between injections.

Introduction interval- the interval between the administered doses, ensuring the maintenance of the therapeutic concentration of the substance in the blood.

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

The peculiarity of the introduction of drugs at a constant rate is a smooth change in its concentration in the blood upon administration, while:

1) the time to reach a steady-state drug concentration 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 (injected dose), the СSS value also increases in a proportional number of times

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

WITHSs- equilibrium stationary concentration- the concentration of drugs achieved at the rate of administration equal to the rate of excretion, therefore:

(from the definition of clearance)

For each subsequent half-life, the drug concentration increases by half of the remaining concentration. All drugs that obey the first order elimination law are Will reachCssafter 4-5 half-lives.

Level C Management ApproachesSs: change the administered drug dose or the interval of administration

17. Intermittent administration of drugs. Kinetics of drug concentration in blood, therapeutic and toxic concentration range. Calculation of the stationary concentration ( CSs), the boundaries of its oscillations and its control. Adequate discrete dosing interval.

Fluctuations in the concentration of drugs in blood plasma: 1 - with constant intravenous drip; 2 - with a fractional introduction 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 drug administration- the introduction of a certain amount of drugs at intervals.

Equilibrium steady-state concentration is reached after 4-5 half-elimination periods, the time to reach 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, therefore, early or a moment will come late when the increased rate of elimination will balance the administered drug dose and further increase in concentration will stop)

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

Css Swing Boundaries: ; Cssmin = Cssmax × (1 - email). Fluctuations in drug concentration are proportional to T / t1 / 2.

Therapeutic range (safety corridor, therapy window)- This is the range of concentrations from the minimum therapeutic to causing the first signs of side effects.

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

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

Oscillation controlCss:

Swing rangeCssdirectly proportional to the dose of drugs and inversely proportional to the interval of its administration.

1. Change the dose of drugs: with an increase in the dose of a drug, the range of fluctuations of its Css proportionally increases

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

3. Simultaneously change the dose and the interval of administration

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

Introductory (loading) dose- a dose administered at a time and fills 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 an effective therapeutic concentration of drugs in the blood, which makes it possible, for example, to quickly stop an attack of asthma, arrhythmias, etc.

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

Limiting the use of VD: if the drug is distributed Significantly slower than its entry into the bloodstream, the introduction of the entire loading dose at once (especially intravenously) will create a concentration significantly higher than the therapeutic one and will cause the occurrence of toxic effects. VD use condition: 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- the dose of drugs administered systematically, which fills the clearance volume, that is, the Vd fragment that is cleared of drugs during the DT interval: PD = (Css * Cl * DT) / F.

Therapeutic meaning: PD compensates for losses with clearance over the interval between drug injections.

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

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

2. Select the interval for the introduction of DT (usually most drugs are prescribed with an interval close to t1 / 2) and calculate the PD: PD = (Css * Cl * DT) / F

3. We check whether the drug fluctuations in the blood do not go beyond the therapeutic range by calculating Cssmax and Cssmin: ; Cssmin = Cssmax × (1 - email). The difference between Cssmax and Cssmin should not exceed two Css.

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

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

NB! If the drug is not intended for the relief of emergency conditions or is taken in pills, the VD is not calculated.

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

1. Age differences in the pharmacokinetics of drugs.

1. The stratum corneum is thinner, therefore, when applied to the skin, drugs are better absorbed. The absorption of drugs by rectal administration is also better.

2. The volume of fluid in the body of children is 70-80%, while in adults it is only »60%, therefore, the Vd of hydrophilic drugs they have is higher and higher doses are required.

3. In a newborn, the level of albumin in plasma is lower than in adults, therefore, 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 methylating systems.

5. The rate of glomerular filtration in the kidneys of children under 6 months is 30-40% of the rate of adults, therefore, 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 the 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 can drop to 50-60% of the rate of a mature patient, therefore renal elimination of drugs is sharply limited.

2. Sex differences in the action of drugs... For women, less body weight is characteristic than for men, therefore, the size of the drug doses 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 disease: F drugs due to the shutdown of the first-pass metabolism, a fraction of unbound drugs due to a 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- a deficiency of certain enzymes of drug metabolism can contribute to the prolongation of their action (pseudocholinesterase, etc.)

Corrections for calculating individual values of the volume of distribution of drugs:

A) for obesity, lipophobic drugs are insoluble in adipose tissue Þ it is necessary to calculate the ideal weight by height (Broca's formula: ideal weight = height (in cm) - 100) and recalculate Vd by the ideal weight by height.

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

Dependence of the main pharmacokinetic parameters on various factors:

1. Absorption of drugs: at age ¯ drug absorption, its metabolism in the course of presystemic elimination, the bioavailability of drugs changes.

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

3. Half-life: changes with age and obesity (since 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, which is cleared of a medicinal substance per unit of time by the kidneys: Cl (ml / min) = U × V / P, where U is the concentration of drugs in ml of urine, V is the volume of urine excreted in min and P = drug concentration in ml of plasma.

Renal clearance mechanisms and their characteristics:

1. Filtration: Drugs emitted Filtration only(insulin) will have a clearance equal to GFR (125-130 ml / min)

Determined by: renal blood flow, unbound drug fraction and kidney filtration capacity.

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

2. Active secretion: Drugs emitted Filtration and total secretion(paraaminogippuric acid), will have a clearance equal to renal plasma clearance (650 ml / min)

The renal tubule contains two transport systems that can separate drugs into an ultrafiltrate, one for organic acids and another for organic bases. These systems require energy to actively transport against the concentration gradient; they are a place of competition for a carrier of some drugs with others.

Determined by: maximum secretion rate, urine volume

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

Reabsorption occurs throughout the entire renal canal and depends on the polarity of the drug, non-polar, lipophilic are reabsorbed.

Determined by: primary pH value and drug ionization

A number of indicators such as Age, joint use of several drugs, diseases significantly affect renal clearance:

A) renal failure ® decrease in drug clearance; high level of drugs in the blood

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

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

Factors affecting renalCl:

A) glomerular filtration

B) renal blood flow rate

B) maximum rate of secretion

D) urine volume

E) fraction unbound in 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 non-ionic substances: filtered only in unbound forms, not secreted, reabsorbed

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

II. Polar non-ionic substances: filtered in unbound form, do not secrete, do not reabsorb

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 drugs unbound in the blood b) the fraction of drugs ionized in the urine c) the volume of urine

IV. Polar ionized in urine 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 drug clearance, its determinants and limitations. Enterohepatic drug cycle.

Mechanisms of hepatic clearance:

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

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

2) secretion (excretion of non-transformed substances into bile)

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

Determinants of hepatic clearance:

A) The rate of blood flow in the liver

B) Maximum rate of excretion or metabolic transformations

B) Km - Michaelis constant

D) Non-protein-bound fraction

Limitations of hepatic clearance:

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

2. If Vmax / Km mean values → Cl = the sum of all factors

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

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

Hepatic elimination of drugs can be significantly altered Liver disease, age, diet, genetics, duration of drug prescription(for example, due to the induction of hepatic enzymes), and other factors.

24. Factors that change the clearance of medicinal substances.

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

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

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. Cancel drugs that are not necessary

2. For kidney disease, use drugs excreted in the liver and vice versa.

3. Reduce the dose or increase the interval between injections

4. Close monitoring of side and toxic effects

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 the plasma and correct the drug Cl therapy individually

7. Use an indirect method of assessing Cl.

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

Dose adjustment : Dind = Dtyp. × Clind. / Cltyp.

