Other

Coronary steal. Brain steal syndrome

The toxic effect of drugs can be divided into both general and local, and organ-specific (neuro-, nephro-, hepato-ototoxicity, etc.).

The local toxic effect of drugs can manifest itself, for example, in the form of abscess formation at the site of intramuscular injection of a 40% glucose solution or in the form of phlebitis (inflammation of the vein wall at the site of intravenous administration of the cytostatic drug emhibin.

A general (generalized, systemic) side effect of a drug is characterized by a systemic manifestation of the damaging effect of the drug. For example, orthostatic hypotension after the administration of the ganglion blocker pentamine or severe hypotension after the administration of the class I antiarrhythmic procainamide.

JICs prescribed in therapeutic doses, but capable of cumulating (accumulating) in the body, for example, cardiac glycosides (digoxin, Celanide, etc.), can also exhibit a general toxic effect.

A number of drugs have organ-specific effects, i.e. toxic effect realized in any specific organ:

Neurotoxic (antimicrobial drug - lomefloxacin - insomnia, dizziness);

Hepatotoxic (a/b lincomycin – jaundice);

Nephrotoxic (a/b gentamicin);

Ototoxic, hematotoxic, visual damage, mutagenic.

Oncogenicity is the ability of a drug to cause malignant neoplasms.

Side effects of drugs caused by increased tissue sensitivity

Idiosyncrasy is a congenital hypersensitivity to JIC, usually caused by hereditary (genetic) enzymopathies.

Allergic reactions. If idiosyncrasy develops after the first dose of a drug, then an allergic reaction to the drug always occurs only after it is taken again, i.e. in cases where the patient’s body was previously sensitized to it. In other words, an allergic reaction to a drug is understood as this type of interaction of a drug or its metabolite with the human body, as a result of which a pathological process develops upon repeated administration of the drug.

There are 4 main types of allergic reactions involving drugs.

The second type of allergic reaction of the body to drugs - a cytotoxic reaction - develops when the drug, having first entered the body, forms antigenic complexes with proteins located on the membrane of blood cells. The resulting complexes are perceived by the body as foreign proteins and specific antibodies are produced to them.

A cytotoxic allergic reaction can be caused by penicillin and cephalosporin antibiotics, class I antiarrhythmic quinidine, the centrally acting antihypertensive drug methyldopa, non-steroidal anti-inflammatory drugs from the salicylates group, etc.

The fourth type of allergic reaction of the body to drugs - a delayed-type allergic reaction - develops 24-48 hours after re-taking the drug.

According to the intensity of clinical manifestations, allergic reactions of the body to JIC are divided into fatal, severe, moderate and mild forms.

Fatal allergic reactions, for example, include allergic shock.

An example of severe allergic reactions is, for example, the development of Morgagni-Adams-Stokes syndrome - a reversible sudden loss of consciousness, accompanied by convulsions, pallor, followed by cyanosis, respiratory failure, and severe hypotension. This syndrome can develop as a result of an allergic reaction to the class I antiarrhythmic drug quinidine.

A moderate reaction is, for example, an attack of bronchial asthma in response to repeated intake of the non-steroidal anti-inflammatory drug acetylsalicylic acid, the so-called “aspirin” asthma.

Naturally, severe and moderate manifestations of an allergic reaction to JIC require immediate discontinuation of the drug and special desensitizing therapy.

Mild forms of an allergic reaction, as a rule, do not require special desensitizing therapy and quickly disappear when the drug that caused the allergy is discontinued.

In addition, allergic reactions to drugs are divided according to the time of their occurrence: into acute - they occur instantly or within several hours from the moment of repeated administration of the drug (for example, anaphylactic shock); subacute - occur within a few hours or the first 2 days from the moment of repeated drug administration (for example, thrombocytopenia); delayed or delayed type (for example, serum sickness).

It should also be remembered that it is also possible to develop a cross-allergy to drugs, i.e. in cases where the patient is allergic to some drug, for example, the sulfonamide drug sulfapyridazine, then the first dose of the sulfonamide drug sulfadimethoxine, which is close to it in chemical structure, may develop an allergic reaction

Side effects of drugs caused by changes in the functional state of the body

This type of side effect of drugs can occur in patients suffering from diseases of any organs when drugs are prescribed in average therapeutic doses.

When cardiac glycosides are prescribed in moderate therapeutic doses to patients with acute myocardial infarction, severe cardiac arrhythmias may develop due to the positive inotropic effect caused by these drugs, i.e. strengthening the contractile function of the myocardium, which entails an increase in the heart’s need for oxygen, worsening the condition of the ischemic focus, etc. At the same time, the same patient, before the development of a heart attack, could take cardiac glycosides in average therapeutic doses without developing any side effects.

Drug withdrawal syndrome

In patients, as a rule, taking certain drugs for a long time (antihypertensive drugs of central action, for example, clonidine. Sudden cessation of their use can lead to a sharp deterioration in their condition. For example, if the antihypertensive drug clonidine is suddenly stopped taking the antihypertensive drug clonidine, a hypertensive crisis may develop (details about methods prevention and side effects of JIC.

Steal syndrome

In the broad sense of the word, “steal” syndrome is understood as this type of side effect when a drug that improves the functional state of an organ causes a parallel deterioration in the functional state of other organs or systems of the body. Most often, the “steal” syndrome is observed at the level of the circulatory bloodstream in cases where expansion under the influence of vasodilators of some vascular areas and, consequently, improvement of blood flow in them, leads to deterioration of blood flow in other adjacent vascular areas. This particular type of side effect of drugs can be considered using the example of coronary “steal” syndrome.

Coronary steal syndrome

develops in cases where two branches of the coronary artery arising from the same main vessel, for example, from the left coronary artery, have different degrees of stenosis (narrowing). In this case, one of the branches is slightly affected by atherosclerosis and retains the ability to expand or contract in response to changes in the myocardial oxygen demand. The other branch is significantly affected by the atherosclerotic process and therefore is constantly expanded to the maximum, even with low myocardial oxygen demand. In this situation, prescribing to the patient any arterial vasodilator, for example, dipyridamole, can cause a deterioration in the nutrition of that area of the myocardium that is supplied with blood by the coronary artery affected by atherosclerosis, i.e. provoke an attack of angina.

Rebound syndrome

“Rebound” syndrome is a type of side effect of a drug when, for some reason, the effect of the drug is reversed. For example, the osmotic diuretic drug urea, due to an increase in osmotic pressure, causes the transition of fluid from edematous tissues into the bloodstream, sharply increases blood circulation volume (BCV), which entails an increase in blood flow in the glomeruli of the kidneys and, as a result, greater filtration of urine. However, urea can accumulate in the tissues of the body, increase the osmotic pressure in them and, ultimately, cause the reverse transfer of fluid from the circulation into the tissues, i.e. do not reduce, but increase their swelling.

Drug addiction

Drug dependence is understood as a type of side effect of drugs, which is characterized by a pathological need to take drugs, usually psychotropic ones, in order to avoid withdrawal syndrome or mental disorders that occur when abruptly stopping taking these JIC. There are mental and physical drug dependence.

Mental dependence is understood as a patient’s condition characterized by an unmotivated need to take any drug, often psychotropic, in order to prevent mental discomfort due to stopping the drug, but not accompanied by the development of abstinence.

Physical dependence is a patient’s condition characterized by the development of abstinence syndrome due to cessation of taking a drug or after the administration of its antagonist. Abstinence or withdrawal syndrome is understood as the patient's condition that occurs after stopping the use of any psychotropic drug and is characterized by anxiety, depression, loss of appetite, cramping abdominal pain, headache, trembling, sweating, lacrimation, sneezing, goose bumps, fever bodies, etc.

Drug resistance

Drug resistance is a condition in which there is no effect from taking a drug, which cannot be overcome by increasing the dose and persists even when a dose of the drug is prescribed that always causes side effects. The mechanism of this phenomenon is not always clear; it is possible that it is not based on the patient’s body’s resistance to any drug, but on a decrease in individual sensitivity to the drug, due to the genetic or functional characteristics of a particular patient.

Paramedicinal effects of drugs

The paramedicinal effect of drugs is not due to their pharmacological properties, but to the emotional, psychogenic reaction of the patient to a particular drug.

