toxic effect. Influence of various factors on the toxic effect of poisons
As the centuries-old practice of using medicines for the treatment, prevention or diagnosis of human diseases shows, not only have a positive effect on the body, but also have an undesirable effect.
As early as the Renaissance, Paracelsus (1493-1541), professor at the University of Basel, emphasized the importance of the dose of drugs in their action. He argued that "everything is poison, nothing is devoid of poison, only the dose makes the poison invisible." Any attempts of mankind to obtain highly effective and completely harmless drugs have not been successful, because such a goal is contradictory from a biological point of view. Therefore, it is argued that almost all drugs, in addition to a positive effect on the body (and this is their desired effect), under appropriate conditions, are capable of causing certain negative reactions.
Some of them, even in medium therapeutic doses, have a very strong negative effect and can cause severe pathology, even death. Any negative manifestations of the action of drugs are commonly referred to as "adverse reactions" or "side effects". According to WHO recommendations, such a classification of negative effects caused by drugs has been adopted. These are, in particular: side effects, adverse reactions, serious adverse reactions, non-serious adverse reactions, adverse reactions that are envisaged, adverse reactions that are not envisaged, etc. The widespread introduction of a large number of new drugs into medical practice, especially highly active, is accompanied by an increase in the incidence of their side effects, i.e. complications of pharmacotherapy.
WHO data show that in industrialized countries, adverse reactions occur in 10-20%, and in developing countries - in 30-40% of hospitalized patients. Patients who were admitted to inpatient treatment due to side effects of drugs account for 25-28% of the total. The economic losses associated with treatment and other costs due to the side effects of drugs reach, for example, US$77 billion a year in the United States.
In England, side effects account for almost 3% of patients admitted to the intensive care unit. In the hospitals of this country, such effects occur in 10-20% of patients, and in 2-10% of them there is a need to continue treatment. Mortality from such complications reaches 0.3%, and with intravenous use of drugs - 1%. Depending on the mechanisms of occurrence of side effects and the conditions contributing to this, there are:
- adverse reactions of an allergic nature;
- toxic reactions;
- embryotoxic, teratogenic and fetotoxic;
- mutagenic and carcinogenic manifestations.
Adverse reactions of a non-allergic nature
Adverse reactions of a non-allergic nature are reactions that occur when using non-allergenic drugs in therapeutic doses. They constitute an inevitable manifestation of the pharmacological characteristics of drugs (primary pharmacological action) or are a consequence of the corresponding pharmacological effects (secondary pharmacological action).
In particular, drowsiness in patients with epilepsy manifests itself when treated with phenobarbital, respiratory depression - with morphine, hypokalemia - with furosemide, etc. Such reactions occur already in the first hours or days after the start of the use of appropriate drugs for therapeutic purposes, especially in patients with cardiovascular diseases diabetes mellitus, respiratory diseases, malignant tumors, etc.
Often they are caused by cardiac glycosides, antibiotics, cytostatics, potassium preparations, analgesics, glucocorticosteroids. With a decrease in the doses of drugs that caused certain side effects, and even more so after their cancellation, such side effects disappear. Secondary adverse reactions of a non-allergic nature occur later and disappear more slowly. So, antibiotics of a wide antimicrobial spectrum, showing a chemotherapeutic effect, can destroy the saprophytic flora of the intestine, which often leads to the development of polyhypovitaminosis, novocainamide - to systemic lupus erythematosus, chlorpromazine - to drug-induced parkinsonism. In such cases, it is necessary not only to cancel the inducing drug, but also to take measures for aftercare of patients with such complications.
Adverse reactions of a non-allergic nature
Adverse reactions of an allergic nature occur only in people who are sensitized to drugs or their metabolites or to other substances that are part of the dosage form, i.e. in people with the presence in their bodies of the corresponding antibodies. Upon repeated contact with such chemical agents, they interact with these antibodies, resulting in an allergic reaction. Allergic reactions to drugs do not depend on their doses.
