Synergy examples. Synergism and antagonism in the action of medicinal substances, use in medical practice. replace one of the medications with another

Pharmacodynamic drug interactions are associated with the following main mechanisms:

¦ Competition of binding to receptors Both agonists and antagonists can compete.

¦ Changes in the kinetics of drugs at the site of action This may be due to changes in their absorption, distribution, metabolism and elimination.

¦ Effect on synaptic transmission Thus, reserpine leads to depletion of catecholamines, which are destroyed by MAO. If MAO inhibitors are used simultaneously with reserpine, the metabolism of catecholamines will be disrupted, which will lead to a sharp increase in blood pressure.

¦ Interaction of drug effects if they cause opposite effects

In some cases, pharmacodynamic interactions of drugs can lead to the development of adverse reactions

Some pharmacodynamic interactions leading to the development of adverse reactions

As follows from the table, there are a large number of different mechanisms of drug interaction. Many of them have not been studied enough.

Therefore, to avoid possible drug interactions and associated adverse reactions, preference should be given to monotherapy (unless the clinical situation allows) over complex treatment.

Pharmacodynamic interaction is defined as the ability of drugs to interact at the level of mechanism of action and pharmacological effects. There are two main types of pharmacodynamic interactions – synergism and antagonism.

Synergy- unidirectional action of two or more drugs, in which a pharmacological effect develops that is more pronounced than that of each substance separately.

Types of synergy:

Sensitizing effect

Additive action

Summation

Potentiation.

A sensitizing effect is the interaction of two drugs, in which one of the drugs increases the body’s sensitivity to the action of the other and enhances its effect (vitamin C + iron supplements = increase in the concentration of iron in the blood).

Additive effect is the interaction of two drugs, in which the effect of the combined action of the drugs is lower than the sum of the individual effects of each drug, but higher than the effect of each of them separately.

Summation is a drug interaction in which the severity of the effect of the combined use of drugs is equal to the sum of the effects of individual drugs.

Potentiation is the interaction of two drugs, in which the effect of the two substances is greater than the sum of the effects of each substance (the effect of drugs A + B > the effect of drug A + the effect of drug B).

Antagonism- reduction or complete elimination of the pharmacological effect of one drug by another when used together. The phenomenon of antagonism is used in the treatment of poisoning and to eliminate unwanted reactions to drugs.

Types of antagonism:

· physical

· chemical

physiological

· receptor

Physical antagonism is determined by the physical properties of drugs and occurs as a result of their physical interaction: adsorption of one drug on the surface of another, resulting in the formation of inactive or poorly absorbed complexes.

Chemical antagonism occurs as a result of a chemical reaction between substances, as a result of which inactive compounds or complexes are formed. Antagonists that act in this way are called antidotes. For example, the use of unithiol in case of overdose or poisoning with cardiac glycosides.

Physiological or functional antagonism develops when two drugs are administered that cause opposite effects on the same type of physiological effects.

Receptor antagonism associated with the interaction of different drugs on the same receptor. At the same time, the drugs have multidirectional effects.

Receptor antagonism is of two types:

· competitive – binding of the antagonist to the active center and the final effect depends on the dose of the agonist and antagonist;

· non-competitive - binding of the antagonist to a specific site of the receptor, but not to the active center, and the final effect depends only on the concentration of the antagonist.

Synergism is the unidirectional action of two or more drugs, providing a stronger pharmacological effect than each drug 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.

Synergism (in pharmacology) is the phenomenon of mutual enhancement of the effectiveness of the main and (or) side effects of drugs when used together. 1. A variant of the body’s reaction to the combined effects of two or more drugs, characterized by the fact that the resulting effect exceeds the effect of each component separately. In medicine, synergism (from the Latin synergia) is the promotion, joint action of drugs in one direction.

An example of synergism is the combined use of any sulfonamide with trimethoprim. Another example of synergism is the use of aminazine and any barbiturate in combination. Each medicinal substance acts on different parts of the brain, and therefore the overall effect is more profound. Secondary in vivo reactions may occur due to drug antagonism, pharmacological or pharmaceutical incompatibility in combinations, and for other reasons.

That is, 1+1=3. Synergism can relate to both desired (therapeutic) and undesirable effects of drugs. 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.

General pharmacology - 15. Pharmacological interactions

It will displace the antagonist from the active center of the receptor and cause a full tissue response. Losartan is a competitive antagonist for angiotensin AT1 receptors; it disrupts the interaction of angiotensin II with receptors and helps lower blood pressure. 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.

Changes in the kinetics of drugs at the site of action This may be due to changes in their absorption, distribution, metabolism and elimination. Pharmacodynamic interaction is defined as the ability of drugs to interact at the level of mechanism of action and pharmacological effects.

Potentiation (pharmacology)

Antagonism is a reduction or complete elimination of the pharmacological effect of one drug by another when used together. Physiological or functional antagonism develops when two drugs are administered that cause opposite effects on the same type of physiological effects.

