Adrenostimulants and adrenomimetics

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

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Adrenergic stimulants and adrenomimetics: place in therapy

In the practice of anesthesiology and intensive care, the dominant method of administering cardiotonics and vasopressors is intravenously. Moreover, adrenomimetics can be administered by bolus and used by infusion. In clinical anesthesiology, adrenomimetics with predominantly positive inotropic and chronotropic action are used mainly for the following syndromes:

• low CO syndrome caused by left or right ventricular (LV or RV) failure (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 decreased diuresis (dopamine, dopexamine, fenoldopam).

Clinical situations in which vasopressors should be used include:

• decreased TPS caused by overdose of vasodilators or endotoxemia (endotoxic shock);
• use of phosphodiesterase inhibitors to maintain the required perfusion pressure;
• treatment of right ventricular failure associated with arterial hypotension;
• anaphylactic shock;
• intracardiac right-to-left shunt;
• emergency correction of hemodynamics against the background of hypovolemia;
• maintenance of the required perfusion pressure in the treatment of patients with myocardial dysfunction that is refractory to inotropic and volume therapy.

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

The most common indications for the use of drugs of this class are listed above, but it should be emphasized that each drug has its own individual indications. Thus, epinephrine is the drug of choice in case of acute cardiac arrest - in this case, in addition to intravenous infusion, the drug is administered intracardiacly. Epinephrine is irreplaceable in anaphylactic shock, allergic edema of the larynx, relief of acute attacks of bronchial asthma, allergic reactions that develop when taking drugs. But still, the main indication for its use is acute heart failure. Adrenergic agonists act on all adrenoreceptors to varying degrees. Epinephrine is often used after cardiac surgery with CPB to correct myocardial dysfunction caused by reperfusion and post-ischemic syndrome. Adrenergic agonists are advisable to use in cases of low cardiac output syndrome against the background of low pulmonary resistance. Epinephrine is the drug of choice in the treatment of severe LV failure. 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, in order to reduce the excessive vasopressor effect of epinephrine, it should be combined with vasodilators (e.g., 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 mcg/kg/min, but causes less tachycardia. To avoid arrhythmia, tachycardia, and myocardial ischemia - effects that develop when using high doses, epinephrine can be combined with beta-blockers (e.g., esmolol at a dose of 20-50 mg).

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

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

Isoproterenol is the drug of choice in the treatment of myocardial dysfunction associated with bradycardia and high vascular resistance. In addition, this drug should be used in the treatment of low CO syndrome in patients with obstructive pulmonary diseases, in particular in patients with bronchial asthma. A negative quality of isoproterenol is its ability to reduce coronary blood flow, so the use of the drug should be limited in patients with coronary artery disease. Isoproterenol is used in pulmonary hypertension, since it is one of the few agents that cause vasodilation of the vessels of the small circle of blood circulation. In this regard, it is widely used in the treatment of RV failure caused by pulmonary hypertension. Isoproterenol increases the automaticity and conductivity of the heart muscle, due to which it is used in bradyarrhythmias, weakness of the sinus node, and AV blocks. The presence of positive chronotropic and bathmotropic effects of isoproterenol in combination with the ability to dilate the vessels of the pulmonary circulation made it the drug of choice for restoring rhythm and creating the most favorable conditions for the functioning of the right ventricle after heart transplantation.

Compared to dopamine and dobutamine, dopexamine has less pronounced inotropic properties. On the contrary, dopexamine has more pronounced diuretic properties, 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. It is used in collapse and hypotension associated with decreased vascular tone. In addition, in combination with cardiotonics, it is used in the treatment of low CO syndrome to ensure the necessary perfusion pressure. For the same purpose, it is used in cases of anaphylactic shock in combination with epinephrine and volume loading. It is characterized by a rapid onset of action (1-2 min), the duration of action after bolus administration is 5 min, therapy is usually initiated with a dose of 50-100 mcg, and then switched to an infusion of the drug at a dose of 0.1-0.5 mcg / kg / min. In anaphylactic and septic shock, phenylephrine doses for the correction of vascular insufficiency can reach 1.5-3 mcg / kg / min.

In addition to situations associated with hypotension itself, norepinephrine is prescribed to patients with myocardial dysfunction that is refractory to inotropic and volume therapy to maintain the required perfusion pressure. Norepinephrine is widely used to maintain blood pressure when using phosphodiesterase inhibitors to correct myocardial dysfunction caused by RV failure. In addition, adrenergic agonists are used in anaphylactoid reactions, when there is a sharp decrease in systemic resistance. Of all vasopressors, norepinephrine begins to act most quickly - the effect is noted after 30 seconds, the duration of action after bolus administration is 2 minutes, therapy is usually started with an infusion of the drug at a dose of 0.05-0.15 mcg / kg / min.