They can manifest in various forms and in various degrees of severity - from completely harmless to life-threatening, for example, in the form of anaphylactic shock. This affects mainly the skin, mucous membranes, gastrointestinal tract (GIT), respiratory tract, blood vessels, etc.
Adverse reactions of an allergic nature are eliminated by measures of integral - applied assistance to patients, the mandatory components of which are the use of adrenaline, glucocorticosteroids, H1 blockers - histamine receptors, often in combination with resuscitation measures.
Toxic effects
Toxic effects are negative reactions that occur after the introduction of any drugs into the body in doses exceeding therapeutic ones. So, an overdose of anticoagulants leads to bleeding, insulin - hypoglycemia, morphine - a sharp respiratory depression, etc. The direct cause of such effects is the toxic concentrations of drugs created in the internal environment of the body. The severity of these effects is determined by the degree of overdose, especially those drugs that can cause material cumulation, i.e. cardiac glycosides, long-acting barbiturates, bromides.
The degree of damage to the skin or mucous membrane is also directly proportional to both the concentration of the drug and the duration of its action. So, salts of heavy metals in small concentrations cause only an astringent effect, while in large concentrations they even cause necrosis of the skin, and especially of the mucous membranes or wound surfaces.
Toxic effects also manifest themselves when using drugs in therapeutic doses, in particular, in patients with insufficiency of the organs for neutralizing chemical agents (mainly the liver) and (or) excretory organs (kidneys). In such conditions, especially with long-term treatment, medications stay longer in the body. Their concentration gradually increases to toxic levels. A situation of relative drug overdose is created. Therefore, to prevent toxic effects in people with functional liver and kidney failure, the doses of drugs, as well as the frequency of their intake or administration, are reduced.
A special place among the negative reactions of the body to drugs is occupied by toxic effects that develop in patients with hereditary diseases. In some of these diseases, such as acute drug-induced hemolytic anemia with hemoglobinuria or favism, dozens of drugs, even at moderate therapeutic doses, can cause a severe hemolytic crisis and anemia.
Embryotoxic, teratogenic and fetotoxic reactions
In other hereditary diseases, some drugs cause their exacerbation. Chemical agents, including drugs, can cause long-term negative effects of their action on the body. This, first of all, concerns the reproductive function and the health of the offspring. In particular, they can damage the genital organs (gonadotoxic effect), disrupt the intrauterine development of the body (embryotoxic and fetotoxic effect), even cause various developmental anomalies (teratogenic effect).
Mutagenic action
In addition, long-term side effects of exposure to chemical agents also include damage to the genetic material of cells, resulting in gene mutations (mutagenic effect), etc. Unlike toxic effects, as manifestations of the side effects of drugs, pathological conditions that arise as a result of exposure to chemicals in large, even lethal doses, are of practical importance.
Such substances can cause acute and chronic poisoning of the body. In Ukraine, the control of the safe use of drugs in medical practice is carried out by the Department of Pharmacological Surveillance of the State Pharmacological Center of the Ministry of Health of Ukraine. According to the requirement, doctors of healthcare institutions, regardless of their departmental subordination and forms of ownership, are required to regularly submit information to this center about any side effects of drugs.
Most poisonings are caused by the absorption of a toxic substance and its entry into the blood. Therefore, the most rapid and effective action of the poison is manifested when it is introduced directly into the bloodstream. For example, the use of alcohol or various drugs by a woman during pregnancy has a harmful effect on the child. The fetus is especially sensitive during fetal development to salicylates and alcohol, which can subsequently lead to congenital malformations. During pregnancy, alcohol easily penetrates through the placenta into the blood of the fetus, reaching the same concentration in it as in the blood of the mother, and this is due to the anatomical features of the blood supply to the fetus.
Toxicity (Greek Toxikon - poison) is the most important characteristic of agents and other poisons, which determines their ability to cause pathological changes in the body that lead a person to loss of combat capability (working capacity) or to death.
The toxicity of 0V is quantified by the dose. The dose of a substance that causes a certain toxic effect is called the toxic dose (D)
The toxic dose that causes damage equal in severity depends on the properties of the 0V or poison, the route of their penetration into the body, the type of organism and the conditions for using the 0V or poison.
