Chapter 9. Sympathomimetics

The sympathomimetics constitute a very important group of drugs used for cardiovascular, respiratory, and other conditions. They are readily divided into subgroups on the basis of their spectrum of action (α-, β-, or dopamine-receptor affinity) or mode of action (direct or indirect).

Spectrum of Action

Adrenoceptors are classified as α, β, or dopamine receptors; these groups are further subdivided into subgroups. The distribution of these receptors is set forth in Table 9–1. Epinephrine may be considered a single prototype agonist with effects at all α- and β-receptor types. Alternatively, separate prototypes, phenylephrine (an α agonist) and isoproterenol (β) may be defined. The just-mentioned drugs have relatively little effect on dopamine receptors, but dopamine itself is a potent dopamine receptor agonist and, when given as a drug, can also activate β receptors (intermediate doses) and α receptors (larger doses).

Mode of Action

Sympathomimetic agonists may directly activate their adrenoceptors, or they may act indirectly to increase the concentration of endogenous catecholamine transmitter in the synapse. Amphetamine derivatives and tyramine cause the release of stored catecholamines; they are therefore mainly indirect in their mode of action. Cocaine and the tricyclic antidepressants exhibit another form of indirect action; these drugs inhibit reuptake of catecholamines by the norepinephrine transporter (NET) and the dopamine transporter (DAT) in nerve terminals (see Figure 6–2) and thus increase the synaptic activity of released transmitter.

Blockade of metabolism (ie, block of catechol-O-methyltransferase [COMT] and monoamine oxidase [MAO]) has little direct effect on autonomic activity, but MAO inhibition increases the stores of catecholamines and related molecules in adrenergic synaptic vesicles and thus may potentiate the action of indirect-acting sympathomimetics that cause the release of stored transmitter.

The endogenous adrenoceptor agonists (epinephrine, norepinephrine, and dopamine) are catecholamines and are rapidly metabolized by COMT and MAO. If used as drugs, these adrenoceptor agonists are inactive by the oral route and must be given parenterally. When released from nerve endings, they are subsequently taken up (by NET or DAT) into nerve endings and into perisynaptic cells; this uptake may also occur with norepinephrine, epinephrine, and dopamine given as drugs. These agonists have a short duration of action. When given parenterally, they do not enter the central nervous system (CNS) in significant amounts. Isoproterenol, a synthetic catecholamine, is similar to the endogenous transmitters but is not readily taken up into nerve endings. Phenylisopropylamines, for example, amphetamines, are resistant to MAO; most of them are not catecholamines and are therefore also resistant to COMT. Phenylisopropylamines are orally active; they enter the CNS, and their effects last much longer than do those of catecholamines. Tyramine, which is not a phenylisopropylamine, is rapidly metabolized by MAO except in patients who are taking an MAO inhibitor drug. MAO inhibitors are sometimes used in the treatment of depression (see Chapter 30).

Alpha Receptor Effects

Alpha1 receptor effects are mediated primarily by the trimeric coupling protein Gq. When Gq is activated, the alpha moiety of this protein activates the enzyme phospholipase C, resulting in the release of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from membrane lipids. Calcium is subsequently released from stores in smooth muscle cells by IP3, and enzymes are activated by DAG. Direct gating of calcium channels may also play a role in increasing intracellular calcium concentration. Alpha2 receptor activation results in inhibition of adenylyl cyclase via the coupling protein Gi.

Beta Receptor Effects

Beta receptors (β1, β2, and β3) stimulate adenylyl cyclase via the coupling protein Gs, which leads to an increase in cyclic adenosine monophosphate (cAMP) concentration in the cell.

Dopamine Receptor Effects

Dopamine D1 receptors activate adenylyl cyclase via Gs and increase cAMP in neurons and vascular smooth muscle. Dopamine D2 receptors are more important in the brain but probably also play a significant role as presynaptic receptors on peripheral nerves. These receptors reduce the synthesis of cAMP via Gi.