Ephedrine can be used in clinical situations where there is a decrease in systemic resistance in patients with obstructive pulmonary diseases, since, by stimulating beta2 receptors, ephedrine causes bronchodilation. In addition, in anesthesiology practice, ephedrine is used to increase blood pressure, especially during spinal anesthesia. Ephedrine has found wide application in myasthenia, narcolepsy, poisoning with drugs and sleeping pills. The effect of the drug is noted after 1 minute and lasts from 5 to 10 minutes after bolus administration. Therapy usually begins with a dose of 2.5-5 mg.

Methoxamine 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 (1-2 min), the duration of action after bolus administration is 5-8 min, therapy is usually started with a dose of 0.2-0.5 mg.

Hyperstimulation of vascular alpha receptors can lead to sharp hypertension, which can lead to hemorrhagic stroke. The combination of tachycardia and hypertension is especially dangerous, as they can provoke angina attacks in patients with coronary heart disease, and dyspnea and pulmonary edema in patients with reduced functional reserves of the myocardium.

By stimulating alpha receptors, adrenergic agonists increase intraocular pressure, so they cannot be used for glaucoma.

The use of high doses of alpha1-stimulating drugs over a long period of time, as well as low doses of these drugs in patients with peripheral vascular diseases, can cause vasoconstriction and peripheral circulatory disorders. The first manifestation of excessive vasoconstriction can be piloerection ("goose bumps").

When using adrenergic agents, stimulation of beta2 receptors inhibits insulin release from pancreatic cells, which can lead to hyperglycemia. Stimulation of alpha receptors can be accompanied by an increase in the tone of the urinary bladder sphincter and urinary retention.

Extravascular administration of adrenergic agents may result in skin necrosis and desquamation.

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Mechanism of action and pharmacological effects

The mechanism of action of most pharmacological effects of drugs in this group is based, as the name suggests, on stimulation of various adrenergic receptors. The positive inotropic effect of these drugs is due to the effect on beta-adrenergic receptors of the heart, vasoconstriction is the result of stimulation of alpha1-adrenergic receptors of the vessels, and vasodilation is due to activation of both alpha2- and beta2-adrenergic receptors. Some adrenergic stimulants of this group (dopamine and dopexamine) stimulate dopamine receptors in addition to adrenergic receptors, which leads to additional vasodilation and a slight increase in cardiac contractility. The new drug fenoldopam is a selective DA1-receptor stimulant. It has a powerful selective effect on renal vessels, causing an increase in PC. Fenoldopam has a very weak positive inotropic effect in combination with vasodilation.

Adrenomimetics have a pronounced effect on the smooth muscles of internal organs. By stimulating beta2-adrenoreceptors of the bronchi, they relax the smooth muscles of the bronchi and eliminate bronchospasm. The tone and motility of the gastrointestinal tract and uterus decrease under the influence of adrenomimetics (due to excitation of alpha- and beta-adrenoreceptors), the sphincters are toned (stimulation of alpha-adrenoreceptors). Adrenomimetics have a beneficial effect on the LUT, especially against the background of muscle fatigue, which is associated with an increase in the release of ACh from presynaptic endings, as well as with the direct effect of adrenomimetics on the muscle.

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

When adrenomimetics affect the central nervous system, excitatory effects predominate - anxiety, tremor, stimulation of the vomiting center, etc. may occur. In general, adrenomimetics stimulate metabolism, increasing oxygen consumption.

The severity of the effects of adrenergic stimulants is determined by the following factors:

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

The affinity of a particular drug to a certain type of receptor is especially important. The latter ultimately determines the drug's action.

The severity and nature of the effects of many adrenergic stimulants largely depend on the dose used, since 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 higher) alpha stimulation predominates. In a dose of 10-40 ng/kg/min epinephrine provides the same hemodynamic effect as dopamine in a dose of 2.5-5 mcg/kg/min, while causing less tachycardia. In large doses (60-240 ng/kg/min) adrenomimetics can cause arrhythmia, tachycardia, increased myocardial oxygen demand and, as a consequence, myocardial ischemia.

