Adrenostimulants and adrenergic agonists

All adrenostimulators have a structural similarity with natural adrenaline. Some of them may have pronounced positive inotropic properties (cardiotonics), others - vasoconstrictive or predominantly vasoconstrictive effect (phenylephrine, norepinephrine, methoxamine and ephedrine) and are combined under the name of vasopressors.

[1]

Adrenostimulators and adrenomimetics: a place in therapy

In the practice of anesthesiology and intensive care, the dominant method of cardiotonic and vasopressor insertion is IV. Moreover, adrenomimetics can be administered bolus and applied infusion. In clinical anesthesiology, adrenomimetics with predominantly positive inotropic and chronotropic effects are used mainly in the following syndromes:

• low SV syndrome caused by left or right ventricular failure (LV or RV) (epinephrine, dopamine, dobutamine, isoproterenol);
• hypotensive syndrome (phenylephrine, norepinephrine, methoxamine);
• bradycardia, with conduction disorders (isoproterenol, epinephrine, dobutamine);
• bronchospastic syndrome (epinephrine, ephedrine, isoproterenol);
• anaphylactoid reaction accompanied by hemodynamic disorders (epinephrine);
• Conditions accompanied by a decrease in diuresis (dopamine, dopexamine, phenol dopa).

The clinical situations in which vasopressors should be used are as follows:

• decreased OPS caused by an overdose of vasodilators or endotoxemia (endotoxic shock);
• use of phosphodiesterase inhibitors to maintain the necessary perfusion pressure;
• treatment of heart failure in the heart on the background of arterial hypotension;
• anaphylactic shock;
• intracardial shunt from right to left;
• emergency correction of hemodynamics against hypovolemia;
• maintenance of the necessary perfusion pressure in the treatment of patients with myocardial dysfunction, which is refractory to inotropic and volumetric therapy.

There are many protocols that regulate the use of cardiotonic or vasopressors in a particular clinical situation.

The above are the most common indications for using drugs of this class, but it should be emphasized that each drug also has its own individual indications. So, epinephrine is the drug of choice in the case of acute cardiac arrest - drugs in this case, in addition to intravenous infusion, are administered intracardiacally. Indispensable epinephrine in anaphylactic shock, allergic edema of the larynx, relief of acute attacks of bronchial asthma, allergic reactions developing with the use of drugs. But still the main indication for its use is acute heart failure. Adrenomimetics in one degree or another act on all adrenergic receptors. Epinephrine is often used after cardiosurgical operations with IR to correct myocardial dysfunction due to reperfusion and post-ischemic syndrome. It is advisable to use adrenomimetics in cases of small-CB syndrome on the background of low OPS. Epinephrine is the drug of choice in the treatment of severe LV deficiency. It should be emphasized that in these cases it is necessary to use doses, sometimes several times exceeding 100 ng / kg / min. In such a clinical situation, to reduce the excessive vasopressor effect of epinephrine, it should be combined with vasodilators (eg, with nitroglycerin 25-100 ng / kg / min). At a dose of 10-40 ng / kg / min, epinephrine provides the same hemodynamic effect as dopamine at a dose of 2.5-5 μg / kg / min, but causes a smaller tachycardia. In order to avoid arrhythmia, tachycardia and myocardial ischemia, the effects developing with the use of large doses, epinephrine can be combined with beta-blockers (eg, with esmolol in a dose of 20-50 mg).

Dopamine is the drug of choice when a combination of inotropic and vasoconstrictor action is necessary. One of the significant negative side effects of dopamine when using large doses of drugs is tachycardia, tachyarrhythmia and increased myocardial oxygen demand. Very often dopamine is used in combination with vasodilators (sodium nitroprusside or nitroglycerin), especially when using drugs in large doses. Dopamine is the drug of choice when combined with LV deficiency and decreased diuresis.

Dobutamine is used as a monotherapy or in combination with nitroglycerin in pulmonary hypertension, because at a dose of up to 5 μg / kg / min, dobutamine reduces pulmonary vascular resistance. This property of dobutamine is used to reduce the afterload of the prostate in the treatment of right ventricular failure.

