In recent years, a huge number of works have been devoted to catecholamines and related compounds. This is due, in particular, to the fact that interactions between endogenous catecholamines and a number of drugs used in the treatment of hypertension, mental disorders, etc. are extremely important for clinical practice. These drugs and interactions will be discussed in detail in subsequent chapters. Here we will analyze the physiology, biochemistry and pharmacology of adrenergic transmission.

Synthesis, storage, release and inactivation of catecholamines

Figure 6.3. Synthesis of catecholamines.

Synthesis. The assumption about the synthesis of adrenaline from tyrosine and the sequence of stages of this synthesis (Fig. 6.3) was first made by Blashko in 1939. Since then, all the corresponding enzymes have been identified, characterized and cloned (Nagatsu, 1991). It is important that all these enzymes do not have absolute specificity and therefore other endogenous substances and drugs can also participate in the reactions they catalyze. Thus, aromatic L-amino acid decarboxylase (DOPA decarboxylase) can catalyze not only the conversion of DOPA into dopamine, but also 5-hydroxytryptophan into serotonin (5-hydroxytryptamine) and methyldopa into α-methyldopamine; the latter, under the influence of dopamine-β-monooxygenase (dopamine-β-hydroxylase), is converted into a “false mediator” - a-methylnorepinephrine.

The limiting reaction in the synthesis of catecholamines is considered to be hydroxylation of tyrosine (Zigmond et al., 1989). The enzyme tyrosine hydroxylase (tyrosine-3-monooxygenase) that catalyzes this reaction is activated by stimulation of adrenergic neurons or adrenal medulla cells. This enzyme serves as a substrate of protein kinase A (cAMP-dependent), Ca2+-calmodulin-dependent protein kinase and protein kinase C. It is believed that it is its phosphorylation under the influence of protein kinases that leads to an increase in its activity (Zigmond et al., 1989; Daubner et al., 1992) . This is an important mechanism for increasing the synthesis of catecholamines with increased activity of the sympathetic nerves. In addition, stimulation of these nerves is accompanied by a delayed increase in tyrosine hydroxylase gene expression. There is evidence that this increase may be due to changes at various levels - transcription, RNA processing, regulation of RNA stability, translation and the stability of the enzyme itself (Kumer and Vrana, 1996). The biological meaning of these effects is that with increased release of catecholamines, their level in the nerve endings (or adrenal medulla cells) is maintained. In addition, tyrosine hydroxylase activity can be inhibited by catecholamines through the mechanism of allosteric modification; thus, there is negative feedback at work here. Mutations of the tyrosine hydroxylase gene have been described in humans (Wevers et al., 1999).

Description for fig. 6.3. Synthesis of catecholamines. To the right of the arrows are enzymes (in italics) and cofactors. The last stage (formation of adrenaline) occurs only in the adrenal medulla and some adrenaline-containing neurons in the brain stem.

Our knowledge about the mechanisms and localization in the cell of the processes of synthesis, storage and release of catecholamines is based on the study of organs with sympathetic innervation and the adrenal medulla. As for organs with sympathetic innervation, almost all of the norepinephrine contained in them is localized in the nerve fibers - a few days after the transection of the sympathetic nerves, its reserves are completely depleted. In adrenal medulla cells, catecholamines are found in so-called chromaffin granules (Winkler, 1997; Aunis, 1998). These are vesicles containing not only catecholamines in extremely high concentrations (about 21% of dry weight), but also ATP and a number of proteins - chromogranins, dopamine-β-monooxygenase, enkephalins, neuropeptide Y and others. Interestingly, the N-terminal fragment of chromogranin A, vasostatin-1, has antibacterial and antifungal properties (Lugardon et al., 2000). Two types of vesicles were found in the endings of sympathetic nerves: large electron-dense vesicles, corresponding to chromaffin granules, and small electron-dense vesicles containing norepinephrine, ATP, and membrane-bound dopamine-β-monooxygenase.

Figure 6.4. Basic mechanisms of synthesis, storage, release and inactivation of catecholamines.

The main mechanisms of synthesis, storage, release and inactivation of catecholamines are shown in Fig. 6.4. In adrenergic neurons, enzymes responsible for the synthesis of norepinephrine are formed in the body and transported along axons to the endings. Hydroxylation of tyrosine to form DOPA and decarboxylation of DOPA to form dopamine (Fig. 6.3) occur in the cytoplasm. Then approximately half of the resulting dopamine is transferred by active transport to vesicles containing dopamine-β-monooxygenase, and here dopamine is converted into norepinephrine. The remaining dopamine undergoes first deamination (to form 3,4-dihydroxyphenylacetic acid) and then O-methylation (to form homovanillic acid). In the adrenal medulla there are 2 types of catecholamine-containing cells: norepinephrine and adrenaline. The latter contain the enzyme phenylethanolamine-N-methyltransferase. In these cells, norepinephrine leaves the chromaffin granules into the cytoplasm (apparently by diffusion) and here it is methylated by the indicated enzyme to adrenaline. The latter re-enters the granules and is stored in them until release. In adults, adrenaline accounts for about 80% of all adrenal medulla catecholamines; the remaining 20% ​​is predominantly norepinephrine (von Euler, 1972).

Description for fig. 6.4. Basic mechanisms of synthesis, storage, release and inactivation of catecholamines. A schematic representation of the sympathetic ending is shown. Tyrosine is transferred by active transport into the axoplasm (A), where, under the action of cytoplasmic enzymes, it is converted into DOPA and then into dopamine (B). The latter enters the vesicles, where it is converted into norepinephrine (B). The action potential causes entry into the Ca2+ terminal (not shown), resulting in vesicle fusion with the presynaptic membrane and release of norepinephrine (G). The latter activates α- and β-adrenergic receptors of the postsynaptic cell (D) and partially enters it (extraneuronal uptake); in this case, it is apparently inactivated by conversion to normetanephrine by COMT. The main mechanism of norepinephrine inactivation is its reuptake by the presynaptic terminal (E), or neuronal uptake. Norepinephrine released into the synaptic cleft can also interact with presynaptic α2-adrenergic receptors (G), suppressing its own release (dotted line). Other mediators (for example, peptides and ATP) may also be present at the adrenergic terminal - in the same vesicles as norepinephrine, or in separate vesicles. AR - adrenoreceptor, DA - dopamine, NA - norepinephrine, NM - normetanephrine, P-peptide

The main factor regulating the rate of adrenaline synthesis (and therefore the secretory reserve of the adrenal medulla) is produced by the adrenal cortex. These hormones, through the adrenal portal system, enter in high concentrations directly to the chromaffin cells of the medulla and induce the synthesis of phenylethanolamine-N-Methyltransferase in them (Fig. 6.3). Under the influence of glucocorticoids, the activity of tyrosine hydroxylase and dopamine-β-monooxygenase in the medulla also increases (Carroll et al., 1991; Viskupic et al., 1994). Therefore, sufficiently long-term stress, causing an increase in the secretion of ACTH, leads to an increase in the synthesis of hormones both cortical (mainly cortisol) and the adrenal medulla.

This mechanism works only in those mammals (including humans) in which the chromaffin cells of the medulla are completely surrounded by cells of the cortex. In burbot, for example, chromaffin and steroid-secreting cells are located in separate glands that are not connected to each other, and adrenaline is not secreted. At the same time, phenylethanolamine-N-methyltransferase in mammals is found not only in the adrenal glands, but also in a number of other organs (brain, heart, lungs), that is, extra-adrenal synthesis of adrenaline is possible (Kennedy and Ziegler, 1991; Kennedy et al., 1993).

