Chapter 9: Adrenergic Agonists

This chapter considers the drugs that mimic the effects of adrenergic nerve stimulation (or stimulation of the adrenal medulla). In other words, these compounds mimic the effects of norepinephrine or epinephrine. These drugs are sometimes referred to as adrenomimetics or sympathomimetics. Remember that the actions of the sympathetic nervous system are mediated through α and β receptors.

There are other effects of sympathetic stimulation, but the three listed in the preceding box are the most important.

The adrenergic agonists are often divided into direct- and indirect-acting agonists. This is a useful distinction for a number of reasons. The indirect-acting drugs do not bind to specific receptors, but act by releasing stored norepinephrine. This means that their actions are nonspecific. The direct-acting drugs bind to the receptors, so specificity of action is a possibility.

The drugs are also sometimes divided into catecholamines and noncatecholamines. This is yet another division based on structure (and our focus here is not on structures). However, this distinction is useful for one concept. Do you remember from Chapter 6 that norepinephrine is metabolized by catechol-o-methyltransferase (COMT) and monoamine oxidase (MAO)? Well, the other catecholamines are also metabolized by these enzymes; however, the noncatecholamines are not.

The focus here is to learn the specificity of the drugs for their receptor targets. If you know the effect of stimulation of the target receptors, then you can deduce the drug actions and adverse effects.

Although this is an oversimplification, it provides a useful starting point. The rest of the direct-acting drugs act on either α or β receptors (Figure 9–1). Epinephrine has approximately equal effects at α and β receptors. In addition, it has approximately equal effects at β₁ and β₂ receptors.

Epinephrine has a number of uses, including the treatment of allergic reactions and shock, the control of localized bleeding, and the prolongation of the action of local anesthetics.

Norepinephrine activates both α and β receptors, but activates β₁ receptors more than β₂ receptors. Because of its relatively low affinity for β₂ receptors, norepinephrine is not as useful in the treatment of bronchospasm as epinephrine. Why? Because the smooth muscle of the bronchioles are relaxed by activation of β₂ receptors.

Now let’s move on to consider the α- and β-specific drugs. The α-specific drugs are easier, so let’s begin with them.

The main effect of α₁ stimulation (with an agonist such as phenylephrine) is vasoconstriction. Local application of a vasoconstrictor to the nasal passages decreases blood flow locally and decreases secretions, thus acting as a nasal decongestant. The action of clonidine is more complex. It activates α₂ receptors in the central nervous system to decrease sympathetic stimulation to the heart and activates presynaptic α₂ receptors on peripheral nerve endings to inhibit the release of norepinephrine.

Basically, the affinity of these drugs for receptors falls on a spectrum from β₁ to β₂ (see Figure 9–1). Dobutamine is closer to the β₁ end of the spectrum; terbutaline and its relatives are closer to the β₂ end. Isoproterenol falls in the middle of the spectrum. The action of dobutamine is actually quite complex and worth reading about.

Dopamine is a catecholamine by structure and is a precursor to norepinephrine (see Figure 6–3). Dopamine receptors are located throughout the body and in the central nervous system. The effects of dopamine are quite complex and are dose dependent. At high doses dopamine acts much like epinephrine. It is worthwhile here to review the section on dopamine in your textbook.

In the treatment of shock, dopamine increases heart rate and cardiac output while simultaneously dilating the renal and coronary arteries. The action of dopamine in the renal vascular bed is useful in attempts to preserve renal blood flow and renal function in the presence of overall decreased tissue perfusion (shock).

Because these drugs act by releasing stored norepinephrine, their effects are widespread and nonspecific. Ephedrine and phenylpropanolamine are nasal decongestants. Phenylpropanolamine has also been used as an appetite suppressant. Don’t worry if you can’t remember these drugs. Be careful, however, not to confuse phenylephrine (the specific α₁ agonist) with these two similarly named indirect agents.

There is also a pro-drug of norepinephrine available (droxidopa). It is metabolized by dopa decarboxylase to norepinephrine and has all the effects of norepinephrine. Droxidopa is used to treat neurogenic orthostatic hypotension.

Amphetamine and its other relatives are indirect-acting sympathomimetics that have been abused because of their psychostimulant abilities. There are quite a number of formulations of amphetamine producing differing durations of action and abuse potential. Methylphenidate has been used to treat narcoplepsy, but newer drugs, modafinil and armodafinil, have less abuse potential. The mechanism of action of modafinil is not understood.

Before we leave the adrenergic activators, it is useful to consider in detail the cardiovascular actions of epinephrine, norepinephrine, and isoproterenol. Some textbooks also consider dopamine in this context. Consider the effects of these agents on heart rate, cardiac output, total peripheral resistance, and mean arterial pressure. If you find these effects easy enough to remember, try adding their effects on systolic and diastolic blood pressure to your mental database.

Through stimulation of α receptors, norepinephrine causes constriction of all major vascular beds. This, in turn, causes an increase in resistance and pressure. The increase in blood pressure causes a reflex increase in parasympathetic output to the heart, which acts to slow the heart down. Therefore, heart rate often decreases after administration of norepinephrine in spite of direct activation of β₁ receptors.

Although epinephrine activates all α and β receptors, if given systemically its effects are predominated by effects on the heart. It increases heart rate, stroke volume, and cardiac output. The effects of epinephrine on blood pressure and peripheral resistance are dose dependent. At low doses, there is a fall in peripheral resistance as a result of vasodilation in the skeletal muscle beds (β₂ effect). At higher doses, there is some vasoconstriction (α₁) balancing the vasodilation (β₂), resulting in little or no change in peripheral resistance. At even higher doses, the vasoconstriction (α₁) will predominate, resulting in an increase in peripheral resistance and blood pressure.

Remember that isoproterenol is an agonist at all β receptors. Therefore, it does not cause vasoconstriction of the vascular smooth muscle (α₁). The vasodilation in the skeletal muscle beds (β₂) is unopposed. This results in a net decrease in peripheral resistance. Isoproterenol also stimulates β₁ receptors in the heart, resulting in an increase in heart rate and stroke volume.

Find graphs of these changes in your textbook and make sure that you understand them.