The concept of cumulation, types (examples). Habituation and tachyphylaxis (examples). The effect of drugs on repeated administration. Cumulation. Addictive. Addiction. Sensitization. Idiosyncrasy Cumulative action in medicine

Cumulation(Late Latin cumulatio accumulation, increase) - strengthening the effect of drugs and poisons with their repeated administration in the same doses.

Distinguish between material and functional K. By material K. they mean the accumulation of the active substance in the body, which is confirmed by direct measurement of its concentrations in the blood and tissues. Material to., as a rule, is characteristic of substances which are slowly metabolized and are not completely removed from an organism. In this regard, with repeated injections, if the intervals between them are not long enough, the concentration of such substances gradually increases in the body, which is accompanied by an increase in their effect and can lead to the development of intoxication. Material coagulation often occurs when taking a number of cardiac glycosides (for example, digitoxin), alkaloids (atropine, strychnine), long-acting hypnotics (phenobarbital), indirect anticoagulants (syncumara, etc.), and salts of heavy metals (for example, mercury).

The development of material K. is facilitated by a decrease in the antitoxic function of the liver and the excretory ability of the kidneys, which may be due not only to pathological changes in these organs in certain diseases (cirrhosis of the liver,

Functional To. is more characteristic of substances that affect the activity of c.

For the prevention of complications associated with the ability of drugs to K., the most important is the correct selection of doses of drugs, the choice of the optimal scheme for their appointment, careful monitoring of the dynamics of functional changes in the body. To prevent possible negative consequences of material K., modern methods of quantitative determination of the content of drugs in the blood and tissues are used.

On the body.

Material cumulation(synonymous with accumulation) is quantitatively characterized in the study of pharmacokinetics, toxicokinetics.

Functional cumulation is detected during the study of cumulation, which is part of a routine experimental study of the general toxic effect of pharmacological substances and other toxicants. The study of general toxic action includes:

• study of acute toxicity - a characteristic of the amount of a substance that causes the death of animals with a single exposure;
• study of cumulativeness - a characteristic of the amount of a substance that causes the death of animals during repeated exposures;
• chronic toxicity study - identifying the nature of poisoning with prolonged exposure and determining safe doses.

The purpose of the study of cumulativeness is to clarify the nature of the action of a substance on the body with repeated injections and the selection of doses for chronic experiments. The selection is carried out on the basis of a comparison of doses of a substance that causes the death of animals during a single and repeated exposure. By cumulative action we mean here gain the effect of the poison upon repeated exposure.

Research methods

For the study of cumulativeness, various methods are used, based on accounting for the death of animals during repeated exposure to the substance under study. Preference is often given to the method of Lim et al., which makes it possible to evaluate in one study not only the cumulative properties of a substance when it affects the body, but also the development of tolerance (addiction) to it.

Scheme for studying cumulation by the method of subchronic toxicity according to Lim

For the first four days, a daily dose of one tenth of the DL 50 ( - dose that causes the death of half in the group of animals; is established during the study of acute toxicity). Then the dose is increased by 1.5 times and the next four days are administered. (After the eighth dose, the accumulated dose is one semi-lethal dose.) If necessary, the study is continued further, increasing the dose by 1.5 times the previous level every four days until half of the animals die (usually 5 out of 10). Calculate the cumulation coefficient:

where is the cumulation coefficient, is the average lethal dose accumulated with n-fold administration, is the average lethal dose with a single injection. When - they talk about cumulation (in the sense of enhancing the action of the poison), if - about tolerance. The resulting qualitative (ordinal at best) estimate is informally used when planning a chronic experiment. An alternative is to quantify the cumulation coefficient, which makes it possible to predict the probability of death of animals when planning studies of chronic toxicity.

