CHAPTER ONE
`
`Adrenergics and Adrenergic-
`Blocking Agents
`
`ROBERT K. GRIFFITH
`School of Pharmacy
`West Virginia University
`Morgantown, West Virginia
`
`Contents
`
`1 Introduction, 2
`2 Clinical Applications, 2
`2.1 Current Drugs, 2
`2.1.1 Applications of General Adrenergic
`Agonists, 9
`2.1.2 Applications of ␣1-Agonists, 12
`2.1.3 Applications of ␣2-Agonists, 13
`2.1.4 Applications of ␤-Agonists, 14
`2.1.5 Applications of Antiadrenergics, 14
`2.1.6 Applications of Nonselective ␣-
`Antagonists, 15
`2.1.7 Applications of Selective ␣1-
`Antagonists, 15
`2.1.8 Applications of ␤-Antagonists, 16
`2.1.9 Applications of ␣/␤-Antagonists, 16
`2.1.10 Applications of Agonists/Antagonists,
`16
`2.2 Absorption, Distribution, Metabolism, and
`Elimination, 16
`2.2.1 Metabolism of Representative
`Phenylethylamines, 16
`2.2.2 Metabolism of Representative
`Imidazolines and Guanidines, 18
`2.2.3 Metabolism of Representative
`Quinazolines, 19
`2.2.4 Metabolism of Representative Aryl-
`oxypropanolamines, 19
`3 Physiology and Pharmacology, 21
`3.1 Physiological Significance, 21
`3.2 Biosynthesis, Storage, and Release
`of Norepinephrine, 22
`3.3 Effector Mechanisms
`of Adrenergic Receptors, 25
`3.4 Characterization of Adrenergic
`Receptor Subtypes, 25
`4 History, 26
`
`Burger’s Medicinal Chemistry and Drug Discovery
`Sixth Edition, Volume 6: Nervous System Agents
`Edited by Donald J. Abraham
`ISBN 0-471-27401-1 © 2003 John Wiley & Sons, Inc.
`
`1
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`2
`
`Adrenergics and Adrenergic-Blocking Agents
`
`5 Structure-Activity Relationships, 28
`5.1 Phenylethylamine Agonists, 28
`5.1.1 R1 Substitution on the Amino Nitrogen,
`28
`5.1.2 R2 Substitution ␣ to the Basic
`Nitrogen, Carbon-2, 28
`5.1.3 R3 Substitution on Carbon-1, 29
`5.1.4 R4 Substitution on the Aromatic Ring,
`29
`
`1 INTRODUCTION
`
`In both their chemical structures and biologi-
`cal activities, adrenergics and adrenergic-
`blocking agents constitute an extremely var-
`ied group of drugs whose clinical utility
`includes prescription drugs to treat
`life-
`threatening conditions such as asthma and
`hypertension as well as nonprescription med-
`ications for minor ailments such as the com-
`mon cold. This extensive group of drugs in-
`cludes synthetic agents as well as chemicals
`derived from natural products that have been
`used in traditional medicines for centuries.
`Many adrenergic drugs are among the most
`commonly prescribed medications in the
`United States,
`including bronchodilators,
`such as albuterol (13) for use in treating
`asthma, and antihypertensives, such as ateno-
`lol (46) and doxazosin (42). Nonprescription
`adrenergic drugs include such widely used na-
`sal decongestants as pseudoephedrine (5) and
`naphazoline (29). Most of these varied drugs
`exert their therapeutic effects through action
`on adrenoceptors, G-protein-coupled cell sur-
`face receptors for the neurotransmitter nor-
`epinephrine (noradrenaline, 1), and the adre-
`nal hormone epinephrine (adrenaline, 2).
`
`Adrenoceptors are broadly classified into ␣-
`and ␤-receptors, with each group being further
`
`5.1.5 Imidazolines and Guanidines, 30
`5.1.6 Quinazolines, 31
`5.1.7 Aryloxypropanolamines, 32
`6 Recent Developments, 33
`6.1 Selective ␣1A-Adrenoceptor Antagonists, 33
`6.2 Selective ␤3-Agonists, 34
`
`subdivided. Identification of subclasses of adre-
`noceptors has been greatly aided by the tools of
`molecular biology and, to date, six distinct ␣-ad-
`renoceptors (␣1A, ␣1B, ␣1D, ␣2A, ␣2B, ␣2C), and
`three distinct ␤-adrenoceptors (␤1, ␤2, ␤3) have
`been clearly identified (1), with conflicting evi-
`dence for a fourth type of ␤(␤4) (1–3). In general
`the most common clinical applications of ␣1-ago-
`nists are as vasoconstrictors employed as nasal
`decongestants and for raising blood pressure in
`shock; ␣2-agonists are employed as antihyper-
`tensives; ␣1-antagonists (␣-blockers) are vasodi-
`lators and smooth muscle relaxants employed as
`antihypertensives and for treating prostatic hy-
`perplasia; ␤-antagonists (␤-blockers) are em-
`ployed as antihypertensives and for treating car-
`diac arrhythmias; and ␤-agonists are employed
`as bronchodilators. The most novel recent ad-
`vances in adrenergic drug research have been
`directed toward development of selective ␤3-ago-
`nists that have potential applications in treat-
`ment of diabetes and obesity (4–8).