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

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

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

Clearance of creatinine- the most important quantitative indicator of renal function, on the basis of which it is possible to adjust the dosage regimen

We know:

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

B) the total clearance of a given drug (CLP / total) and the proportion of renal drug clearance in the total clearance

C) normal creatinine clearance Clcr / normogram

3) Css and F for this LAN (from the reference)

Find: drug dose for this patient

ClPS / renal norm = ClPS / total X share of renal drug clearance in total clearance

CLP / renal patient = Clcr / patient / Clcr / norm * ClLS / renal norm

ClPP / non-renal rate = ClPP / total - ClPP / renal rate

ClPS / general patient = CLPS / renal patient + ClPS / non-renal norm

The dose of this drug inside with normal renal function is: PD norm = Css X Cl / F

The dose of this drug inside for our patient is equal to: PD of the patient = PD norm X СlPS / general patient / СlPS / total

Answer: PDbolny

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

Liver disease can reduce clearance and lengthen the half-life of many drugs. However, in some drugs that are eliminated by the liver, these parameters do not change in case of liver dysfunction, therefore Liver disease does 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 paragraph 26 above, for general principles of correction, see paragraph 25.

28. Strategy for individual drug therapy.

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

1. Choice of target concentration

2. Calculate Vd and Cl based on typical values and make adjustments for factors such as body weight and renal function.

3. Entering the 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. Revision of Vd and Cl based on the results of concentration measurements.

6. Repeat steps 3-6 to adjust the maintenance dose required for optimal drug response.

29. Biotransformation of drugs, its biological meaning, main direction 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.

The biological meaning of biotransformation of drugs: creation of a substrate convenient for subsequent disposal (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 extra-microsomal oxidation, reduction and hydrolysis

2) conjugation (synthetic reactions, phase 2)- biosynthetic process, accompanied by the addition of a number of chemical groups or molecules of endogenous compounds to a drug or its metabolites by a) the formation of glucuronides b) glycerol esters c) sulfoesters d) acetylation e) methylation

The effect of biotransformation on the pharmacological activity of drugs:

1) most often, biotransformation metabolites do not have pharmacological activity or their activity is reduced in comparison with the initial substance

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

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

4) sometimes in the course of biotransformation, metabolites with opposite pharmacological properties are formed (metabolites of nonselective agonists of b2-adrenergic receptors have the properties of blockers of these receptors)

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

30. Clinical significance of drug biotransformation. 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 an effective concentration 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) The functional state of the liver: in case of her diseases, the clearance of drugs usually decreases, and the elimination half-life increases.

B) Influence of environmental factors: smoking promotes the induction of cytochrome P450, as a result of which the metabolism of drugs is accelerated during microsomal oxidation

V) Vegetarians biotransformation of drugs is slowed down

D) in elderly and young patients, hypersensitivity to the pharmacological or toxic effects of drugs is characteristic (in the elderly and in children under 6 months, the activity of microsomal oxidation is reduced)

E) in men, the metabolism of some drugs is faster than in women, since androgens stimulate the synthesis of microsomal liver enzymes (ethanol)

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

F) Alcohol and obesity slow down the metabolism of drugs

31. Metabolic drug interactions. Diseases affecting their biotransformation.

Metabolic interaction of drugs:

1) induction of enzymes of drug metabolism - an absolute increase in their number and activity due to exposure to certain drugs. Induction leads to an acceleration of drug metabolism and (as a rule, but not always) to a decrease in their pharmacological activity (rifampicin, barbiturates - cytochrome P450 inducers)

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

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

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

C) direct inactivation of cytochrome P450 isoenzymes (flavonoids)

Diseases affecting the metabolism of drugs:

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

B) liver disease (primary and alcoholic cirrhosis, hepatitis, hepatoma)

C) diseases of the gastrointestinal tract and endocrine organs

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

32. Ways and mechanisms of drug excretion from the body. Possibilities of drug elimination management.

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

A) by the kidneys by filtration, secretion, reabsorption

B) by the liver by biotransformation, excretion with bile

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

Possibilities for managing the processes of drug withdrawal:

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

2.use of choleretic drugs (cholenzyme, allochol)

3.hemodialysis, peritoneal dialysis, hemosorption, lymphosorption

4.Forced diuresis (IV 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 secondary mediators).

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

The 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 mediates the action of pharmacological antagonists

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

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

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

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

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

Types of transmembrane signaling:

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

B) through 7-TMS receptors associated with G-protein

B) through ion channels (ligand-dependent, voltage-dependent, gap contacts)

Secondary intermediaries: cAMP, Ca2 + ions, DAG, IF3.

34. Physicochemical and chemical mechanisms of action of medicinal substances.

A) Physicochemical interaction with a biosubstrate- non-electrolytic action.

The 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 the reversible destruction of membranes.

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

The main types of chemical interaction with a biosubstrate:

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

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

Significance of drug covalent interactions: the action is specific, critically depends on the chemical structure, is realized through the effect on receptors.

35. Terms and concepts of quantitative pharmacology: effect, efficacy, 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- the measure of the reaction along the axis of the effect - the magnitude of the response of the biological system to the pharmacological effect; This is the ability of drugs to provide the maximum possible effect for it.... That is, in fact, this is the maximum size of the effect that can be achieved with the introduction of a given drug. It is numerically characterized by the value of Emax. The higher the Emax, the higher the effectiveness of the drug.

Activity- a measure of sensitivity to drugs along the concentration axis, characterizes the affinity (affinity of the ligand to 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 drug activity, the lower its dose is required to reproduce the therapeutic effect.

Efficiency: 1 = 2> 3

Activity: 1> 3> 2

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

Agonist- a ligand that binds to the receptor and causes a biological response, the activation of the physiological system. Full agonist- maximum response, Partial- cause less 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 thus compete with agonists. Increasing the concentration of the agonist can completely eliminate the effect of the antagonist. The competitive antagonist shifts the dose-response curve for the agonist, increases the EC50, 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, an increase in the concentration of the agonist does not eliminate the effect of the antagonist. A noncompetitive antagonist decreases Emax, does not change the EC50, and the dose-response curve is compressed about the vertical axis.

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

Clark-Ariens model:

1. The interaction between ligand (L) and 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 with an increase in the number of ligands at some point in time, all receptors will be occupied, then the maximum possible number of ligand-receptor complexes formed is described by the formula:

= [R] × (1)

The effect is determined by the probability of activation of the receptor upon binding to the ligand, i.e., by its intrinsic activity (Ke), therefore E = Ke ×. In this case, the effect is maximal at Ke = 1 and minimal and Ke = 0. Naturally, the maximum effect is described by the ratio 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 [C] receptors, therefore

E = Emax (2)

It follows from the above relations 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 constant of dissociation of the substance from the receptor, at which 50% of the receptors are bound.

The law of decreasing response the parabolic dependence "concentration - efficiency" corresponds. The response to low doses of drugs usually increases in direct proportion to the dose... However, as the dose is increased, the increase in response decreases and ultimately a dose can be reached at which there is no further increase in response (due to the occupation of all receptors for a given ligand).

37. Changing the effect of drugs. Gradual and quantum evaluation of the effect, essence and clinical applications. Measures for quantifying the activity and effectiveness of drugs in experimental and clinical practice.

All pharmacological effects can be roughly divided into two categories:

A) Gradual (continuous, integral) effects- such effects of drugs that can be measured quantitatively (the effect of antihypertensive drugs - by the level of blood pressure). A gradual "dose-effect curve" (see p. 36) is described, on the basis of which it is possible to estimate: 1) individual sensitivity to drugs 2) drug activity 3) maximum drug efficacy

B) Quantum Effects- such effects of drugs, which are a discrete value, a qualitative sign, that is, they are described by only a few variants of states (headache after taking an analgesic, 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 value of the taken drug dose is noted. The dose-effect plot is dome-shaped and is identical to the Gaussian normal distribution curve. Based on the quantum curve, one can: 1) assess the population sensitivity of drugs; 2) note the presence of an effect at a given dose; 3) select an average therapeutic dose.

Differences between gradual and quantum dose-effect characteristics:

A quantitative assessment of the activity and effectiveness of drugs is carried out on the basis of constructing dose-effect curves and their subsequent assessment (see Clause 35)

38. Types of drugs action. Changes in the action of drugs when they are re-administered.

Types of drug action:

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 routes of drug administration and their ability to penetrate biological barriers.