Quantification of the cumulation factor

Cumulation coefficient ( k) is defined as the proportion of a substance (or effect) that continues to have its effect by the time of the next administration in such a way that the sequence of effective doses is presented as:

where is the actually administered constant or variable dose, as in the Lim scheme. The probability of death of animals from a sequence of n+1 introductions is calculated as the probability of occurrence of at least one of the set of events :

where - the probability of death of animals when exposed to a substance in an effective dose is determined from the dependence where - the normal distribution function , the parameters of which are determined by the probit analysis method during the study of acute toxicity The cumulation coefficient in this definition acts as a measure of the relationship between successively administered doses. The numerical value of the cumulation coefficient is selected so that the sequence corresponds to the probability P obtained in the experiment on the study of cumulativeness.

Qualitatively, the value of the coefficient in the range from -1 to 0 can be interpreted as the development of tolerance, 0 - as the absence of dependence between repeated exposures to the substance, from 0 and above - as cumulation (more than 1 - cumulation in the narrow sense of the word). The resulting estimate can be used to determine the potential risk of death from the use of a substance in various doses and terms, or, by setting an acceptable probability, to determine the appropriate modes of administration of the test substance. Obviously, the predictive power of the estimate is limited to a certain area around the point (dose, multiplicity) at which the experimental value is obtained. P in the study of cumulativeness. For example, it is easy to imagine that having determined addiction to ethyl alcohol in a short-term experiment, one should not count on the stability of this quality when exposed to large doses in a long-term experiment.

Cumulation (Late Latin cumulatio accumulation, increase) is an increase in the effect of drugs and poisons when they are repeatedly administered in the same doses.

Distinguish between material and functional cumulation. By material cumulation is meant the accumulation of the active substance in the body, which is confirmed by direct measurement of its concentrations in the blood and tissues. Material cumulation, as a rule, is characteristic of substances that are slowly metabolized and not completely eliminated from the body. In this regard, with repeated injections, if the intervals between them are not long enough, the concentration of such substances gradually increases in the body, which is accompanied by an increase in their effect and can lead to the development of intoxication. Material cumulation often occurs when taking a number of cardiac glycosides (for example, digitoxin), alkaloids (atropine, strychnine), long-acting hypnotics (phenobarbital), indirect anticoagulants (syncumara, etc.), salts of heavy metals (for example, mercury).

The development of material cumulation is facilitated by a decrease in the antitoxic function of the liver and the excretory capacity of the kidneys, which may be due not only to pathological changes in these organs in certain diseases (liver cirrhosis, nephritis, etc.), but also to age-related deviations in their functional activity, for example, in children and the elderly. Sometimes the ability of certain drugs (digital cordial glycosides, amiodarone, etc.) to material cumulation is used for medicinal purposes, prescribing them in relatively high doses at the beginning of treatment in order to ensure the rapid accumulation of active substances in the body at concentrations that have a therapeutic effect, and then switch to the so-called maintenance doses.

Functional cumulation is more characteristic of substances that affect the activity of the central nervous system, and, as a rule, indicates a high sensitivity of the organism to such substances. A classic example of functional cumulation is a mental disorder and personality change in chronic alcoholism and drug addiction. Functional cumulation is also possible when taking antidepressants from the group of monoamine oxidase inhibitors, irreversible anticholinesterase drugs (phosphacol), etc. With functional cumulation, the concentrations of active substances in body media available for measurement do not exceed those after a single administration of the corresponding drugs.

For the prevention of complications associated with the ability of drugs to accumulate, the most important is the correct selection of doses of drugs, the choice of the optimal scheme for their administration, and careful monitoring of the dynamics of functional changes in the body. To prevent possible negative consequences of material cumulation, modern methods of quantitative determination of the content of drugs in the blood and tissues are used.

CUMULATION(lat. cumulatio increase, accumulation) - the accumulation of a biologically active substance (material K.) or the effects caused by it (functional K.) during repeated exposure to medicinal substances and poisons.