`
`2 CLINICAL APPLICATIONS
`
`2.1 Current Drugs
`U.S. Food and Drug Administration (FDA)-
`approved adrenergic and antiadrenergic drugs
`currently available in the United States are
`summarized in Table 1.1, which is organized
`in general according to pharmacological mech-
`anisms of action and alphabetically within
`those mechanistic classes. Structures of the
`currently employed drugs are given in Tables
`1.2–1.6 according to chemical class. Drugs in a
`given mechanistic class often have more than
`one therapeutic application, and may or may
`not all be structurally similar. Furthermore,
`drugs from several different mechanistic
`classes may be employed in a given therapeu-
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`30mg/day
`10–20mg,i.m.
`2–10mg,i.m.
`1:20,000inlocalanesthetics
`
`Phenylethylamine
`Phenylethylamine
`Phenylethylamine
`Phenylethylamine
`
`60–240mg/day
`0.5–30␮g/mini.v.
`30–45mg,i.m.
`160–250␮ginh.
`2–10␮g/mini.v.
`0.3–1.5mgs.c.
`10–25mgi.v.forhypotension
`50–150mg/dayforasthma
`1drop2⫻daily0.1%soln.
`5–60mg/day
`
`Phenylethylamine
`Phenylethylamine
`Phenylethylamine
`
`Sterling
`Wyeth
`
`Various
`Levophed
`Wyamine
`
`(5)
`Pseudoephedrinethreo-
`Norepinephrine(1)
`Mephentermine(6)
`
`Phenylethylamine
`
`Parke-Davis
`
`Adrenaline
`
`Epinephrine(2)
`
`Phenylethylamine
`Phenylethylamine
`Phenylethylamine
`
`Klinge
`SmithKline&French
`
`various
`Propine
`Adderall,Dexedrine
`
`Ephedrineerythro-(5)
`Dipivefrin(4)
`Amphetamine(3)
`
`Generalagonists
`
`Dosebc
`
`ChemicalClass
`
`Originator
`
`TradeNamea
`
`ClassandGenericName
`
`Table1.1AdrenergicandAntiadrenergicPharmaceuticals
`
`Merck
`Wander
`Sandoz
`Boehringer
`Pfizer
`Alcon
`
`Ciba
`Sahyun
`
`Merck
`
`Ciba
`Stickstoffwerke
`Oesterreichische
`BurroughsWellcome
`Sharpe&Dohme
`Winthrop
`
`Aldomet
`Tenex
`Wytensin
`Catapress
`Alphagan
`Iopidine
`
`Various
`
`Various
`
`Various
`
`Various
`
`ProAmatine
`Vasoxyl
`Aramine
`na
`
`Methyldopa(12)
`Guanfacine(37)
`Guanabenz(36)
`Clonidine(35)
`Brimonidine(34)
`Apraclonidine(33)
`
`␣2-Agonists
`
`Xylometazoline(32)
`Tetrahydrozoline(31)
`
`Phenylephrine(11)
`
`Oxymetazoline(30)
`
`Naphazoline(29)
`
`Midodrine(10)
`Methoxamine(9)
`Metaraminol(8)
`Levonordefrin(7)
`
`␣1-Agonists
`
`3
`
`500–2000mg/day
`1–3mg/day
`8–32mg/day
`0.2–1.2mg/day
`1drop0.2%soln.,3⫻daily
`3–6drops0.5–1%soln.
`
`Aromaticaminoacid
`Arylguanidine
`Arylguanidine
`Aminoimidazoline
`Aminoimidazoline
`Aminoimidazoline
`
`2–3dropsof0.1%soln.
`1–2dropsof0.05%soln.
`0.1–0.5mgi.v.forshock
`0.25–0.5%soln.nasal
`1–3drops
`0.025%ophthalmic
`1–2drops0.05%nasal
`0.03%ophthalmic
`1–2drops0.05%nasal
`
`Imidazoline
`Imidazoline
`
`Imidazoline
`
`Imidazoline
`
`Phenylethylamine
`
`F.Stearns&Co.
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`5–20mg/day
`0.4–0.8mg/day
`6–20mg/dayforhypertension
`1–9mg/dayforBPH
`1–16mg/day
`
`Quinazoline
`Phenylethylamine
`
`Quinazoline
`Quinazoline
`
`Abbott
`Yamanouchi
`
`Pfizer
`Pfizer
`
`Hytrin
`Flomax
`
`Minipress
`Cardura
`
`Terazosin(44)
`Tamsulosin(24)
`
`␣1-antagonists
`
`Prazosin(43)
`Doxazosin(42)
`
`Selective
`
`40–200mg/day
`5–10mgi.v.
`20–120mg/day
`2drops0.5%soln.
`
`Imidazoline
`Imidazoline
`Haloalkylamine
`Piperidinlytriazole
`
`Ciba
`Ciba
`SmithKline&French
`Angelini-Francesco
`
`Priscoline
`Regitine
`Dibenzylime
`Rev-Eyes
`
`Tolazoline(41)
`Phentolamine(40)
`Phenoxybenzamine(62)
`Dapiprazole(61)
`
`1–4g/day
`0.05–0.5mg/day
`10–50mg/day
`10–75mg/day
`
`Aromaticaminoacid
`Alkaloid
`Guanidine
`Guanidine
`
`7.5–15mg/day
`42␮g,2⫻daily,inh.
`120mg/day
`150–350␮g/min,i.v.
`0.2–0.4mg4–6⫻daily,inh.
`1.3–1.95mg,6–8xdaily,inh.
