Adrenergic drugs are used because of their ability to act on the cardiovascular system, causing a broncholytic effect, stimulating the CNS, and displaying mydriatic and anorectic action. On the other hand, the wide range of activity is due to an evidently high affinity to the various receptors other than adrenergic receptors, limits their use because of a number of undesirable side effects.
Adrenergic or sympathomimetic drugs comprise a large group of substances that can be subdivided into drugs with direct action, which directly react with adrenergic receptors. Epinephrine, phenylephrine, isoproterenol, dobutamine, terbutaline, albuterol, metapro-terenol, isoetharine, clonidine, naphazoline, oxymetazoline, tetrahydrozoline, and xylometazoline belong to this group.
Nondirect-acting drugs exhibit sympathomimetic effects by causing the release of endo-genic catecholamines. Sympathomimetic activity of these drugs depends on the presence of catecholines in the organism. Tyramine, a compound used primarily as an analyzer in experimental research, belongs to this group.
Finally, a few drugs have dual action—both direct and indirect. Dopamine, ephedrine, phenylpropanolamine, metaraminol, and amphetamines all belong to this group.
The initial reaction between adrenomimetics and effector cells occurs through adrener-gic receptors, which are exceptionally numerous in the brain, various organs, and tissue. The structure of adrenoreceptors is not known.
The concept of receptors, as is well known, is based on the presence of certain structures that are responsible for binding biologically active compounds. The molecular structure of a ligand-binding region of the receptor determines the specific physiological response of the organism. The binding of an adrenergic agonist, as with any other drug using substrate-receptor interaction, with the appropriate receptor on the surface of the membrane causes a cascade of biochemical reactions in the cell, which ultimately lead to a change in its functional-metabolic condition. Accordingly, drugs contain an informational message that is transmitted into the cell and when appropriately diffused, causes measurable effects at the tissue or organ level. Specific binding of the drug activates certain biological processes, which can culminate in gland secretion, regulation of ion channels, changes in enzyme activity, and so on.
Each adrenergic drug independently exhibits significant qualitative and quantitative differences of both a pharmacodynamic and pharmacokinetic character, which permits their sensible therapeutic use.
Two main classes of receptor proteins that bind adrenergic drugs have been postulated, and they have historically been defined as a- and /¡-receptors, which have even been broken down into four subtypes: a1, a2, ¡1, and ¡2.
Despite a few differences, activation of a1-receptors generally leads to excitement, while ¡2-receptors generally are responsible for relaxation of tissue. Activation of ¡1-receptors results in a stimulatory effect on the heart and kidneys, while activation of presy-naptic a2 adrenergic receptors possibly suggests a feedback mechanism, which is the inhibition of neuronal norepinephrine release. At the same time, stimulation of postsynap-tic a2-receptors, as with a1-receptors, causes tissue excitement.
On the basis of anatomical, pharmacological, biological, and other criteria, it has been shown that: a1-receptors are located primarily in effector organs; a2-receptors in adrenergic neurons and presynaptic regions; ¡1-receptors are located predominantly in cardiac and renal tissue; /¡2-receptors are found in many other organs (bronchi, vessels, uterus, among others).
A variety of responses in the body to different adrenergic drugs are based on their relative selectivity when binding with various receptors, which are exclusively found in and unevenly distributed in effector structures (heart, cardiovascular system, lungs, brain, peripheral nervous system, etc.).
In general, the response of effector organs to epinephrine (adrenaline) and/or norepi-nephrine (noradrenaline) is directly determined by the type of adrenoreceptor, as well as by the ratio of a- and /¡-adrenoreceptors.
Typical pharmacological action of adrenergic drugs consists of the following: stimulation of cardiac action—an elevation of frequency and strength of cardiac contractions; vasomotor effects—vasodilation, vasoconstriction; regulation of endocrine conditions— modulation of insulin, renin, and a number of hormones; regulation of metabolic conditions—increased glycogenolysis in the liver and muscles, release of fatty acids from tissues; and from the CNS—psychomotor excitement.
A myriad of cardiovascular, respiratory, hormonal, metabolic, and neuropsychic responses, which can be caused by adrenergic drugs, are generally very similar to many of the adaptive reactions of the organism such as increased physical activity and physical stress.
From the clinical point of view, adrenergic drugs are formally classified in the following manner, although some of them can appear in various groups at the same time.
Endogenic (epinephrine, norepinephrine, and dopamine) and synthetic cate-
cholamines (isoproterenol, dobutamine).
Vasopressor amines (metaraminol, methoxamine, and methentermine).
Antiedematic (tetrahydrozoline, phenylephrine, naphazoline, and ephedrine).
Bronchiolytics (ephedrine, metaproterenol, isoetharine, and terbutaline).
Smooth muscle relaxants (ritodrine, arlidin, and isoxyprine).
CNS stimulants (amphetamines).
From the chemical point of view, adrenergic drugs have a lot in common, and are examined as substituted phenylethylamines.
Some correlations have been made between the structure of sympathomimetics and the biological activity exhibited by them.
1. Sympathomimetic activity is maximal when there are two carbon atoms between the aromatic ring and the amino group.
2. The lesser the degree of substitution at the amino group, the greater selectivity of the compound in activating a-adrenoreceptors, and vice versa, an increase in volume of sub-stituents at the primary amino group adds to the selectivity in relation to ¡-receptors.
3. Substitution at the a-carbon atom prevents oxidative deactivation of the drug molecules by monoaminooxidase, thus considerably increasing the duration of action. At the same time, substitution at the a-carbon atom facilitates indirect action of the drug—the ability to release endogenous catecholamines from neuronal reserves. Activity of the drug depends considerably on the presence of hydroxyl groups at C3 and C4 of the aromatic ring. These conditions are necessary for activation of both a-and /¡-adrenoreceptors. Compounds with hydroxyl groups at C3 of the aromatic ring display a high ratio of direct/indirect agonistic activity. Compounds with hydroxyl groups on C4 of the aromatic ring display a high ratio of direct/indirect activity. Phenylethylamines that do not contain hydroxyl groups in the aromatic ring (noncat-echolamines) exhibit more of a stimulatory effect on the CNS than catecholamines.
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