Agonist-antagonists and partial agonists stimulate some types of receptors (agonist action) and block others (antagonist action). In addition to morphine, its derivatives, which are semi-synthetic or synthetic drugs, have been used in medical practice. These include pentazocine, buprenorphine, butorphanol, nalbuphine.

It was taken into account that some previously synthesized compounds, close to morphine, but not containing an oxygen bridge (levorphanol or lemoran, etc.), have high analgesic activity, and at the same time, the dimethylallyl residue is an important part of the nalorphine molecule, which has a significant least antagonistic properties of morphine. It was expected that this modification of the morphine molecule would result in a compound with greater analgesic activity than nalorphine, but with fewer side effects than morphine (Lasagna, 1964). Pentazocine in to a certain extent satisfies these requirements. It has analgesic activity, although to a slightly lesser extent than morphine, but is less respiratory depressant and less likely to cause constipation and urinary retention (Iwatsuki et al., 1969).

More active agonist-antagonists have now been synthesized, such as nalbuphine (Gear et al., 1999).

The listed properties and features of the action of the drugs described above give reason to believe that their use is limited due to the emergence of dependence on them. It is advisable to use narcotic analgesics only for the treatment of acute pain and for a short term. They are most often used for injuries, burns, myocardial infarction, peritonitis (after the diagnosis has been clarified and the issue of surgery has been decided) (Savyuk, 1997). In addition, chronic pain is a contraindication for the prescription of drugs, with the exception of advanced forms of malignant tumors (

pharmacological groups, which the student should be able to characterize according to the following plan:

Drugs belonging to this group.

Mechanism of action.

1. Indications for use.

   Contraindications for use.

   Complications.

Natural opioid analgesics - full opioid receptor agonists

Synthetic opioid analgesics - full opioid receptor agonists

Opioid analgesics - partial agonists of opioid receptors

Opioid analgesics - opioid/receptor agonists/antagonists

Non-opioid analgesics - cyclooxygenase inhibitors

Analgesics mixed type actions

LIST

drugs that the student must be able to write out in the form of a prescription indicating indications for use.

Morphine tidrochloride solution 1% concentration in 1 ml ampoules;

Promedol solution 1% concentration in ampoules of 1 ml;

Fentaiyl solution 0.005% concentration in ampoules of 2 ml;

4. Buprenorphine hydrochloride solution 0.03% wampulah concentration, 1 ml;

Butorphanol tartrate solution 0.2% concentration in 1 ml ampoules;

Antaxon (Naltrexone) tablets, dose 0.05;

Toradol (Ketorolac) tablets, dose 0.01;

Tramadol capsules, dose 0.05;

Paracetamol tablets, dose 0.5;

10. Analgin solution (metamizole sodium) 50% concentration wampulah 2 ml.

Pain (acute or chronic) is defined as an unpleasant sensory or emotional feeling associated with actual or potential tissue damage.

Pain relief is an essential element of medical practice and requires careful selection of the drug, selection of the required dose and constant objective assessment of the underlying disease. At the same time, there are many situations (trauma, burns, wounds, etc.) in which analgesia must be provided before a final diagnosis is made.

Medicines that reduce or relieve pain (analgesics) can be divided into the following groups.

I. Opioid analgesics1.1. Full agonists

1.2. Partial agonists

1.3. Agonists - antagonists

II. Non-opioid analgesics

II.1 cyclooxygenase inhibitorsII.1.1 Pyrazolone derivatives

II. 1.2. Para-aminophenol derivatives

II.1.3. Derivatives of other chemical compounds

P.2. Drugs of other pharmacological groups that have

analgesic effect

P.2.1. Presynaptic a 2 ~adrenergic agonists

P.2.2. Tricyclic antidepressants

P.2.3. General anesthetics

IL2.4. Others

Sh. Analgesics of mixed action.

I. Opioid analgesics.

The application point of this group of tools is Various types opioid receptors (ts, 8, k).

Classification. Based on the type of action on opioid receptors, drugs are divided into the following groups:

1.1. Full agonists (non-selectively stimulate all types of opioid receptors).

1.1.1. Natural (opium alkaloids)

• Omnopon (mixture of opium alkaloids)1.1.2. Synthetic

Trimeperidine (Promedol)-Fentanyl

Sufentanil

Remifentanil

Alfentanil

Piritramide (Dypidodor)

1.2. Partial agonists (mainly act on beta-opioid receptors).

Buprenorphine

L3. Agonists-antagonists (activate k-receptors and block c-opioid receptors).

