What is an agonist and antagonist. Antagonism in pharmacology: definition of the concept and examples

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Description

This group includes narcotic analgesics (from the Greek algos - pain and an - without), which have a pronounced ability to reduce or eliminate the feeling of pain.

Analgesic activity is exhibited by substances having a different chemical structure, and it is realized by various mechanisms. Modern analgesics are divided into two main groups: narcotic and non-narcotic. Narcotic analgesics, having, as a rule, a strong analgesic effect, cause side effects, the main of which is the development of addiction (drug addiction). Non-narcotic analgesics act less strongly than narcotic ones, but do not cause drug dependence - drug addiction (see).

Opioids are characterized by a strong analgesic activity, which makes them suitable for use as highly effective pain relievers in various fields of medicine, especially in trauma, surgery, wounds, etc. and in diseases accompanied by severe pain syndrome (malignant neoplasms, myocardial infarction, etc.). With a special effect on the central nervous system, opioids cause euphoria, a change in the emotional coloring of pain and reactions to it. Their most significant drawback is the danger of developing mental and physical dependence.

This group of analgesics includes natural alkaloids (morphine, codeine) and synthetic compounds (trimeperidine, fentanyl, tramadol, nalbuphine, etc.). The majority of synthetic drugs are obtained by the principle of modifying the morphine molecule with the preservation of elements of its structure or its simplification. Substances that are its antagonists (naloxone, naltrexone) have also been obtained by chemical modification of the morphine molecule.

According to the severity of the analgesic action and side effects, the drugs differ from each other, which is associated with the peculiarities of their chemical structure and physicochemical properties and, accordingly, with the interaction with the receptors involved in the implementation of their pharmacological effects.

The discovery in the 1970s of specific opiate receptors and their endogenous peptide ligands, enkephalins and endorphins, played a major role in understanding the neurochemical mechanisms of action of opioids. Opiate receptors are concentrated mainly in the CNS, but are also found in peripheral organs and tissues. In the brain, opiate receptors are located mainly in structures that are directly related to the transmission and coding of pain signals. Depending on the sensitivity to different ligands, subpopulations are distinguished among opiate receptors: 1-(mu), 2-(kappa), 3-(delta), 4-(sigma), 5-(epsilon), which have different functional significance.

According to the nature of the interaction with opiate receptors, all opioidergic drugs are divided into:

Agonists (activate all types of receptors) - morphine, trimeperidine, tramadol, fentanyl, etc.;

Partial agonists (activate mainly mu receptors) - buprenorphine;

Antagonist agonists (activate kappa and sigma and block mu and delta opiate receptors) - pentazocine, nalorphine (predominantly blocks mu opiate receptors and is not used as an analgesic);

Antagonists (block all types of opiate receptors) - naloxone, naltrexone.

In the mechanism of action of opioids, the inhibitory effect on the thalamic centers of pain sensitivity, which conduct pain impulses to the cerebral cortex, plays a role.

A number of opioids are used in medical practice. In addition to morphine, its prolonged dosage forms have been created. A significant number of synthetic highly active analgesics of this group (trimeperidine, fentanyl, buprenorphine, butorphanol, etc.) have also been obtained, which have high analgesic activity with varying degrees of "addictive potential" (the ability to cause addiction).

Adrenergic antagonists (also called blockers) bind to adrenergic receptors but do not trigger the usual receptor-mediated intracellular effects. These drugs act by binding reversibly or irreversibly to the receptor, and therefore prevent their activation by endogenous catecholamines. Like agonists, adrenergic antagonists are classified according to their affinity for a or b receptors. Receptor-blocking drugs are summarized in Figure 7.1.

II. a-ADRENOBLOCKERS

Drugs that block a-adrenergic receptors have a pronounced effect on blood pressure. Since normal sympathetic control of the vascular system is mostly carried out through a-adrenergic agonist action, blockade of these receptors leads to a decrease in the sympathetic tone of the blood vessels, causing a decrease in peripheral vascular resistance. This causes reflex tachycardia as a result of a decrease in blood pressure. [Note: β-receptors, including β1-adrenergic receptors of the heart, are not sensitive to α-blockade]. α-receptor blocking agents, with the exception of prozosin and labetalol, have only minor clinical applications.

