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 weaken or eliminate the feeling of pain.

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

Opioids are characterized by strong analgesic activity, which makes them possible to use as highly effective painkillers in various fields of medicine, especially for injuries, surgical interventions, wounds, etc. and for diseases accompanied by severe pain (malignant neoplasms, myocardial infarction, etc.). Having a special effect on the central nervous system, opioids cause euphoria, a change in the emotional coloring of pain and the reaction to it. Their most significant drawback is the risk of developing mental and physical dependence.

This group of analgesics includes natural alkaloids (morphine, codeine) and synthetic compounds (trimeperidine, fentanyl, tramadol, nalbuphine, etc.). Most synthetic drugs are obtained by modifying the morphine molecule while preserving elements of its structure or simplifying it. By chemical modification of the morphine molecule, substances that are its antagonists (naloxone, naltrexone) were also obtained.

In terms of the severity of the analgesic effect and side effects, drugs differ from each other, which is associated with the characteristics of their chemical structure and physicochemical properties and, accordingly, with the interaction with receptors involved in the implementation of their pharmacological effects.

The discovery 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 central nervous system, but are also found in peripheral organs and tissues. In the brain, opiate receptors are found primarily in structures directly related to the transmission and encoding 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.

Based on the nature of their interaction with opiate receptors, all opioidergic drugs are divided into:

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

Partial agonists (predominantly activate mu receptors) - buprenorphine;

Agonists-antagonists (activate kappa and sigma and block mu and delta opiate receptors) - pentazocine, nalorphine (blocks mainly mu opiate receptors and is not used as an analgesic);

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

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

A number of opioids are used in medical practice. In addition to morphine, its prolonged dosage forms have been created. A significant amount 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 “drug addiction potential” (the ability to cause painful addiction).

Adrenergic antagonists (also called blockers) bind to adrenergic receptors, but do not trigger the usual receptor-mediated intracellular effects. These drugs act by reversibly or irreversibly binding 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

Medicines that block α-adrenergic receptors have a pronounced effect on blood pressure. Since the normal sympathetic control of the vascular system is mostly carried out through the α-adrenergic receptor action of agonists, 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 decreased blood pressure. [Note: β-receptors, including cardiac β1-adrenergic receptors, are not sensitive to α-blockade]. Substances that block a-receptors, with the exception of prozosin and labetalol, have only minor clinical use.

A. PHENOXYBENZAMINE

Phenoxybenzamine, a drug related to nitrogen mustard, forms a covalent bond with the a1-postsynaptic and a2-presynaptic receptors.
The blockade is irreversible and non-competitive: Only the body's mechanism can overcome the block by synthesizing new α1-adrenergic receptors. This synthesis occurs within approximately 1 day. Therefore, the action of phenoxybenzamine lasts 24 hours after a single administration. After administration of the drug, its effect develops after several hours, since it takes time to convert it into the active form.

1. ACTION:
A. CARDIOVASCULAR SYSTEM: Phenoxybenzamine blocks a-receptors and prevents the vasoconstrictor effect on peripheral blood vessels of endogenous catecholamines. This leads to a decrease in blood pressure and peripheral resistance, which causes reflex tachycardia. The drug was ineffective in maintaining reduced blood pressure in patients with hypertension and therefore ,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 fainting.
With. REVERSING THE EFFECT OF ADRENALINE: All a-blockers reverse the a-agonist action of adrenaline. For example, the ability of adrenaline to cause vasoconstriction is blocked, but the dilation of other blood vessels in the body caused by the beta-agonist action is not blocked. Therefore, systemic blood pressure is reduced when adrenaline is administered with phenoxybenzamine
[Note: The effects of norepinephrine are not reversed, but are reduced, since norepinephrine has little b-agonist effect on the vascular system]. Phenoxybenzamine has no effect on the action of isoproterenol, which is a pure b-agonist.
d. SEXUAL FUNCTION: Phenoxybenzamine, like all a-blockers, has side effects on sexual function in men. The process of ejaculation is suppressed with possible retrograde ejaculation when it occurs. This occurs due to the inability of the internal bladder sphincter to close during ejaculation.

2. MEDICAL USE.

A. URINARY SYSTEM: Treatment with phenoxybenzamine results in the inability of the internal sphincter of the bladder 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 does not completely empty. In such patients, phenoxybenzamine has invaluable important because it allows the bladder to empty completely.
V. PARAPLEGICS: All paraplegics suffer from autonomic hyperreflexia. Under these conditions, the overt process of micturition raises reflexes, which 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 with its non-dangerous hypertrophy. This helps to normalize urination, since the compression of the urethra by the hypertrophied gland is reduced.
d TREATMENT OF HYPERTENSION CAUSED BY PHEOCHROMOCYTOMA: Phoechromocytoma is a catecholamine-secreting tumor. It originates from adrenal cells and is most often diagnosed by chemical measurements of circulating catecholamines and urinary catechol metabolites. PHENOXYBENZAMINE and PHENTOLAMINE are used to manage this tumor. yu, in particular, in cases when cells secreting catecholamines are distributed diffusely 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 medicine may cause tachycardia due to baroreceptor reflexes.

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.

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.

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 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 tissue response to it (E max).
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 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.

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 resulting from receptor activation. The maximum effect of agonists develops when only a part of the available receptors is bound.

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

Antagonists weaken the effect of agonists by counteracting them. Competitive antagonists have the ability to bind to receptors, but the cell function does not change. In other words, they are devoid of internal activity. When present in the body at the same time, an agonist and a competitive antagonist compete to bind to the receptor. The chemical affinity and concentration of both competitors determines whether the agonist or antagonist binds more actively.

Increasing agonist concentration, it is possible to overcome the block on the part of the antagonist: in this case, the curve of 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 transition to an activated conformation. The agonist binds to the receptor in the non-activated conformation and causes its transition to the activated state. The antagonist attaches to an inactive receptor and does not change its conformation.

Agonist stabilizes the spontaneously occurring activated conformation. The receptor is capable of spontaneously transitioning to an activated conformation state. However, usually the statistical probability of such a transition is so small that spontaneous cell excitation cannot be determined. Selective binding of the agonist occurs only to the receptor in the activated conformation and thereby 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, adding an antagonist has little effect. However, if the system exhibits high spontaneous activity, the antagonist can cause an effect opposite to that of the agonist - the so-called inverse agonist. A “true” agonist without intrinsic activity (neutral agonist) has equal affinity for the activated and non-activated conformations of the receptor and does not change the basal activity of the cell.

According to this models, a partial agonist has less selectivity for the activated state: however, it also binds to some extent to the receptor in the non-activated state.

Other types of antagonism. Allosteric antagonism. The antagonist binds beyond 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 contraction).