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4.1. TERMINOLOGY OF SIDE EFFECTS OF DRUGS

Side effect according to the definition of the World Health Organization (WHO), any unintended effect of a pharmaceutical product (drug) that develops when used in humans in normal doses and is caused by its pharmacological properties.

Adverse drug reactions, according to WHO, - harmful, dangerous reactions for the body that develop unintentionally when taking drugs in doses that are used in humans for the prevention, diagnosis and (or) treatment of diseases, as well as for the correction and modification of physiological functions.

The difference between the concepts is that the occurrence of a side effect is associated with the pharmacological properties of the drug (for example, a pronounced decrease in blood pressure after taking an antihypertensive drug) and can be both favorable and unfavorable, while an adverse reaction does not depend on its pharmacological properties (for example, the development agranulocytosis after taking metamizole sodium).

The WHO definition, used for 30 years, is updated to take into account the severity of adverse reactions to drugs, as well as reactions to contaminants (for example, in herbal medicines) and presumably inactive excipients (for example, preservatives), according to Ralph Edwards and Jeffrey K. Aronson ( 2000), may be as follows: adverse reactions or adverse drug reactions - harmful reactions resulting from an intervention associated with the use of a medicinal product that makes continued use dangerous and requires prophylaxis, or specific treatment, or a change in dosage regimen, or discontinuation of the drug.

The terms “adverse reactions” (adverse reactions - adverse reactions) and "side effects" (adverse effects - adverse effect) are interchangeable, except that reactions are spoken of from the patient's point of view, and effects are spoken of from the point of view of the drug.

Emerging adverse drug reactions should be distinguished from toxic effects that develop as a result of exceeding the dose of the drug and do not occur at commonly used therapeutic doses. It should be noted that the severity of toxic effects is dose-dependent (for example, a headache when using calcium antagonists is a toxic effect).

4.2. EPIDEMIOLOGY OF SIDE EFFECTS

The risk of side effects when using different drugs varies significantly. Thus, when using nystatin or hydroxocobalamin, the risk of side effects is practically zero, and when using immunosuppressants or cytostatic drugs, it increases to high values.

Every year the number of people who cannot tolerate one to several drugs increases. The frequency of adverse reactions and their severity depend on the individual characteristics of the patient, his gender and age, the severity of the underlying and concomitant diseases, the pharmacodynamic and pharmacokinetic characteristics of the drug, its dose, duration of use, routes of administration, as well as drug interactions. One of the reasons for the increase in the number of side effects is the frequent irrational and unjustified use of drugs. It has been shown that only in 13-14% of cases the use of drugs is justified. In addition, the increasing prevalence of self-medication contributes to the increase in drug complications.

It is believed that side effects occur in 4-29% of patients receiving various drugs, but only 4-6% of patients consult a doctor about this. Of those who applied, 0.3-2.4% should be hospitalized due to side effects that have developed, of which 3% require emergency measures in intensive care units. In the United States, adverse reactions are the only reason for 0.4% of all clinic visits. Almost 85% of this number of requests for medical help ends in temporary disability; the rest, as mentioned above, require hospitalization. As a result of complications of drug therapy, approximately 80 million additional prescriptions for corrective therapy are written.

When using certain groups of drugs in outpatient practice: cardiac glycosides, hormones, antihypertensive drugs, direct and indirect anticoagulants, some diuretics, antibiotics, NSAIDs, oral contraceptives - side effects

effects develop much more often. Among the side effects in outpatient settings, allergic reactions occur most often. Glucocorticoids can cause about 40 side effects. And taking NSAIDs (including acetylsalicylic acid) in doses recommended for the prevention of coronary thrombosis and myocardial infarction can cause hematopoietic disorders, severe skin lesions in 1-2% of patients, and in 8% of patients - ulceration of the mucous membrane and bleeding from the upper sections Gastrointestinal tract. In the United States, 50-150 patients per 100 thousand people are hospitalized annually with such bleeding, and in 10% of them, drug side effects lead to death. According to American scientists, long-term use of oral contraceptives by smoking women over 40 years of age significantly increases the risk of developing myocardial infarction compared to younger women (from 7 to 185 cases per 100 thousand people per year). In addition, the incidence of strokes and thromboembolism increases in such women.

According to domestic data, among patients in a hospital, adverse reactions to drugs occur in 17-30% of cases (in the USA this percentage is slightly lower and amounts to 10-20%); in 3-14% of them this causes a longer hospital stay (according to foreign sources, this figure is close to 50%).

In most cases, the development of side effects in inpatients is caused by the use of antibiotics (up to 25-30% of all side effects), chemotherapeutic agents, analgesics, psychotropic drugs, cardiac glycosides, diuretics and hypoglycemic drugs, sulfonamides and potassium preparations. Most often, allergic reactions occur in the hospital, manifested by damage to the skin (up to 20-25%). However, of the total number of undesirable effects, 75-80% are non-allergic reactions, about which doctors are much less informed. These include liver damage, thrombosis and thromboembolism, disorders of hematopoiesis and blood clotting, gastrointestinal damage, mental disorders, changes in the concentrations of potassium and sodium ions in the blood plasma, anaphylactic reactions.

The most common drug complications occur in patients at risk:

Patients with liver and kidney diseases;

Patients who simultaneously take several drugs, which leads to their uncontrolled interaction;

Persons receiving drugs with a “narrow” therapeutic scope;

Children and elderly patients.

Pharmacoepidemiological studies conducted in Scotland and the UK showed that the prevalence of drug complications among gerontological patients is close to 16%. In the elderly and senile age, self-medication and the use of large quantities of drugs (sometimes unreasonably) for a long time are widespread against the background of age-related changes in the functions of organs and systems of the body and a decrease in the volume of distribution of drugs. Studies have shown that simultaneous use of 2-5 drugs leads to the development of drug interactions in 4% of cases, and when taking 20 drugs - in 40-54%. Another reason for the frequent development of side effects in older people is the pharmacodynamics of drugs in different age periods due to different sensitivity of receptors. The literature describes a decrease in the sensitivity of elderly patients to the action of β-adrenergic blockers and β 2 -adrenergic agonists, which is due to a proven decrease in the number of β-adrenergic receptors and their affinity with age; at the same time, the number and affinity of α-adrenergic and cholinergic receptors remains virtually unchanged. Due to the fact that approximately half of all older people take psychotropic drugs with anticoagulants or antiplatelet agents, the main side effects are hemorrhagic complications and gastrointestinal disorders (weakened motility, ulceration). Thus, in order to prevent the development of side effects, elderly and senile patients must be prescribed a lower dose of drugs (sometimes 1.5-2 times) compared to that used to treat young patients.

In the United States, side effects of drugs in children develop much more often than in adults, amounting to approximately 13%, and in children under 3 years of age - almost 30% of cases. About 21% of the total number of children hospitalized suffer from drug complications.

With special care and thoroughness, it is necessary to select drug therapy (if necessary) for pregnant women, especially if the drugs have a teratogenic effect (see Chapter 6).

Side effects cause deaths in approximately 0.1-0.24% of cases, and one out of four deaths in a hospital is associated with drug complications, varying in the mechanism of development, pathological changes and clinical manifestations. Epidemiological studies in the USA have shown that in terms of the frequency of deaths in the overall mortality structure, drug complications occupy fourth place after mortality from cardiovascular diseases, malignant tumors,

lei and strokes and claim more than 100,000 lives per year. According to a meta-analysis conducted in the United States, side effects of drug therapy rank 5th-6th among the causes of death in hospitalized patients.

Lethal outcomes from taking drugs in patients who were treated in a hospital most often occur due to:

Gastrointestinal bleeding and complications of peptic ulcers (when using glucocorticoids, NSAIDs, anticoagulants);

Other bleeding (when using cytostatics);

Aplastic anemia and agranulocytosis (with the prescription of chloramphenicol, cytostatics, gold preparations, some NSAIDs);

Liver damage (among 200 drugs that can cause damage to this organ, anti-tuberculosis and psychotropic drugs, cytostatics, tetracycline are most often mentioned);

Anaphylactic shock that developed after the administration of antibacterial drugs (especially the penicillin group) and procaine (novocaine *);

Kidney damage (when using NSAIDs, aminoglycosides);

Reduced resistance to infections due to the use of drugs that have an immunosuppressive effect (cytostatics, glucocorticoids).

Adverse side effects are not only a serious medical and social problem, but also an economic problem. The cost of complications of drug therapy in the USA is estimated at 4.2 billion dollars annually, in Switzerland - 70-100 million Swiss francs. Costs associated with drug complications account for 5.5-17% of total healthcare costs. According to American researchers, the average length of hospital stay for a patient with a side effect of a drug is 10.6 days versus the corresponding figure in the absence of side effects of 6.8 days.

A third of all side effects are potentially preventable complications, that is, those that can be avoided under conditions of rational use of drugs.

4.3. CLASSIFICATION OF SIDE EFFECTS

MEDICINES

Among the mechanisms for the development of unwanted side effects, 4 main ones can be distinguished.

Direct toxic effect a drug that damages cells and tissues of the body and is dose-dependent (for example, the damaging effect of NSAIDs on the gastrointestinal mucosa).

Pharmacokinetic mechanism- an important role is played by factors that change the pharmacokinetics of drugs, promote the accumulation of drugs in the body and/or slow down their breakdown to inactive metabolites. (For example, digitalis intoxication occurs relatively rarely, but in patients with impaired metabolism and excretion of digoxin, the risk of intoxication increases several times.)

Pharmacodynamic mechanism realized through receptors or targets located in various organs and systems. For example, by inhibiting cyclooxygenase, NSAIDs, on the one hand, reduce the severity of the inflammatory process (direct effect), and on the other, prevent the excretion of sodium and water in the kidneys (pharmacodynamic undesirable effect), leading to the development of heart failure.

The pharmacodynamic mechanism may be influenced by the condition of the patient's body: for example, in elderly patients, sensitivity to the action of β-adrenergic blockers and β 2 -adrenergic agonists decreases as a result of a decrease in the number of β-adrenergic receptors and their affinity with age.

Undesirable effects that occur when drug interactions: in particular, with the simultaneous administration of terfenadine and erythromycin, the interval on the patient’s electrocardiogram lengthens Q-T, which can lead to heart rhythm disturbances. The reason for this phenomenon is the slowdown in the metabolism of terfenadine in the liver under the influence of erythromycin.

It is worth noting the important role of pharmacogenetic mechanisms in the formation of unwanted side effects of drugs. Various inherited changes in genes (allelic variants) can lead to disturbances in the pharmacokinetics and/or pharmacodynamics of drugs. As a result, the pharmacological response also changes, including the development of unwanted side effects.

Several classifications of side effects have been developed. First of all, side effects can be divided into:

projected- caused by the pharmacological action of drugs, dose-dependent, accounting for 80% of all cases of side effects that can develop in any person;

unpredictable- not related to the pharmacological action of drugs, not dose-dependent, relatively rarely developing, caused in most cases by changes in immunoge-

caused by environmental factors and occurring in susceptible individuals.

Predicted side effects of drugs have a certain clinical picture, for example, a hypotensive effect when taking β-blockers, Parkinson's syndrome when taking a course of chlorpromazine (aminazine*) or reserpine, and arterial hypertension when taking glucocorticoids. With unpredictable side effects, the clinical picture develops unpredictably and different patients may develop different reactions to the same drug, which is likely due to the genetic characteristics of individuals.

By the nature of occurrence, side effects are divided into direct and indirect, and by localization - into local and systemic.

