17 Adreergic Agoists Mechaisms of Adreergic Receptor Activatio Overview of the Adreergic Agoists Chemical Classificatio: Catecholamies Versus Nocatecholamies Receptor Specificity Therapeutic Applicatios ad Adverse Effects of Adreergic Receptor Activatio Cliical Cosequeces of Alpha 1 Activatio Cliical Cosequeces of Alpha 2 Activatio Cliical Cosequeces of Beta 1 Activatio Cliical Cosequeces of Beta 2 Activatio Cliical Cosequeces of Dopamie Receptor Activatio Multiple Receptor Activatio: Treatmet of Aaphylactic Shock Properties of Represetative Adreergic Agoists Epiephrie Norepiephrie Isoprotereol Dopamie Dobutamie Pheylephrie Albuterol Discussio of Adreergic Agoists i Other Chapters Box 17 1. The EpiPe: Do t Leave Home Without It! By defiitio, adreergic agoists produce their effects by activatig adreergic receptors. Sice the sympathetic ervous system acts through these same receptors, resposes to adreergic agoists ad resposes to stimulatio of the sympathetic ervous system are very similar. Because of this similarity, adreergic agoists are ofte referred to as sympathomimetics. Adreergic agoists have a broad spectrum of idicatios, ragig from heart failure to asthma to preterm labor. Learig about adreergic agoists ca be a challege. To facilitate the process, our approach to these drugs has four stages. We begi with the geeral mechaisms by which drugs ca activate adreergic receptors. Next we establish a overview of the major adreergic agoists, focusig o their receptor specificity ad chemical classificatio. After that, we address the adreergic receptors themselves; for each receptor type alpha 1, alpha 2, beta 1, beta 2, ad dopamie we discuss the beeficial ad harmful effects that ca result from receptor activatio. Fially, we itegrate all of this iformatio by discussig the characteristic properties of represetative sympathomimetic drugs. Please ote that this chapter is iteded oly as a itroductio to the adreergic agoists. Our objective here is to discuss the basic properties of the sympathomimetic drugs ad establish a overview of their applicatios ad adverse effects. I later chapters, we will discuss the cliical applicatios of these agets i greater depth. MECHANISMS OF ADRENERGIC RECEPTOR ACTIVATION Drugs ca activate adreergic receptors by four basic mechaisms: (1) direct receptor bidig, (2) promotio of orepiephrie (NE) release, (3) blockade of NE reuptake, ad (4) ihibitio of NE iactivatio. Note that oly the first mechaism is direct. With the other three, receptor activatio occurs by a idirect process. Examples of drugs that act by these four mechaisms are preseted i Table 17 1. Direct Receptor Bidig. Direct iteractio with receptors is the most commo mechaism by which drugs activate peripheral adreergic receptors. The direct-actig receptor stimulats produce their effects by bidig to adreergic receptors ad mimickig the actios of atural trasmitters (NE, epiephrie, dopamie). I this chapter, all of the drugs discussed activate receptors directly. Promotio of NE Release. By actig o termials of sympathetic erves to cause NE release, drugs ca brig about activatio of adreergic receptors. Amphetamies act by this mechaism. Ihibitio of NE Reuptake. Recall that reuptake of NE ito termials of sympathetic erves is the major mechaism for termiatig adreergic trasmissio. By blockig NE TABLE 17 1 Mechaisms of Adreergic Receptor Activatio Mechaism of Stimulatio Direct Mechaism Receptor activatio through direct bidig Idirect Mechaisms Promotio of NE release Ihibitio of NE reuptake Ihibitio of MAO Examples Dopamie Epiephrie Isoprotereol Amphetamie Cocaie Tricyclic atidepressats MAO ihibitors MAO 5 mooamie oxidase, NE 5 orepiephrie. 152
CHAPTER 17 Adreergic Agoists reuptake, drugs ca cause NE to accumulate withi the syaptic gap, ad ca thereby icrease receptor activatio. Agets that act by this mechaism iclude cocaie ad the tricyclic atidepressats (eg, imipramie). Ihibitio of NE Iactivatio. As discussed i Chapter 13, some of the NE i termials of adreergic euros is subject to iactivatio by mooamie oxidase (MAO). Hece, drugs that ihibit MAO ca icrease the amout of NE available for release, ad ca thereby ehace receptor activatio. (It should be oted that, i additio to beig preset i sympathetic erves, MAO is preset i the liver ad the itestial wall. The sigificace of MAO at these other sites is cosidered later i the chapter.) I this chapter, which is dedicated to peripherally actig sympathomimetics, all of the drugs discussed act exclusively by direct receptor activatio. Most of the idirect-actig adreergic agoists are used for their ability to activate adreergic receptors i the cetral ervous system (CNS) ot for their effects i the periphery. The idirect-actig sympathomimetics (eg, amphetamie, cocaie) are metioed here to emphasize that, although these agets are employed for effects o the brai, they ca ad will cause activatio of adreergic receptors i the periphery. Peripheral activatio is resposible for certai toxicities of these drugs (eg, cardiac dysrhythmias, hypertesio). OVERVIEW OF THE ADRENERGIC AGONISTS Chemical Classificatio: Catecholamies Versus Nocatecholamies The adreergic agoists fall ito two major chemical classes: catecholamies ad ocatecholamies. As discussed below, the catecholamies ad ocatecholamies differ i three importat respects: (1) oral usability, (2) duratio of actio, ad (3) the ability to act i the CNS. Accordigly, if we kow to which category a particular adreergic agoist belogs, we will kow three of its promiet features. Catecholamies The catecholamies are so amed because they cotai a catechol group ad a amie group. A catechol group is simply a bezee rig that has hydroxyl groups o two adjacet carbos (Fig. 17 1). The amie compoet of the catecholamies is ethylamie. Structural formulas for each of the major catecholamies epiephrie, orepiephrie, isoprotereol, dopamie, ad dobutamie are preseted i Figure 17 1. Because of their chemistry, all catecholamies have three properties i commo: (1) they caot be used orally, (2) they have a brief duratio of actio, ad (3) they caot cross the blood-brai barrier. The actios of two ezymes mooamie oxidase ad catechol-o-methyltrasferase (COMT) explai why the catecholamies have short half-lives ad caot be used orally. MAO ad COMT are located i the liver ad i the itestial wall. Both ezymes are very active ad quickly destroy catecholamies admiistered by ay route. Because these ezymes are located i the liver ad itestial wall, catecholamies that are admiistered orally become iactivated before they ca reach the systemic circulatio. Hece, catecholamies are ieffective if give by mouth. Because of rapid iactivatio by MAO ad COMT, three catecholamies orepiephrie, dopamie, ad dobutamie are effective oly if admiistered by cotiuous ifusio. Admiistratio by other pareteral routes (eg, subq, IM) will ot yield adequate blood levels, owig to rapid hepatic iactivatio. Catecholamies are polar molecules, ad hece caot cross the blood-brai barrier. (Recall from Chapter 4 that polar compouds peetrate membraes poorly.) The polar ature of the catecholamies is due to the hydroxyl groups o the catechol portio of the molecule. Because they caot cross the bloodbrai