Pentazocine

Nalbuphine

Butorphanol

- Nalorphine

Mechanism of action drugs of this pharmacological group are similar to those of endogenous opioid substances (endorphins, dynorphins and enkephalins), and consists of 1) activation of opioid receptors, resulting in the opening of potassium channels, leading to hyperpolarization of the postsynaptic membrane; 2) blockade of calcium channels, causing hyperpolarization of the presynaptic membrane and inhibition of the release of the main pain mediators into the synaptic cleft (substance P, glutamate and Df.); 3) inhibition of adenylate cyclase and subsequent synthesis of cAMP.

Effects.1 . Analgesic.

Suppression of the activity of the nociceptive system as a result of blockade of the transmission of pain impulses from the axon of the first sensitive neuron (the body of which is located in the spinal ganglion) to the second neuron located in the dorsal horns of the spinal cord according to the mechanism described above.

Activation of the antinociceptive system, which enhances the descending inhibitory influences on the nociceptive system through stimulation of brain stem structures (gray periductal substance, raphe nucleus magnesium, substantia gelatinosa, etc.)

Reduced excitability of the emotional and autonomic centers of the hypothalamus, limbic system and cerebral cortex, which leads to a weakening of the negative emotional and mental assessment of pain:. 1. Action on the central nervous system. They have an ambiguous effect, i.e. V

therapeutic doses depress some parts of the central nervous system, and a number

brain structures - excite.

Oppress

Pain centers of the cortex and thalamus - analgesic effect. Hemisphere cortex - sedative effect, development of false euphoria. Cough center - the central antitussive effect. Respiratory center - respiratory depression, up to apnea. Vomiting center (in 70% of cases).

excite

Sensory zones of the cerebral cortex -> formation of auditory, visual Sh yar- hallucinations. The center of the vagus nerve - only complete and partial agonists -> the occurrence of bradycardia,

hypotension, bronchospasm. Autonomic segment of the nucleus of the oculomotor nerve -> miosis. Tritternuk) zone of the vomiting center (in 30% of cases) -> nausea and vomiting of the central location.

Note: ~> as a consequence

3. The cardiovascular system.

Full and partial agonists cause bradycardia and hypotension as a result of activation of the vagus nerve centers, and agonists-antagonists cause tachycardia and increased blood pressure due to an increase in the content of catecholamines in the blood.

If the respiratory center is depressed, carbon dioxide accumulates, leading to expansion of cerebral vessels, reducing their resistance and increasing intracranial pressure,

4. Gastrointestinal tract.

The occurrence of spasm of the intestinal sphincters, which, in combination with more complete absorption of water, increases the viscosity of intestinal contents and slows down its evacuation - obstapation effect (locking effect), the mechanism of which is due to the effect on c-opioid receptors of smooth muscles, a decrease in the release of acetylcholine, prostagdandin SCH and vasoactive intestinal peptide Y from the submucosal nerve plexus.

5. Biliary tract.

Contraction of the sphincter of Oddi leads to reflux of biliary and pancreatic secretions and increases the concentration of amylase and lipase in the blood plasma.

6. Urinary system.

The occurrence of oligo- or anuria due to an increase in the production of antidiuretic hormone and an obstructive effect on the urinary tract.

7. Endocrine system,

Opioid analgesics, especially morphine, secondarily inhibit the secretion of follicle-stimulating and luteinizing hormones, glucocorticoids and testosterone and increase the release of prolactin, somatotropic and antidiuretic hormones. As a result, they develop: in men - gynecomastia, impotence and infertility; in women - galactorrhea, dysmenorrhea and infertility.

Morphine relaxes the uterus, reduces the frequency and amplitude of its contractions during childbirth, prolonging them, and disrupts breathing in the fetus. Promedol, on the contrary, increases the contractile activity of the uterus without interfering with the opening of its cervix; 5, weaker than morphine, it depresses breathing in the fetus.

9. Other effects.

With rapid intravenous administration of large doses of lipophilic drugs (Fentanyl), an increase in skeletal muscle tone is observed. Muscle rigidity that develops at the spinal level impairs the functioning of the pectoral muscles, reducing the efficiency of pulmonary ventilation.