`60–80mg/dayp.o.
`0.63–1.25mg3⫻dailyneb.
`0.5–5.0␮g/min,i.v.
`120–262␮g,2–6⫻dailyinh.
`2mL0.25%soln.inh.
`12␮g,2⫻dailyinh.
`0.74–2.22inh.
`2.5mg3–4⫻daily,neb.
`12–32mg/dayp.o.
`
`Phenylethylamine
`Phenylethylamine
`
`Phenylethylamine
`Pyridylethylamine
`
`Phenylethylamine
`Phenylethylamine
`
`Phenylethylamine
`Phenylethylamine
`Phenylethylamine
`Phenylethylamine
`
`Merck
`Ciba
`Ciba
`Cutter
`
`Draco
`Glaxo
`
`Philips
`Pfizer
`
`Demser
`reserpine
`Ismelin
`Hylorel
`
`Brethine
`Serevent
`
`Yutopar
`Maxair
`
`␣-Antagonists
`
`Metyrosine(23)
`Reserpine(60)
`Guanethidine(39)
`Guanadrel(38)
`
`Antiadrenergics
`
`Terbutaline(22)
`Salmeterol(21)
`
`Ritodrine(20)
`Pirbuterol(19)
`
`4
`
`Boehringer
`Sepracor
`
`Alupent,Metaprel
`Xopenex
`
`Metaproterenol(18)
`Levalbuterol(13)
`
`Boehringer
`I.G.Farben
`Yamanouchi
`Sterling
`
`Isuprel
`Bronkosol
`Foradil
`Tornalate
`
`Isoproterenol(17)
`Isoetharine(16)
`Formoterol(15)
`Bitolterol(14)
`
`Albuterol(13)
`
`␤-Agonists
`
`Phenylethylamine
`
`Allen&Hanburys
`
`Proventil,Ventolin
`
`Dosebc
`
`ChemicalClass
`
`Originator
`
`TradeNamea
`
`ClassandGenericName
`
`Table1.1(Continued)
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`cNotalldosesanddosageformsarelisted.Forfurtherinformationconsultreference(14).
`bAlldoseinformationfromDrugFactsandComparisons2002(14).
`aNotalltradenamesarelisted,particularlyfordrugsnolongerunderpatent.
`
`30–80mg/day
`2–20␮g/kg/min,i.v.
`
`Arylpropanolamine
`Phenylethylamine
`
`Philips
`Lilly
`
`200–2400mg/day
`13–50mg/day
`
`Phenylethylamine
`Aryloxypropanolamine
`
`Allen&Hanburys
`Boehringer
`
`Vasodilan
`Dobutrex
`
`Normodyne
`Coreg
`
`Glaucoma:1drop0.25%soln.,2⫻daily
`Hypertension:10–60mg/day
`160–320mg/day
`160–640mg/day
`10–60mg/day
`20–80mg/day
`40–320mg/day
`XL50–100mg/day
`100–450mg/day
`1drop0.3%soln..,2⫻daily
`1–2drops0.5%soln.,1–2⫻daily
`1drop0.5%soln.,2⫻daily
`50–100␮g/kg/min
`2.5–10mg/day
`1.25–20mg/day
`Glaucoma:1–2drops0.5%soln.2⫻daily
`Hypertension:10–20mgorally
`25–150mg/day
`200–1200mg/day
`
`Aryloxypropanolamine
`Phenylethylamine
`Aryloxypropanolamine
`Aryloxypropanolamine
`Aryloxypropanolamine
`Aryloxypropanolamine
`
`Aryloxypropanolamine
`Aryloxypropanolamine
`Aryloxypropanolamine
`Aryloxypropanolamine
`Aryloxypropanolamine
`Aryloxypropanolamine
`Aryloxypropanolamine
`
`Aryloxypropanolamine
`Aryloxypropanolamine
`Aryloxypropanolamine
`
`Frosst
`MeadJohnson
`ICI
`Sandoz
`Hoechst
`Squibb
`
`ABHässle
`Boehringer
`Warner-Lambert
`Alcon
`AmericanHospitalSupply
`Otsuka
`Merck
`
`Timoptic
`Betapace
`Inderal,InderalLA
`Visken
`Levatol
`Corgard
`Toprol-XL
`Lopressor,Toprol-XL
`OptiPranolol
`Betagan
`Betaxon
`Brevibloc
`Cartrol,Ocupress
`Zebeta
`
`Synthelabo
`ICI
`May&Baker
`
`Betoptic,Kerlone
`Tenormin
`Sectral
`
`Isoxsuprine(28)
`Dobutamine(27)
`Agonist/Antagonists
`
`Labetalol(26)
`Carvedilol(59)
`␤-Antagonists
`
`␣/
`
`Timolol(58)
`Sotalol(25)
`Propranolol(57)
`Pindolol(56)
`Penbutolol(55)