The reserves of norepinephrine in the endings of adrenergic fibers are replenished not only due to its synthesis, but also due to the reuptake of released norepinephrine. In most organs, it is reuptake that ensures the cessation of the action of norepinephrine. In blood vessels and other tissues, where the synaptic clefts are wide enough, the role of norepinephrine reuptake is not so great - a significant part of it is inactivated by extraneuronal uptake (see below), enzymatic cleavage and diffusion. Both the reuptake of norepinephrine into adrenergic terminals and its entry into synaptic vesicles from the axoplasm go against the concentration gradient of this mediator, and therefore they are carried out using two active transport systems, including corresponding carriers. Storage. Because catecholamines are stored in vesicles, their release can be quite precisely controlled; in addition, they are not exposed to cytoplasmic enzymes and do not leak into the environment. The transport systems of biogenic monoamines are quite well studied (Schuldiner, 1994). The uptake of catecholamines and ATP by isolated chromaffin granules appears to be driven by pH and potential gradients created by the H+-ATPase. The transfer of one monoamine molecule into the vesicle is accompanied by the release of two protons (Browstein and Hoffman, 1994). Transport of monoamines is relatively indiscriminate. For example, the same system is capable of transporting dopamine, norepinephrine, epinephrine, serotonin, as well as meta-1 "1-benzylguanidine, a substance used for isotopic diagnosis of tumors from chromaffin cells of pheochromocytoma (Schuldiner, 1994). Vesicular transport of amines is suppressed reserpine; under the influence of this substance, the reserves of catecholamines are depleted in the sympathetic endings and in the brain. Using molecular cloning methods, several cDNAs related to vesicular transport systems were identified, suggesting the coding of proteins with 12 transmembrane domains. must be homologous to other transport proteins, such as transport proteins mediating bacterial drug resistance (Schuldiner, 1994), changes in the expression of these proteins may play an important role in the regulation of synaptic transmission (Varoqui and Erickson, 1997).

Catecholamines (for example, norepinephrine) introduced into the blood of animals quickly accumulate in organs with abundant sympathetic innervation, in particular in the heart and spleen. In this case, labeled catecholamines are found in sympathetic endings; desympathetic organs do not accumulate catecholamines (see review by Browstein and Hoffman, 1994). These and other data suggested the presence of a catecholamine transport system in the membrane of sympathetic neurons. This system was found to be Na+ dependent and selectively blocked by certain drugs, including cocaine and tricyclic antidepressants such as imipramine. It has a high affinity for norepinephrine and somewhat less affinity for adrenaline. This system does not tolerate synthetic isoprenaline. Neuronal uptake of catecholamines was also called type 1 uptake (Iversen, 1975). Protein purification and molecular cloning methods have identified several highly specific neurotransmitter transporters, in particular the high-affinity transporters of dopamine, norepinephrine, serotonin and a number of amino acids (Amara and Kuhar, 1993; Browstein and Hoffman, 1994; Masson et al., 1999). All of them belong to a large family of proteins, the common features of which include, for example, 12 transmembrane domains. Apparently, the specificity of membrane transporters is higher than that of vesicular ones. In addition, these transporters serve as points of application for substances such as (dopamine transporter) and (dopamine transporter).

So-called indirect sympathomimetics (for example, tyramine) exert their effects indirectly, usually by causing the release of norepinephrine from sympathetic endings. Thus, the active principle in prescribing these drugs is norepinephrine itself. The mechanisms of action of indirect sympathomimetics are complex. All of them bind to transporters that ensure the neuronal uptake of catecholamines, and together with them pass into the axoplasm; in this case, the carrier moves to the inner surface of the membrane and thereby becomes available for norepinephrine (metabolic facilitated diffusion). In addition, these drugs cause the release of norepinephrine from the vesicles, competing with it for the vesicular transport systems. Reserpine, which causes depletion of norepinephrine in the vesicles, also blocks vesicular transport, but, unlike indirect sympathomimetics, enters the terminal by simple diffusion (Bonish and Trendelenburg, 1988).

When prescribing indirect sympathomimetics, addiction (tachyphylaxis, desensitization) is often observed. Thus, when tyramine is taken repeatedly, its effectiveness decreases quite quickly. In contrast, repeated administration of norepinephrine is not accompanied by a decrease in effectiveness. Moreover, addiction to tyramine is eliminated. There is no definitive explanation for these phenomena, although some hypotheses have been expressed. One of them is that the fraction of norepinephrine that is displaced by indirect sympathomimetics is small compared to the total reserves of this mediator in the adrenergic endings. It is assumed that this fraction corresponds to vesicles located next to the membrane, and it is from them that norepinephrine is displaced by the less active indirect sympathomimetic. Be that as it may, indirect sympathomimetics do not cause release from the terminal of dopamine-β-monooxygenase and can act in a calcium-free environment - which means their effect is not associated with exocytosis.

There is also a system for extraneuronal catecholamine uptake (type 2 uptake), which has a low affinity for norepinephrine, a slightly higher affinity for adrenaline, and an even higher affinity for isoprenaline. This system is ubiquitous: it is found in glial cells, liver, myocardium and others. Extraneuronal uptake is not blocked by imipramine and cocaine. Under conditions of undisturbed neuronal uptake, its role is apparently small (Iversen, 1975; Trendelenburg, 1980). Perhaps it is more important for the removal of blood catecholamines than for the inactivation of catecholamines released by nerve endings.

Release. The sequence of events as a result of which adrenaline is released from adrenergic endings under the influence of a nerve impulse is not completely clear. In the adrenal medulla, the triggering factor is the action of acetylcholine released by preganglionic fibers on N-cholinergic receptors of chromaffin cells. In this case, local depolarization occurs, Ca2\ enters the cell and the contents of chromaffin granules (adrenaline, ATP, some neuropeptides and their precursors, chromogranins, dopamine-β-monooxygenase) are released through exonitosis. At adrenergic terminals, Ca2+ entry via voltage-gated calcium channels also plays a key role in coupling presynaptic membrane depolarization (action potential) and norepinephrine release. Blockade of N-type calcium channels causes a decrease in AH, apparently by suppressing the release of norepinephrine (Bowersox et al., 1992). The mechanisms of calcium-triggered exocytosis involve highly conserved proteins that ensure the attachment of vesicles to the cell membrane and their degranulation (Aunis, 1998). An increase in sympathetic tone is accompanied by an increase in the concentration of dopamine-β-monooxygenase and chromogranins in the blood. This suggests that vesicle exocytosis is involved in the release of norepinephrine upon stimulation of sympathetic nerves.

If the synthesis and reuptake of norepinephrine is not impaired, then even prolonged irritation of the sympathetic nerves does not lead to depletion of the reserves of this mediator. If the need for the release of norepinephrine increases, then regulatory mechanisms come into play. aimed, in particular, at the activation of tyrosine hydroxylase and dopamine-β-monooxygenase (see above).

Inactivation. The cessation of the action of norepinephrine and adrenaline is due to: 1) reuptake by nerve endings, 2) diffusion from the synaptic cleft and extra neuronal uptake, 3) enzymatic cleavage. The latter is caused by two main enzymes - MAO and COMT (Axelrod, 1966; Kopin, 1972). In addition, catecholamines are degraded by sulfotransferases (Dooley, 1998). At the same time, the role of enzymatic breakdown in the adrenergic synapse is much less than in the cholinergic synapse, and reuptake takes first place in the inactivation of catecholamines. This is evident, for example, from the fact that catecholamine reuptake blockers (cocaine, imipramine) significantly enhance the effects of norepinephrine, and MAO and COMT inhibitors only very weakly. MAO plays a role in the destruction of norepinephrine trapped in the axoplasm. COMT (especially in the liver) is essential for the inactivation of endogenous and exogenous catecholamines in the blood.

MAOI and COMT are widely distributed throughout the body, including the brain. Their concentration is highest in the liver and kidneys. At the same time, COMT is almost absent in adrenergic neurons. These two enzymes also differ in intracellular localization: MAO is predominantly associated with the outer membrane of mitochondria (including in the adrenergic terminals), and COMT is located in the cytoplasm. All these factors determine which pathway catecholamines will take to break down under different conditions, as well as the mechanisms of action of a number of drugs. Two MAO isoenzymes have been identified (MAO A and MAO B), and their ratio in different neurons of the central nervous system and different organs varies widely. Selective inhibitors of these two isoenzymes are available (Chapter 19). Irreversible MAO A inhibitors increase the bioavailability of tyramine contained in a number of foods; Since tyramine enhances the release of norepinephrine from sympathetic endings, when these drugs are combined with tyramine-containing products, a hypertensive crisis is possible. Selective MAO B inhibitors (eg, selegiline) and reversible selective MAO A inhibitors (eg, moclobemide) are less likely to cause this complication (Volz and Geiter, 1998; Wouters, 1998). MAO inhibitors are used to treat Parkinson's disease and depression (Chapters 19 and 22).