In clinical practice, side effects are divided according to their course into:

sharp forms- develop during the first 60 minutes after taking the drug (anaphylactic shock, severe bronchospasm, acute hemolytic anemia, Quincke's edema, vasomotor rhinitis, nausea and vomiting);

subacute forms- develop 1-24 hours after taking the drug (maculopapular exanthema, serum sickness, allergic vasculitis, colitis and diarrhea associated with taking antibiotics, agranulocytosis and thrombocytopenia);

latent forms- occur 2 days or more after taking the drug (eczematous rashes, organ toxicity).

Based on the severity of the clinical course, the following groups of adverse reactions are distinguished.

Mild reactions: skin itching, urticaria, perversion of taste. These are fairly stable manifestations; when they appear, there is no need to discontinue the drug. Side effects disappear when the dose of the drug is reduced or after short-term administration of antihistamines.

Reactions of moderate severity - Quincke's edema, eczematous dermatitis, erythema multiforme, mono or polyarthritis, toxicoallergic myocarditis, fever, hypokalemia. When they appear, it is necessary to change the therapy, discontinue the drug and carry out specific treatment with glucocorticoids at an average dose of 20-40 mg/day for 4-5 days in a hospital setting.

Severe reactions - conditions that threaten life or prolong the patient’s stay in the hospital; anaphylactic shock, exfoliative dermatitis, Lyell's syndrome with damage to internal organs - myocarditis, nephrotic

syndrome. If such reactions occur, it is necessary to discontinue the drug and simultaneously prescribe glucocorticoids, immunomodulators and antihistamines for 7-10 days.

Deadly reactions.

Undesirable side effects are also divided into serious and non-serious. According to WHO definition, to serious complications Drug therapy includes cases that result in death, or there is a threat to life, or hospitalization follows (or is prolonged), and/or persistent decline or loss of ability to work, and/or congenital anomaly. According to the FDA, to serious complications Drug therapy also includes cases requiring surgical treatment to prevent permanent decline or loss of ability to work. According to a meta-analysis based on 39 studies in the United States, serious side effects account for about 7% of all drug complications. Every year, serious side effects of drug therapy are reported in more than 20 million patients in the United States.

According to the clinical classification, there are:

general body reactions- anaphylactic shock, Quincke's edema, hemorrhagic syndrome;

damage to the skin and mucous membranes- Lyell's syndrome, Stevens-Johnson syndrome, Arthus phenomenon;

respiratory tract damage- allergic reactions, bronchial asthma, allergic pleurisy and pneumonia, pulmonary edema;

damage to the cardiovascular system- cardiac conduction disorders, toxic myocarditis.

Below is one of the most common classifications of side effects (according to WHO), taking into account the mechanisms of development, time of occurrence and clinical features.

Type A - predicted (predictable) effects.

Primary toxic reactions or drug overdose (for example, liver failure when prescribing paracetamol in high doses).

Actually side effects and delayed reactions (for example, sedative effects of antihistamines).

Secondary effects (for example, diarrhea when prescribed antibiotics due to suppression of intestinal flora).

Drug interactions (for example, theophylline poisoning while taking erythromycin).

Type B - unpredictable (unpredictable) effects.

Individual drug intolerance is an undesirable effect caused by the pharmacological action of drugs in therapy.

tic or subtherapeutic doses (for example, tinnitus when taking aspirin).

Idiosyncrasy (for example, hemolytic anemia when taking antioxidants in patients with glucose-6-phosphate dehydrogenase deficiency without connection with immunological reactions).

Hypersensitivity or allergy (for example, the development of anaphylaxis when taking penicillin due to immune mechanisms).

Pseudoallergic reactions (for example, non-immunological reactions to radiocontrast agents).

Type C - “chemical” effects that develop with long-term use of drugs: for example, benzodiazepine dependence or nephropathy when taking metamizole sodium (analgin*), secondary adrenal insufficiency when using systemic glucocorticoids, manifestations of chronic toxicity when taking chloroquine (retino- and keratopathy).

Type D - delayed (long-term) effects (reproductive dysfunction, teratogenic and carcinogenic reactions: vaginal adenocarcinoma in daughters of women who used diethylstilbestrol during pregnancy; lymphoma in patients with long-term immunosuppression after transplantation. Withdrawal syndrome, for example, after taking clonidine, opiates, β-blockers).

Type E - unpredictable treatment failure (reduced effectiveness of oral contraceptives with simultaneous administration of inducers of microsomal liver enzymes).

Up to 75% of all side effects are type A reactions (dose-dependent reactions), more than 20% are complications of drug treatment type B (dose-independent reactions), which are also characterized by the highest mortality, less than 5% are complications of other types.

Toxic reactions.

An absolute increase in drug concentrations - overdose

Relative increase in drug concentrations:

■ genetically determined changes in the pharmacokinetics (absorption, metabolism, excretion) and pharmacodynamics (changes in target molecules) of drugs;

■ non-genetically determined changes in pharmacokinetics (concomitant pathology of the liver, kidneys, thyroid gland;

les, gastrointestinal tract, interaction with simultaneous prescription of several drugs) and pharmacodynamics (impaired receptor sensitivity - development of status asthmaticus with uncontrolled excessive intake of inhaled β-adrenergic agonists) of drugs.

Long-term reactions that do not occur against the background of a significant change in drug concentrations (teratogenic and carcinogenic effects).

Effects caused by the pharmacological properties of drugs.

Direct adverse pharmacodynamic effects (ulcerogenic effect of NSAIDs and glucocorticoids, orthostatic reactions after taking ganglion blockers, peripheral vascular spasm after taking β-blockers - Raynaud's syndrome).

Indirect adverse pharmacodynamic effects:

■ superinfection and dysbiosis (diarrhea when antibacterial agents and cytostatics are prescribed);

■ bacteriolysis (Jarisch-Herxheimer reaction when antibiotics are prescribed);

■ withdrawal syndrome (development of severe hypertensive crises with abrupt withdrawal of clonidine and β-blockers);

■ drug dependence.

Truly allergic reactions.

Mediator or reagin type.

Cytotoxic type.

Immunocomplex type.

Delayed hypersensitivity.

Pseudoallergic reactions (an attack of bronchial asthma when using cholinomimetic drugs due to significant release of histamine).

Idiosyncrasy- a genetically determined, pharmacologically perverted response to the first administration of a drug.

Psychogenic side effects (headache, hot flashes, sweating).

Iatrogenic side effects (reactions that occur when drugs are administered incorrectly, for example, the development of embolism during intravenous administration of penicillin depot preparations, polypharmacy).

Sometimes one drug can cause several side effects that differ in the mechanism of development. For example, both toxic reactions and reactions can develop to sulfonamides.

due to their pharmacological properties - cytotoxicity and allergies (erythema multiforme, urticaria, erosive ectodermosis - Stevens-Johnson syndrome, toxic epidermal necrolysis - Lyell's syndrome).

We should not forget that some manifestations characteristic of side effects (for example, Lyell's syndrome - in 50% of cases) are clinical symptoms of other somatic diseases (neoplasia, autoimmune diseases).

4.4. TOXIC EFFECTS

The toxic effects of drugs are quite common in clinical practice. An absolute overdose of drugs is caused by the fact that the recommended doses are aimed at the average person (60 kg), and when prescribing they do not take into account individual body weight, provided that they are taken 3-4 times. Intoxication in this case is directly related to the pharmacological properties of the drug.

In other cases, an overdose is a consequence of the deliberate administration of drugs in large doses. For example, parenteral administration of benzylpenicillin in high doses (more than 200 million units/day) to patients with sepsis leads to the development of confusion and epileptiform seizures due to the introduction of a large amount of potassium with the drug and the development of hyponatremia.

The risk of developing toxic effects is especially high for drugs with a low therapeutic index, when the difference between doses that have a therapeutic and toxic effect is small. Among antibiotics, streptomycin, kanamycin, and neomycin have a low therapeutic index. Other drugs include warfarin, insulin, digoxin, theophylline, phenytoin, carbamazepine, lithium preparations, and antiarrhythmic drugs.

Toxic effects that occur when using drugs in therapeutic doses may be associated with genetically determined pharmacokinetic characteristics of the drug in a given patient. It is known that the risk group for the development of pseudolupus nephritis includes patients with a low rate of acetylation (“slow acetylators”), taking procainamide (procainamide*) or hydralazine (apressin*). Genetic changes leading to an increase in the concentration of drugs in plasma also manifest themselves at the level of oxidative metabolism: the activity of isoenzymes of the microsomal oxidative system of cytochromes P-450 of the liver, intestines, and lungs is reduced.

Concomitant diseases can contribute to drug toxicity. For example, for liver diseases:

Reduced metabolic rate (antiarrhythmic drugs, etc.);

The detoxification function of the organ is inhibited;

The synthesis of free radicals increases, triggering oxidation reactions with the formation of peroxides and hydroperoxides;

Albumin synthesis is suppressed, resulting in high toxicity of drugs that normally have a high percentage of binding to plasma proteins.

Slowing down the elimination of drugs from the body and, accordingly, its accumulation is facilitated by diseases not only of the liver, but also of the kidneys. Severe heart failure leads to a noticeable decrease in excretion due to impaired blood flow in the liver and kidneys (for example, digoxin accumulates in patients suffering from this pathology). A decrease in the functional activity of the thyroid gland can lead to a change in metabolic rate with the development of side effects.

Increased drug absorption can also cause side effects. Thus, taking nifedipine on an empty stomach leads to rapid absorption and the achievement of a peak concentration of the drug in the blood plasma, which is manifested by headache and redness of the skin.

The toxicity of drugs is very often due to their interaction (see chapter “Drug Interactions”), and may be associated with polypharmacy without taking into account possible mutual influence.

Changes in the sensitivity of tissue receptors to drugs are an important reason for the development of side effects. For example, increased sensitivity of the myocardium to epinephrine (adrenaline *) during cyclopropane or fluorotane anesthesia can cause serious cardiac arrhythmias. Depletion of potassium reserves in the body during long-term treatment with diuretics increases the sensitivity of the myocardium to cardiac glycosides.

There are drugs that have specific toxicity to a particular organ, but most drugs have a toxic effect on several organs and systems simultaneously. These drugs include aminoglycoside antibiotics that have nephro-, oto-, and neurotoxicity. Their nephrotoxic effect occurs due to the accumulation of the drug in the proximal renal tubules and damage to the renal epithelium in these sections, manifested by a slowdown in glomerular filtration and the formation of renal failure. The use of aminoglycosides is the cause of the development of induced renal failure approximately

in 45-50% of all cases. It has been proven that nephrotoxicity of aminoglycosides is dose-dependent, and the risk of its development decreases with their single use during the day. Ototoxicity is manifested by decreased hearing up to complete deafness due to the accumulation of the drug in the fluid of the inner ear (endolymph). In addition, vestibulotoxicity (dizziness, nausea, vomiting, nystagmus, imbalance) may occur simultaneously. Fluoroquinolones are most characterized by side effects from the gastrointestinal tract, occurring in 2-3% of cases (nausea, diarrhea, vomiting, increased concentration of hepatic transpeptidases in the blood), less often the central nervous system is affected (headache, stupor, dizziness), nephro- (development interstitial nephritis) and cardiotoxic lesions: heart rhythm disturbances, prolongation of the interval Q-T with electrocardiography (ECG).