Isoproterenol is the drug of choice in the treatment of myocardial dysfunction with bradycardia and high vascular resistance. In addition, this drug should be used in the treatment of low-CB syndrome in patients with obstructive pulmonary disease, in particular in patients with bronchial asthma. The negative quality of isoproterenol is its ability to reduce coronary blood flow, so the use of drugs should be limited in patients with IHD. Isoproterenol is used for pulmonary hypertension, because it is one of the few agents that cause vasodilation of small circulatory vessels. In the same context, it is widely used in the treatment of RV insufficiency due to pulmonary hypertension. Isoproterenol increases the automatism and conduction of the heart muscle, so it is used for bradyarrhythmias, weakness of the sinus node, AV blockades. The presence of positive chronotropic and batmotropic effects of isoproterenol in combination with the ability to dilate the vessels of the small circle of blood circulation has made it a choice of choice for restoring rhythm and creating the most beneficial conditions for the functioning of the prostate after cardiac transplantation.

Dopexamine, in comparison with dopamine and dobutamine, has less pronounced inotropic properties. In contrast, the diuretic properties of dopex-min are more pronounced, so it is often used to stimulate diuresis in septic shock. In addition, in this situation, dopexamine is also used to reduce endotoxemia.

Phenylephrine is the most commonly used vasopressor. Apply it in case of collapse and hypotension, associated with a decrease in vascular tone. In addition, in combination with cardiotonics, it is used in the treatment of low-CB syndrome to provide the necessary perfusion pressure. For the same purpose it is used in cases of anaphylactic shock in combination with epinephrine and bulk load. It is characterized by a rapid onset of action (1-2 min), the duration of action after a bolus injection is 5 min, therapy is usually started with a dose of 50-100 mcg, and then they switch to the drug infusion at a dose of 0.1-0.5 mcg / kg / min . With anaphylactic and septic shock, phenylephrine doses for correction of vascular insufficiency can reach 1.5-3 μg / kg / min.

Norepinephrine, in addition to situations associated with proper hypotension, is prescribed for patients with myocardial dysfunction, which is refractory to inotropic and volumetric therapy, to maintain the necessary perfusion pressure. Norepinephrine is widely used to maintain blood pressure when using phosphodiesterase inhibitors to correct myocardial dysfunction due to PZ failure. In addition, adrenomimetics are used in anaphylactoid reactions, when there is a sharp decrease in system resistance. Of all the vasopressors, norepinephrine begins to act most quickly - the effect is observed after 30 seconds, the duration of action after the bolus is 2 min, and therapy is usually started with a drug infusion of 0.05-0.15 mcg / kg / min.

Ephedrine can be used in clinical situations, when there is a decrease in systemic resistance in patients with obstructive pulmonary diseases, since by stimulating beta2 receptors, ephedrine causes bronchodilation. In addition, in anesthetic practice, ephedrine is used to increase blood pressure, especially with spinal anesthesia. A wide use of ephedrine found in myasthenia gravis, narcolepsy, drug poisoning and sleeping pills. The effect of drugs is observed after 1 minute and lasts after a bolus injection from 5 to 10 minutes. Therapy usually starts with a dose of 2.5-5 mg.

Methoksamine is used in situations where it is necessary to quickly eliminate hypotension, since it is an extremely powerful vasoconstrictor. It is characterized by a rapid onset of action (1 to 2 minutes), duration of action after bolus administration is 5-8 minutes, therapy usually starts with a dose of 0.2-0.5 mg.

Hyperstimulation of alpha receptors in blood vessels can lead to severe hypertension, against which a hemorrhagic stroke may develop. Especially dangerous is the combination of tachycardia and hypertension, which can provoke angina attacks in patients with IHD, and in patients with reduced functional reserves of myocardium dyspnoea and pulmonary edema.

Exciting alpha receptors, adrenomimetics increase intraocular pressure, so they can not be used for glaucoma.

The use of high doses of drugs with alpha-stimulating action for a long time, as well as small doses of these drugs in patients with peripheral vascular disease can cause vasoconstriction and peripheral circulation. The first manifestation of excessive vasoconstriction may be piloerection (goosebump).

When using adrenomimetics, stimulation of beta2 receptors inhibits the release of insulin from pancreatic cells, which can lead to hyperglycemia. Stimulation of alpha receptors may be accompanied by an increase in the tone of the sphincter of the bladder and a delay in urine.

The extravascular administration of adrenomimetics can lead to necrosis and skin sloughing.