Figure 6.5. Metabolism of catecholamines. Both MAO and COMT are involved in the inactivation of catecholamines, but the order of their action may be different.

Most of the epinephrine and norepinephrine entering the blood, whether from the adrenal medulla or adrenergic terminals, is methylated by COMT to form metanephrine and normetanephrine, respectively (Fig. 6.5). Norepinephrine, released from the vesicles into the axoplasm under the influence of certain drugs (for example, reserpine), is first deaminated by MAO to 3,4-hydroxymandehyde; the latter is reduced by aldehyde reductase to 3,4-dihydroxyphenylethylene glycol or oxidized by aldehyde dehydrogenase to 3,4-dihydroxymandelic acid. The main metabolite of catecholamines excreted in urine is 3-methoxy-4-hydroxymandelic acid, which is often (though inaccurately) called vanillylmandelic acid. The corresponding dopamine metabolite, which does not contain a hydroxyl group on the side chain, is homovanillic acid. Other reactions of catecholamine metabolism are shown in Fig. 6.5. Measuring the concentrations of catecholamines and their metabolites in the blood and urine is an important method for diagnosing pheochromocytoma (tumor that secretes catecholamines).

MAO inhibitors (eg, pargyline and nialamide) can cause increased concentrations of norepinephrine, dopamine, and serotonin in the brain and other organs, resulting in a variety of physiological effects. Suppression of COMT activity is not accompanied by any significant reactions. At the same time, the COMT inhibitor entacapone has been shown to be quite effective in Parkinson's disease (Chong and Mersfelder, 2000; see also Chapter 22).

Description for fig. 6.5. Metabolism of catecholamines. Both MAO and COMT are involved in the inactivation of catecholamines, but the order of their action may be different. In the first case, the metabolism of catecholamines begins with oxidative deamination under the influence of MAO; Adrenaline and norepinephrine are first converted to 3,4-hydroxymandehyde, which is then either reduced to 3,4-dihydroxyphenylethylene glycol or oxidized to 3,4-dihydroxymandelic acid. The first reaction of the second pathway is their methylation by COMT to metanephrine and normetanephrine, respectively. Then the second enzyme acts (in the first case - COMT, in the second - MAO), and the main metabolites are formed, excreted in the urine - 3-methoxy-4-hydroxyphenylethylene glycol and 3-methoxy-4-hydroxymandelic (vanillylmandelic) acid. Free 3-meth-ci-4-hydroxyphenylethylene glycol is largely converted to vanillylmandelic acid. 3,4-dihydroxyphenylethylene glycol and, to a certain extent, O-methylated amines and catecholamines can be conjugated with sulfates or glucuronides. Axelrod, 1966, etc.

Classification of adrenergic receptors

Table 6.3. Adrenergic receptors

In order to navigate the amazing variety of effects of catecholamines and other adrenergic substances, it is necessary to have a good knowledge of the classification and properties of adrenergic receptors. Clarification of these properties and those biochemical and physiological processes that are affected by the activation of different adrenergic receptors helped to understand the diverse and sometimes seemingly contradictory reactions of different organs to catecholamines. All adrenergic receptors are similar in structure (see below), but they are associated with different systems of second messengers, and therefore their activation leads to different physiological consequences (Tables 6.3 and 6.4).

Table 6.4. Second messenger systems associated with adrenergic receptors

The existence of different types of adrenergic receptors was first suggested by Ahlquist (1948). This author relied on differences in physiological responses to adrenaline, norepinephrine and other related substances. It was known that these agents could, depending on the dose, organ, and specific substance, cause both contraction and relaxation of smooth muscle. Thus, norepinephrine has a powerful stimulating effect on them, but a weak one - inhibitory, and isoprenaline - on the contrary; adrenaline has both effects. In this regard, Ahlquist proposed using the designations a and β for receptors, the activation of which leads to contraction and relaxation of smooth muscles, respectively. The exception is the smooth muscles of the gastrointestinal tract - activation of both types of receptors usually causes their relaxation. The activity of adrenergic stimulants in relation to β-adrenergic receptors decreases in the series isoprenaline > adrenaline norepinephrine, and in relation to α-adrenergic receptors - in the series adrenaline > norepinephrine » isoprenaline (Table 6.3). This classification was confirmed by the fact that some blockers (for example, phenoxybenzamine) eliminate the influence of sympathetic nerves and adrenergic stimulants only on α-adrenergic receptors, and others (for example, propranolol) - on β-adrenergic receptors.

β-adrenergic receptors were subsequently subdivided into β1 (particularly in the myocardium) and β2 (in smooth muscle and most other cells) subtypes. This was based on the fact that epinephrine and norepinephrine act similarly on β1-adrenergic receptors, but epinephrine is 10-50 times more potent at β2-adrenergic receptors (Lands et al., 1967). Selective β1- and β2-adrenergic receptor blockers have been developed (Chapter 10). Subsequently, the gene encoding the third subtype of β-adrenergic receptors, β3, was isolated (Emorine et al., 1989; Granneman et al., 1993). Since β3-adrenergic receptors are approximately 10 times more sensitive to norepinephrine than to epinephrine, and are relatively resistant to the action of blockers such as propranolol, they may be responsible for the atypical reactions of some organs and tissues to catecholamines. Such tissues include, in particular, adipose tissue. At the same time, the role of β3-adrenergic receptors in the regulation of lipolysis in humans is not yet clear (Rosenbaum et al., 1993; Kriefctal., 1993; Lonnqvist et al., 1993). It is hypothesized that polymorphisms in the gene for this receptor may be associated with susceptibility to obesity or non-insulin-dependent diabetes mellitus in some populations (Armen and HofTstedt, 1999). Of interest is the possibility of using selective β3-blockers in the treatment of these diseases (Weyer et al., 1999).

Alpha adrenergic receptors are also divided into subtypes. The first basis for this division was the finding that norepinephrine and other α-adrenergic stimulants can acutely suppress the release of norepinephrine from neurons (Starke, 1987; see also Fig. 6.4). On the contrary, some α-blockers lead to a significant increase in the amount of norepinephrine released when the sympathetic nerves are stimulated. It turned out that this mechanism of suppression of norepinephrine release according to the principle of negative feedback is mediated by α-adrenergic receptors, which differ in their pharmacological properties from those located on the effector organs. These presynaptic adrenergic receptors were called a2, and the classical postsynaptic adrenergic receptors were called a (Langer, 1997). Clonidine and some other adrenergic stimulants have a stronger effect on α2-adrenergic receptors, and, for example, phenylephrine and methoxamine - on α1-adrenergic receptors. There is little data on the presence of presynaptic α1-adrenergic receptors in neurons of the autonomic nervous system. At the same time, a2-adrenergic receptors were found in many tissues and on postsynaptic structures, and even outside synapses. Thus, activation of postsynaptic α2-adrenergic receptors in the brain leads to a decrease in sympathetic tone and, apparently, largely determines the hypotensive effect of clonidine and similar drugs (Chapter 10). In this regard, ideas about exclusively presynaptic α2-adrenergic receptors and postsynaptic α1-adrenergic receptors should be considered outdated (Table 6.3).

Table 6.5. Subgroups of adrenergic receptors

Using molecular cloning methods, several more subgroups were identified within both subtypes of α-adrenergic receptors (Bylund, 1992). Three subgroups of α-adrenergic receptors have been discovered (a1A, a1B and a1D; Table 6.5), differing in pharmacological properties, structure and distribution in the body. At the same time, their functional features are almost not studied. Among a2-adrenergic receptors, 3 subgroups a2B and a2C were also distinguished; table 6.5), differing in distribution in the brain. It is possible that at least α2A adrenergic receptors may play a role as presynaptic autoreceptors (Aantaa et al., 1995; Lakhlani et al., 1997).