Teratogenic and oncogenic effects are most often caused by drugs that have a cytotoxic effect. Drug teratogenesis can be the result of suppression of reproductive function, disruption of embryogenesis at different stages, drug fetopathy, as well as a consequence of the use of certain drugs in the neonatal period. The following types of teratogenic pathology are classified: chromosomal, monogenic hereditary, polygenic multifactorial and exogenous disorders. The use of drugs is caused by the last two forms, which account for about 80% of all teratogenic pathology. According to the mechanism of development of the teratogenic effect, drugs are divided into substances with a direct toxic effect on the fetus and drugs that disrupt the metabolism of folic acid and hormones. Medicinal drugs that have a teratogenic effect include the following groups:

Vitamin antagonists;

Amino acid antagonists;

Hormones (androgens, progesterone, adrenocorticotropic hormone, glucocorticoids);

Antimitotic agents (colchicine);

Antibiotics (tetracycline, streptomycin);

Antitumor (mercaptopurine, 6-hydroxypurine*, thioguanine);

Iodine preparations, phenindione (phenilin *), chlorpromazine (aminazine *);

Barbiturates;

Ergot alkaloids.

According to WHO, up to 25% of developmental anomalies are caused by genetic changes. Under the influence of the above drugs, gene genes arise (changes in the number or order of nitrogenous bases)

in a gene), chromosomal (changes in position, insertion or deletion of a chromosome section) and genomic mutations (increase or decrease in the total number of chromosomes).

Exposure to teratogenic substances at the stages of organogenesis leads to the development of embryopathies, exposure in late stages of development leads to early (structural and functional immaturity of organs incompatible with fetal life is detected) or late fetopathy (damage to normally formed and developed organs). Thus, the use of teratogenic substances in the first 2 weeks of pregnancy leads to miscarriage, and in subsequent periods - to underdevelopment of internal organs.

Disorders of folic acid metabolism can cause abnormalities in the formation of the skull (for example, with the use of methotrexate), and hormonal drugs can cause masculinization of female children. Taking barbiturates can lead to pathologies of the heart, gastrointestinal tract and genitourinary tract, strabismus, and the formation of a cleft palate.

It is necessary to use drugs with special caution in nursing mothers due to the threat of possible development of functional teratogenic effects. Among this group of drugs, the most dangerous are antimetabolites (cytostatics), anticoagulants, ergot preparations, thyreostatics, iodine and bromine preparations, and antibiotics.

Data regarding carcinogenesis are still controversial. It has been proven that long-term use of estrogens by women during menopause increases the risk of developing endometrial cancer by 4-8 times, and taking immunosuppressants increases the risk of developing lymphoma, sarcoma, and lip skin cancer several times.

The main drugs that induce the development of neoplasia include radioisotope drugs (phosphorus, thorrotrast*), cytostatics (chloronaphthazine*, cyclophosphamide), hormonal drugs, as well as arsenic, phenacetin, chloramphenicol and some other drugs. Thus, cyclophosphamide increases the likelihood of developing bladder cancer. Oral contraceptives have a blastomogenic effect on the liver, resulting in the formation of either an adenoma or nodular hyperplasia.

All drugs are studied for teratogenicity and oncogenicity, but the results of animal experiments do not allow us to accurately assess the risk of congenital anomalies and tumors when using these drugs in humans.

4.5. SIDE EFFECTS DUE TO PHARMACOLOGICAL PROPERTIES OF DRUGS

Some of the most common side effects of drugs used in therapeutic doses are reactions caused by the pharmacological properties of the drug itself. For example, headache, nausea, dry mouth and double vision occur with tricyclic antidepressants. Treatment with cytostatics leads to the death of not only tumor cells, but also other rapidly dividing cells, especially in the bone marrow, which naturally leads to leukemia, thrombocytopenia and anemia. Cardiac glycosides, by blocking Na+,K+-ATPase in the membrane of cardiomyocytes, have a positive inotropic effect. At the same time, interaction with this enzyme in peripheral vessels can lead to an undesirable increase in total peripheral vascular resistance (TPVR), which can be considered as a side effect. The use of atropine for bradycardia can cause dry mouth, dilated pupils, increased intraocular pressure, and slowed intestinal motility.

β-Adrenergic blockers are another group of drugs that are widely used in medicine and have a significant number of adverse pharmacodynamic effects. These drugs (especially propranolol) have an anxiolytic effect, so they should not be prescribed to patients suffering from depression. This effect is less pronounced in nadolol and atenolol. In addition, β-blockers can cause fatigue, sexual dysfunction, and bronchospasm.

Guanethidine*, prazosin, and methyldopa, used to treat hypertension, cause orthostatic hypotension and severe dizziness, which can cause falls and fractures. The use of calcium antagonists, especially short-acting ones, in coronary artery disease can cause “steal syndrome” due to the outflow of blood from sclerotic heart vessels that are not capable of dilation and the development of myocardial infarction, and with long-term use in older people they increase the risk of constipation and bleeding from the heart. Gastrointestinal tract.

Due to the main pharmacological effects of drugs, biological reactions mediated by them can develop, such as dysbiosis, superinfection, the emergence of drug-resistant strains of microorganisms, bacteriolysis, and suppression of immune processes.

Dysbacteriosis implies a quantitative and qualitative change in the microflora of the gastrointestinal tract under the influence of antimicrobial drugs. Most often, dysbiosis develops after prolonged enteral use of antibiotics or sulfonamides. Restoration of the intestinal microflora in some cases occurs after cessation of treatment with these drugs, however, in rare cases, persistent dysfunction of the gastrointestinal tract, protein and vitamin metabolism occurs (the synthesis of B vitamins is especially inhibited), and the absorption of calcium, iron and a number of other substances is reduced.

Superinfection- a complication of drug therapy that appears as a result of suppression of the vital activity of the normal microflora of the gastrointestinal tract. Inhibition of normal microflora occurs under the influence of antibiotics and various immunosuppressants (glucocorticoids and cytostatics, chemotherapeutic agents). During superinfection, foci of opportunistic microflora resistant to the action of this drug arise and intensively develop, which can become the cause of a new disease. Superinfections can be endogenous and exogenous. Endogenous infection is most often caused by staphylococci, Pseudomonas aeruginosa and Escherichia coli, Proteus, and anaerobes. Exogenous superinfections are caused by secondary infection with a new pathogen or a resistant strain of microorganisms of the same species as the causative agent of the original disease (for example, the development of candidiasis or aspergillosis). With superinfection, damage to the intestinal mucosa most often occurs, in some cases resulting in perforation of the mucosa as a result of the necrotizing effect of fungi, peritonitis and death of the patient. Visceral forms develop less frequently and occur with an atypical clinical picture. For example, candidiasis of the lungs most often occurs as interstitial pneumonia with a protracted course, difficult to diagnose radiographically. Candidiasis sepsis often occurs, which almost always ends in the death of the patient. Another example of superinfection is the development of aspergillosis in weakened patients against the background of chronic diseases of the blood, gastrointestinal tract and lungs, as well as against the background of long-term use of antibiotics, especially tetracycline. In this case, the skin and many internal organs are affected, which is manifested by a variety of clinical symptoms.

Pseudomembranous colitis- one of the severe complications of drug therapy with clindamycin, lincomycin or tetracycline, in the pathogenesis of which autoimmune processes and toxic damage play a large role. This complication is fatal in 50% of cases.

When using bactericidal antimicrobial drugs in large doses, the development of Jarisch-Gersheimer bacteriolysis reactions, which is characterized by a rapid deterioration of the patient’s condition or a short-term increase in symptoms of the corresponding pathology. The pathogenesis of this condition is due to the rapid breakdown of microbial cells and the release of significant amounts of endotoxins. Microorganisms capable of producing active toxins include salmonella, spirochetes, some strains of Escherichia coli and Pseudomonas aeruginosa, and Proteus. To prevent the bacteriolysis reaction, it is necessary to use drugs correctly, including the use of intensive pathogenetic therapy.

Antibacterial drugs also have an adverse effect on the immune system. Their effect on immunogenesis depends on the dose, route of administration and duration of use. Orally administered drugs in therapeutic doses have a minor effect on the immune system. At the same time, the use of these drugs (for example, chloramphenicol) in high doses for a long time leads to inhibition of humoral immunity (reduction in the number of B-lymphocytes, inhibition of their proliferative activity due to weak antigenic irritation), and a decrease in the activity of phagocytosis. This fact once again proves the need to use drugs correctly.

Withdrawal syndrome As a rule, it occurs when the drug is suddenly stopped. For example, withdrawal of quinidine can lead to severe arrhythmias, antianginal drugs - to an attack of angina, and anticoagulants - to thromboembolic complications.

4.6. ALLERGIC REACTIONS

Allergic reactions, according to various authors, account for 20 to 70% of all side effects. Allergy is an altered immune response, manifested in the development of specific hypersensitivity of the body to foreign substances (allergens) as a result of their previous contact. As a rule, it does not develop when taking drugs for the first time. The exception is cases of allergy to drugs that have cross-allergic reactions with other drugs that have previously been used by patients.

Allergens are divided into exogenous and endogenous (Table 4-1). Endogenous allergens are formed in the body under the influence of various damaging factors, resulting in a complex of its own cells and foreign substances of a non-antigenic nature.

Table 4-1. Classification of exogenous allergens

Allergic reactions are characterized by a phase course and the presence of a period of sensitization, resolution and desensitization. Sensitization develops within a few days from the moment of initial exposure to the allergen and persists for a considerable time. The duration of sensitization is determined by the nature of the allergen, its dose, method of penetration into the body, duration of exposure, as well as the state of the body's immune reactivity. Resolution of an allergic reaction develops in response to repeated exposure to either the same allergen or a similar allergen that can persist in the body for more than 2 weeks. There is a distinction between immediate resolution (development from a few seconds to 6 hours) and delayed type (development within 24-48 hours). During desensitization, the body's reactivity returns to normal spontaneously - as a result of eliminating exposure to the allergen, or artificially - after courses of allergen administration in microdoses.

The risk of developing drug allergies is increased by polypharmacy, long-term use of drugs, hereditary predisposition, as well as diseases such as bronchial asthma, hay fever, fungal diseases, and food allergies.

Allergic reactions can be caused by any drugs, including glucocorticoids. Immunogens such as vaccines, serums, dextrans, insulin are full-fledged antigens that trigger the formation of antibodies. Other agents (low-molecular compounds - haptens) acquire antigenic properties only after combining with proteins. Drugs can acquire antigenic properties during storage (as a result of transformation), as well as during metabolism (for example, drugs with a pyrimidine core - B vitamins, phenothiazine*). Drugs containing radicals have high antigenic activity.

NH 2 - and Cl-groups associated with the benzene ring, for example procaine (novocaine*), chloramphenicol (synthomycin*), aminosalicylic acid (PAS*). The risk of developing drug allergies is minimal with enteral administration, and maximum with intravenous administration of drugs.

IMMEDIATE HYPERSENSITIVITY

At the core immediate hypersensitivity lies the humoral immune response. Immediate hypersensitivity is divided into three subtypes.

I subtype - mediator (anaphylactic)

It develops against exogenous antigens (medicinal, pollen, food, bacterial antigens through parenteral, inhalation and nutritional routes of entry into the body). In this case, antibodies of the IgE class are produced in response to the antigen, transported to the shock organ into which the allergen has entered, where mast cells and basophils are activated, and a hyperreactivity reaction develops. When the allergen re-enters the body, the resolution stage begins, which occurs in three phases:

Immunological - the formation of an allergen complex with IgE fixed on basophils and mast cells and a change in the properties of cell membranes;

Biochemical - degranulation of mast cells and basophils, release of biogenic amines and mediators (histamine, setoronine, kinins, etc.).