A. phenoxybenzamine

Phenoxybenzamine, a drug related to nitrogen mustard, forms a covalent bond with a1-postsynaptic and a2-presynaptic receptors.
The blockade is irreversible and non-competitive: Only the body's mechanism can overcome the blockade by synthesizing new a1-adrenergic receptors. This synthesis occurs within approximately 1 day. Therefore, the action of phenoxybenzamine lasts 24 hours after a single injection. After administration of the drug, its action develops after several hours, since it takes time to turn it into an active form.

1. ACTION:
A. CARDIOVASCULAR SYSTEM: Phenoxybenzamine blocks a-receptors and prevents the vasoconstrictive effect of endogenous catecholamines on the peripheral blood vessels. This leads to a decrease in blood pressure and peripheral resistance, which causes reflex tachycardia. , is not used for these purposes.
V. ORTHOSTATIC HYPOTENSION: Phenoxybenzamine causes orthostatic hypotension because it blocks a-receptors. When the patient stands up quickly, the blood pool in the lower extremities causes syncope.
With. REVERSE THE ACTION OF ADRENALINE: All α-blockers reverse the α-agonist action of adrenaline. For example, the ability of adrenaline to cause vasoconstriction is blocked, but the expansion of other vessels of the body caused by the β-agonist action is not blocked. Therefore, systemic blood pressure is reduced when adrenaline is administered with phenoxybenzamine
[Note: The action of norepinephrine is not reversed, but is reduced because norepinephrine has a minor β-agonistic effect on the vascular system]. Phenoxybenzamine does not interfere with the action of isoproterenol, which is a pure β-agonist.
d. SEXUAL FUNCTION: Phenoxybenzamine, like all a-blockers, has a side effect on sexual function in men. It suppresses the process of ejaculation with possible retrograde ejaculation when it occurs. This is due to the inability to close the internal bladder sphincter during ejaculation.

2. THERAPEUTIC USE.

A. URINARY SYSTEM: Treatment with phenoxybenzamine results in the inability of the internal bladder sphincter to close completely. In patients with neurogenic vesicular dysfunction, in whom the internal sphincter closes spontaneously during micturition, urine stagnates in the bladder because it is not completely emptied. In these patients, phenoxybenzamine has an invaluable value because it allows the bladder to empty completely.
V. PARAPLEGICS: All paraplegics suffer from autotomous hyperreflexia. Under these conditions, the overt process of micturition elevates reflexes that lead to increased sympathetic activity in the blood vessels and causes an increase in blood pressure. This predisposes paraplegics to strokes. Phenoxybenzamine blunts this action and helps in normalizing blood pressure in paraplegic patients.
With. NON-DANGEROUS PROSTATE HYPERTROPHY: Phenoxybenzamine is valuable in reducing the size of the prostate in its non-dangerous hypertrophy.
d TREATMENT OF HYPERTENSION CAUSED BY PHEOHROMOCYTOMA: Phoechromocytoma is a catecholamine-secreting tumor. in particular, in cases when catecholamine-secreting cells are diffusely distributed and therefore inoperable.
3. SIDE EFFECTS:
A. Phenoxybenzamine can cause orthostatic hypotension, suppress ejaculation, cause nasal stuffiness, and lead to nausea and vomiting.
V. The drug can cause tachycardia due to reflexes from baroreceptors.

In today's 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. 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 is 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 of the therapeutic effect of one or each of them. In this case, the 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 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.

It is possible to talk about antagonism only in the case of exact dosages and specific pharmacological effects of drugs. For example, with their different quantitative ratio, a weakening or complete absence of the action of one or each may occur, 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 chemical substances, the use of coal neutralizes their effect 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 action of the other.

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

Direct antagonism in pharmacology

This species requires a 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.

A lot of drugs 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 non-equilibrium antagonism, two drugs (agonist and 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, medicinal substances 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.

