The dependence of the action of drugs on their structure, physico-chemical properties, dosage form and routes of administration. The dependence of the pharmacological effect on the dose of the drug The dependence of the action of drugs on the dose
6. DEPENDENCE OF THE PHARMACOTHERAPEUTIC EFFECT ON THE PROPERTIES OF MEDICINES AND THE CONDITIONS OF THEIR USE
6. DEPENDENCE OF THE PHARMACOTHERAPEUTIC EFFECT ON THE PROPERTIES OF MEDICINES AND THE CONDITIONS OF THEIR USE
A) CHEMICAL STRUCTURE, PHYSICO-CHEMICAL AND PHYSICAL PROPERTIES OF MEDICINES
The properties of drugs are largely determined by their chemical structure, the presence of functionally active groups, the shape and size of their molecules. For effective interaction of a substance with a receptor, a drug structure is required that provides
its closest contact with the receptor. The strength of intermolecular bonds depends on the degree of convergence of a substance with a receptor. So, it is known that with an ionic bond, the electrostatic forces of attraction of two unlike charges are inversely proportional to the square of the distance between them, and the van der Waals forces are inversely proportional to the 6-7th power of the distance (see Table II.3).
For the interaction of a substance with a receptor, their spatial correspondence is especially important, i.e. complementarity. This is confirmed by differences in the activity of stereoisomers. So, in terms of the effect on blood pressure, D (+) -adrenaline is significantly inferior in activity to L (-) -adrenaline. These compounds differ in the spatial arrangement of the structural elements of the molecule, which is crucial for their interaction with adrenergic receptors.
If a substance has several functionally active groups, then the distance between them must be taken into account. So, in the series of bis-Quaternary ammonium compounds (CH 3) 3 N + - (CH 2) n - N + (CH 3) 3? 2X - for ganglioblocking action, optimally i = 6, and for a block of neuromuscular transmission - n\u003d 10 and 18. This indicates a certain distance between the anionic structures of n-cholinergic receptors, with which the ionic bond of the quaternary nitrogen atoms occurs. For such compounds, the radicals that “screen” the cationic centers, the size of the positively charged atom and the charge concentration, as well as the structure of the molecule connecting the cationic groups are also of great importance.
Elucidation of the relationship between the chemical structure of substances and their biological activity is one of the most important areas in the creation of new drugs. In addition, a comparison of the optimal structures for different groups of compounds with the same type of action allows one to get a certain idea of the organization of those receptors with which these drugs interact.
Many quantitative and qualitative characteristics of the action of substances also depend on such physicochemical and physical properties as solubility in water, lipids, for powdered compounds - on the degree of their grinding, for volatile substances - on the degree of volatility, etc. The degree of ionization is important. For example, muscle relaxants, structurally related to secondary and tertiary amines, are less ionized and less active than fully ionized quaternary ammonium compounds.
B) DOSES AND CONCENTRATIONS
The effect of drugs is largely determined by their dose. Depending on the dose (concentration), the rate of development of the effect, its severity, duration, and sometimes character change. Usually, with an increase in the dose (concentration), the latent period decreases and the severity and duration of the effect increase.
A dose is the amount of a substance per dose (usually referred to as a single dose).
It is necessary to be oriented not only in the dose calculated for a single dose (pro dosi), but also in daily dose (pro die).
Indicate the dose in grams or fractions of a gram. For a more accurate dosage of drugs, their number per 1 kg of body weight is calculated (for example, mg / kg, μg / kg). In some cases, it is preferable to dose substances based on the size of the body surface (per 1 m 2).
The minimum doses at which drugs cause an initial biological effect are called threshold, or minimum active. In practical medicine, average therapeutic doses are most often used, in which drugs in the vast majority of patients have the necessary pharmacotherapeutic effect. If, when administered, the effect is not sufficiently pronounced, the dose is increased to the highest therapeutic dose. In addition, toxic doses are distinguished, in which substances cause toxic effects dangerous for the body, and lethal doses (Fig. II.12).
Rice. II.12.Doses, pharmacotherapeutic and adverse effects of drugs (as an example, the main, side and toxic effects of morphine are given).
In some cases, the dose of the drug for the course of treatment (course dose) is indicated. This is especially important when using antimicrobial chemotherapeutic agents.
If there is a need to quickly create a high concentration of a medicinal substance in the body, then the first dose (shock) exceeds the subsequent ones.
For substances administered by inhalation (for example, gaseous and volatile anesthetics), their concentration in the inhaled air (indicated as a percentage by volume) is of primary importance.