Molecular basis of the functioning of adrenergic receptors

Apparently, reactions to activation of all types of adrenergic receptors are mediated by G-proteins, causing the formation of second messengers or changes in the permeability of ion channels. As already discussed in Chap. 2, such systems include 3 main protein components - a receptor, a G protein and an effector enzyme or channel. The biochemical consequences of activation of adrenergic receptors are in many ways the same as those of M-cholinergic receptors (see above and Table 6.4).

Structure of adrenergic receptors

Adrenergic receptors are a family of related proteins. In addition, they are structurally and functionally

Adrenergic

Adrenergic

(gr. ergon impact) biol. sensitive to adrenaline, excitable yam.

New dictionary of foreign words. - by EdwART,, 2009 .

Adrenergic

(ne), oh, oh ( address(enaline) + Greek ergōn impact).
honey. Sensitive to adrenaline, excited by him.
|| Wed. cholinergic.

Explanatory dictionary of foreign words by L. P. Krysin. - M: Russian language, 1998 .

See what “adrenergic” is in other dictionaries:

adrenergic- adrenergic... Russian spelling dictionary

Adrenergic- 1. characteristics of neurons that release adrenaline when excited; 2. associated with the effects of adrenaline... Encyclopedic Dictionary of Psychology and Pedagogy

ADRENERGIC- Characteristics of neurons, nerve fibers and pathways that release epinephrine (adrenaline) when stimulated. It should be noted that if in the English-language literature the term epinephrine is preferable to use to designate the substance, then the forms... ... Explanatory dictionary of psychology

ADRENERGIC- (adrenergic) to describe nerve fibers that use norepinephrine as a neurotransmitter. For comparison: Cholinergic... Explanatory dictionary of medicine

To describe nerve fibers that use norepinephrine as a neurotransmitter. For comparison: Cholinergic. Source: Medical Dictionary... Medical terms

Beta adrenergic... Spelling dictionary-reference book

- (s. adrenergica) S., in which the mediator is norepinephrine... Large medical dictionary

- (gr. ergon impact) biol. sensitive to acetylcholine, excited by it cf. adrenergic). New dictionary of foreign words. by EdwART, 2009. cholinergic (ne), aya, oe (… Dictionary of foreign words of the Russian language

The secretion of the glands of the small and large intestines; colorless or yellowish liquid with an alkaline reaction, with lumps of mucus and deflated epithelial cells. In a person, it is released per day depending on the nature of nutrition and condition... ... Great Soviet Encyclopedia

ADRENERGIC DRUGS

(DRUGS AFFECTING THE TRANSMISSION OF EXCITATION IN ADRENERGIC SYNAPSES) (ADRENOMIMETIC AND ADRENO-BLOCKING DRUGS)

Let us recall that in adrenergic synapses the transmission of excitation is carried out through the mediator norepinephrine (NA). Within peripheral innervation, norepinephrine takes part in the transmission of impulses from adrenergic (sympathetic) nerves to effector cells.

In response to nerve impulses, norepinephrine is released into the synaptic cleft and its subsequent interaction with adrenergic receptors of the postsynaptic membrane. Adrenergic receptors are found in the central nervous system and on the membranes of effector cells innervated by postganglionic sympathetic nerves.

The adrenergic receptors existing in the body have unequal sensitivity to chemical compounds. With some substances, the formation of a drug-receptor complex causes an increase (excitation), with others a decrease (inhibition) of the activity of the innervated tissue or organ. To explain these differences in the reactions of different tissues, in 1948 Ahlquist proposed the theory of the existence of two types of receptors: alpha and beta. Typically, stimulation of alpha receptors causes excitation effects, and stimulation of beta receptors is usually accompanied by inhibitory effects. Although in general, alpha receptors are excitatory receptors, and beta receptors are inhibitory receptors, there are certain exceptions to this rule. Thus, in the heart, in the myocardium, the predominant beta-adrenergic receptors are stimulating in nature. Excitation of beta receptors of the heart increases the speed and strength of myocardial contractions, accompanied by an increase in automaticity and conductivity in the AV node. In the gastrointestinal tract, both alpha and beta receptors are inhibitory. Their stimulation causes relaxation of the smooth muscles of the intestines.

Adrenergic receptors are localized on the cell surface.

All alpha receptors are subdivided based on the comparative selectivity and potency of the effects of both agonists and antagonists on the alpha 1 and alpha 2 receptors. If alpha-1-adrenergic receptors are localized postsynaptically, then alpha-2-adrenergic receptors are localized on presynaptic membranes. The main role of presynaptic alpha-2 adrenergic receptors is their participation in the NEGATIVE FEEDBACK system that regulates the release of the neurotransmitter norepinephrine. Excitation of these receptors inhibits the release of norepinephrine from varicose thickenings of the sympathetic fiber.

Among the postsynaptic beta-adrenergic receptors, beta-1-adrenergic receptors (localized in the heart) and beta-2-adrenergic receptors (in the bronchi, skeletal muscle vessels, pulmonary, cerebral and coronary vessels, in the uterus) are distinguished.

If the stimulation of beta-1 receptors of the heart is accompanied by an increase in the strength and frequency of heart contractions, then with stimulation of beta 2-adrenergic receptors a decrease in organ function is observed - relaxation of the smooth muscles of the bronchi. The latter means that beta-2 adrenergic receptors are classical inhibitory adrenergic receptors.

The quantitative ratio of alpha and beta receptors in different tissues is different. Alpha receptors are predominantly concentrated in the blood vessels of the skin and mucous membranes, brain and vessels of the abdominal region (kidneys and intestines, gastrointestinal sphincters, trabeculae of the spleen). As you can see, these vessels belong to the category of capacitive vessels.

Mainly beta-1-stimulating adrenergic receptors are localized in the heart; beta-2-inhibitory adrenergic receptors are mainly located in the muscles of the bronchi, cerebral, coronary, and pulmonary vessels. This arrangement is evolutionarily developed, it runs away when danger arises: it is necessary to expand the bronchi, increase the lumen of the blood vessels of the brain, and increase the work of the heart.

The effect of norepinephrine on adrenergic receptors is short-lived, since up to 80% of the released mediator is quickly captured and absorbed through active transport by the endings of adrenergic fibers. Catabolism (destruction) of free norepinephrine is carried out by oxidative deamination in adrenergic endings and is regulated by the enzyme monoamine oxidase (MAO), localized in mitochondria and membrane vesicles. Metabolism of norepinephrine released from nerve endings is carried out by methylation by the cytoplasmic enzyme of effector cells - CATECHOL-O-METHYLTRANSFERASE (COMT). COMT is also present in synapses, and in plasma and cerebrospinal fluid.

The possibilities of pharmacological effects on adrenergic transmission of nerve impulses are quite diverse. The direction of action of substances can be as follows:

1) influence on the synthesis of norepinephrine;

2) impaired deposition of norepinephrine in vesicles;

3) inhibition of enzymatic inactivation of norepinephrine;

4) influence on the release of norepinephrine from the endings;

5) disruption of the process of reuptake of norepinephrine by presynaptic endings;

6) inhibition of extraneuronal neurotransmitter uptake;

7) direct effect on adrenergic receptors of effector cells.

CLASSIFICATION OF ADRENERGIC DRUGS

Taking into account the preferential localization of action, all the main means influencing the transmission of excitation in adrenergic synapses are divided into 3 main groups:

I. ADRENOMIMETIKS, that is, drugs that stimulate adrenergic receptors, acting like the neurotransmitter, imitating it.

II. ADRENO BLOCKERS - drugs that inhibit adrenergic receptors.

III. SYMPATHOLYTICS, that is, agents that have a blocking effect on adrenergic transmission using an indirect mechanism.

In turn, among ADRENOMIMETICS there are:

1) CATECHOLAMINES: adrenaline, norepinephrine, dopamine, isadrin;

2) NON-CATECHOLAMINES: ephedrine.