Application.

In anesthesiology: neuroleptanalgesia - a combination of fentanyl and its derivatives with the neuroleptic droperidol (to prolong the effect of opioid analgesics); balanced analgesia - a combination of the above opioids with anxiolytics (diazepam, chlordiazepoxide); premedication before anesthesia.

5, Complications.

addictive

Withdrawal syndrome

Oppression breathing, up to apnea

Oligo-or anuria

Brady or tachycardia

Hypo- or hypertension

Obstipation

Nausea and vomiting (central origin)

10.Gynecomastia, impotence and infertility - in men; galactorrhea,

dysmenorrhea and infertility in women; 11. Allergic reactions. Contraindications.

Hypersensitivity,

The use of full agonists in combination with antagonist agonists.

Traumatic brain injury (including intracranial hypertension).

Respiratory failure.

Severe liver failure.

Adrenal insufficiency and hypothyroidism.

Alcohol intoxication.

Abdominal pain of unknown etiology.

Age before 3 years and old age.

Pregnancy.

Treatment of acute poisoning with opioid analgesics.

Symptom: loss of consciousness (in severe cases - coma), miosis, bradycardia, hypotension, shallow breathing, even Cheyne-Stokes type breathing, cold, dry pale skin, preserved tendon reflexes.

Treatment: 1. Gastric lavage with a weak solution of potassium permanganate (for any route of administration).

2. Administration of the opioid receptor antagonist - naloxone

9. Other effects.

In therapeutic doses, they cause skin hyperemia and a feeling of warmth, which is caused by the release of histamine from tissue depots.

With rapid intravenous administration of large doses of lyophilic drugs (fentanyl), an increase in skeletal muscle tone is observed. Muscle rigidity that develops at the spinal level* impairs the functioning of the pectoral muscles, reducing the efficiency of pulmonary ventilation.

Application.

1. Pain syndrome during injuries, wounds, burns, colic (renal, hepatic, intestinal), in the postoperative period, myocardial infarction, malignant neoplasms, childbirth (promedol).

In anesthesiology: neuroleptanalgesia - a combination of fentanyl and its derivatives with the neuroleptic droperidol (to prolong the effect of opioid analgesics); balanced analgesia - a combination of the above opioids with anxiolytics (dnazepam, chlordiazepoxide); premedication before anesthesia.

Pulmonary edema. Morphine depresses the respiratory center, due to a decrease in its sensitivity to a physiological stimulant (carbon dioxide), reducing non-productive shortness of breath.

Cough due to malignant neoplasms or due to pulmonary hemorrhage (morphine, for bronchopulmonary diseases - codeine in combination with expectorants).

5. Complications,

Drug dependence (mental and physical)

addictive

Withdrawal syndrome

Respiratory depression, up to apnea

3. Injection of atropine - to remove the vagomimetic effect of opioids.

4. Forced diuresis (with bladder catheterization)

5. Symptomatic therapy (a, beta-adrenergic agonists, antihypertensive drugs).

Chronic exposure to antagonists.

Chronic exposure to naloxone and naltrexone is accompanied by an increase in opioid receptor density. This phenomenon is called up-regulation. Agoists have the opposite effect on the number of receptors - down-regulation.

However, there are studies showing that initial stage interaction of antagonists with opioid receptors, a down-regulation state may develop. This phenomenon indicates the manifestation of agonist properties by ialoxone and ialtrexone. The drugs in question are not used for replacement therapy due to the clear predominance of the antagonistic profile. However, the inclusion of naloxone in the anti-relapse treatment regimen dramatically improves the quality of therapy. Naloxone and naltrexone in low doses (concentrations) enhance the antinociceptive activity of morphine and opioid analgesics.

The inclusion of opioid receptor blockers in pain treatment regimens not only increases the effectiveness of therapy, but also counteracts the development of tolerance And dependencies.

Treatment of opioid addiction.

Oral administration of the opioid receptor antagonist naltrexone, which lasts up to 72 hours. The use of antagonists or agonist-antagonists of opioid receptors in persons with opioid dependence is accompanied by the development of withdrawal syndrome (withdrawal syndrome).

Treatment of withdrawal syndrome.