With both local and resorptive action, drugs can have either Direct or Reflex influence:

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

B) reflex - a change in the function of organs or nerve centers by influencing extero - and interoreceptors (mustard plasters with respiratory pathology reflexively improve their trophism)

Changes in the action of drugs when they are reintroduced:

1. Cumulation- an increase in the effect due to the accumulation of drugs in the body:

a) material cumulation - the accumulation of an 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) - Decrease in the body's response to repeated drug injections; in order to restore the reaction to drugs, it has to be administered in larger and larger doses (diazepam):

A) true tolerance - observed both with enteral and parenteral administration of drugs, 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 (b-adrenomimetics, with prolonged use, lead to phosphorylation of b-adrenergic receptors, which are not able to respond to b-adrenergic agonists)

2) Down-regulation - a decrease in the number of drug receptors (with repeated administration of narcotic analgesics, the number of opioid receptors decreases and more and more doses of the drug are required to induce 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 drug receptors (b-blockers)

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

B) relative tolerance (pseudo-tolerance) - develops only with the introduction of drugs inside and is associated with a decrease in the rate and completeness of drug absorption

3. Tachyphylaxis- a condition in which frequent administration of drugs causes the development of tolerance after a few hours, but with rather rare administrations of drugs, its effect is fully preserved. The development of tolerance is usually associated with the depletion of the effector systems.

4. Drug addiction- an irresistible desire to take a substance previously administered. Allocate mental (cocaine) and physical (morphine) drug addiction.

5. Hypersensitivity- an allergic or other immunological reaction to drugs upon repeated administration.

39. The dependence of the action of drugs on age, sex and individual characteristics of the organism. The meaning of circadian rhythms.

A) From age: in children and the elderly, the sensitivity to drugs is increased (since children have a deficiency of many enzymes, renal function, increased BBB permeability, absorption of drugs is slowed down in old age, metabolism is less efficient, the rate of excretion of drugs by the kidneys is reduced):

1. Newborns have reduced sensitivity to cardiac glycosides, since they have more Na + / K + -ATPases (targets of glycoside action) per unit area of the cardiomyocyte.

2. Children have lower sensitivity to succinylcholine and atracuria, 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 so-called. atypical agitation.

1. The sensitivity to cardiac glycosides increases sharply due to a decrease in the number of Na + / K + -ATPases.

2. Decreases sensitivity to b-blockers.

3. The sensitivity to calcium channel blockers increases, since 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 dysfunctions in men, but do not affect the functioning of the reproductive system of women.

2) anabolic steroids are more effective in women than in men.

V) From the individual characteristics of the organism: 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 drugs on the body, quantitatively and qualitatively, depending on the time of day (maximum effect with maximum activity).

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

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

The reasons for the variability of the drug action:

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

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

3) changes in the density or function of receptors.

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

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

Hyporeactivity- a decrease in the effect of a given dose of drugs in comparison with the effect that is observed in most patients. Hyperreactivity- an increase in the effect of a given dose of drugs in comparison with the effect that is observed in most patients.

Tolerance, tachyphylaxis, hypersensitivity - see item 38

Idiosyncrasy- a perverse reaction of the body to this drug, associated with the genetic characteristics of drug metabolism or with individual immunological reactivity, including allergic reactions.

41. Assessment of drug safety. Therapeutic index and standard safety margins.

Safety assessment is carried out at two levels:

A) preclinical (obtaining information on 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 grow, then after a certain period of time its toxic effect will begin to manifest itself. The dependence of the toxic effect on the dose (concentration) of the drug is of the same nature as its beneficial effect and can be described by gradual or quantum curves. These curves can also be used to determine the value TD50 or TC50- toxic dose (concentration) of drugs, which causes a toxic effect equal to 50% of the maximum (for a quantum curve - 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 a drug is characterized on the basis of gradule or quantum dose-effect curves and the following indicators:

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

B) Therapeutic latitude (therapeutic window) Is the dose range between the minimum therapeutic and minimum toxic doses of drugs. 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.

V) Reliable safety factor- this is the ratio of the minimum toxic dose to the maximum effective dose (PNF = TD1 / ED99), shows how many times the therapeutic dose of the drug can be exceeded without the risk of developing intoxication (unwanted 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 in order to achieve the desired therapeutic effect.

42.46. Interaction of drugs. Incompatibility of drugs (since the questions are interrelated, choose according to the circumstances)

Drug interaction- this is a change in the severity and nature of the 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 drugs are less than 6.

2) doctors' mistakes

3) violation of the dosage regimen

Rationale for combination therapy:

1. Monotherapy is not effective enough.

2. Absence of etiotropic therapy in most diseases Þ the need for medicinal effects on different links of pathogenesis

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

4. The need to correct the unwanted effects of drugs

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

Types of interaction:

I. Pharmaceutical interactions - The type of interaction associated with a physicochemical reaction between drugs during the manufacture of a medicinal product, even before the introduction of these agents into the human body

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

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

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 suspensions before use 4) Interaction can occur without visible changes in solutions 5) Drugs cannot be added to blood and AK solutions 6) In the absence of special instructions, the preparations should be dissolved in 5% glucose solution (pH 3.5-6.5), isotonic NaCl solution (pH 4.5-7.0).

HCl-stabilized glucose solution is incompatible with epinephrine, benzylpenicillin, apomorphine, kanamycin, vitamin C, oleandomycin, cardiac glycosides. Cardiac glycosides are incompatible with atropine, papaverine, platifillin. AB are incompatible with heparin, hydrocortisone. Vitamins of group B are incompatible with each other, with vitamins PP, C. Vitamin PP and C are also incompatible with each other.

Cannot be mixed with any other drugs: phenothiazide, chlorpromazine, barbiturates, vitamin C preparations, amphotericin B, furosemide, sulfadiazine, aminophylline, adrenomimetics.

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

A) pharmacokinetic

1) during the suction phase.

When introducingPer 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, varvarine, digoxin, digitoxin, fat-soluble vitamins, trimethoprim, clindamycin, cephalexin, tetracycline. Iron preparations are better absorbed with vitamin C. Iron preparations with carbonates, tetracyclines are poorly absorbed.

3.Gastrointestinal motility

Slow down peristalsis: some antidepressants, antihistamine drugs, phenothiazine antipsychotic drugs, narcotic drugs, increase the absorption of digoxin, corticosteroids, anticoagulants, reduce the absorption of levodopa. Strengthen peristalsis and increase evacuation from the gastrointestinal tract: metoclopramide, laxatives. Reduce drug absorption: phenobarbital - griseofulvin, aspirin - indomethacin and diclofenac, PASK - rifampicin.

Methods for controlling absorption during parenteral administration: local anesthetics + epinephrine + phenylephrine - absorption of local anesthetics decreases

4.intestinal flora

5.changing the suction mechanism

2) when distributing and depositing:

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 associated with blood proteins by 90-98%, therefore, a twofold increase in the free fraction of drugs is a sharp increase in toxic effects; NSAIDs are replacing: warfarin, phenytoin, methotrexate.

Determinants that determine the clinical significance of this interaction:

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

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

3.Displacement from tissue protein binding: quinidine displaces digoxin + reduces renal excretion, 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. Antivirals: indinavir, retonavir, saquinavir

8. Others: disulfiram, sodium valproate

Drugs that give toxic effects in MAO inhibition: adrenomimetics, sympathomimetics, antiparkinsonian, narcotic analgesics, phenothiazines, sedatives, antihypertensive diuretics, hypoglycemic drugs

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

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

1. interaction during passive diffusion: part of the drug is excreted unchanged, part of the drug is ionized at urine pH 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 urine acidity: increased excretion of amphetamine (of practical importance for the detection of this drug in athletes)

2.interaction during the period of active transport: probenezid + penicillin increases the duration of the movement of penicillin, probenecid + salicylates - elimination of the uricosuric action of probenecid, penicillin + CA - a decrease in the excretion of penicillin

Influence of urine composition on drug excretion:

An increase in sugar in urine - an increase in excretion of: vitamin C, chloramphenicol, morphine, isoniazid, glutathione and their metabolites.

