Dependence of the pharmacological effect on the dose of the active substance. Dose types

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 magnesia sulphate, 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.

drug effect depends on its amount that has entered the body, i.e. on the dose. If the prescribed dose is below the threshold (subthreshold), there is no effect. Depending on the nature of the effect, increasing the dose may lead to its increase. So, the effect of antipyretic or antihypertensive drugs can be quantified using a graph that indicates, respectively, the degree of decrease in body temperature or.

Dependency Variations drug effect on dose due to the sensitivity of a particular person taking the drug; Different patients require different doses to achieve the same effect. Differences in sensitivity are particularly pronounced in all-or-nothing phenomena.

As an illustration, we present experiment, in which the test subjects react on the principle of "all or nothing" - the Straub test. In response to the administration of morphine, mice develop arousal, which manifests itself in the form of an abnormal position of the tail and limbs. The dependence of this phenomenon on the dose is observed in groups of animals (10 mice per group), which are administered increasing doses of morphine.

At low dose administration only the most sensitive individuals react, with an increase in the dose, the number of those reacting increases, and at the maximum dose, the effect develops in all animals in the group. There is a relationship between the number of responders and the dose administered. At a dose of 2 mg/kg, 1 in 10 animals responds; at a dose of 10 mg/kg - 5 out of 10 animals. This dependence of the frequency of effect and dose is the result of different sensitivity of individuals, which, as a rule, is characterized by a log-normal distribution.

If a cumulative frequency(total number of animals that develop a response to a particular dose) note on the logarithm of the dose (abscissa), an S-curve appears. The lower point of the curve corresponds to the dose to which half of the animals in the group respond. The range of doses, covering the dependence of dose and frequency of effect, reflects variations in individual sensitivity to the drug. The dose vs. frequency of effect plot is similar in shape to the dose versus effect plot, but there are some differences. Dose-dependence can be assessed in one person, i.e. it represents the dependence of the effect on the concentration of the drug in the blood.

Grade dose dependent effect in the group is difficult due to different sensitivity in individual patients. To assess biological variation, the measurement is carried out in representative groups, and the result is averaged. Thus, the recommended therapeutic doses appear to be adequate for most patients, but not always for a particular individual.

At the core variations sensitivity lies differences in pharmacokinetics (the same dose - a different concentration in the blood) or different sensitivity of the target organ (the same concentration in the blood - a different effect).

For amplification therapeutic safety Clinical pharmacologists are trying to find out the reasons for the differences in sensitivity in different patients. This area of ​​pharmacology is called pharmacogenetics. Often the cause is a difference in the properties or activity of enzymes. In addition, ethnic variability in sensitivity is observed. Knowing this, the doctor should try to find out the metabolic status of the patient before prescribing this or that drug.

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 size of the particles or the 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 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.

The effect of drugs is largely determined by their dose.

Dose(dosis, intake, serving) is the amount of drug injected into the body. Therefore, it is necessary to correctly determine the dose. As the dose increases, the effect, as a rule, increases to a certain maximum.

Depending on the dose of the drug, the rate of development of the effect, its duration, severity, and sometimes the nature of the action may change. So, calomel acts in small doses as a choleretic agent, in medium doses as a diuretic, in large doses as a laxative. Therefore, with increasing doses, not only quantitative changes occur.

Dosing of drugs should be carried out taking into account the route of administration, the type, age of animals, the characteristics of the prescribed agent, the patient's condition and the purpose of prescribing the drug. Medicines are dosed in weight units (g, mg, mcg), volume units (ml, drops) and activity units (ME - international unit).

Depending on the purpose of application, it is customary to distinguish between:

stimulation doses;

prophylactic doses;

therapeutic (therapeutic) doses (doses, the use of which causes a therapeutic effect).

Therapeutic doses according to the strength of action are:

threshold;

maximum.

Threshold dose called the smaller dose that produces the effect inherent in this drug.

Maximum (or highest) dose called the typical limiting dose that gives a therapeutic effect and is accepted by the pharmacopoeia.

Doctors usually work with average therapeutic doses. The value of these doses is usually 1/3 or 1/2 of the maximum therapeutic dose.

There are also:

Toxic doses- doses that cause a picture of poisoning.

Lethal or lethal doses, i.e. doses that cause the death of the organism.

Throughout the entire course of study, we will be mainly interested in therapeutic doses, that is, doses that give a therapeutic effect. Knowledge of toxic and lethal doses is of great importance in the fight against poisoning.

To ensure a high concentration of the drug and obtain a rapid therapeutic effect, it is administered in the so-called loading dose. The loading dose exceeds the maximum therapeutic dose. It is prescribed for the first administration of drugs (antibiotics, sulfonamides, etc.). Then the drugs are administered in medium doses.

It is also customary to distinguish between single (pro dosi), daily (pro die), fractional and course doses.

single dose is the amount of drug used per dose. In many pathological conditions, it is necessary to maintain the therapeutic concentration of the drug in the blood for a long time, therefore, daily doses are determined.

Daily dose- the amount of the drug to be taken during the day.

Fractional dose is the use of a single dose in several doses.

coursework dose - the amount of a drug needed to treat a specific disease.

Course therapeutic doses help to determine the required amount of the drug for the course of treatment.

The safety of the use of each drug can be characterized by the concept of the breadth of pharmacological action.

Breadth of pharmacological action is the range between the minimum therapeutic and minimum toxic doses. This value is different for different drugs and the larger it is, the safer the drug. For example, the breadth of the pharmacological action of thiopental = 1.7, while for predion it is 7.0. Both of these substances are non-inhalation anesthetics. Naturally, predion is less dangerous than thiopental.

When choosing a dose of a drug, it is important to know the therapeutic index of its action.

under the therapeutic index refers to the ratio of the dose that causes the death of 50% of animals (LD 50) to the average dose (ED 50) that causes a specific pharmacological effect. With a large therapeutic index of action of the drug, it is easier to select a dose, moreover, undesirable side effects are manifested to a lesser extent. The higher the therapeutic index, the safer the drug. For example, the therapeutic index of benzylpenicillin is above 100, while for digitoxin it is 1.5-2.

For different routes of administration of drugs, the following ratio of doses is accepted: inside 1, rectally 1.5-2, under the skin 1/3-1/2, intramuscularly 1/3-1/2, intravenously 1/4 dose (it should be remembered that these ratios are very relative.

Taking into account the type of animals and their live weight, the ratio of doses was established: cows (500 kg) 1, horses (500 kg) 1.5, sheep (60 kg) 1/5-1/4, pigs (70 kg) 1/6- 1/5, dogs (12 kg) 1/10.

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 different 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).