Dose-dependence of drugs are examples. Dependence of the pharmacological effect on the dose of the active substance

The body's sensitivity to medicinal substancesvaries with age. For different pharmacological agents the patterns in this respect 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 to adults. First, 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, proserin 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 various substances in different ways. It is therefore difficult to give general dosage recommendations. medicinal substances for children. In order to determine the therapeutic dose of each poisonous or potent medicinal substance, you should use State Pharmacopoeia.

When prescribing medicinal substances 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, antipsychotics, drugs of the morphine group, bromides), as well as cardiac glycosides, diuretics are reduced to 1/2 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 the same as for adults. ”

Body mass

The action of the drug at a certain dose depends on the body weight of the person to whom it is administered. Naturally, the greater the body weight, the greater the dose of the medicinal substance should be. In some cases, for more accurate dosage of medicinal substances, their doses are calculated per 1 kg of the patient's body weight.

Individual sensitivity

On different people same medications in the same doses can act in different degrees. The difference in the magnitude of the effect may be due to individual, genetically determined characteristics. For some people, certain drugs may act in unusual, unusual ways. So, the anti-tuberculosis drug isoniazid causes polyneuritis in about 10-15% of patients, curariform remedy ditilin usually acts for 5-10 minutes, and in some people - 5-6 hours, the antimalarial agent primaquine in a number of patients causes the destruction of erythrocytes (hemolysis), hydrogen peroxide, when applied to the wound surface, does not foam in some patients, etc.

Such unusual reactions to the action of drugs are denoted by the term "idiosyncrasy" (idios - peculiar; synkrasis - confusion). Typically, idiosyncrasy is associated with genetic deficiencies in certain enzymes.

The dependence of the action of medicinal substances 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 the stimulating type manifest their effect more strongly when the functions of the organ on which they act are suppressed, and, conversely, depressing 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 under 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 anesthetics reduce their activity in conditions of tissue inflammation).

Drug effect depends on the amount that has entered the body, that is, 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 intensification. So, the effect of antipyretic or antihypertensive drugs can be quantified using a graph, which indicates, respectively, the degree of decrease in body temperature or.

Dependency variations effect of the drug on the dose due to the sensitivity of a particular person taking the drug; to achieve the same effect, different patients require different doses. Differences in sensitivity are especially pronounced in phenomena of the "all or nothing" type.

As an illustration, we present experiment, in which the test subjects react according to the principle "all or nothing" - the Straub test. In response to the introduction of morphine, mice develop excitement, 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 injected with increasing doses of morphine.

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

If cumulative frequency (total number of animals that develop a response to a specific dose) mark on the logarithm of the dose (abscissa axis), an S-shaped curve appears. The lower point of the curve corresponds to the dose to which half of the animals in the group respond. The dose range, covering the dose-response relationship, reflects variations in individual drug sensitivity. The dose-response graph is similar in shape to the dose-response graph, but there are some differences. Dose dependence can be assessed in one person, that is, it is the dependence of the effect on the concentration of the drug in the blood.

Assessment dose-response 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 are adequate for most patients, but not always for a particular person.

At the heart of variations sensitivity is the difference in pharmacokinetics (the same dose - different concentration in the blood) or different sensitivity of the target organ (the same concentration in the blood - a different effect).

To enhance therapeutic safety clinical pharmacologists are trying to figure out the reasons for differences in sensitivity in different patients. This area of \u200b\u200bpharmacology is called pharmacogenetics. Differences in the properties or activity of the enzymes are often the cause. In addition, there is ethnic variation in sensitivity. Knowing this, the doctor should try to find out the metabolic status of the patient before prescribing a particular drug.

For the quantitative and qualitative characteristics of the action of medicines, such concepts as the maximum therapeutic effect, its variability and selectivity are used. The action of the drug in time can be divided into the latency period, the time of maximum therapeutic effect and its duration. Each of the stages is due to certain physicochemical, physiological and biochemical processes in cells and organs.

So, the latency period is determined mainly by the introduction, the rate of absorption and distribution of drugs in organs and tissues, and to a lesser extent - by the rate of biotransformation and excretion. The duration of action is mainly due to the features of deposition, the rate of withdrawal of the drug from the body.

A certain dose (or concentration) of a drug produces a pharmacological effect in the body, which is quantified. The rule of doses is known: small doses excite the functions of organs, medium doses intensify them, large doses oppress and excessive ones paralyze.