C) RE-USE OF DRUGS
With repeated use of drugs, their effect may change in the direction of both increasing and decreasing the effect.
The increase in the effect of a number of substances is associated with their ability to accumulate 1 . Under material cumulation refers to the accumulation of a pharmacological substance in the body. This is typical for long-acting drugs that are slowly released or are persistently bound in the body (for example, some cardiac glycosides from the digitalis group). The accumulation of the substance during its repeated appointments can be the cause of toxic effects. In this regard, it is necessary to dose such drugs taking into account cumulation, gradually reducing the dose or increasing the intervals between doses of the drug.
There are known examples of the so-called functional cumulation, in which the effect, and not the substance, “accumulates”. So, with alcoholism, increasing changes in the function of the central nervous system can lead to the development of delirium tremens. In this case, the substance (ethyl alcohol) is rapidly oxidized and does not linger in the tissues. Only its neurotropic effects are summarized. Functional cumulation also occurs with the use of MAO inhibitors.
A decrease in the effectiveness of substances with their repeated use - addiction (tolerance 2) - is observed when using a variety of drugs (analgesics, antihypertensives, laxatives, etc.). It may be associated with a decrease in the absorption of the substance, an increase in the rate of its inactivation and (or) an increase in the intensity of excretion. It is possible that addiction to a number of substances is due to a decrease in the sensitivity of receptor formations to them or a decrease in their density in tissues.
In case of addiction, to obtain the initial effect, the dose of the drug must be increased or one substance replaced with another. In the latter case, it should be taken into account that there is cross addiction to substances interacting with the same receptors (substrates).
A special kind of addiction is tachyphylaxis 3- addiction that occurs very quickly, sometimes after the first administration of the substance. Thus, ephedrine, when repeated with an interval of 10-20 minutes, causes a smaller rise in blood pressure than with the 1st injection.
To some substances (usually to neurotropic) with their repeated introduction, drug dependence develops (Table II.5). It is manifested by an irresistible desire to take a substance, usually with the aim of improving mood, improving well-being, eliminating unpleasant experiences and sensations, including those that occur during the abolition of substances that cause drug dependence. Distinguish between mental and physical drug dependence. When mental drug addiction stopping the administration of drugs (for example, cocaine, hallucinogens) causes only emotional
1 From lat. cumulatio- increase, accumulation.
2 From lat. tolerance- patience.
3 From Greek. tachys- fast, phylaxis- vigilance, protection.
Table II.5.Examples of Substances That Cause Drug Dependence
discomfort. When taking certain substances (morphine, heroin) develops physical drug addiction. This is a more pronounced degree of dependence. Cancellation of the drug in this case causes a serious condition, which, in addition to sudden mental changes, manifests itself in various and often serious somatic disorders associated with the dysfunction of many body systems, up to death. This so-called withdrawal syndrome 1, or deprivation phenomena.
Prevention and treatment of drug dependence is a serious medical and social problem.
D) DRUG INTERACTIONS
In medical practice, several drugs are often used simultaneously. At the same time, they can interact with each other, changing the severity and nature of the main effect, its duration, as well as strengthening or weakening side and toxic effects.
Drug interactions can be classified as follows.
I. Pharmacological interaction:
1) based on changes in the pharmacokinetics of drugs;
2) based on changes in the pharmacodynamics of drugs;
3) based on the chemical and physico-chemical interaction of drugs in the environment of the body.
II. pharmaceutical interaction.
Combinations of different drugs are often used to enhance or combine effects useful in medical practice. For example, using some psychotropic drugs in conjunction with opioid analgesics, you can significantly increase the analgesic effect of the latter. There are preparations containing antibacterial or antifungal agents with steroidal anti-inflammatory agents, which are also among the appropriate combinations. There are many such examples. However, when combining substances, an unfavorable interaction can also occur, which is denoted as drug incompatibility. Incompatibility is manifested by the weakening, complete loss or change in the nature of the pharmaco-
1 From lat. abstinence- abstinence.
therapeutic effect or increased side or toxic effects (the so-called pharmacological incompatibility). This can occur when two or more drugs are used together. For example, drug incompatibility can cause bleeding, hypoglycemic coma, seizures, hypertensive crisis, pancytopenia, etc. Incompatibility is also possible during the manufacture and storage of combined drugs (pharmaceutical incompatibility).
