Interaction of drugs. Effects when taking drugs together Antagonism in the action of pharmacological substances

AT modern world there is a huge number medicines. In addition to the fact that each of them has specific physical and chemical properties, they are still participants in certain reactions in the body. So, for example, with the simultaneous use of two or more drugs, they can interact with each other. This can lead to both mutual strengthening of the action of one or both agents (synergism), and their weakening (antagonism).

The second type of interaction will be discussed in detail below. So, antagonism in pharmacology. What's this?

Description of this phenomenon

The definition of antagonism in pharmacology comes from the Greek: anti - against, agon - struggle.

This is the type in which there is a weakening or disappearance therapeutic effect one or each of them. In this case, the substances are divided into two groups.

1. Agonists are those that, when interacting with biological receptors, receive a response from them, thereby exerting their effect on the body.
2. Antagonists are those that are unable to stimulate receptors on their own, as they have zero intrinsic activity. The pharmacological effect of such substances is due to interaction with agonists or mediators, hormones. They can occupy both the same receptors and different ones.

One can speak of antagonism only if exact dosages and specific pharmacological effects of drugs. For example, with a different quantitative ratio, a weakening or complete absence the actions of one or each, or, on the contrary, their strengthening (synergism) may occur.

An accurate assessment of the degree of antagonism can only be given using graphing. This method clearly demonstrates the dependence of the relationship between substances on their concentration in the body.

Types of drug interactions with each other

Depending on the mechanism, there are several types of antagonism in pharmacology:

• physical;
• chemical;
• functional.

Physical antagonism in pharmacology - the interaction of drugs with each other is due to their physical properties. For example, activated carbon is an absorbent. When poisoned by any chemicals the use of coal neutralizes their action and removes toxins from the intestines.

Chemical antagonism in pharmacology - the interaction of drugs due to the fact that they enter into chemical reactions with each other. This type has found great application in the treatment of poisoning with various substances.

For example, with cyanide poisoning and the introduction of sodium thiosulfate, the process of sulfonation of the former occurs. As a result, they turn into less dangerous thiocyanates for the body.

The second example: in case of poisoning with heavy metals (arsenic, mercury, cadmium and others), "Cysteine" or "Unithiol" are used, which neutralize them.

The types of antagonism listed above are united by the fact that they are based on processes that can occur both inside the organism and in the environment.

Functional antagonism in pharmacology differs from the two previous ones in that it is possible only in the human body.

This species is divided into two subspecies:

• indirect (indirect);
• direct antagonism.

In the first case, drugs affect different elements of the cell, but one eliminates the effect of the other.

For example: curare-like drugs ("Tubocurarine", "Ditilin") act on skeletal muscles through cholinergic receptors, while they eliminate convulsions, which are side effect strychnine on neurons spinal cord.

Direct antagonism in pharmacology

This type requires more detailed study, as it includes many different options.

In this case, the drugs act on the same cells, thereby suppressing each other. Direct functional antagonism is divided into several subspecies:

• competitive;
• non-equilibrium;
• not competitive;
• independent.

Competitive antagonism

Both substances interact with the same receptors, while acting as rivals for each other. The more molecules of one substance bind to the cells of the body, the fewer receptors molecules of another can occupy.

Lots of medicines enter into competitive direct antagonism. For example, Diphenhydramine and Histamine interact with the same H-histamine receptors, while they are competitors for each other. The situation is similar with the pairs of substances:

• sulfonamides ("Biseptol", "Bactrim") and (abbreviated: PABA);
• phentolamine - adrenaline and norepinephrine;
• hyoscyamine and atropine - acetylcholine.

In the examples listed, one of the substances is a metabolite. However, competitive antagonism is also possible in cases where none of the compounds is such. For example:

• "Atropine" - "Pilocarpine";
• "Tubocurarine" - "Ditilin".

At the heart of the mechanisms of action of many drugs is an antagonistic relationship with other substances. So sulfonamides, competing with PABA, have an antimicrobial effect on the body.

The blocking of choline receptors by Atropine, Ditilin and some other drugs is explained by the fact that they compete with acetylcholine in synapses.