The effect of drugs depends on their dose. In some cases, there is a direct relationship between dose, concentration and effect. However, in practice, a direct relationship between the concentration of a substance in serum and the magnitude of the effect is not often observed due to the fact that curative action influenced by many factors from the side of drugs and the body. So, decrease or increase blood pressure can be the result not only of the dose, routes of administration, pharmacokinetic parameters, mechanism of action, but also changes in cardiac activity, vascular tone, circulating blood volume and nervous regulation, the level of blood pressure, as well as their simultaneous or sequential combinations.

The effect caused by a certain dose of a medicinal substance also depends on: the amount of metabolites formed in the process of biotransformation, the proportion of active isomers and the rate of their metabolism in the liver, the reactivity of the corresponding receptors, the nature of the disease, etc. In this regard, the dose-effect curve can be straight, curved up or down, sigmoid type. If we isolate any one component, then the "dose - effect" curve takes on a certain character with parameters reflecting the strength and maximum efficiency. In many biological systems, with an increase in the dose, the effect increases to a certain value ("ceiling"), a further increase in the dose no longer causes an increase in the effect, but quite often, on the contrary, decreases it. In other cases, the dose is all-or-nothing (eg, convulsions, anesthesia).

Depending on the characteristics of the dose-effect curve (placement, slope, shape of the curve), one can judge the strength of drug action, pharmacokinetic parameters (absorption, distribution, conversion and output), as well as the relationship of drugs with receptors. To compare the strength of the action of two or more agents, the relative strength of their action is used - the definition of equivalent (equivalent) doses. The character of the rise in the "dose - effect" curve characterizes the mechanism of drug action, and the maximum characterizes the internal activity of the drug. Analysis of the curves "dose - effect" of morphine and butadione shows that morphine has sufficient internal activity to relieve strong and weak pain, while butadione, even in maximum doses, can relieve only pain syndrome without detecting toxic manifestations moderate neurological origin.

Due to the existence of individual differences, pharmacological studies are carried out on large populations of biological objects. Usually, when studying the quantitative relationship "dose → effect → response", one determines the dose that produces an effect in 50% of the representatives of a certain population. This is an average dose, depending on the effect studied, it can be effective (DE50). Comparing effective and le-

At a high dose, the hazard of a given drug can be determined using the therapeutic index. (TU.

where Te is the therapeutic index, DL50 is the dose of the substance that causes the death of half of the experimental animals, DE50 is the dose that causes the effect in 50% of cases. These results are obtained in experiments on animals, then extrapolated to the patient.

In the case of a change in the dose (concentration) of a medicinal substance, not only the effect changes, but also the speed of its achievement. Thus, the dose determines not only quantitative but also qualitative changes in the pharmacological effect.

And conditions of use

The dependence of the action of drugs on their chemical structure and physical properties. The properties of drugs largely depend on their physical properties and chemical structure. The chemical structure of a substance determines which of the receptors it can interact with, how strong, specific and complete their connection will be (for example, L (-) - adrenaline is much more active than D (+) - adrenaline in terms of its effect on the level of blood pressure, since the spatial location elements of the molecule in the levorotatory isomer contributes to a more complete connection of this isomer with the adrenergic receptor). The effect of the drug will also vary depending on its physical and physical and chemical properties: solubility in water, fats, degree of fineness, volatility, degree of ionization (for example, ferrous iron is better absorbed in the gastrointestinal tract; inhalants for anesthesia, readily soluble in lipids, easily pass through the blood-brain barrier and have their effect on brain tissue) ...

Doses of medicines. Dose types. Dose-dependent drug action. A dose is a specific amount of a drug administered to the body. Indicate the dose in grams or fractions of a gram. For a more accurate dosage of drugs, their amount is calculated per 1 kg of body weight (for example, mg / kg; μg / kg). In some cases, the substances are dosed based on the size of the body surface (per 1 m 2).

The amount of substance per dose is single dose, for a day - daily, for the course of treatment - coursework.

Therapeutic doses:

1. Minimum therapeutic (minimum effective, threshold) dose - the minimum amount of a drug that causes a therapeutic effect;

2. Average therapeutic dose - the range of doses in which the drug has the optimal prophylactic or therapeutic effect in most patients;

3. The highest therapeutic dose is the maximum amount of a drug that does not cause toxic effects.

Toxic dose - This is the dose in which the drug has toxic effects dangerous to the body. Minimum toxic dose Is the dose that causes initial manifestations intoxication.

ABOUT lethal doses they speak more often in experiment. For quantitative characterization lethal dose the most commonly used indicator is LD 50 (the dose, the introduction of which causes the death of 50% of the experimental animals).

If you need to quickly create a high concentration of a drug in the body, the first dose ( shock) exceeds the subsequent ones.