Pharmacological interaction
Pharmacological interaction is associated with the fact that one substance changes the pharmacokinetics and/or pharmacodynamics of another substance. Pharmacokinetic type of interaction may be associated with impaired absorption, biotransformation, transport, deposition and excretion of one of the substances. Pharmacodynamic type of interaction is the result of direct or indirect interaction of substances at the level of receptors, ion channels, cells, enzymes, organs or physiological systems. In this case, the main effect can change quantitatively (strengthen, weaken) or qualitatively. In addition, it is possible chemical and physico-chemical interaction substances when used together.
The pharmacokinetic type of interaction (Table II.6) can appear already at the stage suction substances, which can change for various reasons. So, in the digestive tract, the binding of substances by adsorbing agents (activated charcoal, white clay) or anion-exchange resins (for example, the lipid-lowering agent cholestyramine), the formation of inactive chelate compounds or chelating agents are possible (in particular, antibiotics of the tetracycline group interact with iron and calcium ions according to this principle). , magnesium). All these interaction options prevent the absorption of drugs and, accordingly, reduce their pharmacotherapeutic effects. For the absorption of a number of substances from the digestive tract, the pH of the medium is essential. Thus, by changing the reaction of digestive juices, one can significantly affect the rate and completeness of the absorption of weakly acidic and weakly alkaline compounds. It was previously noted that with a decrease in the degree of ionization, the lipophilicity of such substances increases, which contributes to their absorption.
Changes in the peristalsis of the digestive tract also affect the absorption of substances. Thus, an increase in intestinal motility by cholinomimetics reduces the absorption of the cardiac glycoside digoxin, while the anticholinergic atropine, which reduces peristalsis, favors the absorption of digoxin. There are known examples of the interaction of substances at the level of their passage through the intestinal mucosa (for example, barbiturates reduce the absorption of the antifungal agent griseofulvin).
Inhibition of enzyme activity can also affect absorption. Thus, the antiepileptic drug difenin inhibits folate deconjugation and disrupts the absorption of folic acid from foods. As a result, folic acid deficiency develops.
Some substances (almagel, vaseline oil) form a layer on the surface of the mucous membrane of the digestive tract, which can somewhat hinder the absorption of drugs.
The interaction of substances is possible at the stage of their binding to blood proteins. In this case, one substance can displace another from the complex with blood plasma proteins. Thus, the anti-inflammatory drugs indomethacin and butadione
Table II.6.Examples of pharmacokinetic drug interactions
Group of combined drugs | The result of the interaction of drugs of groups I and II |
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Effect | mechanism |
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Almagel | Almagel hinders the absorption of group I substances in the gastrointestinal tract |
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Indirect anticoagulants (warfarin, neodicoumarin, etc.) | Cholestyramine | Weakening of the anticoagulant effect of group I substances | Cholestyramine binds group I substances in the intestinal lumen and reduces their absorption. |
Salicylates (acetylsalicylic acid, etc.) | Phenobarbital | Weakening actions salicylates | Phenobarbital enhances the biotransformation of salicylates in the liver |
Opioid analgesics (morphine, etc.) | Non-selective MAO inhibitors | Strengthening and prolonging the action of group I substances with possible respiratory depression | Non-selective MAO inhibitors inhibit inactivation of group I substances in the liver |
Synthetic antidiabetic agents (chlorpropamide, etc.) | Butadion | Increased hypoglycemic effect up to coma | Butadione displaces group I substances from their association with blood plasma proteins, increasing their concentration in the blood |
Salicylates (acetylsalicylic acid) | Antacids facilities, providing systemic action | Some weakening of the action of salicylates | Antacids reduce the reabsorption of salicylates in the kidneys (in an alkaline environment), increasing their excretion in the urine. The concentration of salicylates in the blood decreases |
they release anticoagulants of indirect action (coumarin group) from the complex with blood plasma proteins. This increases the concentration of the free fraction of anticoagulants and can lead to bleeding. By a similar principle, butadione and salicylates increase the concentration in the blood of the free fraction of hypoglycemic agents (such as chlorpropamide) and can cause hypoglycemic coma.
Some drugs may interact at the level biotransformation substances. There are drugs that increase (induce) the activity of microsomal liver enzymes (phenobarbital, difenin, griseofulvin, etc.). Against the background of the action of the latter, the biotransformation of many substances proceeds more intensively, and this reduces the severity and duration of their effect (as well as the enzyme inducers themselves). However, in clinical conditions, this manifests itself quite clearly only when enzyme inducers are used in large doses and for a sufficiently long time.
