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					  10                        Adrenomimetic Drugs
                            Tony J.-F. Lee and Robert E. Stitzel




                  DRUG LIST

         GENERIC NAME                                PAGE        GENERIC NAME                                PAGE
         Albuterol                                     105       Isoproterenol                                102
         Amphetamine                                   106       Metaraminol                                  105
         Dobutamine                                    105       Methoxamine                                  105
         Dopamine                                      103       Norepinephrine                               101
         Ephedrine                                     105       Phenylephrine                                105
         Epinephrine                                   101       Terbutaline                                  105




    The adrenomimetic drugs mimic the effects of adren-      tal structure of the catecholamines is shown in Figure
ergic sympathetic nerve stimulation on sympathetic           10.1.
effectors; these drugs are also referred to as sympatho-         The L-isomers are the naturally occurring forms
mimetic agents. The adrenergic transmitter norepineph-       of epinephrine and norepinephrine and possess consid-
rine and the adrenal medullary hormone epinephrine           erably greater pharmacological effects than do the
also are included under this broad heading. The              D-isomers. Throughout most of the world, epinephrine
adrenomimetic drugs are an important group of thera-         and norepinephrine are known as adrenaline and nora-
peutic agents that can be used to maintain blood pres-       drenaline, respectively.
sure or to relieve a life-threatening attack of acute            Noncatecholamine adrenomimetic drugs differ from
bronchial asthma. They are also present in many over-        the basic catecholamine structure primarily by having
the-counter cold preparations because they constrict         substitutions on their benzene ring.
mucosal blood vessels and thus relieve nasal congestion.

                                                             MECHANISM OF ACTION
CHEMISTRY                                                    Many adrenomimetic drugs produce responses by inter-
The adrenomimetic drugs can be divided into two ma-          acting with the adrenoceptors on sympathetic effector
jor groups on the basis of their chemical structure: the     cells. An examination of Table 9.1 reveals that sympa-
catecholamines and the noncatecholamines. The cate-          thetic effectors have activity at 1-, 2-, 1-, or 2-
cholamines include norepinephrine, epinephrine, and          adrenoreceptors or in some cases, combinations of these
dopamine, all of which are naturally occurring, and sev-     adrenoceptors. Adrenomimetic drugs vary in their affini-
eral synthetic substances, the most important of which       ties for each subgroup of adrenoceptors. Some, like epi-
is isoproterenol (isopropyl norepinephrine). The skele-      nephrine, have a high affinity for all of the adrenocep-


96
                                                     10 Adrenomimetic Drugs                                               97



                OH (para)
                                                                      An important characteristic of indirectly acting
                                                                  adrenomimetic drugs is that repeated injections or pro-
                        OH (meta)       Catechol
                                                                  longed infusion can lead to tachyphylaxis (gradually di-
                                                                  minished responses to repeated administration). This is
                                                                  a result of a gradually diminishing availability of re-
                                                                  leasable norepinephrine stores on repeated drug ad-
                 C                                                ministration. The time frame of the tachyphylaxis will
                 C                                                vary with individual agents.
                                        Ethylamine
                                                                      The actions of many indirectly acting adreno-
                 N                                                mimetic drugs are reduced or abolished by the prior ad-
                                                                  ministration of either cocaine or tricyclic antidepressant
FIGURE 10.1                                                       drugs (e.g., imipramine). These compounds can block
Skeletal structure of catecholamines.                             the adrenergic neuronal transport system and thereby
                                                                  prevent the indirectly acting drug from being taken up
                                                                  into the nerve and reaching the norepinephrine storage
tors. Others are relatively selective. For example, isopro-       vesicles. Lipophilic drugs (e.g., amphetamine), however,
terenol has a high affinity for 1- and 2-adrenoceptors             can enter nerves by diffusion and do not need mem-
but a very low affinity for -adrenoceptors; isopro-                brane transport systems.
terenol is considered a nearly pure -agonist. Nor-                    Destruction or surgical interruption of the adrener-
epinephrine has a high affinity for - and 1-adrenocep-             gic nerves leading to an effector tissue renders indirectly
tors but a relatively low affinity for 2-receptors.                acting adrenomimetic drugs ineffective because neu-
    The effect of a given adrenomimetic drug on a partic-         ronal norepinephrine is no longer available for release
ular type of effector cell depends on the receptor selectiv-      since the nerves have degenerated. Also, patients being
ity of the drug, the response characteristics of the effector     treated for hypertension with reserpine or guanethidine,
cells, and the predominant type of adrenoceptor found on          which deplete the norepinephrine stores in adrenergic
the cells. For example, the smooth muscle cells of many           neurons (see Chapter 20), respond poorly to administra-
blood vessels have only or predominantly -adrenocep-              tion of indirectly acting adrenomimetic drugs.
tors. The interaction of compounds with these adreno-                 Some adrenomimetic drugs act both directly and in-
ceptors initiates a chain of events in the vascular smooth        directly; that is, they release some norepinephrine from
muscle cells that leads to activation of the contractile          storage sites and also directly activate tissue receptors.
process. Thus, norepinephrine and epinephrine, which              Such drugs are called mixed-action adrenomimetics.
have high affinities for -adrenoceptors, cause the vas-            However, most therapeutically important adreno-
cular muscle to contract and the blood vessels to con-            mimetic drugs in humans act either directly or indirectly.
strict. Since bronchial smooth muscle contains 2-
adrenoceptors, the response in this tissue elicited by the
                                                                  Structure–Activity Relationships Among
action of 2-adrenoceptor agonists is relaxation of
                                                                  Adrenomimetic Drugs
smooth muscle cells. Epinephrine and isoproterenol,
which have high affinities for 2-adrenoceptors, cause re-          The nature of the substitutions made on the basic
laxation of bronchial smooth muscle. Norepinephrine               phenylethylamine skeleton at the para and meta positions
has a lower affinity for 2-adrenoceptors and has rela-             of the benzene ring or on the -carbon of the side chain
tively weak bronchiolar relaxing properties.                      determine whether an adrenomimetic drug will act di-
    Adrenomimetic drugs can be divided into two major             rectly or indirectly. Directly acting adrenomimetic drugs,
groups on the basis of their mechanism of action.                 which have two or more carbon atoms (e.g., isopro-
Norepinephrine, epinephrine, and some closely related             terenol) added to their amino group, are virtually pure
adrenomimetics produce responses in effector cells by               -adrenoceptor agonists. Directly acting drugs, which have
directly stimulating - or -adrenoceptors and are re-              only small substitutions on their amino groups (e.g., nor-
ferred to as directly acting adrenomimetic drugs.                 epinephrine and epinephrine), are usually -adrenocep-
    Many other adrenomimetic drugs, such as ampheta-              tor agonists, but may be -adrenoceptor agonists as well.
mine, do not themselves interact with adrenoceptors, yet          Norepinephrine has very weak actions on 2-adrenocep-
they produce sympathetic effects by releasing norepi-             tors but strong 1-adrenoceptor actions. Epinephrine has
nephrine from neuronal storage sites (vesicles). The              a high affinity for both 1- and 2-adrenoceptors.
norepinephrine that is released by these compounds                    Adrenomimetic drugs with no substitutions on their
interacts with the receptors on the effector cells. These         benzene ring (e.g., amphetamine and ephedrine) are
adrenomimetics are called indirectly acting adreno-               generally quite lipid soluble, readily cross the blood-
mimetic drugs. The effects elicited by indirectly acting          brain barrier, and can cause central nervous system
drugs resemble those produced by norepinephrine.                  (CNS) stimulation.
98                               II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM


    The structure of a particular adrenomimetic drug will                  for example contraction, secretion, relaxation, or al-
influence its susceptibility to metabolism by catechol-                     tered metabolism. The total process of converting the
O-methyltransferase (COMT) and monoamine oxidase                           action of an external signal (e.g., norepinephrine inter-
(MAO). The actions of COMT are specific for the cate-                       acting with its receptor) to a physiological response
chol structure. If either the meta or para hydroxyl group                  (e.g., vascular smooth muscle contraction) is called sig-
is absent, COMT will not metabolize the drug. The pres-                    nal transduction.
ence of a substitution, such as a methyl group, on the -                       Following the binding of the agonist (the first mes-
carbon of the side chain reduces the affinity of the                        senger) to its appropriate receptor on the external sur-
adrenomimetic drug for MAO. Also, drugs with a large                       face of the effector cell, a second messenger is generated
substitution on the terminal nitrogen will not be de-                      (or synthesized) and participates in a particular series of
graded by MAO. A noncatecholamine that has a methyl                        biochemical reactions that ultimately result in the gen-
group attached to its -carbon will not be metabolized                      eration of a specific physiological response by that cell
by either enzyme and will have a greatly prolonged du-                     (Figs. 10.2 and 10.3). For both - and -adrenoceptors,
ration of action (e.g., amphetamine).                                      the signal transduction process seems to involve the
                                                                           participation of G proteins (see Chapter 2).
                                                                               The specific second-messenger pathways constitute a
The Role of Second Messengers in                                           highly versatile signaling system that can modify (stimu-
Receptor-mediated Responses                                                late or inhibit) numerous cellular processes including
The adrenomimetic drugs, including the naturally oc-                       secretion, contraction and relaxation, metabolism, neu-
curring catecholamines, initiate their responses by com-                   ronal excitability, cell growth, and apoptosis. The sec-
bining with -, -, or dopamine adrenoceptors. This in-                      ond messengers that participate in signal transduction
teraction triggers a series of biochemical events starting                 include cyclic adenosine monophosphate (cAMP),
within the effector cell membrane that eventually cul-                     diacylglycerol, and inositol triphosphate. Once liberated
minates in the production of a physiological response,                     within the cell, second messengers will activate specific


                                         Catecholamine
      Calcium                                                         Adenylyl
      channel                                –adrenoceptor            cyclase


                                                                                               Cell
                        GS                       GS                                            Membrane
                      protein                  protein


                                                                                                       phosphorylation
                                                                                                       of other proteins
                                                         ATP           Cyclic AMP                      (e.g., ion channels)
                       phosphorylation

                                                        Protein              Protein            Protein
                                                        kinaseA              kinaseA            kinaseA



                                         phosphorylation                           phosphorylation



                                             Inactive             Active               Phosphory-         Phosphory-
                                              lipase              lipase                 lase b             lase a


                                                          Fat                 Free                  Glycogen             Glucose - 1 - PO4
                                                                           fatty acids


                                                                                                                    Glucose           Lactate
                                                                                                                     (liver)         (muscle)

FIGURE 10.2
The role of cyclic 3 ,5 -adenosine monophosphate (cAMP) as a second messenger in the actions
                                           ,
of catecholamines acting on -receptors. ATP adenosine triphosphate.
                                                                                                                         Catecholamines
                                                                     Ca2 channel


                                                                                                            Phospholipase C
                                                                                                                      G-protein          1-adrenoceptor

                                         e
                                   ran
                          e   mb
                Ce   ll m

                                                                                              Ptdins 4, 5 P2

                                                                                                                                          DAG        OH
                                                                                                                                          Ca2                Pro
                                                                                                                                                           kin tein
                                                              um                                P                                                             ase
                                                                                                                                                                  C
                                                      i   cu l                                                                P
                                            c   ret                                                                                                                   Ser
                                                                                                                                                                            ine
                                         mi                                 Ca2 store     P
                                     plas                                                        P      P                           P




                            do
                                                                                                                              P




                          En
                                                                                        Ins 1, 3, 4, 5 P4              Ins 1, 4, 5 P3                                   Protein




                                                                                                                                                     Protein-P              Metabolism
                                                                   Ca2   Calmodulin                                                                                         Secretion
                                                                                                                                                                                                    10 Adrenomimetic Drugs




                                                                                                                                                                            Contraction
                                                                                                                                                                            Synaptic transmission
                                                                                                                                                     Protein-P              Cell growth




