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II

Section

150

Autonomic Drugs

Additional Therapeutic Uses

Although the primary use of the 2 agonist clonidine is in the


treatment of hypertension (see Chapter 11), the drug has been
found to have efficacy in the treatment of diarrhea in diabetics
with autonomic neuropathy, perhaps because of its ability to
enhance salt and water absorption from the intestine. In addition,
clonidine has efficacy in diminishing craving for narcotics and
alcohol during withdrawal and may facilitate cessation of cigarette
smoking. Clonidine has also been used to diminish menopausal

hot flushes and is being used experimentally to reduce hemodynamic instability during general anesthesia. Dexmedetomidine is
an 2 agonist used for sedation under intensive care circumstances
and during anesthesia (see Chapter 25). It blunts the sympathetic
response to surgery, which may be beneficial in some situations. It
lowers opioid requirements for pain control and does not depress
ventilation. Clonidine is also sometimes used as a premedication
before anesthesia. Tizanidine is an 2 agonist that is used as a
muscle relaxant (see Chapter 27).

SUMMARY Sympathomimetic Drugs

Subclass, Drug

Mechanism of Action

Effects

Activates phospholipase C,
resulting in increased
intracellular calcium and
vasoconstriction

Vascular smooth muscle


contraction increasing blood
pressure (BP)

Pharmacokinetics,
Clinical Applications Toxicities, Interactions

`1 AGONISTS

Midodrine

Orthostatic hypotension

Oral prodrug converted to


active drug with a 1-h peak
effect Toxicity: Supine
hypertension, piloerection
(goose bumps), and urinary
retention

Phenylephrine: Can be used IV for short-term maintenance of BP in acute hypotension and intranasally to produce local vasoconstriction as a decongestant
`2 AGONISTS

Clonidine

Inhibits adenylyl cyclase and


interacts with other
intracellular pathways

Vasoconstriction is masked
by central sympatholytic
effect, which lowers BP

Hypertension

Oral transdermal peak effect


13 h t1/2 of oral drug
~12 h produces dry mouth and
sedation

-Methyldopa, guanfacine, and guanabenz: Also used as central sympatholytics

Dexmedetomidine: Prominent sedative effects and used in anesthesia

Tizanidine: Used as a muscle relaxant

Apraclonidine and brimonidine: Used topically in glaucoma to reduce intraocular pressure


a1 AGONISTS

Dobutamine1

Activates adenylyl cyclase,


increasing myocardial
contractility

Positive inotropic effect

Cardiogenic shock, acute


heart failure

IV requires dose titration to


desired effect

Activates adenylyl cyclase

Bronchial smooth muscle


dilation

Asthma

Inhalation duration 46 h
Toxicity: Tremor, tachycardia

Activates adenylyl cyclase

Reduces bladder tone

Urinary urgency

Oral duration 50 h
Toxicity: Possible hypertension

Activates adenylyl cyclase

Vascular smooth muscle


relaxation

Hypertension

Requires dose titration to


desired effect

Inhibits adenylyl cyclase and


interacts with other
intracellular pathways

Mimics dopamine actions in


the CNS

Parkinsons disease,
prolactinemia

Oral Toxicity: Nausea, headache,


orthostatic hypotension

a2 AGONISTS

Albuterol

See other b2 agonists in Chapter 20


a3 AGONISTS

Mirabegron
DOPAMINE AGONISTS
D1 Agonists

Fenoldopam
D2 Agonists

Bromocriptine

See other D2 agonists in Chapters 28 and 37


1

Dobutamine has other actions in addition to b1-agonist effect. See text for details.