It is also possible the interaction of drugs associated with the inhibitory effect on microsomal and non-microsomal enzymes. Thus, a xanthine oxidase inhibitor is known - the anti-gout drug allopurinol, which increases the toxicity of the antitumor agent mercaptopurine (increases its inhibitory effect on hematopoiesis). Teturam, at-
changed in the treatment of alcoholism, inhibits aldehyde dehydrogenase and, by disrupting the metabolism of ethyl alcohol, increases its toxic effects.
breedingdrugs can also change significantly with the combined use of substances. It was previously noted that the reabsorption of weakly acidic and weakly alkaline compounds in the renal tubules depends on the pH values of the primary urine. By changing its reaction, it is possible to increase or decrease the degree of ionization of the substance. The lower the ionization, the higher the lipophilicity of the substance and the more intense its reabsorption in the renal tubules. Naturally, more ionized substances are poorly reabsorbed and more excreted in the urine. For alkalinization of urine, sodium bicarbonate is used, and for acidification, ammonium chloride is used (there are other drugs of a similar effect). With the combined use of drugs, their secretion in the renal tubules may be impaired. So, probenecid inhibits the secretion of penicillins in the renal tubules and thereby prolongs their antibacterial action.
It should be borne in mind that when substances interact, their pharmacokinetics can change at several stages simultaneously (for example, barbiturates affect the absorption and biotransformation of neodicumarin).
The pharmacodynamic type of interaction reflects the interaction of substances based on the features of their pharmacodynamics (Table II.7). If the interaction is carried out at the level of receptors, then it mainly concerns agonists and antagonists of various types of receptors (see above). In this case, one compound can enhance or weaken the effect of another. When synergy 1 the interaction of substances is accompanied by an increase in the final effect.
Table II.7.Examples of pharmacodynamic drug interactions
1 From Greek. synergos- acting together.
Continuation of the table.
Drug synergism can be manifested by simple summation or potentiation of effects. The summed (additive 1) effect is observed by simply adding the effects of each of the components (for example, this is how anesthetic drugs interact). If, with the introduction of two substances, the total effect exceeds (sometimes significantly) the sum of the effects of both substances, this indicates potentiation (for example, antipsychotic drugs potentiate the effect of anesthetics).
Synergism can be direct (if both compounds act on the same substrate) or indirect (with different localization of their action).
The ability of one substance to some extent to reduce the effect of another is called antagonism. By analogy with synergy, a direct
1 From lat. additio- addition.
or indirect antagonism (for the nature of the interaction at the level of receptors, see above).
In addition, the so-called synergoantagonism is distinguished, in which some effects of the combined substances are enhanced, while others are weakened. So, against the background of α-blockers, the stimulating effect of adrenaline on α-adrenergic receptors of vessels decreases, and on β-adrenergic receptors it becomes more pronounced.
The chemical and physico-chemical interactions of substances in body media are most often used in cases of overdose or acute drug poisoning. Thus, the ability of adsorbents to impede the absorption of substances from the digestive tract has already been mentioned. In case of an overdose of the anticoagulant heparin, its antidote, protamine sulfate, is prescribed, which inactivates heparin due to electrostatic interaction with it. These are examples of physico-chemical interaction.
An illustration of a chemical interaction is the formation of complexones. So, calcium ions are bound by the disodium salt of ethylenediaminetetraacetic acid (trilon B; Na 2 EDTA), ions of lead, mercury, cadmium, cobalt, uranium - tetatsin-calcium (CaNa 2 EDTA), ions of copper, mercury, lead, iron, calcium - penicillamine .
Thus, the possibilities of pharmacological interaction of substances are very diverse (see Tables II.6 and II.7).
Pharmaceutical interaction
There may be cases of pharmaceutical incompatibility, in which during the manufacture of drugs and (or) their storage, as well as when mixed in one syringe, the components of the mixture interact and such changes occur, as a result of which the drug becomes unsuitable for practical use. At the same time, the pharmacotherapeutic activity previously present in the initial components decreases or disappears. In some cases, new, sometimes unfavorable (toxic) properties appear.
Chemical structure medicines determines the following features of its action:
The spatial configuration of drug molecules and its ability to activate or block receptors. So, for example, the l-enantiomer of propranolol is able to block 1 and 2 -adrenergic receptors, while its d-enantiomer is several times weaker adrenoblocker.
The type of biosubstrate with which the substance is able to interact. For example, ring-aromatized steroid molecules from the C 18 class of steroids activate estrogen receptors, and when saturated, the ring acquires the ability to stimulate androgen receptors.
The nature of the bonds established with the biosubstrate and the duration of action. For example, acetylsalicylic acid forms a covalent bond with cyclooxygenase, acetylates the active site of the enzyme and irreversibly deprives it of activity. On the contrary, sodium salicylate forms an ionic bond with the active center of the enzyme and only temporarily deprives it of its activity.