`Nadolol(54)
`
`5
`
`Metoprolol(53)
`Metipranolol(52)
`Levobunolol(51)
`LevobetaxololS-(⫺)-(47)
`Esmolol(50)
`Carteolol(49)
`Bisoprolol(48)
`
`Betaxolol(47)
`Atenolol(46)
`Acebutolol(45)
`
`␤-Antagonists
`
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`␤2
`␤2
`␤2
`
`␤
`
`␤
`
`c
`
`c
`
`␤2
`␤2
`␤2
`␣2
`
`␣
`
`␣
`
`␣
`
`␣
`
`␣
`
`(␣⫹␤)b
`(␣⫹␤)d
`(␤ⱖ␣)c
`(␣⫹␤)b
`␤ⱖ␣
`␣⫹␤
`
`4⬘-OH
`2⬘-aza,3⬘-CH2OH,4⬘-OH
`3⬘,5⬘-diOH
`3⬘,4⬘-diOH
`3⬘,4⬘-diOH
`
`3⬘-NHCHO,4⬘-OH
`3⬘,4⬘-bis(O2CC4H4-p-CH3)
`3⬘-CH2OH,4⬘-OH
`3⬘,4⬘-diOH
`3⬘-OH
`2⬘,5⬘-diOCH3
`2⬘,5⬘-diOCH3
`3⬘-OH
`3⬘,4⬘-diOH
`
`H
`
`3⬘,4⬘-di-O2CC(CH3)3
`
`H
`
`H
`
`3⬘,4⬘-diOH
`3⬘,4⬘-diOH
`
`ReceptorActivitya
`
`R4
`
`OH
`OH
`OH
`OH
`OH
`
`OH
`OH
`OH
`
`H
`
`OH
`OH
`OH
`OH
`OH
`OH
`OH
`OH
`
`H
`
`OH
`OH
`
`R3
`
`CH3
`
`H
`
`H
`
`CH2CH3
`
`H
`
`H
`
`H
`
`2-CH3,2-CO2H
`
`H
`
`H
`
`CH3
`CH3
`CH3
`2,2-diCH3
`CH3
`
`H
`
`CH3
`
`H
`
`H
`
`H
`
`R2
`
`C(CH3)3
`C(CH3)3
`CH(CH3)2
`CH(CH3)2
`
`C(CH3)3
`C(CH3)3
`
`CH3
`COCH2NH2
`
`H
`
`H
`
`H
`
`CH3
`CH3
`CH3
`
`H
`
`CH3
`
`H
`
`H
`
`(20)
`(19)
`(18)
`(17)
`(16)
`
`(15)
`(14)
`(13)
`(12)
`(11)
`(10)
`(9)
`(8)
`(7)
`(6)
`(5)
`(4)
`(3)
`(2)
`(1)
`
`6
`
`R1
`
`Compound
`
`Table1.2Phenylethylamines(Structures1–28)
`
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`fNetsumofeffectsofenantiomers.
`eNorepinephrinebiosynthesisinhibitor.
`dMixeddirectandindirectactivity.
`cProdrug.
`bIndirectactivitythroughreleaseofnorepinephrineandreuptakeinhibition.
`aAgonistactivityunlessindicatedotherwise.
`
`␤-agonist
`␣1-blocker,
`
`4⬘-OH
`
`OH
`
`CH3
`
`(28)
`
`f
`
`␤1
`
`3⬘,4⬘-diOH
`
`H
`
`␣1,␤1,␤2-blocker
`␤-blocker
`
`3⬘-CONH2,4⬘-OH
`4⬘-NHSO2CH3
`
`␣1-blocker
`nae
`␤2
`
`3⬘-SO2NH2,4⬘-OCH3
`4⬘-OH
`3⬘,5⬘-diOH
`
`␤2
`
`3⬘-CH2OH,4⬘-OH
`
`OH
`OH
`
`H
`
`H
`
`OH
`
`OH
`
`H
`
`H
`
`H
`
`CH3
`2-CH3,2-CO2H
`
`H
`
`H
`
`(27)
`
`7
`
`CH(CH3)2
`
`C(CH3)3
`
`H
`
`(26)
`(25)
`
`(24)
`(23)
`(22)
`
`(21)
`
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`8
`
`Adrenergics and Adrenergic-Blocking Agents
`
`Table 1.3 Imidazolines and Guanidines (Structures 29 – 41)
`
`Compound
`
`(29)
`
`Structure
`
`Receptor Activity
`
`␣1-agonist
`
`(30)
`
`(31)
`
`(32)
`
`(33)
`
`(34)
`
`(35)
`
`(36)
`
`␣1-agonist
`
`␣1-agonist
`
`␣1-agonist
`
`␣2-agonist
`
`␣2-agonist
`
`␣2-agonist
`
`␣2-agonist
`
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`2 Clinical Applications
`
`Table 1.3 (Continued)
`
`Compound
`
`(37)
`
`Structure
`
`(38)
`
`(39)
`
`(40)
`
`(41)
`
`9
`
`Receptor Activity
`
`␣2-agonist
`
`naa
`
`naa
`
`␣1-antagonist
`
`␣1-antagonist
`
`aInhibit release of norepinephrine.
`
`tic application; for example, ␤-blockers, ␣1-
`blockers, and ␣2-agonists are all employed to
`treat hypertension.
`
`2.1.1 Applications of General Adrenergic
`Agonists. The mixed ␣- and ␤-agonist norepi-
`nephrine (1) has limited clinical application
`because of the nonselective nature of its action
`in stimulating the entire adrenergic system.