1. Methadone is a synthetic long-acting (24 - 36 hours) opioid receptor agonist. Reduces the need to take the drug without developing euphoria, respiratory depression, analgesia, while maintaining puff performance, the ability to engage in mental and physical labor. Methadone detoxification is carried out for 30 to 180 days (this drug is not used in the Russian Federation for these indications).

2. Clonidine (clonidine) is an agonist of presynaptic £%-adrenergic receptors, softens the physiological symptoms of withdrawal syndrome, but only slightly weakens the psychological manifestations (craving for taking drugs, etc.)* The advantages of the drug are the absence of euphoria and the development of addiction. For maintenance treatment of opioid addiction, the use of buprenorphine (a partial opioid receptor agonist), acetorphan (an active eikephalinase inhibitor) and ibogaine (an alkaloid with hallucinogenic and stimulant properties) is being studied.

Agonist characteristics

Agonists can be endogenous(such as hormones and neurotransmitters) and exogenous(medicines). Endogenous agonists are normally produced within the body and mediate receptor function. For example, dopamine is an endogenous dopamine receptor agonist.

Physiological agonist is a substance that causes a similar response, but acts on a different receptor.

Range of effects

Range of agonist effects

Agonists vary in the strength and direction of the physiological response they produce. This classification is not related to the affinity of the ligands and is based only on the magnitude of the receptor response.

Superagonist- a compound capable of inducing a stronger physiological response than an endogenous agonist. Full agonist- a compound that causes the same response as an endogenous agonist (for example, isoprenaline, a β-adrenergic agonist). In the case of a smaller response, the connection is called partial agonist(for example, aripiprazole is a partial agonist of dopamine and serotonin receptors).

If the receptor has basal (constitutive) activity, some substances - inverse agonists- can reduce it. In particular, GABA A receptor inverse agonists have anxiogenic or spasmogenic effects, but may enhance cognitive abilities.

Mechanism

If the activation of a receptor requires interaction with several different molecules, the latter are called coagonists. An example is NMDA receptors, which are activated by the simultaneous binding of glutamate and glycine.

Irreversible An agonist is called if, after binding to it, the receptor becomes permanently activated. IN in this case it does not matter whether the ligand forms a covalent bond with the receptor or whether the interaction is non-covalent but extremely thermodynamically favorable.

Selectivity

Selective An agonist is called if it activates only one specific receptor or subtype of receptors. The degree of selectivity may vary: dopamine activates five different receptor subtypes but does not activate serotonin receptors. Currently, there is experimental evidence of the possibility of different interactions of the same ligands with the same receptors: depending on the conditions, the same substance can be a full agonist, antagonist or inverse agonist.

Activity

Notes

Wikimedia Foundation. 2010.

See what “Agonist” is in other dictionaries:

- (by this, see the previous word). Fighter. Dictionary of foreign words included in the Russian language. Chudinov A.N., 1910. AGONIST Greek. agonistes, from agon, struggle. Opponent, persecutor of opinions. Explanation of 25,000 foreign words that came into use in... ... Dictionary of foreign words of the Russian language

Noun, number of synonyms: 3 fighter (39) persecutor (5) enemy (26) ASIS Dictionary of Synonyms ... Synonym dictionary

agonist- Small proteins or organic molecules that bind to certain cellular proteins, which are receptors, cause their conformational changes, which enhances the effect of hormones, neurotransmitters, etc... ... Technical Translator's Guide

AGONIST- 1. A muscle that contracts and acts in the opposite direction compared to another muscle, the antagonist; when bending the elbow, for example, the biceps is the agonist and the triceps is the antagonist. See antagonist muscles. 2. Any medicine... ... Explanatory dictionary of psychology

agonist- (Grch agonistes) kaј age Grtsi wrestler, megdanџiјa, natprevaruvach v viteshki games ... Macedonian dictionary

AGONIST- (agonist) 1. Prime mover muscle, due to the contraction of which a certain movement of one or another part of the body occurs. Contraction of the agonist muscle is accompanied by relaxation of the opposing muscle of the antagonist. 2. Medicine or... ... Explanatory dictionary of medicine

Receptor agonists - medicinal substances, stimulating receptors, are similar to natural mediators or hormones. Their value in pathological conditions lies in the fact that they are more resistant than true mediators to destructive substances, therefore their action lasts longer than the action of natural substances, the effects of which they imitate.