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CHAPTER 9 Adrenoceptor Agonists &Sympathomimetic Drugs151

P R E P A R A T I O
N S
A V A I L A B L E *
Generic Name
Amphetamine, racemic mixture
1:1:1:1 mixtures of amphetamine
sulfate, amphetamine aspartate,
dextroamphetamine sulfate, and
dextroamphetamine saccharate
Apraclonidine
Armodafinil
Brimonidine
Dexmedetomidine
Dexmethylphenidate
Dextroamphetamine
Dobutamine
Dopamine
Droxidopa
Ephedrine
Epinephrine

Fenoldopam
Hydroxyamphetamine
Isoproterenol
Metaraminol
Methamphetamine
Methylphenidate
Midodrine
Mirabegron
Modafinil
Naphazoline
Norepinephrine
Olodaterol
Oxymetazoline
Phenylephrine
Pseudoephedrine
Tetrahydrozoline
Tizanidine
Xylometazoline

Available As
Generic
Adderall

Iopidine
Nuvigil
Alphagan
Precedex
Focalin
Generic, Dexedrine
Generic, Dobutrex
Generic, Intropin
Northera
Generic
Generic, Adrenalin Chloride,
Primatene Mist, Bronkaid Mist,
EpiPen, Auvi-Q
Corlopam
Paremyd (includes 0.25%
tropicamide)
Generic, Isuprel
Aramine
Desoxyn
Generic, Ritalin, Ritalin-SR
ProAmatine
Myrbetriq
Provigil
Generic, Privine
Generic, Levophed
Striverdi respimat
Generic, Afrin, Neo-Synephrine
12 Hour, Visine LR
Generic, Neo-Synephrine
Generic, Sudafed
Generic, Visine
Zanaflex
Generic, Otrivin

REFERENCES
Callaway CW: Epinephrine for cardiac arrest. Curr Opin Cardiol 2013;28:36.
Cotecchia S: The 1-adrenergic receptors: Diversity of signaling networks and
regulation. J Recept Signal Transduct Res 2010;30:410.
De Backer D et al: Comparison of dopamine and norepinephrine in the treatment
of shock. New Engl J Med 2010;362:779.
DeWire SM, Violin JD: Biased ligands for better cardiovascular drugs: Dissecting
G-protein-coupled receptor pharmacology. Circ Res 2011;109:205.
Gurevich EV et al: G-protein-coupled receptor kinases: More than just kinases and
not only for GPCRs. Pharmacol Ther 2012;133:40.
Hawrylyshyn KA et al: Update on human alpha1-adrenoceptor subtype signaling
and genomic organization. Trends Pharmacol Sci 2004;25:449.
Hollenberg SM: Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med
2011;183:847.
Holmes A, Lachowicz JE, Sibley DR: Phenotypic analysis of dopamine receptor
knockout mice: Recent insights into the functional specificity of dopamine
receptor subtypes. Neuropharmacology 2004;47:1117.
Insel PA: (2)-Adrenergic receptor polymorphisms and signaling; Do variants
influence the memory of receptor activation? Sci Signal 2011;4:pe37.
Johnson JA, Liggett SB: Cardiovascular pharmacogenomics of adrenergic receptor
signaling: Clinical implications and future directions. Clin Pharmacol Ther
2011;89:366.
Johnson M: Molecular mechanisms of 2-adrenergic receptor function, response,
and regulation. J Allergy Clin Immunol 2006;117:18.
Lefkowitz RJ, Shenoy SK: Transduction of receptor signals by beta-arrestins.
Science 2005;308:512.
Minzenberg MJ, Carter CS: Modafinil: A review of neurochemical actions and
effects on cognition. Neuropsychopharmacol 2008;33:1477.
Philipp M, Hein L: Adrenergic receptor knockout mice: Distinct functions of 9
receptor subtypes. Pharmacol Ther 2004;101:65.
Sandilands AJ, OShaughnessy KM: The functional significance of genetic variation within the beta-adrenoceptor. Br J Clin Pharmacol 2005;60:235.
Simons FE: Anaphylaxis. J Allergy Clin Immunol 2008;121:S402.
Whalen EJ, Rajagopal S, Lefkowitz RJ: Therapeutic potential of -arrestin- and G
protein-biased agonists. Trends Mol Med 2011;17:126.

2 agonists used in hypertension are listed in Chapter 11. 2 Agonists used in asthma
are listed in Chapter 20. Norepinephrine transporter inhibitors are listed in Chapter 30.