Central Nervous System

Catecholamines do not enter the CNS effectively. Sympathomimetics that do enter the CNS (eg, amphetamines) have a spectrum of stimulant effects, beginning with mild alerting or reduction of fatigue and progressing to anorexia, euphoria, and insomnia. Some of these central effects probably reflect the release of dopamine in certain dopaminergic tracts. Repeated dosing of amphetamines results in the rapid development of tolerance and dependence. These CNS effects reflect the amplification of dopamine's action in the ventral tegmental area and other CNS nuclei (see Chapter 32). Very high doses of amphetamines lead to marked anxiety or aggressiveness, paranoia, and, less commonly, seizures. Overdoses of cocaine very commonly result in seizures.

Eye

The smooth muscle of the pupillary dilator responds to topical phenylephrine and similar α agonists with contraction and mydriasis. Accommodation is not significantly affected. Outflow of aqueous humor may be facilitated by nonselective α agonists, with a subsequent reduction of intraocular pressure. This probably occurs via the uveoscleral drainage system. Alpha2-selective agonists also reduce intraocular pressure, apparently by reducing synthesis of aqueous humor.

Bronchi

The smooth muscle of the bronchi relaxes markedly in response to β2 agonists. These agents are the most efficacious and reliable drugs for reversing bronchospasm.

Gastrointestinal Tract

The gastrointestinal tract is well endowed with both α and β receptors, located both on smooth muscle and on neurons of the enteric nervous system. Activation of either α or β receptors leads to relaxation of the smooth muscle. Alpha2 agonists may also decrease salt and water secretion into the intestine.

Genitourinary Tract

The genitourinary tract contains α receptors in the bladder trigone and sphincter area; these receptors mediate contraction of the sphincter. In men, α1 receptors mediate prostatic smooth muscle contraction. Sympathomimetics are sometimes used to increase sphincter tone. Beta2 agonists may cause significant uterine relaxation in pregnant women near term, but the doses required also cause significant tachycardia.

Vascular System

Different vascular beds respond differently, depending on their dominant receptor type (Tables 9–1 and 9–2).

Alpha1 Agonists

Alpha1 agonists (eg, phenylephrine) contract vascular smooth muscle, especially in skin and splanchnic blood vessels, and increase peripheral vascular resistance and venous pressure. Because these drugs increase blood pressure, they often evoke a compensatory reflex bradycardia.

Alpha2 Agonists

Alpha2 agonists (eg, clonidine) cause vasoconstriction when administered intravenously or topically (eg, as a nasal spray), but when given orally they accumulate in the CNS and reduce sympathetic outflow and blood pressure as described in Chapter 11.

Beta Agonists

Beta2 agonists (eg, albuterol, metaproterenol, terbutaline) cause significant reduction in arteriolar tone in the skeletal muscle vascular bed and can reduce peripheral vascular resistance and arterial blood pressure. Beta1 agonists have relatively little effect on vessels.

Dopamine

Dopamine causes vasodilation in the splanchnic and renal vascular beds by activating D1 receptors. This effect can be very useful in the treatment of renal failure associated with shock. At higher doses, dopamine activates β receptors in the heart and elsewhere; at still higher doses, α receptors are activated.

Heart

The heart is well supplied with β1 and β2 receptors. The β1 receptors predominate in some parts of the heart; both β receptors mediate increased rate of cardiac pacemakers (normal and abnormal), increased atrioventricular node conduction velocity, and increased cardiac force.

Net Cardiovascular Actions

Sympathomimetics with both α and β1 effects (eg, norepinephrine) may cause a reflex increase in vagal outflow because they increase blood pressure and evoke the baroreceptor reflex. This reflex vagal effect may dominate any direct beta effects on the heart rate, so that a slow infusion of norepinephrine typically causes increased blood pressure and bradycardia (Figure 9–1; Table 9–2). If the reflex is blocked (eg, by a ganglion blocker or antimuscarinic drug), norepinephrine will cause a direct β1-mediated tachycardia. A pure α agonist (eg, phenylephrine) routinely slows heart rate via the baroreceptor reflex, whereas a pure β agonist (eg, isoproterenol) almost always increases the rate.