[2], [3]

Mechanism of action and pharmacological effects

The mechanism of action of most pharmacological effects of drugs of this group is, as the name suggests, stimulation of various adrenergic receptors. The positive inotropic effect of these drugs is due to the effect on the beta-adrenoreceptors of the heart, vasoconstriction is the result of stimulation of alpha 1-adrenergic receptors of the vessels, and vasodilation is due to the activation of both alpha2- and beta2-adrenoreceptors. Some adrenostimulators of this group (dopamine and dopexamine) stimulate dopamine receptors in addition to adrenergic ones, which leads to additional vasodilation and a slight increase in heart contractility. The new drug phenol dopam is a selective stimulator of DA1 receptors. It has a powerful selective effect on the vessels of the kidneys, causing an increase in PC. Fenolopa has a very weak positive inotropic effect in combination with vasodilation.

Adrenomimetics have a pronounced effect on the smooth muscles of internal organs. Stimulating beta2-adrenergic receptors of the bronchi, they relax the smooth muscles of the bronchi and eliminate bronchospasm. Tonus and motility of the gastrointestinal tract, uterus under the influence of adrenomimetics is reduced (due to the excitation of alpha and beta adrenoreceptors), sphincters are toned (stimulation of alpha-adrenergic receptors). Adrenomimetics have a beneficial effect on NRM, especially against muscle fatigue, which is associated with increased isolation from the presynaptic end of AX, as well as with the direct action of adrenomimetics on the muscle.

A rather significant effect is exerted by adrenomimetics on metabolism. Adrenomimetics stimulate glycogenolysis (hyperglycemia occurs, the content of lactic acid and potassium ions increases in blood) and lipolysis (an increase in the blood plasma content of free fatty acids). The glycogenolytic effect of adrenomimetics is apparently associated with a stimulating effect on the beta2 receptors of muscle cells, the liver, and the activation of the membrane enzyme adenylate cyclase. The latter leads to the accumulation of cAMP, which catalyzes the transition of glycogen to glucose-1-phosphate. This property of adrenomimetics, in particular epinephrine, is used in the treatment of hypoglycemic coma or with an overdose of insulin.

Effects of adrenomimetics on the CNS are dominated by excitation effects - there may be anxiety, tremors, stimulation of the vomiting center, etc. In general, adrenomimetics stimulate metabolism, increasing oxygen consumption.

The severity of the effects of adrenostimulants is determined by the following factors:

• concentration of drugs in plasma;
• sensitivity of the receptor and its ability to bind the agonist;
• conditions for the transport of calcium ions into the cell.

Particularly important is the affinity of one or another drug for a specific type of receptor. The last, ultimately, due to the effect of drugs.

The severity and nature of the effects of many adrenostimulants largely depend on the dose used, the sensitivity of adrenergic receptors to different drugs is not the same.

For example, in small doses (30-60 ng / kg / min) epinephrine acts mainly on beta receptors, in large doses (90 ng / kg / min and above) alpha stimulation prevails. At a dose of 10-40 ng / kg / min, epinephrine provides the same hemodynamic effect as dopamine at a dose of 2.5-5 μg / kg / min, while causing a smaller tachycardia. In large doses (60-240 ng / kg / min), adrenomimetics can cause arrhythmia, tachycardia, an increase in myocardial oxygen demand and, as a consequence, myocardial ischemia.

Dopamine, as well as epinephrine, is a cardiotonic. It should be noted that in terms of the effect on alpha receptors, dopamine is about half as good as epinephrine, but the effects of inotropic action are comparable. In small doses (2.5 μg / kg / min), dopamine predominantly stimulates dopaminergic receptors, and in a dose of 5 μg / kg / min activates beta1 and alpha receptors, with its positive inotropic effects predominant. At a dose of 7.5 μg / kg / min and higher, alpha stimulation, accompanied by vasoconstriction, predominates. In large doses (more than 10-5 μg / kg / min) dopamine causes a rather pronounced tachycardia, which limits its use, especially in patients with IHD. It was found that dopamine causes more pronounced tachycardia compared with epinephrine in doses that lead to the same inotropic effect.

Dobutamine, in contrast to epinephrine of idopamine, refers to inoditors. At a dose of up to 5 μg / kg / min, it has mainly inotropic and vasodilating effect, stimulating beta1 and beta2-adrenergic receptors and practically not affecting a-adrenergic receptors. In a dose of more than 5-7 mcg / kg / min, the drug begins to exert an effect on the a receptors and, due to this, increases the afterload. Due to the inotropic effect, dobutamine is not inferior to epinephrine and exceeds dopamine. The main advantage of dobutamine in relation to dopamine and epinephrine is that dobutamine less increases oxygen consumption in the myocardium and more increases the delivery of oxygen to the myocardium. This is especially important when used in patients with IHD.