barrier, catecholamies have miimal effects o the CNS. Be aware that catecholamie-cotaiig solutios, which are colorless whe first prepared, tur pik or brow over time. This pigmetatio is caused by oxidatio of the catecholamie molecule. As a rule, catecholamie solutios should be discarded as soo as discoloratio develops. The oly exceptio is dobutamie, which ca be used up to 24 hours after the solutio was made, eve if discoloratio appears. Nocatecholamies The ocatecholamies have ethylamie i their structure (see Fig. 17 1), but do ot cotai the catechol moiety that characterizes the catecholamies. I this chapter, we discuss two ocatecholamies: albuterol ad pheylephrie. The ocatecholamies differ from the catecholamies i three importat respects. First, because they lack a catechol group, ocatecholamies are ot substrates for COMT ad are metabolized slowly by MAO. As a result, the half-lives of ocatecholamies are much loger tha those of catecholamies. Secod, because they do ot udergo rapid degradatio by MAO ad COMT, ocatecholamies ca be give orally, whereas catecholamies caot. Third, ocatecholamies are cosiderably less polar tha catecholamies, ad hece are more able to cross the blood-brai barrier. Receptor Specificity To uderstad the actios of idividual adreergic agoists, we eed to kow their receptor specificity. Sice the sympathomimetic drugs differ widely with respect to the receptors they ca activate, learig the receptor specificity of these drugs will take some effort. Variability i receptor specificity amog the adreergic agoists ca be illustrated with three drugs: albuterol, isoprotereol, ad epiephrie. Albuterol is highly selective, actig at beta 2 receptors oly. Isoprotereol is less selective, actig at beta 1 receptors ad beta 2 receptors. Epiephrie is less selective yet, actig at all four adreergic receptor subtypes: alpha 1, alpha 2, beta 1, ad beta 2. The receptor specificities of the major adreergic agoists are summarized i Table 17 2. I the upper part of the table, receptor specificity is preseted i tabular form. I the lower part, the same iformatio is preseted schematically. By learig (memorizig) the cotet of Table 17 2, you will be well o your way toward uderstadig the pharmacology of the sympathomimetic drugs. Please ote that the cocept of receptor specificity is relative, ot absolute. The ability of a drug to selectively activate 153
CHAPTER 17 Adreergic Agoists Albuterol Figure 17 1 Structures of represetative catecholamies ad ocatecholamies. Catecholamies: Note that all of the catecholamies share the same basic chemical formula. Because of their biochemical properties, the catecholamies caot be used orally, caot cross the blood-brai barrier, ad have short half-lives (owig to rapid iactivatio by MAO ad COMT). Nocatecholamies: Although structurally similar to catecholamies, ocatecholamies differ from catecholamies i three importat ways: they ca be used orally; they ca cross the blood-brai barrier; ad, because they are ot rapidly metabolized by MAO or COMT, they have much loger half-lives. certai receptors to the exclusio of others depeds o the dosage: at low doses, selectivity is maximal; as dosage icreases, selectivity declies. For example, whe albuterol is admiistered i low to moderate doses, the drug is highly selective for beta 2 -adreergic receptors. However, if the dosage is high, albuterol will activate beta 1 receptors as well. The iformatio o receptor specificity i Table 17 2 refers to usual therapeutic doses. So-called selective agets will activate additioal adreergic receptors if the dosage is abormally high. THERAPEUTIC APPLICATIONS AND ADVERSE EFFECTS OF ADRENERGIC RECEPTOR ACTIVATION I this sectio we discuss the resposes both therapeutic ad adverse that ca be elicited with sympathomimetic drugs. Sice may adreergic agoists activate more tha oe type of receptor (see Table 17 2), it could be quite cofusig if we were to talk about the effects of the sympathomimetics 154
CHAPTER 17 Adreergic Agoists TABLE 17 2 Receptor Specificity of Represetative Adreergic Agoists Catecholamies Nocatecholamies Drug Receptors Activated Drug Receptors Activated Epiephrie a 1, a 2, b 1, b 2 Pheylephrie a 1 Norepiephrie a 1, a 2, b 1 Albuterol b 2 Isoprotereol b 1, b 2 Dobutamie b 1 Dopamie* a 1, b 1, dopamie Receptors Activated Alpha 1 Alpha 2 Beta 1 Beta 2 Dopamie Epiephrie Norepiephrie Pheylephrie Isoprotereol Dobutamie Albuterol Dopamie* Dopamie* Dopamie* a 5 alpha, b 5 beta. *Receptor activatio by dopamie is dose depedet. This chart represets i graphic form the same iformatio o receptor specificity give above. Arrows idicate the rage of receptors that the drugs ca activate (at usual therapeutic doses). while employig specific drugs as examples. Cosequetly, rather tha attemptig to structure this presetatio aroud represetative drugs, we discuss the actios of the adreergic agoists oe receptor at a time. Our discussio begis with alpha 1 receptors, ad the moves to alpha 2 receptors, beta 1 receptors, beta 2 receptors, ad fially dopamie receptors. For each receptor type, we discuss both the therapeutic ad adverse resposes that ca result from receptor activatio. To uderstad the effects of ay specific adreergic agoist, all you eed is two types of iformatio: (1) the idetity of the receptors at which the drug acts ad (2) the effects produced by activatig those receptors. Combiig these two types of iformatio will reveal a profile of drug actio. This is the same approach to uderstadig europharmacologic agets that we discussed i Chapter 12. Before you go deeper ito this chapter, I ecourage you (strogly advise you) to review Table 13 3. Sice we are about to discuss the cliical cosequeces of adreergic receptor activatio, ad sice Table 13 3 summarizes the resposes to activatio of those receptors, the beefits of beig familiar with Table 13 3 are obvious. If you choose ot to memorize Table 13 3 ow, at least be prepared to refer back to it as we discuss the cosequeces of receptor activatio. Cliical Cosequeces of Alpha 1 Activatio I this sectio we discuss the therapeutic ad adverse effects that ca result from activatio of alpha 1 -adreergic receptors. As show i Table 17 2, drugs capable of activatig alpha 1 receptors iclude epiephrie, NE, pheylephrie, ad dopamie. Therapeutic Applicatios of Alpha 1 Activatio Activatio of alpha 1 receptors elicits two resposes that ca be of therapeutic use: (1) vasocostrictio (i blood vessels of the ski, viscera, ad mucous membraes); ad (2) mydriasis. Of the two, vasocostrictio is the oe for which alpha 1 agoists are used most ofte. Usig these drugs for mydriasis is rare. Hemostasis. Hemostasis is defied as the arrest of bleedig, which alpha 1 agoists accomplish through vasocostrictio. Alpha 1 stimulats are give to stop bleedig primarily i the ski ad mucous membraes. Epiephrie, applied topically, is the alpha 1 agoist used most for this purpose. Nasal Decogestio. Nasal cogestio results from dilatio ad egorgemet of blood vessels i the asal mucosa. Drugs ca relieve cogestio by causig alpha 1 -mediated vasocostrictio. Specific alpha 1 -activatig agets employed as asal decogestats iclude pheylephrie (applied topically) ad pseudoephedrie (take orally). Adjuct