C ASE STUDY ANSWER


The clinical picture is that of autonomic failure. The best
indicator of this is the profound drop in orthostatic blood
pressure without an adequate compensatory increase in
heart rate. Pure autonomic failure is a neurodegenerative
disorder selectively affecting peripheral autonomic fibers.
Patients blood pressure is critically dependent on whatever
residual sympathetic tone they have, hence the symptomatic
worsening of orthostatic hypotension that occurred when

Katzung-Ch09_p133-151.indd 151

this patient was given the a blocker tamsulosin. Conversely,


these patients are hypersensitive to the pressor effects of a
agonists and other sympathomimetics. For example, the a
agonist midodrine can increase blood pressure significantly
at doses that have no effect in normal subjects and can be
used to treat their orthostatic hypotension. Caution should
be observed in the use of sympathomimetics (including
over-the-counter agents) and sympatholytic drugs.

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ion

II

ect

166

Autonomic Drugs

The incidence of hypoglycemic episodes exacerbated by


-blocking agents in diabetics is unknown. Nevertheless, it is
inadvisable to use antagonists in insulin-dependent diabetic
patients who are subject to frequent hypoglycemic reactions if
alternative therapies are available. Beta1-selective antagonists offer
some advantage in these patients, since the rate of recovery from

hypoglycemia may be faster compared with that in diabetics


receiving nonselective -adrenoceptor antagonists. There is considerable potential benefit from these drugs in diabetics after a
myocardial infarction, so the balance of risk versus benefit must be
evaluated in individual patients.

SUMMARY Sympathetic Antagonists


Mechanism of Action

ALPHA-ADRENOCEPTOR ANTAGONISTS
Phenoxybenzamine
Irreversibly blocks 1 and 2
indirect baroreflex activation

Pharmacokinetics,
Toxicities, Interactions

Effects

Clinical Applications

Lowers blood pressure (BP)


heart rate (HR) rises due
to baroreflex activation

Pheochromocytoma
high catecholamine states

Irreversible blocker duration


> 1 day Toxicity: Orthostatic
hypotension tachycardia
myocardial ischemia

Subclass, Drug

Reversibly blocks 1 and 2

Blocks -mediated vasoconstriction, lowers BP,


increases HR (baroreflex)

Pheochromocytoma

Half-life 45 min after IV


injection

Prazosin
Doxazosin
Terazosin

Block 1, but not 2

Lower BP

Hypertension benign
prostatic hyperplasia

Larger depressor effect with


first dose may cause orthostatic hypotension

Tamsulosin

Tamsulosin is slightly selective


for 1A

1A blockade may relax


prostatic smooth muscle
more than vascular
smooth muscle

Benign prostatic
hyperplasia

Orthostatic hypotension
may be less common with
this subtype

Yohimbine

Blocks 2 elicits increased


central sympathetic activity
increased norepinephrine
release

Raises BP and HR

Male erectile dysfunction


hypotension

May cause anxiety excess


pressor effect if norepinephrine transporter is blocked

Labetalol (see
carvedilol section below)

> 1 block

Lowers BP with limited HR


increase

Hypertension

Oral, parenteral Toxicity:


Less tachycardia than other
1 agents

Lower HR and BP reduce


renin

Hypertension angina
pectoris arrhythmias
migraine hyperthyroidism glaucoma (topical
timolol)

Oral, parenteral Toxicity:


Bradycardia worsened
asthma fatigue vivid
dreams cold hands

Block 1 > 2

Lower HR and BP reduce


renin may be safer in
asthma

Angina pectoris hypertension arrhythmias


glaucoma (topical
betaxolol)