For example, the patient took the calcium ion antagonist nifedipine, manufactured by AWD (Germany) under the name “Corinfar,” for a long time. At the pharmacy where he usually bought this drug, the drug produced by AWD was not available, and the patient was offered nifedipine under the name “adalat”, produced by Bayer (Germany). However, taking Adalat caused the patient severe dizziness, weakness, etc. In this case, we can talk not about the own side effects of Fedipine, but about a paramedicinal, psychogenic reaction that arose in the patient subconsciously due to the reluctance to exchange Corinfar for a similar drug.

4.Drug interactions

At present, no one doubts that effective therapy for many diseases can only be achieved with the combined use of drugs. The simultaneous prescription of several drugs to one patient is called polypharmacy. Naturally, polypharmacy can be rational, that is, useful for the patient, and vice versa, harm him.

Knowledge of the theoretical and practical aspects of the interaction of drugs with each other is necessary for every practical medical worker, since, on the one hand, they allow, through a rational combination of drugs, to enhance the effect of the therapy, and on the other hand, to avoid complications that arise when using irrational combinations of drugs, in as a result of which their side effects intensify, including death.

So, drug interaction is understood as a change in the pharmacological effect of one or more drugs when used simultaneously or sequentially. The result of such interaction may be an increase in pharmacological effects, i.e. the combined drugs are synergists, or a decrease in the pharmacological effect, i.e. interacting drugs are antagonists.

Synergism is a type of drug interaction in which the pharmacological effect or side effect of one or more drugs is enhanced.

There are 4 types of drug synergy:

sensitization or sensitizing effect of drugs;

additive effect of drugs;

summation of effect;

potentiation of the effect.

An example of the sensitizing effect of drugs can be an increase in the concentration of iron ions in the blood plasma when ascorbic acid (vitamin C) is co-administered with drugs containing iron.

This type of JIC interaction is expressed by the formula 0 + 1 = 1.5.

Steal syndrome is the general name of clinical syndromes caused by unfavorable redistribution of blood between organs and tissues through collaterals, leading to the occurrence or worsening of ischemia. Thus, with occlusion of the superior mesenteric artery, which has anastomoses with the celiac trunk system, mesenteric steal syndrome can be observed: the outflow of blood through the anastomoses causes ischemia of the organs supplied by the branches of the celiac trunk, clinically manifested by abdominal pain. Abdominal pain when walking, which goes away at rest, in patients with damage to the iliac and mesenteric arteries can arise as a result of an actively functioning mesenteric-ilio-femoral collateral circulation. Cerebral steal syndrome with the development of ischemia of a section of brain tissue occurs as a result of worsening circulatory failure in the affected vascular system due to the redistribution of blood flow in favor of the adjacent, usually more intact vascular system. For example, when the subclavian artery is blocked at a certain level, the blood supply in the affected arm is compensated by the vertebral artery on the opposite side, which leads to the development of brain steal syndrome. In this case, with an increase in the functional load on the hand, dizziness, imbalance, and transient visual impairment occur. Worsening of ischemia in the affected area of brain tissue is also possible with the use of vasodilating drugs that affect hl. arr. on intact vessels (eg, papaverine). In angina pectoris, coronary steal syndrome can also develop with the use of certain medications. For example, dipyridamole, expanding the preem. unaffected vessels of the heart, impairs blood supply to the ischemic area of the myocardium. Its intravenous administration is used for diagnostic purposes to provoke myocardial ischemia, detected using radionuclide testing.

The clinical picture is usually characterized by symptoms of vertebrobasilar vascular insufficiency and symptoms of ischemia of the upper limb.

The dominant one, as a rule, is cerebrovascular insufficiency, which usually manifests itself as short-term paroxysmal crises lasting several minutes: headache, dizziness, short-term attacks of loss of consciousness, darkening of the eyes, loss of visual fields, a feeling of rotation of objects, paresthesia, unsteady gait, dysarthria . The attacks usually pass without leaving permanent neurological damage.

It is typical for the condition to worsen or for brain symptoms to appear when blood flow to the upper limb increases, for example after exercising the upper limb.

Signs of ischemia of the upper extremities are usually mildly expressed in the form of fatigue, weakness, numbness, chilliness, and moderate pain when loading the extremities.

During clinical examination, neurological symptoms are usually not detected, but signs of arterial insufficiency of the upper extremities are detected - decreased skin temperature, decreased blood pressure, noise in the neck during auscultation.

The exact topical diagnosis and the nature of blood flow reversal are established using angiography.

Differential diagnosis is aimed at establishing the cause that caused vertebrobasilar vascular insufficiency: occlusive vascular lesions, pathological tortuosity, anomaly, compression of the vertebral artery or still syndrome. This is necessary for choosing a method of surgical treatment. In addition, it is important to identify possible multiple lesions of the brachiocephalic arteries.

It is necessary to exclude intracranial tumors, cerebral hemorrhage, intracranial aneurysms, embolism of cerebral vessels and extracranial arteries, Meniere's syndrome, eye diseases, spondylosis and other pathologies of the cervical spine.

Aortoarteriography data, as well as other clinical and special research methods (radiography of the skull and cervical spine, examination of the fundus and neurological status) are of decisive importance for establishing a diagnosis.

“CLINICAL PHARMACOLOGY Approved by the Ministry of Education of the Russian Federation as a textbook for students of medical schools and colleges UDC 615 BBK 52.8J K 85 Reviewers: ...”

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An increase in drug reabsorption may also play an important role in the development of toxic effects. Therefore, reducing the reabsorption of drugs during an overdose is a way to combat intoxication. For example, in case of poisoning with acetylsalicylic acid, the urine becomes acidified, as a result of which the molecules of acetylsalicylic acid are in non-ionized form and are easily reabsorbed, i.e. their excretion decreases. In this case, alkalinization of urine by administering sodium bicarbonate to the patient causes the acetylsalicylic acid molecules to become more ionized, i.e. less soluble in fats and, as a consequence, will be less reabsorbed, which will entail increased excretion of acetylsalicylic acid by the kidneys.

Excretion of drugs by the liver. Drugs metabolized by the liver can be excreted in the bile into the intestine. In this case, part of the drug is eliminated with feces, and part of the drug is reabsorbed into the blood plasma as a result of deconjugation under the influence of intestinal enzymes. This phenomenon is called gastrointestinal or enterohepatic circulation. The ability of the liver to excrete drugs with bile can also be used for therapeutic purposes.

For example, for inflammatory diseases of the biliary tract, antibiotics are prescribed that are excreted by the liver unchanged (for example, tetracycline, erythromycin), which leads to a sharp increase in their concentration in the bile and the implementation of local antimicrobial action.

Excretion of drugs by the lungs. Mainly gaseous drugs (inhalation anesthetics) and ethyl alcohol are excreted from the body through the lungs. Excretion of ethanol (ethyl alcohol) by the lungs is of great practical importance, since the ethanol content in exhaled air is directly proportional to its content in the blood.

Drugs can also be excreted from the body through sweat, tear fluid, saliva, vaginal secretions, etc. However, from a practical point of view, these ways of removing drugs from the body are not of significant importance.

A special place is occupied by the excretion of drugs with the milk of a nursing mother. This is due to the fact that the drugs in milk, once they enter the body of a newborn, can have a wide variety of effects on him, including damaging ones (this issue will be discussed in detail later - see page 83).

CHAPTER 4 INCIDENTAL

EFFECT OF MEDICINES

It has now become obvious that drugs used in the treatment of various diseases can themselves cause the development of severe pathological conditions. According to statistics, drugs exhibit their harmful effects in 10-20% of outpatients and in 25-50% of patients undergoing intensive care. Moreover, in 0.5% of cases, these harmful effects of drugs are life-threatening, and in 0.2% of patients they lead to death.

In accordance with the currently accepted definition by the World Health Organization (WHO), a side effect of a drug includes “any reaction to a drug that is harmful or undesirable for the body, which occurs when it is used for the treatment, diagnosis and prevention of diseases.”

From a practical point of view, it is necessary to distinguish between the side (toxic) effect of a drug and the side (concomitant) effect of a drug. The term “side effect of a drug” always refers to the harmful effect of a drug on the patient’s body. For example, the calcium channel blocker nifedipine causes swelling of the lower extremities in many patients; class III antiarrhythmic amiodarone causes pigment deposition in the cornea of the eye; The centrally acting antihypertensive drug methyldopa causes orthostatic hypotension in most patients in the first week of administration. A side (concomitant) effect of a drug is understood as a spectrum of pharmacological effects of a drug that do not harm the health of patients, but are “useless” in the treatment of this particular pathology. For example, the spectrum of pharmacological activity of acetylsalicylic acid includes its anti-inflammatory (the drug was created as a non-steroidal anti-inflammatory and antipyretic agent) and anti-aggregation properties. Currently, acetylsalicylic acid is widely used as an antiplatelet agent for the prevention of thrombotic complications in patients with coronary artery disease and the prevention of transient cerebrovascular accidents. The anti-inflammatory and antipyretic properties included in the spectrum of its pharmacological activity are harmless but also useless for this category of patients.