For substances penetrating the body in a liquid or aerosol state through the skin, gastrointestinal tract or through wounds, the damaging effect for each specific type of organism under stationary conditions depends only on the amount of 0V or poison, which can be expressed in any mass units. In chemistry, 0V is usually expressed in milligrams.
In poisons, they are determined experimentally on various animals, therefore, the concept of specific toxodose is more often used - a dose related to a unit of animal live weight and expressed in milligrams per kilogram.
There are lethal, incapacitating and threshold toxodoses
TOXIC EFFECT
TOXIC EFFECT change in any indicator or vital functions under the influence of toxicant. It depends on the characteristics of the poison, the specifics of the organism and the environment (pH, temperature, etc.).
Ecological encyclopedic dictionary. - Chisinau: Main edition of the Moldavian Soviet Encyclopedia. I.I. Grandpa. 1989
See what "TOXIC EFFECT" is in other dictionaries:
toxic effect- 3.17 toxic effect: The result of the action of a toxicant on an aquatic organism, manifested in a change in its vital signs or death. Source: GOST R 53857 2010: Hazard classification of chemical products by impact ... Dictionary-reference book of terms of normative and technical documentation
I Diffuse toxic goiter (struma diffusa toxica; synonym: Graves' disease, Graves' disease, diffuse thyrotoxic goiter, Parry's disease, Flayani's disease) is a disease of an autoimmune nature, which is based on a genetically determined ... ... Medical Encyclopedia
Diffuse toxic goiter ... Wikipedia
The toxic effect of the action of a medicinal substance resulting from its repeated use in small doses with such intervals between doses that are insufficient either for its splitting or for removing it from the body. ... ... medical terms
I Poisonous plants constantly or periodically contain substances that are toxic to humans and animals. Poisoning can be caused by actually poisonous plants and non-poisonous cultivated plants that acquire toxic properties due to ... ... Medical Encyclopedia
I Poisoning (acute) Poisoning diseases that develop as a result of exogenous exposure to the human or animal body of chemical compounds in quantities that cause violations of physiological functions and endanger life. AT … Medical Encyclopedia
WAR POISON SUBSTANCES- (0. V.). Contents: I. Poisonous substances, their characteristics and combat use....................... 602 II. Pharmacology of poisonous substances. . . 611 III. General tasks and principles of chemical defense .............................. 620 Combat poisons ... ... Big Medical Encyclopedia
poisonous plants- Altai aconite. Altai aconite. Poisonous plants. Poisoning can be caused by actually poisonous plants and non-poisonous cultivated plants that acquire toxic properties due to improper storage or infection with fungi. ... ... First aid - popular encyclopedia
Active ingredient ›› Lamotrigine * (Lamotrigine *) Latin name Lamolep ATX: ›› N03AX09 Lamotrigine Pharmacological group: Antiepileptic drugs Nosological classification (ICD 10) ›› F31 Bipolar affective disorder ... ...
Active ingredient ›› Hydrochlorothiazide* + Irbesartan* (Hydrochlorothiazide* + Irbesartan*) Latin name Coaprovel ATX: ›› C09DA04 Irbesartan in combination with diuretics Pharmacological group: Angiotensin II receptor antagonists (AT1 … Medicine Dictionary
Books
- Honey treats hypertension, conjunctivitis, bedsores and burns, tonsillitis and colds, male and female diseases, Makunin D. Honey is a unique natural remedy! Its beneficial properties have been known for many millennia, and the antiseptic effect has been and is still being used. . Honey can help treat 100…
toxic effect, as already mentioned, it consists of the interaction of at least three main factors - the organism, the toxic substance and the external environment. The biological characteristics of the organism can often play a role.
It's a well known fact different species susceptibility to poisons. This is of particular importance to toxicologists studying toxicity in animal experiments. The transfer of the data obtained to humans is possible only if there is reliable information about the qualitative and quantitative characteristics of the sensitivity of various animal species to the studied poisons, as well as about the individual characteristics of the susceptibility to poisons of individuals, taking into account their gender, age and other differences.