                                                                                                     Protein   Ca2     Calmodulin       Kinase

FIGURE 10.3
The role of diacylglycerol (DAG) and inositol triphosphate (Ins 1,4,5 P3) as second messengers linked to agonist-receptor ( 1-adrenoceptor) interactions. Ptdins 4,5 P2 is
a phosphatidylinositol precursor in cell membranes that is hydrolyzed following receptor activation to form the two second messengers, Ins 1,4,5 P3 and DAG. Once
liberated within the cell, these second messengers activate separate but interacting pathways. Ins 1,4,5 P3 releases Ca stored in cells and can be phosphorylated to
form a tetraphosphate (Ins 1,3,4,5 P4), which can open Ca channels in the membrane. DAG triggers protein phosphorylation through the activation of protein kinase
C. Ca -induced activation of the enzyme calmodulin also phosphorylates protein. Adenylyl cyclase traverses the membrane. Cyclic AMP–dependent protein kinase can
phosphorylate and inactivate the -adrenoceptors. This kinase may have a role in homologous desensitization of Gs-protein–coupled -adrenoceptors. -Receptor
stimulation can (1) activate Ca channels through an action of Gs proteins without the participation of cAMP and (2) affect other ion channels through phosphorylation
via kinases. (Modified from Berridge MJ. Inositol triphosphate and diacylglycerol: Two interacting second messengers. ISI Atlas of Science: Pharmacology, 1:91, 1987.)
                                                                                                                                                                                                    99
100                                      II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM


signal pathways. For example, inositol triphosphate                                   affinities possessed by the catecholamines for - and
functions by mobilizing calcium from intracellular stores                               -adrenoceptors and to differences in the relative dis-
or opening channels; the calcium can be used to initi-                                tribution of the receptors in a particular vascular bed.
ate vascular smooth muscle contraction, probably                                      The hemodynamic responses of the major vascular beds
through a protein phosphorylation pathway (Fig. 10.3).                                to these amines are shown in Table 10.2.
Diacylglycerol is known to stimulate an enzyme, protein                                    The blood vessels of the skin and mucous mem-
kinase C, that phosphorylates specific intracellular pro-                              branes predominantly contain -adrenoceptors. Both
teins, some of which regulate ionic mechanisms such as                                epinephrine and norepinephrine produce a powerful
the Na /H exchanger and potassium channels.                                           constriction in these tissues, substantially reducing
    The basic features of the signaling system found in                               blood flow through them. Isoproterenol, which is almost
different cells are remarkably similar. It appears that                               a pure -adrenoceptor agonist, has little effect on the
protein phosphorylation is a final common pathway in                                   vasculature of the skin and mucous membranes. The
the molecular mechanisms through which neurotrans-                                    blood vessels in visceral organs, including the kidneys,
mitters, hormones, and the nerve impulse produce many                                 contain predominantly -adrenoceptors, although some
of their biological effects in target cells.                                            2-adrenoceptors are also present. Consequently, epi-
                                                                                      nephrine and norepinephrine cause vasoconstriction
PHARMACODYNAMIC ACTIONS OF                                                            and reduced blood flow through the kidneys and other
NOREPINEPHRINE, EPINEPHRINE,                                                          visceral organs. Isoproterenol produces either no effect
AND ISOPROTERENOL                                                                     or weak vasodilation.
                                                                                           The blood vessels in skeletal muscle contain both -
                                                                                      and 2-adrenoceptors. Norepinephrine constricts these
Vascular Effects                                                                      blood vessels and reduces blood flow through an inter-
The cardiovascular effects of norepinephrine, epineph-                                action with -adrenoceptors. Isoproterenol dilates the
rine, and isoproterenol are shown in Table 10.1.                                      vessels in skeletal muscle and consequently increases
Differences in the action of these three catecholamines                               blood flow through the tissue by interaction with the
on various vascular beds are due both to the different                                  2-adrenoceptors. Epinephrine has a more complex ac-




      TA B L E        1 0 . 1 Cardiovascular Effects of Catecholamines in Humans (in therapeutic doses of
                                   0.1-0.4 g/kg/min IV or 0.5–1.0 mg SC)

      Cardiovascular function                                    Epinephrine                         Norepinephrine                         Isoproterenol

      Systolic blood pressure                                                                                                                     0
      Diastolic blood pressure
      Mean blood pressure                                              0
      Total peripheral resistance
      Heart rate (chronotropic effect)
      Stroke output (inotropic effect)
      Cardiac output                                                                                          0

      Key: 0   no effect;     increased;            decreased. The number of symbols indicates the approximate magnitude of the response.




      TA B L E        1 0 . 2 Response of the Major Vascular Beds to Usual Doses of the Catecholamines

      Vascular bed                          Receptor type*                 Norepinephrine              Epinephrine                  Isoproterenol

      Cutaneous blood vessels                                              Constriction                Constriction                  None
      Visceral blood vessels                                               Constriction                Constriction                  None (weak dilation)
      Renal blood vessels                                                  Constriction                Constriction                  None (weak dilation)
      Coronary blood vessels                    ,                          Dilation                    Dilation                      Dilation
      Skeletal muscle blood vessels             ,       2
                                                                           Constriction                Dilation                      Dilation
      Pial blood vessels                        ,       1
                                                                           Constriction/dilation       Constriction/dilation         Dilation

      *While virtually all blood vessels have       -receptors, some also have
                                                    1                             -receptors. Stimulation of either subtype generally results in vasocon-
                                                                                  2
      striction.
                                                 10 Adrenomimetic Drugs                                              101