In principle, side effects are divided into two main groups:

1. A side effect of a drug, noted in most patients when the dose of the drug is increased and associated with exceeding the usually known pharmacological effect.

Such adverse reactions include orthostatic hypotension, characteristic of many drugs (hypotensive - apressin, clonidine, pentamine, etc., antiarrhythmics - novocaine-amide, neuroleptic aminazine, etc.), hypoglycemia (sharp decrease in blood sugar, for example, after use non-selective (3-blocker propranolol), hypokalemia (a sharp decrease in the level of potassium in the blood, for example, when taking thiazide or loop diuretics), arrhythmogenicity (i.e. the ability to cause or increase cardiac arrhythmias) in many antiarrhythmic drugs, etc. .

2. Side effects of drugs that are not related to their known pharmacological action.

This group of adverse drug reactions consists of: immunologically determined side effects (see details on page 51) and genetically determined adverse reactions. For example:

in patients suffering from the genetically determined disease von Willebrand disease (angiohemophilia - a hereditary disease characterized by a sharp increase in bleeding time due to a reduced level of blood clotting factor VIII in the body), even the administration of small doses of acetylsalicylic acid can cause massive bleeding;

Prescribing the antimicrobial drug primaquine to patients with a genetically determined deficiency of the enzyme glucose-6-phosphodehydrogenase, which plays an important role in the metabolism of carbohydrates (including in red blood cells), can lead to the development of a hemolytic crisis (massive breakdown of red blood cells in the bloodstream).

This type of side effect of drugs is called idiosyncrasy.

Idiosyncrasy, as a rule, is caused by congenital enzymopathy (absence or impaired activity of any enzymes). However, idiosyncrasy can also be acquired. In this case, enzymopathy develops as a result of previous or existing diseases.

Another classification of side effects of drugs is based on their pharmacokinetic characteristics:

side effects of drugs that occur at their therapeutic concentrations in the blood plasma (bronchial spasm when using non-selective (3-blockers);

side effects of drugs that occur at toxic concentrations in the blood plasma, i.e., with an overdose of drugs;

a side effect of drugs that is not related to their concentration in the blood plasma (dysbacteriosis, i.e. qualitative and quantitative disturbances of the natural intestinal microflora caused by long-term use of antibiotics).

However, for medical practitioners, the most convenient classification of side effects of drugs is based on the pathogenetic principle:

side effects of drugs associated with their pharmacological properties;

toxic complications caused by relative and absolute overdose of drugs;

side effects of drugs caused by increased tissue sensitivity (idiosyncrasy, allergic reactions);

side effects of drugs caused by the peculiarities of the functional state of the body;

withdrawal syndrome;

"steal" syndrome;

rebound syndrome;

drug addiction;

drug resistance;

paramedicinal side effects of drugs.

4.1. Side effects of drugs associated with their pharmacological properties This type of side effect is understood as a pharmacological effect that develops when taking drugs in therapeutic doses and is caused by their influence on the same type of receptors located in various organs and tissues of the body, or on other types of receptors and/ or specialized areas of receptive tissues of target organs. This type of side effect of drugs is quite widespread. For example:

The non-selective β- and β2-adrenergic blocker propranolol, by blocking β-adrenergic receptors of the heart muscle, reduces the frequency and strength of heart contractions.

This effect of the drug has found its application in the treatment of patients with coronary artery disease and arterial hypertension. At the same time, the drug also blocks β2-adrenergic receptors located in the bronchi, causing an increase in the tone of their smooth muscles, which in patients with broncho-obstructive syndrome can provoke bronchospasm, i.e. propranolol in moderate therapeutic doses, influencing the 3-adrenergic receptors of the heart and lungs, on the one hand, has a positive effect in ischemic heart disease, and on the other hand, a harmful side effect, manifested by a worsening of the broncho-obstructive syndrome;

The drug nifedipine, by blocking slow calcium channels in vascular smooth muscle cells, mainly arterioles, lowers blood pressure, i.e. forms a therapeutic hypotensive effect, and at the same time has a similar effect on intestinal smooth muscle cells, promoting the development of constipation, i.e. has side, harmful effects on the body.

Another example of a side effect of drugs associated with their pharmacological properties. The cardiotonic (increasing force of heart contractions) effect of cardiac glycosides used in the treatment of heart failure is associated with their ability to block the membrane K+-, Ia+-ATPase of contractile cardiomyocytes (muscle cells of the heart). Blockade of membrane ATPase of vascular smooth muscle cells by cardiac glycosides leads to their contraction and, thereby, to an increase in total peripheral resistance, i.e.

a harmful side effect of the drug is realized, since an increase in total peripheral resistance increases the afterload on the heart muscle.

4.2. Toxic complications caused by relative and absolute overdose of drugs As a rule, the development of the toxic (damaging) effect of a drug is based on an excessive increase in its concentration. in blood plasma and/or organs and tissues of the body.

Such a damaging effect of drugs, on the one hand, can be caused by an overdose, i.e. taking an excessive amount of the drug, and on the other hand, a violation of its pharmacokinetics (decreased binding to protein and, as a consequence, an increase in the content of its active fraction in the blood plasma;

slowdown of biotransformation; decreased renal excretion, etc.).

The toxic effect of drugs can be divided into both general and local, and organ-specific (neuro-, nephro-, hepato-, ototoxicity, etc.).

The local toxic effect of drugs can manifest itself, for example, in the form of an abscess at the site of intramuscular injection of a 40% glucose solution or in the form of phlebitis (inflammation of the vein wall) at the site of intravenous administration of the cytostatic drug emhibin.

A general (generalized, systemic) side effect of a drug is characterized by a systemic manifestation of the damaging (harmful) effect of the drug. For example, orthostatic hypotension after the administration of the ganglion blocker pentamine or severe hypotension after the administration of the class I antiarrhythmic procainamide. A systemic toxic effect may include inhibition of hematopoiesis during treatment with cytostatics. Quite often, toxic effects occur in drugs that have a small therapeutic breadth and are treated for a long time (for example, class I antiarrhythmics - quinidine, novocainamide, allapinine, etc.; cardiac glycosides, etc.).

Drugs prescribed in therapeutic doses, but capable of cumulating (accumulating) in the body, for example, cardiac glycosides (digoxin, Celanide, etc.), can also exhibit a general toxic effect.

The general toxic effect of a drug can also be caused by a violation of the functional state of the organ through which it is excreted from the body. In these cases, the drug prescribed in a therapeutic dose will gradually accumulate in the body, resulting in its concentration exceeding the therapeutic one. For example, when the metabolic function of the liver is impaired, lipophilic drugs accumulate in the body (hypnotics, tranquilizers, indirect anticoagulants, etc.), and when the excretory function of the kidneys is impaired, drugs excreted in the urine accumulate in the body (for example, cardiac glycosides - strophanthin and corglycone).

A number of drugs have an organ-specific effect, i.e. a toxic effect realized in any specific organ.

Neurotoxic (damaging tissue of the nervous system) effect. For example, the antimicrobial drug from the fluoroquinolone group, lomefloxacin, causes insomnia, dizziness, and headache; An antibiotic from the tetracycline group, minocycline, causes vestibular disorders, dizziness, and ataxia.

Another example of a neurotoxic effect is the CNS-damaging effect of the local anesthetic novocaine and the class I antiarrhythmic drug novocainamide, which is similar in chemical structure. When administered intravenously, dizziness, paresthesia (unpleasant sensations, often in the extremities, manifested by numbness, tingling, burning, “crawling”, etc.), motor agitation, etc. may develop.

The antibiotic for treating tuberculosis patients, cycloserine, can even cause the development of psychoses, hallucinations, and pseudoepileptic seizures.

Hepatotoxic (damaging liver tissue) effect. For example, lincosamide antibiotics (lincomycin and clindamycin) cause jaundice with an increase in the level of hepatic transaminases in the blood plasma, indicating damage to the liver tissue.