Species differences largely depend on on the characteristics of metabolism. At the same time, it is not so much the quantitative side that is of particular importance, but the qualitative one: the differences in the reactions of various biological structures to the effects of poisons. For example, in response to the inhalation action of benzene, the activity of liver catalase in rats and white mice (having approximately the same quantitative expression) decreases markedly in the former, and does not change in the latter.
A number of other factors are also important. These include: the level of evolutionary complexity of the central nervous system, the development and training of regulatory mechanisms of physiological functions, body size and weight, life expectancy, etc. body. Weight loss usually causes an increase in the toxicity of most harmful substances. Along with species differences in sensitivity individual characteristics are important. The role of nutrition is well known, the qualitative or quantitative deficiency of which adversely affects the course of poisoning. Starvation leads to disruption of many links of natural detoxification, in particular the synthesis of glucuronic acids, which are of major importance in the implementation of conjugation processes.
Undernourished individuals have reduced resistance to the chronic effects of many industrial poisons. Excess nutrition with a high content of lipids leads to an increase in the toxicity of many hydrophobic fat-soluble substances (for example, chlorinated hydrocarbons) due to the possibility of their deposition in adipose tissue and a longer presence in the body.
Somewhat relevant to the problem under consideration is combined action of harmful substances and physical activity , which, exerting a strong influence on many organs and systems of the body, cannot but affect the course of poisoning. However, the final result of this influence depends on many conditions: the nature and intensity of the load, the degree of fatigue, the route of entry of the poison, etc. (hemic) and tissue hypoxia (carbon monoxide, nitrites, cyanides, etc.) or subject to "lethal synthesis" in the body (methyl alcohol, ethylene glycol, FOI).
For other poisons, the biotransformation of which is largely related to their oxidation, strengthening of enzymatic processes can contribute to their faster neutralization (this is known, for example, in relation to ethyl alcohol). It is known that the pathogenic action of poisons is increased during inhalation poisoning due to an increase in pulmonary ventilation and their entry into the body in large quantities in a shorter time (carbon monoxide, carbon tetrachloride, carbon disulfide, etc.). It has also been established that physically trained people are more resistant to the action of many harmful substances. This serves as the basis for the inclusion of physical education and sports in the system of preventive measures in the fight against diseases of chemical etiology.
The influence of the sexual characteristics of the body on the manifestations and nature of the toxic effect in general and in humans in particular has not been studied enough. There is evidence of a great sensitivity of the female body to certain organic poisons, especially in the case of acute poisoning. On the contrary, with chronic poisoning (for example, with metallic mercury), the female body is less sensitive. Thus, the influence of gender on the formation of a toxic effect is not unambiguous: men are more sensitive to some poisons (FOS, nicotine, insulin, etc.), women are more sensitive to others (carbon monoxide, morphine, barbital, etc.). There is no doubt about the increased danger of poisons during pregnancy and menstruation.
The influence of age on the sensitivity of the human body to poisons is different. : some poisons are more toxic for young people, others for old people, and the toxic effect of the third does not depend on age at all. It is widely believed that young and old are more likely to be more sensitive to toxic substances than middle-aged people, especially in acute poisoning. However, this is not always confirmed in the study of age-related sensitivity to the effects of a particular poison. In addition, data on general hospital mortality in acute poisoning in adults (about 8%) and children (about 0.5 ° / o) come into clear conflict with this opinion. The high resistance of the child's body (up to 5 years) to hypoxia is well known. and the expressed sensitivity to it of teenagers and young men, and also old men. With poisoning by toxic substances that cause hypoxia, these differences are especially noticeable. Clinical data on this extremely important issue are presented in Chapter 9.
All of these factors are manifested against the background of individual differences in sensitivity to poisons. It is obvious that the latter is based on "biochemical individuality", the causes and mechanisms of which have been little studied so far. In addition, species, gender, age and individual sensitivity is subject to the inevitable influence of another important factor associated with individual biorhythms.
