SYMPATHOMIMETICS

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SYMPATHOMIMETICS

• Philip J. Kadowitz, Ph.D.

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Learning Objectives

• Describe the actions of sympathomimetics with
  respect to receptor subtype selectivity.
• Explain the actions of dobutamine in the
  treatment of cardiogenic shock and clonidine in
  essential hypertension.
• Drugs dobutamine, albuterol, terbutyline,
  phenylephrine, clonidine, dopamine

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Figure 9-3. Phenylethylamine and some important
catecholamines. Catechol is shown for reference.
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Figure 9-1. Activation of ?1 responses.
Stimulation of ?1 receptors by catecholamines
leads to the activation of a Gq coupling protein.
The ? subunit of this G protein activates the
effector, phospholipase C, which leads to the
release of IP3 (inositol 1,4,5-trisphosphate) and
DAG (diacylglycerol) from phosphatidylinositol
4,5-bisphosphate (PtdIns 4,5-P2). IP3 stimulates
the release of sequestered stores of calcium,
leading to an increased concentration of
cytoplasmic Ca2. Ca2 may then activate
Ca2-dependent protein kinases, which in turn
phosphorylate their substrates. DAG activates
protein kinase C. See text for additional
effects of ?1 receptor activation.
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Gs
Gi
??
??
?s
?i
?s
?i
Figure 9-2. Activation and inhibition of adenylyl
cyclase by agonists that bind to catecholamine
receptors. Binding to ? adrenoceptors stimulates
adenylyl cyclase by activating the stimulatory G
protein, Gs, which leads to the dissociation of
its ? subunit charged with GTP. This ?s subunit
directly activates adenylyl cyclase, resulting in
an increased rate of synthesis of cAMP. Alpha2
adrenoceptor ligands inhibit adenylyl cyclase by
causing dissociation of the inhibitory G protein,
Gi, into its subunits ie, an ?i subunit charged
with GTP and a ?-? unit. The mechanism by which
these subunits inhibit adenylyl cyclase is
uncertain. cAMP binds to the regulatory subunit
(R) of cAMP-dependent protein kinase, leading to
the liberation of active catalytic subunits (C)
that phosphorylate specific protein substrates
and modify their activity. These catalytic units
also phosphorylate the cAMP response element
binding protein (CREB), which modifies gene
expression. See text for other actions of ? and
?2 adrenoceptors.
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RECEPTOR SUBTYPE

• ? ?
• Non selective (1 and 2) norepinephrine epinephr
  ine
• epinephrine isoproterenol
• ? 1 ? 1
• Selective (1 gt 2) phenylephrine dobutamine
• methoxamine
• ? 2 ? 2
• Selective (2 gt 1) clonidine albuterol
• methydopa terbutyline

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1. Epinephrine - ? and ? effects

• low dose - ? effects predominate
• high dose - ? effects predominate
• ? used as bronchodilator and cardiac
  stimulant
• ? causes arrhythmias
• 2. Isoproterenol - ?1 ?2 gtgt ? effects
• ? bronchodilator and cardiac stimulant
• ? causes arrhythmias
• 3. Dobutamine (Dobutrex) - ?1 gtgt ?2 effects
• ? selective cardiac stimulant
• ? causes arrhythmias

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4. Albuterol, Terbutyline - ?2 gtgt ?1 effects

• ? bronchodilator
• ? relaxes uterus
• 5. Phenylephrine (Neosynephrine) - ? 1 gtgt ? 2
  effects
• ? nasal decongestant and pressor agent
• 6. Clonidine (Catapres) - ? 2 gtgt ? 1 effects
• ? antihypertensive
• ? acts in the CNS (NTS) to inhibit the
  vasomotor center
• 7. Norepinephrine - ? 1 , ? 2 , ?1 gtgt ?2
  effects
• ? pressor agent for treatment of circulatory
  shock

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Figure 9-4. Some examples of noncatecholamine
sympathomimetic drugs.
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Figure 9-6. Effects of an ?-selective
(phenylephrine), ?-selective (isoproterenol), and
nonselective (epinephrine) sympathomimetic, given
as an intravenous bolus injection to a dog. (BP,
blood pressure HR, heart rate.) Reflexes are
blunted but not eliminated in this anesthetized
animal.
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Figure 9-5. Effect of epinephrine on the
transmembrane potential of a pacemaker cell in
the frog heart. The arrowed trace was recorded
after the addition of epinephrine. Note the
increased slope of diastolic depolarization and
decreased interval between action potentials.
This pacemaker acceleration is typical of
É1-stimulant drugs. (Modified and reproduced,
with permission, from Brown H, Giles W, Noble S
Membrane currents underlying rhythmic activity in
frog sinus venosus. In The Sinus Node
Structure, Function, and Clinical Relevance.
Bonke FIM editor. Martinus Nijhoff, 1978.)
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Figure 9-7. Examples of beta1- and
beta2-selective agonists.