Figure 18-1 depicts the divisions of the nervous system and shows the relationship of the SNS to the entire nervous system. The SNS is the counterpart of the parasympathetic nervous system; together they make up the autonomic nervous system. They provide a checks-and-balances system for maintaining the normal homeostasis of the autonomic functions of the human body.

There are receptor sites for the catecholamines norepinephrine and epinephrine throughout the body. These are referred to as adrenergic receptors. It is at these receptor sites that adrenergic drugs bind and produce their effects. Many physiologic responses are produced when they are stimulated or blocked. Adrenergic receptors are further divided into alpha-adrenergic receptors and beta-adrenergic receptors, depending on the specific physiologic responses caused by their stimulation. Both types of adrenergic receptors have subtypes (designated 1 and 2), which provide a further means of checks and balances that control stimulation and blockade, vasoconstriction and vasodilation of blood vessels, and the increased and decreased production of various substances. The alpha₁– and alpha₂-adrenergic receptors are differentiated by their location relative to nerves. The alpha₁-adrenergic receptors are located on postsynaptic effector cells (the tissue, muscle, or organ that the nerve stimulates). The alpha₂-adrenergic receptors are located on the presynaptic nerve terminals. They control the release of neurotransmitters. The predominant alpha-adrenergic agonist response is vasoconstriction and central nervous system (CNS) stimulation.

The beta-adrenergic receptors are all located on postsynaptic effector cells. The beta₁-adrenergic receptors are primarily located in the heart, whereas the beta₂-adrenergic receptors are located in the smooth muscle fibers of the bronchioles, arterioles, and visceral organs. A beta-adrenergic agonist response results in bronchial, gastrointestinal (GI), and uterine smooth muscle relaxation; glycogenolysis; and cardiac stimulation. Table 18-1 provides a more detailed listing of the adrenergic receptors and the responses elicited when they are stimulated by a neurotransmitter or a drug that acts like a neurotransmitter (Figure 18-2).

Catecholamine neurotransmitters are produced by the SNS and are stored in vesicles or granules located in the ends of nerves. Here the transmitter waits until the nerve is stimulated, then the vesicles move to the walls of nerve endings and release their contents into the space between the nerve ending and the effector organ, known as the synaptic cleft or synapse. The released contents of the vesicles (catecholamines) then have the opportunity to bind to the receptor sites located all along the effector organ (see Figure 18-2). Once the neurotransmitter binds to the receptors, the effector organ responds. Depending on the function of the particular organ, this response may involve smooth muscle contraction (e.g., skeletal muscles) or relaxation (e.g., GI and airway smooth muscles), an increased heart rate, the increased production of one or more substances (e.g., stress hormones), or constriction of a blood vessel.

This process is halted by the action of specific enzymes and by reuptake of the neurotransmitter molecules back into the nerve cell (neuron). Catecholamines are metabolized by two enzymes, monoamine oxidase (MAO) and catechol ortho-methyltransferase (COMT). Each enzyme breaks down catecholamines but is responsible for doing it in different areas. MAO breaks down the catecholamines that are in the nerve ending, whereas COMT breaks down the catecholamines that are outside the nerve ending at the synaptic cleft (see Figure 18-2). Neurotransmitter molecules may also be taken back up into the presynaptic nerve fiber by various protein pumps within the cell membrane. This phenomenon is known as active transport. This restores the catecholamine to the vesicle and provides another means of maintaining an adequate supply of the substance for future sympathetic nerve impulses. This process is illustrated in Figure 18-2. The sympathetic branch of the autonomic nervous system is often described as having a “fight-or-flight” function, because it allows the body to respond in a self-protective manner to dangerous situations.

A direct-acting sympathomimetic binds directly to the receptor and causes a physiologic response (Figure 18-3). Epinephrine is an example of such a drug. An indirect-acting sympathomimetic causes the release of the catecholamine from the storage sites (vesicles) in the nerve endings; it then binds to the receptors and causes a physiologic response (Figure 18-4). Amphetamine and other related anorexiants (see Chapter 13) are examples of such drugs. A mixed-acting sympathomimetic both directly stimulates the receptor by binding to it and indirectly stimulates the receptor by causing the release of the neurotransmitter stored in vesicles at the nerve endings (Figure 18-5). Ephedrine is an example of a mixed-acting adrenergic drug.

Adrenergic agents can also be classified as either selective or nonselective in their actions. For example, phenylephrine and clonidine are considered selective agonists, meaning they only affect one receptor subtype. Epinephrine and norepinephrine are considered nonselective agonists, because they have action at both alpha and beta receptors. Adrenergic drugs can also act at different types of adrenergic receptors depending on the amount of drug administered. For example, dopamine may produce dopaminergic, beta₁, or alpha₁ effects, depending on the dose given. See Table 18-2 for other examples of catecholamines and the dose-specific selectivity.

To fully understand the mechanism of action of adrenergics, one must have a working knowledge of normal adrenergic transmission. This transmission takes place at the junction between the nerve (postganglionic sympathetic neuron) and the receptor site of the innervated organ or tissue (effector). The process of SNS stimulation is illustrated in Figure 18-2 and was discussed earlier in this chapter. When adrenergic drugs stimulate alpha₁-adrenergic receptor sites located on smooth muscles, vasoconstriction usually occurs. Binding to these alpha₁ receptors can also cause the relaxation of GI smooth muscle, contraction of the uterus and bladder, male ejaculation, and contraction of the pupillary muscles of the eye, which causes the pupils to dilate (see Table 18-1). Stimulation of alpha₂-adrenergic receptors, on the other hand, actually tends to reverse sympathetic activity but is not of great significance either physiologically or pharmacologically.

There are beta₁-adrenergic receptors on the myocardium and in the conduction system of the heart, including the sinoatrial node and the atrioventricular node. When these beta₁-adrenergic receptors are stimulated by an adrenergic drug, three things result: (1) an increase in the force of contraction (positive inotropic effect), (2) an increase in heart rate (positive chronotropic effect), and (3) an increase in the conduction of cardiac electrical nerve impulses through the atrioventricular node (positive dromotropic effect). In addition, stimulation of beta₁ receptors in the kidney causes an increase in renin secretion. Activation of beta₂-adrenergic receptors produces relaxation of the bronchi (bronchodilation) and uterus, and also causes increased glycogenolysis (glucose release) from the liver (see Table 18-1).

Adrenergics, or sympathomimetics, are used in the treatment of a wide variety of illnesses and conditions. Their selectivity for either alpha- or beta-adrenergic receptors and their affinity for certain tissues or organs determine the settings in which they are most commonly used. Some adrenergics are used as adjuncts to dietary changes in the short-term treatment of obesity. These drugs are discussed in more detail in Chapter 13.