Physico-chemical properties of the drug. This group of properties mainly determines the kinetics of the drug and its concentration in the area of the biological substrate. The leading role here is played by the degree of polarity of the substance molecule, the combination of lipophilic and hydrophilic properties. All these factors have already been considered previously.
Dosage form. The dosage form determines the rate of entry of the drug into the systemic circulation and the duration of its action. So, in the series aqueous solution > suspension > powder > tablet, the rate of entry into the bloodstream decreases. This effect is associated, in part, with the surface area of the dosage form - the larger it is, the faster absorption occurs, because. most of the drug comes into contact with the biological membrane. This relationship can be illustrated by the following example: the surface area of a cube with an edge of 1 cm is 6 cm 2, and if this cube is divided into smaller cubes with an edge of 1 mm, then the surface area will be 60 cm 2 with the same total volume.
Sometimes the particle size or type of dosage form are the determining factors for the implementation of the pharmacological effect of the drug. For example, the absorption of griseofulvin or lithium salts is possible only if they are in the form of the smallest particles, therefore, all dosage forms of these agents are microcrystalline suspensions, tablets or powders.
Ways of introduction. The route of administration also determines the rate at which the drug enters the systemic circulation. In the series intravenous > intramuscular > subcutaneous administration, the rate of drug entry into the body decreases and the time for the development of the drug effect slows down. Sometimes the route of administration can determine how a drug works. For example, a solution of magnesium sulfate, when administered orally, has a laxative effect, when injected into a muscle, it has a hypotensive effect, and when administered intravenously, it has a narcotic effect.
The problem of bioequivalence of drugs
It has already been mentioned above that each drug can be presented on the market in both branded and generic forms, and generic drugs can have several variants of trade names. For example, the tranquilizer diazepam is represented on the market by 10 generic drugs, the anti-inflammatory drug diclofenac - 14. All this variety of drugs often differs not only in appearance, but also in cost (moreover, the price difference can sometimes be quite noticeable).
Naturally, the doctor and the patient assume that all this variety of drugs should provide an equal treatment of the disease in terms of effectiveness. Those. they are based on the assumption of the equivalence of different preparations of the same drug produced by different companies.
There are 3 types of equivalence:
Chemical (pharmaceutical) equivalence means that 2 medicinal products contain the same medicinal substance in equal amounts and in accordance with current standards (pharmacopoeia articles). In this case, the inactive ingredients of drugs may vary. For example, Renitec and Enam 10mg tablets are chemically equivalent as contain 10 mg of enalapril maleate (ACE inhibitor).
Bioequivalence means that two chemically equivalent drugs from different manufacturers, when administered to the human body in equal doses and according to the same scheme, are absorbed and enter the systemic circulation to the same extent, i.e. have comparable bioavailability. Proof of bioequivalence of a generic drug to its branded counterpart is a necessary condition for registration of any generic drug.
The main criterion for bioequivalence is the ratio of the areas under the pharmacokinetic curve for the two studied drugs, as well as the ratio of the maximum concentrations of these drugs in the patient's blood:
And 
It is believed that the range of 0.8-1.2 is acceptable for these parameters (i.e., the bioavailability of the two compared drugs should not differ by more than 20%).
If a generic medicinal product is non-bioequivalent to its branded counterpart, then this medicine cannot be registered and approved for use. An illustrative example is with preparations of pyridinolcarbamate. This remedy was presented on the market in the form of tablets parmidin (Russia), prodectin (Hungary) and anginin (Japan) 2 . The difference in bioavailability between parmidine and anginin was 7.1%, while the same difference for prodectin and anginin was 46.4%. Not surprisingly, the dose of prodectin had to be 2 times the dose of anginine in order to have a comparable therapeutic effect.
Evidence of bioequivalence is not required for individual drugs: digoxin, phenytoin, oral contraceptives. This is due to the fact that it is difficult to ensure equal bioavailability for these drugs even within the same manufacturer - sometimes different batches of a drug manufactured at the same plant can have significant fluctuations in bioavailability.
It should be remembered that the bioequivalence of drugs does not yet say anything about their therapeutic equivalence. Below is an example of such a situation.