CATECHOLAMINES are substances containing a catechol or ortho-dioxybenzene nucleus (ortho is the top position of the carbon atom).

Group I of drugs, ADRENOMIMETICS, consists of 3 subgroups of drugs.

First of all, there are:

1) DRUGS THAT SIMULTANEOUSLY STIMULATE ALPHA AND BETA ADRENO RECEPTORS, that is, ALPHA, BETA ADRENO MIMETICS:

a) ADRENALINE - as a classic, direct alpha, beta-adrenergic agonist;

b) EPHEDRINE - indirect alpha, beta-adrenergic agonist;

c) NORADRENALINE - acting as a mediator on alpha, beta adrenergic receptors, as a medicine - on alpha adrenergic receptors.

2) DRUGS STIMULATING PRIMARILY ALPHA-ADRENORESCEPTORS, that is, ALPHA-ADRENOMIMETIICS: MEZATONE (alpha-1), NAPHTHYZIN (alpha-2), GALAZOLIN (alpha-2).

3) DRUGS THAT STIMULATE PRIMARILY BETA-ADRENORESCEPTORS, BETA-ADRENOMIMETICS:

a) NON-SELECTIVE, that is, acting on both beta-1 and beta-2 adrenergic receptors - IZADRIN;

b) SELECTIVE - SALBUTAMOL (mainly beta-2 receptors), FENOTEROL, etc.

II. ADRENO BLOCKING DRUGS (ADRENO BLOCKERS)

The group is also represented by 3 subgroups of drugs.

1) ALPHA BLOCKERS:

a) NON-SELECTIVE - TROPAPHEN, FENTOLAMINE, as well as dihydrogenated ergot alkaloids - DIHYDROERGOTOXIN, DIHYDROERGOCHRISTINE, etc.;

b) SELECTIVE - PRAZOSIN;

2) BETA BLOCKERS:

a) NON-SELECTIVE (beta-1 and beta-2) - ANAPRILINE or PROPRANOLOL, OXPRENOLOL (TRAZICOR) ETC.;

b) SELECTIVE (beta-1 or cardioselective) - METOPROLOL (BETALOK).

III. SYMPATHOLYTICS: OCTADINE, RESERPINE, ORNID.

We will begin the analysis of the material with drugs acting on alpha and beta adrenergic receptors, that is, with drugs from the alpha group, beta adrenergic agonists.

The most typical, classic representative of alpha, beta-adrenergic agonists is ADRENALINE (Adrenalini hydrochloridum, in amp. 1 ml, 0.1% solution).

Adrenaline is obtained synthetically or by isolating it from the adrenal glands of slaughtered cattle.

MECHANISM OF ACTION: has a direct, immediate, stimulating effect on alpha and beta adrenergic receptors, therefore it is a direct adrenergic agonist.

EFFECTS OF ADRENALINE ON ALPHA ADRENORESCEPTORS

Adrenaline constricts most blood vessels, especially those of the skin, mucous membranes, abdominal organs, etc. In this situation, adrenaline increases blood pressure. The drug acts on veins and arteries. The effect of adrenaline when administered intravenously develops almost at the tip of the needle, but the developing effect is short-lived, up to only 5 minutes. The effect of adrenaline on alpha-adrenergic receptors is associated with its effects on the organ of vision. Stimulating the sympathetic innervation of the radial muscle of the iris - m. dilatator pupillae - adrenaline dilates the pupil (mydriasis). This effect is short-term, has no practical significance, has only physiological significance (a feeling of fear, “fear has big eyes”).

The next effect associated with the action of adrenaline on alpha-adrenergic receptors is contraction of the spleen capsule. Contraction of the spleen capsule is accompanied by the release of a large number of red blood cells into the blood. The latter is protective in nature during stress reactions, for example, due to hypoxia and blood loss.

EFFECTS ASSOCIATED WITH THE ACTION OF ADRENALINE ON BETA-ADRENORESCEPTORS.

Beta-1 adrenergic receptors are stimulating receptors, their localization is in the heart and myocardium. By exciting them, adrenaline increases all 4 functions of the heart:

Increases the force of contractions, that is, increases myocardial contractility (positive inotropic effect);

Increases contraction frequency (positive chronotropic effect);

Improves conductivity (positive dromotropic effect);

Increases automaticity (positive bathmotropic effect).

As a result, stroke and minute volumes increase. This is accompanied by an increase in metabolism in the myocardium and an increase in oxygen consumption, which reduces the efficiency of the heart. The heart works uneconomically, efficiency becomes low.

METABOLIC EFFECTS ARE ALSO ASSOCIATED WITH STIMULATION OF BETA-1 AND BETA-2 ADRENORESCEPTORS. Adrenaline stimulates GLYCOGENOLYSIS (glycogen breakdown), which leads to increased blood sugar (hyperglycemia). The blood levels of lactic acid, potassium, and the level of free fatty acids (lipolysis) increase.

Excitation of beta-2 adrenergic receptors (this is the inhibitory classic type of beta-adrenergic receptors) leads to dilation of the bronchi - bronchodilation. The effect of adrenaline on the bronchi is especially pronounced if they are in spasm, that is, with bronchospasm. It is very important that adrenaline as a bronchodilator has a stronger effect (like other adrenergic agonists) than M-anticholinergics (for example, atropine).

In addition, adrenaline reduces the secretion of the glands of the tracheobronchial tree (especially due to vasoconstriction of the bronchial mucosa). Beta 2-reception is also associated with the dilation of coronary, pulmonary vessels, skeletal muscle vessels, and brain under the influence of adrenaline.

EFFECT OF ADRENALINE ON THE CNS

The drug has a weak stimulating effect on the central nervous system, which is more of a physiological effect. Has no pharmacological significance.

INDICATIONS FOR THE USE OF ADRENALINE RELATED TO ALPHA-ADRENORESCEPTION

1) As an antishock agent (for acute hypotension, collapse, shock). Moreover, this indication is associated with 2 effects: an increase in vascular tone and a stimulating effect on the heart. Administration of i.v.

2) As an antiallergic agent (anaphylactic shock, bronchospasm of allergic origin). This indication has something in common with the 1st indication. In addition, adrenaline is indicated as an important remedy for angioedema of the larynx. Administration also i.v.

3) As an additive to solutions of local anesthetics to prolong their effect and reduce absorption (toxicity).

These effects are associated with stimulation of alpha-adrenergic receptors.

INDICATIONS FOR THE USE OF ADRENALINE RELATED TO BETA RECEPTION

1) When the heart stops (drowning, electrical injury). It is administered intracardially. The effectiveness of the procedure reaches 25%. But sometimes this is the only opportunity to save the patient. However, it is better to use a defibrillator in this case.

2) Adrenaline is indicated for the most severe forms of AV - heart block, that is, for severe heart arrhythmias.

3) The drug is also used to relieve bronchospasm in a patient with bronchial asthma. In this case, subcutaneous injection of adrenaline is used.

We administer it subcutaneously, since beta-adrenergic receptors, in particular beta2-adrenergic receptors, are well stimulated by small concentrations of adrenaline for 30 minutes (prolongation of the effect).

4) In a single dose of 0.5 mg, adrenaline can be used with subcutaneous administration as an urgent remedy to eliminate hypoglycemic coma. Of course, it is better to administer glucose solutions, but in some forms they use adrenaline (they count on the effect of glycogenolysis).

SIDE EFFECTS OF ADRENALINE

1) When administered intravenously, adrenaline can cause cardiac arrhythmias, in the form of ventricular fibrillation.

Arrhythmias are especially dangerous when adrenaline is administered against the background of the action of drugs that sensitize the myocardium to it (anesthetics, for example, modern fluorine-containing general anesthetics ftorotan, cyclopropane). This is a significant undesirable effect.

2) Mild restlessness, tremor, agitation. These symptoms are not scary, since the manifestation of these effects is short-term, and besides, the patient is in an extreme situation.

3) When adrenaline is administered, pulmonary edema may occur, so it is better to use the drug Dobutrex in case of shock.