Pathophysiological - the effect of mediators on myocytes, endothelium, nerve cells.

This type of immediate hypersensitivity is most often caused by benzylpenicillin, streptomycin, procaine (novocaine *), vitamin B1, serums and vaccines. Clinically, it manifests itself as anaphylaxis or atopic reaction. Anaphylaxis is characterized by the development of anxiety, dizziness, a sharp drop in blood pressure, suffocation, severe abdominal pain, nausea and vomiting, involuntary urination and defecation, as well as convulsions. When anaphylactic shock develops, the patient loses consciousness.

Atopic reaction develops with a hereditary predisposition and manifests itself:

Bronchial asthma;

Urticaria - the appearance of erythema and itchy pink blisters;

Hay fever is an allergic rhinitis that often develops due to pollen allergens and is called hay fever;

Angioedema - swelling of the skin and subcutaneous fat, sometimes spreading to the muscles;

Children's eczema developing from food allergens.

Drugs characterized by a high risk of initiating an anaphylactic or anaphylactoid reaction and the mechanisms of their development are presented in Table. 4-2.

Table 4-2. Medicines characterized by a high risk of developing an anaphylactic or anaphylactoid reaction, and the mechanisms of their development

II subtype - cytotoxic

Develops onto chemicals, cell membranes, and some non-cellular structures. After the attachment of these structures, the surface of shock cells (blood cells, endothelial cells, hepatocytes, kidney epithelial cells) is recognized by the body’s own immune system as foreign in antigenic composition, as a result of which the formation of IgG is initiated, which destroys these cells. This type of allergy underlies the development of leukemia, thrombocytopenia, autoimmune

murine hemolytic anemia (for example, when using methyldopa), post-transfusion complications. Drugs that cause this type of immediate hypersensitivity include quinidine, phenacetin, salicylates, sulfonamides, cephalosporins, and penicillins. The cytotoxic reaction underlies the pathogenesis of drug-induced lupus, which develops with the use of procainamide, hydralazine, chlorpromazine, isoniazid, methyldopa, and penicillamine. In this case, fever occurs, body weight decreases, the musculoskeletal system is affected, the lungs and pleura are involved in the process (in more than 50% of cases), the liver, sometimes the kidneys (in this case glomerulonephritis develops), blood vessels (in this case vasculitis occurs). Almost always, with drug-induced lupus, hemolytic anemia, leuko- and thrombocytopenia, as well as lymphadenopathy develop. The main serological criteria for the diagnosis of drug-induced lupus are the detection of antibodies to nuclear histones (99% of cases) and the absence of antibodies to DNA, which distinguishes it from systemic lupus erythematosus. Symptoms of drug-induced lupus and serological manifestations develop on average a year after the start of therapy with the above drugs and disappear spontaneously within 4-6 weeks after discontinuation. Antinuclear antibodies persist for another 6-12 months.

III subtype - immunocomplex

Develops with insufficient phagocytic activity and the introduction of high doses of allergen. In this case, when the allergen first enters the body, antibodies of the IgG and IgA classes are produced. Allergens that re-enter the body combine with pre-synthesized antibodies, and circulating immune complexes are formed. Adsorbed on the vascular endothelium, circulating immune complexes activate the complement system, especially its C3a-, C4a- and C5a-fractions, which increase vascular permeability and induce neutrophil chemotaxis. At the same time, the kinin system is activated, active bioamines are released and platelet aggregation increases, which causes the development of systemic vasculitis and microthrombosis, dermatitis, nephritis, alveolitis. In addition, immune complexes damage many other tissues, causing immune complex disease:

“serum sickness 1” (for example, on the administration of antithymocyte immunoglobulin) is clinically manifested by swelling of the skin,

1 Sometimes “serum-like reactions” develop 1-3 weeks after the start of taking drugs; they differ from “serum sickness” in the absence of hypocomplementemia, vasculitis, and kidney damage.

mucous and subcutaneous fatty tissue, increased body temperature, the appearance of rashes and skin itching, joint damage, lymphadenopathy, gastrointestinal upset, weakness, proteinuria (without signs of glomerulonephritis);

The Arthus phenomenon develops with repeated local injection of antigen as a result of damage to the vessel by immune complexes and the development of ischemia, tissue necrosis and, ultimately, a sterile abscess;

Glomerulonephritis occurs when immune complexes “precipitate” in the renal epithelium;

Rheumatoid arthritis;

Systemic lupus erythematosus;

Hashimoto's thyroiditis;

Hepatitis.

Drugs that cause this type of reaction include NSAIDs, especially paracetamol, retinol, isoniazid, methotrexate, quinidine, and penicillins.

Delayed hypersensitivity is a cellular immune response. It develops against substances of hapten nature, microbial and drug allergens, and altered own cells.

Delayed-type hypersensitivity occurs in two phases:

First, sensitization of the body occurs, during which a large number of T-lymphocytes are formed;

Then, after 24-48 hours, the resolution phase begins, when sensitized T-lymphocytes recognize antigens and begin to synthesize lymphokines (chemotactic factor, migration inhibitory factor, macrophage activation factor, etc.), which, together with lysosomal enzymes and kinins, induce the development of an inflammatory reaction.

Cell-mediated reactions underlie the development of morbilliform rash and allergic contact dermatitis.

Drug allergic side effects manifest themselves in a wide variety of forms of skin reactions - from erythema at the injection site and fixed drug rash to a generalized papular or vesicular rash. Exfoliative dermatitis is especially severe with rejection of the surface layers of the epidermis, electrolyte imbalance and hypoproteinemia, as well as muscle wasting. There are special forms of allergic skin reactions:

Lyell's syndrome is characterized by the appearance of erythematous rashes that evolve to the formation of bullae;

Stevens-Johnson syndrome is a severe form of exudative polymorphic erythema.

The most common causes of Lyell and Stevens-Johnson syndrome are antibacterial drugs (sulfonamides), anticonvulsants, NSAIDs (piroxicam), allopurinol, vaccines and serums.

At toxic epidermal necrolysis the body temperature suddenly rises to febrile, urticarial and erythematous spots appear on the skin, quickly turning into easily opened blisters with serous contents, and the epidermis exfoliates (positive Nikolsky's sign). At the same time, enanthems appear on the mucous membranes of the mouth and larynx, which are then eroded, as well as lesions of the mucous membranes of the eyes, respiratory tract, pharynx, esophagus, gastrointestinal tract and genitourinary tract. A picture of leukemia or malignant reticulosis is detected in the blood. At erosive ectodermosis body temperature also suddenly rises to high values, cough, headache, hyperemia and erosion of the oral mucosa appear, which turn into confluent ulcers covered with a dirty gray coating. Erythematous spots appear on the skin, turning into a bullous confluent form of exanthema and localized mainly around the mouth and genitals. When diagnosed, a sore throat, pain in muscles and joints, hepato- and splenomegaly, damage to the eyes and internal organs are detected. Blood test results show leukocytosis and eosinophilia. These two life-threatening conditions require urgent measures to eliminate them.

An example of a drug, the introduction of which can cause the development of all types of allergic reactions, is benzylpenicillin. The use of this drug may be complicated by urticaria, anaphylactic shock, hemolytic anemia, the development of serum sickness and contact dermatitis at the injection site.

Each drug has its own sensitization index, which varies from 1-3% for benzylpenicillin to 90% for phenytoin (diphenin *). Large doses, frequency and frequency of use, various types of additives (emulsifiers, solvents), long-acting forms significantly increase the frequency of sensitization of the body to the administered drug.

Factors predisposing to the development of allergic reactions:

Transitional age;

Pregnancy;

Menses;

Climax;

Exposure to solar radiation;

Emotional stress;

Genetic predisposition - the HLA B40 and Cw1 antigens, as well as the A2B40 and A3B40 haplotypes are considered markers of drug allergies (for example, individuals with the HLA Cw3 phenotype or the A2B17 haplotype have an increased risk of developing an allergy to antibiotics, and the presence of HLA D7 or the A9B7 haplotype is associated with the development of multivalent drug intolerance).

In 78-80% of patients, drug allergies end in recovery, and only in 10-12% of cases does it take a chronic course in the form of atopic bronchial asthma, recurrent agranulocytosis, drug-induced hepatitis or interstitial nephritis. In 0.005% of cases, an allergic reaction leads to death, the most common causes of which are anaphylactic shock, agranulocytosis, hemorrhagic encephalitis, myocarditis and aplastic anemia.

4.7. PSEUDOALLERGIC REACTIONS

It is worth distinguishing pseudo-allergies from true allergic reactions, which may resemble them in clinical manifestations. The immune system plays no role in the pathogenesis of pseudo-allergies. The main pathogenetic factors are mast cell histamine, liberin and other mediators of allergic reactions with deficiency of the C1 component of complement. Drugs that can cause reactions of this type include iodine-containing radiocontrast agents, neuromuscular transmission blockers (muscle relaxant tubocurarine*), opioids, colloidal solutions to restore circulating blood volume, some antibacterial agents (vancomycin, polymyxin B), complexing compounds (deferoxamine) .

The severity of pseudoallergic reactions depends on the dose of administered drugs. Clinically, in these conditions, one can observe the occurrence of urticaria, hyperemia and skin itching, headache, and decreased blood pressure. When drugs are administered intramuscularly, edema and hyperemia with skin itching may develop locally. Patients with an allergic predisposition may experience asthma attacks and nasal congestion.

Drugs such as methyldopa, phentolamine, rauwolfia preparations, acting on cholinergic receptors, can cause swelling and hyperemia of the nasal mucosa, and taking NSAIDs can cause bronchospasm in patients with

asthmatic triad due to impaired metabolism of arachidonic acid.

4.8. IDIOSYNCRASY

Idiosyncrasy is a genetically determined pathological reaction to certain drugs. A pathological reaction is manifested by increased sensitivity to a particular drug and a strong and/or long-lasting effect. Idiosyncratic reactions are based on genetically determined defects in enzyme systems. An example of such reactions is the development of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency taking sulfonamides, furazolidone, chloramphenicol, acetylsalicylic acid, antimalarial drugs, or the appearance of methemoglobinemia when taking nitroglycerin preparations in patients with methemoglobin reductase deficiency. The same type of reactions may include the appearance of renal excretion of purines during the treatment of gout in patients with hypoxanthine-guanine phosphoriboxyltransferase deficiency, as well as the development of an attack of hepatic porphyria due to the induction of aminolevulinic acid synthetase by barbiturates. Hereditary deficiency of serum cholinesterase explains the fact that the effect of the muscle relaxant suxamethonium iodide (ditylin *) increases from 5 minutes (normal) to 2-3 hours. In case of glucuronyltransferase deficiency in children, chloramphenicol should not be used due to the possibility of developing Gray's syndrome (flatulence , diarrhea, vomiting, cyanosis, circulatory disorders).

4.9. DRUG DEPENDENCE

Drug dependence is a special mental and physical condition, accompanied by certain reactions, which always include an urgent need for constant or periodically renewed use of certain drugs. The patient uses the drug in order to experience its effect on the psyche, and sometimes to avoid unpleasant symptoms caused by stopping taking this drug.

The development of the syndrome of dependence on psychotropic drugs obviously occurs through the formation of certain conditioned reflex connections and is due to the influence of the drug on some neurotransmitter and biochemical processes occurring in the central nervous system. It is also possible that in the development of dependence on analgesics of the morphine group

a certain role is played by the influence of these substances on the system of opiate receptors and their endogenous ligands (endorphins and enkephalins).