At the beginning of this century it was suggested that some drugs cause effects as a result of binding to specialized receptors on cells. The fact that curare abolishes muscle contraction caused by nicotine and does not prevent contraction caused by electrical stimulation led Langley (1905) to conclude that both substances act as a result of the formation of a complex with a certain component on the muscle cell, but not with contractile substance. It was called a receptor substance, or receptor. In subsequent years, the concept of “receptor” was used as the basis for a concept that allows not only to discuss the mechanisms of action of known drugs, but also to search for new ones. Quantification of receptors and studies of their distribution became possible after it was discovered that snake venom α-toxin (which can be radioactively labeled) selectively binds to acetylcholine receptors at synapses in skeletal muscle. Using electron micrographs, receptor molecules were identified in this tissue. It became obvious that the classical concept, according to which the relationship between substance and receptor was considered as a “key and lock,” was too limited. The method using radioligands makes it possible to determine the quantity and study the binding ability of receptors both on whole cells and in preparations prepared from their membranes.

It was found that the number of receptors is not constant, but changes under different circumstances. It decreases with prolonged exposure to the tissue of the antagonist, which can lead to the development of tachyphylaxis, i.e. to loss of effectiveness with repeated frequent use of the drug, for example, the bronchodilatory effect of sympathomimetics in bronchial asthma. Long-term exposure to an agonist is accompanied by the formation of new receptors. In this regard, rapid withdrawal of beta-blockers in patients suffering from angina or arrhythmia may be accompanied by a worsening of the condition, since catecholamines circulating in the blood have a stronger effect due to an increase in the number of beta-adrenergic receptors.
Most receptors are protein molecules. Upon binding to an agonist receptor the conformation of the protein molecule changes, which is accompanied by a change in intracellular processes that determine the response to the drug. For example, activation of beta-adrenergic receptors by catecholamine (primary messenger) increases the activity of adenylate cyclase, which accelerates the formation of cAMP (secondary messenger), which regulates the activity of several enzymatic systems that activate the cell. The effect of a drug on the receptor may also be mediated by affecting the function of membrane ion channels closely associated with the receptor (for example, with the nicotine-sensitive acetylcholine receptor), or by changing the level of intracellular calcium (for example, the implementation of some effects through muscarinic-sensitive receptors).

Receptor agonists

Receptor agonists- drugs that stimulate receptors are similar to natural mediators or hormones. Their value in pathological conditions lies in the fact that they are more resistant than true mediators to destructive substances, therefore their action lasts longer than the action of natural substances, the effects of which they imitate. For example, the bronchodilator effect of salbutamol is longer than that of adrenaline.

Receptor antagonists

Receptor antagonists (blockers) are close to natural agonists, so the receptor “recognizes” them, but by occupying the receptor, the antagonists do not activate it, and the natural agonist cannot activate it. Drugs that occupy and do not activate the receptor are called pure antagonists .
Partial agonists. Some drugs that block the receptor are also capable of partially stimulating it, i.e., they have the properties of both an antagonist and an agonist. Their effects depend on the circumstances, for example, nalorphine in moderate doses acts as an antagonist of opioids in relation to their depressant effect on the respiratory center, but in large doses it can increase respiratory depression. In this regard, with the advent of naloxone, a pure antagonist, nalorphine lost its clinical significance. Substances such as pentazocine are called partial agonist agents. Pindolol and oxprenolol are beta-blockers that have these properties. They are often called beta-blockers with intrinsic sympathomimetic activity, in contrast to propranolol (anaprilin), which does not have agonist properties and is therefore a pure antagonist. The difference between them in terms of clinical signs is quite significant, since in patients at rest, propranolol (anaprilin) ​​significantly reduces the pulse, unlike pindolol, despite the fact that both drugs protect the body from the effects of changing concentrations of catecholamines in the blood, since they block the beta receptor . In this regard, during physical activity, both drugs equally neutralize reflex tachycardia. It is possible that under certain conditions such differences in action may have therapeutic significance.