Nephrotoxic (damaging kidney tissue) action develops due to the fact that most drugs secreted by the kidneys can cause damage to kidney tissue due to direct contact with them. The development of so-called drug nephropathy can be caused by drugs such as aminoglycoside antibiotics (amikacin, gentamicin, kanamycin), a drug containing gold (crisanol), bismuth salts (bijoquinol and bismoverol), etc.

Ototoxic (damaging to hearing organs) effect. For example, long-term use of aminoglycoside antibiotics can lead to hearing loss, including the development of irreversible deafness.

Most cytostatic agents have a hematotoxic (inhibitory) effect, since in addition to their effect on tumor cells, they usually have an inhibitory effect on the hematopoietic system (bone marrow).

Damage to the organs of vision. For example, the class III antiarrhythmic amiodarone, which contains iodine in its chemical structure, can cause microdetachment of the retina, optic neuritis, and the cornea of the eye may acquire a bluish tint.

Special types of organotoxic effects of drugs include mutagenic (damaging the chromosomal apparatus of male and female germ cells, as well as the fetus). Drugs that have a mutagenic effect, as a rule, are not widely used in the clinic due to their ability to cause chromosomal aberrations (deviations from the normal chromosome structure), i.e. the ability to have a potentially damaging effect on the fetus. Typically, therapy with mutagenic drugs is carried out only for health reasons - for the treatment of cancer patients with cytostatics or suppressing the immune system with immunosuppressants in order to prevent tissue incompatibility reactions during organ and tissue transplantation, etc. In these cases, patients must be warned about the possibility of a mutagenic effect of the drug and a minimum period of time during which they should refrain from conceiving children must be specified. For example, patients taking the immunosuppressant azathioprim are advised to abstain from conceiving children for 3 months for men and for one year after stopping the drug. Cytostatic drugs especially often cause chromosomal aberrations in both therapeutic and toxic doses.

If the number of mutagenic drugs in the clinic is insignificant, then the number of drugs that have a damaging effect on the fetus is quite large and, unfortunately, this type of side effect of drugs cannot always be identified at the preclinical stage of drug study. For example, widespread use in the early 1960s of GT. The sleeping pill thalidomide led to the fact that about 7,000 children were born in Germany and England with congenital pathology of the limbs. Only after the congress of gynecologists in the city.

Kiel (Germany) managed to find out that the basis of this pathology is the damaging effect of thalidomide on the fetus.

The complexity of this issue also lies in the fact that up to 60-80% of pregnant women during pregnancy often take drugs without consulting a doctor, i.e. self-medicate.

Depending on the timing of pregnancy, there are 3 types of damaging effects of drugs on the fetus: embryotoxic (0-3 weeks.

after fertilization); teratogenic (4-10 weeks after fertilization); fetotoxic (10-36 weeks after fertilization).

The features of the damaging effect of drugs on the fetus will be discussed in detail below (see page 85).

Also, oncogenicity is classified as a special type of drug toxicity.

Oncogenicity is the ability of a drug to cause malignant neoplasms. If such a side effect is detected in a drug, it is immediately prohibited from clinical use.

4.3. Side effects of drugs caused by increased tissue sensitivity Idiosyncrasy is a congenital hypersensitivity to drugs, usually caused by hereditary (genetic) enzymopathies (discussed in detail - p. 46).

Allergic reactions. If idiosyncrasy develops after the first dose of a drug, then an allergic reaction to the drug always occurs only after taking it again, that is, in cases where the patient’s body was previously sensitized to it. In other words, an allergic reaction to a drug is understood as this type of interaction of a drug or its metabolite with the human body, as a result of which a pathological process develops upon repeated administration of the drug.

Since most drugs have a relatively small molecular weight, they cannot be considered as complete antigens (substances with a fairly large molecular weight - proteins, peptides, polysaccharides, etc.), but are incomplete antigens - haptens. Drugs become a complete antigen only after they enter the patient’s body and form a complex with proteins.

There are 4 main types of allergic reactions involving drugs.

The first type of allergic reaction of the body to drugs is reagin (or immediate type allergic reactions - anaphylaxis). This type of allergic reaction develops in cases where drugs that first enter the body sensitize tissues and become fixed on mast cells. In this case, immunoglobulin E (IgE) acts as an antibody, which interacts with mast cell receptors. When taking the same drugs again, immunoglobulin E stimulates the release of so-called allergy mediators - histamine, bradykinin, prostaglandins, serotonin, etc. The result of a sharp release of allergy mediators into the blood is a decrease in blood pressure, increased capillary permeability, tissue swelling, etc. up to the development of anaphylactic shock. Allergic reactions of the reagin type can be caused by various vaccines, serums, antibiotics of the penicillin group, local anesthetic novocaine, etc.

The resulting complexes are perceived by the body as foreign proteins and specific antibodies are produced to them.

When taking drugs repeatedly, antibodies interact with antigenic complexes located on the membrane of blood cells, resulting in the development of an immune cytotoxic reaction. In cases where an immune cytotoxic reaction occurs on the platelet membrane, thrombocytopenia develops (a decrease in the number of platelets in the blood plasma), and if the reaction occurs on the erythrocyte membrane, hemolytic anemia develops, etc.

The third type of allergic reaction of the body to drugs - the formation of toxic immune complexes - develops in cases where the drug, having first entered the body, causes the formation of toxic immune complexes with the participation of immunoglobulins M and G (IgM, IgG), the largest part of which is formed in endothelial cells vessels. When drugs re-enter the body, damage to the vascular wall occurs due to the release of biologically active substances (bradykinin, histamine, etc.). Lymphocytes are attracted to the reaction zone and an inflammatory process develops. Clinically, this manifests itself as vasculitis, alveolitis, nephritis, etc. This type of allergic reaction includes serum sickness, which is manifested by fever, joint pain, swollen lymph nodes, and itchy skin rash. The disease develops gradually and reaches its maximum by 8-10 days from the moment of re-taking the drug.

The fourth type of allergic reaction of the body to drugs - a delayed-type allergic reaction - develops 24-48 hours after the drug is re-administered. When a drug enters the patient’s body for the first time, it causes the appearance of antigen-specific receptors on T-lymphocytes. Upon repeated admission, drug molecules interact with sensitized T-lymphocytes, resulting in the release of biologically active substances - lymphokinins, for example, interleukin-2, which have a damaging effect on tissue. This type of allergic reaction usually develops with the transdermal method of using drugs, for example, the Mantoux and Pirquet tests (allergy tests for the diagnosis of tuberculosis).

According to the intensity of clinical manifestations, allergic reactions of the body to drugs are divided into fatal, severe, moderate and mild forms.

Fatal allergic reactions, for example, include allergic shock.

A moderate reaction is, for example, an attack of bronchial asthma in response to repeated intake of the non-steroidal anti-inflammatory drug acetylsalicylic acid, the so-called “aspirin” asthma.

Naturally, severe and moderate manifestations of an allergic reaction to drugs require immediate discontinuation of the drug and special desensitizing therapy.

Mild forms of an allergic reaction, as a rule, do not require special desensitizing therapy and quickly disappear when the drug that caused the allergy is discontinued.

In addition, allergic reactions to drugs are divided according to the time of their occurrence: acute - they occur instantly or within several hours from the moment of re-administration of the drug (for example, anaphylactic shock); subacute - occur within a few hours or the first 2 days from the moment of repeated administration of drugs (for example, thrombocytopenia); delayed or delayed type (for example, serum sickness).

It should also be remembered that it is also possible to develop a cross-allergy to drugs, i.e. in cases where the patient is allergic to some drug, for example, the sulfonamide drug sulfapyridazine, then an allergic reaction may develop upon the first dose of the sulfonamide drug sulfadimethoxine, which is close to it in chemical structure.

4.4. Side effects of drugs caused by changes in the functional state of the body This type of side effect of drugs can occur in patients suffering from diseases of any organs when drugs are prescribed in average therapeutic doses.

strengthening the contractile function of the myocardium, which entails an increase in the heart’s need for oxygen, worsening the condition of the ischemic focus, etc. At the same time, the same patient, before the development of a heart attack, could take cardiac glycosides in average therapeutic doses without developing any side effects.

