Autonomic nervous system lecture 5
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  • 1. Copyright © 2001. W. B. Saunders Company. All Rights Reserved. Adrenergic Agonists • Produce their effects by activating adrenergic receptors • Adrenergic receptors are – Alpha 1 – Alpha 2 – Beta 1 – Beta 2 – Dopamine
  • 2.  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).).
  • 3. • 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 receptors.receptors.
  • 4.  αα11 Receptors:Receptors:  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.
  • 5. MCMP 407 NH3 COOH Gq Phospho- lipase C (+) PIP2 IP3 Diacylglycerol Increase Ca2+ Activate Protein Kinase C Response Receptor agonists activate signal transduction pathwaysReceptor agonists activate signal transduction pathways α1 adrenergic receptor HO HO CH OH CH2 NH2 Norepinephrine
  • 6.  αα22 Receptors:Receptors:  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 .
  • 7.  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 neuron.neuron.  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.]
  • 8.  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
  • 9.  ββ Receptors:Receptors:  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 antagonists.antagonists.
  • 10.  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 norepinephrine.norepinephrine.  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
  • 11.  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.
  • 12. Copyright © 2001. W. B. Saunders Company. All Rights Reserved. Dopamine Receptor Activation  Dopamine receptors are located in the kidney Stimulated by dopamine  Causes dilation of the following blood vessels, resulting in increased blood flow  Renal  Mesenteric  Coronary  Cerebral. • Therapeutic uses – Dilates renal vasculature – Enhances cardiac performance
  • 13. • 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 predominate.predominate. • TheThe heart containsheart contains predominantlypredominantly ββ11 receptors.receptors.
  • 14. • 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 pressure.pressure.
  • 15. • Conversely, stimulation ofConversely, stimulation of ββ11 receptorsreceptors characteristically causescharacteristically causes cardiaccardiac stimulationstimulation,, • whereas stimulation ofwhereas stimulation of ββ22 receptorsreceptors produces vasodilationproduces vasodilation (in skeletal(in skeletal vascular beds) andvascular beds) and bronchiolarbronchiolar relaxation.relaxation.
  • 16. • 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.
  • 17. • 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.
  • 18. Characteristics of Adrenergic AgonistsCharacteristics of Adrenergic Agonists CatecholaminesCatecholamines  Sympathomimetic amines :Sympathomimetic amines :  (such as epinephrine, norepinephrine,(such as epinephrine, norepinephrine, isoproterenol, and dopamine) are calledisoproterenol, and dopamine) are called catecholamines.catecholamines.  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.
  • 19. 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.
  • 20. 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 CNS.CNS.
  • 21. NoncatecholaminesNoncatecholamines  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.
  • 22.  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.
  • 23. Copyright © 2001. W. B. Saunders Company. All Rights Reserved. Adrenergic Agonists • Differences in – catecholamines and non- catecholamines – Cannot use orally Can use orally – Cannot cross blood-brain barrier Can cross blood-brain barrier – Short-half live Longer half life Examples: – Norepinephrine Ephedrine – Epinephrine Phenulephrine – Isoproteronol Terbutaline – Dopamine – Dobutamine MenuB F F
  • 24. Copyright © 2001. W. B. Saunders Company. All Rights Reserved. Basic Mechanisms of Adrenergic Receptor Activation • Direct receptor binding • Promotion of norepinephrine release • Blockage of norepinephrine reuptake • Inhibition of norepinephrine inactivation
  • 25.  Mechanism of action of the adrenergicMechanism of action of the adrenergic agonistsagonists • 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.
  • 26. ANS - Adrenergic Drugs Response to Direct-Acting Sympathomimetics
  • 27. • 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 .
  • 28. • 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 receptors.receptors. • Examples ofExamples of uptake blockers isuptake blockers is (cocaine(cocaine ) and agents that cause) and agents that cause norepinephrine release isnorepinephrine release is (amphetamines)(amphetamines)..
  • 29. ANS - Adrenergic Drugs Indirect-acting sympathomimetic
  • 30. • 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 .
  • 31. 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 clinically.clinically.
  • 32. A-EpinephrineA-Epinephrine  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 therapy.therapy.  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.
  • 33.  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 receptors.receptors.  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.