Fluctuations in various functional indicators of the body are directly related to the intensity of detoxification reactions. For example, in the period from 15 to 3 hours in the liver there is an accumulation of glycogen, and in the period from 3 to 15 hours glycogen is released. The maximum blood sugar content is observed by 9 am, and the minimum by 6 pm. The internal environment of the body in the first half of the day (from 3 to 3 pm) is predominantly acidic, and in the second half (from 15 to 3 am) - alkaline. The content of hemoglobin in the blood is maximum at 11-13 hours, and minimum at 16-18 hours.
Considering the toxic effect as the interaction of the poison, the body and the environment, one cannot ignore the differences in the levels of indicators of the physiological state of the body, due to internal biorhythms. Under the action of hepatotoxic poisons, the most pronounced effect should probably be expected in the evening (18-20 hours), when the content of glycogen in cells and blood sugar is minimal. An increase in the toxicity of "blood poisons" that cause hemic hypoxia should also be expected at the indicated time.
Thus, the study of the activity of the body as a function of time (biochronometry) is directly related to toxicology, since the influence of biorhythms, reflecting the physiological changes in the internal environment of the body, can be a significant factor associated with the toxic effect of poisons.
With prolonged exposure to medicinal and other chemical compounds on the human body in a subtoxic dose, the development of phenomena idiosyncrasies, sensitizations and allergies , as well as "dependence states" (substance abuse).
Idiosyncrasy - a kind of hyperreaction of a given organism to a certain chemical preparation introduced into the body in a subtoxic dose. It is manifested by the symptoms characteristic of the toxic effect of this drug. Such increased sensitivity is probably genetically determined, as it persists throughout the life of a given person and is explained by the individual characteristics of the enzyme or other biochemical systems of the body.
Allergic reaction is determined not so much by the dose as by the state of the body's immune systems and is manifested by typical allergic symptoms (rash, itching, swelling, hyperemia of the skin and mucous membranes, etc.), up to the development of anaphylactic shock. Substances that bind to plasma proteins have the most pronounced antigenic properties.
In the medical literature, the terms "drug side effects" and "drug disease" are often used to refer to lesions caused by the use of pharmacological agents in therapeutic doses. The pathogenesis of these lesions is varied and includes, along with direct side effects caused by the direct pharmacological action and its secondary effects, idiosyncrasy, allergic reactions and drug overdose. The latter is directly related to clinical toxicology and constitutes a special chapter.
With the development of dependence on chemical preparations (toxicomania), its mental and physical variants are distinguished. In the first case, we are talking about the constant use of drugs with a predominantly narcotic effect in order to cause pleasant or unusual sensations. This becomes a necessity for the life of this person, who is forced to continue taking it without any medical indications. The physical variant of substance abuse necessarily includes the development of abstinence - a painful condition with a number of severe psychosomatic disorders directly related to the withdrawal of this drug. The latter most often develops in chronic alcoholism, morphine and barbituric addiction. An important link in the pathogenesis of physical dependence is the development of tolerance (reduced susceptibility) to this drug, which forces the patient to constantly increase its dosage to obtain the usual effect.
A great influence on the realization of the toxicity of poisons has general health . It is known that people who are sick or who have suffered a serious illness, weakened people are much more difficult to tolerate any poisoning. In persons suffering from chronic nervous, cardiovascular and gastrointestinal diseases, poisoning is much more likely to end in death. This is especially noticeable in such adverse situations in patients suffering from diseases of the excretory organs, when a small toxic dose of poison can be fatal. For example, in patients with chronic glomerulonephritis, even non-toxic doses of nephrotoxic poisons (sublimate, ethylene glycol, etc.) cause the development of acute renal failure.
Such an increase in the toxicity of chemicals against the background of acute or chronic diseases corresponding to them in terms of "selective toxicity" of organs or body systems, we call "situational toxicity", which is very widespread in clinical toxicology.