Toxicity: Bradycardia fatigue


vivid dreams cold hands

Butoxamine1

Blocks 2 > 1

Increases peripheral
resistance

No clinical indication

Toxicity: Asthma provocation

Pindolol

1, 2, with intrinsic sympathomimetic (partial agonist)


effect

Lower BP modestly lower


HR

Hypertension arrhythmias migraine may


avoid worsening of
bradycardia

Oral Toxicity: Fatigue vivid


dreams cold hands

Phentolamine

Metoprolol
Atenolol
Betaxolol
Nebivolol

BETA-ADRENOCEPTOR ANTAGONISTS
Propranolol
Block 1 and 2
Nadolol
Timolol

Acebutolol
Carteolol
Bopindolol1
Oxprenolol1
Celiprolol1
Penbutolol

(continued )

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CHAPTER 10 Adrenoceptor Antagonist Drugs 167

Subclass, Drug

Mechanism of Action

Carvedilol
Medroxalol1
Bucindolol1
(see labetalol above)

> 1 block

Esmolol

1 > 2

TYROSINE HYDROXYLASE INHIBITOR


Metyrosine
Blocks tyrosine hydroxylase
reduces synthesis of dopamine, norepinephrine, and
epinephrine

Effects

Clinical Applications

Pharmacokinetics,
Toxicities, Interactions

Heart failure

Oral, long half-life Toxicity:


Fatigue

Very brief cardiac


blockade

Rapid control of BP and


arrhythmias, thyrotoxicosis, and myocardial ischemia intraoperatively

Parenteral only half-life 10


min Toxicity: Bradycardia
hypotension

Lowers BP may elicit


extrapyramidal effects
(due to low dopamine in
CNS)

Pheochromocytoma

Toxicity: Extrapyramidal
symptoms orthostatic
hypotension crystalluria

Not available in the USA.

P R E P A R A T I O N S
Generic Name
Available As
ALPHA BLOCKERS
Alfuzosin
Uroxatral
Doxazosin
Generic, Cardura
Phenoxybenzamine
Dibenzyline
Phentolamine
Generic
Prazosin
Generic, Minipress
Silodosin
Rapaflo
Tamsulosin
Flomax
Terazosin
Generic, Hytrin
Tolazoline
Priscoline
BETA BLOCKERS
Acebutolol
Generic, Sectral
Atenolol
Generic, Tenormin
Betaxolol
Oral
Kerlone
Ophthalmic
Generic, Betoptic
Bisoprolol
Generic, Zebeta
Carteolol
Oral
Cartrol
Ophthalmic
Generic, Ocupress

A V A I L A B L E *
Generic Name
Carvedilol
Esmolol
Labetalol
Levobunolol
Metipranolol
Metoprolol

Available As
Coreg
Brevibloc
Generic, Normodyne,
Trandate
Betagan Liquifilm,
others
OptiPranolol
Generic, Lopressor,
Toprol
Generic, Corgard
Bystolic
Levatol
Generic, Visken
Generic, Inderal
Generic, Betapace

Nadolol
Nebivolol
Penbutolol
Pindolol
Propranolol
Sotalol
Timolol
Oral
Generic, Blocadren
Ophthalmic
Generic, Timoptic
TYROSINE HYDROXYLASE INHIBITOR
Metyrosine
Demser

*In the USA

REFERENCES
Ambrosio G et al: -Blockade with nebivolol for prevention of acute ischaemic
events in elderly patients with heart failure. Heart 2011;97:209.
Ayers K et al: Differential effects of nebivolol and metoprolol on insulin sensitivity
and plasminogen activator inhibitor in the metabolic syndrome.
Hypertension 2012;59:893.
Bell CM et al: Association between tamsulosin and serious ophthalmic adverse
events in older men following cataract surgery. JAMA 2009;301:1991.
Berruezo A, Brugada J: Beta blockers: Is the reduction of sudden death related to
pure electrophysiologic effects? Cardiovasc Drug Ther 2008;22:163.
Bird ST et al: Tamsulosin treatment for benign prostatic hyperplasia and risk of
severe hypotension in men aged 40-85 years in the United States: risk

Katzung-Ch10_p152-168.indd 167

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w
2013;347:f6320.
Blakely RD, DeFelice LJ: All aglow about presynaptic receptor regulation of neurotransmitter transporters. Mol Pharmacol 2007;71:1206.
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