To assess the therapeutic value of a medicinal product, it is used therapeutic index (the ratio of the lethal dose LD 50 and the average therapeutic dose). Latitude therapeutic action - the range between the minimum therapeutic and minimum toxic doses.

The size of the administered dose is one of the most important factors determining the rate of development of the effect, its severity and duration. The outstanding scientist of the Renaissance, Paracelsus, said on this score: "Dosis sola facit venenum" (Only a dose makes a substance poisonous). Quite often, the qualitative characteristics of the effect can also depend on the size of the dose (for example, sodium oxybutyrate in small doses has an analgesic and sedative effect, in medium doses - an anticonvulsant and hypnotic effect, in large doses - anesthetic effect). The concentration of the drug in the body's fluids is proportional to its dose, so the pharmacological effect increases with increasing dose. However, the concentration of the drug in the body also depends on the characteristics of its pharmacokinetics, therefore, the pharmacological effect is not necessarily directly proportional to the dose. Sigmoid (S-shaped), hyper- and parabolic dependence is more common (Fig. 3.).

Fig 3. Shapes of curves reflecting the relationship between the pharmacological effect and the dose (concentration) of the drug:

hyperbolic (1), straight-line (2), parabolic (3), sigmoid (4) dependence.

To select a particular drug in a certain dose, the doctor must know its pharmacological activity and maximum effectiveness (Fig. 4). The activity of a drug is assessed by the dose (concentration) required to obtain a pharmacological effect equal to 50% of the maximum. The effectiveness of the drug is assessed by the severity of the pharmacological effect.

Fig. 4 Dose-effect curves reflecting different pharmacological activity and maximum drug efficacy.

1 - drug with the highest activity and lowest efficacy;

4 - the drug with the lowest activity;

2,3,4 - drugs with the same effectiveness.

The value of the individual characteristics of the organism and its state for the manifestation of the action of drugs.

Age.The metabolic rate of drugs changes with age. In children, several time periods are distinguished, which differ significantly in the characteristics of pharmacokinetics and pharmacodynamics. In this regard, were allocated:

1. Perinatal pharmacology - the field of pharmacology, which studies the features of the effect of drugs on the fetus from 24 weeks and the newborn - up to 4 weeks.

2. Pediatric Pharmacology - the field of pharmacology, which studies the characteristics of the action of substances on children's organism.

In newborns and children in the first years of life, the rate of absorption of drugs, the binding capacity of proteins, the intensity of metabolism and excretion are reduced. On the other hand, the sensitivity of receptors to drugs and the volume of their distribution are increased. All these factors determine the high sensitivity of newborns and children in the first years of life to drugs. In children after 5 years of age, the main clinical and pharmacological parameters differ little from those in adults.

The State Pharmacopoeia contains tables of the highest single and daily doses of poisons and potent substances for children different ages... For non-potent substances, the calculation is simplified: for each year of the child's life, 1/20 of the adult dose is assigned.

3. Geriatric Pharmacology studies the features of the action and use of drugs in the elderly and old age... Individuals of this age group there is a slowdown in the rate of hepatic metabolism and a decrease in excretory activity of the kidneys. In this regard, they have an increased sensitivity to medicinal substances, therefore, dosage adjustments for most medications are required. Patients over 60 years of age are advised to reduce the dose of most drugs by 1/3 - 1/2.

Floor... Differences in the action of drugs, caused by sex, are to a certain extent associated with the influence of sex hormones on the interaction of drugs with receptors and metabolic processes. It is known, for example, that the male sex is more resistant to the action of nicotine, strychnine, etc., and the female sex is more resistant to the action of morphine, cocaine, lead salts, etc.

Genetic factors... Currently, the field of pharmacology has emerged, which studies the role of a genetic factor in the body's sensitivity to drugs - pharmacogenetics. It has been established that the different tolerability of drugs by different patients is often determined by genetic factors. For example, the yellow race is more sensitive to the β-blocker propranolol than the white race. Many atypical drug reactions are caused by hereditary deficiencies in enzymes involved in biotransformation processes. Sometimes there is a congenital perverse reaction or hypersensitivity for certain medicines (idiosyncrasy).

Body conditionalso influences action drugs... The founder of the national school of pharmacologists N.P. Kravkov believed that "the same substance under different conditions ..., at different temperatures, under different conditions of the body, may turn out to be either a medicine or a poison." Some substances act only in pathological conditions (antipyretic drugs, antidepressants, and others). Medicines that stimulate certain functions are more effective in suppressing them (psychostimulants, hormones, etc.). Patients with liver and / or kidney pathology are more sensitive to the action of drugs due to a slowdown in the processes of biotransformation and excretion, respectively.