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- a type of 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. Those. 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. Those. 1+1=3 . Synergism can relate to both desired (therapeutic) and undesirable effects of drugs. The combined administration of the thiazide diuretic dichlothiazide and the 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. Those. 1+0=3 (clavulanic acid does not have an antimicrobial effect, but is able to enhance the effect of the -lactam antibiotic amoxicillin due to the fact that it blocks -lactamase; adrenaline does not have a local anesthetic effect, but when added to 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 binds reversibly 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 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 of baseline and increases the EC 50 for an 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, it is necessary to keep the level sufficiently high at all times during treatment with competitive antagonists. In other words, the clinical effect of a 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 value max decreases, while the affinity of the receptor for the agonist does not change, so the EC value 50 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 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 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, because. their action 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 drug occurs, it will be extremely difficult to eliminate its effect.

Competitive antagonist	Non-competitive antagonist
Similar in structure to an agonist	Structurally different 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 the sensitivity of the tissue to the agonist (EC 50 ), but does not affect the maximum effect (E max) that can be achieved at a higher concentration.	The antagonist does not change the sensitivity of the tissue to the agonist (EC 50), but reduces the internal activity of the agonist and the maximum response of the tissue to it (E max).
Antagonist action can be eliminated by a high dose of agonist	The action of an antagonist cannot be eliminated by a high dose of an 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 AT 1 receptors, it disrupts the interaction of angiotensin II with receptors and helps to lower 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 AT 1 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 medicinal substances 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, which increases the transport of glucose into the cell and lowers the level of glycemia. Adrenaline activates  2 -adrenergic receptors of 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 the emergency care of patients with an insulin overdose that has led to hypoglycemic coma.

Agonists are able to attach to receptor proteins, changing the function of the cell, i.e., they have internal activity. The biological effect of an agonist (i.e., change in cell function) depends on the efficiency of intracellular signal transduction as a result of receptor activation. The maximum effect of agonists develops even when only a part of the available receptors is bound.

Another agonist, which has the same affinity, but less ability to activate receptors and the corresponding intracellular signaling (i.e., having less internal activity), will cause a less pronounced maximum effect, even if all receptors are bound, i.e., it has less efficiency. Agonist B is a partial agonist. The activity of agonists is characterized by a concentration at which half of the maximum effect (EC 50) is achieved.

Antagonists weaken the effect of agonists, counteracting them. Competitive antagonists have the ability to bind to receptors, but the function of the cell does not change. In other words, they are devoid of inner activity. While in the body at the same time, the agonist and competitive antagonist compete for binding to the receptor. The chemical affinity and concentration of both competitors determine who will bind more actively: the agonist or the antagonist.

Increasing agonist concentration, it is possible to overcome the block on the part of the antagonist: in this case, the dependence of the effect on the concentration shifts to the right, to a higher concentration while maintaining the maximum effectiveness of the drug.

Models of molecular mechanisms of action of agonists and antagonists

Agonist causes the receptor to switch to an activated conformation. The agonist binds to the receptor in an inactivated conformation and causes it to transition to an activated state. The antagonist attaches to the inactive receptor and will not change its conformation.

Agonist stabilizes the spontaneously appeared activated conformation. The receptor is able to spontaneously switch to an activated conformation. However, usually the statistical probability of such a transition is so small that spontaneous excitation of cells cannot be determined. Selective binding of the agonist occurs only to the receptor in the activated conformation and thus favors this state.

Antagonist is able to bind to a receptor that is only in an inactive state, prolonging its existence. If the system has low spontaneous activity, the addition of an antagonist has little effect. However, if the system exhibits high spontaneous activity, the antagonist may produce an effect opposite to that of the agonist, the so-called inverse agonist. A "true" agonist without intrinsic activity (neutral agonist) has the same affinity for activated and non-activated receptor conformations and does not change the basal activity of the cell.

According to this models, the partial agonist is less selective for the activated state: however, it also binds to some extent to the receptor in the inactivated state.

Other types of antagonism. allosteric antagonism. The antagonist binds outside the site of attachment of the agonist to the receptor and causes a decrease in the affinity of the agonist. The latter increases in the case of allosteric synergism.

Functional antagonism. Two agonists acting through different receptors change the same variable (diameter) in opposite directions (adrenaline causes expansion, histamine causes constriction).