The diastolic blood pressure is affected mainly by peripheral vascular resistance and the heart rate. (The heart rate is important because the diastolic interval determines the outflow of blood from the arterial compartment.) The adrenoceptors with the greatest effects on vascular resistance are α and β2 receptors. The pulse pressure (the systolic minus the diastolic pressure) is determined mainly by the stroke volume (a function of force of cardiac contraction), which is influenced by β1 receptors. The systolic pressure is the sum of the diastolic and the pulse pressures and is therefore a function of both α and β effects.

Metabolic and Hormonal Effects

Beta1 agonists increase renin secretion. Beta2 agonists increase insulin secretion. They also increase glycogenolysis in the liver. The resulting hyperglycemia is countered by the increased insulin levels. Transport of glucose out of the liver is associated initially with hyperkalemia; transport into peripheral organs (especially skeletal muscle) is accompanied by movement of potassium into these cells, resulting in a later hypokalemia. All β agonists appear to stimulate lipolysis via the β3 receptor.

See Chapter 6.

Patients with pheochromocytoma may have this tumor for several months or even years before symptoms or signs lead to a diagnosis. Predict the probable compensatory responses to a chronic increase in blood pressure caused by a tumor releasing large amounts of norepinephrine. The Skill Keeper Answer appears at the end of the chapter.

Pharmacokinetic characteristics and clinical applications of selected sympathomimetics are shown in the Drug Summary Table.

Anaphylaxis

Epinephrine is the drug of choice for the immediate treatment of anaphylactic shock because it is an effective physiologic antagonist of many of the mediators of anaphylaxis. Antihistamines and corticosteroids may also be used, but these agents are neither as efficacious as epinephrine nor as rapid acting.

Central Nervous System

The phenylisopropylamines such as amphetamine are widely used and abused for their CNS effects. Legitimate indications include narcolepsy and, with appropriate adjuncts, weight reduction. The anorexiant effect may be helpful in initiating weight loss but is insufficient to maintain the loss unless patients also receive intensive dietary and psychological counseling and support. Methylphenidate and other amphetamine analogs have been heavily used in attention deficit disorder. The drugs are abused or misused for the purpose of deferring sleep and for their mood-elevating, euphoria-producing action. They have a high addiction liability (see Chapter 32).

Eye

The α agonists, especially phenylephrine and tetrahydrozoline, are often used to reduce the conjunctival itching and congestion caused by irritation or allergy. Phenylephrine is also an effective mydriatic. These drugs do not cause cycloplegia. Newer α2 agonists are in current use for glaucoma and include apraclonidine and brimonidine. As noted, the α2-selective agonists appear to reduce aqueous synthesis. See Table 10–2 for a summary of drugs used in glaucoma.

Bronchi

The β agonists, especially the β2-selective agonists, are drugs of choice in the treatment of acute asthmatic bronchoconstriction. The short-acting β2-selective agonists (eg, albuterol, metaproterenol, terbutaline) are not recommended for prophylaxis, but they are safe and effective and may be lifesaving in the treatment of bronchospasm. Much longer-acting β2-selective agonists, salmeterol,formoterol, and indacaterol are used in combination with corticosteroids for prophylaxis; they are not indicated for the treatment of acute symptoms, see Chapter 20.

Cardiovascular Applications

Conditions in Which an Increase in Blood Flow Is Desired

In acute heart failure and some types of shock, an increase in cardiac output and blood flow to the tissues is needed. Beta1 agonists may be useful in this situation because they increase cardiac contractility and reduce (to some degree) afterload by decreasing the impedance to ventricular ejection through a small β2 effect. Norepinephrine, in contrast to earlier impressions, is an effective agent in septic and cardiogenic shock. Dobutamine and dopamine are also used. Unfortunately, the arrhythmogenic effects of these drugs may be dose-limiting.