Many drugs are classified precisely on the basis of their belonging to antagonists.

Disequilibrium antagonism

With nonequilibrium antagonism, two drugs (an agonist and an antagonist) also interact with the same bioreceptors, but the interaction of one of the substances is almost irreversible, since after that the activity of the receptors is significantly reduced.

The second substance fails to successfully interact with them, no matter how much it tries to have an effect. This is the kind of antagonism in pharmacology.

An example that is the most striking in this case: dibenamine (in the role of an antagonist) and norepinephrine or histamine (in the role of agonists). In the presence of the former, the latter are unable to exert their maximum effect even at very high dosages.

Noncompetitive antagonism

Non-competitive antagonism is that one of the drugs interacts with the receptor outside its active site. As a result, the effectiveness of interaction with these receptors of the second drug is reduced.

An example of such a ratio of substances is the effect of histamine and beta-agonists on the smooth muscles of the bronchi. Histamine stimulates H1 receptors on cells, thereby causing bronchial constriction. Beta-agonists ("Salbutamol", "Dopamine") act on beta-adrenergic receptors and cause bronchial dilation.

Independent antagonism

With independent antagonism, drugs act on different receptors of the cell, changing its function in opposite directions. For example, spasm of smooth muscles caused by carbacholine as a result of its action on the m-cholinergic receptors of muscle fibers is reduced by adrenaline, which relaxes smooth muscles through adrenoreceptors.

Conclusion

It is extremely important to know what antagonism is. In pharmacology, there are many types of antagonistic relationships between drugs. This must be taken into account by doctors when simultaneously prescribing several drugs to the patient and the pharmacist (or pharmacist) when they are dispensed from the pharmacy. This will help avoid unforeseen consequences. Therefore, in the instructions for the use of any drug there is always a separate paragraph on the interaction with other substances.

Reverse agonism is the initiation of an overt cellular response by inhibition of spontaneous receptor activation.

Molecular response for reverse agonism can be:
inactivation of the activated receptor;
stabilization of the receptor in an inactive conformation.

This model looks like RR and I+RIR, where R is the activated state, I is the inverse agonist.

Antagonism is to prevent the action of the agonist. Many drugs bind to the receptor to form a drug-β complex that does not elicit a cellular response. Moreover, occupation of the receptor by the antagonist prevents either the binding of the agonist or the elicitation of a cellular response when the agonist binds to the receptor. Thus, antagonism may result from various molecular mechanisms. Mathematical description of effects various types antagonists are listed below. Briefly - antagonism can occur due to:

Bindings antagonist in the same receptor site normally occupied by an agonist. Antagonist binding prevents the agonist from occupying the center (competitive antagonism);

Bindings antagonist with a receptor site that is not normally occupied by an agonist (allosteric center), leading to conformational changes in the agonist binding center, which either prevents agonist binding or makes it impossible for a molecular response to occur.

Antagonist that binds to the allosteric center only in the absence of an agonist is called a non-competitive antagonist. If an antagonist can bind to an allosteric center even in the presence of a bound agonist, it is called a non-competitive antagonist. In this case, the center is often referred to as a ligand-binding center (where the ligand can be an agonist, antagonist, partial agonist, etc.).

Binding Antagonist may be reversible or irreversible. There are at least six possible types of antagonism. The effects exhibited by the antagonist in response to the action of the agonist are described in detail below.

Physiological antagonism different from pharmacological antagonism. Often the term "physiological (or functional) antagonism" is used incorrectly. This term describes the ability of an agonist (more often than an antagonist) to inhibit the response to another agonist by activating different, physically separate receptors. This can occur if two agonist receptors share the same cellular response components but act differently on them, or are linked by different cellular response components that elicit opposite tissue responses.

visual example is the interaction between norepinephrine and acetylcholine in arterioles. Norepinephrine causes contraction and acetylcholine causes relaxation. Of course, it is meaningless to describe norepinephrine as an acetylcholine antagonist, since acetylcholine can also be regarded as a norepinephrine antagonist, so the terms "agonist" and "antagonist" become interchangeable and do not make sense. The term "antagonist" is best used to describe drugs that inhibit the molecular response to an agonist. The term "functional antagonist" is best avoided.