Unlike adrenaline, which acts directly on alpha- and beta-adrenergic receptors, there are drugs that have similar pharmacological effects indirectly. These are the so-called indirect adrenergic agonists or sympathomimetics.

Indirectly acting adrenergic drugs that indirectly stimulate alpha and beta adrenergic receptors include EPHEDRINE, an alkaloid from the leaves of the Effedra plant. In Rus' it was called Kuzmichev's grass.

The Latin name Effedrini hydrochloridum is available in table. - 0.025; amp. - 5% - 1 ml; 5% solution externally, nasal drops).

Ephedrine has a dual direction of action: firstly, influencing presynaptically on varicose thickenings of the sympathetic nerves, it promotes the release of the neurotransmitter norepinephrine. And from these positions it is called a sympathomimetic. Secondly, it has a weaker stimulating effect directly on adrenergic receptors.

BY PHARMACOLOGICAL EFFECTS - similar to adrenaline. Stimulates the activity of the heart, increases blood pressure, causes a bronchodilator effect, suppresses intestinal motility, dilates the pupil, increases skeletal muscle tone, and causes hyperglycemia.

The effects develop more slowly but last longer. Let's say, in terms of its effect on blood pressure, ephedrine acts for a longer time - about 7-10 times. It is less active than adrenaline. Active when taken orally. Penetrates well into the central nervous system and stimulates it. When ephedrine is re-administered 10-30 minutes after the first administration, the phenomenon of TACHYPHYLAXIS develops, that is, a decrease in the degree of response. This is due to the fact that norepinephrine reserves in the depot are depleted.

What is practically important is that ephedrine strongly stimulates the central nervous system. This finds application in psychiatric and anesthesiology clinics.

INDICATIONS FOR USE:

As a bronchodilator for bronchial asthma, hay fever, serum sickness;

Sometimes to increase blood pressure, with chronic hypotension, hypotension;

Effective for a runny nose, i.e. rhinitis, when ephedrine solution is instilled into the nasal passages (local vasoconstriction, secretion of the nasal mucosa decreases);

Used for AV block, for arrhythmias of this origin;

In ophthalmology to dilate the pupil (drops);

In psychiatry in the treatment of patients with narcolepsy (a special mental state with increased drowsiness and apathy), when the administration of ephedrine is aimed at stimulating the central nervous system.

Ephedrine is used for myasthenia gravis, in combination with AChE drugs;

In addition, in case of poisoning with sleeping pills and narcotic drugs, that is, with drugs that depress the central nervous system;

Sometimes with enuresis;

In anesthesiology during spinal anesthesia (prevention of lowering blood pressure).

A representative of the group of drugs that excite alpha and beta receptors is also L-NORADRENALINE. Acts as a mediator on alpha and beta receptors; as a medicine, it affects only alpha receptors. Norepinephrine has a direct, powerful stimulating effect on alpha-adrenergic receptors.

The Latin name is Noradrenalini hydrоtatis (amp. 1 ml - 0.2% solution).

The main effect of NA is a pronounced but short-lived (within a few minutes) increase in blood pressure (BP). This is due to the direct stimulating effect of norepinephrine on vascular alpha-adrenergic receptors and an increase in their peripheral resistance. Unlike adrenaline, systolic, diastolic and mean arterial pressure increases.

Veins narrow under the influence of NA. The rise in blood pressure is so significant that in response to rapidly developing hypertension due to stimulation of the baroreceptors of the carotid sinus against the background of AN, the heart rate is significantly reduced, which is a reflex from the carotid sinus to the centers of the vagus nerves. In accordance with this, bradycardia that develops with the administration of norepinephrine can be prevented by the administration of atropine.

Under the influence of norepinephrine, cardiac output (minute volume) remains virtually unchanged, but stroke volume increases.

The drug has a unidirectional effect with adrenaline on the smooth muscles of internal organs, metabolism and the central nervous system, but is significantly inferior to the latter.

The main route of administration of norepinephrine is intravenously (in the gastrointestinal tract - decomposes; subcutaneously - necrosis at the injection site). It is administered intravenously, by drip, as it acts for a short time.

INDICATIONS FOR THE USE OF NORADRENALINE.

Used for conditions accompanied by an acute drop in blood pressure. Most often this is traumatic shock, extensive surgical interventions.

In case of cardiogenic (myocardial infarction) and hemorrhagic shock (blood loss) with severe hypotension, norepinephrine cannot be used, since the blood supply to tissues will worsen to an even greater extent due to spasm of arterioles, that is, microcirculation will deteriorate (centralization of blood circulation, microvessels are spasmed - against this background, norepinephrine will further worsen the patient’s situation).

ADVERSE REACTIONS with the use of norepinephrine are rare. They may be related to possible:

1) breathing problems;

2) headache;

3) manifestation of cardiac arrhythmias when combined with drugs that increase myocardial excitability;

4) tissue necrosis (spasm of arterioles) may appear at the injection site, so it is administered intravenously, by drip.

ALPHA, BETA AND DOPAMINE RECEPTOR STIMULANTS

Dopamine is a biogenic amine formed from L-tyrosine. It is a precursor to norepinephrine.

DOPAMINE or dopamine (lat. - Dofaminum - amp. 0.5% - 5 ml) is now obtained synthetically, stimulates alpha, beta and D receptors (dopamine) of the sympathetic nervous system. The severity of the effect is determined by the dose. In low doses it acts on D-receptors, in higher doses - on adrenergic receptors.

In low doses - 0.5-2 mcg/kg/min, it affects predominantly dopaminergic receptors (D-1), which leads to dilation of the vessels of the kidneys and intestines, brain and coronary vessels (mesenteric vessels), reduces total peripheral vascular resistance (TPV) ).

At doses of 2-10 mcg/kg/min - has a positive inotropic effect due to stimulation of beta-1 adrenergic receptors of the heart and indirect action due to the accelerated release of norepinephrine from reserve granules (the main difference from adrenaline is that it increases the strength of heart contractions more than their frequency) .

All this leads to:

To increase the contractile activity of the myocardium;

Increased heart function;

Increased systolic blood pressure and pulse blood pressure with unchanged diastolic blood pressure;

To increase coronary blood flow;

To increase renal blood flow by 40%, as well as sodium excretion by the kidneys by 3 times;

The introduction of dopamine helps to increase the antitoxic function of the liver.

At doses of 10 mcg/kg/min, it stimulates alpha-adrenergic receptors, which leads to an increase in OPS and a narrowing of the lumen of the renal vessels. If contractility is not impaired, then systolic and diastolic blood pressure increases, contractility, cardiac and stroke volume increase. Doses are conditional - depend on individual sensitivity. The main thing is the gradual influence of dopamine on different receptor zones.

INDICATIONS: shock developing against the background of myocardial infarction, trauma, septicopyemia, open heart surgery, liver and kidney failure. Route of administration: i.v. The effect of the drug stops 10-15 minutes after administration.

SIDE EFFECTS:

Chest pain, difficulty breathing;

Anxiety, palpitations;

Headache, vomiting;

Increased sensitivity.

DOBUTAMINE (Dobutrex) - available in 20 ml bottles containing 0.25 of the substance. Synthetic product.

Selectively stimulates beta-1 adrenergic receptors, thereby exhibiting a strong positive inotropic effect, increases coronary blood flow, improves blood circulation. Does not affect dopamine receptors. Administered intravenously, by drip.

INDICATIONS: shock developing against the background of myocardial infarction, septopyemia, acute respiratory failure.

SIDE EFFECTS:

Tachycardia;

Arrhythmias;

A sharp increase in blood pressure (pulmonary hypertension);

Heartache;

When using high doses, vasoconstriction is observed, leading to a deterioration in blood supply to tissues.

DRUGS THAT PRIMARILY STIMULATE ALPHA-ADRENORESCEPTORS

(ALPHA ADRENOMYMETICS)

First of all, MEZATONE is such a remedy.

Mesatonum (amps containing 1% solution 1 ml, administered subcutaneously, intravenously, intramuscularly; powder 0.01-0.025 - orally).