Mental dependence syndrome is a condition of the body characterized by a pathological need to take any psychotropic substance in order to avoid mental disorders or discomfort that arise when stopping taking it. This syndrome occurs without signs of withdrawal.

Physical dependence syndrome is a condition characterized by the development of abstinence when stopping taking a drug or after introducing its antagonists. This syndrome occurs when taking medications that have a narcotic effect. According to the conclusion of the WHO Expert Committee, the concept of “drug dependence” should mean a mental and sometimes physical condition that arises as a result of the interaction between a living organism and a drug and is characterized by behavioral and other reactions, which always include the desire to take drugs on an ongoing or periodic basis in order to avoid the discomfort that occurs without taking the drug. A person can become dependent on more than one drug. The need to increase the dose may be due to changes in the metabolism of the drug, cellular, physiological or behavioral adaptation to its action.

4.10. DIAGNOSIS OF SIDE EFFECTS OF DRUGS

To diagnose the side effects of drugs, it is necessary to carry out a number of measures.

Determine whether the patient is taking medications (including over-the-counter drugs, herbs, oral contraceptives).

Establish a connection between a side effect and a drug:

According to the time of taking the drug and the time of occurrence of the adverse reaction;

According to the correspondence of the type of adverse reaction to the pharmacological action of the drug;

According to the frequency of occurrence of this side effect in the population, including from the intended drug;

Based on the concentration of the “suspected” drug or its metabolites in the blood plasma;

According to the reaction to provocative tests with a “suspected” drug (the drug is first discontinued and then given again);

According to the results of the patch test (contact test) for different types of hypersensitivity;

Based on skin biopsy for unclear skin rash (in some cases);

Based on reaction to skin tests 1. Diagnostic tests.

General laboratory tests for organ-specific lesions (for example, determining the concentration of transpeptidases in the blood for liver damage).

Biochemical and immunological markers of activation of the immunobiological response:

■ determination of the concentration of the total hemolytic component and antinuclear antibodies in drug-induced lupus;

■ detection of histamine metabolites in urine collected per day during anaphylaxis;

■ determination of the content of tryptase 2 - a marker of mast cell activation;

■ lymphocyte transformation test.

Unfortunately, there are no tests that could clearly confirm or refute an adverse reaction.

4.11. PREVENTION AND TREATMENT OF SIDE EFFECTS

MEDICINES

Prevention of side effects is based on knowledge of pharmacokinetics, pharmacodynamics and principles of drug interaction. A special role in ensuring the safety of pharmacotherapy is given to

1 Used for immediate reactions to polypeptides - antilymphocyte globulin, insulin, streptokinase. They are less applicable when studying low-molecular substances (penicillin), since immunogenic determinants have not been identified for them. A positive skin test result indicates the presence of specific IgE antibodies. A negative result indicates either the absence of specific IgE antibodies or the nonspecificity of the test reagent.

2 Tryptase exists in α- and β-form. An increased concentration of the α-form indicates systemic mastocytosis (increased number of mast cells), and an increase in the concentration of the β-form indicates activation of mast cells during anaphylactoid and anaphylactic reactions. It is preferable to determine the concentration of tryptase rather than histamine, which lasts for minutes. To determine the concentration of tryptase, it is recommended to take blood samples within 1-2 hours from the development of anaphylaxis (T 1/2 of tryptase is about 2 hours). Normal tryptase concentrations<1 мкг/л, в то время как содержание >1 μg/L indicates activation of mast cells, and >5 μg/L indicates systemic anaphylaxis.

pharmacogenetics, since pharmacogenetic studies allow a differentiated approach to the selection of drugs, which helps improve safety.

The strategy for combating adverse drug reactions is based on the following areas:

Creation of drugs with the most selective action;

Replacement in medical practice of drugs with a narrow range of therapeutic concentrations with safer drugs;

Development of methods for optimizing dosing regimens - the use of long-acting drugs, slow-release dosage forms, the use of special delivery vehicles that allow penetration exclusively into the “target” organ.

In case of side effects, treatment tactics primarily include drug withdrawal. If the drug cannot be discontinued, it is necessary to reduce its dose, carry out desensitization and symptomatic treatment.

To reduce the risk of developing side effects of drugs, you should consider:

The drug belongs to a pharmacological group, which determines all possible pharmacological effects;

Age and anthropometric characteristics of patients;

Functional state of organs and body systems that affect the pharmacodynamics and pharmacokinetics of drugs;

Presence of concomitant diseases;

Lifestyle (with intense physical activity the rate of drug elimination increases), diet (vegetarians have a reduced rate of drug biotransformation), bad habits (smoking speeds up the metabolism of some drugs).

4.12. DRUG SAFETY CONTROL SERVICE

FACILITIES IN RUSSIA

The history of the creation of a pharmacological surveillance service in Russia begins with the organization by the USSR Ministry of Health of a department for recording, systematization and express information on the side effects of drugs in 1969. In 1973, it was approved as the All-Union Organizational and Methodological Center for the Study of Side Effects of Drugs.

According to the order of the Ministry of Health of the Russian Federation? 114 of 04/14/1997, 05/01/1997, the Federal Center for the Study of Side Effects of Drugs of the Ministry of Health of the Russian Federation was created, as well as a number of regional centers

troves for registration of side effects of drugs, which currently number about thirty. Thanks to the activity of the staff of the regional centers, a small number of first spontaneous reports were received, which the Federal Center sent to the WHO Collaborating Center for Drug Monitoring (Uppsala, Sweden). Thanks to the latter’s recommendations, on December 2, 1997, Russia was accepted as the 48th member of the WHO International Drug Monitoring Program. In July 1998, the Federal Center was transformed into the Scientific and Practical Center for the Control of Side Effects of Drugs (SPC KPDL). In July 1999, the Scientific Center for Expertise and State Control of Medicines (SC EGKLS) was created in Russia, the SPC KPDL was transformed into a division of the NC EGKLS, and safety work was coordinated by the department of toxicology and the study of side effects of drugs of the Institute of Preclinical and Clinical Expertise of Medicines NC EGKLS, which began to play the role of the federal center of the Russian Federation for the study of side effects of drugs, informing the WHO Center, collaborating with national centers in 52 countries. The legal basis for drug safety control in our country is laid down in the adopted Federal Law of June 5, 1998? 86-FZ “On Medicines”.

After a number of transformations, responsibility for work related to drug monitoring was assigned to the Scientific Center for Expertise of Medical Products of Roszdravnadzor.

4.13. METHODS FOR MONITORING SIDE EFFECTS

Monitoring of drug complications is carried out using various methods; preference is given to a specific one depending on the specifics of each region. Post-marketing studies, active monitoring of hospitals and the spontaneous reporting method are considered the most universal. In Russia, the official form of notification of the development of side effects has been adopted (Table 4-3). Less popular, but no less effective, are prescription monitoring, literary meta-analyses, analysis of single cases described in the literature, comparative studies, etc.

The main method of the Federal Center is the method of spontaneous messages. It involves voluntary reporting by medical practitioners of suspected side effects of medications. Messages are provided on a single form - notification of side effects, containing the necessary information to verify spontaneous messages. Unfortunately-

According to us, this method has a number of disadvantages: a low rate of registration of side effects (no more than 2% of the total number of drug complications), as well as the personal bias of the reporting person. This method is the most widespread in Russia.

Post-marketing clinical studies are usually carried out at the initiative of manufacturing companies. It is extremely rare for safety to be examined as the primary objective of the study, but is usually assessed in accordance with the requirements of good clinical practice (GCP). This method makes it possible to determine the occurrence of adverse reactions, but it allows only occasional detection of rare adverse reactions.

Active monitoring of the hospital is carried out in the form of retrospective and prospective analysis. Such a study involves collecting demographic, social and medical data and identifying all adverse reactions. This technique is quite expensive, requires the involvement of a specialist - a clinical pharmacologist, and takes a lot of time to work with the archive or a doctor. This method makes it possible to assess the incidence of drug complications, as well as the dependence on the duration of monitoring. The data obtained during such an analysis are applicable only in a specific medical institution.

The essence of prescription monitoring is to compare the numerical and qualitative characteristics of the developed adverse reaction with the number of drug prescriptions. This method is indispensable when it is necessary to quickly identify adverse reactions of a particular drug, as well as when it is necessary to identify complications that arise when taking new drugs.

Meta-analysis is a statistical method that combines the results of independent studies and is used to evaluate pharmacoepidemiological data on the safety of drugs. This is the simplest and cheapest method, which is widely used abroad.

Analysis of single clinical cases described in the medical press does not provide complete information, but serves only as an addition to the studies conducted in the event of clarification of the causality of an adverse reaction.

Thus, according to data obtained during the analysis of spontaneous messages (about 2.5 thousand), received in most cases from medical workers, the maximum number of errors (about

75%) were accepted by doctors during combination therapy as a result of polypharmacy. In 20% of cases described in reports, patients received 12 medications at the same time, in approximately 41% - 8 drugs. Other reasons for the development of adverse reactions and undesirable effects were underestimation of concomitant diseases and incorrect dosage of drugs. In more than 70% of cases, side effects could have been prevented.

From previous publications we know about the abortifacient effect of hormonal contraceptives (GC, OK). Recently in the media you can find reviews of women who suffered from the side effects of OK, we will give a couple of them at the end of the article. To shed light on this issue, we turned to a doctor who prepared this information for the ABC of Health and also translated for us fragments of articles with foreign studies on the side effects of GCs.

Side effects of hormonal contraceptives.

The actions of hormonal contraceptives, like other medications, are determined by the properties of the substances they contain. Most birth control pills prescribed for routine contraception contain 2 types of hormones: one gestagen and one estrogen.

Gestagens

Progestogens = progestogens = progestins- hormones that are produced by the corpus luteum of the ovaries (a formation on the surface of the ovaries that appears after ovulation - the release of the egg), in small quantities - by the adrenal cortex, and during pregnancy - by the placenta. The main gestagen is progesterone.

The name of the hormones reflects their main function - “pro gestation” = “to [maintain] pregnancy” by restructuring the uterine endothelium into the state necessary for the development of a fertilized egg. The physiological effects of gestagens are combined into three main groups.

1. Vegetative effects. It is expressed in the suppression of endometrial proliferation caused by the action of estrogens and its secretory transformation, which is very important for a normal menstrual cycle. When pregnancy occurs, gestagens suppress ovulation, lower the tone of the uterus, reducing its excitability and contractility (“protector” of pregnancy). Progestins are responsible for the “maturation” of the mammary glands.
2. Generative action. In small doses, progestins increase the secretion of follicle-stimulating hormone (FSH), which is responsible for the maturation of follicles in the ovary and ovulation. In large doses, gestagens block both FSH and LH (luteinizing hormone, which is involved in the synthesis of androgens, and together with FSH ensures ovulation and progesterone synthesis). Gestagens affect the thermoregulation center, which is manifested by an increase in temperature.
3. General action. Under the influence of gestagens, amine nitrogen in the blood plasma decreases, the excretion of amino acids increases, the secretion of gastric juice increases, and the secretion of bile slows down.

Oral contraceptives contain various gestagens. For some time it was believed that there was no difference between progestins, but it is now certain that differences in molecular structure provide a variety of effects. In other words, progestogens differ in spectrum and in the severity of additional properties, but the 3 groups of physiological effects described above are inherent to all of them. The characteristics of modern progestins are reflected in the table.