to Local Aesthesia. Alpha 1 agoists are frequetly combied with local aesthetics to delay aesthetic absorptio. The mechaism is alpha 1 -mediated vasocostrictio, which reduces blood flow to the site of aesthetic admiistratio. Why delay aesthetic absorptio? Because doig so prologs aesthesia, allows a reductio i aesthetic dosage, ad reduces the systemic effects that a local aesthetic might produce. The drug used most frequetly to delay aesthetic absorptio is epiephrie. Elevatio of Blood Pressure. Because of their ability to cause vasocostrictio, alpha 1 agoists ca elevate blood pressure i hypotesive patiets. Please ote, however, that alpha 1 agoists are ot the primary therapy for hypotesio. Rather, they are reserved for situatios i which fluid replacemet ad other measures have failed to restore blood pressure to a satisfactory level. Mydriasis. Activatio of alpha 1 receptors o the radial muscle of the iris causes mydriasis (dilatio of the pupil), which ca facilitate eye examiatios ad ocular surgery. Note that producig mydriasis is the oly cliical use of alpha 1 activatio that is ot based o vasocostrictio. Adverse Effects of Alpha 1 Activatio All of the adverse effects caused by alpha 1 activatio result directly or idirectly from vasocostrictio. 155
CHAPTER 17 Adreergic Agoists Hypertesio. Alpha 1 agoists ca produce hypertesio by causig widespread vasocostrictio. Severe hypertesio is most likely with pareteral dosig. Accordigly, whe alpha 1 agoists are give pareterally, cardiovascular status must be moitored cotiuously. Never leave the patiet uatteded. Necrosis. If the IV lie employed to admiister a alpha 1 agoist becomes extravasated, local seepage of the drug may result i ecrosis (tissue death). The cause is lack of blood flow secodary to itese local vasocostrictio. If extravasatio occurs, the area should be ifiltrated with a alpha 1 -blockig aget (eg, phetolamie), which will couteract alpha 1 -mediated vasocostrictio, ad thereby help miimize ijury. Bradycardia. Alpha 1 agoists ca cause reflex slowig of the heart. The mechaism is this: Alpha 1 -mediated vasocostrictio elevates blood pressure, which triggers the baroreceptor reflex, causig heart rate to declie. I patiets with margial cardiac reserve, the decrease i cardiac output may compromise tissue perfusio. Cliical Cosequeces of Alpha 2 Activatio As discussed i Chapter 13, alpha 2 receptors i the periphery are located presyaptically, ad their activatio ihibits NE release. Several adreergic agoists (eg, epiephrie, NE) are capable of causig alpha 2 activatio. However, their ability to activate alpha 2 receptors i the periphery has little cliical sigificace. There are o therapeutic applicatios related to activatio of peripheral alpha 2 receptors. Furthermore, activatio of these receptors rarely causes sigificat adverse effects. I cotrast to alpha 2 receptors i the periphery, alpha 2 receptors i the CNS are of great cliical sigificace. By activatig cetral alpha 2 receptors, we ca produce two useful effects: (1) reductio of sympathetic outflow to the heart ad blood vessels ad (2) relief of severe pai. The cetral alpha 2 agoists used for effects o the heart ad blood vessels, ad the agets used to relieve pai, are discussed i Chapters 19 ad 28, respectively. Cliical Cosequeces of Beta 1 Activatio All of the cliically relevat resposes to activatio of beta 1 receptors result from activatig beta 1 receptors i the heart; activatio of real beta 1 receptors is ot associated with either beeficial or adverse effects. As idicated i Table 17 2, beta 1 receptors ca be activated by epiephrie, NE, isoprotereol, dopamie, ad dobutamie. Therapeutic Applicatios of Beta 1 Activatio Heart Failure. Heart failure is characterized by a reductio i the force of myocardial cotractio, resultig i isufficiet cardiac output. Because activatio of beta 1 receptors i the heart has a positive iotropic effect (ie, icreases the force of cotractio), drugs that activate these receptors ca improve cardiac performace. Shock. This coditio is characterized by profoud hypotesio ad greatly reduced tissue perfusio. The primary goal of treatmet is to maitai blood flow to vital orgas. By icreasig heart rate ad force of cotractio, beta 1 stimulats ca icrease cardiac output ad ca thereby improve tissue perfusio. Atriovetricular Heart Block. Atriovetricular (AV) heart block is a coditio i which impulse coductio from the atria to the vetricles is either impeded or blocked etirely. As a cosequece, the vetricles are o loger drive at a appropriate rate. Sice activatio of cardiac beta 1 receptors ca ehace impulse coductio through the AV ode, beta 1 stimulats ca help overcome AV block. It should be oted, however, that drugs are oly a temporary form of treatmet. For log-term maagemet, a pacemaker is implated. Cardiac Arrest Caused by Asystole. By activatig cardiac beta 1 receptors, drugs ca iitiate cotractio i a heart that has stopped beatig. It should be oted, however, that drugs are ot the preferred treatmet. Iitial maagemet focuses o cardiopulmoary resuscitatio (CPR), exteral pacig (if available), ad idetificatio ad treatmet of the uderlyig cause (eg, hypoxia, severe acidosis, drug overdose). Whe a beta 1 agoist is idicated, epiephrie, admiistered IV, is the preferred drug. If IV access is ot possible, epiephrie ca be ijected directly ito the heart. Adverse Effects of Beta 1 Activatio All of the adverse effects of beta 1 activatio result from activatig beta 1 receptors i the heart. Activatig real beta 1 receptors is ot associated with utoward effects. Altered Heart Rate or Rhythm. Overstimulatio of cardiac beta 1 receptors ca produce tachycardia (excessive heart rate) ad dysrhythmias (irregular heartbeat). Agia Pectoris. I some patiets, drugs that activate beta 1 receptors ca precipitate a attack of agia pectoris, a coditio characterized by substeral pai i the regio of the heart. Agial pai occurs whe cardiac oxyge supply (blood flow) is isufficiet to meet cardiac oxyge eeds. The most commo cause of agia is coroary atherosclerosis (accumulatio of lipids ad other substaces i coroary arteries). Sice beta 1 agoists icrease cardiac oxyge demad (by icreasig heart rate ad force of cotractio), patiets with compromised coroary circulatio are at risk of a agial attack. Cliical Cosequeces of Beta 2 Activatio Therapeutic Applicatios of Beta 2 Activatio Therapeutic applicatios of beta 2 activatio are limited to the lugs ad the uterus. Drugs used for their beta 2 -activatig ability iclude epiephrie, isoprotereol, ad albuterol. Asthma. Asthma is a chroic coditio characterized by iflammatio ad brochocostrictio occurrig i respose to a variety of stimuli. Durig a severe attack, the airflow reductio ca be life threateig. Sice drugs that activate beta 2 receptors i the lug promote brochodilatio, these drugs ca help relieve or prevet asthma attacks. For therapy of asthma, adreergic agoists that are selective for beta 2 receptors (eg, albuterol) are preferred to less selective agets (eg, isoprotereol). This is especially true for patiets who also suffer from agia pectoris or tachycardia. Why? Because drugs that ca activate beta 1 receptors would aggravate these cardiac disorders. Most beta 2 agoists used to treat asthma are admiistered by ihalatio. This route is desirable i that it helps miimize adverse systemic effects. It should be oted, however, that ihalatio does ot guaratee safety: Serious systemic toxic- 156