B) pharmacodynamic 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 undesirable synergistic interactions:

NSAIDs + varvarine - increased risk of bleeding

Alcohol + benzodiazepines - potentiation of the sedative effect

ACE inhibitors + K + -saving 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 to anesthetic and hypnotics), increases the risk of drug dependence.

43. Drug interaction. Antagonism, synergy, their types. The nature of the change in the effect of drugs (activity, effectiveness) depending on the type of antagonism.

With the interaction of drugs, the following conditions may develop: a) enhancement of the effects of a combination of drugs b) weakening of the effects of a combination of drugs c) drug incompatibility

Strengthening the effects of a combination of drugs is implemented in three ways:

1) Summation of effects or additive interaction- the type of drug interaction in which the effect of the combination is equal to the simple sum of the effects of each of the drugs separately. Ie. 1+1=2 ... It is characteristic of drugs from one pharmacological group that have a common target of action (the acid-neutralizing activity of a 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 a combination exceeds the sum of the effects of each of the substances taken separately. Ie. 1+1=3 ... Synergy can relate to both the desired (therapeutic) and undesirable effects of drugs. The combined administration of the thiazide diuretic dichlothiazide and the ACE inhibitor enalapril leads to an increase in the hypotensive effect of each of the drugs, 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 ototoxic action and the development of deafness.

3) potentiation is a type of drug interaction in which one of the drugs, which in itself does not have this effect, can lead to a sharp increase in the effect of another drug. Ie. 1+0=3 (clavulanic acid does not have an antimicrobial effect, but it is able to 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 lengthens its anesthetic effect by slowing down absorption anesthetic from the injection site).

Attenuating Effects Drugs when used together are called antagonism:

1) Chemical antagonism or antidote- 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 - a 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 medicinal substances on the same receptors in the tissues. Pharmacological antagonism can be competitive (reversible) and 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 a 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 site of the receptor and induce a full tissue response. That. a competitive antagonist does not alter the maximum effect of the agonist, but a higher concentration is required for the agonist to interact 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.

Competitive antagonism is often used in medical practice. 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 elimination half-life and the concentration of the full agonist.

B) non-competitive antagonism: a non-competitive antagonist binds almost irreversibly with the active center of the receptor or interacts in general with its allosteric center. Therefore, no matter how 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 be activated , the value of EMax decreases, the affinity of the receptor for the agonist does not change, so the EC50 value remains the same. On the dose-response curve, the action of a non-competitive antagonist manifests itself as compression of the curve relative to the vertical axis without shifting it to the right.

Scheme 9. Types of antagonism.

A - the competitive antagonist shifts the dose-effect curve to the right, that is, it reduces the tissue sensitivity to the agonist without changing its effect. B - a noncompetitive antagonist reduces the magnitude of the tissue response (effect), but does not affect its sensitivity to the agonist. C - a variant of using a partial agonist against the background of a full agonist. As the concentration increases, the partial agonist displaces the complete 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, since their effect cannot be overcome after binding to the receptor, and therefore does not depend on the half-elimination period 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 medication occurs, it will be extremely difficult to eliminate its effect.

Competitive antagonist	Non-competitive antagonist
Similar in structure to an agonist	Structurally different from an agonist
Binds to the active center 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 alter the tissue sensitivity to the agonist (EC50), but decreases the internal activity of the agonist and the maximum tissue response to it (Emax).
Antagonist action can be reversed with a high dose of the agonist	The action of the antagonist cannot be reversed with a high dose of the agonist.
The effect of the antagonist depends on the dose ratio of the agonist and the antagonist	The effect of the antagonist depends only on its dose.

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

Interesting is the interaction that takes place between the full and partial receptor agonists. If the concentration of the full agonist exceeds the level of the partial one, then the maximum response is observed in the tissue. If the level of the partial agonist begins to rise, 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 medicinal substances 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 level of glycemia decreases. Epinephrine activates the b2-adrenergic receptors of the liver, 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 the 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 substances are used 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 effect of this drug on a certain substrate (hyposalivation when using atropine to eliminate bradyarrhythmia)

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

Toxic effects- undesirable effects manifested in this drug when it leaves the therapeutic range (drug overdose)

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

Teratogenic action- the ability of drugs, when administered to a pregnant woman, to cause anatomical anomalies of fetal development (thalidomide: phocomelia, antiblastoma drugs: multiple defects)

Embryotoxic action- adverse effects not associated with organogenesis disorders in the first three months of pregnancy. At a later date, it appears Fetotoxic action.

Mutagenic effect of drugs- damage to the germ cell and its genetic apparatus of 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 combating drug dependence, drug addiction and alcoholism. The concept of substance abuse.

« It is unlikely that humanity as a whole will ever do without an artificial paradise. Most men and women lead such a painful life, which at best is so monotonous, wretched and limited that the desire to "leave" it, to disconnect at least for a few moments, is and has always been one of the main Wished Ny soul"(Huxley, work" The Doors of Perception ")

1) Drug addiction- a state of mind and / or a physical state, which is a consequence of the effect on the body of drugs and is characterized by specific behavioral reactions, it is difficult to overcome the desire to re-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 addiction- the development of emotional distress when you stop taking drugs. A person feels empty, plunges into depression, experiences a feeling of fear, anxiety, his behavior becomes aggressive. All these psychopathological symptoms arise against the background of thoughts about the need to inject yourself with a drug that has 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 introduction of drugs. The basis of psychological dependence is a person's belief in the action of the drug (cases of the development of psychological dependence on placebo are described in the literature).

B) Physical addiction- 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 a dysfunction in the direction opposite to that which is characteristic of the action (morphine eliminates pain, depresses the respiratory center, narrows the pupils, causes constipation; with withdrawal symptoms, the patient develops excruciating pain, frequent noisy breathing, pupils are dilated and persistent diarrhea develops)

V) Tolerance... Tolerance to drugs that cause drug dependence is often cross-cutting, that is, it arises not only to a given chemical compound, but also to all structurally similar compounds. For example, in patients with drug dependence to morphine, tolerance arises not only to it, but also to other opioid analgesics.

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

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

2) Addiction (drug addiction)- This is an extremely severe form of drug dependence, compulsive use of drugs, characterized by an ever-increasing, irresistible urge to administer this drug, increasing its dose. Desire compulsiveness means that the patient's need to administer the drug dominates all other (even vital) needs. From the standpoint of this definition, craving for morphine is drug addiction, while craving for nicotine is drug dependence.

3) Addicted to medicine- characterizes a less intense urge to take medications, when refusal from the medication causes only a feeling of mild discomfort, without the development of physical dependence or a detailed picture of psychological dependence. That. addiction encompasses that part of drug addiction that does not fit the definition of addiction. For example, the aforementioned drug addiction to nicotine is a form of addiction.

4) Drug abuse- unauthorized use of drugs in such doses and in such ways that differ from the accepted medical or social standards in a given culture and at a given 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 to improve physique by young men.

5) Alcoholism- chronic abuse of alcohol (ethyl alcohol), leading nowadays to damage to a number of organs (liver, gastrointestinal tract, central nervous system, cardiovascular system, immune system) and accompanied by psycho-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, social degradation.

Drug addiction treatment difficult and thankless task. Until now, no effective method has been created that would ensure the success of treatment in more than 30-40% of patients. Achievement of 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 (the principle of voluntariness and individuality). Modern techniques are based on the following principles:

ü psychotherapeutic and occupational therapy methods;

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

ü gradual or abrupt withdrawal of the drug against the background of detoxification therapy

ü carrying out substitution therapy (replacement of a narcotic drug with slow and long-acting analogues with their subsequent cancellation; 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 (FT) - a set of treatment methods based on the use of drugs. The main types of FT:

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

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

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

4.Substitutional FT - the use of drugs in case of insufficiency of natural biologically active substances (insulin in diabetes)

5.prophylactic FT (vaccines, serums, acetylsalicylic acid for ischemic heart disease)

Society's attitude to drugs at the present stage: 1) desire to get benefits without risk 2) hope for a miracle, visions 3) misunderstanding of the risk of drug use 4) indignation and "righteous indignation", hasty drug assessments 5) desire to get new drugs

Doctor's attitude to drugs: therapeutic optimism (reliance on 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) striving to follow the doctor's prescriptions exactly.