Dopamine, like epinephrine, is a cardiotonic. It should be noted that dopamine is approximately 2 times less potent than epinephrine in its effect on alpha receptors, but their effects are comparable in their inotropic effects. In small doses (2.5 μg/kg/min), dopamine primarily stimulates dopaminergic receptors, and in a dose of 5 μg/kg/min, it activates beta1 and alpha receptors, with its positive inotropic effects predominating. In a dose of 7.5 μg/kg/min and higher, alpha stimulation predominates, accompanied by vasoconstriction. In large doses (more than 10-5 μg/kg/min), dopamine causes quite pronounced tachycardia, which limits its use, especially in patients with coronary heart disease. It has been established that dopamine causes more pronounced tachycardia compared to epinephrine in doses leading to the same inotropic effect.

Dobutamine, unlike epinephrine and idopamine, is an inodilator. At a dose of up to 5 mcg/kg/min, it has mainly an inotropic and vasodilating effect, stimulating beta1 and beta2-adrenoreceptors and having virtually no effect on a-adrenoreceptors. At a dose of more than 5-7 mcg/kg/min, the drug begins to act on a-receptors and thereby increases afterload. In terms of inotropic effect, dobutamine is not inferior to epinephrine and exceeds dopamine. The main advantage of dobutamine over dopamine and epinephrine is that dobutamine increases myocardial oxygen consumption to a lesser extent and increases oxygen delivery to the myocardium to a greater extent. This is especially important when used in patients with coronary heart disease.

Isoproterenol should be ranked first in terms of its positive inotropic effect. To achieve only the inotropic effect, isoproterenol is used in a dose of 25-50 ng/kg/min. In high doses, the drug has a powerful positive chronotropic effect and, due to this effect, increases cardiac performance even more.

Dopexamine is a synthetic catecholamine, structurally similar to dopamine and dobutamine. Its structural similarity to the above-mentioned drugs is reflected in its pharmacological properties - it is a combination of the effects of dopamine and dobutamine. Compared to 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 mcg/kg/min.

Adrenomimetics, which have a beta-stimulating effect in their spectrum of action, can shorten atrioventricular (AV) conduction and thus contribute to the development of tachyarrhythmia. Adrenomimetics with a predominant effect on alpha-adrenoreceptors are able to increase vascular tone and can be used as vasopressors.

Pharmacokinetics

The bioavailability of adrenomimetics largely depends on the route of administration. After oral administration, drugs are not effective because they are quickly conjugated and oxidized in the gastrointestinal mucosa. With subcutaneous and intramuscular administration, drugs are absorbed more completely, but the rate of their absorption is determined by the presence or absence of a vasoconstrictor effect, which delays this process. When entering the systemic bloodstream, adrenomimetics weakly (10-25%) bind to alpha-1-acid glycoproteins of blood plasma. In therapeutic doses, adrenomimetics practically do not penetrate the BBB and do not have central effects.

In the systemic circulation, most adrenomimetics are metabolized by specific enzymes MAO and catechol orthomethyltransferase (COMT), which are present in varying amounts in the liver, kidneys, lungs and blood plasma. An exception is isoproterenol, which is not a substrate for MAO. Some drugs are conjugated with sulfuric and glucuronic acids (dopamine, dopexamine, dobutamine). High activity of COMT and MAO in relation to adrenomimetics determines the short duration of action of drugs in this group by any route of administration. Metabolites of adrenomimetics do not have pharmacological activity with the exception of metabolites of epinephrine. Its metabolites have beta-adrenolytic activity, which may explain the rapid development of tachyphylaxis to epinephrine. The second mechanism of tachyphylaxis, established relatively recently, is the blocking of the action of drugs by the beta-arrestin protein. This process is initiated by binding of adrenomimetics to the corresponding receptors. Adrenomimetics appear unchanged in urine only in small quantities.

Tolerability and side effects

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

Adrenomimetics should not be prescribed in cases of severe arterial hypertension (e.g., pheochromocytoma), severe atherosclerosis, tachyarrhythmia, thyrotoxicosis. Adrenomimetics with predominantly vasoconstrictor action should not be used in cases of:

• LV failure against the background of high systemic vascular resistance;
• RV failure against the background of increased pulmonary resistance;
• renal hypoperfusion.

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

Interaction

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

Tricyclic antidepressants enhance the hypertensive effect of dobutamine, epinephrine, norepinephrine, and reduce the hypertensive effect of dopamine and ephedrine; the effect of phenylephrine can either be enhanced or weakened.

MAO inhibitors greatly enhance the effects of dopamine, epinephrine, norepinephrine and ephedrine, so their concomitant use should be avoided.

The use of adrenergic agents in obstetrics against the background of the use of oxytocin can cause severe hypertension.

Bretylium 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 CG due to the increased risk of developing intoxication.

It is not advisable to use adrenomimetics with hypoglycemic agents, since the effect of the latter is weakened.