CHAPTER 17 Adreergic Agoists ity ca result from overdosig with ihaled sympathomimetics. Accordigly, patiets must be wared agaist ihalig too much drug. Delay of Preterm Labor. Activatio of beta 2 receptors i the uterus relaxes uterie smooth muscle. This actio ca be exploited to delay preterm labor. Adverse Effects of Beta 2 Activatio Hyperglycemia. The most importat adverse respose to beta 2 activatio is hyperglycemia (elevatio of blood glucose). The mechaism is activatio of beta 2 receptors i the liver ad skeletal muscles, which promotes breakdow of glycoge ito glucose. As a rule, beta 2 agoists cause hyperglycemia oly i patiets with diabetes; i patiets with ormal pacreatic fuctio, isuli release will maitai blood glucose at a appropriate level. If hyperglycemia develops i the diabetic patiet, isuli dosage should be icreased. Tremor. Tremor is the most commo side effect of beta 2 agoists. It occurs because activatio of beta 2 receptors i skeletal muscle ehaces cotractio. Tremor geerally fades over time ad ca be miimized by iitiatig therapy at low doses. Cliical Cosequeces of Dopamie Receptor Activatio Activatio of peripheral dopamie receptors causes dilatio of the real vasculature. This effect is exploited i the treatmet of shock: by dilatig real blood vessels, we ca improve real perfusio ad ca thereby reduce the risk of real failure. Dopamie itself is the oly drug available that ca activate dopamie receptors. It should be oted that, whe dopamie is give to treat shock, the drug also ehaces cardiac performace (because it activates beta 1 receptors i the heart). Multiple Receptor Activatio: Treatmet of Aaphylactic Shock Pathophysiology of Aaphylaxis. Aaphylactic shock is a maifestatio of severe allergy. The reactio is characterized by hypotesio (from widespread vasodilatio), brochocostrictio, ad edema of the glottis. Although histamie cotributes to these resposes, symptoms are due largely to release of other mediators (eg, leukotriees). Aaphylaxis ca be triggered by a variety of substaces, icludig bee veom, wasp veom, latex rubber, certai foods (eg, peauts, shellfish), ad certai drugs (eg, peicillis). Treatmet. Epiephrie, ijected IM, is the treatmet of choice for aaphylactic shock. Beefits derive from activatig three types of adreergic receptors: alpha 1, beta 1, ad beta 2. By activatig these receptors, epiephrie ca reverse the most severe maifestatios of the aaphylactic reactio. Activatio of beta 1 receptors icreases cardiac output, thereby helpig elevate blood pressure. Blood pressure is also icreased because epiephrie promotes alpha 1 -mediated vasocostrictio. I additio to icreasig blood pressure, vasocostrictio helps suppress glottal edema. By activatig beta 2 receptors, epiephrie ca couteract brochocostrictio. Idividuals who are proe to severe allergic resposes should carry a epiephrie autoijector (eg, EpiPe) at all times (Box 17 1). Atihistamies are ot especially useful agaist aaphylaxis because histamie is oly a mior cotributor to the reactio. PROPERTIES OF REPRESENTATIVE ADRENERGIC AGONISTS Our aim i this sectio is to establish a overview of the adreergic agoists. The iformatio is preseted i the form of drug digests that highlight characteristic features of represetative sympathomimetic agets. As oted, there are two keys to uderstadig idividual adreergic agoists: (1) kowledge of the receptors that the drug ca activate ad (2) kowledge of the therapeutic ad adverse effects that receptor activatio ca elicit. By itegratig these two types of iformatio, you ca easily predict the spectrum of effects that a particular drug ca produce. Ufortuately, kowig the effects that a drug is capable of producig does ot always idicate how that drug is actually used i a cliical settig. Why? Because some adreergic agoists are ot used for all the effects they ca produce. Norepiephrie, for example, ca activate alpha 1 receptors ad ca therefore produce mydriasis. However, although NE ca produce mydriasis, the drug is ot actually used for this purpose. Similarly, although isoprotereol is capable of producig uterie relaxatio (through beta 2 activatio), isoprotereol is ot employed cliically for this effect. Because receptor specificity is ot always a predictor of the therapeutic applicatios of a particular adreergic agoist, for each of the drugs discussed below, approved cliical applicatios are idicated. Epiephrie Receptor specificity: alpha 1, alpha 2, beta 1, beta 2 Chemical classificatio: catecholamie Epiephrie [Adreali, others] was amog the first adreergic agoists employed cliically ad ca be cosidered the prototype of the sympathomimetic drugs. Because of its prototypic status, epiephrie is discussed i detail. Therapeutic Uses Epiephrie ca activate all four subtypes of adreergic receptors. As a cosequece, the drug ca produce a broad spectrum of beeficial sympathomimetic effects: Because it ca cause alpha 1 -mediated vasocostrictio, epiephrie is used to (1) delay absorptio of local aesthetics, (2) cotrol superficial bleedig, ad (3) elevate blood pressure. I the past, epiephrie-iduced vasocostrictio was also used for asal decogestio. Activatio of alpha 1 receptors o the iris ca be used to produce mydriasis durig ophthalmologic procedures.* Because it ca activate beta 1 receptors, epiephrie is used to (1) overcome AV heart block ad (2) restore cardiac fuctio i patiets experiecig cardiac arrest caused by asystole. Activatio of beta 2 receptors i the lug promotes brochodilatio, which ca be useful i patiets with asthma (although other drugs are preferred). Because it ca activate a combiatio of alpha ad beta receptors, epiephrie is the treatmet of choice for aaphylactic shock. *Epiephrie for ophthalmic use is o loger available i the Uited States. 157
CHAPTER 17 Adreergic Agoists BOX 17 1 SPECIAL INTEREST TOPIC THE EPIPEN: DON T LEAVE HOME WITHOUT IT! The EpiPe is a epiephrie auto-ijector, oe of three brads available i the Uited States. * The device is idicated for emergecy treatmet of aaphylaxis, a life-threateig allergic reactio caused by severe hypersesitivity to isect veoms (eg, from bees, wasps, fire ats), certai foods (eg, peauts, waluts, shellfish), ad certai drugs (especially peicillis). Every year, aaphylaxis kills about 6000 Americas: 125 who have food allergies, betwee 40 ad 400 who have veom allergies, ad over 5400 who have peicilli allergy. Could most of these deaths be avoided? Yes through immediate ijectio of epiephrie. Ufortuately, may of the people at risk do t carry a epiephrie ijector, ad may of those who do are t sure how to use it. So liste up: By ecouragig highly allergic cliets to carry a EpiPe, ad by teachig them whe ad how to use it, you could well save someoe s life. EpiPe Descriptio ad Dosage The EpiPe auto-ijector is a sigle-use delivery device, featurig a sprig-activated eedle, desiged for IM ijectio of epiephrie. Two stregths are available. The larger oe, sold as EpiPe, delivers a 0.3-mg dose (for idividuals weighig 66 pouds