Adrenergic agonists

By definition, adrenergic agonists produce their effects by activating adrenergic receptors. Since the sympathetic nervous system acts through these same receptors, responses to adrenergic agonists and responses to stimulation of the sympathetic nervous system are very similar. Because of this similarity, adrenergic agonists are often referred to as sympathomimetics. Adrenergic agonists have a broad spectrum of indications, ranging from heart failure to asthma to preterm labor.

Learning about adrenergic agonists can be a challenge. To facilitate the process, our approach to these drugs has four stages. We begin with the general mechanisms by which drugs can activate adrenergic receptors. Next we establish an overview of the major adrenergic agonists, focusing on their receptor specificity and chemical classification. After that, we address the adrenergic receptors themselves; for each receptor type—alpha₁, alpha₂, beta₁, beta₂, and dopamine—we discuss the beneficial and harmful effects that can result from receptor activation. Finally, we integrate all of this information by discussing the characteristic properties of representative sympathomimetic drugs.

Please note that this chapter is intended only as an introduction to the adrenergic agonists. Our objective here is to discuss the basic properties of the sympathomimetic drugs and establish an overview of their applications and adverse effects. In later chapters, we will discuss the clinical applications of these agents in greater depth.

Mechanisms of adrenergic receptor activation

Drugs can activate adrenergic receptors by four basic mechanisms: (1) direct receptor binding, (2) promotion of norepinephrine (NE) release, (3) blockade of NE reuptake, and (4) inhibition of NE inactivation. Note that only the first mechanism is direct. With the other three, receptor activation occurs by an indirect process. Examples of drugs that act by these four mechanisms are presented in Table 17–1.

TABLE 17–1

Mechanisms of Adrenergic Receptor Activation

Mechanism of Stimulation	Examples
Direct Mechanism
Receptor activation through direct binding	Dopamine Epinephrine Isoproterenol Ephedrine*
Indirect Mechanisms
Promotion of NE release	Amphetamine Ephedrine*
Inhibition of NE reuptake	Cocaine Tricyclic antidepressants
Inhibition of MAO	MAO inhibitors

MAO = monoamine oxidase, NE = norepinephrine.

^*Ephedrine is a mixed-acting drug that activates receptors directly and by promoting release of norephinephrine.

Inhibition of ne inactivation.

As discussed in Chapter 13, some of the NE in terminals of adrenergic neurons is subject to inactivation by monoamine oxidase (MAO). Hence, drugs that inhibit MAO can increase the amount of NE available for release, and can thereby enhance receptor activation. (It should be noted that, in addition to being present in sympathetic nerves, MAO is present in the liver and the intestinal wall. The significance of MAO at these other sites is considered later in the chapter.)

In this chapter, which is dedicated to peripherally acting sympathomimetics, nearly all of the drugs discussed act exclusively by direct receptor activation. The only exception is ephedrine, a drug that works by a combination of direct receptor activation and promotion of NE release.

Most of the indirect-acting adrenergic agonists are used for their ability to activate adrenergic receptors in the central nervous system (CNS)—not for their effects in the periphery. The indirect-acting sympathomimetics (eg, amphetamine, cocaine) are mentioned here to emphasize that, although these agents are employed for effects on the brain, they can and will cause activation of adrenergic receptors in the periphery. Peripheral activation is responsible for certain toxicities of these drugs (eg, cardiac dysrhythmias, hypertension).

Overview of the adrenergic agonists

Chemical classification: catecholamines versus noncatecholamines

The adrenergic agonists fall into two major chemical classes: catecholamines and noncatecholamines. As discussed below, the catecholamines and noncatecholamines differ in three important respects: (1) oral usability, (2) duration of action, and (3) the ability to act in the CNS. Accordingly, if we know to which category a particular adrenergic agonist belongs, we will know three of its prominent features.

Catecholamines

The catecholamines are so named because they contain a catechol group and an amine group. A catechol group is simply a benzene ring that has hydroxyl groups on two adjacent carbons (Fig. 17–1). The amine component of the catecholamines is ethylamine. Structural formulas for each of the major catecholamines—epinephrine, norepinephrine, isoproterenol, dopamine, and dobutamine—are presented in Figure 17–1. Because of their chemistry, all catecholamines have three properties in common: (1) they cannot be used orally, (2) they have a brief duration of action, and (3) they cannot cross the blood-brain barrier.

The actions of two enzymes—monoamine oxidase and catechol-O-methyltransferase (COMT)—explain why the catecholamines have short half-lives and cannot be used orally. MAO and COMT are located in the liver and in the intestinal wall. Both enzymes are very active and quickly destroy catecholamines administered by any route. Because these enzymes are located in the liver and intestinal wall, catecholamines that are administered orally become inactivated before they can reach the systemic circulation. Hence, catecholamines are ineffective if given by mouth. Because of rapid inactivation by MAO and COMT, three catecholamines—norepinephrine, dopamine, and dobutamine—are effective only if administered by continuous infusion. Administration by other parenteral routes (eg, subQ, IM) will not yield adequate blood levels, owing to rapid hepatic inactivation.

