Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 9. Sympathomimetics

Sympathomimetics: Introduction

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 (- or -receptor affinity) or mode of action (direct or indirect).

High-Yield Terms to Learn

Anorexiant A drug that decreases appetite (causes anorexia) Catecholamine A dihydroxyphenylethylamine derivative (eg, norepinephrine, epinephrine), a relatively polar molecule that is readily metabolized by catechol-O-methyltransferase Decongestant An -agonist drug that reduces conjunctival, nasal, or oropharyngeal mucosal vasodilation by constricting blood vessels in the submucosal tissue Mydriatic A drug that causes dilation of the pupil; opposite of miotic Phenylisopropylamine A derivative of phenylisopropylamine (eg, amphetamine, ephedrine). Unlike catecholamines, phenylisopropylamines usually have oral activity, a long half-life, some CNS activity, and an indirect mode of action Selective agonist,  agonist Drugs that have relatively greater effects on  or  adrenoceptors; none are absolutelyselective or specific Sympathomimetic A drug that mimics stimulation of the sympathetic autonomic nervous system Reuptake inhibitor An indirect-acting drug that increases the activity of transmitters in the synapse by inhibiting their reuptake into the presynaptic nerve ending. May act selectively on noradrenergic, serotonergic, or both types of nerve endings

Classification

Mode of Action

Sympathomimetic agonists may directly activate their adrenoceptors, or they may act indirectly to increase the concentration of catecholamine transmitter in the synapse. Amphetamine derivatives and tyramine cause the release of stored catecholamines; these sympathomimetics are therefore mainly indirect in their mode of action. Another form of indirect action is seen with cocaine and the tricyclic antidepressants; 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.

Spectrum of Action

Adrenoceptors are classified as  or  receptors; both 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 receptor types (1, 2, 1, 2, and 3). Alternatively, separate prototypes, phenylephrine (an  agonist) and isoproterenol () may be defined. Dopamine receptors constitute a third class of adrenoceptors. 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  receptors (intermediate doses) and  receptors (larger doses).

TABLE 9-1 Types of adrenoceptors, some of the peripheral tissues in which they are found, and their major effects.

Type Tissue Actions 1

Most vascular smooth muscle Contracts ( vascular resistance) Pupillary dilator muscle Contracts (mydriasis) Pilomotor smooth muscle Contracts (erects hair) Liver (in some species, eg, rat) Stimulates glycogenolysis 2

Adrenergic and cholinergic nerve terminals Inhibits transmitter release Platelets Stimulates aggregation Some vascular smooth muscle Contracts Fat cells Inhibits lipolysis Pancreatic  (B) cells Inhibits insulin release 1

Heart Stimulates rate and force Juxtaglomerular cells of kidney Stimulates renin release 2

Airways, uterine, and vascular smooth muscle Relaxes Liver (human) Stimulates glycogenolysis Pancreatic  (B) cells Stimulates insulin release Somatic motor neuron terminals (voluntary muscle) Causes tremor Heart Stimulates rate and force 3

Fat cells Stimulates lipolysis Dopamine 1 (D1)

Renal and other splanchnic blood vessels Dilates ( resistance) Dopamine 2 (D2)

Nerve terminals Inhibits adenylyl cyclase

Chemistry & Pharmacokinetics

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).

Mechanisms of Action

Alpha1 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 (IP 3) 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 Effects

Alpha2 receptor activation results in inhibition of adenylyl cyclase via the coupling protein Gi.

Beta Receptor Effects

Beta receptors (1, 2, and 3) 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 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 act via Gi and reduce the synthesis of cAMP.

Organ System Effects

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  agonists with contraction and mydriasis. Accommodation is not significantly affected. Outflow of aqueous humor may be facilitated by nonselective  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 2 agonists. These agents are the most efficacious and reliable drugs for reversing bronchospasm.

Gastrointestinal Tract

The gastrointestinal tract is well endowed with both  and  receptors, located both on smooth muscle and on neurons of the enteric nervous system. Activation of either  or  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  receptors in the bladder trigone and sphincter area; these receptors mediate contraction of the sphincter. In men, 1 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).

TABLE 9-2 Effects of prototypical sympathomimetics on vascular resistance, blood pressure, and heart rate.

Effect on Drug Skin, Splanchnic Vascular Resistance Skeletal Muscle Vascular Resistance Renal Vascular Resistance Mean Blood Pressure Heart Rate Phenylephrine      Isoproterenol —  —   Norepinephrine     

Alpha1 Agonists

Alpha1 agonists (eg, phenylephrine) constrict 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) 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 receptors in the heart and elsewhere; at still higher doses,  receptors are activated.

Heart

The heart is well supplied with 1 and 2 receptors. The 1 receptors predominate in some parts of the heart; both  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  and 1 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), norepinephrine will cause a direct 1-mediated tachycardia. A pure  agonist (eg, phenylephrine) routinely slows heart rate via the baroreceptor reflex, whereas a pure  agonist (eg, isoproterenol) almost always increases the rate.

FIGURE 9-1

Typical effects of norepinephrine and isoproterenol on blood pressure and heart rate. Note that the pulse pressure is only slightly increased by norepinephrine but is markedly increased by isoproterenol. The reduction in heart rate caused by norepinephrine is the result of baroreceptor reflex activation of vagal outflow to the heart.