or more). The smaller oe, sold as EpiPe Jr, delivers a 0.15-mg dose (for idividuals betwee 33 ad 66 pouds). If oe ijectio fails to completely reverse symptoms, a secod ijectio (usig a secod EpiPe) may be give. The EpiPe is available oly by prescriptio. EpiPe Storage ad Replacemet Epiephrie is sesitive to extreme heat ad light, ad hece the EpiPe should be stored at room temperature i a dark place. The factory-issue storage tube provides additioal protectio from UV light. Refrigeratio ca compromise the ijectio mechaism, ad should be avoided. If the epiephrie solutio turs brow, if a precipitate forms, or if the expiratio date has passed, the uit should be replaced. (The distributor offers a free service to remid patiets whe their EpiPe is about to expire.) Who Should Carry a EpiPe ad Whe Should They Use It? Ayoe who has experieced a severe, systemic allergic reactio should always carry at least oe epiephrie auto-ijector! Aaphylaxis ca develop withi miutes after allerge exposure. To prevet a full-blow reactio, epiephrie should be ijected as soo as early symptoms appear (eg, swellig, shortess of breath). People who do ot carry a EpiPe, ad hece must wait for a emergecy respose team, greatly icrease their risk of death. What s the Self-Ijectio Procedure? The EpiPe auto-ijector is a tubular device with three promiet exteral features: a black tip (the eedle comes out through this ed), a clear widow (for examiig the epiephrie solutio), ad a gray cap (which prevets activatio util beig removed). Black tip (eedle comes out durig use) Clear widow EPIPEN EINEPHRINE AUTO-INJECTOR Gray activatio cap (do ot remove util ready to iject) Ijectios are made ito the outer thigh as follows: 1. Form a fist aroud the uit with the black tip poitig dow. 2. With the free had, pull off the gray activatio cap. 3. Jab the device firmly ito the outer thigh, at a agle perpedicular to the thigh, ad hold it there for 10 secods. (The ijectio may be made directly through clothig.) 4. Remove the uit ad massage the area for 10 secods to facilitate absorptio. To esure the ijectio was made, examie the used EpiPe: If the eedle is projectig through the black tip, the procedure was a success; if the eedle is ot projectig, jab the device i agai. Note: The EpiPe cotais 2 ml of epiephrie solutio, but oly 0.3 ml is actually ijected. Hece, eve after a successful ijectio, the device will ot be empty. What Should Be Doe After the Ijectio? Followig epiephrie ijectio, it is importat to get immediate medical attetio. Why? Because (1) the effects of epiephrie begi to fade i 10 to 20 miutes ad (2) aaphylactic reactios ca be biphasic ad prologed. Accordigly, to esure a good outcome, hospitalizatio (up to 6 hours) is recommeded. Hospital staff should be iformed that epiephrie has bee ijected, ad should be show the used EpiPe (to cofirm the dosage). Predisoe may be give to maage delayed or persistet symptoms. Does IM Epiephrie Have Side Effects? Of course. The ijectio itself may cause discomfort, ad the epiephrie may cause tachycardia, palpitatios, ad a feelig of ervousess. The drug may also cause sweatig, dizziess, headache, ausea, ad vomitig. * I additio to the EpiPe, two other epiephrie auto-ijectors Adreaclick ad Twiject are ow available. The Adreaclick ijector is early idetical to the EpiPe. Twiject differs from the other two products i that it ca deliver two separate doses. The first dose is ijected automatically, just as with EpiPe ad Adreaclick. The secod dose, if eeded, is ijected maually. 158
CHAPTER 17 Adreergic Agoists Pharmacokietics Absorptio. Epiephrie may be admiistered topically or by ijectio. The drug caot be give orally because, as discussed, epiephrie ad other catecholamies udergo destructio by MAO ad COMT before reachig the systemic circulatio. Followig subq ijectio, absorptio is slow owig to epiephrie-iduced local vasocostrictio. Absorptio is more rapid followig IM ijectio. Iactivatio. Epiephrie has a short half-life because of two processes: ezymatic iactivatio ad uptake ito adreergic erves. The ezymes that iactivate epiephrie ad other catecholamies are MAO ad COMT. Adverse Effects Because it ca activate the four major adreergic receptor subtypes, epiephrie ca produce multiple adverse effects. Hypertesive Crisis. Vasocostrictio secodary to excessive alpha 1 activatio ca produce a dramatic icrease i blood pressure. Cerebral hemorrhage ca occur. Because of the potetial for severe hypertesio, patiets receivig pareteral epiephrie must udergo cotiuous cardiovascular moitorig. Dysrhythmias. Excessive activatio of beta 1 receptors i the heart ca produce dysrhythmias. Because of their sesitivity to catecholamies, hyperthyroid patiets are at high risk for epiephrie-iduced dysrhythmias. Agia Pectoris. By activatig beta 1 receptors i the heart, epiephrie ca icrease cardiac work ad oxyge demad. If the icrease i oxyge demad is big eough, a agial attack may esue. Causig agia is especially likely i patiets with coroary atherosclerosis. Necrosis Followig Extravasatio. If a IV lie cotaiig epiephrie becomes extravasated, the resultat localized vasocostrictio may result i ecrosis. Because of this possibility, patiets receivig IV epiephrie should be moitored closely. If extravasatio occurs, ijury ca be miimized by local ijectio of phetolamie, a alpha-adreergic atagoist. Hyperglycemia. I diabetic patiets, epiephrie ca cause hyperglycemia. How? By causig breakdow of glycoge secodary to activatio of beta 2 receptors i liver ad skeletal muscle. If hyperglycemia develops, isuli dosage should be icreased. Drug Iteractios MAO Ihibitors. As their ame implies, MAO ihibitors suppress the activity of MAO. These drugs are used primarily to treat depressio (see Chapter 32). Because MAO is oe of the ezymes that iactivate epiephrie ad other catecholamies, ihibitio of MAO will prolog ad itesify epiephrie s effects. As a rule, patiets receivig a MAO ihibitor should ot receive epiephrie. Tricyclic Atidepressats. Tricyclic atidepressats block the uptake of catecholamies ito adreergic euros. Sice euroal uptake is oe mechaism by which the actios of orepiephrie ad other catecholamies are termiated, blockig uptake ca itesify ad prolog epiephrie s effects. Accordigly, patiets receivig a tricyclic atidepressat may require a reductio i epiephrie dosage. Geeral Aesthetics. Several ihalatio aesthetics reder the myocardium hypersesitive to activatio by beta 1 agoists. Whe the heart is i this hypersesitive state, exposure to epiephrie ad other beta 1 agoists ca cause tachydysrhythmias. Alpha-Adreergic Blockig Agets. Drugs that block alpha-adreergic receptors ca prevet receptor activatio by epiephrie. Alpha blockers (eg, phetolamie) ca be used to treat toxicity (eg, hypertesio, local vasocostrictio) caused by excessive epiephrie-iduced alpha activatio. Beta-Adreergic Blockig Agets. Drugs that block beta-adreergic receptors ca prevet receptor activatio by epiephrie. Beta-blockig agets (eg, propraolol) ca reduce adverse effects (eg, dysrhythmias, agial pai) caused by epiephrie ad other beta 1 agoists. Preparatios, Dosage, ad Admiistratio Epiephrie [Adreali, EpiPe, Primatee Mist, others] is supplied i solutio for admiistratio by several routes: IV, IM, subq, itracardiac, itraspial, ihalatio, ad topical. As idicated i Table 17 3, the stregth of the epiephrie solutio employed depeds o the route of admiistratio. Note that solutios iteded for itraveous admiistratio are less cocetrated tha solutios iteded for admiistratio by most other routes. Why? Because itraveous admiistratio of a cocetrated epiephrie solutio ca produce potetially fatal reactios (severe dysrhythmias ad hypertesio). Therefore, before you give epiephrie IV, check to esure that the cocetratio is appropriate! Aspirate prior to IM or subq ijectio to avoid iadvertet ijectio ito a vei. Patiets receivig IV epiephrie should be moitored costatly. They should be observed for sigs of excessive cardiovascular activatio (eg, tachydysrhythmias, hypertesio) ad for possible extravasatio of the IV lie. If systemic toxicity develops, epiephrie should be discotiued; if idicated, a alpha-adreergic blocker, a beta-adreergic blocker, or both should be give to suppress symptoms. If a epiephriecotaiig IV lie becomes extravasated, admiistratio should be discotiued ad the regio of extravasatio ifiltrated with a alpha-adreergic blocker. Treatmet of aaphylaxis usig a epiephrie auto-ijector [EpiPe, Twiject, Adreaclick] is discussed i Box 17 1. Norepiephrie Receptor specificity: alpha 1, alpha 2, beta 1 Chemical classificatio: catecholamie Norepiephrie [Levophed] is similar to epiephrie i several respects. With regard to receptor specificity, NE differs from epiephrie oly i that NE does ot activate beta 2 receptors. Accordigly, NE ca elicit all of the resposes that epiephrie ca, except those that are beta 2 mediated. Because NE is a catecholamie, the drug is subject to rapid iactivatio by MAO ad TABLE 17 3 Epiephrie Solutios: Cocetratios for Differet Routes of Admiistratio Cocetratio of Epiephrie Solutio Route of Admiistratio 1% (1:100) Oral ihalatio 0.1% (1:1000) Subcutaeous Itramuscular Itraspial 0.01% (1:10,000) Itraveous Itracardiac 0.001% (1:100,000) I combiatio with local aesthetics 159
CHAPTER 17 Adreergic Agoists COMT, ad hece caot be give orally. Adverse effects are early idetical to those of epiephrie: tachydysrhythmias, agia, hypertesio, ad local ecrosis upo extravasatio. I cotrast to epiephrie, NE does ot promote hyperglycemia, a respose that is beta 2 mediated. As with epiephrie, resposes to NE ca be modified by MAO ihibitors, tricyclic atidepressats, geeral aesthetics, ad adreergic blockig agets. Despite its similarity to epiephrie, NE has limited cliical applicatios. The oly recogized idicatios are hypotesive states ad cardiac arrest. Norepiephrie is supplied i solutio (1 mg/ml) for admiistratio by IV ifusio oly. Never leave the patiet uatteded. Moitor cardiovascular status cotiuously. Take care to avoid extravasatio. Isoprotereol Receptor specificity: beta 1 ad beta 2 Chemical classificatio: catecholamie Isoprotereol (formerly available as Isuprel) differs sigificatly from NE ad epiephrie i that isoprotereol acts oly at beta-adreergic receptors. Isoprotereol was the first beta-selective aget employed cliically ad will serve as our prototype of the beta-selective adreergic agoists. Therapeutic Uses Cardiovascular. By activatig beta 1 receptors i the heart, isoprotereol ca beefit patiets with cardiovascular disorders. Specifically, it ca help overcome AV heart block, restart the heart followig cardiac arrest, ad icrease cardiac output durig shock. Brochospasm. Although isoprotereol is o loger used for asthma, it is used to treat brochospasm durig aesthesia. Beefits derive from activatig beta 2 receptors i the lug. Asthma. By activatig beta 2 receptors i the lug, isoprotereol ca cause brochodilatio, thereby decreasig airway resistace. Followig its itroductio, isoprotereol became a maistay of asthma therapy. However, because we ow have eve more selective beta-adreergic agoists (ie, drugs that activate beta 2 receptors oly), use of isoprotereol for asthma has bee abadoed. Adverse Effects Because isoprotereol does ot activate alpha-adreergic receptors, it produces fewer adverse effects tha NE or epiephrie. The major udesired resposes, caused by activatig beta 1 receptors i the heart, are tachydysrhythmias ad agia pectoris. I diabetic patiets, isoprotereol ca cause hyperglycemia (by promotig beta 2 -mediated glycogeolysis). Drug Iteractios The major drug iteractios of isoprotereol are early idetical to those of epiephrie. Effects are ehaced by MAO ihibitors ad tricyclic atidepressats ad reduced by beta-adreergic blockig agets. Like epiephrie, isoprotereol ca cause dysrhythmias i patiets receivig certai ihalatio aesthetics. Preparatios ad Admiistratio Isoprotereol hydrochloride is available i solutio (0.2 ad 0.02 mg/ml) for pareteral admiistratio. Whe used to stimulate the heart, isoprotereol ca be admiistered IV ad IM ad by itracardiac ijectio. The dosage for IM admiistratio is about 10 times greater tha the dosage employed for the other two routes. Whe used to relieve brochospasm, isoprotereol is admiistered IV. Dopamie Receptor specificity: dopamie, beta 1, ad, at high doses, alpha 1 Chemical classificatio: catecholamie Receptor Specificity Dopamie has dose-depedet receptor specificity. Whe admiistered i low therapeutic doses, dopamie acts o dopamie receptors oly. At moderate therapeutic doses, dopamie activates beta 1 receptors i additio to dopamie receptors. Ad at very high doses, dopamie activates alpha 1 receptors alog with beta 1 ad dopamie receptors. Therapeutic Uses Shock. The major idicatio for dopamie is shock. Beefits derive from effects o the heart ad real blood vessels. By activatig beta 1 receptors i the heart, dopamie ca icrease cardiac output, thereby improvig tissue perfusio. By activatig dopamie receptors i the kidey, dopamie ca dilate real blood vessels, thereby improvig real perfusio. Success ca be evaluated by moitorig output of urie. Heart Failure. Heart failure is characterized by reduced tissue perfusio secodary to reduced cardiac output. Dopamie ca help alleviate symptoms by activatig beta 1 receptors o the heart, which icreases myocardial cotractility, ad thereby icreases cardiac output. Acute Real Failure. Because of its ability to icrease real blood flow ad urie output, low-dose dopamie has log bee used i efforts to preserve real fuctio i patiets with evolvig acute real failure (ARF). However, we ow have evidece that the drug is ot effective: I patiets with early ARF, dopamie failed to protect real fuctio, shorte hospital stays, or reduce the umber of patiets eedig a kidey trasplat. Accordigly, it would appear that it is time to abado low-dose dopamie as a treatmet for ARF. Adverse Effects The most commo adverse effects of dopamie tachycardia, dysrhythmias, ad agial pai result from activatio of beta 1 receptors i the heart. Because of its cardiac actios, dopamie is cotraidicated for patiets with tachydysrhythmias or vetricular fibrillatio. Sice high cocetratios of dopamie cause alpha 1 activatio, extravasatio may result i ecrosis from localized vasocostrictio. Tissue ijury ca be miimized by local ifiltratio of phetolamie, a alphaadreergic atagoist. Drug Iteractios MAO ihibitors ca itesify the effects of dopamie o the heart ad blood vessels. If a patiet is receivig a MAO ihibitor, the dosage of dopamie must be reduced by at least 90%. Tricyclic atidepressats ca also itesify dopamie s actios, but ot to the extet see with MAO ihibitors. Certai geeral aesthetics ca sesitize the myocardium to stimulatio by dopamie ad other catecholamies, thereby icreasig the risk of dysrhythmias. Diuretics ca complemet the beeficial effects of dopamie o the kidey. Preparatios, Dosage, ad Admiistratio Preparatios. Dopamie hydrochloride is supplied i aqueous solutios that rage i cocetratio from 0.8 to 160 mg/ml. Dosage. Cocetrated solutios must be diluted prior to ifusio. For treatmet of shock, a cocetratio of 400 mcg/ml ca be used. The recommeded iitial rate of ifusio is 2 to 5 mcg/kg/mi. If eeded, the ifusio rate ca be gradually icreased to a maximum of 20 to 50 mcg/kg/mi. Admiistratio. Dopamie is admiistered IV. Because of extremely rapid iactivatio by MAO ad COMT, the drug must be give by cotiuous ifusio. A meterig device is eeded to cotrol flow rate. Cardiovascular 160