Pronounced or very pronounced gestagenic effect common to all progestogens. The gestagenic effect refers to those main groups of properties that were mentioned earlier.

Androgenic activity characteristic of not many drugs, its result is a decrease in the amount of “good” cholesterol (HDL cholesterol) and an increase in the concentration of “bad” cholesterol (LDL cholesterol). As a result, the risk of developing atherosclerosis increases. In addition, symptoms of virilization (male secondary sexual characteristics) appear.

Explicit antiandrogenic effect only three drugs have it. This effect has a positive meaning - improvement in skin condition (cosmetic side of the issue).

Antimineralocorticoid activity associated with increased diuresis, sodium excretion, and decreased blood pressure.

Glucocorticoid effect affects metabolism: the body's sensitivity to insulin decreases (risk of diabetes), the synthesis of fatty acids and triglycerides increases (risk of obesity).

Estrogens

Another component of birth control pills is estrogens.

Estrogens- female sex hormones, which are produced by the ovarian follicles and the adrenal cortex (and in men also by the testicles). There are three main estrogens: estradiol, estriol, estrone.

Physiological effects of estrogens:

- proliferation (growth) of the endometrium and myometrium according to the type of their hyperplasia and hypertrophy;

— development of genital organs and secondary sexual characteristics (feminization);

- suppression of lactation;

- inhibition of resorption (destruction, resorption) of bone tissue;

- procoagulant effect (increased blood clotting);

- increasing the content of HDL (“good” cholesterol) and triglycerides, reducing the amount of LDL (“bad” cholesterol);

- retention of sodium and water in the body (and, as a result, increased blood pressure);

— ensuring an acidic vaginal environment (normal pH 3.8-4.5) and the growth of lactobacilli;

- increased antibody production and phagocyte activity, increasing the body's resistance to infections.

Estrogens in oral contraceptives are needed to control the menstrual cycle; they do not take part in protection against unwanted pregnancy. Most often, the tablets contain ethinyl estradiol (EE).

Mechanisms of action of oral contraceptives

So, taking into account the basic properties of gestagens and estrogens, the following mechanisms of action of oral contraceptives can be distinguished:

1) inhibition of the secretion of gonadotropic hormones (due to gestagens);

2) a change in vaginal pH to a more acidic side (the influence of estrogens);

3) increased viscosity of cervical mucus (gestagens);

4) the phrase “ovum implantation” used in instructions and manuals, which hides the abortive effect of GC from women.

Commentary by a gynecologist on the abortifacient mechanism of action of hormonal contraceptives

When implanted into the wall of the uterus, the embryo is a multicellular organism (blastocyst). An egg (even a fertilized one) is never implanted. Implantation occurs 5-7 days after fertilization. Therefore, what is called an egg in the instructions is in fact not an egg at all, but an embryo.

Unwanted estrogen...

In the course of a thorough study of hormonal contraceptives and their effects on the body, it was concluded that undesirable effects are associated to a greater extent with the influence of estrogens. Therefore, the lower the amount of estrogen in the tablet, the fewer side effects, but it is not possible to completely eliminate them. It was precisely these conclusions that prompted scientists to invent new, more advanced drugs, and oral contraceptives, in which the amount of the estrogen component was measured in milligrams, were replaced by tablets containing estrogen in micrograms ( 1 milligram [ mg] = 1000 micrograms [ mcg]). There are currently 3 generations of birth control pills. The division into generations is due to both a change in the amount of estrogens in the drugs and the introduction of newer progesterone analogues into the tablets.

The first generation of contraceptives include Enovid, Infekundin, Bisekurin. These drugs have been widely used since their discovery, but later their androgenic effects were noticed, manifested in deepening of the voice, growth of facial hair (virilization).

Second generation drugs include Microgenon, Rigevidon, Triregol, Triziston and others.

The most frequently used and widespread drugs are the third generation: Logest, Merisilon, Regulon, Novinet, Diane-35, Zhanin, Yarina and others. A significant advantage of these drugs is their antiandrogenic activity, most pronounced in Diane-35.

The study of the properties of estrogens and the conclusion that they are the main source of side effects from the use of hormonal contraceptives led scientists to the idea of ​​​​creating drugs with an optimal reduction in the dose of estrogens in them. It is impossible to completely remove estrogens from the composition, since they play an important role in maintaining a normal menstrual cycle.

In this regard, a division of hormonal contraceptives into high-, low- and micro-dose drugs has appeared.

Highly dosed (EE = 40-50 mcg per tablet).

• "Non-ovlon"
• "Ovidon" and others
• Not used for contraceptive purposes.

Low dosage (EE = 30-35 mcg per tablet).

• "Marvelon"
• "Janine"
• "Yarina"
• "Femoden"
• "Diane-35" and others

Microdosed (EE = 20 mcg per tablet)

• "Logest"
• "Mersilon"
• "Novinet"
• "Miniziston 20 fem" "Jess" and others

Side effects of hormonal contraceptives

Side effects from the use of oral contraceptives are always described in detail in the instructions for use.

Since the side effects from the use of various birth control pills are approximately the same, it makes sense to consider them, highlighting the main (severe) and less severe.

Some manufacturers list conditions that require immediate discontinuation of use if they occur. These conditions include the following:

1. Arterial hypertension.
2. Hemolytic-uremic syndrome, manifested by a triad of symptoms: acute renal failure, hemolytic anemia and thrombocytopenia (decreased platelet count).
3. Porphyria is a disease in which hemoglobin synthesis is disrupted.
4. Hearing loss caused by otosclerosis (fixation of the auditory ossicles, which should normally be mobile).

Almost all manufacturers list thromboembolism as a rare or very rare side effect. But this serious condition deserves special attention.

Thromboembolism- This is a blockage of a blood vessel by a thrombus. This is an acute condition that requires qualified assistance. Thromboembolism cannot occur out of the blue; it requires special “conditions” - risk factors or existing vascular diseases.

Risk factors for thrombosis (formation of blood clots inside vessels - thrombi - interfering with the free, laminar flow of blood):

— age over 35 years;

- smoking (!);

- high level of estrogen in the blood (which occurs when taking oral contraceptives);

- increased blood clotting, which is observed with a deficiency of antithrombin III, proteins C and S, dysfibrinogenemia, Marchiafava-Michelli disease;

- injuries and extensive operations in the past;

- venous stasis with a sedentary lifestyle;

- obesity;

- varicose veins of the legs;

- damage to the valvular apparatus of the heart;

- atrial fibrillation, angina pectoris;

- diseases of the cerebral vessels (including transient ischemic attack) or coronary vessels;

- moderate or severe arterial hypertension;

— connective tissue diseases (collagenosis), and primarily systemic lupus erythematosus;

- hereditary predisposition to thrombosis (thrombosis, myocardial infarction, cerebrovascular accident in close blood relatives).

If these risk factors are present, a woman taking hormonal birth control pills has a significantly increased risk of developing thromboembolism. The risk of thromboembolism increases with thrombosis of any location, either currently present or suffered in the past; in case of myocardial infarction and stroke.

Thromboembolism, whatever its location, is a serious complication.

In addition to thromboembolism, there are other, less severe, but still inconvenient side effects. For example, candidiasis (thrush). Hormonal contraceptives increase the acidity of the vagina, and fungi reproduce well in an acidic environment, in particular Candidaalbicans, which is a conditionally pathogenic microorganism.

A significant side effect is the retention of sodium, and with it water, in the body. This may lead to swelling and weight gain. Decreased tolerance to carbohydrates, as a side effect of the use of hormonal pills, increases the risk of developing diabetes mellitus

Other side effects, such as: decreased mood, mood swings, increased appetite, nausea, stool disorders, satiety, swelling and tenderness of the mammary glands and some others - although not severe, however, affect a woman’s quality of life.

In addition to side effects, the instructions for the use of hormonal contraceptives list contraindications.

Contraceptives without estrogen

Exist progestin-containing contraceptives (“mini-pill”). Judging by the name, they contain only gestagen. But this group of drugs has its own indications:

- contraception for nursing women (they should not be prescribed estrogen-progestin drugs, because estrogen suppresses lactation);

— prescribed for women who have given birth (since the main mechanism of action of the “mini-pill” is suppression of ovulation, which is undesirable for nulliparous women);

- in late reproductive age;

- if there are contraindications to the use of estrogens.

In addition, these drugs also have side effects and contraindications.

Particular attention should be paid to " emergency contraception". These drugs contain either a progestin (Levonorgestrel) or an antiprogestin (Mifepristone) in a large dose. The main mechanisms of action of these drugs are inhibition of ovulation, thickening of cervical mucus, acceleration of desquamation (squamation) of the functional layer of the endometrium in order to prevent the attachment of a fertilized egg. And Mifepristone has an additional effect - increasing the tone of the uterus. Therefore, a single use of a large dose of these drugs has a very strong immediate effect on the ovaries; after taking emergency contraceptive pills, there can be serious and long-term disturbances in the menstrual cycle. Women who regularly use these drugs are at great risk to their health.

Foreign studies of side effects of GCs

Interesting studies examining the side effects of hormonal contraceptives have been conducted in foreign countries. Below are excerpts from several reviews (translation by the author of fragments of foreign articles)

Oral contraceptives and the risk of venous thrombosis

May, 2001

CONCLUSIONS

Hormonal contraception is used by more than 100 million women worldwide. The number of deaths from cardiovascular diseases (venous and arterial) among young, low-risk patients - non-smoking women from 20 to 24 years old - is observed worldwide in the range from 2 to 6 per year per million, depending on the region of residence expected cardiovascular -vascular risk and the volume of screening studies that were carried out before prescribing contraceptives. While the risk of venous thrombosis is more important in younger patients, the risk of arterial thrombosis is more relevant in older patients. Among older women who smoke and use oral contraceptives, the death rate ranges from 100 to just over 200 per million each year.

Reducing the dose of estrogen reduced the risk of venous thrombosis. Third-generation progestins in combined oral contraceptives have increased the incidence of adverse hemolytic changes and the risk of thrombus formation, so they should not be prescribed as first-choice drugs for new users of hormonal contraception.

The judicious use of hormonal contraceptives, including avoidance of their use by women who have risk factors, is absent in most cases. In New Zealand, a series of deaths from pulmonary embolism were investigated, and the cause was often due to a risk that doctors had not considered.

Judicious administration can prevent arterial thrombosis. Almost all women who had a myocardial infarction while using oral contraceptives were either of an older age group, smoked, or had other risk factors for arterial disease - in particular, arterial hypertension. Avoidance of oral contraceptives in these women may reduce the incidence of arterial thrombosis reported in recent studies from industrialized countries. The beneficial effect that third-generation oral contraceptives have on the lipid profile and their role in reducing the number of heart attacks and strokes has not yet been confirmed by control studies.

To avoid venous thrombosis, the doctor asks whether the patient has ever had venous thrombosis in the past to determine whether there are contraindications to the use of oral contraceptives, and what is the risk of thrombosis while taking hormonal medications.

Low-dose progestogen oral contraceptives (first or second generation) were associated with a lower risk of venous thrombosis than combination drugs; however, the risk in women with a history of thrombosis is unknown.

Obesity is considered a risk factor for venous thrombosis, but it is unknown whether this risk is increased by oral contraceptive use; thrombosis is rare among obese people. Obesity, however, is not considered a contraindication to the use of oral contraceptives. Superficial varices are not a consequence of pre-existing venous thrombosis or a risk factor for deep venous thrombosis.