Diurnal rhythms... The direction of pharmacology, called chronopharmacology, studies the dependence of the pharmacological effect on the daily periodism. It was found that the effects of drugs are most pronounced during the period of maximum activity (glucocorticoids are most active at 5-7 hours, insulin - 8-13 hours, histamine - at 21-24 hours). On the other hand, the drugs themselves can affect the phases and amplitude of the circadian rhythm.

In order for a medicinal substance to have its effect on the body, it is necessary that it can dissolve. The speed of absorption and the onset of one or another therapeutic action is influenced by the form of the drugs administered. Drugs administered as solutions are absorbed faster than drugs administered as solid dosage forms (powders, tablets, pills). The speed of absorption of solutions will depend on the solvent; So, alcohol solutions absorbed faster than water. The absorption of powders, and even more so of 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. When drugs are administered through the mouth, absorption is also influenced 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 substance being introduced itself, on its ability to penetrate deep into the tissues and on whether it contains easily or difficultly diffusing ions. The absorption rate also changes 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 effect of a substance changes quantitatively, and sometimes also qualitatively, from the amount of the administered agent. The size of the dose (dosis- portion, reception) depends not only on the nature of the action obtained, but often the speed of the onset of the effect and strength. By increasing, for example, the intravenously administered dose of adrenaline, one can note an increase in its effect on the increase in blood pressure.

The change in the nature of the action depending on the quantity can be demonstrated by the following examples. Emetics, used in small doses, cause only an expectorant effect, 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.

Small doses of hypnotics are used to calm the central nervous system, in large doses - as sleeping pills, etc.

The introduction of small doses of the drug may not have any visible effect on the body. The smallest fraction that begins to exert an effect inherent in a given substance is called the threshold. Doses used for treatment are called curative or therapeutic. In addition, as mentioned above, there are also higher (maximum) doses, then poisonous (toxic) and lethal (lethal). The distance between the treatment dose and the toxic dose is called the therapeutic latitude. The greater this distance, the safer the use of such a medicine, 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 we are dealing in this case with a large therapeutic breadth. Some medicinal substances, for example, hexenal and magnesia sulfate, have a very small therapeutic breadth and therefore must be used very carefully, since otherwise respiratory arrest occurs due to inhibition of the respiratory center.

A single dose is called a single dose. Sometimes it is necessary to create a sufficiently large concentration in the body immediately medicinal product with a single dose. To do this, from the very beginning, an increased dose of the drug is given, 2 or 3 times more than a single dose, and this dose is called a shock dose. Such doses, for example, are prescribed sulfonamides, akrikhin. The amount of the substance intended for intake 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 small amounts. Such doses are called fractional doses. Doses of substances intended for the whole course of treatment, such as acriquine for malaria, sulfonamides for croupous pneumonia, novarsenol and bioquinol for syphilis, are called general.

The dependence of the action of the drug 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 physical effects on the body. For example, 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 system. 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, heart drugs, quinine, laxatives, etc. quite well. Therefore, with regard to the dosage of some substances, it is necessary to deviate from the norms given in the Pharmacopoeia, both in one direction and in the other direction.

The body of people over the age of 60, and sometimes even earlier, due to 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 the 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 for the weight of active tissues. Only some substances are prescribed per unit of patient weight, for example, narcolan.

The dosage of a medicinal substance, the nature of its action or contraindications for use may also change in connection with some physiological and pathological conditions.

So, for example, in the early months of pregnancy, strong laxatives and emetics are contraindicated. During feeding, it is dangerous to prescribe certain substances that pass into the child's body with the mother's milk and can cause poisoning (antipyrine, morphine, strychnine, etc.). The ability of substances to pass through the mother's milk is often used to treat a child.

With 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 affect a healthy or a sick organism. 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 effect of substances can also be influenced by the time of day, year and body condition.

So, sleeping pills taken in therapeutic doses in the evening, at the usual hour, in a quiet, calm atmosphere, cause a state of sleep, while being taken in the morning, they do not have such an effect. In the hot summer season, the action of diaphoretic substances that expand peripheral vessels, etc., is especially easily manifested.

To obtain a good therapeutic effect in emaciated, frail patients, smaller than usual doses are sufficient; the appointment of large doses to such patients should be avoided due to the possibility of manifestation 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 medicinal substances. This phenomenon is called idiosyncrasy (idios - your own, peculiar and synkrasis - mixing, merging). Medium therapeutic or even lower doses of certain medicinal substances (quinine, antipyrine, aspirin, iodine, bromine, arsenic) in such persons cause an unusually strong effect, often accompanied by symptoms of 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. The phenomena of idiosyncrasy are sometimes observed with the introduction of nutrients, 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 are usually noted.