`In addition to nonselective activity, it is orally
`inactive because of rapid first-pass metabo-
`lism of the catechol hydroxyls by catechol-O-
`methyl-transferase (COMT) and must be ad-
`ministered intravenously. Rapid metabolism
`limits its duration of action to only 1 or 2 min,
`even when given by infusion. Because its ␣-ac-
`tivity constricts blood vessels and thereby
`
`raises blood pressure, (1) is used to counteract
`various hypotensive crises and as an adjunct
`treatment in cardiac arrest where its ␤-activ-
`ity stimulates the heart. Although it also lacks
`oral activity because it is a catechol, epineph-
`rine (2) is far more widely used clinically than
`(1). Epinephrine, like norepinephrine, is used
`to treat hypotensive crises and, because of its
`greater ␤-activity, is used to stimulate the
`heart in cardiac arrest. When administered in-
`travenously or by inhalation, epinephrine’s
`␤2-activity makes it useful in relieving bron-
`choconstriction in asthma. Because it has sig-
`nificant ␣-activity, epinephrine is also used in
`topical nasal decongestants. Constriction of
`dilated blood vessels by ␣-agonists in mucous
`membranes shrinks the membranes and re-
`
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`
`Table 1.4 Quinazolines (Structures 42– 44)
`
`Compound
`
`(42)
`
`R
`
`Receptor Activity
`
`␣1-antagonist
`
`(43)
`
`(44)
`
`␣1-antagonist
`
`␣1-antagonist
`
`duces nasal congestion. Dipivefrin (4) is a pro-
`drug form of (2), in which the catechol hy-
`droxyls are esterified with pivalic acid.
`Dipivefrin is used to treat open-angle glau-
`coma through topical application to the eye
`where the drug (4) is hydrolyzed to epineph-
`rine (2), which stimulates both ␣- and ␤-recep-
`tors, resulting in both decreased production
`and increased outflow of aqueous humor,
`which in turn lowers intraocular pressure.
`Amphetamine (3)
`is orally active and,
`through an indirect mechanism, causes a gen-
`eral activation of the adrenergic nervous sys-
`tem. Unlike (1) and (2), amphetamine readily
`crosses the blood-brain barrier to activate a
`number of adrenergic pathways in the central
`nervous system (CNS). Amphetamine’s CNS
`activity is the basis of its clinical utility in
`treating attention-deficit disorder, narco-
`lepsy, and use as an anorexiant. These thera-
`peutic areas are treated elsewhere in this
`volume.
`Ephedrine erythro-(5) and pseudoephed-
`rine threo-(5) are diastereomers with ephed-
`rine, a racemic mixture of the R,S and S,R
`stereoisomers, and pseudoephedrine, a race-
`
`mic mixture of R,R and S,S stereoisomers.
`Ephedrine is a natural product isolated from
`several species of ephedra plants, which were
`used for centuries in folk medicines in a vari-
`ety of cultures worldwide (9). Ephedrine has
`both direct activity on adrenoceptors and indi-
`rect activity, through causing release of nor-
`epinephrine from adrenergic nerve terminals.
`Ephedrine is widely used as a nonprescription
`bronchodilator. It has also been used as a va-
`sopressor and cardiac stimulant. Lacking phe-
`nolic hydroxyls, ephedrine crosses the blood-
`brain barrier far better than does epinephrine.
`Because of its ability to penetrate the CNS,
`ephedrine has been used as a stimulant and
`exhibits side effects related to its action in the
`brain such as insomnia, irritability, and anxi-
`ety. It suppresses appetite and in high doses
`can cause euphoria or even hallucinations. In
`the United States the purified chemical ephed-
`rine is considered a drug and regulated by the
`FDA. However, the dried plant material ma
`huang is considered by law to be a dietary sup-
`plement, and not subject to FDA regulation.
`As a result there are a large number of ma
`huang-containing herbal remedies and “nu-
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`11
`
`Table 1.5 Aryloxypropanolamines (Structures 45–59)
`
`Compound
`
`(45)
`
`(46)
`
`(47)
`
`(48)
`
`(49)
`
`(50)
`
`(51)
`
`(52)
`
`(53)
`
`(54)
`
`ARYL
`
`R
`
`Receptor Selectivitya
`
`CH(CH3)2
`
`CH(CH3)2
`
`CH(CH3)2
`
`CH(CH3)2
`
`␤1
`
`␤1
`
`␤1
`
`␤1
`
`C(CH3)3
`
`␤1, ␤2
`
`CH(CH3)2
`
`␤1
`
`C(CH3)3
`
`␤1, ␤2
`
`CH(CH3)2
`
`␤1, ␤2
`
`CH(CH3)2
`
`␤1
`
`C(CH3)3
`
`␤1, ␤2
`
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`
`Adrenergics and Adrenergic-Blocking Agents
`
`Table 1.5 (Continued)
`
`Compound
`
`(55)
`
`ARYL
`
`R
`
`Receptor Selectivitya
`
`C(CH3)3
`
`␤1, ␤2
`
`(56)
`
`(57)
`
`(58)
`
`(59)
`
`CH(CH3)2
`
`␤1, ␤2
`
`CH(CH3)2
`
`␤1, ␤2
`
`C(CH3)3
`
`␤1, ␤2
`
`␣1, ␤1, ␤2
`
`aAntagonists.
`
`triceuticals” on the market whose active in-
`gredient is the adrenergic agonist ephedrine.
`Pseudoephedrine, the threo diastereomer, has
`virtually no direct activity on adrenergic re-
`ceptors but acts by causing the release of nor-
`epinephrine from nerve terminals, which in
`turn constricts blood vessels. Although it too
`crosses the blood-brain barrier, pseudoephed-
`rine’s lack of direct activity affords fewer CNS
`side effects than does ephedrine. Pseudo-
`ephedrine is widely used as a nasal deconges-
`tant and is an ingredient in many nonprescrip-
`tion cold remedies.