Interaction of drugs.

Antagonism, synergy, their types. The nature of the change in the effect of drugs (activity, effectiveness) depending on the type of antagonism.

In the interaction of drugs, the following conditions may develop: a) strengthening the effects of a combination of drugs b) weakening the effects of a combination of drugs c) drug incompatibility

Strengthening the effects of a combination of drugs is implemented in three ways:

1) Summation of effects or additive interaction- view drug interaction in which the effect of the combination is equal to the simple sum of the effects of each of the drugs taken separately. i.e. 1+1=2 . It is typical for drugs from the same pharmacological group that have a common target of action (the acid-neutralizing activity of a combination of aluminum and magnesium hydroxide is equal to the sum of their acid-neutralizing abilities separately)

2) synergism - a type of interaction in which the effect of a combination exceeds the sum of the effects of each of the substances taken separately. i.e. 1+1=3 . Synergism can relate to both desired (therapeutic) and undesirable effects of drugs. The combined administration of the thiazide diuretic dichlothiazide and ACE inhibitor enalapril leads to an increase in the hypotensive effect of each of the drugs, which is used in the treatment of hypertension. However, the simultaneous administration of aminoglycoside antibiotics (gentamicin) and the loop diuretic furosemide causes a sharp increase in the risk of ototoxicity and the development of deafness.

3) potentiation - a type of drug interaction in which one of the drugs, which in itself does not have this effect, can lead to a sharp increase in the action of another drug. i.e. 1+0=3 (clavulanic acid does not have an antimicrobial effect, but is able to enhance the effect of the b-lactam antibiotic amoxicillin due to the fact that it blocks b-lactamase; adrenaline does not have a local anesthetic effect, but when added to the ultracaine solution, it sharply lengthens its anesthetic effect by slowing down absorption anesthetic from the injection site).

Weakening effects Drugs when used together are called antagonism:

1) Chemical antagonism or antidotism- chemical interaction of substances with each other with the formation of inactive products (chemical antagonist of iron ions deferoxamine, which binds them into inactive complexes; protamine sulfate, the molecule of which has an excess positive charge - a chemical antagonist of heparin, the molecule of which has an excess negative charge). Chemical antagonism underlies the action of antidotes (antidotes).

2) Pharmacological (direct) antagonism- antagonism caused by the multidirectional action of 2 drugs on the same receptors in tissues. Pharmacological antagonism can be competitive (reversible) and non-competitive (irreversible):

A) competitive antagonism: a competitive antagonist reversibly binds to the active center of the receptor, i.e. shields it from the action of the agonist. Since the degree of binding of a substance to the receptor is proportional to the concentration of this substance, the effect of a competitive antagonist can be overcome if the concentration of the agonist is increased. It will displace the antagonist from the active center of the receptor and cause a full tissue response. That. a competitive antagonist does not change the maximum effect of the agonist, but a higher concentration is required for the agonist to interact with the receptor. Competitive antagonist Shifts the dose-response curve for the agonist to the right relative to baseline values ​​and increases the EC50 for the agonist without affecting the E value Max.

In medical practice, competitive antagonism is often used. Since the effect of a competitive antagonist can be overcome if its concentration falls below the level of the agonist, it is necessary to constantly maintain its level sufficiently high during treatment with competitive antagonists. In other words, clinical effect competitive antagonist will depend on its elimination half-life and the concentration of the full agonist.

B) non-competitive antagonism: a non-competitive antagonist binds almost irreversibly to the active center of the receptor or interacts in general with its allosteric center. Therefore, no matter how the concentration of the agonist increases, it is not able to displace the antagonist from its connection with the receptor. Since, the part of the receptors that is associated with a non-competitive antagonist is no longer able to be activated , E valueMax decreases, while the affinity of the receptor for the agonist does not change, so the EC50 value remains the same. On the dose-response curve, the action of a non-competitive antagonist appears as a compression of the curve about the vertical axis without shifting it to the right.