Receptor binding

If the binding to the receptor is weak (hydrogen, van der Waals, or electrostatic bonds), then it is reversible, but if it is strong (covalent), then it is irreversible.
Antagonist that reversibly binds to the receptor, can be displaced from this connection by the law of mass action, according to which the speed chemical reaction proportional to the concentration of reactants. When the agonist concentration increases sufficiently (competition), the receptor response is restored. This phenomenon is often observed in clinical practice. If a patient taking beta-blockers has an increased pulse rate during physical activity compared to its resting rate, this indicates the ability of his sympathetic nervous system release that amount of norepinephrine (agonist) that eliminates the blocking effect of the used dose of the drug. Increasing the dose of beta-blocker may limit or even completely eliminate exercise-induced tachycardia, indicating a greater severity of the blockade, which has intensified due to large quantity a drug that can compete with an endogenous mediator. Because the agonist and antagonist compete for binding to the receptor According to the law of mass action, this relationship between drugs is called competitive antagonism (for example, the use of competitive antagonists in an overdose of beta-blockers). By graphically depicting the dependence of the effect on the logarithm of the dose and using data from studies of the response to the agonist, mediated through the receptor in isolated tissues, or from the functional response of the body, an S-shaped (sigmoid) curve is obtained, the central part of which forms a straight line. If measurements are taken in the presence of an antagonist and the curve parallel to the first one shifts to the right, this indicates a competitive interaction between the agonist and antagonist - competitive antagonism .
Phenoxybenzamine is a drug that binds irreversibly to alpha-adrenergic receptors. Because it cannot be displaced from the receptor, increasing the concentration of the agonist cannot fully restore the response to receptor stimulation. This type of antagonism is called irreversible. The curves graphically depicting the logarithm of dose-response for an agonist in the absence and presence of a noncompeting antagonist are not parallel. Some toxins act in this way, for example alpha-bungarotoxin, which is part of the venom of some snakes, irreversibly binds to the acetylcholine receptor and is therefore used in pharmacological research. Normalization of the reaction after irreversible binding occurs only after the elimination of the drug from the body and the synthesis of new receptors, therefore the effect of such substances continues even after their administration is stopped.