Luzhnikov E. A. Clinical toxicology, 1982
Published in the magazine:
PEDIATRIC PRACTICE, PHARMACOLOGY, June 2006
S.S. POSTNIKOV, MD, Professor, Department of Clinical Pharmacology, Russian State Medical University, Moscow Unfortunately, there are no harmless drugs and, moreover, apparently, there cannot be. Therefore, we continue to talk about the side effects of one of the most prescribed group of drugs - antibacterial agents.
AMINOGLYCOSIDES (AMG)
Aminoglycosides include compounds that contain 2 or more amino sugars linked by a glycosidic bond to the core of the molecule, aminocyclitol.
Most of the first AMGs are natural ABs (fungi of the genus Streptomices and Micromonospore). The newest AMGs - amikacin (a derivative of kanamycin A) and netilmicin (a semi-synthetic derivative of gentamicin) were obtained by chemical modification of natural molecules.
AMHs play an important role in the treatment of infections caused by Gram-negative organisms. All AMGs, both old (streptomycin, neomycin, monomycin, kanamycin) and new ones (gentamicin, tobramycin, sisomycin, amikacin, netilmicin) have a wide spectrum of action, bactericidal activity, similar pharmacokinetic properties, similar features of adverse and toxic reactions (oto- and nephrotoxicity). ) and synergistic interaction with β-lactams (Soyuzpharmacy, 1991).
When administered orally, AMHs are poorly absorbed and are therefore not used to treat infections outside the intestinal tube.
However, AMG can be largely absorbed (especially in newborns) when applied topically from the surface of the body after irrigation or application and have a nephro- and neurotoxic effect (systemic effect).
AMH crosses the placenta, accumulates in the fetus (about 50% of the maternal concentration) with the possible development of total deafness.
NEPHROTOXICITY OF AMH
AMH almost do not undergo biotransformation and are excreted from the body mainly by glomerular filtration. Their reabsorption by the proximal tubules is also indicated. Due to the predominantly renal route of elimination, all representatives of this group of ABs are potentially nephrotoxic(up to the development of tubular necrosis with acute renal failure), only to varying degrees. On this basis, AMH can be arranged in the following order: neomycin > gentamicin > tobramycin > amikacin > netilmicin (E.M. Lukyanova, 2002).
AMH nephrotoxicity (2-10%) develops more often in polar age groups (young children and the elderly) - age-dependent toxic effect. The likelihood of nephrotoxicity also increases with increasing daily dose, duration of treatment (more than 10 days), as well as the frequency of administration, and depends on the previous renal dysfunction.
The most informative indicators of damage to the proximal tubules (a target for the toxic effects of AMH) are the appearance in the urine of microglobulins (β 2 -microglobulin and α 1 -microglobulin), which are normally almost completely reabsorbed and catabolized by the proximal tubules and enzymes (increased levels of N-acetyl-β -glucosaminidase), as well as proteins with a molecular weight of more than 33 KD, which are filtered by the glomeruli. As a rule, these markers are found after 5-7 days of treatment, are moderately pronounced and reversible.
Violation of the nitrogen excretion function of the kidneys as a manifestation of renal failure (an increase in serum urea and creatinine by more than 20%) is detected only with significant kidney damage due to prolonged use of high doses of AMG, potentiation of their nephrotoxicity by loop diuretics and / or amphotericin B.
GENTAMICIN: the kidneys accumulate about 40% of AB distributed in the tissues of the patient (more than 80% of "renal" AB in the renal cortex). In the cortical layer of the kidneys, the concentration of gentamicin exceeds that observed in the blood serum by more than 100 times. It should be emphasized that gentamicin is characterized by a higher degree of tubular reabsorption and greater accumulation in the renal cortex than other AMHs. Gentamicin also accumulates (albeit in smaller amounts) in the medulla and papillae of the kidneys.