Therapeutic equivalence. This concept means that 2 drugs containing the same drug, which are used in equal doses and according to the same scheme, cause a comparable therapeutic effect. Therapeutic equivalence does not depend on the bioequivalence of drugs. Two drugs may be biologically equivalent but have different therapeutic equivalence. An example is the situation that developed after the launch of 2 drugs of colloidal bismuth subcitrate on the market - the branded drug De-nol (Yamanouchi Europe B.V., the Netherlands) and Tribimol (TorrentHouse, India), which were bioequivalent. However, the study of their anti-helicobacter activity showed that a slight change in the production technology by Torrent has practically deprived tribimol of activity against H. pylori. We should pay tribute to the employees of the company - they corrected the mistake (although the reputation of the company suffered somewhat at the same time).
Another situation is possible, when two biologically non-equivalent drugs are therapeutically equivalent. In particular, two oral contraceptives - Novinet (GedeonRichter) and Mercilon (Organon) contain 150 mg of desogestrel and 20 micrograms of ethinyl estradiol. Despite the same composition, they are bio-inequivalent, but equally effective in preventing pregnancy.
In order for a drug to have its effect on the body, it must be able to dissolve. The form of administered drugs affects the speed of absorption and the onset of a particular therapeutic effect. Medicines administered in the form of solutions are absorbed faster than those administered in the form of solid dosage forms (powders, tablets, pills). The absorption rate of solutions will depend on the solvent; Thus, alcoholic solutions are absorbed faster than water. The absorption of powders, and even more tablets, is much slower and depends on the degree of their grinding and the solubility of their constituent parts. The pills are absorbed even more slowly and gradually. With the introduction of medicinal substances through the mouth, absorption is also affected by the degree of filling of the stomach: substances introduced into an empty stomach are absorbed and exert their effect much faster than those introduced into a full stomach.
It should also be noted that substances that are soluble in lipoids (fats) of our body have a good absorption capacity.
Absorption depends on the injected substance itself, on its ability to penetrate deep into the tissues and on whether it contains easily or difficultly diffusing ions. The absorption rate also varies from the concentration of solutions: the more concentrated the solution, the slower it will be absorbed and exert its effect on the body.
The dependence of the action of drugs on the dose. The action of a substance varies quantitatively, and sometimes qualitatively, from the amount of the administered agent. Not only the nature of the effect obtained, but often the speed of the onset of the effect and the strength depend on the size of the dose (dosis - portion, intake). By increasing, for example, the dose of adrenaline administered intravenously, one can note an increase in its action in relation to an increase in blood pressure.
The following examples can demonstrate the change in the nature of the action depending on the quantity. Emetics used in small doses cause only an expectorant effect, while in large doses - the onset of vomiting. Salts of heavy metals in weak concentrations have an astringent effect, in stronger ones - irritating, and in even stronger ones - cauterizing.
Hypnotics in small doses are used to calm the central nervous system, while in large doses they are used as sleeping pills, etc.
The introduction of small doses of the drug may not have any visible effect on the body. The smallest share, which begins to have an effect inherent in this substance, is called the threshold. Doses used for treatment are called therapeutic, or therapeutic. In addition, as mentioned above, there are also higher (maximum) doses, then poisoning (toxic) and lethal (lethal) doses. The distance between the therapeutic and toxic dose is called the therapeutic latitude. The greater this distance, the safer the use of such a drug, and vice versa. For example, the distance between the therapeutic dose of caffeine (0.1-0.2) and the toxic dose (over 1.0) is very large, and in this case we are dealing with a large therapeutic latitude. Some medicinal substances, for example, hexenal and magnesium sulfate, have a very small therapeutic latitude and therefore must be used very carefully, otherwise respiratory arrest occurs due to depression of the respiratory center.
A single dose is called a single dose. Sometimes it is necessary to immediately create a sufficiently large concentration of a therapeutic drug in the body with a single dose. To do this, from the very beginning they give an increased dose of the drug, 2 or 3 times more than a single dose, and this dose is called shock. Such doses, for example, are prescribed sulfonamides, quinacrine. The amount of a substance intended to be taken during the day is called the daily dose. Some medicinal substances, for example, male fern extract, are not recommended to be administered immediately, but are administered fractionally, in separate small amounts. Such doses are called fractional. Doses of substances intended for the whole course of treatment, such as quinacrine for malaria, sulfonamides for lobar pneumonia, novarsenol and bioquinol for syphilis, are called general.