If a patient has a prostate adenoma, if he is prescribed in moderate therapeutic doses a drug that has an M-anticholinergic (atropine-like) effect, for example, the class I antiarrhythmic disopyramide, acute urinary retention may develop due to the drug reducing the tone of the smooth muscles of the bladder and increasing the tone of the sphincters bladder. In patients who do not suffer from prostate adenoma, the development of acute urinary retention is unlikely when disopyramide is used in moderate therapeutic doses. Acute urinary retention in patients with prostate adenoma can also be caused by narcotic analgesics (for example, morphine), which cause an increase in the tone of the bladder sphincter.

There are a lot of similar examples, but the greatest clinical significance is the violation of the pharmacodynamics and pharmacokinetics of drugs when they are prescribed in average therapeutic doses to patients suffering from liver and kidney disease. In patients with this type of disease, both the metabolic rate and the rate of elimination from the body of a wide variety of drugs may be impaired, as a result of which their concentration in the blood plasma increases and their toxic effect is realized. Therefore, for this category of patients, drug doses are selected strictly individually.

For example, in patients with reduced renal excretory function, the dose of drugs eliminated (excreted) by the kidneys is selected strictly depending on the amount of renal clearance. Currently, for drugs excreted by the kidneys, the annotations provide a dosage calculation for patients with impaired renal excretory function. For example, when prescribing the antiviral drug acyclovir to patients of this kind, it is always dosed as follows: when creatinine clearance (CC) is more than 50 ml/min, it is prescribed at 5 mg/kg every 8 hours, when CC decreases to 25-50 ml/min - 5 mg/kg every 12 hours, with CC 10-25 ml/min - 5 mg/kg every 24 hours, and with CC below 10 ml/min - 2.5 mg/kg every 24 hours immediately after hemodialysis .

4.5. Drug withdrawal syndrome

In patients who, as a rule, take certain drugs for a long time (antihypertensive drugs of central action, for example, clonidine, (3-blockers - propranolol, indirect anticoagulants - neodicoumarin, antianginal drugs from the group of organic nitrates and others), sudden cessation of their use may lead to This will lead to a sharp deterioration in their condition. For example, if you suddenly stop taking the antihypertensive drug clonidine, a hypertensive crisis may develop (for details on methods of prevention and side effects of drugs, see page 242).

4.6. Steal syndrome

Coronary steal syndrome develops when two branches of the coronary artery arising from the same main vessel, for example, the left coronary artery, have different degrees of stenosis (narrowing). In this case, one of the branches is slightly affected by atherosclerosis and retains the ability to expand or contract in response to changes in the myocardial oxygen demand. The other branch is significantly affected by the atherosclerotic process and therefore is constantly expanded to the maximum, even with low myocardial oxygen demand. In this situation, prescribing to the patient any arterial vasodilator, for example, dipyridamole, can cause a deterioration in the nutrition of that area of the myocardium that is supplied with blood by the coronary artery affected by atherosclerosis, i.e. provoke an attack of angina (Fig. 10).

Rice. 10. Scheme of development of coronary “steal” syndrome:

A, B, A", Z" - Diameters of the coronary artery The branch of the coronary artery A affected by atherosclerosis is maximally expanded in order to ensure adequate blood supply to the area of the myocardium irrigated by it (see Fig. 10, a).

After the administration of a coronary agent, i.e. With a drug that dilates the coronary arteries, for example, dipyridamole, the coronary vessels dilate and, therefore, the volumetric velocity of coronary blood flow through them increases. However, vessel A had already been maximally expanded (diameter A is equal to diameter L"). The vessel located nearby expands (diameter B is less than diameter B"), as a result of which the volumetric flow rate of blood flow in vessel B increases, and in vessel A ", according to the laws of hydrodynamics, decreases significantly. In this case, a situation is possible when the direction of blood in vessel A" changes and it begins to flow into vessel B" (see Fig. 10, 6).

4.7. Rebound syndrome

“Rebound” syndrome is a type of side effect of a drug when, for some reason, the effect of the drug is reversed. For example, the osmotic diuretic drug urea, due to an increase in osmotic pressure, causes the transition of fluid from edematous tissues into the bloodstream, sharply increases blood circulation volume (BCV), which entails an increase in blood flow in the glomeruli of the kidneys and, as a result, greater filtration of urine. However, urea can accumulate in the tissues of the body, increase the osmotic pressure in them and, ultimately, cause the reverse transfer of fluid from the circulatory bed into the tissues, i.e. do not reduce, but increase their swelling.

4.8. Drug dependence Drug dependence is understood as a type of side effect of drugs, which is characterized by a pathological need to take drugs, usually psychotropic ones, in order to avoid withdrawal syndrome or mental disorders that occur when taking these drugs abruptly. There are mental and physical drug dependence.

4.9. Drug resistance Drug resistance is a condition in which there is no effect from taking a drug, which cannot be overcome by increasing the dose and persists even when a dose of the drug is prescribed that always causes side effects. The mechanism of this phenomenon is not always clear; it is possible that it is not based on the patient’s body’s resistance to any drug, but on a decrease in individual sensitivity to the drug, due to the genetic or functional characteristics of a particular patient.

4.10. Paramedicinal effect of drugs The paramedicinal effect of drugs is not due to their pharmacological properties, but to the emotional, psychogenic reaction of the patient to a particular drug.

For example, the patient had been taking the calcium ion antagonist nifedipine, manufactured by AWD (Germany) under the name “Corinfar,” for a long time. At the pharmacy where he usually bought this drug, the drug produced by AWD was not available, and the patient was offered nifedipine under the name “adalat”, produced by Bayer (Germany). However, taking Adalat caused the patient severe dizziness, weakness, etc. In this case, we can talk not about the own side effects of nifedipine, but about a paramedicinal, psychogenic reaction that arose in the patient subconsciously due to the reluctance to exchange Corinfar for a similar drug.

CHAPTER 5 INTERACTION

MEDICINES

In practical healthcare settings, doctors very often have to deal with a situation where the same patient has to prescribe several drugs at the same time. This is largely due to two fundamental reasons.

L Currently, no one doubts that effective therapy for many diseases can only be achieved with the combined use of drugs. (For example, hypertension, bronchial asthma, gastric ulcer, rheumatoid arthritis and many, many others.)

2. Due to the increasing life expectancy of the population, the number of patients suffering from combined pathology, which includes two, three or more diseases, is constantly increasing, which, accordingly, requires the prescription of several drugs simultaneously and/or sequentially.

The simultaneous prescription of several drugs to one patient is called polypharmacy. Naturally, polypharmacy can be rational, i.e. useful for the patient, and vice versa, harm him.

As a rule, in practical conditions, the prescription of several drugs simultaneously for the treatment of one specific disease has 3 main goals:

increasing the effectiveness of therapy;

reducing the toxicity of drugs by reducing the doses of combined drugs;

prevention and correction of side effects of drugs.

In this case, combined drugs can affect both the same parts of the pathological process and different parts of the pathogenesis.

For example, a combination of two antiarrhythmics ethmosin and disopyramide, which belong to class IA antiarrhythmic drugs, i.e. drugs that have similar mechanisms of action and realize their pharmacological effects at the level of the same link in the pathogenesis of cardiac arrhythmias provide a high level of antiarrhythmic effect (66-92% of patients). Moreover, this high effect is achieved in most patients when using drugs in doses reduced by 50%. It should be noted that during monotherapy (therapy with one drug), for example, supraventricular extrasystole, disopyramide at the usual dose was active in 11% of patients, and ethmozin - in 13%, and with monotherapy at half the dose, a positive effect could not be achieved in any from patients.

In addition to influencing one link of the pathological process, a combination of drugs is very often used to correct different links of the same pathological process. For example, in the treatment of hypertension, a combination of calcium channel blockers and diuretics may be used.

Calcium channel blockers have powerful vasodilating (vasodilating) properties, mainly in relation to peripheral arterioles, reducing their tone and thereby helping to lower blood pressure. Most diuretics lower blood pressure by increasing the excretion (removal) of Na+ ions in the urine, reducing blood volume and extracellular fluid, and reducing cardiac output, i.e. two different groups of drugs, acting on different parts of the pathogenesis of hypertension, enhance the effectiveness of antihypertensive therapy.

An example of combining drugs to prevent side effects is the prescription of nystatin to prevent the development of candidiasis (fungal infections of the mucous membranes) during long-term treatment with antibiotics such as penicillin, tetracycline, neomycin, etc., or the prescription of drugs containing K+ ions to prevent the development of hypokalemia during treatment with cardiac glycosides in patients with heart failure.