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. The study of pharmacology helps not to drown in the sea of drugs.

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

Classification of toxic substances (OM):

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 MB (botulinum toxin), plant origin (alkaloids, glycosides), animal origin (snake and bee venoms)

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

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

6. Depending on the toxicity of drugs: List A - drugs, the purpose, use, dosing and storage of which, due to their high toxicity, should be done with great care. The same list includes drugs that cause drug addiction; list B - drugs, the appointment, use, dosing and storage of which should be carried out with caution in connection with possible complications when using them without medical supervision.

Selectively toxic effect of drugs.

A) cardiotoxic: cardiac glycosides, potassium supplements, antidepressants

B) neurotoxic: psychopharmacological agents, oxyquinolines, aminoglycosides

B) hepatotoxic: tetracyclines, chloramphenicol, erythromycin, paracetamol

D) nephrotoxic: vancomycin, aminoglycosides, sulfonamides

E) gastroenterotoxic: steroid 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 rate and completeness of absorption reflects the rate of development of the toxic effect and its severity.

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

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

The kinetics of the first order with an increase in the concentration of the drug transforms into the kinetics of the zero order.

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

Toxicodynamics . The main mechanisms of toxic action:

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

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

C) metabolism by the type of lethal synthesis (ethyl alcohol, thiophos)

D) enzymatic (snake venoms, etc.)

Types of action: local, reflex, resorptive.

Poisoning classification:

1. Etiopathogenetic:

a) accidental (self-medication, mistaken reception)

b) deliberate (with the aim of suicide, murder, development of a helpless state in the victim)

2. Clinical:

a) depending on the rate of development of poisoning: acute (intake of a single dose or with a short time interval of a toxic dose of a substance), subacute (delayed 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 in case of poisoning:

A) defeat of the CVS:

1) lowering blood pressure, hypovolemia of peripheral vessels, 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)

C) convulsions, muscle hyperreactivity and rigidity ® hyperthermia, myoglobinuria, renal failure, hyperkalemia

Toxicological triad:

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

2) assessment of the state of consciousness by symptoms: respiration, blood pressure, body temperature

3) laboratory data

Basic principles of treatment:

I. First aid: artificial respiration, heart massage, anti-shock therapy, control of water-electrolyte balance

II... Delayed absorption and removal of non-absorbed OM from the body:

Purpose: to end contact with OV

1. Parenteral route:

a) through the lungs:

1) stop inhalation

2) irritating substances (ammonia, formaldehyde) ® to consolidate active movements, warm, give oxygen and antifoaming agents (for ammonia, the defoamer is vinegar, and for formaldehyde, a diluted solution of ammonia)

b) through the skin: wash off with a copious amount of warm water with soap or detergent, specific antidotes, neutralize and stop the exposure of the OM to the skin (FOS: wash with water, remove with 10-15% ammonia or 5-6% sodium bicarbonate solution with water; phenolcresol: vegetable oil or ethylene glycol, but not vaseline oil, KMNO4: 0.5-1% ascorbic acid solution or equal volumes of 3% hydrogen peroxide and 3% acetic acid solution, CCl4, turpentine, gasoline: warm soapy water )

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

d) in case of contact with eyes: rinse with warm saline or milk for 10-20 minutes, drip a local anesthetic; in case of contact with acids and alkalis, they cannot be neutralized. Consultation with an ophthalmologist is required.

2. Enteral route: to free the stomach from OM, accelerate the passage

a) removal of OM:

1) preliminary intake of water. Do not take milk (with the exception of caustic poisonous substances) and ethanol (with the exception of methanol).

2) vomiting - indicated mainly in case of poisoning with large tablets or capsules that cannot pass through the probe. Can be provoked by reflex or emetic (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 ingestion: organic solvents - danger of inhalation, detergents - foaming, convulsive substances - danger of aspiration, caustic substances - damage to the esophagus)

3) probe 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 pre-intubated with a tube with an inflatable cuff: in a coma in the absence of a cough and laryngeal reflex. The stomach is washed with water or saline solution 30 ° C, the procedure takes 4 hours or more. At the end of the wash, activated carbon and sodium sulfate.

b) decrease in absorption from the gastrointestinal tract: activated charcoal inside 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 carbon + liquid paraffin

2) detergents: do not induce vomiting and wash out the stomach, it is necessary to give a lot of water + antifoaming agents (simethicone)

3) acids and alkalis: vomiting cannot be induced, gastric lavage through a tube lubricated with vegetable oil after the 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 OM from the body

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

b) peritoneal hemodialysis

c) hemosorption

d) exchange blood transfusion

e) forced hyperventilation

IV... Symptomatic therapy of functional disorders.

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

2) toxicokinetic - accelerate the biotransformation of OM (trimedoxime bromide, sodium thiosulfate, ethanol, AO)

3) pharmacological - atropine, naloxone

4) immunological antidotes

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

49. The 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 appeal from a doctor to a pharmacist with a requirement to release the medicine in a certain form and dosage, indicating the method of its use

The following parts are distinguished in the recipe:

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

2. Invocatio - contacting a pharmacist. It is expressed by the word “Recipe” (take) or by an abbreviation (Rp.)

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

4. Subscriptio - prescription (indication) to the pharmacist. It indicates the dosage form, pharmaceutical operations required for its manufacture, the number of dispensed doses of the drug.

5. Signatura - instructing 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 appeal 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 name of medicines, botanical names of plants are written with a capital letter. The prescription for the patient is written in Russian or national languages.

General rules for prescribing:

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

2. The prescription contains the date, month, year, surname, name, patronymic and age of the patient, surname, name and patronymic of the doctor. Then comes the text of the recipe, which lists the names of substances included in the recipe in the genitive case with an indication of their amount

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

4. If the maximum dose of poisonous 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 State regulation of the rules for prescribing and dispensing drugs.

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

List A includes drugs, the appointment, use, dosing and storage of which, due to their high toxicity, should be carried out with great care. The same list includes drugs that cause drug addiction.

List B includes drugs, the appointment, use, dosing and storage of which should be carried out with caution in connection with possible complications when using them without medical supervision.

For poisonous and potent drugs, the maximum higher single and daily doses have been established. These doses are for adults over 25 years of age. When recalculating doses for people over 60 years old, 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%, the doses of other poisonous and potent drugs are reduced to 2/3 of the adult dose. Doses of AB, sulfonamides and vitamins are usually the same for all age groups, starting from 25 years.

1. Narcotic drugs (List A) are prescribed on a prescription form 2. One form - one drug. There must be: the signature and seal of the attending physician, the signature of the head physician of the healthcare facility, the round stamp of the healthcare facility.

2. Poisonous drugs (list A), potent (list B) are prescribed on the form 1 prescription form. There must be a signature and personal seal of the doctor, the seal of the healthcare facility.

51. Medicines under control. Prescription drugs.

Narcotic, poisonous and potent drugs are under control (see section 20)

A) Medicines not registered in the Republic of Belarus and not authorized 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, pentamine, fluorothane, sodium oxybutyrate in ampoules, lithium oxybutyrate, barium sulfate for fluoroscopy.

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

Single chamber model.

The whole organism 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 blood volume

3) Elimination of drugs obeys first-order kinetics: the rate of decrease in the drug content in the blood is proportional to its concentration

If the mechanisms for elimination of the drug (biotransformation in the liver, renal secretion) are not saturated with the introduction of a therapeutic dose, a log-normal graph of changes in plasma concentration over time will be linear.

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

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

Two-chamber model.

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

The resulting graph shows the initial The 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.

C0 value, obtained by extrapolation Elimination phases before crossing the ordinate. C0 is used to calculate the volume of distribution and the elimination constant. The formulas for calculating Ct and Cl given for the single chamber model are also applied during the elimination phase for drugs that satisfy the conditions of the two chamber model.

53. Selectivity and specificity of drug action. Therapeutic, side and toxic effects of drugs, their nature from the standpoint of the concept of receptors. A therapeutic strategy for combating side and toxic effects of drugs.