The dependence of the action of the medicinal substance on the state of the body. In childhood and adolescence (under 25 years of age), doses are reduced accordingly. This applies not only to medicinal plants, but also to the physical effects on the body. For example, as sports, stretching, massage and other orthopedic procedures. Above was a table from the Pharmacopoeia of dose changes depending on age. But it turns out that the child's body is especially sensitive to certain medicinal substances, which it does not tolerate even in very small doses. This primarily applies to substances that depress the nervous and cardiovascular systems. These include, for example, alcohol, morphine, opium, and many others. In addition, one should be very careful when prescribing expectorants, emetics, strychnine, etc. to children. This is due to the fact that in childhood some systems and centers are not well developed and stable (muscles, respiratory center, etc.). Along with this, children tolerate sulfonamides, cardiac drugs, quinine, laxatives, etc. quite well. Therefore, with regard to the dosage of certain substances, one has to deviate from the norms given in the Pharmacopoeia, both in one direction and the other.
The body of people over the age of 60, and sometimes even earlier, due to the changes that have occurred in it, is not able to tolerate the doses that are intended for adults according to the Pharmacopoeia. Laxatives, emetics and substances that increase blood pressure are especially poorly tolerated by the elderly.
Dosing of medicinal substances, depending on weight, is very difficult and may not always be correct (the presence of tumors with a large weight, edema, a large amount of adipose tissue), since the calculation should be made only on the weight of active tissues. Only some substances are prescribed per unit weight of the patient, for example, narcolan.
The dosage of a medicinal substance, the nature of its action or contraindications for use may also change in connection with certain physiological and pathological conditions.
So, for example, in the early months of pregnancy, strong laxatives, emetics are contraindicated. During feeding, it is dangerous to prescribe certain substances that pass into the child's body with mother's milk and can cause poisoning (antipyrine, morphine, strychnine, etc.). The ability of substances to pass with mother's milk is often used to treat a child.
In various pathological processes occurring in the body, the action of medicinal substances often changes, and in the action of some of them there is a significant difference depending on whether they act on a healthy or diseased body. This group of substances includes antipyretics, camphor, valerian, etc. It should also be noted that usually organs or systems of the body that are in a state of oppression are more easily exposed to stimulating substances, and vice versa.
The action of substances can also be influenced by the time of day, year, and the state of the body.
So, sleeping pills taken in therapeutic doses in the evening, at the usual hour, in a quiet, calm environment, cause a state of sleep, but when taken in the morning, they do not have such an effect. In the hot summer season, the action of diaphoretic substances that dilate peripheral vessels, etc., is especially easily manifested.
To obtain a good therapeutic effect in debilitated, weak patients, doses smaller than usual are sufficient; the appointment of such patients with large doses should be avoided because of the possibility of an extremely strong effect, often undesirable and dangerous for the patient (laxatives, emetics, etc.).
Occasionally, there is an unusual reaction to the introduction of certain drugs. This phenomenon is called idiosyncrasy (idios - one's own, peculiar and synkrasis - mixing, merging). Average therapeutic or even smaller doses of certain medicinal substances (quinine, antipyrine, aspirin, iodine, bromine, arsenic) in such individuals cause an unusually strong effect, often accompanied by irritation of the skin, mucous membranes, etc. This can be expressed by the appearance of edema, various rashes and spasms of smooth muscles, especially bronchi and other organs. Phenomena of idiosyncrasy are sometimes observed with the introduction of food substances, such as cottage cheese, honey, apples, strawberries, tomatoes, fish and crayfish. In this case, phenomena from the gastrointestinal tract (diarrhea, vomiting), fever, skin rashes, poor general health, and sometimes collapse phenomena are usually noted.
The body's sensitivity to medicinal substances varies with age. For different pharmacological agents patterns in this regard are different. However, in general, children and the elderly (over 60 years of age) are more sensitive to the effects of drugs than middle-aged people.
Medicinal substances for children prescribed in smaller doses compared with adults. Firstly, this is due to the fact that children have less body weight than adults. Secondly, children are more sensitive to many pharmacological substances than adults. Children are especially sensitive to drugs of the morphine group - morphine, ethylmorphine, codeine, as well as to strychnine, neoserine and some other drugs, and therefore, in the first period of a child's life, these drugs are not prescribed to him at all, and if they are prescribed, then in significantly reduced doses.
With age, body weight increases and at the same time the sensitivity of the child's body to medicinal substances changes, and to different substances in different ways. Therefore, it is difficult to give general recommendations regarding the dosage of medicinal substances for children. In order to determine the therapeutic dose of each poisonous or potent drug, one should use State Pharmacopoeia.
When prescribing drugs To old people(over 60 years old) their different sensitivity to different groups is taken into account medicines. “Doses of drugs that depress the central nervous system (hypnotics, neuroleptics, drugs of the morphine group, bromides), as well as cardiac glycosides, diuretics are reduced to 1/2 of the adult dose. Doses of other potent and poisonous drugs are 2/3 of the adult dose. Doses of antibiotics, sulfonamides and vitamins are usually equal to adult doses.