Conditions in Which a Decrease in Blood Flow or Increase in Blood Pressure Is Desired

Alpha1 agonists are useful in situations in which vasoconstriction is appropriate. These include local hemostatic (epinephrine) and decongestant effects (phenylephrine) as well as spinal shock (norepinephrine, phenylephrine), in which temporary maintenance of blood pressure may help maintain perfusion of the brain, heart, and kidneys. Shock due to septicemia or myocardial infarction, on the other hand, is usually made worse by vasoconstrictors, because sympathetic discharge is usually already increased. Alpha agonists are often mixed with local anesthetics to reduce the loss of anesthetic from the area of injection into the circulation. Chronic orthostatic hypotension due to inadequate sympathetic tone can be treated with oral ephedrine or a newer orally active α1 agonist, midodrine.

Conditions in Which Acute Cardiac Stimulation Is Desired

Epinephrine has been used in cardiac arrest by intravenous and direct intracardiac injection. Isoproterenol has been used for atrioventricular (AV) block.

Genitourinary Tract

Beta2 agonists (ritodrine, terbutaline) are sometimes used to suppress premature labor, but the cardiac stimulant effect may be hazardous to both mother and fetus. Nonsteroidal anti-inflammatory drugs, calcium channel blockers, and magnesium are also used for this indication.

Long-acting oral sympathomimetics such as ephedrine are sometimes used to improve urinary continence in the elderly and in children with enuresis. This action is mediated by α receptors in the trigone of the bladder and, in men, the smooth muscle of the prostate.

Because of their limited penetration into the brain, catecholamines have little CNS toxicity when given systemically. In the periphery, their adverse effects are extensions of their pharmacologic alpha or beta actions: excessive vasoconstriction, cardiac arrhythmias, myocardial infarction, hemorrhagic stroke, and pulmonary edema or hemorrhage.

The phenylisopropylamines may produce mild to severe CNS toxicity, depending on dosage. In small doses, they induce nervousness, anorexia, and insomnia; in higher doses, they may cause anxiety, aggressiveness, or paranoid behavior. Convulsions may occur. Peripherally acting agents have toxicities that are predictable on the basis of the receptors they activate. Thus, α1 agonists cause hypertension, and β1 agonists cause sinus tachycardia and serious arrhythmias. Beta2 agonists cause skeletal muscle tremor. It is important to note that none of these drugs is perfectly selective; at high doses, β1-selective agents have β2 actions and vice versa. Cocaine is of special importance as a drug of abuse: its major toxicities include cardiac arrhythmias or infarction and convulsions. A fatal outcome is more common with acute cocaine overdose than with any other sympathomimetic.

See Chapter 6.

Because the control mechanisms that attempt to maintain blood pressure constant are intact in patients with pheochromocytoma (they are reset in patients with ordinary “essential” hypertension), a number of compensatory changes are observed in pheochromocytoma patients (see Figure 6–4). These include reduced renin, angiotensin, and aldosterone levels in the blood. Reduced aldosterone causes more salt and water to be excreted by the kidney, reducing blood volume. Since the red cell mass is not affected, hematocrit is often increased. If the tumor releases only norepinephrine, a compensatory bradycardia may also be present, but most patients release enough epinephrine to maintain heart rate at a normal or even increased level.

When you complete this chapter, you should be able to:

• □ Name a typical nonselective α agonist, a selective α2 agonist, a nonselective β agonist, a selective β1 agonist, selective β2 agonists, an α1, α2, β1 agonist, and an α1, α2, β1, β2 agonist.
• □ List tissues that contain significant numbers of α1 or α2 receptors.
• □ List tissues that contain significant numbers of β1 or β2 receptors.
• □ Describe the major organ system effects of a pure α agonist, a pure β agonist, and a mixed α and β agonist.
• □ Describe a clinical situation in which the effects of an indirect sympathomimetic would differ from those of a direct agonist.
• □ List the major clinical applications of the adrenoceptor agonists.