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

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, since 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 of astronomical significance.

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

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 manifested in this 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 at a high 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, vision due to blockade of Na + / K + -ATPase of the cell membrane)

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

Therapeutic strategy to combat the therapeutic and side effects of drugs:

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

2. Reduction of the dose of one drug due to the appointment of 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 region of receptors of various parts of the body (local application of drugs - inhalation use of salbutamol in bronchial asthma)

PHARMACOLOGY is the science of the interaction of chemical compounds with living organisms. Basically, pharmacology studies drugs used for the prevention and treatment of various pathological conditions.
Pharmacology is a biomedical science closely related to various areas of theoretical and practical medicine. Pharmacology, on the one hand, relies on the latest achievements of such sciences as physical chemistry, biochemistry, microbiology, biotechnology, etc., and on the other hand, it has a revolutionary, without exaggeration, influence on the development of related biomedical disciplines: physiology, biochemistry, various areas of practical medicine. So, with the help of synaptically active substances, it was possible to reveal the mechanisms of synaptic transmission, to study in detail the functions of various parts of the central nervous system, to develop theoretical prerequisites for the treatment of mental diseases, etc. The progress of pharmacology is also of great importance for practical medicine. Suffice it to recall how important it was and remains to this day the introduction into medical practice of drugs for anesthesia, local anesthetics, the discovery of penicillin, etc.
Due to the great importance of pharmacotherapy for practical medicine
dicina, knowledge of the basics of pharmacology is absolutely necessary for
a doctor of any specialty.
The most important task of pharmacology is the search for new drugs. Currently, the development, clinical trials and introduction of drugs into practice are carried out in many directions: experimental pharmacology, clinical pharmacology, toxicology, pharmacy, psychopharmacology, chemotherapy of infections, tumor diseases, radiation and environmental pharmacology, etc.
The history of pharmacology is as long as the history of mankind. The first drugs were obtained, as a rule, from plants empirically. Currently, the main way of creating new drugs is directed chemical synthesis, however, along with it, there is also the isolation of individual substances from medicinal raw materials; the release of medicinal substances from the waste products of fungi, microorganisms, biotechnological production.
Search for new connections
I. Chemical synthesis
1. Directed synthesis
- reproduction of biogenic substances (AX, NA, vitamins);
- creation of antimetabolites (SA, antineoplastic drugs, ganglion blockers);
- modification of molecules with known biological activity (HA-synthetic HA);
- synthesis based on the study of the biotransformation of a substance in the body (prodrugs, agents that affect the biotransformation of other substances).
2. Empirical way: random finds, screening of various chemical compounds.
II. Isolation of individual medicinal substances from medicinal raw materials
1. Vegetable;
2. Animal;
3. Mineral.
III. Isolation of drugs from the waste products of microorganisms, biotechnology (antibiotics, hormones, monoclonal antibodies to tumor cells in combination with a drug, etc.)
The creation of a new drug substance goes through a number of stages, which can be schematically represented as follows:
Idea or hypothesis
Creation of substance
Animal research
1. Pharmacological: assessment of the expected main effect;
classification of other effects by organs and systems; ...
2. Toxicological: acute and chronic toxicity. Causes
death of animals: biochemical, physiological and morphological methods of assessment.
3. Special toxicological: mutagenicity, carcinogenicity
(two species of animals, histological examination of 30 tissues with chronic administration), influence on reproductive processes (ability to conceive, embryotoxicity, teratogenicity).
Clinical trials
1. Clinical pharmacology (on healthy volunteers):,;
2. Clinical studies (on patients): pharmacodynamics,;
3. Official clinical trials (on patients): blind and double-blind control, comparison with the action of other medicinal substances - clinical practice;
4. Post-registration studies.

1. Routes of drug administration. Suction. Existing routes of administration of medicinal substances are divided into
enteral (through the gastrointestinal tract) and parenteral (bypassing
gastrointestinal tract).
The enteral routes include: introduction through the mouth - orally (per os), under the tongue (sublingually), into the duodenum (duodenally), into the rectum (rectally). The most convenient and common route of administration is through the mouth (oral). At the same time, sterility conditions, the participation of medical personnel, and special devices (as a rule) are not required. When administered orally, the substance reaches the systemic circulation by absorption.
Absorption to a greater or lesser extent occurs along the entire gastrointestinal tract, but it occurs most intensively in the small intestine.
With sublingual administration of the substance, absorption is fast enough. In this case, the drugs enter the systemic circulation, bypassing the liver, and are not exposed to the gastrointestinal tract.
Sublingual substances with high activity are prescribed, the dose of which
rykh is very small (low absorption intensity): nitroglycerin, certain hormones.
A number of medicinal substances, such as acetylsalicylic acid, derivatives of barbituric acid, are partially absorbed in the stomach. Moreover, they, being weak acids, are in an undissociated form and are absorbed by simple diffusion.
When introduced into the rectum (per rectum), a significant part (up to
50%), medicinal substances enter the bloodstream bypassing the liver. In addition, in the lumen of the rectum, the drug is not exposed to the action of the gastrointestinal tract. Absorption is carried out by simple diffusion. Rectally medicinal substances are used in suppositories (suppositories) or medicinal enemas. Moreover, depending on the nature of the pathological process, substances can be prescribed for both systemic and local exposure.
The following absorption mechanisms are distinguished.
1. Passive diffusion through the cell membrane. Determined by the concentration gradient on both sides of the membrane. By passive diffusion, lipophilic non-polar substances are absorbed, which are readily soluble in the lipid bilayer of the membrane. The higher the lipophilicity, the better the substance penetrates the membrane.
2. Filtration through protein (hydrophilic) pores of the membrane. Depends on hydrostatic and osmotic pressure. The pore diameter in the membrane of intestinal epithelial cells is small (0.4 nm), so only small molecules can penetrate through them: water, some ions, a number of hydrophilic
substances.
3. Active transport using specific transport systems of the cell membrane. Active transport is characterized by selectivity for a certain substance, the possibility of competition of various substrates for the transport mechanism, saturation and energy dependence of the transfer of substances against the concentration gradient. In this way, some hydrophilic molecules, sugars, pyrimidines are absorbed.
4. Pinocytosis is carried out due to invagination of the cell membrane, the formation of a transport pinocytosis vesicle containing the transported substance and fluid, its transfer through the cytoplasm to the opposite side of the cell (from luminal to basal) and exocytosis of the contents of the vesicle to the outside. Vitamin B12 (in combination with Castle's intrinsic factor) and some protein molecules are absorbed by pinocytosis.
The main mechanism of drug absorption in the small intestine is passive diffusion. It is important to note that from the small intestine, substances with the blood flow enter the liver, where some of them are inactivated; in addition, part of the substance directly in the intestinal lumen is exposed to the action of the digestive system and is destroyed. Thus, only a part of the orally administered dose of the drug enters the systemic circulation (from where the drug spreads throughout the body). That part of the medicinal substance
VA that has reached systemic blood flow in relation to the initial dose
drug is called bioavailability. Bioavailability is expressed as a percentage:
the amount of substance in the systemic circulation (max) x 100%
injected amount of substance
Factors affecting bioavailability
1. Pharmaceutical factors. The amount of the medicinal substance,
released from the tablet depends on the manufacturing technology: solubility, fillers, etc. Different branded tablets of the same substance (eg, digoxin) can take such different forms that they can produce very different effects.
2. Biological factors associated with bowel function. To them
the destruction of substances in the gastrointestinal tract itself, disturbing
absorption due to high peristalsis, binding of medicinal substances with calcium, iron, various sorbents, as a result of which they cease to be absorbed.
3. Presystemic (first pass) elimination. Some ve-
substances have a very low bioavailability (10-20%), despite the fact that it is well absorbed in the gastrointestinal tract. This is due to the high degree of their metabolism in the liver.
It should be borne in mind that in liver diseases (cirrhosis), the destruction of medicinal substances is slow, in this regard, even the usual dosage can cause a toxic effect, especially with repeated administration.
Parenteral routes of drug administration: subcutaneous, intramuscular, intravenous, intraarterial, intraperitoneal, inhalation, subarachnoid, suboccipital, intranasal, application to the skin (mucous membranes), etc. The choice of a specific route of administration is determined by the properties of the drug itself (for example, complete destruction in the gastrointestinal tract) and the specific therapeutic goal of pharmacotherapy.
Distribution of medicinal substances in the body.
Biological barriers. Escrow
From the blood, the drug enters the organs and tissues. Most medicinal substances are distributed unevenly in the body, since they pass through the so-called biological barriers in different ways: the capillary wall, cell membrane, blood-brain barrier (BBB), placenta and other histo-hematic barriers. The capillary wall is sufficiently permeable to most medicinal substances; substances penetrate through the plasma membrane either by means of special transport systems, or (lipophilic) - by simple diffusion.
The BBB is of great importance for the distribution of various drugs. It should be noted that polar compounds pass poorly through the BBB, while non-polar (lipophilic) compounds pass relatively easily. The placental barrier has similar properties. When prescribing drugs, the doctor needs to know exactly about the ability of the substance to penetrate or not to penetrate the appropriate barrier.
The distribution of the administered drug depends to a certain extent on its deposition. Distinguish between cellular and extracellular depots. The latter include blood proteins such as albumin. Binding to albumin for some drugs can reach 80-90%. Medicines can be deposited in bone tissue and dentin (tetracycline), in adipose tissue (deposition of lipophilic compounds - drugs for anesthesia). The deposition factor has a certain value for the duration of the drug's action.
It should be noted that the distribution of a substance in certain organs and tissues does not characterize its action, which depends on the specific sensitivity of the corresponding biological structures to it.
Biotransformation of medicinal substances in the body
Most of the medicinal substances that have entered the body undergo biotransformation, i.e. certain chemical transformations, in a number of cases as a result of which they, as a rule, lose their activity; however, as a result of bioransformation of the drug substance, a new, more active compound is formed (in this case, the administered drug is a so-called precursor or prodrug).
The most important role in biotransformation processes is played by microsomal livers, which metabolize substances foreign to the body (xenobiotics) of a hydrophobic nature, converting them into more hydrophilic compounds. Mixed-acting microsomal oxidases without substrate specificity oxidize hydrophobic xenobiotics with the participation of NADPH, oxygen and cytochrome P450. Inactivation of hydrophilic substances occurs with the participation of non-microsomal enzymes of different localization (liver, gastrointestinal tract, blood plasma, etc.).
There are two main types of drug transformation:
1. metabolic transformation,
2. conjugation.
Medicinal substance
———————- —————————
| Metabolic | | Conjugation: |
| transformation: | | - with glucuronic acid; |
| - oxidation; | | - with sulfuric acid; |
| - recovery ————- - with glutathione; |
| hydrolase | | - methylation; |
| | | - acetylation |
———————- —————————

