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Synergism and antagonism of medicinal plants. Drug interactions

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Antagonism (from the Greek anti- against, agon- fight) of drugs in combinations manifests itself in the weakening or complete disappearance of their pharmacotherapeutic effect. In medicine, antagonism as a type of pharmacological incompatibility can be divided into physicochemical and physiological. Physico-chemical include the so-called competitive, physical and chemical antagonisms (pharmaceutical incompatibility); to the physiological - direct and indirect (pharmacological incompatibility).

Competitive antagonism in pharmacology is observed between structurally similar substances, for example, sulfonamides and PABA, which is a normal metabolic product (metabolite) in a number of bacteria. In this case, sulfonamides are regarded as antimetabolites. Similar situations can occur with hormones, vitamins and other compounds.

Physical antagonism in pharmacology is possible between adsorbents (activated carbon, proteins, bentonite) and active medicinal substances, the effect of which is eliminated due to their adsorption on adsorbents.

Chemical antagonism in pharmacology manifests itself as a result of the chemical interaction of drugs in combinations with the subsequent formation of pharmacologically inert products. For example, the effect of cationic surfactant antiseptics can be neutralized by anionic surfactants.

Physical and chemical antagonists in practice are more often used as antidotes, or antidotes (from the Greek antidotos - antidote). Thus, in case of barium chloride poisoning, sodium sulfate can be used as an antidote; heavy metals are firmly bound and neutralized by unithiol, etc.

Physiological antagonism in pharmacology is caused by the interaction of drugs with cells and/or their receptors. In such cases, a distinction is made between direct antagonism, when drugs in combination act oppositely (for example, the M-cholinomimetic aceclidine and the M-cholinolytic atropine sulfate, both acting on M-cholinergic receptors), and indirect antagonism, when drugs in combination act on physiological systems - targets exhibiting antagonistic functions (for example, the M-cholinomimetic aceclidine, which excites the inhibitory M-cholinergic receptors of the heart and slows down the frequency of its contractions, is an antagonist of the P-adrenomimetic isadrin, which excites adrenergic receptors and thereby accelerates the heartbeat).

In the modern world there are a huge number of medicines. In addition to the fact that each of them has specific physical and chemical properties, they are also participants in certain reactions in the body. For example, if two or more drugs are used simultaneously, they may interact with each other. This can lead to either a mutual enhancement of the effect of one or both drugs (synergism) or to their weakening (antagonism).

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

Description of this phenomenon

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

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

Agonists are those that, when interacting with biological receptors, receive a response from them, thereby exerting their effect on the body.
Antagonists are those that are unable to independently stimulate receptors, since they have zero internal 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.

We can talk about antagonism only in the case of precise dosages and specific pharmacological effects of the drugs. For example, if their quantitative ratio is different, a weakening or complete absence of the action of one or each may occur, or, on the contrary, their strengthening (synergy) may occur.

An accurate assessment of the degree of antagonism can only be given by plotting graphs. This method clearly demonstrates the dependence of the relationships 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. In case of poisoning by any chemicals, consuming charcoal neutralizes their effect and removes toxins from the intestines.

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

For example, in case of cyanide poisoning and the administration of “sodium thiosulfate”, the process of sulfonation of the former occurs. As a result, they turn into thiocyanates, which are less dangerous for the body.

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 within the body and in the environment.

Functional antagonism in pharmacology differs from the previous two 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”, “Ditiline”) act on skeletal muscles through cholinergic receptors, and they eliminate seizures, which are a side effect of strychnine on spinal cord neurons.

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 subtypes:

competitive;
nonequilibrium;
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 the molecules of another can occupy.

A lot of drugs enter into direct competitive 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 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";
"Tubokurarin" - "Ditilin".

The mechanisms of action of many drugs are based on an antagonistic relationship with other substances. Thus, 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 at synapses.

Many drugs are classified based on their antagonist status.

Non-equilibrium antagonism

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

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

An example that is the most striking in this case: dibenamine (as an antagonist) and norepinephrine or histamine (as agonists). In the presence of the former, the latter are not able to exert their maximum effect even at very high dosages.

Non-competitive antagonism

Non-competitive antagonism is when 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 decreases.