Catecholamines are polar molecules, and hence cannot cross the blood-brain barrier. (Recall from Chapter 4 that polar compounds penetrate membranes poorly.) The polar nature of the catecholamines is due to the hydroxyl groups on the catechol portion of the molecule. Because they cannot cross the blood-brain barrier, catecholamines have minimal effects on the CNS.

Be aware that catecholamine-containing solutions, which are colorless when first prepared, turn pink or brown over time. This pigmentation is caused by oxidation of the catecholamine molecule. As a rule, catecholamine solutions should be discarded as soon as discoloration develops. The only exception is dobutamine, which can be used up to 24 hours after the solution was made, even if discoloration appears.

Noncatecholamines

The noncatecholamines have ethylamine in their structure (see Fig. 17–1), but do not contain the catechol moiety that characterizes the catecholamines. In this chapter, we discuss three noncatecholamines: ephedrine, albuterol, and phenylephrine.

The noncatecholamines differ from the catecholamines in three important respects. First, because they lack a catechol group, noncatecholamines are not substrates for COMT and are metabolized slowly by MAO. As a result, the half-lives of noncatecholamines are much longer than those of catecholamines. Second, because they do not undergo rapid degradation by MAO and COMT, noncatecholamines can be given orally, whereas catecholamines cannot. Third, noncatecholamines are considerably less polar than catecholamines, and hence are more able to cross the blood-brain barrier.

Receptor specificity

To understand the actions of individual adrenergic agonists, we need to know their receptor specificity. Since the sympathomimetic drugs differ widely with respect to the receptors they can activate, learning the receptor specificity of these drugs will take some effort.

Variability in receptor specificity among the adrenergic agonists can be illustrated with three drugs: albuterol, isoproterenol, and epinephrine. Albuterol is highly selective, acting at beta₂ receptors only. Isoproterenol is less selective, acting at beta₁ receptors and beta₂ receptors. Epinephrine is less selective yet, acting at all four adrenergic receptor subtypes: alpha₁, alpha₂, beta₁, and beta₂.

The receptor specificities of the major adrenergic agonists are summarized in Table 17–2. In the upper part of the table, receptor specificity is presented in tabular form. In the lower part, the same information is presented schematically. By learning (memorizing) the content of Table 17–2, you will be well on your way toward understanding the pharmacology of the sympathomimetic drugs.

TABLE 17–2

Receptor Specificity of Representative Adrenergic Agonists

Catecholamines		Noncatecholamines
Drug	Receptors Activated		Drug	Receptors Activated
Epinephrine	α₁, α₂, β₁, β₂		Ephedrine*	α₁, α₂, β₁, β₂
Norepinephrine	α₁, α₂, β₁		Phenylephrine	α₁
Isoproterenol	β₁, β₂		Albuterol	β₂
Dobutamine	β₁
Dopamine^†	α₁, β₁, dopamine
Receptors Activated^‡
Alpha₁	Alpha₂	Beta₁	Beta₂	Dopamine
	Epinehrine Ephedrine*
	Norepinephrine
Phenylephrine		Isoproterenol
		Dobutamine	Albuterol
Dopamine^†		Dopamine^†		Dopamine^†

α = alpha, β = beta.

^*Ephedrine is a mixed-acting agent that causes NE release and also activates alpha and beta receptors directly.

^†Receptor activation by dopamine is dose dependent.

^‡This chart represents in graphic form the same information on receptor specificity given above. Arrows indicate the range of receptors that the drugs can activate (at usual therapeutic doses).

Please note that the concept of receptor specificity is relative, not absolute. The ability of a drug to selectively activate certain receptors to the exclusion of others depends on the dosage: at low doses, selectivity is maximal; as dosage increases, selectivity declines. For example, when albuterol is administered in low to moderate doses, the drug is highly selective for beta₂-adrenergic receptors. However, if the dosage is high, albuterol will activate beta₁ receptors as well. The information on receptor specificity in Table 17–2 refers to usual therapeutic doses. So-called selective agents will activate additional adrenergic receptors if the dosage is abnormally high.

Therapeutic applications and adverse effects of adrenergic receptor activation

In this section we discuss the responses—both therapeutic and adverse—that can be elicited with sympathomimetic drugs. Since many adrenergic agonists activate more than one type of receptor (see Table 17–2), it could be quite confusing if we were to talk about the effects of the sympathomimetics while employing specific drugs as examples. Consequently, rather than attempting to structure this presentation around representative drugs, we discuss the actions of the adrenergic agonists one receptor at a time. Our discussion begins with alpha₁ receptors, and then moves to alpha₂ receptors, beta₁ receptors, beta₂ receptors, and finally dopamine receptors. For each receptor type, we discuss both the therapeutic and adverse responses that can result from receptor activation.