Gentamicin, absorbed by the proximal tubules of the kidneys, accumulates in the lysosomes of cells. Being in cells, it inhibits lysosomal phospholipase and sphingomyelinase, which causes lysosomal phospholipidosis, accumulation of myeloid particles and cellular necrosis. An electron microscopic study in the experiment and a biopsy of the kidneys in humans revealed swelling of the proximal tubules, the disappearance of the villi of the brush border, changes in intracellular organelles with the introduction of gentamicin in average therapeutic doses. Treatment with high (>7 mg/kg per day) doses of gentamicin may be accompanied by acute tubular necrosis with the development of acute renal failure and the need for hemodialysis in some cases, the duration of the oliguric phase is about 10 days, while, as a rule, there is a complete recovery of kidney function after discontinuation of the drug.
Factors that increase the possibility of gentamicin nephrotoxicity include: previous kidney failure, hypovolemia, simultaneous use of other nephrotoxic drugs (hydrocortisone, indomethacin, furosemide and ethacrynic acid, cephaloridine, cyclosporine, amphotericin B), radiopaque substances; patient's age.
The incidence of nephrotoxic reactions during treatment with gentamicin varies from 10-12 to 25% and even 40%, depending on the dose and duration of treatment. These reactions are more often observed at the maximum concentration of AB in the blood of 12-15 µg/ml. However, the expediency of determining the minimum (residual) concentrations is emphasized, since an increase in these values above 1-2 μg / ml before each subsequent administration is evidence of drug accumulation and, therefore, possible nephrotoxicity. Hence the need for drug monitoring for AMH.
OTOTOXICITY OF AMH
When using streptomycin, gentamicin, tobramycin, vestibular disorders often occur, and kanamycin and its derivative amikacin mainly affect hearing. However, this selectivity is purely relative and all AMGs have a "wide" spectrum of ototoxicity. Thus, gentamicin penetrates and persists for a long time in the fluid of the inner ear, in the cells of the auditory and vestibular apparatus. Its concentration in the endo- and perilymph is significantly higher than in other organs and approaches the blood concentration, and at the level of 1 μg / ml it remains there for 15 days after stopping treatment, causing degenerative changes in the outer cells of the ciliated epithelium of the main gyrus of the cochlea (Yu .B.Belousov, S.M.Shatunov, 2001). In the clinical picture, these changes correspond to hearing impairment within high tones, and as degeneration progresses to the apex of the cochlea, also medium and low tones. Early reversible manifestations of vestibular disorders (after 3-5 days from the start of the drug) include: dizziness, tinnitus, nystagmus, impaired coordination. With prolonged use of AMG (more than 2-3 weeks), their excretion from the body slows down with an increase in concentration in the inner ear, as a result of which severe disabling changes in the organs of hearing and balance can develop. However, in the case of gentamicin, there was no sufficient correlation between its concentration in the inner ear and the degree of ototoxicity, and, unlike kanamycin, monomycin and neomycin, deafness practically does not develop during treatment with gentamicin. At the same time, there are marked variations among AMH in the incidence of these disorders. So, in one study on 10,000 patients, it was found that amikacin causes hearing loss in 13.9% of cases, gentamicin in 8.3% of patients, tobramycin in 6.3%, and neomycin in 2.4%. The frequency of vestibular disorders is 2.8, respectively; 3.2; 3.5 and 1.4%.
Ototoxic reactions during treatment with gentamicin develop much less frequently in adults than in children. Theoretically, newborns are at increased risk for the development of ototoxic reactions due to the immaturity of elimination mechanisms and a lower glomerular filtration rate. However, despite the widespread use of gentamicin in pregnant women and newborns, neonatal ototoxicity is extremely rare.
Auditory and vestibular toxic effects of tobramycin are also associated with its overdose, duration of treatment (>10 days) and patient characteristics - impaired renal function, dehydration, receiving other drugs that also have ototoxicity or hinder the elimination of AMH.
In some patients, ototoxicity may not manifest itself clinically, in other cases, patients experience dizziness, tinnitus, loss of acuity of perception of high tones as ototoxicity progresses. Signs of ototoxicity usually begin to appear long after discontinuation of the drug - a delayed effect. However, a case is known (V.S. Moiseev, 1995) when ototoxicity developed after a single injection of tobramycin.