Material cumulation characteristic of substances that are slowly excreted and (or) slowly inactivated in the body. At the same time the quantity of the substance entered repeatedly is summed up with that its quantity, a cut remained in an organism from the previous introduction; the total effective dose increases, which leads to an increase in the effect of the substance. The accumulation of a substance in the body in the process of material To. to the level of toxic doses leads to the development of intoxication (see). In almost all cases, when the rate of entry of a substance into the body (high doses, frequent doses) for a sufficiently long time is higher than the rate of its biotransformation and excretion from the body, a cumulative effect of this substance should be expected. Material K. is characteristic of some heavy metals (mercury), rare earth and radioactive elements (iridium, plutonium), many alkaloids (atropine, strychnine), a number of cardiac glycosides (digitalis preparations, etc.), hypnotics (barbital, phenobarbital), anticoagulants (dicumarin), long-acting sulfonamides (sulfadimethoxine), etc. The low rate of release and inactivation of such substances finds quantitative expression in high values ​​of "action time" (t) or "hemicresis" - the time of disappearance from the blood of half of the administered substance (T 50). Since the rate of excretion and neutralization of medicinal substances is not constant, but can significantly decrease with pathology of the liver or kidneys, the likelihood of material K. increases with diseases of these organs. To. medicinal substances is usually undesirable. However, in some cases, for example, when prescribing digitalis preparations (see Digitalis) or indirect anticoagulants (dicumarin, neodicoumarin, etc.), this phenomenon is used to obtain the maximum therapeutic effect in a short time. Thanks to the ability of these funds to material K., it is possible to maintain a stable therapeutic effect for a long time by adjusting the amount of the daily dose.

Functional cumulation proved experimentally for lead preparations, with prolonged exposure to which cats die with symptoms of bulbar paralysis, despite the absence of signs of material K. of these preparations. Delirium tremens in alcoholics is also regarded as a manifestation of functional K. Functional K. is observed, as a rule, with repeated exposure to substances that have an irreversible effect. So, for example, organophosphorus compounds (see) (diisopropylfluorophosphate, etc.) inhibit acetylcholinesterase almost irreversibly (for many hours and days). With repeated exposure to small doses of these substances, the amount of acetylcholinesterase, gradually decreasing, may be insufficient to inactivate synaptic acetylcholine, as a result of which signs of K develop. The action of cytotoxic substances also has features of functional K.

Bibliography: Goldstein A., Aronow L. a. K a 1 m a n S. M. Principles of drug action, p. 326, N.Y., 1974.

I. V. Komissarov.

EFFECTS WITH REPEATED DRUGS

Cumulation (lat. cumulatio- increase, accumulation) - accumulation in the body of drug molecules (material cumulation) or their effects (functional cumulation).

Material cumulation occurs when taking lipophilic drugs with low hepatic and / or renal clearance and a long half-life. In the clinic, it is necessary to take into account the accumulation of phenobarbital, bromides, digitalis digitalis cardiac glycosides (digitoxin, celanide, digoxin), indirect anticoagulants.

Cumulation has both positive and negative meanings. A positive value is associated with the prolongation of the action of drugs, the possibility of their rare use, for example, patients with severe congestive heart failure may not take cardiac glycosides at night. The negative value is due to the risk of intoxication as a result of summing up the dose of the re-introduced drug with its amount remaining from the previous appointment. In order to exclude intoxication, it is necessary to take cumulative agents in a maintenance dose equal to the amount of the drug eliminated per day:

EC - elimination coefficient (percentage of the dose eliminated per day).

Relative material cumulation develops in diseases of the liver and kidneys, as well as in children and the elderly. With liver pathology, cumulation of active metabolites of drugs is possible.

Examples functional cumulation - chronic alcoholism with the abuse of ethyl alcohol; paralysis of the centers of the medulla oblongata with lead poisoning, which occurs after the elimination of the poison from the body.

addiction (tolerance)

Habituation - the weakening of the effects of repeated use of drugs. To resume the therapeutic effect, an increase in the dose is necessary. So, the dose of the tranquilizer sibazon (diazepam), which has an anti-anxiety effect, is usually 5-10 mg / day, against the background of addiction, it increases to 1000 mg / day.