Pharmacodynamic interaction can be direct, when both drugs act on the same biosubstrate, and indirect, realized with the inclusion of different biosubstrates.

This type of interaction is realized during the development of the pharmacological action of two or more drugs. Synergistic and antagonistic interactions are of greatest importance. LW. The synergistic interaction of substances provides a higher therapeutic effect than the effect of each drug separately.

Summarized synergism represents the interaction of a drug when the total pharmacological effect is equal to the sum of the effects of the two components (AB = A + B). Direct cumulative synergism is said to exist if substances act on the same target in the same direction. The phenomenon of potentiation develops when substances act in one direction, but their action is realized through different molecular mechanisms.

Combined effects of medicinal substances

Spectrum and mechanism of action of drugs. This synergistic effect is not necessarily beneficial, and in some cases it can be dangerous. The following types of synergism are distinguished: additive action (simple summation of effects), potentiation (significant enhancement of effects), direct synergism, indirect synergism.

See what “SYNERGISM” is in other dictionaries:

When prescribing one or more drugs, you need to make sure that there is no antagonistic effect between them; which precludes their simultaneous use. With rational combination, it is possible to reduce the doses of active medicinal substances, as a result of which unwanted side effects are reduced or do not appear.

As a result of a synergistic pharmacodynamic interaction, the main and/or side effects are enhanced. Potentiation is the result of a combination of drugs in severity that is greater than the sum of the effects of each component.

See also Drug compatibility. SYNERGISM - (new Latin, from Greek synergia assistance). Synergy is a phenomenon when the total effect of two or more factors exceeds the sum of the influence of individual factors. Terminological dictionary of concrete and reinforced concrete. At the same time, they strive to get a better effect from a combination of drugs than from each one separately.

Chemical antagonism occurs as a result of a chemical reaction between substances, which results in the formation of inactive compounds or complexes. Potentiation (in pharmacology) is a type of drug interaction, which is a special case of synergy.

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In medicine, synergism (from the Latin synergia) is the promotion, joint action of drugs in one direction. At the same time, they strive to get a better effect from a combination of drugs than from each one separately. An example of synergism is the combined use of any sulfonamide with trimethoprim. Sulfanilamide is a competitor to PABA. PABA is required by certain bacteria for the synthesis of dihydrofolic acid. Trimethoprim inhibits the action of the enzyme dihydrofolate reductase, which catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid, and in bacteria this enzyme is inhibited 10,000 times more strongly than in human cells (and other mammals). Sulfanilamide and trimethoprim simultaneously block sequential reactions in the biosynthesis pathways of purines and nucleic acids; this effect is deeper than the effect of one of the drugs in this combination.

Another example of synergism is the use of aminazine and any barbiturate in combination. Each medicinal substance acts on different parts of the brain, and therefore the overall effect is more profound.

From the examples given, it follows that the above-mentioned drugs in combination act more powerfully than each one individually (and even when it would be taken in a larger dose). In such cases, they talk about potentiation as a form of synergism. Another form of synergism is summation, when the overall effect of using drugs in a combination of norepinephrine and adrenaline gives a total effect, since both substances act on the same target in the body - adrenergic receptors of cells.

The indifference (from the Latin indifferens - indifferent) of drugs in combinations is due primarily to the chemical structure of the medicinal substances. In practice, this effect of drugs in combinations is often referred to as antibiotics and is presented in the following forms:

1) the effect of drugs X and Y in combination corresponds to the effect of the more active X;

2) the effect of drugs X and Y in combination is equal to the arithmetic sum of the effects of X and Y in the selected doses (see summation above);

3) the effect of drugs X and Y in combination is similar to the effect of X alone (as well as Y alone), taken in a dose equivalent to the dose of the X + Y mixture.

An example of the first combination is the anti-blastoma cyclophosphamide and one of any glycans (for example, rodexman). Of these, the first is more active than the second. An example of the 2nd combination is the anti-tuberculosis drugs rifampicin and ethambutol. Finally, an example of a 3rd combination would be a combination of antibiotics (cephalexin + ampicillin) against sensitive bacteria.

Secondary in vivo reactions may occur due to drug antagonism, pharmacological or pharmaceutical incompatibility in combinations, and for other reasons.

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. Those. 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. Those. 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. Those. 1+0=3 (clavulanic acid does not have an antimicrobial effect, but can enhance the effect of the β-lactam antibiotic amoxicillin due to the fact that it blocks β-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 site of the receptor, i.e. shields it from the action of the agonist. Because The degree of binding of a substance to the receptor is proportional to the concentration of this substance, then 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 EC 50 for the agonist, without affecting the value of E 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 value max decreases, but the affinity of the receptor for the agonist does not change, so the EC value 50 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. 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 either on the half-life of the antagonist or on 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.

Losartan is a competitive antagonist for angiotensin AT 1 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 AT 1 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  2 -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.