Scheme 9. Types of antagonism.

A - a competitive antagonist shifts the dose-effect curve to the right, i.e., reduces tissue sensitivity to the agonist without changing its effect. B - non-competitive antagonist reduces the magnitude of the tissue response (effect), but does not affect its sensitivity to the agonist. C - option of using a partial agonist against the background of a full agonist. As the concentration increases, the partial agonist displaces the full agonist from the receptors and, as a result, the tissue response decreases from the maximum response to the full agonist to the maximum response to the partial agonist.

Non-competitive antagonists are rarely used in medical practice. On the one hand, they have an undeniable advantage, since their action cannot be overcome after binding to the receptor, and therefore does not depend on either the half-life of the antagonist or the level of the agonist in the body. The effect of a non-competitive antagonist will be determined only by the rate of synthesis of new receptors. But on the other hand, if an overdose occurs this medicine, it will be extremely difficult to eliminate its effect.

Losartan is a competitive antagonist for angiotensin AT1 receptors; it disrupts the interaction of angiotensin II with receptors and helps to reduce blood pressure. The effect of losartan can be overcome if a high dose of angiotensin II is administered. Valsartan is a non-competitive antagonist for the same AT1 receptors. Its action cannot be overcome even with the introduction of high doses of angiotensin II.

Of interest is the interaction that takes place between full and partial receptor agonists. If the concentration of a full agonist exceeds the level of a partial agonist, then a maximum response is observed in the tissue. If the level of the partial agonist begins to rise, it displaces the full agonist from its binding to the receptor, and the tissue response begins to decrease from the maximum for the full agonist to the maximum for the partial agonist (i.e., the level at which it will occupy all the receptors).

3) Physiological (indirect) antagonism- antagonism associated with the influence of 2 drugs on different receptors (targets) in tissues, which leads to a mutual weakening of their effect. For example, physiological antagonism is observed between insulin and adrenaline. Insulin activates insulin receptors, which increases the transport of glucose into the cell and lowers the level of glycemia. Adrenaline activates b2-adrenergic receptors of the liver, skeletal muscles and stimulates the breakdown of glycogen, which ultimately leads to an increase in glucose levels. This type of antagonism is often used in rendering emergency care patients with an overdose of insulin, which led to hypoglycemic coma.

Patients who are on inpatient treatment are prescribed from 4 - 6 to 10 medicines. Along with the means of therapy for the underlying disease, the number of drugs taken by the patient includes restorative drugs, substances for the treatment of comorbidities and complications of the underlying disease. Combination drugs can interact as synergists, antagonists and synergists.

Synergy

Synergy (gr. synergos- acting together) - strengthening the action of one drug by another. Distinguish between summed and potentiated synergism.

summed synergy, or addition(lat. additio- addition) - the action of the combination is equal to the arithmetic sum of the effects of the combined drugs. It is typical for drugs of the same pharmacological group that affect the same cytoreceptors, cells, organs (synergism of general anesthetics for inhalation anesthesia, paracetamol and ibuprofen for chronic pain).

potent synergy, or superaddition - the effect of the combination exceeds the arithmetic sum of the effects of the combined drugs. Occurs as a result of pharmacokinetic and pharmacodynamic mechanisms:

change in absorption - adrenomimetics, narrowing blood vessels, prevent absorption into the blood local anesthetics with an increase in their local anesthetic effect; substances that create an acidic environment in the digestive tract (ascorbic acid, acetylsalicylic acid), increase the absorption of drugs with the properties of weak acids (salicylates, indomethacin, furosemide, indirect anticoagulants, sulfonamides, tetracycline); on the contrary, antacids that cause a pH shift to the alkaline side activate the absorption of bases (alkaloids, tranquilizers, antihistamines);

Displacement of drugs from association with blood proteins - anti-inflammatory drugs butadion and indomethacin release anticoagulants and sugar-lowering drug glibenclamide from association with albumin, with the risk of bleeding and hypoglycemia, respectively;

Increased membrane permeability - insulin facilitates the penetration of glucose and potassium ions through the cell membrane;

Inhibition of metabolism - anticholinesterase agents prolong and enhance the action of acetylcholine; aldehyde dehydrogenase blocker teturam potentiates the effects of the product of the oxidation of ethyl alcohol - acetaldehyde; cytochrome inhibitors R-450 increase the effect of drugs with metabolic clearance;

· the effect of drugs on various systems of regulation of functions and synergistic cytoreceptors - potentiated anesthesia with the use of muscle relaxants, tranquilizers, analgesics; a significant increase in the hypotensive effect of vasodilators when co-administered with diuretics.

