Adrenergic receptors (adrenoceptors)Adrenergic receptors (adrenoceptors)
Two families of receptors:Two families of receptors: αα andand ββ, were, were
identified on the basis of their responses to theidentified on the basis of their responses to the
adrenergic agonists:adrenergic agonists: epinephrine,epinephrine,
norepinephrine, and isoproterenol.norepinephrine, and isoproterenol.
• αα receptor divided to :receptor divided to : αα11 andand αα22 ReceptorsReceptors..
• TheThe αα-adrenoceptors : a-adrenoceptors : a weak responseweak response to theto the
syntheticsynthetic agonistagonist isoproterenolisoproterenol, but they are, but they are
responsive to theresponsive to the naturally occurringnaturally occurring
catecholamines (catecholamines (epinephrine and norepinephrineepinephrine and norepinephrine).).
• ForFor αα receptors,receptors, the rank order of potencythe rank order of potency isis
epinephrineepinephrine >> norepinephrine >> isoproterenol.norepinephrine >> isoproterenol.
• TheThe αα-adrenoceptors are subdivided into two-adrenoceptors are subdivided into two
subgroups,subgroups, αα11 andand αα22,, based on theirbased on their affinitiesaffinities
forfor αα agonists and antagonistagonists and antagonist drugs.drugs.
• For example, theFor example, the αα11 receptorsreceptors have a higherhave a higher
affinity foraffinity for phenylephrinephenylephrine thanthan αα22 receptors.receptors.
• Conversely,Conversely, the drugthe drug clonidineclonidine selectivelyselectively
binds tobinds to αα22 receptors and has less effectreceptors and has less effect onon αα11
These receptors are present on theThese receptors are present on the
postsynapticpostsynaptic membranemembrane of theof the effector organseffector organs
Activation ofActivation of αα11 receptorsreceptors initiatesinitiates a series ofa series of
reactions through areactions through a G protein activationG protein activation ofof
phospholipase C, resulting in thephospholipase C, resulting in the generation ofgeneration of
inositol trisphosphate (IPinositol trisphosphate (IP33)) and diacylglyceroland diacylglycerol
(DAG)(DAG) from phosphatidylinositol.from phosphatidylinositol.
IPIP33 initiates theinitiates the release of Carelease of Ca2+2+
from thefrom the
endoplasmic reticulum into the cytosol, andendoplasmic reticulum into the cytosol, and
DAG turns on other proteins within the cell.DAG turns on other proteins within the cell.
Increase Ca2+ Activate Protein
Receptor agonists activate signal transduction pathwaysReceptor agonists activate signal transduction pathways
These receptors, located onThese receptors, located on presynaptic nervepresynaptic nerve
endingsendings and on other cells, such as theand on other cells, such as the ββ cellcell
of the pancreas, and on certain vascularof the pancreas, and on certain vascular
smooth muscle cells.smooth muscle cells.
When a sympathetic adrenergic nerve isWhen a sympathetic adrenergic nerve is
stimulated, the releasedstimulated, the released norepinephrinenorepinephrine in thein the
synaptic cleft and interacts with thesynaptic cleft and interacts with the αα11 receptors.receptors.
A portion of the releasedA portion of the released norepinephrinenorepinephrine
(circles back) and reacts with(circles back) and reacts with αα22 receptors onreceptors on
the neuronal membrane .the neuronal membrane .
The stimulation of theThe stimulation of the αα22 receptor causesreceptor causes
feedback inhibitionfeedback inhibition thethe release ofrelease of
norepinephrine from the stimulated adrenergicnorepinephrine from the stimulated adrenergic
This inhibitory actionThis inhibitory action decreases furtherdecreases further
outputoutput from the adrenergic neuron and servesfrom the adrenergic neuron and serves
as a localas a local modulating mechanism formodulating mechanism for
reducing sympathetic neuromediatorreducing sympathetic neuromediator outputoutput
when there is high sympathetic activity.when there is high sympathetic activity.
[Note: In this instance these receptors are[Note: In this instance these receptors are
acting as inhibitory autoreceptors.]acting as inhibitory autoreceptors.]
αα22 Receptors are also found on presynpaticReceptors are also found on presynpatic
parasympathetic neurons.parasympathetic neurons.
NorepinephrineNorepinephrine released fromreleased from aa presynapticpresynaptic
sympatheticsympathetic neuron canneuron can diffuse to anddiffuse to and
interact with these (receptorsinteract with these (receptors αα2)2) ReceptorsReceptors,,
inhibiting acetylcholine release .inhibiting acetylcholine release .
This is another local modulating mechanism to controlThis is another local modulating mechanism to control
autonomic activity in a given area.autonomic activity in a given area.