Body mass
The action of the drug in a certain dose depends on the body weight of the person to whom it is administered. Naturally, the greater the body weight, the greater should be the dose of the drug. In some cases, for a more accurate dosage of medicinal substances, their doses are calculated per 1 kg of the patient's body weight.
Individual sensitivity
For different people the same medications in the same doses can act to varying degrees. The difference in the magnitude of the effect may be due to individual, genetically determined characteristics. For some people, certain drugs may work in an unusual, unusual way. Thus, the anti-tuberculosis drug isoniazid causes polyneuritis in about 10-15% of patients, the curare-like drug dithylin usually acts for 5-10 minutes, and in some people - 5-6 hours, the antimalarial drug primaquine in a number of patients causes the destruction of red blood cells (hemolysis), hydrogen peroxide when applied to the wound surface, in some patients it does not foam, etc.
This kind of unusual reaction to the action of drugs is referred to as "idiosyncrasy" (idios - peculiar; synkrasis - mixing). As a rule, idiosyncrasy is associated with a genetic deficiency of certain enzymes.
The dependence of the action of drugs on the state of the body
Medicinal substances can act on the body in different ways depending on its functional state. As a rule, substances of a stimulating type show their effect more strongly when the functions of the organ they act on are suppressed, and, conversely, inhibitory substances act more strongly against the background of excitation.
The effect of drugs may vary depending on pathological condition organism. Some pharmacological substances show their effect only in pathological conditions. So, antipyretic substances (for example, acetylsalicylic acid) lower body temperature only if it rises; cardiac glycosides clearly stimulate the activity of the heart only in heart failure.
Pathological conditions of the body can change the effect of drugs: enhance (for example, the effect of barbiturates in liver diseases) or, conversely, weaken (for example, local anesthetic substances reduce their activity in conditions of tissue inflammation).
Chemistry and pharmacology
Threshold is the minimum dose that causes any biological effect. The average therapeutic dose that causes the optimal therapeutic effect. The highest therapeutic dose that produces the greatest effect. The breadth of therapeutic action is the interval between the threshold and highest therapeutic doses.
Dependence of the pharmacological effect on the dose of the active substance. Dose types. The breadth of the therapeutic action of drugs. Biological standardization.
Doses of a pharmacological substance
The action of each pharmacological substance depends on its quantity dose (or concentration). As the dose increases, the effect of the substance increases. The most typical S -shaped dependence of the magnitude of the effect on the dose. In other words, at first, with an increase in the dose, the effect increases slowly, then faster, then the increase in effect slows down and the maximum effect is reached, after which the increase in dose no longer leads to an increase in the effect. When comparing two equally active substances, their doses are compared, in which the substances cause effects of the same magnitude, and the activity of the substances is judged on this indicator. So, if substance A increases blood pressure by 40 mm Hg. Art. at a dose of 0.25 g, and substance B at a dose of 0.025 g, it is believed that substance B is 10 times more active than substance A. Comparison of the maximum effects of the two substances makes it possible to judge their comparative effectiveness. So, if with the help of substance A it is possible to increase urination by a maximum of 6 liters per day, and with the help of substance B only by 2 liters, it is believed that substance A is 3 times more effective than substance B.
Dose types.
Threshold is the minimum dose that causes any biological effect.
Srednerapnvticheskaya dose, which causes the optimal therapeutic effect.
The highest therapeutic dose that produces the greatest effect.
The breadth of therapeutic action is the interval between the threshold and highest therapeutic doses.
Toxic - the dose at which symptoms of poisoning occur.
Lethal dose that causes death.
Single pro dosi single dose.
Course dose per course of treatment.
Loading dose prescribed at the beginning of treatment, which exceeds the average therapeutic dose by 2-3 times and is prescribed in order to quickly achieve the concentration of the drug in the blood.
Maintenance dose prescribed after shock and it usually corresponds to the average therapeutic dose.
The effect of drugs on repeated administration
With repeated use, the effectiveness of drugs can change both upward and downward, that is, undesirable effects occur. Cumulation is of two types: material (physical) and functional. Material cumulation - an increase in the therapeutic effect due to the accumulation of drugs in the body. Functional cumulation - an increase in the therapeutic effect and the appearance of overdose symptoms occurs faster than the accumulation in the body of the drug itself.
Habituation is a decrease in the pharmacological activity of the drug with its constant administration.
Cross-addiction is addiction to a drug that is similar in chemical structure.
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