Knowledge of the theoretical and practical aspects of the interaction of drugs with each other is necessary for every practical medical worker, since, on the one hand, they allow, through a rational combination of drugs, to enhance the effect of the therapy, and on the other hand, to avoid complications that arise when using irrational combinations of drugs, as a result of which their side effects increase, including death.

Synergism is a type of drug interaction in which the pharmacological effect or side effect of one or more drugs is enhanced.

There are 4 types of drug synergy:

sensitization or sensitizing effect of drugs;

additive effect of drugs;

summation of effect;

potentiation of the effect.

When sensitization occurs as a result of the use of several drugs that have different, often heterogeneous, mechanisms of action, the pharmacological effect of only one of the drugs included in the combination is enhanced. For example, the therapeutic effect of a polarizing mixture used in the clinic of acute myocardial infarction (500 ml of 5% glucose solution, 6 units of insulin, 1.5 g of potassium chloride and 2.5 g of magnesium sulfate is based on this principle. In the absence of potassium chloride and magnesium sulfate, they can be replaced with 20 ml of panangin solution). The mechanism of action of this combination is based on the ability of glucose and insulin to enhance the transmembrane flow of K+ ions into the heart cell, which makes it possible to prevent or stop cardiac arrhythmias.

Another example of the sensitizing effect of drugs may be an increase in the concentration of iron ions in the blood plasma when ascorbic acid (vitamin C) is co-administered with drugs containing iron.

This type of drug interaction is expressed by the formula 0 + 1 = 1.5.

The additive effect of a drug is a type of interaction in which the pharmacological effect of a combination of drugs is greater than the effect of each individual drug included in the combination, but less than the mathematical sum of their effect. For example, the therapeutic effect of the joint administration of the adrenal stimulant salbutamol and the phosphodiesterase inhibitor theophylline to patients suffering from bronchial asthma. Salbutamol and theophylline have bronchodilator properties, i.e. bronchodilator effect. Let us assume that the administration of salbutamol alone expands the lumen of the bronchi by 23%, and theophylline by 18%. When drugs are prescribed together, the lumen of the bronchi expands by 35%, i.e. the therapeutic effect of the combination is greater than the effect of each individual drug, but less than the mathematical sum of their individual effects (23% + 18% = 41%).

This type of drug interaction is expressed by the formula 1 + 1 = 1.75.

As a result of the summation of drug effects, the pharmacological effect of a drug combination is equal to the mathematical sum of the pharmacological effects of each of the jointly prescribed drugs. For example, the joint administration of two diuretics ethacrynic acid and furosemide (belonging to the “loop” group

diuretics, i.e. having a similar mechanism of action) in patients with heart failure leads to the summation of their diuretic effect.

This type of interaction is expressed by the formula 1 + 1=2.

Potentiation of the effect of a drug is a type of interaction in which the pharmacological effect of a combination of drugs is greater than the mathematical sum of the pharmacological effects of each individual drug prescribed together. For example, the hypertensive effect in shock from the administration of a combination of the glucocorticosteroid prednisolone and the α-adrenergic agonist norepinephrine, or the bronchodilator effect from the administration of a combination of the same prednisolone and the phosphodiesterase inhibitor aminophylline in status asthmaticus.

This type of drug interaction is expressed by the formula 1 + 1 = 3.

In drug antagonism, as a result of the combined use of several drugs, the pharmacological effect of one or more drugs included in this combination is weakened or blocked. For example, when organic nitrates and 3-adrenergic receptor blockers are jointly prescribed for the treatment of coronary artery disease, the latter, by blocking Pj-receptors of the heart, prevent the development of reflex tachycardia caused by nitroglycerin preparations.

This type of interaction is expressed by the formula 1 + 1 = 0.5.

Naturally, both synergism and antagonism of drugs can lead not only to optimization of the therapeutic effect, but also have an undesirable, harmful effect on the patient’s body.

For example, when combining aminoglycoside antibiotics and loop diuretics (furosemide, ethacrynic acid), their ototoxic side effects are mutually enhanced; with the combined use of tetracycline antibiotics and aminoglycoside antibiotics, pharmacological antagonism develops, as a result of which their antimicrobial activity is leveled.

The interaction of drugs with each other is based on 4 main mechanisms that determine the main types of their interaction:

pharmaceutical or physicochemical interaction;

pharmacodynamic interaction;

physiological interaction;

pharmacokinetic interaction.

5.1. Peculiarities of pharmaceutical drug interactions This type of drug interaction refers to the physico-chemical processes that occur during the combined use of drugs before their introduction into the patient’s body (in a syringe, dropper, etc.) and/or at the injection site, or in the lumen of the gastrointestinal tract and etc. This situation develops when drugs that enter into a simple chemical interaction are used in combination. For example:

It is known that cardiac glycosides precipitate in the presence of tannins in the solution. Adding hawthorn extract containing tannins to drops containing tincture of lily of the valley and motherwort leads to precipitation of cardiac glycosides of lily of the valley;

When a solution of the phosphodiesterase inhibitor aminophylline with the antihistamine diphenhydramine or aminophylline and the cardiac glycoside strophanthin is mixed in one syringe, a white suspension is formed - “milk”. This is due to the fact that the pH of the aminophylline solution is 9.0-9.7, the pH of the solution of diphenhydramine and strophanthin is 5.0-5.7, i.e. one solution is alkaline and the other is acidic. Due to a simple chemical interaction of drugs, a neutralization reaction occurs, as a result of which the mixed drugs lose their pharmacological activity.

The same reactions can occur in the lumen of the gastrointestinal tract when drugs are co-administered per os. In this case, drugs can enter into simple chemical interactions not only with each other, but also with food and/or digestive juices, although the latter can be attributed to the peculiarities of pharmacokinetic interactions of drugs (see below). This happens when, in the lumen of the gastrointestinal tract, one of the combined drugs enters into a physicochemical interaction with another, as a result of which it loses its pharmacological activity. For example:

anti-sclerotic (antilipidemic) drug cholestyramine, being an ion-exchange resin in its mechanism of action, when co-administered with drugs such as indirect anticoagulants (neodicoumarin, phenylin, etc.), cardiac glycosides (digoxin, digitoxin), non-steroidal anti-inflammatory drugs (butadione, acetylsalicylic acid acid, etc.) due to the release of C1~ ions, converts them into insoluble, inactive compounds;

the effectiveness of therapy with indirect anticoagulants (neodicoumarin, phenylin, etc.) largely depends on the composition of the food:

If the diet includes a large amount of ingredients containing vitamin K (leafy vegetables - cabbage, spinach, etc.), then due to antagonism with vitamin K, the anticoagulants will lose their activity.

5.2. Features of pharmacodynamic interaction of drugs As mentioned above (see page 19), most drugs realize their pharmacological effects at the receptor level.

This is where their pharmacological interaction occurs. Currently, there are 4 main types of pharmacological interactions of drugs at the receptor level:

competition of drugs for binding to the receptor;

changes in the kinetics of drug binding at the receptor level;

interaction of drugs at the level of mediators;

change in receptor sensitivity under the influence of a combination of drugs.

Competition of drugs for binding to the receptor. Compete, i.e. drugs of both unidirectional action (agonist-agonist; antagonist-antagonist) and opposite action (agonist-antagonist) can fight for communication with the receptor. The competitiveness of drugs in relation to the receptor mainly depends on the degree of their affinity for it. Competition between drugs for binding to the receptor can have both positive therapeutic significance and be extremely dangerous for the patient’s body. For example: to treat an overdose of M-cholinergic receptors, which are agonists of cholinergic receptors, atropine is usually used, a blocker of cholinergic receptors, which, due to its greater affinity for cholinergic receptors, displaces cholinomimetics and thereby stops their action, i.e. has a positive therapeutic effect.

However, the prescription of the same atropine as an antispasmodic (for example, for renal colic) to patients receiving the Mcholinomimetic pilocarpine for the treatment of glaucoma may be accompanied by a sharp increase in intraocular pressure and, as a consequence, vision loss. This is based on 2 mechanisms:

greater affinity for the M-cholinergic receptor of the antagonist atropine than the agonist pilocarpine, and the ability of pilocarpine to increase the sensitivity of M-cholinergic receptors.

Changes in drug kinetics at the receptor level. This type of drug interaction implies a change by one drug in the processes of local transport of another or a change in its distribution at the site of action (in the biophase). As a rule, these processes occur in the area of receptors specific to these drugs and are directly determined by the peculiarities of their mechanism of action.