Mechanism of action of drugs based on receptor regulation

The cell response is provided by receptors. Into the structure and Chemical properties Each chemical regulator has built-in certain biological information. In order for it to be perceived by a cell, it must be deciphered, just as a radio receiver deciphers exactly those radio waves to which it is tuned. The receptor to a certain extent resembles the active site of an enzyme, i.e. it is a macromolecular region, in its configuration and distribution of ionic charges complementary to the corresponding hormone. However, while chemical changes occur in the substrate upon interaction with the enzyme, but the enzyme does not change, the hormone upon interaction with the receptor also does not change, but their interaction leads to a change in the receptor. After changes in the structure and distribution of charges in the receptor, a directed change in cellular activity begins.
Like enzymes, receptors serve as a common site of action for drugs. Under physiological conditions, selective chemical influences are directed at enzymes and receptors, and if the drug contains information that is sufficiently clear to the cells, it will be able to “deceive” the body’s regulatory mechanism. Just as enzyme inhibitors such as allopurinol are often very similar in chemical composition with a common substrate, receptor antagonists are similar to natural hormones. Understanding Physiological Function specific system a hormone receptor can be used to suggest what properties a new substance that interferes with regulatory mechanisms (antagonist) should have. There are numerous examples of speculation of this kind, but there is also a known case that led to the creation of propranolol (Inderal, Anaprilin), effective for heart disease and severe hypertension.
A person can live for several months without food and several days without water, but is not able to withstand even a few minutes without air and oxygen. When the oxygen supply is cut off, the heart is the first to suffer. It enters the heart muscle through the arteries, through which blood passes mainly during the short pause between contractions. Oxygen delivery is so important that the heart has its own dedicated blood supply - the coronary arteries. Without oxygen, the heart muscle stops contracting and dies. The coronary arteries are the heart's own life support system. The heart responds to increased activity of the body, be it physical activity or excitement, by increasing the frequency and intensity of contractions, which is due to the release of norepinephrine by special (sympathetic) nerve endings in the fibers of the heart muscle. In order to complete this extra work, the heart requires more oxygen, so the coronary arteries must deliver blood faster. Normally, the arteries do this, like a water tap, expanding their lumen. However, with the disease, thickenings appear on the inner lining of the arteries, which causes the narrowing of their openings to such an extent that the blood flow cannot increase and meet the body's needs for oxygen (as with the formation of plaque in water pipe: No matter how much you open the tap, the flow of water will not increase). A person feels the first sign of trouble when the coronary arteries are unable to provide the heart’s need for blood and oxygen, for example during intensive physical activity. At a critical moment, when the need for oxygen exceeds the supply, pain occurs, which can be very severe - this is how an attack of angina begins. The condition of the heart muscle can normalize when the additional load due to pain stops. Thus, the work of the heart is reduced to a level that the coronary arteries are able to maintain. The patient's activity in this case is limited. However, irreversible changes may occur in some part of the heart muscle. Thus, myocardial infarction develops. After a fairly common heart attack, intact areas of the heart muscle can still support required level its pumping function, provided that a sufficient amount of norepinephrine is released in the nerve endings. The sad paradox of cardiac infarction is that the stimulation by norepinephrine, necessary to maintain adequate contraction, also increases the likelihood of impaired stimulation of the heart muscle at the border of the intact and damaged areas. Such abnormal stimulation can disrupt the coordinated contraction of the heart: its wall begins to contract convulsively and asynchronously and suddenly loses its ability to be an effective pump. This condition is called cardiac fibrillation, which usually results in sudden death, however, rendering urgent assistance(electrical shock caused by a defibrillator) helps normalize the rhythm.
Traditionally, patients with angina are treated with nitrates, and myocardial infarction with rest and analgesics. Nitrates cause a feeling of warmth and redness of the face. It is believed that a similar dilation of blood vessels occurs in the heart muscle, which can allow more blood to flow into it. A broad search for drugs that have the most pronounced properties to dilate coronary vessels, more selectively and for a long time, has proven to be quite successful. Latest drugs do increase coronary blood flow, but are often unable to prevent or alleviate an attack of angina! This, apparently, is not surprising: the affected arteries cannot expand in the same way as intact ones. The drug can actually increase the blood supply to the heart muscle, causing changes in nerve reflexes. Such reflex effects can lead to an increase in myocardial oxygen demand. If it is impossible to effectively increase the supply of oxygen with the help of a drug, why not try to reduce the need for it in the heart muscle? This is exactly what happens when a patient with angina attacks gives himself rest, or a patient with a heart attack observes bed rest. The problem is that the stimulation of the heart by norepinephrine, which mainly determines its oxygen demand, is only partially controlled by exercise; excitement, fear, pain or even physical discomfort also stimulate its function. Just rest is not enough. The idea arises of searching for drugs that could prevent the effects of norepinephrine and thus control the oxygen demand of the heart muscle.
Norepinephrine receptors are special areas of heart muscle cells that are the first to “recognize” norepinephrine and combine with it, and then change cellular enzymes that “make” the heart contract faster and stronger. It was found that propranolol (anaprilin) ​​is “recognized” by norepinephrine receptors of heart cells and binds to them; at the same time, it not only does not act on the mechanisms that cause an increase in enzymatic activity in the heart, but also, by binding to the receptor, prevents a similar effect of norepinephrine. This property of propranolol alone might be enough to make it a useful drug, but another extremely important property has been identified. Norepinephrine receptors in the blood vessels appear to be different from those in the heart muscle. The former are currently classified primarily as alpha-adrenergic receptors, while propranolol has proven to be a selective antagonist of cardiac muscle beta-adrenergic receptors. This means that it is effective against changes that occur in the heart during physical or emotional stress, but has virtually no effect on the nervous regulation in relation to the blood vessels. During physical activity, the nerve endings in them, as a result of the release of norepinephrine, cause the redistribution of blood, which from the skin and internal organs begins to flow to the muscles, increasing their blood supply. Propranolol does not affect this effect of norepinephrine, since beta-adrenergic receptors are practically not involved in this process.