Due to the strength of the positive inotropic action, isoproterenol should be put on the first place. To achieve only an inotropic effect, isoproterenol is used in a dose of 25-50 ng / kg / min. In large doses, the drug has a powerful positive chronotropic effect and, thanks to this effect, further increases the productivity of the heart.

Dopexamine, a synthetic catecholamine, is structurally similar to dopamine and dobutamine. Its structural similarity with the named drugs is reflected in its pharmacological properties - it's like a combination of effects of dopamine and dobutamine. Compared with dopamine and dobutamine, dopexamine has less pronounced inotropic properties. Optimal doses of dopexamine, at which its clinical effects are maximally expressed, range from 1 to 4 μg / kg / min.

Adrenomimetics, whose spectrum of action has a beta-stimulating effect, can shorten atrioventricular (AB) conduction and thus contribute to the development of tachyarrhythmias. Adrenomimetics with a predominant effect on alpha-adrenergic receptors are able to increase vascular tone and can be used as vasopressors.

Pharmacokinetics

Bioavailability of adrenomimetics largely depends on the route of administration. After ingestion, drugs are not effective, because they are not effective. They are rapidly exposed to conjugation and oxidation in the gastrointestinal mucosa. With n / k and / m administration of drugs are absorbed more fully, but the rate of their absorption is determined by the presence or absence of vasoconstrictive effect, which delays this process. Getting into the systemic blood stream, adrenomimetics weakly (10-25%) bind to the a1-acid glycoproteins of the blood plasma. In therapeutic doses, adrenomimetics practically do not penetrate the BBB and do not have central effects.

In the systemic blood stream, most adrenomimetics are metabolized by specific MAO enzymes and catecholortomethyltransferase (COMT), which are in various amounts in the liver, kidneys, lungs and blood plasma. An exception is isoproterenol, which is not a substratum for MAO. Some drugs are conjugated to sulfuric and glucuronic acids (dopamine, dopexamine, dobutamine). The high activity of COMT and MAO with respect to adrenomimetics determines the short duration of action of drugs of this group in any route of administration. Metabolites of adrenomimetics do not have pharmacological activity except for epinephrine metabolites. Its metabolites have beta-adrenolytic activity, which, perhaps, explains the rapid development of tachyphylaxis to epinephrine. The second mechanism of tachyphylaxis, established relatively recently, is the blocking of the action of drugs with protein beta-arestin. This process is triggered by the binding of adrenomimetics to the corresponding receptors. Adrenomimetics only appear in small amounts in the urine in unchanged form.

Tolerance and side effects

The spectrum of side effects of adrenomimetics is due to their excessive stimulation of the corresponding adrenergic receptors.

Adrenomimetics should not be prescribed with severe arterial hypertension (for example, with pheochromocytoma), severe atherosclerosis, tachyarrhythmia, thyrotoxicosis. Adrenomimetics with predominantly vasoconstrictive action should not be used when:

• LV deficiency against a background of high systemic vascular resistance;
• Insufficiency of the prostate on the background of increased pulmonary resistance;
• kidney hyperperfusion.

When treating with MAO inhibitors, the dose of adrenomimetics should be reduced severalfold or not used at all. It is not recommended to combine these drugs with some common anesthetics (halothane, cyclopropane). You can not use adrenomimetics as an initial therapy for hypovolemic shock. If to use, then only in small doses against the background of intensive volemic therapy. One of the contraindications is the presence of any obstacle to filling the ventricles or for its emptying: cardiac tampons, constrictive pericarditis, hypertrophic obstructive cardiomyopathy, stenosis of the aortic estuary.

Interaction

Halogenated inhalation anesthetics increase the sensitivity of the myocardium to catecholamines, which can lead to life-threatening cardiac arrhythmias.

Tricyclic antidepressants increase the hypertensive effect of dobutamine, epinephrine, norepinephrine, reduce the hypertensive effect of dopamine and ephedrine; the effect of phenylephrine can both intensify and attenuate.

MAO inhibitors multiply the action of dopamine, epinephrine, norepinephrine and ephedrine, so their simultaneous use should be avoided.

The use of adrenomimetics in obstetrics against the background of the use of oxytacin can cause severe hypertension.

Brethil and guanethidine potentiate the action of dobutamine, epinephrine, norepinephrine and can provoke the development of cardiac arrhythmias or hypertension.

It is dangerous to combine adrenomimetics (in particular, epinephrine) with SG because of the increased risk of intoxication.

It is inappropriate to use adrenomimetics with hypoglycemic agents, since the effect of the latter is weakened.