`Mephentermine (6) is another general ad-
`renergic agonist with both direct and indirect
`activity. Mephentermine’s therapeutic utility
`is as a parenteral vasopressor used to treat
`hypotension induced by spinal anesthesia or
`other drugs.
`
`2.1.2 Applications of ␣
`1-Agonists. All se-
`lective ␣1-agonists are vasoconstrictors, which
`is the basis of their therapeutic activity. The
`sole use of levonordefrin (7) is in formulations
`with parenteral local anesthetics employed in
`dentistry. Vasoconstriction induced by the
`␣-agonist activity of (7) helps retain the local
`anesthetic near the site of injection and pro-
`longs the duration of anesthetic activity. Met-
`araminol (8) and methoxamine (9) are both
`parenteral vasopressors selective for ␣-recep-
`tors and so have few cardiac stimulatory prop-
`erties. Because they are not substrates for
`COMT, their duration of action is significantly
`longer than that of norepinephrine, but their
`primary use is limited to treating hypotension
`during surgery or shock. Methoxamine is also
`used in treating supraventricular tachycardia.
`Midodrine (10) is an orally active glycine-
`
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`13
`
`Table 1.6 Miscellaneous Adrenergic/Antiadrenergics (Structures 60 – 62)
`
`Compound
`
`(60)
`
`Structure
`
`Pharmacological Activity
`
`Antiadrenergic
`
`(61)
`
`(62)
`
`␣-Antagonist
`
`␣-Antagonist
`
`amide prodrug, hydrolyzed in vivo to (63), an
`analog of methoxamine, and a vasoconstrictor.
`Midodrine is used to treat orthostatic hypo-
`tension.
`
`Phenylephrine (11), also a selective ␣-ago-
`nist, may be administered parenterally for
`
`severe hypotension or shock but is much
`more widely employed as a nonprescription
`nasal decongestant in both oral and topical
`preparations.
`The imidazolines naphazoline (29), oxy-
`metazoline (30), tetrahydozoline (31), and xy-
`lometazoline (32) are all selective ␣1-agonists,
`widely employed as vasoconstrictors in topical
`nonprescription drugs for treating nasal con-
`gestion or bloodshot eyes. Naphazoline and
`oxymetazoline are employed in both nasal de-
`congestants and ophthalmic preparations,
`whereas tetrahydrozoline is currently mar-
`keted only for ophthalmic use and xylometa-
`zoline only as a nasal decongestant.
`
`2.1.3 Applications of ␣
`2-Agonists. Amino-
`imidazolines apraclonidine (33) and bri-
`monidine (34) are selective ␣2-agonists em-
`ployed topically in the treatment of glaucoma.
`Stimulation of ␣2-receptors in the eye reduces
`production of aqueous humor and enhances
`outflow of aqueous humor, thus reducing in-
`traocular pressure. Brimonidine is substan-
`tially more selective for ␣2-receptors over ␣1-
`
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`receptors than is apraclonidine. Although both
`are applied topically to the eye, measurable
`quantities of these drugs are detectable in
`plasma, so caution must be employed when
`the patient is also taking cardiovascular
`agents. Structurally related aminoimidazoline
`clonidine (35) is a selective ␣2-agonist taken
`orally for treatment of hypertension. The anti-
`hypertensive actions of clonidine are mediated
`through stimulation of ␣2-adrenoceptors
`within the CNS, resulting in an overall decrease
`in peripheral sympathetic tone. Guanabenz (36)
`and guanfacine (37) are ring-opened analogs of
`(35), acting by the same mechanism and em-
`ployed as centrally acting antihypertensives.
`Methyldopa (12) is another antihyperten-
`sive agent acting as an ␣2-agonist in the CNS
`through its metabolite, ␣-methyl-norepineph-
`rine (65). Methyldopa [the drug is the L-(S)-
`stereoisomer] is decarboxylated to ␣-methyl-
`dopamine (64) followed by stereospecific
`␤-hydroxylation to the (1R,2S) stereoisomer
`of ␣-methylnorepinephrine (65). This stereo-
`isomer is an ␣2-agonist that, like clonidine,
`guanabenz, and guanfacine, causes a decrease
`in sympathetic output from the CNS.
`
`2.1.4 Applications of ␤-Agonists. Most of
`the ␤-selective adrenergic agonists, albuterol
`(13; salbutamol in Europe), bitolterol (14),
`
`formoterol (15), isoetharine (16), isoprotere-
`nol (17), levalbuterol [R-(⫺)-(13)], metapro-
`terenol (18), pirbuterol (19), salmeterol (21),
`and terbutaline (22) are used primarily as
`bronchodilators in asthma and other constric-
`tive pulmonary conditions. Isoproterenol (17)
`is a general ␤-agonist, and the cardiac stimu-
`lation caused by its ␤1-activity and its lack of
`oral activity attributed to first-pass metabo-
`lism of the catechol ring have led to dimin-
`ished use in favor of selective ␤2-agonists.