In contrast toIn contrast to αα11 receptors, the effects ofreceptors, the effects of
binding atbinding at αα22 receptors are mediated byreceptors are mediated by
inhibition of adenylyl cyclase and a fall in theinhibition of adenylyl cyclase and a fall in the
These are characterized by aThese are characterized by a strong responsestrong response
toto isoproterenol,isoproterenol, withwith lessless sensitivity tosensitivity to
epinephrine and norepinephrine.epinephrine and norepinephrine.
ForFor ββ receptors, the rank order ofreceptors, the rank order of potency is :potency is :
isoproterenol > epinephrine > norepinephrine.isoproterenol > epinephrine > norepinephrine.
TheThe ββ -adrenoceptors can be subdivided into-adrenoceptors can be subdivided into
major subgroupsmajor subgroups ββ11 andand ββ22 based on theirbased on their
affinities for adrenergic agonists andaffinities for adrenergic agonists and
ββ11 Receptors have approximatelyReceptors have approximately equalequal
affinities for epinephrine and norepinephrineaffinities for epinephrine and norepinephrine,,
whereaswhereas ββ22 receptors have areceptors have a higherhigher
affinity foraffinity for epinephrineepinephrine than forthan for
Thus, tissues with a predominance ofThus, tissues with a predominance of ββ22
receptors (such asreceptors (such as the vasculature ofthe vasculature of
skeletal muscleskeletal muscle)) are particularlyare particularly
responsive to the hormonal effects ofresponsive to the hormonal effects of
circulatingcirculating epinephrineepinephrine released by thereleased by the
Binding of a neurotransmitter at anyBinding of a neurotransmitter at any
ofof ββ rereceptorsceptors results in activationresults in activation
of adenylyl cyclase and, therefore,of adenylyl cyclase and, therefore,
increased concentrations of cAMPincreased concentrations of cAMP
within the cell.within the cell.
• Distribution of receptors:Distribution of receptors:
• Tissues such as theTissues such as the vasculature tovasculature to
skeletalskeletal muscle have bothmuscle have both αα11 andand ββ22
receptors, but thereceptors, but the ββ22 receptorsreceptors
• TheThe heart containsheart contains predominantlypredominantly ββ11
• Characteristic responses mediatedCharacteristic responses mediated
by adrenoceptors:by adrenoceptors:
• As a generalization, stimulation ofAs a generalization, stimulation of αα11
receptorsreceptors produces vasoconstrictionproduces vasoconstriction
(particularly in skin and abdominal(particularly in skin and abdominal
viscera)viscera) and an increase in totaland an increase in total
peripheral resistance and bloodperipheral resistance and blood
• Conversely, stimulation ofConversely, stimulation of ββ11 receptorsreceptors
characteristically causescharacteristically causes cardiaccardiac
• whereas stimulation ofwhereas stimulation of ββ22 receptorsreceptors
produces vasodilationproduces vasodilation (in skeletal(in skeletal
vascular beds) andvascular beds) and bronchiolarbronchiolar
• Desensitization of receptors:Desensitization of receptors:
• Prolonged exposureProlonged exposure to theto the catecholaminescatecholamines
reduces the responsiveness of these receptors,reduces the responsiveness of these receptors,
a phenomenon knowna phenomenon known as desensitization.as desensitization.
• Three mechanisms have been suggested toThree mechanisms have been suggested to
explain this phenomenon:explain this phenomenon:
• 1)1) sequestrationsequestration of the receptors so that theyof the receptors so that they
areare unavailableunavailable for interactionfor interaction with the ligand.with the ligand.
• 2)2) down-regulationdown-regulation, that is, a disappearance, that is, a disappearance
of the receptors either byof the receptors either by destruction ordestruction or
decreased synthesis.decreased synthesis.
• 3)3) Inability to couple to G proteinInability to couple to G protein,,
because thebecause the receptorreceptor has beenhas been
phosphorylatedphosphorylated on the cytoplasmic side.on the cytoplasmic side.
Characteristics of Adrenergic AgonistsCharacteristics of Adrenergic Agonists
Sympathomimetic amines :Sympathomimetic amines :
(such as epinephrine, norepinephrine,(such as epinephrine, norepinephrine,
isoproterenol, and dopamine) are calledisoproterenol, and dopamine) are called
These compounds have the following properties:These compounds have the following properties:
1- High potency:1- High potency: Drugs that areDrugs that are catecholcatechol
derivatives show thederivatives show the highest potencyhighest potency inin
directly activatingdirectly activating αα oror ββ receptors.receptors.
2-2- Rapid inactivation:Rapid inactivation:
•The catecholamines are metabolized byThe catecholamines are metabolized by COMTCOMT
postsynaptically and bypostsynaptically and by MAOMAO intraneuronallyintraneuronally,,
they are also metabolizedthey are also metabolized in other tissues.in other tissues.
•For example,For example, COMTCOMT is in theis in the gut wallgut wall, and MAO is, and MAO is
in thein the liver and gut wall.liver and gut wall.