The drug has a powerful stimulating effect on alpha-adrenergic receptors. At the same time, it also has some indirect effect, since it contributes to a small extent to the release of NA from the presynaptic terminals.

Its pressor action leads to an increase in blood pressure. With subcutaneous administration, the effect lasts up to 40-50 minutes, and with intravenous administration - for 20 minutes. An increase in blood pressure is accompanied by bradycardia due to reflex stimulation of the vagus nerve. It does not directly affect the heart; it has only a slight stimulating effect on the central nervous system. Effective when taken orally (powders).

INDICATIONS FOR USE are the same as ON. Used exclusively as a pressor. In addition, it can be prescribed locally for rhinitis (as a decongestant) - 1-2% solutions (drops). Can be combined with local anesthetics. Can be used in the treatment of open-angle glaucoma (eye drops 1-2%). The drug is effective for paroxysmal atrial tachycardia.

In addition to these agents, the alpha-adrenergic agonist NAPHTHYZIN (Czech drug Sanorin) has found widespread use locally in the form of drops for instillation into the nose.

Naphtyzinum (10 ml bottles - 0.05-0.1%).

It differs in chemical structure from NA and mesatone. It is an imidazoline derivative. Compared to NA and mesaton, it causes a longer vasoconstrictor effect. By causing spasm of the vessels of the nasal mucosa, the drug significantly reduces the secretion of exudate and improves the patency of the airways (upper respiratory tract). Naphthyzin has a depressant effect on the central nervous system.

Used topically for acute rhinitis, allergic rhinitis, sinusitis, inflammation of the middle ear with obstruction of the auditory tube, laryngitis, inflammation of the maxillary sinus (sinusitis).

A similar drug, often used for the same indications, is GALAZOLIN, also an imidazoline derivative.

Halazolinum (10 ml bottles - 0.1%).

Indications for use are the same as for naphthyzine. It should only be taken into account that it has a slight irritant effect on the nasal mucosa.

DRUGS THAT PRIMARILY STIMULATE BETA-ADRENORESCEPTORS (BETA-ADRENOMIMETICS)

IZADRIN is a classic beta-adrenergic agonist.

Isadrinum (bottles of 25 ml and 100 ml, respectively, 0.5% and 1% solutions; tablets of 0.005). The drug is the most powerful, synthetic beta-adrenergic receptor stimulant. Let us remember that beta-2 adrenergic receptors are located in the bronchi (inhibitory), and beta-1 adrenergic receptors are located in the heart (excitatory). Isadrine stimulates beta-1 and beta2 adrenergic receptors, therefore it is considered a non-selective beta-adrenergic agonist. Its effect on alpha-adrenergic receptors has no clinical significance.

MAIN PHARMACOLOGICAL EFFECTS OF ISADRINA

The main effects are associated with the effect on the smooth muscles of the bronchi, the vessels of skeletal muscles, and the heart. By stimulating beta-2 adrenergic receptors of the bronchi, isadrin leads to a strong relaxation of the muscles of the latter, to a decrease in bronchial tone, that is, a strong bronchodilator effect develops. Isadrin is one of the powerful bronchodilators.

The effect of beta-adrenergic agonists, and isadrin in particular, on the bronchi also promotes the release of water by the glands of the mucous membrane (thinning of sputum) and stimulates ciliary clearance of the bronchi (mucociliary transport). The last 2 effects can be combined as activation of mucociliary transport.

The extrabronchial effect of isadrin is manifested by a decrease in pulmonary and systemic vascular resistance (decreased vascular resistance), an increase in minute volume of blood circulation due to an increase in stroke volume, as well as tachycardia (beta-1 adrenergic receptors), relaxation of the uterine muscles.

This implies one of the main indications for the use of the drug, namely the use of isadrin solutions in the form of inhalations to relieve attacks of bronchial asthma. When isadrin is inhaled, the bronchodilator effect develops very quickly and lasts approximately 1 hour.

Isadrinum hydrochloride solution for inhalation is available in special cylinders and the patient pours 1-2 ml into the inhaler for 1 inhalation.

Sometimes, with a less pronounced attack of bronchospasm, a tablet form of the drug (0.005) is used under the tongue for these purposes. In this case, the effect develops more slowly and weaker. Sometimes for chronic treatment the drug is used for internal use - per os, by swallowing a tablet. The effect is even weaker. Prescribed for bronchial asthma, bronchitis with bronchospasm, etc.

Acting on the smooth muscles of the gastrointestinal tract (both alpha- and beta-adrenergic receptors are inhibitory), isadrin reduces the tone of the intestinal muscles, relaxes the uterus, and by stimulating the beta-1-adrenergic receptors of the heart, the drug causes a powerful cardiotonic effect, which is realized by increasing the strength and frequency of heart contractions. Under the influence of isadrin, all 4 functions of the heart are enhanced: excitability, conductivity, contractility and automatism. Systolic pressure rises. However, by stimulating beta-2 adrenergic receptors of blood vessels, especially skeletal muscles, isadrin reduces diastolic pressure.

The influence of the adrenergic system extends to many important physiological processes regulated by the central and peripheral sympathetic nervous system. Both effectors of the β-adrenergic system - epinephrine and norepinephrine - are ligands for a whole family of adrenergic receptors, which includes nine representatives: three subtypes of the α1-group, three subtypes of the α2-receptor and three types of β-receptors.

Both norepinephrine and epinephrine are synthesized from the precursor L-DOPA (L-3,4-dihydroxyphenylalanine; L-Dopa) through a series of enzymatic transformations and stored in intracellular vesicles. Norepinephrine, deposited in the axon terminals of neurons of the sympathetic nervous system, acts as a neurotransmitter. In the chromaffin cells of the adrenal medulla, adrenaline is synthesized from norepinephrine by methylation. Unlike norepinephrine, adrenaline is released into the bloodstream and, acting as a hormone, adrenaline exerts its effect on tissue cells of various locations. Norepinephrine and adrenaline exert a biological effect on tissue through specialized receptors located in the cell membrane of target cells. Such receptors, called adrenergic, belong to a large class of G-protein-coupled receptors (GPCRs), mediating the transmission of many signals in our body, such as rhodopsin receptors that perceive light stimulation, receptors for endogenous neurotransmitters ( serotonin, dopamine, etc.), hormone receptors and proteases (thrombin). In 1987, clones were first obtained and expression of the human β2-adrenergic receptor was carried out. Since then, through many detailed molecular studies, an understanding of the binding of epinephrine to β-receptors and their further functioning has been formed, and the general principles of cellular signaling through G-protein coupled receptors have been elucidated. It is worth noting that all receptors of this type are not the easiest objects to establish their spatial structure, since their crystallization is an extremely difficult task, which is true for all membrane proteins. It was not until 2007 that the high-resolution crystal structure of the β2-adrenergic receptor was published, allowing conclusions to be drawn about the molecular mechanism of receptor activation.

So, as already stated, the adrenergic receptor family covers a large number of types and subtypes. The group of α1 receptors includes α1A, α1B, α1D; α2 receptors combine α2A, α2B, α2C receptors; and finally, β-receptors are divided into β1, β2, β3. Such a variety of receptors exists for a reason; they are all characterized by the localization and functions they perform that are predominant for one type or another. For example, if α1 receptors mainly mediate the effect of norepinephrine and adrenaline in the blood vessels (increased blood pressure), then α2 receptors regulate the release of norepinephrine and adrenaline in the structures of the sympathetic nervous system and adrenal glands, respectively. β-adrenergic receptors are involved in the regulation of cardiac activity (β1), cause relaxation of the smooth muscles of blood vessels, bronchi, and uterus (β2), and are also involved in energy supply processes in stressful situations (β2- and β3-receptors).