tion on these blood vessels because of its high affinity            The net effect of norepinephrine administration on
for both - and 2-adrenoceptors. Whether epinephrine           heart rate and ventricular contractile force therefore
produces vasodilation or vasoconstriction in skeletal         varies with the dose of norepinephrine, the physical ac-
muscle depends on the dose administered. Low doses of         tivity of the subject, any prior cardiovascular and baro-
epinephrine will dilate the blood vessels; larger doses       receptor pathology, and the presence of other drugs that
will constrict them.                                          may alter reflexes.
    Although several factors can influence the flow of               In a normal resting subject who is receiving no
blood through the coronary vessels, the most important        drugs, there is a moderate parasympathetic tone to the
of these is the local production of vasodilator metabolites   heart, and sympathetic activity is relatively low. The
that results from stimulation-induced increased work by       ventricular muscle receives little, if any, parasympathetic
the heart. -Adrenoreceptors and -adrenoceptors in             innervation. As the blood pressure rises in response to
the coronary vascular beds do not play a major role in        norepinephrine, the baroreceptor reflex is activated,
determining the vasodilator effects of the administra-        parasympathetic impulses (which are inhibitory) to the
tion of epinephrine or norepinephrine.                        heart increase in frequency, and what little sympathetic
                                                              outflow there is may be reduced. Heart rate is slowed so
                                                              much that the direct effect of norepinephrine to in-
Effects on the Intact Cardiovascular System
                                                              crease the rate is masked and there is a net decrease in
An increase in sympathetic neuronal activity causes an        rate. Under the conditions described, however, the im-
increase in heart rate (positive chronotropic effect, or      pact of the reflex on the ventricles is very slight because
tachycardia) and an increase in cardiac contractile force     there is no parasympathetic innervation and the preex-
(positive inotropic effect) such that the stroke output is    isting level of sympathetic activity is already low. A fur-
increased. Cardiac output, which is a function of rate        ther decrease in sympathetic activity therefore would
and stroke output, is thus increased. A physiological in-     have little further effect on contractility in this subject.
crease in sympathetic tone is almost always accompanied       Thus, a decrease in heart rate and an increase in stroke
by a diminution of parasympathetic vagal tone; this al-       volume will occur, and cardiac output will change very
lows full expression of the effects of increased sympa-       little.
thetic tone on the activity of the heart.                          The reflex nature of the bradycardia induced by
    An increase in sympathetic tone constricts blood          parenterally administered norepinephrine can readily
vessels in most vascular beds and therefore causes a net      be demonstrated by administration of atropine, a choli-
increase in total peripheral resistance. Increased sympa-     noreceptor antagonist. Atropine abolishes the com-
thetic tone increases neural release of norepinephrine        pensatory vagal reflexes. Under conditions of vagal
and its interaction both with -adrenoceptors on car-          blockade, the direct cardiac stimulatory effects of nor-
diac cells and with -adrenoceptors on vascular smooth         epinephrine are unmasked. There is marked tachycar-
muscle cells. As a consequence, the systolic and diastolic    dia, an increase in stroke volume, and as a consequence,
blood pressures are elevated. It follows that the mean        a marked increase in cardiac output (Fig. 10.4).
arterial blood pressure must also be increased.
                                                                  Epinephrine
    Norepinephrine                                                A small dose of epinephrine causes a fall in mean
    Norepinephrine, administered to a normotensive            and diastolic pressure with little or no effect on systolic
adult either subcutaneously or by slow intravenous in-        pressure. This is due to the net decrease in total periph-
jection, constricts most blood vessels. Venules as well as    eral resistance that results from the predominance of
arterioles are constricted. As a consequence, there is a      vasodilation in the skeletal muscle vascular bed. The in-
net increase in the total peripheral resistance.              travenous infusion or subcutaneous administration of
    The effects of norepinephrine on cardiac function         epinephrine in the range of doses used in humans gen-
are complex because of the dynamic interaction of the         erally increases the systolic pressure, but the diastolic
direct effects of norepinephrine on the heart and the         pressure is decreased. Therefore, the mean pressure
initiation of powerful cardiac reflexes. The baroreceptor      may decrease, remain unchanged, or increase slightly,
reflexes are discussed in detail in Chapter 9.                 depending on the balance between the rise in systolic
    Important considerations are as follows: (1) The di-      and fall in diastolic blood pressures (Fig. 10.4).
rect effect of norepinephrine on the heart is stimulatory.        The cardiac effects of epinephrine are due to its ac-
(2) The reflex initiated is inhibitory, that is, opposite to   tion on -adrenoceptors in the heart. The rate and con-
the direct effect. (3) The reflex varies with the level of     tractile force of the heart are increased; consequently,
sympathetic and parasympathetic activity just before          cardiac output is markedly increased. Because total pe-
the initiation of the reflex. (4) The distribution of sym-     ripheral resistance is decreased, the increase in cardiac
pathetic and parasympathetic nerves is not uniform in         output is largely responsible for the increase in systolic
the heart.                                                    pressure. Since epinephrine causes little change in the
102                                        II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM


                                           Norepinephrine   Epinephrine          Isoproterenol        Dopamine




                    Pulse rate
                                     100




                      (min)
                                     50



                    Blood pressure
                                     180

                      (mm Hg)
                                     150
                                     120
                                      90
                                      60
                                                10 g/min                                             0.5 mg/min
                                                            10 g/min              10 g/min
                             Peripheral
                             resistance




                                            0          15   0        15        0            15       0        15
                                                                      Time (min)

FIGURE 10.4
Cardiovascular effects of infusion of norepinephrine, epinephrine, isoproterenol, and dopamine in
humans. Infusions were made intravenously during the time indicated by the broken lines. Heart
rate is given in beats per minute, blood pressure in millimeters of mercury, and peripheral
resistance in arterial blood pressure. (Reprinted with permission from Allwood MJ, Cobbald AF,
and Ginsburg J. Peripheral vascular effects of noradrenaline, isopropyl-noradrenaline, and
dopamine. Br Med Bull 19:132, 1963. Reproduced by permission of the Medical Department,
The British Council.


mean arterial blood pressure, reflex slowing of the heart                  messenger system. This system plays an important role
is usually not seen in humans.                                            in the regulation of blood pressure and vascular tone.
                                                                               Vascular endothelium also plays an important role in
    Isoproterenol                                                         maintaining vascular tone.The endothelium can modulate
    Slow intravenous infusion of therapeutic doses of                     both vasodilation and vasoconstriction through its ability
isoproterenol in humans produces a marked decrease in                     to locally synthesize and release vasodilators such as nitric
total peripheral resistance, owing to the predominance                    oxide, endothelium-derived hyperpolarizing factor, and
of vasodilation in skeletal muscle vascular beds. As a                    PGI2, and vasoconstrictors such as endothelin, which in
consequence, diastolic and mean blood pressures fall                      turn directly affect vascular smooth muscle activity.
(Fig. 10.4). The depressor action of isoproterenol is more                Stimulation of 2-adrenoceptors located on the endothe-
pronounced than that of epinephrine because isopro-                       lial cells in certain vascular beds (such as the coronary ar-
terenol causes no vasoconstriction, whereas epinephrine                   tery) results in the release of nitric oxide and vasodilation.
does in some vascular beds. Systolic blood pressure may                        In any blood vessel, the final integrated response to
remain unchanged or may increase. When an increase in                     either neuronally released norepinephrine or to circu-
systolic blood pressure is seen, it is due to the marked in-              lating epinephrine probably depends on the relative
crease in cardiac output produced by isoproterenol.                       participation of at least four populations of -adreno-
    Isoproterenol usually increases the heart rate and                    ceptors: postjunctional 1- and 2-adrenoceptors medi-
stroke volume more than does epinephrine. This is                         ate constriction of vascular smooth muscle, while pre-
partly due to its ability to decrease mean blood pres-                    junctional and endothelial 2-adrenoceptors mediate
sure, which then reflexively diminishes vagal activity,                    vasodilation. An understanding of the vessel vascular
and partly to its action on the heart.                                    response to adrenomimetic drugs also must include the
                                                                          effects of drugs on adventitial innervation, smooth mus-
                                                                          cle, and other vascular factors that may be present.
Effects on Vascular Smooth Muscle
Postjunctional 1-adrenoceptors are always found in
                                                                          Effects on Nonvascular Smooth Muscle
veins, arteries, and arterioles. Activation of these recep-
tors results in the entry of extracellular calcium through                In general, the responses to administered catechol-
receptor-operated channels and in the release of intra-                   amines are similar to those seen after sympathetic nerve
cellularly stored calcium; this is brought about through                  stimulation and depend on the type of adrenoceptor in
the participation of the inositol triphosphate second-                    the muscle.
                                                 10 Adrenomimetic Drugs                                              103