METABOLITES CONJUGATES
EXCRETION
The excretion of most medicinal substances is carried out through the kidneys and liver (with bile into the gastrointestinal tract). The exception is volatile gaseous substances used for anesthesia - they are released mainly by the lungs.
Water-soluble, hydrophilic compounds undergo excretion through the kidneys by filtration, reabsorption, secretion in various combinations. It is clear that a process such as reabsorption significantly reduces the excretion of a drug from the body. It should be borne in mind that the reabsorption process significantly depends on the polarity (ionized or non-ionized form) of the substance. The higher the polarity, the worse the reabsorption of the substance. For example, with an alkaline reaction of urine, weak acids are ionized and, therefore, are less reabsorbed and more excreted. These are, in particular, barbiturates and other hypnotics, acetylsalicylic acid, etc. This circumstance is important to consider in case of poisoning.
If the drug is hydrophobic (lipophilic), then it cannot be excreted in this form through the kidneys, since it undergoes almost complete reabsorption. Such a substance is excreted through the kidneys only after the transition to the hydrophilic form; this process is carried out in the liver by biotransformation of this substance.
A number of drugs and products of their transformation are excreted in significant quantities with bile into the intestines, from where they are partially excreted with excrement, and partly reabsorbed into the blood, re-enters the liver and excreted into the intestines (the so-called enterohepatic recirculation). It should be emphasized that the consumption of fiber and other natural or artificial sorbents in food, as well as the acceleration of gastrointestinal motility, can significantly accelerate the elimination of these drugs.
One of the most common pharmacokinetic parameters is the so-called half-life (t1 / 2). This is the time during which the content of the substance in the blood plasma is reduced by 50%.
This decrease is due to both biotransformation processes and drug excretion. Knowledge (t1 / 2) facilitates the correct dosage of the substance to maintain its stable (therapeutic) concentration in blood plasma.