β-adrenergic receptors are of important therapeutic importance. All three types of these adrenergic receptors are found in the heart, but the most functionally significant are the β1 and β2 receptors, the ratio of which in human heart tissue is approximately 70:30. β3-adrenergic receptors are probably involved in the control of the NO-mediated mechanism for regulating the force of contraction of the heart muscle, exerting a restraining effect on it. Unlike adrenaline, which activates both β1- and β2-adrenergic receptors, norepinephrine has a greater affinity for β1-receptors, therefore the sympathetic influence, leading to an increase in heart rate and force of contraction of the heart, and, as a consequence, stroke volume of the heart, is carried out in mainly through β1 receptors. The strength of cardiac contraction is based on an increase in the release of calcium ions from the sarcoplasmic reticulum of cardiac muscle cells, which is controlled by protein kinase A: phosphorylation of L-type calcium channels causes the entry of calcium ions into cells, phosphorylation of ryanodine receptors and phospholamban increases both the release and reuptake of Ca2+ . Protein kinase A also regulates the sensitivity of myofibrils to calcium ions, which directly affects the force of contraction they develop.

Constant activation of cardiac β-receptors can also harm the heart muscle: first, hypertrophy of muscle cells occurs; continued stimulation not only leads to a decrease in the sensitivity of cells to norepinephrine, but can also trigger apoptosis in cardiomyocytes and promote the proliferation of connective tissue in the heart (fibrosis). Desensitization of β-adrenergic receptors can be used in the treatment of chronic heart failure, since in CHF the sympathetic-adrenal system is in a state of chronic hyperactivation (at the stage of decompensation).

The variety of β-blockers used in clinical practice can be simplified into three generations. This division is based on the historical development of drugs and their selectivity in relation to the receptors on which they act. For example, propranolol, as a non-selective β-blocker, belongs to the first generation. In the treatment of cardiovascular diseases, preference is given to selective β1-receptor antagonists, and such drugs are classified as second generation (atenolol, bisoprolol, metoprolol). Other β-blockers, which do not quite fit into the described groups, and also have additional effects, are already in the third generation (for example, carvedilol, celiprolol, nebivolol, which have vasodilating properties).

Among the therapeutic effects of β-blockers in hypertension and CHF, their direct β1-antagonistic property is important. The benefit of additional effects on α1- or β2-receptors does not yet have a strong evidence base. The vasodilating effect due to α1-adrenergic blocking activity (carvedilol) or stimulation of NO synthesis in the endothelium (nebivolol), the combination of blockade of α2- and stimulation of β2-receptors (celiprolol) certainly expand the range of use of such drugs, since they have less negative effects. inotropic effect, improve tissue perfusion, have a positive effect on hemostasis and the level of oxidative processes. However, evidence of the effectiveness of β-blockers with these additional properties regarding patient survival is obtained only for carvedilol in patients with CHF. Non-selective β-blockers should be prescribed with caution to patients with bronchial asthma, COPD, and those diagnosed with diabetes mellitus, since these drugs act as antagonists not only for β1 receptors, but also for β2. Therefore, patients with such diseases are recommended to be prescribed selective β1-blockers.

Sources:
K. Page et al. Pharmacology, clinical approach, 2012
Lutz Hein, Pharmakologische Charakterisierung von β-AR, 2006

Cholinergic mechanisms of the nervous system- these are substances that ensure the transmission of excitation at the cholinergic synapse.

The mediator acetylcholine (an ester of choline and acetic acid) is formed from the amino acid choline and acetyl-CoA at the presynaptic terminal of the nerve fiber. The resulting mediator enters the vesicles, and some may remain in a free state. When excited, the transmitter is released from the vesicles. The process of mediator release is C-dependent. For the normal functioning of the synapse, a supply of transmitter is necessary, so acetylcholine is resynthesized on the presynaptic membrane. For this purpose, the amino acid choline is released from the postsynaptic membrane, partially from the synaptic cleft (transmitter return). The formation of a mediator requires the energy of metochondrions.

An enzyme that promotes the synthesis of acetylcholine- acetylcholine transferase or choline acetylase. This enzyme is formed in the body of the neuron and enters the nerve endings. For normal transmitter formation, the integrity of the neuron body is necessary. An isolated nerve fiber cannot release transmitter for a long time.

Enzyme that breaks down acetylcholine- acetylcholinesterase. This enzyme has a high affinity for acetylcholine, which is found in the form of a complex and the X receptor. There are true acetylcholinesterase (located in synapses and red blood cells), which breaks down acetylcholine in physiological concentrations, and false acetylcholinesterase (in body fluids - saliva, plasma, etc.), which breaks down acetylcholine in high concentrations and also destroys various acetylcholine derivatives (curarecodes). drugs). The released choline, with the help of transporters, enters the presympathetic membrane, and acetic acid and glucose enter the blood through the interstitial fluid.

X receptors- protein molecules with a high affinity for acetylcholine.

There are 2 types of cholinergic receptors - M and N.

M-cholinergic receptors- sensitive to muscalin (fly agaric poison) - located mainly in internal organs, endocrine glands, heart, blood vessels, respiratory tract, gastrointestinal tract. They have a slow but long-lasting effect and can add up to excitement. There are 2 types of M-cholinergic receptors: one in the internal organs, the other in the endocrine glands. When the M-cholinergic receptor is excited, cardiac activity is inhibited, blood vessels dilate, the gastrointestinal tract is activated, and the secretion of some endocrine glands changes.

N-cholinergic receptors- sensitive to nicotine. They are located in the autonomic ganglia, myoneural synapses, and in the chlorophyll tissue of the adrenal glands. These receptors have a fast, short-term effect and cannot summarize excitation. There are 3 varieties. Due to the presence of varieties, receptors can be blocked by various substances. There are more H-cholinergic receptors in the central nervous system. M-cholinergic receptors predominate in the brain stem, subcortical nodes, limbic system, reticular formation, and hypothalamus.

Adrenergic mechanisms of the nervous system

Adrenergic mechanisms of the nervous system are carried out due to norepinephrine- makes up 90% and other catecholamines - 10%.

Precursor to norepinephrine- isopropylnoradenaline, dopamine. Synthesis requires the amino acids thyronine and phenylamine, which come from the postsynaptic membrane and from the neuron body. Any structure can form norepinephrine, but 95% of it is formed on the presympathetic membrane.

Enzymes for the synthesis of norepinephrine - transaminases.

Noadrenaline destruction enzymes- a group of catecholamine transferases, often monoaminoacetic acid and monoamine oxidant.

Adrenergic receptors- protein molecules with an affinity for norepinephrine and its derivatives. These receptors are the outer subunit of the outermost protein molecule; the inner subunit can be an enzyme (ademylate and guanylate cyclase). When interacting with the receptor, the structure of the protein molecule changes and, as a result, the activity of the enzyme changes.

There are 2 types of adrenergic receptors:

Alpha adrenergic receptors- blocked by dehydroergotamine, have increased sensitivity and norepinephrine, have a low threshold of irritation, when the required amount of mediator is released, alpha receptors are excited. They are located in some internal organs and the vascular wall, found in the central nervous system. There are alpha 1 and alpha 2 adrenergic receptors.

Alpha 1 adrenergic receptors- when they are excited, vasoconstriction occurs, contraction of the capsule of the spleen, uterus (especially in a pregnant woman), constriction of the pupil, etc. Inhibition of the gastrointestinal tract (motor and secretory) and contraction of sphincters occurs.

Alpha 2 adrenergic receptors- mainly in the central nervous system.

Beta adrenergic receptors- blocked by beta blockers (propranolol). They have a high threshold of irritation, because they have less affinity for norepinephrine. Sensitive to various norepinephrine derivatives (isoproterenolol).

Beta 1 adrenergic receptors- in the myocardium; when they are excited, the force of heart contractions increases, metabolic processes in the myocardium accelerate, and the heart rate slightly increases.

Betta 2 adrenergic receptors- in blood vessels, internal organs, endocrine glands. When they are excited, an inhibitory effect, dilation of blood vessels (coronary, skeletal muscles), relaxation of smooth muscles and respiratory tract is ensured. Alpha 1 and beta 2 receptors can be found in blood vessels. Alpha 1 receptors provide vasoconstriction, and beta 2 receptors provide vasodilation. The effect depends on: the number of mediators, the number of receptors of this type.