    Bronchial smooth muscle is relaxed by epinephrine         bolic processes. Most of these are mediated through an
and isoproterenol through their interaction with 2-           interaction with -adrenoceptors. Norepinephrine is
adrenoceptors. Epinephrine and isoproterenol are po-          usually effective only in large doses. Epinephrine and
tent bronchodilators, while norepinephrine has a rela-        isoproterenol in therapeutic doses increase oxygen con-
tively weak action in this regard (see Chapter 39).           sumption by 20 to 30%. Endogenous epinephrine se-
    Smooth muscle of the gastrointestinal tract is gener-     creted by the adrenal medulla in response to stress such
ally relaxed by catecholamines, but this may depend on        as exercise increases blood levels of glucose, lactic acid,
the existing state of muscle tone. Usually motility of the    and free fatty acids.
gut is reduced by catecholamines while the gastroin-              Epinephrine, the most potent stimulant of hepatic
testinal sphincters are contracted. Catecholamines ap-        glycogenolysis, gives rise to glucose, which readily en-
pear to produce relaxation of the gut through an action       ters the circulation; isoproterenol produces relatively
on 2-adrenoceptors on ganglionic cells. Activation of         weak hyperglycemia. Administration of both - and
these receptors reduces acetylcholine release from              -adrenoceptor blocking agents is necessary for com-
cholinergic neurons. Catecholamines also may produce          plete antagonism of glycogenolysis in this tissue.
gastrointestinal relaxation through an action on 2-               Isoproterenol is the most potent stimulant of skele-
adrenoceptors on smooth muscle cells. Contraction of          tal muscle glycogenolysis, followed by epinephrine
the sphincters occurs through an action on 1-adreno-          and norepinephrine. 2-Adrenoceptors mediate muscle
ceptors. These effects are quite transient in humans and      glycogenolysis. Stimulation of skeletal muscle glyco-
therefore have no therapeutic value.                          genolysis will raise blood lactic acid levels rather than
    The radial (dilator) muscle of the iris contains -        blood glucose levels because skeletal muscle lacks the
adrenoceptors. Epinephrine and norepinephrine cause           enzyme glucose-6-phosphatase, which catalyzes the
dilation of the pupil (mydriasis) by contracting the dila-    conversion of glucose-6-phosphate to glucose.
tor muscle.                                                       The release of free fatty acids from adipose tissue
    Uterine muscle contains both - and -adrenocep-            (lipolysis) is mediated through 3-adrenoceptors. Iso-
tors, which mediate contraction and relaxation, respec-       proterenol is the most potent agonist, followed by epi-
tively. The response of the human uterus to cate-             nephrine and norepinephrine.
cholamines is variable and depends on the endocrine
balance of the individual at the time of amine adminis-
tration (see Chapter 62). During the last stage of preg-      Potassium Homeostasis
nancy and during parturition, epinephrine inhibits the        The catecholamines can play an important role in the
uterine muscle, as does isoproterenol; norepinephrine         short-term regulation of plasma potassium levels.
contracts the uterus.                                         Stimulation of hepatic -adrenoceptors will result in the
    The detrusor muscle (which contains 2-adrenocep-          release of potassium from the liver. In contrast, stimula-
tors) in the body of the urinary bladder is relaxed by        tion of 2-adrenoceptors, particularly in skeletal muscle,
epinephrine and isoproterenol. On the other hand, the         will lead to the uptake of potassium into this tissue. The
trigone and sphincter (which contain 1-receptors) are           2-adrenoceptors are linked to the enzyme Na , K
contracted by norepinephrine and epinephrine; this ac-        adenosine triphosphatase (ATPase). Excessive stimula-
tion inhibits the voiding of urine.                           tion of these 2-adrenoceptors may produce hy-
                                                              pokalemia, which in turn can be a cause of cardiac ar-
Central Nervous System Effects                                rhythmias.

Epinephrine, in therapeutic doses, mildly stimulates the
CNS. The most noticeable features of this stimulation
                                                              PHARMACOLOGICAL ACTIONS
are apprehension, restlessness, and increased respira-
                                                              OF DOPAMINE
tion. In therapeutic doses both isoproterenol and nor-
epinephrine also have minor CNS stimulant properties.         Dopamine is a naturally occurring catecholamine; it is
Since these compounds do not easily cross the blood-          the immediate biochemical precursor of the norepi-
brain barrier, the mechanism of their stimulatory effects     nephrine found in adrenergic neurons and the adrenal
is not clear. It is likely that the stimulating effects are   medulla. It is also a neurotransmitter in the CNS, where
primarily, if not entirely, due to actions in the periphery   it is released from dopaminergic neurons to act on spe-
that alter the neural input to the CNS.                       cific dopamine receptors (see Chapter 31).
                                                                   Dopamine is a unique adrenomimetic drug in that it
                                                              exerts its cardiovascular actions by (1) releasing norepi-
Metabolic Effects                                             nephrine from adrenergic neurons, (2) interacting with
The catecholamines, primarily epinephrine and isopro-           -and 1-adrenoceptors, and (3) interacting with spe-
terenol, exert a number of important effects on meta-         cific dopamine receptors.
104                               II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM


    The cardiovascular response to dopamine in hu-              useful in the therapy of urticaria, angioneurotic edema,
mans depends on the concentration infused. Low rates            and serum sickness.
of dopamine infusion can produce vasodilation in the                Epinephrine also has been used to lower intraocular
renal, mesenteric, coronary, and intercerebral vascular         pressure in open-angle glaucoma. Its use promotes an
beds with little effect on other blood vessels or on the        increase in the outflow of aqueous humor. Because epi-
heart. The vasodilation produced by dopamine is not             nephrine administration will decrease the filtration an-
antagonized by the -adrenoceptor blocking agent pro-            gle formed by the cornea and the iris, its use is con-
pranolol but is antagonized by haloperidol and other            traindicated in angle-closure glaucoma; under these
dopamine receptor–blocking agents.                              conditions the outflow of aqueous humor via the filtra-
    Dopamine can exert pronounced cardiovascular                tion angle and into the venous system is hindered, and
and renal effects through the activation of both D1- and        intraocular pressure may rise abruptly.
D2-receptor subtypes. Stimulation of the D1-receptor,               The vasoconstrictor actions of epinephrine and nor-
which is present on blood vessels and certain other pe-         epinephrine have been used to prolong the action of lo-
ripheral sites, will result in vasodilation, natriuresis, and   cal anesthetics by reducing local blood flow in the re-
diuresis. D2-receptors are found on ganglia, on sympa-          gion of the injection. Epinephrine has been used as a
thetic nerve terminals, on the adrenal cortex, and within       topical hemostatic agent for the control of local hemor-
the cardiovascular centers of the CNS; their activation         rhage. Norepinephrine is infused intravenously to com-
produces hypotension, bradycardia, and regional va-             bat systemic hypotension during spinal anesthesia or
sodilation (e.g., renal vasodilation). The kidney appears       other hypotensive conditions in which peripheral resist-
to be a particularly rich source for endogenous                 ance is low, but it is not used to combat the hypotension
dopamine in the periphery.                                      due to most types of shock. In shock, marked sympa-
    The infusion of moderately higher concentrations of         thetic activity is already present, and perfusion of or-
dopamine increases the rate and contractile force of the        gans, such as the kidneys, may be jeopardized by norepi-
heart and augments the cardiac output. This action is           nephrine administration.
mediated by 1-adrenoceptors and norepinephrine re-                  Dopamine is used in the treatment of shock owing
lease and is antagonized by propranolol. In contrast to         to inadequate cardiac output (cardiogenic shock),
isoproterenol, which has a marked effect on both the            which may be due to myocardial infarction or conges-
rate and the contractile force of the heart, dopamine has       tive heart failure. It is also used in the treatment of
a greater effect on the force than on cardiac rate. The         septic shock, since renal circulation is frequently com-
advantage of this greater inotropic than chronotropic           promised in this condition. An advantage of using
effect of dopamine is that it produces a smaller increase       dopamine in the treatment of shock is that its in-
in oxygen demand by the heart than does isoproterenol.          otropic action increases cardiac output while dilating
Systolic blood pressure is increased by dopamine,               renal blood vessels and thereby increasing renal blood
whereas diastolic pressure is usually not changed signif-       flow.
icantly. Total peripheral resistance is decreased because
of the vasodilator effect of dopamine (Fig. 10.4).
    At still higher concentrations, dopamine causes
                                                                Adverse Effects
  -adrenoceptor-mediated vasoconstriction in most vas-          Because they increase the force of the heartbeat, all
cular beds and stimulates the heart. Total peripheral re-       three catecholamines may produce an excessively rapid
sistance may be increased. If the concentration of              heart rate. Palpitations produced by epinephrine and
dopamine reaching the tissue is high enough, vasocon-           isoproterenol are accompanied by tachycardia, whereas
striction of the renal and mesenteric beds also occurs.         those produced by norepinephrine usually are accom-
The vasoconstrictive action of dopamine is antagonized          panied by bradycardia owing to reflex slowing of the
by -adrenoceptor blocking agents such as phentol-               heart. Headache and tremor are also common.
amine.                                                          Epinephrine is especially likely to produce anxiety, fear,
                                                                and nervousness.
                                                                    The greatest hazards of accidental overdosage with
                                                                epinephrine and norepinephrine are cardiac arrhyth-
CLINICAL USES OF CATECHOLAMINES                                 mias, excessive hypertension, and acute pulmonary
The clinical uses of catecholamines are based on their          edema. Large doses of isoproterenol can produce such
actions on bronchial smooth muscle, blood vessels, and          excessive cardiac stimulation, combined with a decrease
the heart. Epinephrine is also useful for the treatment         in diastolic blood pressure, that coronary insufficiency
of allergic reactions that are due to liberation of hista-      may result. It also may cause arrhythmias and ventricu-
mine in the body, because it produces certain physio-           lar fibrillation. Tissue sloughing and necrosis due to se-
logical effects opposite to those produced by histamine.        vere local ischemia may follow extravasation of norepi-
It is the primary treatment for anaphylactic shock and is       nephrine at its injection site.
                                                 10 Adrenomimetic Drugs                                                 105