In patients with coronary insufficiency receiving propranolol, intense physical activity may not be accompanied by pain. There is also evidence that long-term blockade of beta-adrenergic receptors increases life expectancy. A pleasant surprise in clinical trials was the effectiveness of propranolol in severe hypertension. If its action is also associated with the ability to reduce cardiac function and cardiac output during exercise (which seems likely), this will shed light on the possible origins of this widespread disease.
Thus, we're talking about about a drug that not only brings relief to patients, but also provides a lot of grounds for understanding the role of norepinephrine and related hormones both in normal conditions and in pathology. Currently, this is one of the most important aspects of studying medicines. They not only bring relief to the patient, but serve as important tools for medical research, helping to understand the nature of the disease.
Another example of the effective use of new drugs is histamine. Beta blockers were discovered after it was discovered that existing antagonists (alpha-adrenergic receptor blockers) are not able to prevent the reaction of the heart muscle to adrenaline. New histamine blockers were discovered after the inability of old antihistamines to prevent the reaction of the glands of the gastric mucosa to it was discovered. It secretes hydrochloric acid, which, contrary to popular belief, appears to play much less of a role in digestion than in sterilizing the upper intestine. For example, the incidence of tuberculosis is higher in individuals who do not secrete hydrochloric acid. Every time you eat, acid secretion begins in the stomach. Some individuals secrete too much of it because the stimulus is extremely strong or perhaps because of a defect in the mechanism that stops secretion at the end of the digestive process. Anyway excess secretion hydrochloric acid carries a risk of developing stomach or duodenal ulcers. These ulcers (peptic ulcers) can cause a lot of trouble due to pain and insufficient digestion, or lead to serious, even fatal complications: severe bleeding or perforation of the stomach wall, in which its contents enter the abdominal cavity, resulting in peritonitis. These glands in the gastric mucosa can be removed surgically, thereby blocking acid secretion; the nerves can also be cut, which stops the stimulation of secretion. However, after these operations, death often occurs (more than 1:200).
The endings of the nerves that the surgeon cuts secrete acetylcholine. Therefore, atropine, a competitive antagonist of acetylcholine, should cause the same effect. For many years it and related drugs were used for peptic ulcers of the stomach, but the results were disappointing. The doses of atropine required to reduce the secretion of hydrochloric acid also block other acetylcholine receptors, causing blurred vision, dry mucous membranes in the mouth and difficulty urinating. It also blocks the receptors of the nerves going to the muscles of the stomach wall, so that the evacuation from it slows down. All this neutralizes the positive effect of atropine in reducing the acidity of gastric juice. Its action is not selective enough.
In addition to acetylcholine, two other substances were found in the stomach, which are powerful stimulants of its secretion: histamine and gastrin. Gastrin (a polypeptide), released from food in another part of the intestine, serves as the main hormone that controls secretion in the stomach. It reaches its receptors on the cells of the gastric mucosa, entering them from the blood, and stimulates the secretion of both digestive enzymes and hydrochloric acid. Histamine comes from a single amino acid (histidine) and is concentrated in the area of ​​acid-secreting cells. It only stimulates the secretion of hydrochloric acid. Some researchers believe that this stimulation is mediated by the local release of histamine from its stores.
Like norepinephrine, histamine acts on two types of receptors: H1 and H2. Antihistamines used for hay fever block H1 receptors. Several years ago, antagonists that block H2 receptors were discovered. One of them [cimetidine (Tagamet)] is currently used in the clinic. Although it is a competitive antagonist of histamine, it also inhibits the action of gastrin. This is good news for patients with peptic ulcers, since acid secretion in the stomach can now be selectively reduced. More patients may recover faster than with drugs that block the effect of acetylcholine. They have a chance to avoid serious complications that accompany surgical intervention. In 1985, after almost 10 years of intensive clinical use of cimetidine, no unexpected side effects. Medical workers received at the same time new tool to study the function of histamine. Considering that it plays a protective role in inflammation and restoration of damaged tissues, it can be assumed that the secretion
hydrochloric acid in the stomach can be considered part of protective system. Still, the presence of histamine in the brain is puzzling. It is synthesized in the brain, but its function is unclear. However, now that it has become possible to distinguish between histamine receptors using drugs like cimetidine, progress may be made in the creation of new drugs.
More and more people are beginning to understand how drugs “use” the body's control mechanisms (receptors, hormones, binding sites, etc.) to ensure selectivity of action. This understanding provides hope for more in the future. larger number completely new drugs, which will increase the number of patients who benefit from modern medicine.
However, no art in obtaining more selectively acting and effective drugs will not lead the researcher away from the problem of their toxicity. This is an undeniable truth. The interaction of a drug with its target is determined by its correspondence to the active site on the cell wall and the likelihood that the random movement of molecules promotes contact of the drug molecule with the active site. The possibility of this contact is determined mainly by the number of molecules. In cases where drug molecules have a high affinity for active sites on the cell membrane, even a small number of them can ensure interaction. However, as the drug concentration increases, it may interact effectively with active sites that have less affinity for the drug. This may cause additional effects, including unwanted and even harmful ones. The drug becomes less selectively active, regardless of whether the substance is a natural compound or synthesized.