For example, a change in the pharmacological activity of the sympatholytic octadine against the background of the prescription of tricyclic antidepressants (for example, imipramine). The mechanism of action of octadin is based on its ability to deplete norepinephrine reserves in adrenergic synapses and thereby reduce high blood pressure.

Octadine can penetrate adrenergic synapses only with the help of a specific transport system. Tricyclic antidepressants, by blocking the activity of enzymes that ensure the penetration of octadine into adrenergic synapses, prevent the implementation of its hypotensive effect.

Interaction of drugs at the mediator level. As is well known, mediators are biologically active substances secreted by nerve endings and transmitting a nerve impulse (signal) at the synapse from the presynaptic to the postsynaptic ending. There are three main types of effects of drug combinations on mediators:

Type I - blockade by one drug of subsequent stages of action of another drug at the level of one biological process. For example, when the central α2-adrenergic receptor stimulant methyldopa and the ganglion blocker pentamine are co-administered, a consistent blockade of the process of blood pressure regulation occurs. Methyldopa, by stimulating central α2-adrenoreactive receptors, activates inhibitory processes in the central nervous system, leading to a decrease in sympathetic stimulation to the vessels, and pentamine, by blocking impulse transmission in the sympathetic ganglia, also reduces sympathetic impulses to the vessels.

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Temporary improvement can be obtained by reducing myocardial oxygen demand with medications ( β-blockers) or by improving coronary blood flow ( nitrates, calcium antagonists). However, repeated ischemic episodes may occur.

The only real way to treat hibernating myocardium is timely revascularization, performed before the development of irreversible morphological changes in the myocardium.

Fixed and dynamic obstruction of the coronary arteries

Fixed Coronary obstruction causes a permanent decrease in blood flow, usually corresponding to the degree of atherosclerotic narrowing of the coronary arteries. Clinical manifestations of myocardial ischemia in patients with fixed coronary obstruction, as a rule, develop when the coronary artery narrows in excess of 70%.

Dynamic obstruction is associated: (1) with increased tone and spasm of the coronary artery, (2) thrombus formation. The addition of a dynamic component of obstruction leads to episodes of ischemia even with hemodynamically insignificant narrowing of the coronary artery.

To characterize the severity of coronary obstruction, not only the degree of narrowing of the coronary arteries at rest, but also the severity of the decrease in coronary reserve is of great importance. Coronary reserve refers to the ability of the coronary vessels to dilate and, as a result, increase blood flow when the load on the heart increases.

The development of dynamic obstruction in atherosclerotic lesions of the coronary vessels is caused by impaired reactivity of the coronary arteries and activation of thrombogenic mechanisms. These processes are facilitated by systemic endothelial dysfunction, which occurs, for example, with hyperhomocysteinemia, diabetes mellitus, dyslipoproteinemia and other diseases.

Impaired reactivity of coronary arteries affected by atherosclerosis is caused by the following mechanisms:

Reduced formation of vasodilators;

Reduced bioavailability of vasodilators;

Damage to smooth muscle cells of the coronary vessels.

Increased thrombogenicity in atherosclerotic damage to the coronary arteries and ischemia is explained by the following factors:

Increased formation of thrombogenic factors (tissue thromboplastin, plasminogen activator inhibitor, von Willebrand factor, etc.);

Reducing the formation of atrombogenic factors (antithrombin III, proteins C and S, prostacyclin, NO, tissue plasminogen activator, etc.).

The significance of dynamic obstruction increases with endothelial damage and destabilization of the atherosclerotic plaque, which leads to platelet activation, the development of local spasm and acute thrombotic occlusive complications, in particular acute coronary syndrome.

Thus, atherosclerotic lesions of the coronary vessels, in addition to a mechanical reduction in the lumen of the vessel (fixed obstruction), can be the cause of dynamic obstruction.

The phenomenon of stealing

The phenomenon of coronary steal consists of a sharp decrease in coronary blood flow in the myocardial zone, supplied with blood from a partially or completely obstructed coronary artery with an increase in the number of vasodilators, as well as with physical activity.

The steal phenomenon occurs as a result of blood flow redistribution and can form either within the basin of one epicardial artery (intracoronary steal), or between the blood supply basins of different coronary arteries in the presence of collateral blood flow between them (intercoronary steal).

With intracoronary steal at rest, there is a compensatory maximum expansion of the arteries of the subendocardial layer with a loss of their sensitivity to vasodilators, while the arteries of the epicardial (outer) layer still retain the ability to expand under the influence of vasodilators. With physical exertion or the predominance of humoral vasodilators, rapid expansion of the epicardial arteries occurs. This leads to a decrease in resistance in the segment “poststenotic area - epicardial arterioles” and a redistribution of blood flow in favor of the epicardium with depletion of the subendocardial blood supply.

Rice. 1.9. Mechanism of intracoronary steal phenomenon

(according to Gewirtz N., 2009).

For intercoronary steal phenomenon a “donor” section of the heart is distinguished, which receives blood from a normal artery, and an “acceptor” section, which lies in the vascularization zone of the stenotic artery. At rest, the “donor” region supplies blood to the “acceptor” region due to collaterals. Under these conditions, the arterioles of the “acceptor” region are in a state of submaximal dilatation and are practically insensitive to vasodilators, and the arteries of the “donor” region fully retain the ability to dilate. The occurrence of a vasodilator stimulus leads to dilation of the arterioles of the “donor” region and a redistribution of blood flow in its favor, which causes ischemia of the acceptor region. The more developed the collaterals between the normal and ischemic parts of the heart, the greater the likelihood of intercoronary steal.

Rice. 1.9. The mechanism of the intercoronary steal phenomenon

Drug interaction is a change in the pharmacological effect of one or more drugs when used simultaneously or sequentially (increased effect - synergists, decreased effect - antagonists).

Aspects of pharmacotherapy

1. selection of drugs for joint use (to enhance the therapeutic effect and reduce side effects, it is advisable to prescribe drugs with different mechanisms of action);

2. achieving selectivity of action:

Structure modification - synthesis of drugs similar to natural biologically active substances (hormones, enzymes);

Selective delivery of drugs - improving the technology of manufacturing dosage forms with targeted delivery of drugs to the affected organ.

Quantitative aspects of pharmacotherapy:

1. drug doses;

2. breadth of therapeutic action - the range between the minimum toxic and minimum therapeutic dose;

3. The effectiveness of a drug is the ability of a drug to provide the maximum possible effect.

Synergy - a type of drug interaction characterized by an increase in the pharmacological effect or side effect of one or more drugs.

Types of synergy:

1. sensitizing effect of drugs(interaction formula - 0 + 1 = 1.5) - enhancing the pharmacological effect of only one of the combination of drugs (polarizing mixture - glucose and insulin enhance the effect of potassium, ascorbic acid enhances the effect of iron);

2. additive effect of drugs(interaction formula - 1 + 1 = 1.75) - a type of interaction in which the pharmacological effect of a combination of drugs is greater than the effect of each individual drug included in the combination, but less than the mathematical sum of their effect (salbutamol + theophylline);

3. summation of effect(interaction formula - 1 + 1 = 2) - type of interaction in which the pharmacological effect of a combination of drugs is equal to the mathematical sum of the effects of each of the jointly prescribed drugs (ethacrynic acid + furosemide);

4. potentiation of effect(interaction formula - 1 + 1 = 3) - a type of interaction in which the pharmacological effect of a combination of drugs is greater than the mathematical sum of the effects of each individual drug (prednisolone + norepinephrine, prednisolone + aminophylline).

Antagonism of drugs(interaction formula - 1 + 1 = 0.5) - weakening or blocking the pharmacological action of one or more drugs included in the combination of drugs (nitrates + β 1 -blockers - reduction of reflex tachycardia caused by nitrates; astringents and laxatives; hypotensive and hypertensive means).

Synergism and antagonism have both positive and harmful effects on the patient’s body (aminoglycosides + loop diuretics - mutual enhancement of ototoxic side effects; tetracyclines + aminoglycosides - leveling of antimicrobial activity).