Heredity may play a role in the development of venous thrombosis, but its significance as a high-risk factor remains unclear. A history of superficial thrombophlebitis can also be considered a risk factor for thrombosis, especially if it is combined with a family history.

Venous thromboembolism and hormonal contraception

Royal College of Obstetricians and Gynecologists, UK

July, 2010

Do combined hormonal contraceptive methods (pills, patch, vaginal ring) increase the risk of venous thromboembolism?

The relative risk of venous thromboembolism increases with the use of any combined hormonal contraceptives (pills, patch and vaginal ring). However, the rarity of venous thromboembolism in women of reproductive age means that the absolute risk remains low.

The relative risk of venous thromboembolism increases in the first few months after starting combined hormonal contraception. As the duration of taking hormonal contraceptives increases, the risk decreases, but it remains as a background risk until you stop using hormonal drugs.

In this table, researchers compared the annual incidence of venous thromboembolism in different groups of women (per 100,000 women). It is clear from the table that in women who are not pregnant and do not use hormonal contraceptives (non-pregnant non-users), an average of 44 (with a range from 24 to 73) cases of thromboembolism per 100,000 women were registered per year.

Drospirenone-containingCOCusers - users of drospirenone-containing COCs.

Levonorgestrel-containingCOCusers - using levonorgestrel-containing COCs.

Other COCs not specified - other COCs.

Pregnantnon-users - pregnant women.

Strokes and heart attacks when using hormonal contraception

New England Journal of Medicine

Massachusetts Medical Society, USA

June, 2012

CONCLUSIONS

Although the absolute risks of stroke and heart attack associated with hormonal contraceptives are low, the risk increased from 0.9 to 1.7 with products containing 20 mcg ethinyl estradiol and from 1.2 to 2.3 with using drugs containing ethinyl estradiol in a dose of 30-40 mcg, with a relatively small difference in risk depending on the type of progestogen included in the composition.

Risk of thrombosis of oral contraception

WoltersKluwerHealth is a leading provider of expert health information.

HenneloreRott - German doctor

August, 2012

CONCLUSIONS

Different combined oral contraceptives (COCs) have different risks of venous thromboembolism, but the same unsafe use.

COCs with levonorgestrel or norethisterone (so-called second generation) should be the drugs of choice, as recommended by national contraceptive guidelines in the Netherlands, Belgium, Denmark, Norway and the UK. Other European countries do not have such guidelines, but they are urgently needed.

In women with a history of venous thromboembolism and/or known coagulation defects, the use of COCs and other contraceptives containing ethinyl estradiol is contraindicated. On the other hand, the risk of venous thromboembolism during pregnancy and the postpartum period is much higher. For this reason, such women should be offered adequate contraception.

There is no reason to withhold hormonal contraception in young patients with thrombophilia. Pure progesterone preparations are safe with respect to the risk of venous thromboembolism.

Risk of venous thromboembolism among users of drospirenone-containing oral contraceptives

American College of Obstetricians and Gynecologists

November 2012

CONCLUSIONS
The risk of venous thromboembolism is increased among oral contraceptive users (3-9/10,000 women per year) compared with non-pregnant and non-users (1-5/10,000 women per year). There is evidence that drospirenone-containing oral contraceptives have a higher risk (10.22/10,000) than drugs containing other progestins. However, the risk is still low and much lower than that during pregnancy (approximately 5-20/10,000 women per year) and in the postpartum period (40-65/10,000 women per year) (see table).

Table Risk of thromboembolism.

Photo: Syda_Productions/depositphotos.com

Birth control pills are oral contraceptives that are classified as hormonal drugs. Their function is to prevent unwanted pregnancy. The composition contains a combination of female sex hormones, long-term exposure to which changes the functioning of the ovaries.

Types of hormonal oral contraceptives

If we talk about combined drugs, it is understood that they contain several hormones, usually two: progestin and estrogen. Progestin is a derivative of progesterone, a male hormone in the female body. Estrogen, on the contrary, is an exclusively female hormone produced by the ovaries from puberty until menopause.

Ovulation is accompanied by the release of maximum estrogen levels, and the hormonal agent regulates its level, preventing ovulation.

According to the principle of action, they are monophasic (without changing the level of hormones throughout the entire period) and triphasic (the combination of hormones changes during the menstrual cycle). There are the following groups:

Low-dose products

This group of drugs is suitable for young women who have not yet given birth and who have a permanent relationship with a partner. Recommended products include: Lindinet-30, Belara, Silest, Janine, Miniziston, Marvelon, Rigevidon, Femoden, Regulon, Microgynon.

Medium-dose drugs

Created for women who have already given birth or middle-aged women. These are: Chloe, Diana-35, Milvane, Tri-Regol, Demoulin, Triquilar, Triziston.

High-dose contraceptives

Mini-pill

Mini-pills are the most gentle among all other drugs. They contain only one analogue of the hormone progesterone. They do not guarantee 100% protection against unwanted pregnancy, but there are situations when the use of only such drugs is recommended.

The principle of action of contraceptives

In addition to preventing ovulation, hormonal pills act on the lining of the uterus and make it impossible for sperm to penetrate the fallopian tube. The uterine mucosa becomes thinner, which is why even with the penetration of a sperm, the fertilized egg is not able to gain a foothold in the uterine cavity.

Pros and cons of birth control pills

Fear of hormonal contraceptives and anxiety about health are understandable and justified. Modern drugs have virtually no side effects.

The advantage of using oral contraceptives is the improvement in the condition of the skin, nails and hair. Studies have confirmed that taking oral contraceptives reduces the risk of ovarian and cervical cancer. They are often used to treat various hormonal disorders and menstrual irregularities.

A positive effect when taking OCs can be considered a significant reduction in the amount of blood lost during menstruation and a decrease in pain.

Another advantage is that their contraceptive effect does not interfere with the reproductive function of the female body. She recovers completely within a few months after finishing treatment.

Side effects

Oral contraceptives are prescribed by gynecologists individually to each patient. But it is difficult to predict the tolerability of a particular drug in advance. An additional dose of hormones can lead to undesirable consequences, such as acne or weight gain.

Taking birth control pills at the initial stage can lead to headaches, pressure changes, nausea or vomiting. If these symptoms appear, this may indicate individual intolerance to the drug. Therefore, it is worth changing your contraceptive.

Side effects may include vaginal discharge or bleeding. Hormonal agents often create a favorable environment for the development of bacteria.

It is worth distinguishing two types of bleeding: spotting bleeding and heavy bleeding. Spotting bleeding in the first months of prescription may simply be a consequence of changes in the body. However, in case of heavy bleeding, you should stop taking the drug and consult a doctor.

Selection of birth control pills

The selection of the drug is made by the doctor. First you need to pass the following examinations:

• Gynecological examination.
• Pelvic ultrasound, which will check for fibroids and cysts.
• Hormone analysis, which is done to prevent unwanted hormonal fluctuations.
• Mammography of the mammary glands.
• General blood test and smear.
• Cardiogram.
• Consultation with a nephrologist.

In addition to the general condition of the body, when prescribing the drug, the doctor is guided by the woman’s age category, weight and sugar level.

Factors that reduce the effectiveness of contraceptives:

• Smoking while taking birth control pills. It is better to reduce the dose of nicotine consumed, as this can cause complications of cardiovascular diseases.
• Drinking alcohol is also undesirable in combination with oral contraceptives, as the effect of the drug can be significantly reduced.
• Taking antidepressants, antibiotics, tranquilizers and other medications.

How to take hormonal pills

In order for contraceptives to have an effect, you must follow the recommendations for use.

Hormonal contraceptives are used according to a strictly designated scheme. It should not be violated, as this can lead to an unplanned pregnancy or disrupt the menstrual cycle.

Birth control pills must be taken daily and preferably at the same time. It is best to do this in the evening before bed, then it will be easier not to forget about taking it. Before starting, you should rule out pregnancy, so start taking the pills on the first day of your period.

They do not begin to act immediately, so to avoid unplanned pregnancy, use additional methods of contraception in the first weeks of use.

The tablets are taken for 21 days of each menstrual cycle, then a break is taken for 7 days.

If you forget to take your pill on time, do it as quickly as possible. Next, adhere to the dosage regimen.

If the drug is interrupted for more than 12 hours, it would be correct to use additional contraception.

The process of stopping birth control pills is different for everyone, but in general the body's adjustment period ranges from 6 to 12 months. However, women often became pregnant in the first months after stopping the drug. Like all medications, oral contraceptives are eliminated from the body within 36 hours. Therefore, it is not recommended to interrupt use for longer than 12 hours.

Taking birth control pills after childbirth

Taking oral contraceptives after childbirth has its own nuances. Be sure to wait 3-4 weeks after delivery. This is associated with the risk of blood clots.

When breastfeeding, only progestogen drugs are prescribed. After cessation of lactation, you can proceed to taking combined oral contraceptives.

Are there blood pressure medications without side effects? In the modern world, many are faced with the problem of high blood pressure, which indicates diseases of the heart and blood vessels. These diseases lead in the number of deaths. Serious illnesses often begin with a slight increase in blood pressure, which most of us do not pay attention to. Over time, severe complications develop, leading to loss of ability to work and even death.

Causes of hypertension

Hypertension is a common disease, the first symptoms of which are headaches, memory problems, and increased fatigue. A person does not pay attention to the symptoms for a long time, which worsen over time. Ringing in the ears, swelling of the face, and increased sweating appear. If such symptoms are present, regular monitoring of blood pressure is necessary. With a constant increase in this indicator, we are talking about hypertension. Arterial hypertension is a chronic disease that leads to disruption of all body systems. There is a decrease in visual acuity, loss of coordination, and chronic fatigue.

Stress is considered the main cause of hypertension. When stressed, the body produces an increased amount of adrenaline, leading to an increase in blood pressure. There are some other factors leading to the development of this disease:

• excess sodium in the body, which retains fluid;
• overweight;
• alcohol consumption;
• smoking;
• sedentary lifestyle.

Once a definitive diagnosis is made, treatment should begin immediately. In modern medicine, there is a wide range of drugs to treat this disease.

Before prescribing a particular medicine, the doctor must conduct a complete examination of the patient. Most drugs have unwanted side effects, which must be taken into account when treating the patient. Almost all high blood pressure pills have negative effects, but you should choose those that have minimal harmful effects on the body. In the early stages of the disease, it is possible to do without the use of chemicals. It is necessary to activate the body's own defense mechanisms and eliminate the main cause of hypertension.

You need to start by reviewing your daily routine and nutrition. Reduce the amount of salt you consume, as it contributes to the accumulation of excess fluid in the body and can significantly increase blood pressure. Introduce foods rich in vitamins into your diet. Additionally, it is recommended to take multivitamin complexes. Especially if the cause of high blood pressure is not excess weight and endocrine diseases.

Light physical activity is beneficial. Learn to react less harshly to stressful situations. Psychotherapy should be used. These methods are a kind of medicine for hypertension without side effects. In the initial stages of the disease, it is possible to treat hypertension with herbal remedies. These include medicinal plants such as mint, hawthorn, chamomile, and lemon balm. By detecting the disease in time and starting treatment with non-drug means, it is possible to control blood pressure and avoid serious complications.