Qualitative aspects of pharmacotherapy.
Types of drug action
Distinguish between local and resorptive; direct and reflex action of drugs.
The action of a substance that occurs at the site of its application is called local. For example, enveloping substances, a number of external anesthetics, various ointments, etc. act locally.
The action of a substance that develops after its absorption (resorption) is called resorptive.
With both local and resorptive action, drugs can have either a direct or reflex effect. Direct influence is realized by direct contact with tissue. organo target. For example, adrenaline has a direct effect on the heart, increasing strength and heart rate. However, the same adrenaline, reflexively increasing the tone of the vagus nerve, can cause bradycardia after a while. Reflexive substances such as the so-called respiratory analeptics (cytiton, lobelin), which, when administered intravenously, stimulate the respiratory center of the medulla oblongata by stimulating the receptors of the sino-carotid zone.
Mechanisms of drug action
There are several main types of drug action.
I. Action on cell membranes:
a) effect on receptors (insulin);
b) impact on ion permeability (directly or through enzyme systems - transport ATPases, etc. - calcium channel blockers, cardiac glycosides;
c) the effect on the lipid or protein components of the membrane (drugs for anesthesia).
II. Effects on intracellular metabolism:
a) the effect on the activity of enzymes (hormones, salicylates, aminophylline, etc.);
b) impact on protein synthesis (antimetabolites, hormones). III. Action on extracellular processes:
a) violation of the metabolism of microorganisms (antibiotics);
b) direct chemical interaction (antacids);
c) the osmotic effect of substances (laxatives, diuretics), etc.
Let us dwell in more detail on the interaction of drugs with receptors and their influence on the activity of enzymes.
Receptors are called active groups of substrate macromolecules (usually membranes) with which the drug interacts. More often we will talk about receptors for neurotransmitters and neuromodulators. So, on the postsynaptic membrane and outside it, various types of receptors can be located. Depending on the name of the ligand (a substance that interacts with the receptor), they distinguish: adreno-, choline-, dopamine, histamine, opiate and other receptors. Most often, the receptors are membrane lipoprotein complexes. The number of receptors on the cell membrane is not constant; it depends on the amount and duration of the action of the ligand. There is an inverse relationship between the amount of ligand (agonist) and the number of receptors on the membrane: with an increase in the amount or duration of use of a synaptically active substance, the number of receptors to it decreases sharply. Which leads to a decrease in the effect of the drug. This is a phenomenon called tachyphylaxis. On the contrary, with prolonged action of the antagonist (as with denervation), the number of receptors increases, which leads to an increase in the effect of endogenous ligands (for example, after prolonged use of beta-blockers, their withdrawal leads to an increase in the sensitivity of the myocardium to endogenous catecholamines - tachycardia develops, in some cases - arrhythmias, etc.).
The affinity of a substance (ligand) for a receptor leading to the formation of a ligand-receptor complex is denoted by the term affinity. The ability of a substance, when interacting with a receptor, to cause one or another effect is called internal activity.
Substances that, when interacting with receptors, cause changes in them, leading to a biological effect similar to the effect of a natural mediator or hormone, are called agonists. They also have inner activity. If an agonist, interacting with a receptor, causes the maximum effect, it is called a full agonist. Unlike full agonists, partial agonists do not produce maximum effect when interacting with receptors.
Substances that do not cause an appropriate effect when interacting with receptors, but reduce or eliminate the effects of agonists, are called antagonists. If they (bind) to the same receptors as agonists, then they are called competitive antagonists; if
- with other parts of the macromolecule that are not related to the receptor part, then these are non-competitive antagonists.
If the same compound simultaneously possesses the properties of both an agonist and an antagonist (i.e., it produces an effect, but eliminates the action of another agonist), then it is designated an agonist-antagonist.
The drug substance can interact with the receptor using covalent bonds, ionic (electrostatic interaction), van der Waals, hydrophobic and hydrogen bonds.
Depending on the strength of the "substance-receptor" bond, there is a distinction between reversible (typical for most cases) and irreversible (covalent bond) action of medicinal substances.
If a substance interacts with one type of receptor and does not affect others, then the action of this substance is considered selective (selective) or, better to say, predominant, because there is practically no absolute selectivity of the action of substances.
The interaction of both the natural ligand and the agonist with the receptor causes various effects: 1) direct change in the ionic permeability of the membrane; 2) action through the system of so-called "secondary messengers" - G-proteins and cyclic nucleotides; 3) influence on DNA transcription and protein synthesis (Dale). In addition, the drug can interact with the so-called nonspecific binding sites: albumin, tissue glycosaminoglycans (GAGs), etc. These are the places where matter was lost.
The interaction of a drug with enzymes is largely
similar to its interaction with the receptor. Drugs can change
enzyme activity, since they may be similar to natural
substrate and compete with it for the enzyme, and this competition
can also be reversible and irreversible. It is also possible
allosteric regulation of enzyme activity.
So, the mechanism of action of a medicinal substance from the point of view of qualitative aspects determines the direction of influence on a particular process. However, for each drug, there are also quantitative criteria that are very important, because the dose of the substance must be carefully selected, otherwise the drug will either not provide the desired effect, or it will cause intoxication.
In the area of so-called therapeutic doses, there is a certain proportional dependence of the effect on the dose (the so-called dose-dependent effect of the substance), however, the nature of the dose-effect curve is individual for each drug. In general, we can say that with an increase in the dose, the latency period decreases, the severity and duration of the effect increase.
At the same time, with an increase in the dose of the drug, an increase in a number of side and toxic effects is also noted. In addition, a further increase in the dose of the drug (after reaching the maximum therapeutic effect) does not lead to an increase in the effect, but various undesirable reactions are observed. For practice, the ratio of doses of the drug caused by the therapeutic and toxic effects is important. Therefore, Paul Ehrlich introduced the concept of "therapeutic index", which is equal to the ratio:
maximum tolerated dose
maximum therapeutic dose
In fact, such an index in patients is not determined, but in animals it is determined by the ratio
LD50x100%,
ED50
where LD50 is the dose that causes the death of 50% of animals;
ED50 is the dose that produces the desired effect in 50% of animals.
Among the doses used in clinical practice, there are:
- a single dose;
- daily dose (pro die);
- average therapeutic dose;
- the highest therapeutic dose;
- course dose.
Calculation of doses: in addition to standard pharmacopoeial ones, in some cases the dose is calculated per kg of body weight or body surface area.
Re-use of medicines
With repeated use of medicinal substances, both weakening and intensifying effects of medicinal substances can be observed.
I. Weakening of the effect: a) addiction (tolerance); b) tachyphylaxis.
II. Strengthening the effect - cumulation a) functional (ethyl alcohol), b) material (glycosides)].
III. A special reaction that develops with repeated use of drugs is drug dependence (mental and physical), in which a "withdrawal syndrome" develops. Withdrawal syndrome, in particular, is characteristic of antihypertensive substances, beta-blockers, agents that depress the central nervous system; hormones (HA).
Drug interaction
As a rule, during treatment, the patient is prescribed not one, but several drugs. It is important to consider the ways in which medicinal substances interact with each other.
Distinguish:
I. Pharmaceutical interactions;
II. Pharmacological interactions:
a) based on the interaction on pharmacokinetics (absorption,
binding, biotransformation, enzyme induction, excretion);
b) based on mutual influence on pharmacodynamics;
c) based on chemical and physical interaction in the internal environment of the body.
The most important pharmacodynamic interaction. At the same time, the following types of interaction are distinguished:
I. Synergism: summation (additive effect) - when the effect from
the use of two drugs is equal to the sum of the effects of two drugs A and
B. Potentiation: the combined effect is greater than the simple sum of effects
preparations A and B.
II. Antagonism: chemical (antidote); physiological (be-
ta blockers - atropine; hypnotics - caffeine, etc.).
The main types of drug therapy:
- Preventive use of medicines;
- Etiotropic therapy (AB, CA, etc.);
- Pathogenetic therapy (antihypertensive drugs);
- Symptomatic therapy (analgesics);
- Substitution therapy (insulin).
The main and side effects of medicinal substances. Allergic reactions. Idiosyncrasy.
Toxic effects
The main effect of medicinal substances is determined by the purpose of pharmacotherapy, for example, the appointment of analgesics for the purpose of pain relief, levamisole as an immunomodulator or as an anthelmintic agent, etc. Along with the main one, almost all substances have a number of side effects. Side effects (of non-allergic nature) are due to the spectrum of pharmacological action of a particular drug. For example, the main effect of aspirin is an antipyretic effect, a side effect is a decrease in blood clotting. Both of these effects are due to a decrease in the metabolism of arachidonic acid.
There are primary and secondary side effects of drugs. The primary one arises as a direct consequence of the action of this drug on any substrate or organ: for example, when using the drug atropine in order to reduce gastric secretion, dry mouth, tachycardia, etc. Secondary - refers to indirect adverse effects - for example, dysbiosis and candidiasis with antibiotic therapy. Adverse effects are very diverse, and include inhibition of hematopoiesis, damage to the liver, kidneys, hearing, etc. With prolonged use of various drugs, secondary diseases arise (steroid diabetes, immunodeficiencies, aplastic anemias, etc.).
The negative effects of pharmacological drugs include allergic reactions of varying severity. It should be emphasized that the occurrence of allergic reactions does not depend on the dose of the drug; they can occur even during a cutaneous test. The most dangerous is anaphylactic shock that occurs when using penicillin and other drugs.
Idiosyncrasy - an atypical, often genetically determined, associated with a specific enzymopathy, the reaction of an individual to a drug. For example, in individuals with a deficiency of glucose-6-phosphate dehydrogenase, the use of sulfonamides can cause a hemolytic crisis.
All of these reactions occur mainly with the use of medium therapeutic doses. When using the maximum therapeutic doses or in case of an overdose, toxic effects occur - damage to the auditory nerve, arrhythmias, depression of the respiratory center, hypoglycemia, etc. Toxic effects can also be observed when using usual doses in patients with damage to the main excretory systems (liver, kidneys,) or the so-called "slow acetylators".
In addition to somatic toxic effects, there are toxic effects on the embryo and the fetus - embryo- and fetotoxicity. Although most drugs are tested for embryo fetotoxicity, however, in humans during pregnancy, these drugs, of course, have not been tested, therefore, it is better during pregnancy (especially in the first three months) to refrain from using any drugs other than those prescribed for health reasons.
Basic principles of treatment of acute drug poisoning
I. Delayed absorption of the drug into the blood
- vomiting, gastric lavage, activated carbon;
- sorbents;
- laxatives;
- tourniquet on a limb.
II. Removal of a toxic substance from the body
- forced diuresis;
- peritoneal dialysis, hemodialysis, plasmapheresis;
- hemosorption, etc .;
- blood substitution.
III. Neutralization of an absorbed medicinal (toxic) substance
- antidotes;
- pharmacological (physiological antagonists).
IY. Pathogenetic and symptomatic treatment of acute poisoning Control over the function of vital organs and homeostasis indicators
- central nervous system;
- breathing;
- of cardio-vascular system;
- kidneys;
- homeostasis: acid-base state, ionic and water balance, glucose, etc.
One of the most important measures is the prevention of acute poisoning (especially in children). Keep medicinal substances out of the reach of children.