`Noncatechol-selective ␤2-agonists, such as al-
`buterol (13), metaproterenol (18), and ter-
`butaline (22), are available in oral dosage
`forms as well as in inhalers. All have similar
`activities and durations of action. Pirbuterol
`(19) is an analog of albuterol, in which the
`benzene ring has been replaced by a pyridine
`ring. Similar to albuterol, (19) is a selective
`␤2-agonist, currently available only for admin-
`istration by inhalation. Bitolterol (14) is a pro-
`drug, in which the catechol hydroxyl groups
`have been converted to 4-methylbenzoic acid
`esters, providing increased lipid solubility and
`prolonged duration of action. Bitolterol is ad-
`ministered by inhalation, and the ester groups
`are hydrolyzed by esterases to liberate the ac-
`tive catechol drug (66), which is subject to me-
`tabolism by COMT, although the duration of
`action of a single dose of the prodrug is up to
`8 h, permitting less frequent administration
`and greater convenience to the patient. More
`recently developed selective ␤2-agonist bron-
`chodilators are formoterol (15) and salmeterol
`(21), which have durations of action of 12 h or
`more. Terbutaline (22), in addition to its use
`as a bronchodilator, has also been used for
`halting the contractions of premature labor.
`Ritodrine (20) is a selective ␤2-agonist that is
`used exclusively for relaxing uterine muscle
`and inhibiting the contractions of premature
`labor.
`
`2.1.5 Applications of Antiadrenergics. Gua-
`nadrel (38) and guanethidine (39) are orally
`active antihypertensives, which are taken up
`into adrenergic neurons, where they bind to
`the storage vesicles and prevent release of
`neurotransmitter in response to a neuronal
`impulse, which results in generalized decrease
`in sympathetic tone. These drugs are available
`but seldom used.
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`15
`
`in pheochromocytoma tumors, it is not useful
`for treating essential hypertension.
`
`2.1.6 Applications of Nonselective ␣-An-
`tagonists. Because antagonism of ␣1-adreno-
`ceptors in the peripheral vascular smooth
`muscle leads to vasodilation and a decrease in
`blood pressure attributed to a lowering of pe-
`ripheral resistance, alpha-blockers have been
`employed as antihypertensives for decades.
`However, nonselective ␣-blockers such as phe-
`noxybenzamine (62), phentolamine (40), and
`tolazoline can also increase sympathetic out-
`put through blockade of inhibitory presynap-
`tic ␣2-adrenoceptors, resulting in an increase
`in circulating norepinephrine, which causes
`reflex tachycardia. Thus the use of these
`agents in treating most forms of hypertension
`has been discontinued and replaced by use of
`selective ␣1-antagonists discussed below. Cur-
`rent clinical use of the nonselective agents
`(40), (41), and (62) is primarily treatment of
`hypertension induced by pheochromocytoma,
`a tumor of the adrenal medulla, which se-
`cretes large amounts of epinephrine and nor-
`epinephrine into the circulation. Dapiprazole
`(61) is an ophthalmic nonselective ␣-antago-
`nist applied topically to reverse mydriasis in-
`duced by other drugs and is not used to treat
`hypertension.
`
`2.1.7 Applications of Selective ␣
`1-Antago-
`nists. Quinazoline-selective ␣1-blockers dox-
`azosin (42), prazosin (43), and terazosin (44)
`have replaced the nonselective ␣-antagonists
`in clinical use as antihypertensives. Their abil-
`ity to dilate peripheral vasculature has also
`made these drugs useful in treating Raynaud’s
`syndrome. The ␣1-selective agents have a fa-
`vorable effect on lipid profiles and decrease
`low density lipoproteins (LDL) and triglycer-
`ides, and increase high density lipoproteins
`(HDL).
`Contraction of the smooth muscle of the
`prostate gland, prostatic urethra, and bladder
`neck is also mediated by ␣1-adrenoceptors,
`with ␣1A being predominant, and blockade of
`these receptors relaxes the tissue. For this rea-
`son the quinazoline ␣1-antagonists doxazosin
`(42), prazosin (43), and terazosin (44) have
`also found use in treatment of benign pros-
`tatic hyperplasia (BPH). However, prazosin,
`
`Reserpine (60) is an old and historically im-
`portant drug that affects the storage and re-
`lease of norepinephrine. Reserpine is one of
`several indole alkaloids isolated from the roots
`of Rauwolfia serpentina, a plant whose roots
`were used in India for centuries as a remedy
`for snakebites and as a sedative. Reserpine
`acts to deplete the adrenergic neurons of their
`stores of norepinephrine by inhibiting the ac-
`tive transport Mg-ATPase responsible for se-
`questering norepinephrine and dopamine
`within the storage vesicles. Monoamine oxi-
`dase (MAO) destroys the norepinephrine and
`dopamine that are not sequestered in vesicles.
`As a result the storage vesicles contain little
`neurotransmitter; adrenergic transmission is
`dramatically inhibited; and sympathetic tone
`is decreased, thus leading to vasodilation.
`Agents with fewer side effects have largely re-
`placed reserpine in clinical use.
`Metyrosine (23, ␣-methyl-L-tyrosine), a
`norepinephrine biosynthesis inhibitor, is in
`limited clinical use to help control hyperten-
`sive episodes and other symptoms of catechol-
`amine overproduction in patients with the
`rare adrenal tumor pheochromocytoma (10).