AMIKACIN. The presence in the 1st position of the amikacin molecule - 4-amino-2-hydroxybutyryl-butyric acid provides not only protection of AB from the destructive action of most enzymes produced by resistant bacterial strains, but also causes less ototoxicity compared to other AMGs (except methylmycin) : auditory - 5%, vestibular - 0.65% per 1500 treated with this AB. However, in another series of studies (10,000 patients) controlled by audiometry, a frequency of hearing disorders close to gentamicin was shown, although in the experiment it was found that amikacin, like other AMGs, penetrates into the inner ear and causes degenerative changes in hair cells, however, as in the case of gentamicin, there was no relationship between the concentration of amikacin in the inner ear and the degree of ototoxicity. It was also shown that the hair cells of the auditory and vestibular system survived despite the fact that gentamicin was found inside the cells and 11 months after the cessation of treatment. This proves that there is no simple correlation between the presence of AMH and damage to the organs of hearing and balance. That is why it was suggested that some patients have a genetic predisposition to the damaging effects of AMH (MG Abakarov, 2003). This position was confirmed by the discovery in 1993 in 15 patients with hearing loss from 3 Chinese families (after AMG treatment) of the genetic mutation A1555G of the 12S RNA position encoding mitochondrial enzymes, which was not detected in 278 patients without hearing loss who also received AMG. This led to the conclusion that the use of AMH is a trigger for the phenotypic detection of this mutation.
In recent years, a new dosing regimen for AMH has become increasingly popular - a single administration of the entire daily dose of gentamicin (7 mg/kg) or tobramycin (1 mg/kg) as a 30-60-minute infusion. This proceeds from the fact that AMHs have a concentration-dependent bactericidal effect and therefore the ratio Cmax / mic > 10 is an adequate predictor of the clinical and bacteriological effect.
The effectiveness of the new method of AMH administration was shown in infections of various localization - abdominal, respiratory, genitourinary, skin and soft tissue, both acute and chronic (cystic fibrosis). However, the peak concentrations of AMH that occur with this dosing regimen, often exceeding 20 μg / ml, can theoretically create a threat of nephro- and ototoxicity. Meanwhile, studies by D. Nicolau, 1995; K. Kruger, 2001; T. Schroeter et al, 2001 show that a single administration of AMH is not only not inferior, but even superior in safety to the usual 3-time use of AMH, possibly due to a longer washout period.
TETRACYCLINES
Tetracyclines - osteotropic and therefore accumulate in bone tissue, especially young, proliferating. In the experiment in dogs, tetracycline deposition was also noted in permanent teeth.
Due to their lipophilicity, tetracyclines penetrate the placental barrier and are deposited in the bones of the fetus (in the form of chelate complexes with calcium devoid of biological activity), which may be accompanied by a slowdown in their growth.
The use of tetracycline antibiotics in preschool children in some cases leads to the deposition of drugs in tooth enamel and dentin, which causes hypomineralization of teeth, their darkening (discoloration), hypoplasia of tooth enamel, an increase in the frequency of caries, and tooth loss. The incidence of these complications in the use of tetracyclines is approximately 20%.
In case of careless or erroneous use of tetracyclines in a large dose (more than 2 g per day), tubulotoxicity(tubular necrosis) with acute renal failure and the need, in some cases, hemodialysis.
Therefore, the use of tetracyclines in pregnant women, breastfeeding (tetracycline passes into breast milk) and children under 8 years of age is not recommended.
Summing up the above, I would like to emphasize once again that any medicine (and therefore antibiotics) is a double-edged weapon, which, by the way, was noticed and reflected in the Old Russian definition, where the word "potion" was used in a double meaning - and as a healing, and as a poison. Therefore, starting pharmacotherapy, one should not leave the patient alone with the medicine in the future, telling him (as is often the case in the same clinic) "drink it (the medicine) for a week or two and then come back." For some patients, this "later" may not come. By emphasizing the therapeutic effect in our medical consciousness, we (perhaps unwittingly ourselves) diminish the importance of another important rule of treatment - its safety. This loss of vigilance makes us unprepared to act when adverse reactions occur, which can sometimes lead to irreparable consequences.