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  and 2 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 1 receptors. The systolic pressure is the sum of the diastolic and the pulse pressures and is therefore a function of both  and  effects.

Metabolic & Hormonal Effects

Beta1 agonists increase renin secretion. Beta2 agonists increase insulin secretion by the pancreas. 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 agonists appear to stimulate lipolysis via the 3 receptor.

Skill Keeper: Blood Pressure Control Mechanisms in Pheochromocytoma

(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.

Clinical Uses

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

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. Epinephrine is sometimes supplemented with antihistamines and corticosteroids, 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, attention deficit disorder, 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. The drugs are abused or misused for the purpose of deferring sleep and for their mood-elevating, euphoria-producing action (see Chapter 32). They have a high addiction liability.

Eye

The  agonists, especially phenylephrine and tetrahydrozoline, are often used topically to produce mydriasis and to reduce the conjunctival itching and congestion caused by irritation or allergy. These drugs do not cause cycloplegia. Epinephrine and a prodrug, dipivefrin, now obsolete, were used topically in the treatment of glaucoma. Phenylephrine has also been used for glaucoma, mainly outside the United States. Newer 2 agonists are in current use for glaucoma and include apraclonidine and brimonidine. As noted, the 2-selective agonists appear to reduce aqueous synthesis. See Table 10-3 for a summary of drugs used in glaucoma.

Bronchi

The  agonists, especially the 2-selective agonists, are drugs of choice in the treatment of acute asthmatic bronchoconstriction. The short-acting 2-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 2-selective agonists, salmeterol and formoterol, 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 2 effect. Dobutamine and dopamine are 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 1 agonist, midodrine .

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  receptors in the trigone of the bladder and, in men, the smooth muscle of the prostate.

Toxicity

Catecholamines

Because of their limited penetration into the brain, these drugs 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.

Other Sympathomimetics

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, 1 agonists cause hypertension, and 1 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, 1-selective agents have 2 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.

Skill Keeper Answer: Blood Pressure Control Mechanisms in Pheochromocytoma

(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 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. With the reduced aldosterone effect on the kidney, more salt and water are excreted, 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.

Checklist

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

 Name a typical nonselective  agonist, a selective 2 agonist, a nonselective  agonist, a selective 1 agonist, selective 2 agonists, an 1, 2, 1 agonist, and an 1, 2, 1, 2 agonist.

 List tissues that contain significant numbers of 1 or 2 receptors.

 List tissues that contain significant numbers of 1 or 2 receptors.

 Describe the major organ system effects of a pure  agonist, a pure  agonist, and a mixed  and  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.

Drug Summary Table: Sympathomimetics

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions Direct-acting catecholamines Epinephrine 1, 2, 1, 2, 3 agonist

Anaphylaxis; hemostatic Parenteral and topical only; does not enter CNS Duration: 1-15 min Excessive sympathomimetic effects: hypertension, arrhythmia, stroke, myocardial infarction, pulmonary edema Norepinephrine 1, 2, 1 agonist

Neurogenic shock; last resort therapy in shock Like epinephrine; IV only Extreme vasospasm, tissue necrosis; excessive blood pressure increase, arrhythmias, infarction Dopamine D1, 1, 2, 1, 2, 3 agonist

Shock, especially with renal shutdown; sometimes used in heart failure Like epinephrine; IV only Cardiovascular disturbance, arrhythmias Isoproterenol: 1, 2, 3 agonist; primary use is in acute asthma, by nebulizer Dobutamine: 1 agonist; primary use is in acute heart failure to increase cardiac output Noncatecholamines Phenylephrine 1, 2 agonist

Decongestant, mydriatic, neurogenic hypotension Oral, inhalant, topical, and parenteral Duration: 15-60 min Hypertension, stroke, myocardial infarction Noncatecholamine-selective Albuterol, metaproterenol, terbutaline 2 agonist

Prompt onset for acute bronchospasm Inhalant via aerosol canister Duration: 2-6 h Tachycardia, tremor Salmeterol, formoterol: 2 agonists; slow onset, long action. Not useful in acute bronchospasm, used only with corticosteroids for prophylaxis

Indirect-acting phenylisopropylamines Amphetamine, methamphetamine Displaces stored catecholamines Anorexiant, ADHD, narcolepsy Oral and parenteral Duration: 4-6 h High addiction liability. Paranoia, aggression; insomnia; hypertension Ephedrine: Displacer like amphetamine; oral activity; duration 4-6 h. Sometimes used for narcolepsy, idiopathic postural hypotension, enuresis. Lower addiction liability than amphetamines Cocaine Cocaine Blocks norepinephrine reuptake (NET) and dopamine reuptake in CNS (DAT) Local anesthetic with intrinsic hemostatic action Parenteral only Duration: 2 h Very high addiction liability. Hypertension, arrhythmias, seizures Tyramine Tyramine Displaces stored catecholamines No clinical use but found in fermented foods Normally high first-pass effect, but in patients taking MAO inhibitors it is absorbed Hypertension, arrhythmias, stroke, myocardial infarction

ADHD, attention-deficit hyperactivity disorder; CNS, central nervous system; DAT, dopamine transporter; MAO, monoamine oxidase.



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