Habituation can be innate or acquired. Congenital (hereditary) addiction is due to enzymopathy. Mutation of the aldehyde dehydrogenase gene disrupts the metabolism of ethyl alcohol. At the same time, the product of ethanol oxidation, acetaldehyde, is not oxidized to acetic acid. The accumulation of acetaldehyde is accompanied by toxic effects, which makes it necessary to refrain from drinking alcoholic beverages.

Acquired addiction is based on pharmacokinetic and pharmacodynamic mechanisms.

Pharmacokinetic mechanisms of addiction

1. Malabsorption

It is known that arsenic anhydride is absorbed from the intestine only in the presence of an alkaline environment of the intestinal juice. With repeated doses, arsenic, causing an inflammatory process (enteritis), creates an acidic environment in the intestines. This reduces the resorptive toxic effect (dogs treated intragastrically for 2 years with arsenic anhydride in small doses tolerate 2.5 g of the toxin without symptoms of poisoning, but its parenteral administration at a dose of 2 mg causes death).

2. Change in the activity of metabolic enzymes

The induction of metabolic transformation enzymes is accompanied by addiction if drugs are converted to inactive products. Inhibition leads to addiction when using prodrugs that require metabolic activation, for example, the depletion of reduced glutathione resources in the vascular endothelium stops the reduction of the -NO 2 group of nitroglycerin into the functional group -NO.

Pharmacodynamic mechanisms of addiction

1. Desensitization (decrease in sensitivity) of cytoreceptors:

Heterologous desensitization - rapid (within milliseconds) phosphorylation of the carboxyl terminal region of cytoreceptors by protein kinases, followed by loss G-proteins and the ability to transmit a signal to effector systems;

Homologous desensitization - slower (within minutes) phosphorylation of the agonist + cytoreceptor complex by a specific kinase with further attachment of arrestin proteins that disrupt the connection of the regulatory domain with G-proteins.

2. Decrease in the number of cytoreceptors (downregulation)

Cytoreceptors disappear due to disruption of gene transcription, mRNA degradation, proteolysis, and sequestration in the cell.

3. Decreased release of neurotransmitters

Cytoreceptor agonists inhibit the release of neurotransmitters according to the principle of negative feedback (narcotic analgesics disrupt the release of endogenous analgesic peptides - enkephalins, β - endorphins and dynorphins).

4. Decreased excitability of sensory nerve endings

This mechanism underlies the addiction to laxatives during their long-term administration.

5. Inclusion of compensatory mechanisms of regulation

The therapeutic effect of antihypertensive drugs is weakened either due to tachycardia and an increase in cardiac output, or due to a deterioration in renal blood flow, a decrease in diuresis and an increase in circulating blood volume.

Learning habituation is known. In such situations, life experience and heightened vigilance can correct behavioral disorders caused by chemicals. Patients with chronic alcoholism learn to walk in a straight line after taking ethyl alcohol, despite functional disorders in the motor sphere.

Tachyphylaxis(gr. tachys- quick, phylaxis- vigilance, protection) is a rapid, within a few hours, addiction to drugs. It is most often caused by the depletion of mediator resources in synaptic endings. The indirect adrenomimetic ephedrine displaces norepinephrine from granules in adrenergic synapses and inhibits its neuronal uptake. This is accompanied by the emptying of the granules and the weakening of the hypertensive effect.

Addiction may not occur simultaneously to different effects of drugs. With prolonged use of phenobarbital, addiction to the hypnotic effect occurs while maintaining the anticonvulsant effect; therapy with tranquilizers is accompanied by a weakening of the muscle relaxant effect, although the anti-anxiety effect does not change.