OTHER ADRENOMIMETIC AGENTS                                     damage has occurred from injudicious use of the nasal
                                                               spray. It is also employed in ophthalmology as a mydri-
A number of adrenomimetic amines are not cate-                 atic agent. Phenylephrine, however, should not be given
cholamines. Some of these are directly acting amines           to patients with closed-angle glaucoma before iridec-
that must interact with adrenoceptors to produce a re-         tomy, since further increases in intraocular pressure
sponse in effector tissues. Some directly acting com-          may result. In dentistry, phenylephrine is used to pro-
pounds, such as phenylephrine and methoxamine, acti-           long the effectiveness of a local anesthetic.
vate     -adrenoceptors almost exclusively, whereas
others, like albuterol and terbutaline, are nearly pure -
                                                               Dobutamine
adrenoceptor agonists. Drugs that exert their pharma-
cological actions by releasing norepinephrine from its         Dobutamine (Dobutrex), in contrast to dopamine, does
neuronal stores (indirectly acting) produce effects that       not produce a significant proportion of its cardiac effects
are similar to those of norepinephrine. They tend to ex-       through the release of norepinephrine from adrenergic
ert strong -adrenoceptor activity, but 1-adrenoceptor          nerves; dobutamine acts directly on 1-adrenoceptors in
activity typical of norepinephrine, such as myocardial         the heart. Dobutamine exerts a greater effect on the
stimulation, also occurs.                                      contractile force of the heart relative to its effect on the
     Some of the indirectly acting adrenomimetic amines        heart rate than does dopamine. Dobutamine increases
are used primarily for their vasoconstrictive properties.      the oxygen demands on the heart to a lesser extent than
They are applied locally to the nasal mucosa or to the         does dopamine. Like dopamine, although at higher
eye. Other amines are used as bronchodilators, while           doses, it produces vasodilation of renal and mesenteric
still others are used exclusively for their ability to stim-   blood vessels. Dobutamine may be more useful than
ulate the CNS. Many noncatecholamine adrenomimetic             dopamine in the treatment of cardiogenic shock.
amines resist enzymatic destruction, have prolonged ac-
tions, and are orally effective. The indirectly acting         Terbutaline and Albuterol
drugs are effective only when given in large doses, and
they often produce tachyphylaxis.                              Terbutaline and albuterol are relatively selective 2-
                                                               adrenoceptor agonists. Both have a longer duration of
                                                               action than isoproterenol because they are not metabo-
Directly Acting Adrenomimetic Drugs                            lized by COMT. Like isoproterenol, they are not me-
Phenylephrine, Metaraminol, and Methoxamine                    tabolized by MAO and are not transported into adren-
                                                               ergic neurons. Terbutaline and albuterol are effectively
These drugs are directly acting adrenomimetic amines           administered either orally or subcutaneously. Because
that exert their effects primarily through an action on        of their selectivity for 2-adrenoceptors, they produce
  -adrenoceptors. Consequently, these agents have little       less cardiac stimulation than does isoproterenol but are
or no direct action on the heart. All three drugs increase     not completely without effects on the heart.
both systolic and diastolic blood pressures through their          Therapeutically, terbutaline and albuterol are used
vasoconstrictor action. The pressor response is accom-         to treat bronchial asthma and bronchospasm associated
panied by reflex bradycardia, no change in the contrac-         with bronchitis and emphysema (see Chapter 39).
tile force of the heart, and little change in cardiac out-         Side effects include nervousness, tremor, tachycar-
put. They do not precipitate cardiac arrhythmias and do        dia, palpitations, headache, nausea, vomiting, and sweat-
not stimulate the CNS.                                         ing. The frequency of appearance of these adverse ef-
    Phenylephrine is not a substrate for COMT, while           fects is minimized, however, when the drugs are given
metaraminol and methoxamine are not metabolized by             by inhalation.
either COMT or MAO. Consequently, their duration of
action is considerably longer than that of norepineph-
                                                               Indirectly Acting Adrenomimetic Drugs
rine. Following intravenous injection, pressor responses
                                                               Ephedrine
to phenylephrine may persist for 20 minutes, while pres-
sor responses to metaraminol and methoxamine may               Ephedrine is a naturally occurring alkaloid that can cross
last for more than 60 minutes.                                 the blood-brain barrier and thus exert a strong CNS-stim-
    The clinical uses of these drugs are associated with       ulating effect in addition to its peripheral actions. The lat-
their potent vasoconstrictor action. They are used to re-      ter effects are primarily due to its indirect actions and de-
store or maintain blood pressure during spinal anesthe-        pend largely on the release of norepinephrine. However,
sia and certain other hypotensive states. The reflex            ephedrine may cause some direct receptor stimulation,
bradycardia induced by their rapid intravenous injec-          particularly in its bronchodilating effects. Because it re-
tion has been used to terminate attacks of paroxysmal          sists metabolism by both COMT and MAO, its duration
atrial tachycardia. Phenylephrine is commonly used as a        of action is longer than that of norepinephrine. As is the
nasal decongestant, although occasional nasal mucosal          case with all indirectly acting adrenomimetic amines,
106                             II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM


ephedrine is much less potent than norepinephrine; in         insomnia, nervousness, nausea, vomiting, and emotional
addition, tachyphylaxis develops to its peripheral actions.   disturbances may develop. Ephedrine should not be
Unlike epinephrine or norepinephrine, however, ephe-          used in patients with cardiac disease, hypertension, or
drine is effective when administered orally.                  hyperthyroidism.

    Pharmacological Actions                                   Amphetamine
    Ephedrine increases systolic and diastolic blood
                                                              Amphetamine is an indirectly acting adrenomimetic
pressure; heart rate is generally not increased.
                                                              amine that depends for its action on the release of nor-
Contractile force of the heart and cardiac output are
                                                              epinephrine from noradrenergic nerves. Its pharmaco-
both increased. Ephedrine produces bronchial smooth
                                                              logical effects are similar to those of ephedrine; how-
muscle relaxation of prolonged duration when adminis-
                                                              ever, its CNS stimulant activity is somewhat greater.
tered orally. Aside from pupillary dilation, ephedrine
                                                              Both systolic and diastolic blood pressures are increased
has little effect on the eye.
                                                              by oral dosing with amphetamine. The heart rate is fre-
                                                              quently slowed reflexively. Cardiac output may remain
    Clinical Uses
                                                              unchanged in the low- and moderate-dose range.
    Ephedrine is useful in relieving bronchoconstriction
                                                                  The therapeutic uses of amphetamine are based on
and mucosal congestion associated with bronchial
                                                              its ability to stimulate the CNS. The D-isomer (dex-
asthma, asthmatic bronchitis, chronic bronchitis, and
                                                              troamphetamine) is three to four times as potent as the
bronchial spasms. It is often used prophylactically to
                                                              L-isomer in producing CNS effects. It has been used in
prevent asthmatic attacks and is used as a nasal decon-
                                                              the treatment of obesity because of its anorexic effect,
gestant, as a mydriatic, and in certain allergic disorders.
                                                              although tolerance to this effect develops rapidly. It
Although its bronchodilator action is weaker than that
                                                              prevents or overcomes fatigue and has been used as a
of isoproterenol, its oral effectiveness and prolonged
                                                              CNS stimulant. Amphetamine is no longer recom-
duration of action make it valuable in the treatment of
                                                              mended for these uses because of its potential for abuse.
these conditions. Because of their oral effectiveness and
                                                              Amphetamine is useful in certain cases of narcolepsy or
greater bronchiolar selectivity, terbutaline and albuterol
                                                              minimal brain dysfunction.
are replacing ephedrine for bronchodilation.
                                                                  Further discussion of amphetamine can be found in
                                                              Chapters 29 and 35.
   Adverse Effects
   Symptoms of overdose are related primarily to car-
diac and CNS effects. Tachycardia, premature systoles,