Possible synergy side effects medicines. So, with the joint appointment of aminoglycoside antibiotics (streptomycin, kanamycin, gentamicin) and diuretic drugs (furosemide, ethacrynic acid), the risk of oto- and vestibulotoxic complications increases; the introduction of calcium chloride into a vein during therapy with cardiac glycosides causes arrhythmia.

Antagonism

Antagonism is accompanied by a weakening of the action of one drug by another. There are several types of antagonism.

1. Physical antagonism- reduction of absorption into the blood and resorptive action:

adsorbents (activated carbon, ion-exchange resin cholestyramine) prevent the absorption of many drugs taken orally; saline laxatives (magnesium and sodium sulfates), increasing the osmotic pressure in the intestinal lumen, delay the absorption of drugs dissolved in intestinal juice;

ions of calcium, magnesium, iron form non-absorbable complexes with tetracycline, chloramphenicol, sulfonamides, acetylsalicylic acid, butadione;

means that create an acidic or alkaline environment in the digestive tract, inhibit the absorption of drugs with the properties of bases or acids, respectively;

The vasoconstrictor adrenaline reduces the absorption of drugs injected under the skin or into muscles.

2. Chemical antagonism - chemical interaction of drugs in the blood with the formation of inactive products. Chemical antagonists are potassium permanganate, sodium thiosulfate, a donator of sulfhydryl groups unithiol, complexing agents disodium salt of ethylenediaminetetraacetic acid, tetacin-calcium and other antidotes used to treat poisoning. For example, sodium thiosulfate converts toxic molecular iodine into non-toxic iodides, cyanides into safe thiocyanates:

3. Physiological (functional) antagonism - the interaction of drugs that have a multidirectional effect on the functions of cells and organs. Physiological antagonism is divided into indirect and direct:

indirect antagonism - the result of action on various cells (adrenomimetic adrenaline dilates pupils due to contraction of the radial muscle of the iris, cholinomimetic acetylcholine constricts pupils, causing contraction of the circular muscle);

Direct antagonism - the result of action on the same cells: non-competitive antagonism occurs when drugs bind to different cytoreceptors, competitive antagonism - between agonists and antagonists of some cytoreceptors.

Examples of non-competitive antagonism are bronchial constriction by histamine, which excites H 1-receptors of smooth muscles, and expansion of the bronchi with β-adrenergic agonists; antagonism between acetylcholinesterase blockers and cholinergic receptor blockers.

Competitive antagonists are M-cholinomimetic pilocarpine and M-anticholinergic atropine; a-adrenomimetic norepinephrine and a-blocker phentolamine; histamine and blocker H 2-receptor ranitidine.

Synergy antagonism

By synergo-antagonism is meant the phenomenon when some effects of combined drugs are enhanced, while others are weakened. As part of Aeron tablets, scopolamine and hyoscyamine are synergists in their inhibitory effect on the vomiting center. Scopolamine depresses the respiratory center, on the contrary, hyoscyamine tones it. a-Adrenergic blockers weaken the hypertensive phase and enhance the hypotensive phase of the action of adrenaline.

With the combined use of medicinal substances, their action may be enhanced (synergism) or weakened (antagonism).

Synergy(from Greek. syn- together, erg- work) - the unidirectional action of two or more medicinal substances, in which a pharmacological effect develops that exceeds the effects of each substance separately. The synergism of medicinal substances occurs in two forms: summation and potentiation of effects.