Pharmaceutical or physicochemical interaction - This is an interaction characterized by physicochemical processes that occur during the joint use of drugs before their introduction into the patient’s body (in a syringe, in a dropper, at the injection site, in the lumen of the gastrointestinal tract). Combinations are not compatible: sodium bicarbonate + valerian + papaverine; lily of the valley + motherwort + hawthorn extract; aminophylline + diphenhydramine; aminophylline + strophanthin; cholestyramine + indirect anticoagulants or cardiac glycosides or acetylsalicylic acid. Physico-chemical interaction can occur without external signs, but the formation of a precipitate in solutions, a change in their color, and the release of gas are possible.

Pharmacodynamic interaction- this is the interaction of drugs at the receptor level.

Types of interaction at the receptor level:

1. competition of drugs for binding to the receptor (atropine - pilocarpine);

2. change in the kinetics of drug binding at the receptor level - a change in the transport or distribution of another drug by one drug (sympatholytic octadin - tricyclic antidepressants);

3. interaction of drugs at the level of mediators (three types of influence):

Blockade by one drug of subsequent stages of action of another drug at the level of one biological process (methyldopa - pentamine);

Violation by one drug of the possible interaction of a mediator with a receptor (prozerin - atropine);

Violation by one drug of the metabolic pathways, distribution, binding or transport of a mediator involved in the implementation of the effect of another drug (ephedrine - antidepressant nialamide);

4. change in receptor sensitivity under the influence of a combination of drugs (fluorotane - adrenaline, cardiac glycosides - β-blockers).

Physiological interaction- interaction of drugs at the level of the physiological systems of the body through a complex therapeutic effect on different parts of the pathogenesis of the same pathological process (for hypertension - diuretics + calcium antagonists + ACE inhibitors; combined contraceptives).

Pharmacokinetic interaction - a change by one drug in the plasma concentration of another drug due to a change in the rate of its absorption, distribution, binding to plasma proteins, metabolism and/or excretion.

Features of drug interaction at the site of absorption. The interaction of drugs mainly occurs through the enteral route of administration, but is also possible through the parenteral route.

Factors influencing the interaction of drugs in the gastrointestinal tract:

1. changes in the pH of gastric juice (antacids - decreased absorption of indirect anticoagulants, non-steroidal anti-inflammatory drugs, sulfonamides, barbiturates);

2. the presence of cations in the gastrointestinal tract (the presence of cations Ca ++, Fe ++, Al +++, Mg ++ in the intestine slows down the absorption of many drugs; ferrous sulfate - tetracyclines, drinking paracetamol with milk);

3. direct interaction of drugs in the lumen of the gastrointestinal tract (cholestyramine - indirect anticoagulants);

4. impaired gastrointestinal motility (drugs, anticholinergics, antidepressants slow down the evacuation of gastric contents and intestinal motility and change the rate of absorption of many drugs; slowing intestinal motility increases the concentration of cardiac glycosides and glucocorticosteroids in the blood; laxatives reduce the effect of many drugs);

5. peculiarities of blood supply to the gastrointestinal tract (in case of heart failure - decreased absorption of drugs);

6. interaction of drugs with food (captopril, acetylsalicylic acid together with food - decreased effect; propranolol, lobetalol - increased effect; spicy seasonings that irritate the gastrointestinal mucosa of drugs - decreased effect).

When administered parenterally, the effect of novocaine in combination with adrenaline is enhanced.

Features of drug interaction at the distribution level.

Factors influencing the interaction of drugs:

1. blood flow speed (in heart failure, cardiac glycosides enhance the effect of diuretics; reducing the effect of diuretics in hypotension);

2. state of the microcirculatory bed;

9. drug resistance;

10. Paramedicinal side effects of drugs.

4. According to the severity of the current:

1. fatal, i.e. that can lead to death (for example, anaphylactic shock);

2. severe, requiring immediate drug withdrawal and corrective measures;

3. moderate severity, not requiring corrective measures (only drug withdrawal is necessary, for example, for urticaria);

4. mild, not requiring drug withdrawal (for example, the sedative effect of clonidine).

Side effects of drugs associated with their pharmacological properties occurs when taking a drug in a therapeutic dose due to the effect of the drug on various receptors of organs and tissues of the body (propranolol - bronchospasm, nifedipine - constipation, cardiac glycosides - increased peripheral resistance).

Toxic complications caused by relative and absolute overdose of drugs, are characterized by an excessive increase in the concentration of drugs in the blood plasma and/or organs and tissues due to taking an excessive amount of the drug or a violation of its pharmacokinetics (decreased binding to protein, slower biotransformation, decreased excretion, etc.).

Types of toxic effects of drugs:

1. local action (abscess, phlebitis);

2. general (generalized, systemic) effect - manifests itself in case of drug overdose, in case of accumulation of individual drugs in a therapeutic dose, in case of disturbance of the functional state of the excretory organ;

3. organ-specific action:

Neurotoxic (lomefloxacin, cycloserine);

Hepatotoxic (lincosamides);

Nephrotoxic (aminoglycosides, crizanol, bijoquinol, bismoverol);

Ototoxic (aminoglycosides);

Hematotoxic (cytostatics);

Ophthalmotoxic (amiodarone);

Mutagenic effect (immunosuppressants);

Oncogenic effect.

Side effects of drugs caused by increased tissue sensitivity manifested by idiosyncrasy and allergic reactions.

Idiosyncrasy- this is a congenital hypersensitivity to drugs, usually caused by hereditary enzymopathies and develops upon the first dose of drugs.

Allergic reactions - immunopathological reactions that develop after repeated use of drugs in sensitized people.

Types of allergic reactions:

1. immediate type hypersensitivity reactions (reagin type with the participation of IgE interacting with mast cell receptors that secrete biologically active substances: histamine, bradykinin, prostaglandin, serotonin): anaphylactic shock, Quincke's edema, acute urticaria, etc. - vaccines, serums, local anesthetics, penicillin;

2. cytotoxic reactions (formation of antibodies to “drug + protein” complexes on the membranes of blood cells): thrombocytopenia, hemolytic anemia - penicillins, cephalosporins, quinidine, salicylates;

3. immunocomplex reactions (formation of immune complexes with the participation of IgM and IgG in vascular endothelial cells): vasculitis, alveolitis, nephritis, serum sickness;

4. delayed-type hypersensitivity reactions (formation of sensitized T-lymphocytes with the presence of antigen-specific receptors and the release of biologically active substances (lymphokinins) when drugs interact with them): Mantoux and Pirquet allergy tests, etc.

Classification of allergic reactions:

1. According to the intensity of clinical manifestations:

1. fatal (deadly): anaphylactic shock;

2. severe: Morgagni-Adams-Stokes syndrome - quinidine;

3. moderate severity: attack of bronchial asthma - aspirin;

4. lungs.

2. By time of occurrence:

1. acute (seconds - hours): anaphylactic shock, Quincke's edema;

2. subacute (hours - 2 days): thrombocytopenia;

3. slow or delayed (days): serum sickness.

Side effects of drugs caused by changes in the functional state of the body, occurs in patients suffering from diseases of any organs when drugs are prescribed in therapeutic doses (cardiac glycosides - arrhythmias in myocardial infarction; anticholinergics, morphine - acute urinary retention in prostate adenoma; in diseases of the liver and kidneys - various side effects).

Drug withdrawal syndrome occurs when a person suddenly stops taking certain drugs for a long time (clonidine - hypertensive crisis, propranolol, neodicoumarin, nitrates - deterioration of the patient's condition).

Steal syndrome is characterized by a parallel deterioration in the functional state of other organs or systems of the body along with an improvement in the condition of the main organ (chime - an attack of angina in atherosclerosis of the coronary arteries).

Rebound syndrome characterized by a change in the pharmacological effect to the opposite (urea - tissue edema).

Drug addiction characterized by a pathological need to take drugs.

There are mental and physical drug dependence.

Mental dependence - state , characterized by an unmotivated need to take any drug in order to prevent mental discomfort due to stopping taking the drug, but not accompanied by the development of abstinence.

Physical dependence - a condition characterized by the development of withdrawal syndrome due to cessation of taking a drug (psychotropic drugs) or after the administration of its antagonist. Withdrawal (withdrawal syndrome) is characterized by symptoms: anxiety, depression, loss of appetite, abdominal cramps, headache, sweating, lacrimation, sneezing, fever, goose bumps.

Drug resistance- a condition characterized by the absence of a pharmacological effect, even when a toxic dose of drugs is prescribed.

Paramedicinal action of drugs is not due to their pharmacological properties, but to the emotional, psychogenic reaction of the patient to this or that drug (replacing Corinfar with Adalat - dizziness, weakness).