      Study Questions


1. Selective 2-agonists, such as terbutaline                     (C) Decreases peripheral resistance through stimu-
   (A) Have shorter durations of action than cate-               lation of 1-receptors on the vascular smooth mus-
   cholamines when taken orally                                  cle cells.
   (B) Have stronger cardiac stimulant effects than              (D) Decreases peripheral resistance through 2-
   epinephrine                                                   adrenoceptor stimulation predominantly in skeletal
   (C ) Can be taken orally because these agents are             muscle vascular beds.
   not degraded by COMT                                       4. The pressor response to amphetamine is
   (D) Are definitely no better than methylxanthines              (A) Decreased in the presence of a monoamine ox-
   for asthmatic patients who are hypertensive.                  idase (MAO) inhibitor.
2. Which drug does not induce mydriasis?                         (B) Potentiated by a reuptake inhibitor, such as co-
   (A) Phenylephrine                                             caine
   (B) Cocaine                                                   (C) Associated with marked tolerance (tachyphy-
   (C) Phentolamine                                              laxis)
   (D) Norepinephrine                                            (D) Potentiated by pretreatment with reserpine
   (E) Ephedrine                                              5. When phenylephrine is administered by slow infu-
3. Epinephrine given in small therapeutic doses                  sion of the therapeutic dose, which is the most likely
   (A) Increases systolic blood pressure through 2 re-           effect illustrated in the following table: increase (↑);
   ceptor stimulation in the left ventricle                      decrease (↓); no change (0)?
   (B) Decreases heart rate reflexively.
                                                10 Adrenomimetic Drugs                                               107




                                                       Heart Rate Effect

                    Blood Pressure (total
                    peripheral resistance)          Reflex (via baroreceptor)          Direct           Reflex and Direct

     (A)                      ↑                                ↓                        ↑                   ↑ or ↓
     (B)                      ↑                                ↓                        0                     ↓
     (C)                      ↓                                ↑                        ↑                   ↑ or ↓



ANSWERS
1. C. Structural modification by placing the hydroxy           5. B. Phenylephrine is an 1-selective agonist. It
   groups at positions 3 and 5 of the phenyl ring has            causes an increase in peripheral vascular resistance.
   resulted in compounds that are not substrates for             The major cardiovascular response to this drug is a
   COMT, resulting in lower rates of metabolism and              rise in blood pressure associated with reflex brady-
   enhanced oral bioavailability compared to cate-               cardia. The slowing of the heart rate is blocked by
   cholamines.                                                   atropine.
2. C. -Adrenoceptors mediate contraction of the ra-
   dial muscle of the iris. The shortening of the radial      SUPPLEMENTAL READING
   muscle cells opens the pupil. Phentolamine blocks          Burnstock G and Griffith SG. Nonadrenergic
     -adrenoceptors, allowing parasympathetic nerves             Innervation of Blood Vessels. Boca Raton, FL:
   innervating the sphincter muscle to take over. This           CRC, 1988.
   leads to a less opposed contraction of the sphincter       Gootman PM (ed.). Developmental Neurobiology of
   muscle induced by transmitter acetylcholine and a             the Autonomic Nervous System. Clifton, NJ:
   constriction of the pupil or miosis.                          Humana, 1986.
3. D. A small dose of epinephrine (0.1 g/kg) given            Insel PA and Feldman RD. -Adrenergic Receptors in
   by intravenous route may cause the blood pressure             Health and Disease. Boca Raton, FL: CRC, 1994.
   to fall, decreasing peripheral resistance. The depres-     Lee TJF. Endothelial messengers and cerebral vascular
   sor effect of small doses is due to greater sensitivity       tone regulation. In: Olesen J and Edvinsson L
   to epinephrine of vasodilator 2-adrenoceptors than            (eds.). Headache Pathogenesis: Monoamines,
   of constrictor -adrenoceptors and a dominant ac-              Neuropeptides, Purines, and Nitric Oxide.
   tion on 2-adrenoceptors of vessels in skeletal mus-           Philadelphia: Lippincott-Raven, 1997:61–72.
   cle. Consequently, diastolic blood pressure usually        Limbird E (ed.). The Alpha-2 Adrenergic Receptors.
   falls. The mean blood pressure in general, however,           Clifton, NJ: Humana, 1988.
   is not greatly elevated. The compensatory barore-          Missale C et al. Dopamine receptors: From structure to
   ceptor reflexes do not appreciably antagonize the              function. Physiol Rev 1998;78:189–225.
   direct cardiac actions.                                    Moncada SR, Palmer MJ, and Higgs EA. Nitric oxide:
4. C. Amphetamine is an indirectly acting adreno-                Physiology, pathophysiology, and pharmacology.
   mimetic amine that depends on the release of nor-             Pharmacol Rev 1991;43:109–142.
   epinephrine from noradrenergic nerves for its ac-          Patel TB et al. Molecular biological approaches to un-
   tion. Thus, its effect depends on neuronal uptake             ravel adenylyl cyclase signaling and function. Gene
   (blocked by cocaine) to displace norepinephrine               2001;16:13–25.
   from the vesicles and the availability of norepineph-      Post SR, Hammond HR, and Insel PA. Beta-adrenergic
   rine (depleted by reserpine). The substitution on the         receptors and receptor signaling in heart failure.
     -carbon atom blocks oxidation by monoamine oxi-             Annu Rev Pharmacol Toxicol 1999;39:343–360.
   dase. With no substitution on its benzene ring, am-
   phetamine resists metabolism by COMT.
108                             II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM




      Case      Study        Help for the Heart




      T    . L. is a highly successful scientist who spends
           long hours in the laboratory and is constantly in
      demand as a speaker and reviewer for scientific
                                                               ANSWER: Dobutamine injection would provide
                                                               particular benefit in meeting the therapeutic needs
                                                               of this patient. Dobutamine augments ventricular
      papers and grants. He has a family history of            contractility and thus enhances cardiac output,
      cardiovascular disease, having lost both his father      especially stroke volume, in patients with depressed
      and grandfather before either reached age 60. He         cardiac function. It does this by stimulating
      has recently noticed decreased energy, especially          -adrenoceptors in the heart while producing
      during exercise, and had symptoms (difficulty in          relatively little increase in chronotropic activity or
      breathing, chest pain) that took him to the              any significant elevation in systemic blood pressure
      emergency department. The examining physician            since it lacks -adrenoceptor stimulating effects.
      thought the best treatment would be short-term           Thus, in contrast to a nonselective -adrenoceptor
      therapy with a directly acting inotropic agent,          stimulant such as isoproterenol, which increases
      especially one that would not markedly increase an       cardiac output primarily by increasing heart rate,
      already elevated heart rate. Based on a knowledge        dobutamine’s actions increase cardiac output
      of the distribution of cardiovascular autonomic          without being accompanied by either a marked
      receptors, which of the following agents—                increase in heart rate or a significant increase in
      epinephrine, norepinephrine, amphetamine, or             systemic vascular resistance.
      dobutamine—would be a logical choice to use in
      this initial short-term treatment?

				
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