Drug therapy

In advanced forms of the disease, the patient needs to take medications for high blood pressure. The right medicine can lead to a complete cure with minimal impact on the body. Modern high blood pressure pills have minor side effects. When choosing a drug, it is necessary to take into account the severity of the disease and the presence of concomitant pathologies. Several types of medications are used to treat high blood pressure:

1. Diuretic tablets for blood pressure help remove excess fluid from the body. This helps reduce the load on the kidneys and heart muscle. It is very important to choose the correct dosage of the medicine, taking into account existing contraindications. For example, diuretics are not recommended for gout. Medicines in this group help remove beneficial substances from the body, so they must be used together with vitamins. The main diuretics used for hypertension are Furosemide, Diacordin, Bumetanide, etc.
2. Vasodilators increase the lumen of blood vessels, lowering blood pressure. They are prescribed together with drugs from other groups. They have the greatest number of side effects. Taking them is advisable in cases where other drugs do not give positive results or the disease is detected in an advanced stage.
3. ACE inhibitors have a complex effect on the problem; they improve the functioning of the heart, kidneys and blood vessels. Drugs in this group reduce the production of hormones and relieve spasms. Most often, these drugs are prescribed to patients with diabetes mellitus and patients with renal failure. These drugs include Enalapril, Monopril, Captopril.
4. Beta blockers reduce the production of adrenaline, which increases during myocardial infarction and angina. Drugs of this series should not be taken for bradycardia, bronchial asthma, or low blood pressure.
5. Calcium antagonists free heart cells from calcium deposits, resulting in a decrease in heart rate. They have a diuretic effect. Drugs in this group have a number of contraindications and side effects, so they should be used under the constant supervision of the attending physician. The effectiveness of therapy depends on the correct choice of high blood pressure medications with minimal side effects.

Cheap analogues

Treatment of hypertension, like any other disease, leads to financial waste. Drug prices fluctuate widely. Cheaper drugs tend to have more side effects. The latest generation blood pressure tablets undergo multi-stage purification, which reduces their harmful effects on the body. More expensive drugs have a longer shelf life, which makes their use convenient. When purchasing certain blood pressure pills, you should also pay attention to the country of origin.

Injections are the safest and most convenient form of medications for treating hypertension. In Switzerland, a drug is currently being developed that can normalize blood pressure for a long time. Injections are used in the later stages of the disease, when taking pills does not lead to positive results. Injections also become more effective during a hypertensive crisis. In severe cases, it is recommended to immediately call an ambulance. The most common medications for blood pressure in the form of injections are Enalprilat (a vasoconstrictor), Clonidine (reduces the frequency of heart muscle contractions), Furosemide (a diuretic).

When treating a patient in a hospital setting, medications are administered, the use of which requires constant monitoring of the body’s condition. Nitroglycerin has a vasodilating effect, Metoprolol reduces heart rate, Pentamin has a positive effect on the sympathetic nervous system, lowers blood pressure. These drugs have a large number of side effects, so their use at home is unacceptable.

When treating older people, it should be taken into account that the human body becomes susceptible to many diseases. More attention should be paid to the psycho-emotional state of the patient. Elderly people should be careful about their diet, lead a healthy lifestyle, and maintain a special daily routine.

Drugs should be prescribed to such patients with particular caution.

Side effects in older age are more pronounced due to age-related changes in the body. It is recommended to prescribe drugs with complex action.

Traditional methods

When choosing a particular folk remedy, you should consult your doctor. There are several groups of herbal preparations used in the treatment of hypertension: sedatives (valerian, motherwort), diuretics (bearberry, dill seeds), strengthening the walls of blood vessels (arnica, chokeberry). The most effective are herbal infusions, which include sedative, diuretic and restorative plants. The following mixture gives a good effect in the treatment of hypertension: 10 g each of cornflower and horsetail, 15 g each of hawthorn, valerian root and chokeberry are mixed. 1 tbsp. l. herbal mixture, pour 200 ml of boiling water and leave for half an hour. The medicine is filtered and brought to the original volume with boiled water. The medicine is taken 3 times a day, 1/3 cup.

Medicine for hypertension is prescribed if the patient is at risk. It includes people whose blood pressure consistently exceeds 160/100 mm Hg. Art. For people who fall into the low-risk category, experts first of all advise lifestyle modifications and.

If these measures do not help, doctors prescribe special medications. What are the most effective medications for hypertension?

Blood pressure indicators are influenced by a number of factors that must be taken into account when choosing treatment tactics:

1. Vascular tone. The greater the vascular spasm, the higher the pressure. This indicator depends on the condition of small arteries - arterioles.
2. Circulating blood volume. The higher this indicator, the higher the pressure.
3. Functioning of the heart. The harder it beats, the more blood is pumped. This also provokes an increase in pressure.

To choose the best medicine for hypertension, you need to consult a doctor. Such drugs are prescribed in the following situations:

• When the pressure increases to 160-90 mm Hg. Art.;
• When the indicator increases to 130/85 mm Hg. Art. – this is important for people with heart or kidney failure, as well as diabetes.

It is recommended to give preference to medications that need to be taken once a day, or to medications that last for 12 hours. However, in most cases, doctors prescribe combination therapy, which includes two drugs at once. This allows you to reduce the dosage and minimize the risk of side effects.

Main groups of drugs for hypertension

There are a number of remedies that help reduce blood pressure. To get the desired result and choose the most effective medicine for hypertension, you should consult a doctor.

Beta blockers

These drugs can be used for monotherapy or complex therapy. They give results in the development of a resistant form of the disease. They can be used in the presence of a history of heart attack and angina. Also, these drugs are approved for chronic forms of heart failure and atrial fibrillation.

The mechanism of action of these drugs is based on stopping the production of angiotensin, which leads to vasoconstriction. These medications block beta receptors. Isolated therapy with assistance lasts 2-4 weeks. Your doctor may then prescribe a combination with a diuretic or calcium channel blocker.

Non-selective agents include the following:

• Carvedilol;
• Propranolol;
• Sotalol;
• Oxprenolol.

• Atenolol;
• Bisoprolol;
• Betaxolol.

Alpha blockers

These drugs block alpha-adrenergic receptors, which provides the irritating effects of norepinephrine. This leads to a decrease in blood pressure.

An effective drug in this category is doxazosin. It is used to eliminate attacks of high blood pressure or long-term therapy. However, many other products from this group have now been discontinued.

Calcium antagonists

These drugs are usually divided into several categories:

• Dihydropyridines - this group includes,;
• Benzodiazepines - these include;
• Phenylalkylamines - belongs to this category.

These products increase stress tolerance. They can be used in combination with ACE inhibitors. Thanks to this, it is possible to avoid the use of diuretics.

Calcium antagonists are often prescribed to older people with cerebral atherosclerosis. They are used for a combination of hypertension with angina or arrhythmia.

Angiotensin 2 antagonists

These are relatively new medications for hypertension that successfully lower blood pressure throughout the day. They can be used once a day - in the morning or before bed.

Angiotensin 2 antagonists are relatively new medications for hypertension that successfully lower blood pressure throughout the day.

The maximum duration of action for candesartan is up to 2 days. Also in this group are medications for hypertension that lower blood pressure for 24 hours.

These drugs rarely provoke a dry cough. They do not cause a rapid drop in pressure and do not lead to the development of withdrawal syndrome. A sustainable effect can be achieved 4-6 weeks after the start of therapy.

These modern medications for hypertension can be used for the renal form of the disease, since they eliminate spasm of the vessel wall. Also, these medications can be part of combination therapy for a stable form of the disease.

Diuretics

Thiazide diuretics and sulfonamides, which are included in the category of saluretics, help improve the synthesis and excretion of urine. This ensures a reduction in the swelling of the vessel wall, which leads to an increase in their lumen. Thanks to this, it is possible to reduce pressure.

This category includes hydrochlorothiazide, hypothiazide. These substances prevent the reabsorption of chlorine and sodium ions by the kidney tubules, which provokes their excretion. Medicines from this group do not affect normal blood pressure.

Sulfonamides include, arifon, indal. These drugs are used for complex forms of hypertension. They can also be part of a combination treatment for the development of resistant hypertension.

Indapamide is an approved medicine for hypertension in type 2 diabetes mellitus because it does not affect blood glucose levels.

Angiotensin-converting enzyme inhibitors

These drugs block the enzyme that converts angiotensin into renin. Thanks to their use, it is possible to reduce blood flow to the heart muscle. Drugs from this group become a reliable prevention of cardiac muscle hypertrophy and restore it in the presence of this problem.

ACE inhibitors with the sulfhydryl category are used to eliminate hypertensive crises. These include captopril, benazepril.

ACE inhibitors with a carboxyl group include, lisinopril,. Thus, enalapril has a positive effect on the life expectancy of patients. However, it provokes an undesirable side effect in the form of a dry cough.

How to choose a medicine for hypertension

To choose the safest medicine for hypertension, you need to consult a doctor. When prescribing medications, a specialist takes into account a number of criteria. These include the following:

• Patient's age;
• Pathologies of the cardiovascular system;
• Complications that exist in other organs.

The doctor will select a combination treatment that includes a number of drugs. This will provide a comprehensive effect on the mechanism of hypertension. Taking several medications at once reduces the volume of each of them. This will reduce the risk of side effects.

List of the best drugs for hypertension of the new generation

Each new generation of hypertension medications has many advantages. These include excellent effectiveness of therapy and a minimum of side effects. Today there are two categories of such drugs. These include:

• ACE inhibitors - from this group you can choose a new medicine for hypertension such as lisinopril, monopril or;
• Calcium channel blockers - this category includes lacidipine, nimodipine,.

Effective medications for hypertension have a gentle effect on the body. They do not lead to potency disorders or mental disorders. Thanks to their use, it is possible to improve the quality of life. However, such drugs cannot be used without a doctor’s prescription.

Fast acting high blood pressure tablets

Such drugs are required to eliminate the symptoms of a hypertensive crisis. They should be present in the first aid kit of every person with arterial hypertension. First aid means include the following:

• Nifedipine;
• Clonidine.

Side effects and contraindications

Contraindications directly depend on the category of the drug. However, many drugs are prohibited from being used in the following situations:

• Pregnancy;
• Lactation;
• Obstruction of the biliary tract;
• Complex kidney and liver diseases;
• Bronchial asthma;
• Hypersensitivity to the components of the product;
• Decompensated heart failure;
• Age less than 18 years.

Finding a medicine for hypertension without side effects is quite problematic. Each drug can lead to undesirable health effects. The most common side effects include the following:

• Allergic reactions;
• Pain in the digestive organs;
• Nausea and vomiting;
• Stool disorders;
• A sharp drop in pressure;
• Depressive states;
• Feeling of dryness in the mouth;
• Sleep disorders.

If such symptoms appear, the drug should be discontinued immediately and consult a doctor.. A specialist will be able to select a more suitable analogue. Sometimes symptomatic therapy is required.

The safest medicine for hypertension

So far, there are no medications for hypertension without side effects. Scientists have not been able to develop a substance that will bring the desired result without harm to health.

However, if we consider new drugs, they have many advantages compared to drugs of previous generations. These include the following:

• High efficiency;
• Prolonged action - this makes it possible to minimize the dosage of the drug and minimize the risk of side effects;
• Complex action - this list of drugs for hypertension includes drugs that perform several functions at once.

The category of third generation drugs includes. It causes almost no side effects such as dry mouth or increased drowsiness. This drug is allowed to be used by patients with bronchial asthma and diabetes.

New drugs that have been successfully used to eliminate hypertension include selective imidazoline receptor agonists. They reduce blood pressure, have a minimum of contraindications and very rarely cause side effects. This group includes rilmenidine and monoxidine.

New generation beta blockers that are actively used to combat hypertension include nebivolol and labetalol. They rarely cause side effects and almost do not harm human health. With the help of such means it is possible to prevent the occurrence of complications of hypertension.