`Metyrosine, a competitive inhibitor of ty-
`rosine hydroxylase, inhibits the production of
`catecholamines by the tumor. Although mety-
`rosine is useful
`in treating hypertension
`caused by excess catecholamine biosynthesis
`
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`
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`
`doxazosin, and terazosin show no significant
`selectivity for any of the three known ␣1-adre-
`noceptor subtypes, ␣1A, ␣1B, and ␣1D (11). The
`structurally unrelated phenylethylamine ␣1-
`antagonist tamsulosin (24) is many fold more
`selective for ␣1A-receptors than for the other
`␣1-adrencoceptors. Tamsulosin is employed
`only for treatment of BPH, given that it has
`little effect on the ␣1B- and ␣1D-adrenoceptors,
`which predominate in the vascular bed (12)
`and have little effect on blood pressure (13).
`
`2.1.8 Applications of ␤-Antagonists. ␤-An-
`tagonists are among the most widely employed
`antihypertensives and are also considered the
`first-line treatment for glaucoma. There are
`16 ␤-blockers listed in Table 1.1 and 15 of
`them are in the chemical class of aryloxypro-
`panolamines. Only sotalol (25) is a phenyleth-
`ylamine. Acebutolol (45), atenolol (46), biso-
`prolol (48), metoprolol (53), nadolol (54),
`penbutolol (55), pindolol (56), and proprano-
`lol (57) are used to treat hypertension but not
`glaucoma. Betaxolol (47), carteolol (49), and
`timolol (58) are used both systemically to treat
`hypertension and topically to treat glaucoma.
`Levobetaxolol [S-(⫺)-(47)], levobunolol (51),
`and metipranolol (52) are employed only in
`treating glaucoma. Betaxolol (racemic 47) is
`available in both oral and ophthalmic dosage
`forms for treating hypertension and glau-
`coma, respectively, but levobetaxolol, the en-
`antiomerically pure S-(⫺)-stereoisomer is cur-
`rently available only in an ophthalmic dosage
`form. Esmolol (50) is a very short acting
`␤-blocker administered intravenously for
`acute control of hypertension or certain su-
`praventricular arrhythmias during surgery.
`Sotalol (25) is a nonselective ␤-blocker used to
`treat ventricular and supraventricular ar-
`rhythmias not employed as an antihyperten-
`sive or antiglaucoma agent. ␤-Antagonists
`must be used with caution in patients with
`asthma and other reactive pulmonary diseases
`because blockade of ␤2-adrenoceptors may ex-
`acerbate the lung condition. Even the agents
`listed as being ␤1-selective have some level of
`␤2-blocking activity at higher therapeutic
`doses. Betaxolol is the most ␤1-selective of the
`currently available agents.
`
`2.1.9 Applications of ␣/␤-Antagonists. Car-
`vedilol (59), an aryloxypropanolamine, has
`both ␣- and ␤-antagonist properties and is
`used both as an antihypertensive and to treat
`cardiac failure. Both enantiomers have selec-
`tive ␣1-antagonist properties but most of the
`␤-antagonism is attributable to the S-(⫺) iso-
`mer. Labetalol (26) is also an antihypertensive
`with both selective ␣1-antagonist properties
`and nonselective ␤-antagonism. Labetalol is
`an older drug than carvedilol and is not as
`potent as carvedilol, particularly as a ␤-antag-
`onist.
`
`of Agonists/Antago-
`2.1.10 Applications
`nists. Dobutamine (27) is a positive inotropic
`agent administered intravenously for conges-
`tive heart failure. The (⫹)-isomer has both ␣
`and ␤ agonist effects, whereas the (⫺)-isomer
`is an ␣-antagonist but a ␤-agonist like the en-
`antiomer. The ␤-stimulatory effects predomi-
`nate as the ␣-effects cancel. As a catechol it
`has no oral activity and even given intrave-
`nously has a half-life of only 2 min. Isoxsu-
`prine (28) is an agent with ␣-antagonist and
`␤-agonist properties, which has been used for
`peripheral and cerebral vascular insufficiency
`and for inhibition of premature labor. Isoxsu-
`prine is seldom used any more.
`
`2.2 Absorption, Distribution, Metabolism,
`and Elimination
`Because of the large numbers of chemicals act-
`ing as either adrenergics or adrenergic-block-
`ing drugs, only representative examples will
`be given and limited to metabolites identified
`in humans. Because drugs with similar struc-
`tures are often metabolized by similar routes,
`the examples chosen are representative of
`each structural class. Although it contains no
`structural details of metabolic pathways,
`Drug Facts and Comparisons (14) is an out-
`standing comprehensive compilation of phar-
`macokinetic parameters such as absorption,
`duration of action, and routes of elimination
`for drugs approved by the FDA for use in the
`United States.
`
`2.2.1 Metabolism of Representative Phenyl-
`ethylamines. Norepinephrine (1) and epi-
`nephrine (2) are both substrates for MAO,
`
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`2 Clinical Applications
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`17
`
`which oxidatively deaminates the side chain of
`either to form the same product DOPGAL
`(67), and for catechol-O-methyltransferase
`(COMT), which methylates the 3⬘-phenolic
`OH of each to form (68). Metabolite (68) is
`subsequently oxidized by MAO to form alde-
`hyde (69), and aldehyde (68) may be methyl-
`ated by COMT to also form (69). This alde-
`hyde may then be either oxidized by aldehyde
`dehydrogenase (AD) to (70) or reduced by al-
`dehyde reductase to alcohol (71). Alternate
`routes to (70) and (71) from (67) are also
`shown. Several of these metabolites are ex-
`creted in the urine as sulfate and glucuronide
`conjugates (15). As previously mentioned, nei-
`ther (1) nor (2) is orally active because of ex-
`tensive first-pass metabolism by COMT, and
`both have sh