CHAPTER 17 Adreergic Agoists status must be closely moitored. If extravasatio occurs, the ifusio should be stopped ad the affected area ifiltrated with a alpha-adreergic atagoist (eg, phetolamie). Dobutamie Receptor specificity: beta 1 Chemical classificatio: catecholamie Actios ad Uses. At therapeutic doses, dobutamie causes selective activatio of beta 1 -adreergic receptors. The oly idicatio for the drug is heart failure. Adverse Effects. The major adverse effect is tachycardia. Blood pressure ad the electrocardiogram (ECG) should be moitored closely. Drug Iteractios. Effects of dobutamie o the heart ad blood vessels are itesified greatly by MAO ihibitors. Accordigly, i patiets receivig a MAO ihibitor, dobutamie dosage must be reduced at least 90%. Cocurret use of tricyclic atidepressats may cause a moderate icrease i the cardiovascular effects. Certai geeral aesthetics ca sesitize the myocardium to stimulatio by dobutamie, thereby icreasig the risk of dysrhythmias. Preparatios, Dosage, ad Admiistratio. Dobutamie hydrochloride is supplied i cocetrated ad dilute solutios. The cocetrated solutio (12.5 mg/ml i 20- ad 40-mL vials) must be diluted prior to use. The dilute solutios (1, 2, ad 4 mg/ml i 250-mL sigle-use cotaiers) ca be used as is. Because of rapid iactivatio by MAO ad COMT, dobutamie is admiistered by cotiuous IV ifusio. The usual rate is 2.5 to 10 mcg/kg/mi. Pheylephrie Receptor specificity: alpha 1 Chemical classificatio: ocatecholamie Pheylephrie [Neo-Syephrie, others] is a selective alpha 1 agoist. The drug ca be admiistered locally to reduce asal cogestio ad pareterally to elevate blood pressure. I additio, pheylephrie eye drops ca be used to dilate the pupil. Also, pheylephrie ca be coadmiistered with local aesthetics to retard aesthetic absorptio. Albuterol Receptor specificity: beta 2 Chemical classificatio: ocatecholamie Therapeutic Uses Asthma. Albuterol [Vetoli, VoSpire, others] ca reduce airway resistace i asthma by causig beta 2 -mediated brochodilatio. Because albuterol is selective for beta 2 receptors, it produces much less activatio of cardiac beta 1 receptors tha does isoprotereol. As a result, albuterol ad other beta 2 -selective agets have replaced isoprotereol for therapy of asthma. Remember, however, that receptor selectivity is oly relative: If admiistered i large doses, albuterol will lose selectivity ad activate beta 1 receptors as well as beta 2 receptors. Accordigly, patiets should be wared ot to exceed recommeded doses, sice doig so may cause udesired cardiac stimulatio. Preparatios ad dosages for asthma are preseted i Chapter 76. Adverse Effects Adverse effects are miimal at therapeutic doses. Tremor is most commo. If dosage is excessive, albuterol ca cause tachycardia by activatig beta 1 receptors i the heart. DISCUSSION OF ADRENERGIC AGONISTS IN OTHER CHAPTERS All of the drugs preseted i this chapter are discussed agai i chapters that address specific applicatios. For example, the use of alpha 1 agoists to relieve asal cogestio is discussed i Chapter 77. Table 17 4 summarizes the chapters i which adreergic agoists are discussed agai. TABLE 17 4 Discussio of Adreergic Agoists i Other Chapters Drug Class Discussio Topic Chapter Alpha 1 Agoists Nasal cogestio 77 Ophthalmology 104 Alpha 2 Agoists Cardiovascular effects Pai relief Hypertesio Ophthalmology 19 28 47 104 Beta 1 Agoists Heart failure 48 Beta 2 Agoists Asthma 76 Preterm labor 64 Amphetamies Basic pharmacology Attetio-deficit/hyperactivity disorder Drug abuse Appetite suppressio 36 36 40 82 161
CHAPTER 17 Adreergic Agoists KEY POINTS Adreergic agoists are also kow as sympathomimetics. Why? Because their effects mimic those caused by the sympathetic ervous system. Most adreergic agoists act by direct activatio of adreergic receptors. A few act by idirect mechaisms: promotio of orepiephrie release, blockade of orepiephrie uptake, ad ihibitio of orepiephrie breakdow. Adreergic agoists fall ito two chemical classes: catecholamies ad ocatecholamies. Agets i the catecholamie family caot be take orally (because of destructio by MAO ad COMT), have a brief duratio of actio (because of destructio by MAO ad COMT), ad caot cross the blood-brai barrier (because they are polar molecules). Adreergic agoists that are ocatecholamies ca be take orally, have a loger duratio tha the catecholamies, ad ca cross the blood-brai barrier. Activatio of alpha 1 receptors causes vasocostrictio ad mydriasis. Alpha 1 agoists are used for hemostasis, asal decogestio, ad elevatio of blood pressure, ad as adjucts to local aesthetics. Major adverse effects that ca result from alpha 1 activatio are hypertesio ad local ecrosis (if extravasatio occurs). Activatio of alpha 2 receptors i the periphery is of miimal cliical sigificace. I cotrast, drugs that activate alpha 2 receptors i the CNS produce useful effects (see Chapters 19 ad 28). All of the cliically relevat resposes to activatio of beta 1 receptors result from activatig beta 1 receptors i the heart. Activatio of cardiac beta 1 receptors icreases heart rate, force of cotractio, ad coductio through the AV ode. Drugs that activate beta 1 receptors ca be used to treat heart failure, AV block, ad cardiac arrest caused by asystole. Potetial adverse effects from beta 1 activatio are tachycardia, dysrhythmias, ad agia. Drugs that activate beta 2 receptors are used primarily for asthma. Pricipal adverse effects from beta 2 activatio are hyperglycemia (maily i diabetic patiets) ad tremor. Activatio of dopamie receptors dilates real blood vessels, which helps maitai real perfusio i shock. Epiephrie is a catecholamie that activates alpha 1, alpha 2, beta 1, ad beta 2 receptors. Epiephrie is the drug of choice for treatig aaphylactic shock: By activatig alpha 1, beta 1, ad beta 2 receptors, epiephrie ca elevate blood pressure, suppress glottal edema, ad couteract brochocostrictio. Epiephrie ca also be used to cotrol superficial bleedig, restart the heart after cardiac arrest, ad delay absorptio of local aesthetics. Epiephrie should ot be combied with MAO ihibitors, ad should be used cautiously i patiets takig tricyclic