An example of such a relationship 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 constriction of the bronchi. Beta-adrenergic agonists (Salbutamol, Dopamine) act on beta-adrenergic receptors and cause dilation of the bronchi.

Independent antagonism

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

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 a patient and by a pharmacist (or pharmacist) when dispensing them from a pharmacy. This will help avoid unintended consequences. Therefore, the instructions for use of any medicine always contain a separate paragraph on interactions with other substances.

Patients undergoing hospital treatment are prescribed from 4 - 6 to 10 medications. Along with the means of treating the underlying disease, the medications taken by the patient include restorative drugs, substances for the treatment of concomitant pathologies and complications of the underlying disease. Combined drugs can interact as synergists, antagonists and synergistic antagonists.

Synergy

Synergism (Greek) synergos - acting together) - enhancing the effect of one drug by another. There are summed and potentiated synergism.

Summed up synergy, or addiction(lat. additio - addition) - the effect 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).

Potentiated synergism, 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 - adrenergic agonists, by constricting blood vessels, prevent the absorption of local anesthetics into the blood, increasing their local analgesic 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, which cause a shift in pH to the alkaline side, activate the absorption of bases (alkaloids, tranquilizers, antihistamines);

· displacement of drugs from their connection with blood proteins - the anti-inflammatory drugs butadione and indomethacin release anticoagulants and the sugar-lowering drug glibenclamide from their connection 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 drugs prolong and enhance the effect of acetylcholine; aldehyde dehydrogenase blocker teturam potentiates the effects of the oxidation product of ethyl alcohol - acetaldehyde; cytochrome inhibitors R-450 increase the effect of drugs that have metabolic clearance;

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

Synergistic side effects of drugs are possible. Thus, with the joint prescription of aminoglycoside antibiotics (streptomycin, kanamycin, gentamicin) and diuretics (furosemide, ethacrynic acid), the risk of oto- and vestibulotoxic complications increases; injection of calcium chloride into a vein during therapy with cardiac glycosides causes arrhythmia.

Antagonism

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

1. Physical antagonism- decreased absorption into the blood and resorptive effect:

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

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

· agents 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 the muscles.

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

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

· indirect antagonism - the result of an effect on various cells (the adrenergic agonist adrenaline dilates the pupils due to contraction of the radial muscle of the iris, the cholinomimetic acetylcholine constricts the pupils, causing contraction of the orbicularis muscle);

· direct antagonism is the result of an effect on the same cells: non-competitive antagonism occurs when drugs bind to different cytoreceptors, competitive antagonism occurs between agonists and antagonists of the same cytoreceptors.

Examples of non-competitive antagonism are constriction of the bronchi by histamine, an stimulant N 1 - smooth muscle receptors, and bronchodilation with β-adrenergic agonists; antagonism between acetylcholinesterase blockers and cholinergic receptor blockers.

Competitive antagonists are the M-cholinomimetic pilocarpine and the M-cholinergic blocker atropine; a-adrenergic agonist norepinephrine and a-adrenergic blocker phentolamine; histamine and blocker N 2-receptor ranitidine.

Synergo-antagonism

Synergistic antagonism refers to the phenomenon when some effects of combined drugs are enhanced, while others are weakened. Aeron tablets contain scopolamine and hyoscyamine, which are synergistic 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.

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

Molecular answer 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- This is the prevention of the action of the agonist. Many drugs bind to the receptor to form a drug-drug complex, which does not cause a cellular response. Moreover, occupancy of the receptor by an antagonist prevents either the binding of the agonist or the initiation of a cellular response when the agonist binds to the receptor. Thus, antagonism may result from different molecular mechanisms. A mathematical description of the effects of various types of antagonists is given below. Briefly, antagonism can arise due to:

Bindings antagonist in the same receptor site that is normally occupied by the agonist. Binding of the antagonist prevents the agonist from occupying the center (competitive antagonism);

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

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

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

Physiological antagonism different from pharmacological antagonism. The term “physiological (or functional) antagonism” is often 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 separated receptors. This can occur if two agonist receptors share the same cellular response components but act on them differently, or are linked by different cellular response components that produce opposing tissue responses.