If the effect combined application medicinal substances is equal to the sum of the effects of the individual substances included in the combination, the action is defined as summation , or additive action . Summation occurs when drugs are introduced into the body that affect the same substrates (receptors, cells, etc.). For example, the vasoconstrictive and hypertensive effects of norepinephrine and phenylephrine, which stimulate a-adrenergic receptors of peripheral vessels, are summarized; the effects of means for inhalation anesthesia are summed up.

If one substance significantly enhances the pharmacological effect of another, such an interaction is called potentiation . In potentiation, the total effect of the combination of two substances exceeds the sum of these effects. For example, chlorpromazine (an antipsychotic) potentiates the action of anesthetics, which reduces the concentration of the latter.

Medicinal substances can act on the same substrate ( direct synergy ) or have different localization of action ( indirect synergy ).

The phenomenon of synergism is often used in medical practice, as it allows you to get the desired pharmacological effect when prescribing several drugs in smaller doses. At the same time, the risk of increasing side effects is reduced.

Antagonism(from Greek. anti- against. agon- struggle) - reduction or complete elimination pharmacological effect one medicinal substance to another when they are used together. The phenomenon of antagonism is used in the treatment of poisoning and to eliminate unwanted reactions to the drug.

There are the following types of antagonism: direct functional antagonism, indirect functional antagonism, physical antagonism, chemical antagonism.

Direct functional antagonism develops when medicinal substances have an opposite (multidirectional) effect on the same functional elements (receptors, enzymes, transport systems, etc.). For example, functional antagonists include stimulants and blockers of b-adrenergic receptors, stimulants and blockers of M-cholinergic receptors. A special case of direct antagonism - competitive antagonism. It occurs when drugs have a similar chemical structure and compete for binding to the receptor. So, as a competitive antagonist of morphine and other narcotic analgesics use naloxone.

Some medicinal substances have a similar chemical structure with the metabolites of microorganisms or tumor cells and compete with them for participation in one of the links in the biochemical process. Such substances are called antimetabolites . Substituting one of the elements of the chain of biochemical reactions, antimetabolites disrupt the reproduction of microorganisms, tumor cells. For example, sulfonamides are competitive antagonists of para-aminobenzoic acid, which is necessary for the development of certain microorganisms, methotrexate is a competitive antagonist of dihydrofolate reductase in tumor cells.

Indirect functional antagonism develops in cases where medicinal substances have an opposite effect on the functioning of an organ and, at the same time, their action is based on different mechanisms. For example, indirect antagonists in relation to the action on smooth muscle organs include aceclidine (increases the tone of smooth muscle organs by stimulating m-cholinergic receptors) and papaverine (reduces the tone of smooth muscle organs due to direct myotropic action).

Physical antagonism occurs as a result of the physical interaction of drugs: the adsorption of one drug on the surface of another, resulting in the formation of inactive or poorly absorbed complexes (for example, the adsorption of drugs and toxins on the surface activated carbon). The phenomenon of physical antagonism is used in the treatment of poisoning.

Chemical antagonism occurs as a result of a chemical reaction between substances, as a result of which inactive compounds or complexes are formed. Antagonists acting in this way are called antidotes . For example, in case of poisoning with arsenic, mercury, and lead compounds, sodium thiosulfate is used, as a result of a chemical reaction with which non-toxic sulfates are formed. In case of overdose or poisoning with cardiac glycosides, dimercaprol is used, which forms inactive complex compounds with them. In case of an overdose of heparin, prothiamine sulfate is administered, the cationic groups of which bind to the anionic centers of heparin, neutralizing its anticoagulant effect.

If, as a result of the combined use of medicinal substances, a more pronounced therapeutic effect, weakened or prevented negative reactions, such a combination of drugs is considered rational and therapeutically appropriate. For example, to prevent the neurotoxic effect of isoniazid, vitamin B 6 is prescribed, to prevent candidiasis as a complication in the treatment of broad-spectrum antibiotics - nystatin or levorin, to eliminate hypokalemia in the treatment of saluretics - potassium chloride.

If, as a result of the simultaneous use of several drugs, the therapeutic effect is weakened, prevented or distorted, or undesirable effects develop, such combinations are considered irrational, therapeutically inappropriate ( drug incompatibility ).