atidepressats. Isoprotereol is a catecholamie that activates beta 1 ad beta 2 receptors. Isoprotereol ca be used to ehace cardiac performace (by activatig beta 1 receptors) ad to treat brochospasm (by activatig beta 2 receptors). Dopamie is a catecholamie whose receptor specificity is highly dose depedet: at low therapeutic doses, dopamie acts o dopamie receptors oly; at moderate doses, dopamie activates beta 1 receptors i additio to dopamie receptors; ad at high doses, dopamie activates alpha 1 receptors alog with beta 1 receptors ad dopamie receptors. Albuterol is a ocatecholamie that produces selective activatio of beta 2 receptors. Albuterol is used to treat asthma. Because albuterol is selective for beta 2 receptors, it produces much less stimulatio of the heart tha does isoprotereol. Accordigly, albuterol ad related drugs have replaced isoprotereol for therapy of asthma. Please visit http://evolve.elsevier.com/lehe for chapterspecific NCLEX examiatio review questios. Summary of Major Nursig Implicatios EPINEPHRINE Preadmiistratio Assessmet Therapeutic Goal Epiephrie has multiple idicatios. The major use is treatmet of aaphylaxis. Other uses iclude cotrol of superficial bleedig, delay of local aesthetic absorptio, ad maagemet of cardiac arrest. Idetifyig High-Risk Patiets Epiephrie must be used with great cautio i patiets with hyperthyroidism, cardiac dysrhythmias, orgaic heart disease, or hypertesio. Cautio is also eeded i patiets with agia pectoris or diabetes ad i those receivig MAO ihibitors, tricyclic atidepressats, or geeral aesthetics. 162
CHAPTER 17 Adreergic Agoists Summary of Major Nursig Implicatios cot d Implemetatio: Admiistratio Routes Topical, ihalatio, ad pareteral (IV, IM, subq, itracardiac, itraspial). Rapid iactivatio by MAO ad COMT prohibits oral use. Admiistratio The cocetratio of epiephrie solutios varies accordig to the route of admiistratio (see Table 17 3). To avoid serious ijury, check solutio stregth to esure that the cocetratio is appropriate for the iteded route. Aspirate prior to IM ad subq admiistratio to avoid iadvertet ijectio ito a vei. Epiephrie solutios oxidize over time, causig them to tur pik or brow. Discard discolored solutios. Ogoig Evaluatio ad Itervetios Evaluatig Therapeutic Effects I patiets receivig IV epiephrie, moitor cardiovascular status cotiuously. Miimizig Adverse Effects Cardiovascular Effects. By stimulatig the heart, epiephrie ca cause agial pai, tachycardia, ad dysrhythmias. These resposes ca be reduced with a beta-adreergic blockig aget (eg, propraolol). By activatig alpha 1 receptors o blood vessels, epiephrie ca cause itese vasocostrictio, which ca result i severe hypertesio. Blood pressure ca be lowered with a alpha-adreergic blockig aget (eg, phetolamie). Necrosis. If a IV lie deliverig epiephrie becomes extravasated, ecrosis may result. Exercise care to avoid extravasatio. If extravasatio occurs, ifiltrate the regio with phetolamie to miimize ijury. Hyperglycemia. Epiephrie may cause hyperglycemia i diabetic patiets. If hyperglycemia develops, isuli dosage should be icreased. Miimizig Adverse Iteractios MAO Ihibitors ad Tricyclic Atidepressats. These drugs prolog ad itesify the actios of epiephrie. Patiets takig these atidepressats require a reductio i epiephrie dosage. Geeral Aesthetics. Whe combied with certai geeral aesthetics, epiephrie ca iduce cardiac dysrhythmias. Dysrhythmias may respod to a beta 1 -adreergic blocker. DOPAMINE Preadmiistratio Assessmet Therapeutic Goal Dopamie is used to improve hemodyamic status i patiets with shock or heart failure. Beefits derive from ehaced cardiac performace ad icreased real perfusio. Baselie Data Full assessmet of cardiac, hemodyamic, ad real status is eeded. Idetifyig High-Risk Patiets Dopamie is cotraidicated for patiets with tachydysrhythmias or vetricular fibrillatio. Use with extreme cautio i patiets with orgaic heart disease, hyperthyroidism, or hypertesio, ad i patiets receivig MAO ihibitors. Cautio is also eeded i patiets with agia pectoris ad i those receivig tricyclic atidepressats or geeral aesthetics. Implemetatio: Admiistratio Route Itraveous. Admiistratio Admiister by cotiuous ifusio, employig a meterig device to cotrol flow rate. If extravasatio occurs, stop the ifusio immediately ad ifiltrate the regio with a alpha-adreergic atagoist (eg, phetolamie). Ogoig Evaluatio ad Itervetios Evaluatig Therapeutic Effects Moitor cardiovascular status cotiuously. Icreased urie output is oe idex of success. Diuretics may complemet the beeficial effects of dopamie o the kidey. Miimizig Adverse Effects Cardiovascular Effects. By stimulatig the heart, dopamie may cause agial pai, tachycardia, or dysrhythmias. These reactios ca be decreased with a beta-adreergic blockig aget (eg, propraolol). Necrosis. If the IV lie deliverig dopamie becomes extravasated, ecrosis may result. Exercise care to avoid extravasatio. If extravasatio occurs, ifiltrate the regio with phetolamie. Miimizig Adverse Iteractios MAO Ihibitors. Cocurret use of MAO ihibitors ad dopamie ca result i severe cardiovascular toxicity. If a patiet is takig a MAO ihibitor, dopamie dosage must be reduced by at least 90%. Tricyclic Atidepressats. These drugs prolog ad itesify the actios of dopamie. Patiets receivig them may require a reductio i dopamie dosage. Geeral Aesthetics. Whe combied with certai geeral aesthetics, dopamie ca iduce dysrhythmias. These may respod to a beta 1 -adreergic blocker. Cotiued 163
CHAPTER 17 Adreergic Agoists Summary of Major Nursig Implicatios cot d DOBUTAMINE Preadmiistratio Assessmet Therapeutic Goal Improvemet of hemodyamic status i patiets with heart failure. Baselie Data Full assessmet of cardiac, real, ad hemodyamic status is eeded. Idetifyig High-Risk Patiets Use with great cautio i patiets with orgaic heart disease, hyperthyroidism, tachydysrhythmias, or hypertesio ad i those takig a MAO ihibitor. Cautio is also eeded i patiets with agia pectoris ad i those receivig tricyclic atidepressats or geeral aesthetics. Implemetatio: Admiistratio Route Itraveous. Admiistratio Admiister by cotiuous IV ifusio. Dilute cocetrated solutios prior to use. Ifusio rates usually rage from 2.5 to 10 mcg/kg/mi. Adjust the ifusio rate o the basis of the cardiovascular respose. Ogoig Evaluatio ad Itervetios Evaluatig Therapeutic Effects Moitor cardiac fuctio (heart rate, ECG), blood pressure, ad urie output. Whe possible, moitor cetral veous pressure ad pulmoary wedge pressure. Miimizig Adverse Effects Major adverse effects are tachycardia ad dysrhythmias. Moitor the ECG ad blood pressure closely. Adverse cardiac effects ca be reduced with a beta-adreergic atagoist. Miimizig Adverse Iteractios MAO Ihibitors. Cocurret use of a MAO ihibitor with dobutamie ca cause severe cardiovascular toxicity. If a patiet is takig a MAO ihibitor, dobutamie dosage must be reduced by at least 90%. Tricyclic Atidepressats. These drugs ca prolog ad itesify the actios of dobutamie. Patiets receivig them may require a reductio i dobutamie dosage. Geeral Aesthetics. Whe combied with certai geeral aesthetics, dobutamie ca cause cardiac dysrhythmias. These may respod to a beta 1 -adreergic atagoist. 164