Visual example serves as an interaction between norepinephrine and acetylcholine in arterioles. Norepinephrine causes contraction, and acetylcholine causes relaxation. Of course, it makes no sense to describe norepinephrine as an acetylcholine antagonist, since acetylcholine can also be regarded as an antagonist to norepinephrine, so the terms "agonist" and "antagonist" become interchangeable and meaningless. The term antagonist is best used to describe drugs that inhibit the molecular response to an agonist. It is better not to use the term “functional antagonist”.

Drug interactions.

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

When drugs interact, the following conditions may develop: a) increased effects of a combination of drugs b) weakened effects of a combination of drugs c) drug incompatibility

Strengthening the effects of a drug combination is implemented in three options:

1) Summation of effects or additive interaction– a type of drug interaction in which the effect of the combination is equal to the simple sum of the effects of each drug separately. That is 1+1=2 . Characteristic of drugs from the same pharmacological group that have a common target of action (the acid-neutralizing activity of the 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 the combination exceeds the sum of the effects of each of the substances taken separately. That is 1+1=3 . Synergism can relate to both desired (therapeutic) and undesirable effects of drugs. The combined administration of the thiazide diuretic dichlorothiazide and the ACE inhibitor enalapril leads to an increase in the hypotensive effect of each drug, 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 by itself does not have this effect, can lead to a sharp increase in the effect of another drug. That is 1+0=3 (clavulanic acid does not have an antimicrobial effect, but can 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 prolongs its anesthetic effect by slowing down absorption anesthetic from the injection site).

Reducing 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 (the chemical antagonist of iron ions deferoxamine, which binds them into inactive complexes; protamine sulfate, the molecule of which has an excess positive charge - the 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) or 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 by increasing the concentration of the agonist. 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 of the agonist is required for the interaction of the agonist with the receptor. Competitive antagonist Shifts the dose-response curve for the agonist to the right relative to the initial 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, during treatment with competitive antagonists it is necessary to constantly maintain its level sufficiently high. In other words, the clinical effect of a competitive antagonist will depend on its 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 generally interacts with its allosteric center. Therefore, no matter how much the concentration of the agonist increases, it is not able to displace the antagonist from its connection with the receptor. Since some of the receptors that are associated with a non-competitive antagonist are no longer able to activate , E valueMax decreases, but the affinity of the receptor for the agonist does not change, so the EC50 value remains the same. On a dose-response curve, the effect of a non-competitive antagonist appears as a compression of the curve relative to 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., it reduces the sensitivity of the tissue to the agonist without changing its effect. B – a 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 one 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 used less frequently in medical practice. On the one hand, they have an undoubted advantage, because their effect 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 of this medicine occurs, it will be extremely difficult to eliminate its effect.

Competitive antagonist	Non-competitive antagonist
Similar in structure to an agonist	It differs in structure from the agonist
Binds to the active site of the receptor	Binds to the allosteric site of the receptor
Shifts the dose-response curve to the right	Shifts the dose-response curve vertically
The antagonist reduces tissue sensitivity to the agonist (EC50), but does not affect the maximum effect (Emax) that can be achieved at a higher concentration.	The antagonist does not change the sensitivity of the tissue to the agonist (EC50), but reduces the internal activity of the agonist and the maximum tissue response to it (Emax).
The antagonist effect can be reversed by a high dose of the agonist	The effects of the antagonist cannot be reversed by a high dose of the agonist.
The effect of the antagonist depends on the ratio of doses of agonist and antagonist	The effect of an antagonist depends only on its dose.

Losartan is a competitive antagonist for angiotensin AT1 receptors; it disrupts the interaction of angiotensin II with receptors and helps lower blood pressure. The effect of losartan can be overcome by administering a high dose of angiotensin II. Valsartan is a non-competitive antagonist for these same AT1 receptors. Its effect cannot be overcome even with the administration of high doses of angiotensin II.

Of interest is the interaction that takes place between full and partial receptor agonists. If the concentration of the full agonist exceeds the level of the partial agonist, then a maximum response is observed in the tissue. If the level of a partial agonist begins to increase, it displaces the full agonist from 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 occupies all receptors).

3) Physiological (indirect) antagonism– antagonism associated with the influence of 2 drugs on various 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, as a result of which the transport of glucose into the cell increases and the glycemic level decreases. Adrenaline activates b2-adrenergic receptors in the liver and 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 emergency care of patients with an insulin overdose that has led to hypoglycemic coma.