•Thus, catecholamines have only aThus, catecholamines have only a brief period ofbrief period of
actionaction whenwhen given parenterallygiven parenterally,,
•and they areand they are ineffective when administered orallyineffective when administered orally
because of inactivation.because of inactivation.
3- Poor penetration into the CNS:3- Poor penetration into the CNS:
• CatecholaminesCatecholamines are polarare polar and,and,
therefore, do not readily penetrate into thetherefore, do not readily penetrate into the
CompoundsCompounds lacking the catechollacking the catechol
hydroxyl groups,hydroxyl groups,
have longer half-lives, because they arehave longer half-lives, because they are
not inactivated by COMT.not inactivated by COMT.
These includeThese include phenylephrine, ephedrine,phenylephrine, ephedrine,
and amphetamine.and amphetamine.
These areThese are poor substrates for MAOpoor substrates for MAO and,and,
thus, show a prolongedthus, show a prolonged duration ofduration of
actionaction, because MAO is an important, because MAO is an important
route of detoxification.route of detoxification.
Increased lipid solubility of many of theIncreased lipid solubility of many of the
noncatecholaminesnoncatecholamines permits greaterpermits greater
access to the CNS.access to the CNS.
Mechanism of action of the adrenergicMechanism of action of the adrenergic
• Direct-acting agonists:Direct-acting agonists:
• These drugs act directly onThese drugs act directly on αα oror ββ receptors,receptors,
producing effects similar to those that occurproducing effects similar to those that occur
followingfollowing stimulation of sympathetic nervesstimulation of sympathetic nerves
or release of theor release of the hormone epinephrine fromhormone epinephrine from
the adrenal medulla .the adrenal medulla .
• Examples of direct-acting agonists includeExamples of direct-acting agonists include
epinephrine, norepinephrine, isoproterenol,epinephrine, norepinephrine, isoproterenol,
and phenylephrine.and phenylephrine.
ANS - Adrenergic Drugs
Response to Direct-Acting
• Indirect-acting agonists:Indirect-acting agonists:
• These agents, which includeThese agents, which include
amphetamine, cocaine and tyramine,amphetamine, cocaine and tyramine,
maymay block the uptake ofblock the uptake of norepinephrinenorepinephrine
(uptake blockers)(uptake blockers)
• or areor are taken uptaken up into the presynapticinto the presynaptic
neuron andneuron and cause the release ofcause the release of
norepinephrine from the cytoplasmicnorepinephrine from the cytoplasmic
pools or vesiclespools or vesicles of the adrenergicof the adrenergic
neuron .neuron .
• As with neuronal stimulation, theAs with neuronal stimulation, the
norepinephrine then traverses thenorepinephrine then traverses the
synapse and binds to thesynapse and binds to the αα oror ββ
• Examples ofExamples of uptake blockers isuptake blockers is
(cocaine(cocaine ) and agents that cause) and agents that cause
norepinephrine release isnorepinephrine release is
ANS - Adrenergic Drugs
• Mixed-action agonists:Mixed-action agonists:
• Some agonists, such asSome agonists, such as ephedrine,ephedrine,
pseudoephedrine and metaraminol,pseudoephedrine and metaraminol,
have the capacity both to stimulatehave the capacity both to stimulate
adrenoceptors directlyadrenoceptors directly andand to releaseto release
norepinephrine from the adrenergicnorepinephrine from the adrenergic
neuron .neuron .
11--Direct-Acting Adrenergic AgonistsDirect-Acting Adrenergic Agonists
Direct-acting agonistsDirect-acting agonists bind to adrenergicbind to adrenergic
receptorsreceptors without interacting withwithout interacting with thethe
presynaptic neuronpresynaptic neuron..
The activatedThe activated receptor initiatesreceptor initiates synthesis ofsynthesis of
second messengers and subsequentsecond messengers and subsequent
intracellular signalsintracellular signals..
As a group, these agents areAs a group, these agents are widely usedwidely used
Epinephrine is one of four catecholamines ,Epinephrine is one of four catecholamines ,
(epinephrine, norepinephrine, dopamine(epinephrine, norepinephrine, dopamine,,
andand dobutaminedobutamine ), commonly used in), commonly used in
The first three catecholamines occur naturallyThe first three catecholamines occur naturally
in the body as neurotransmitters; thein the body as neurotransmitters; the latter is alatter is a
synthetic compound.synthetic compound.
EpinephrineEpinephrine is synthesizedis synthesized fromfrom
tyrosinetyrosine in thein the adrenal medulla andadrenal medulla and
releasedreleased, while small quantities of, while small quantities of
norepinephrine,norepinephrine, into the bloodstream.into the bloodstream.
EpinephrineEpinephrine interacts with bothinteracts with both αα andand ββ
At low doses,At low doses, ββ effects (vasodilation) oneffects (vasodilation) on
the vascular system predominate, whereasthe vascular system predominate, whereas
at high doses,at high doses, αα effects (vasoconstriction)effects (vasoconstriction)
are strongest.are strongest.