To understand the effects of any specific adrenergic agonist, all you need is two types of information: (1) the identity of the receptors at which the drug acts and (2) the effects produced by activating those receptors. Combining these two types of information will reveal a profile of drug action. This is the same approach to understanding neuropharmacologic agents that we discussed in Chapter 12.

Before you go deeper into this chapter, I encourage you (strongly advise you) to review Table 13–3. Since we are about to discuss the clinical consequences of adrenergic receptor activation, and since Table 13–3 summarizes the responses to activation of those receptors, the benefits of being familiar with Table 13–3 are obvious. If you choose not to memorize Table 13–3 now, at least be prepared to refer back to it as we discuss the consequences of receptor activation.

Clinical consequences of alpha₁ activation

In this section we discuss the therapeutic and adverse effects that can result from activation of alpha₁-adrenergic receptors. As shown in Table 17–2, drugs capable of activating alpha₁ receptors include epinephrine, NE, phenylephrine, ephedrine, and dopamine.

Therapeutic applications of alpha₁ activation

Activation of alpha₁ receptors elicits two responses that can be of therapeutic use: (1) vasoconstriction (in blood vessels of the skin, viscera, and mucous membranes); and (2) mydriasis. Of the two, vasoconstriction is the one for which alpha₁ agonists are used most often. Using these drugs for mydriasis is rare.

Hemostasis.

Hemostasis is defined as the arrest of bleeding, which alpha₁ agonists accomplish through vasoconstriction. Alpha₁ stimulants are given to stop bleeding primarily in the skin and mucous membranes. Epinephrine, applied topically, is the alpha₁ agonist used most for this purpose.

Nasal decongestion.

Nasal congestion results from dilation and engorgement of blood vessels in the nasal mucosa. Drugs can relieve congestion by causing alpha₁-mediated vasoconstriction. Specific alpha₁-activating agents employed as nasal decongestants include phenylephrine (applied topically) and pseudoephedrine (taken orally).

Adjunct to local anesthesia.

Alpha₁ agonists are frequently combined with local anesthetics to delay anesthetic absorption. The mechanism is alpha₁-mediated vasoconstriction, which reduces blood flow to the site of anesthetic administration. Why delay anesthetic absorption? Because doing so prolongs anesthesia, allows a reduction in anesthetic dosage, and reduces the systemic effects that a local anesthetic might produce. The drug used most frequently to delay anesthetic absorption is epinephrine.

Elevation of blood pressure.

Because of their ability to cause vasoconstriction, alpha₁ agonists can elevate blood pressure in hypotensive patients. Please note, however, that alpha₁ agonists are not the primary therapy for hypotension. Rather, they are reserved for situations in which fluid replacement and other measures have failed to restore blood pressure to a satisfactory level.

Mydriasis.

Activation of alpha₁ receptors on the radial muscle of the iris causes mydriasis (dilation of the pupil), which can facilitate eye examinations and ocular surgery. Note that producing mydriasis is the only clinical use of alpha₁ activation that is not based on vasoconstriction.

Adverse effects of alpha₁ activation

All of the adverse effects caused by alpha₁ activation result directly or indirectly from vasoconstriction.

Hypertension.

Alpha₁ agonists can produce hypertension by causing widespread vasoconstriction. Severe hypertension is most likely with parenteral dosing. Accordingly, when alpha₁ agonists are given parenterally, cardiovascular status must be monitored continuously. Never leave the patient unattended.

Necrosis.

If the IV line employed to administer an alpha₁ agonist becomes extravasated, local seepage of the drug may result in necrosis (tissue death). The cause is lack of blood flow secondary to intense local vasoconstriction. If extravasation occurs, the area should be infiltrated with an alpha₁-blocking agent (eg, phentolamine), which will counteract alpha₁-mediated vasoconstriction, and thereby help minimize injury.

Bradycardia.

Alpha₁ agonists can cause reflex slowing of the heart. The mechanism is this: Alpha₁-mediated vasoconstriction elevates blood pressure, which triggers the baroreceptor reflex, causing heart rate to decline. In patients with marginal cardiac reserve, the decrease in cardiac output may compromise tissue perfusion.

Clinical consequences of alpha₂ activation

As discussed in Chapter 13, alpha₂ receptors in the periphery are located presynaptically, and their activation inhibits NE release. Several adrenergic agonists (eg, epinephrine, NE) are capable of causing alpha₂ activation. However, their ability to activate alpha₂ receptors in the periphery has little clinical significance. There are no therapeutic applications related to activation of peripheral alpha₂ receptors. Furthermore, activation of these receptors rarely causes significant adverse effects.

In contrast to alpha₂ receptors in the periphery, alpha₂ receptors in the CNS are of great clinical significance. By activating central alpha₂ receptors, we can produce two useful effects: (1) reduction of sympathetic outflow to the heart and blood vessels and (2) relief of severe pain. The central alpha₂ agonists used for effects on the heart and blood vessels, and the agents used to relieve pain, are discussed in Chapters 19 and 28, respectively.