iiiiiiiiiiiiiiiiiiiiiiiii NR565 Week 3 Study Outline
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Chapter 14: Drugs Affecting the Autonomic Nervous System
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Adrenergic iAgonists i(p. i174): iBind idirectly ito iorgans ior itissues iand ipromote inorepinephrine irelease ior imimickithe
iaction iof inorepinephrine ior iepinephrine. iTarget ithe iSNS iby idirect ireceptor ibinding ito iorgans ior itissues.
There iare ifour imain ireceptor itypes iinvolved iin ithis iprocess: ialpha1, ialpha2, ibeta1, iand ibeta2.
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Alpha1 iReceptors: iMostly iassociated iwith iexcitation ior istimulation iand iare ifound imainly iin ithe ieye, isalivary
iglands, iarterioles, ipostcapillary ivenules, iand iGI iand iGU isphincters.
Alpha2 iReceptors: iMostly iassociated iwith irelaxation ior iwith iinhibition iof inorephinephrine irelease, iand ithe
imajority iare ilocated iin ithe ipresynaptic inerve iterminals iof ismooth imuscles, ithe iislet icells iof ithe ipancreas, isalivary
iglands, iskin, iand imucosa.
Beta1 iReceptors: iFound imostly iin ithe iheart, ibrain, ikidney, iand ilipocytes iare iassociated iwith istimulation iof
iadenylyl icyclase ivia iG5-G-protein-coupled ireceptors ito iincrease icAMP iproduction.
Beta2 iReceptors: iLocated iin ithe ismooth imuscle iof ithe ieye, iarterioles, ivenules, ibronchioles, iliver, ipancreas, iandiGI
iand iGU isystems. iThey istimulate iadenylyl icyclase, iincrease icAMP, iand iactivate icardiac iG1 iunder icertain
iconditions.
Norepinephrine: iStimulates ithe ialpha iand ibeta1 ireceptors.
Epinephrine: iStimulates iall ifour itypes iof ireceptors.
Alpha2 iAgonists iCentral i(p. i174):
Drug iNames:Clonidine i(Catapres), iguanabenz i(Wytensin), iguanfacine i(Tenex), iand imethyldopa.
Pharmacodynamics: iActivation iof icentral ialpha2 ireceptors iresults iin iinhibition iof icardio iacceleration iand
ivasoconstriction icenters iin ithe ibrain i(The imedulla). iThis ileads ito ia idecrease iin iperipheral ioutflow iof
inorepinephrine, ileading ito ia idecrease iin iperipheral iresistance, irenal ivascular iresistance, iheart irate, iand iblood
ipressure. iThey ican iproduce icompensatory ieffects ion iblood ipressure iresulting iin iretention iof isodium iand
iexpansion iof iblood ivolume ithrough imechanisms ithat iare inot idependent ion iadrenergic inerves. iFor ithis ireason,
ithey imay ibe igiven iin icombination iwith ia idiuretic.
Hypertension: iUsually iused ias isecond iline ior ithird iline idrugs iin ithe itreatment iof imild ito imoderate
ihypertension.
Elderly: iDrugs iin ithis iclass imay ibe iinappropriate ifor iuse iin igeriatric ipatients.
, Tapering ithe iDrug: iThese idrugs ishould inot ibe istopped iabruptly ibecause ithe irelative i“lack” iof ialpha2
ireceptors iimpair ithe ihomeostatic ibalance ithat iregulates iSNS iaction. iThe iprescriber ishould igradually
taper ithe idose iwhen idiscontinuing ithe imedication iover i4 idays.
i
Pharmacokinetics:
Absorption iand iDistribution: iAbsorption ifollowing ioral iadministration ivaries iamong ithe idrugs iin ithis
iclass. iClonidine iis ieasily iabsorbed ifrom ithe iGI itract iand ithe iskin iand iis ilipid-soluble, iallowing iit ito
irapidly ienter ithe ibrain iform ithe icirculation. iGuanabenz iand iguanfacine iare ialso iwell iabsorbed. iAll iof ithe
idrugs iare iwidely idistributed iin ibody itissues. iBoth iclonidine iand imethyldopa icross ithe iplacenta iand iare
ifound iin ibreast imilk. iMethyldopa iis inot icompletely iabsorbed iin ithe igut iand iis iabsorbed ivia ian iaromatic
iamino iacid itransport isystem.
Metabolism iand iExcretion: iThe iliver, iin ivarying idegrees, imetabolizes ieach iof ithese idrugs. iThe ikidney iis
ithe iorgan iof iexcretion ifor ieach iof ithese idrugs. iPatients iwith irenal ifailure iwill iexperience iincreased
iadverse ieffects ias imethyldopa iand iits imetabolites iaccumulate, iresulting iin iprolonged ihypotensive iaction.
Guanfacine: iHas ia isignificant ifirst-pass ieffect. iThe idrug iis imetabolized iby iCYP3A4 iwith iabout i50% iofithe
ioral idose imetabolized ito iinactive isulfate imetabolites iand i50% ieliminated iunchanged iin ithe iurine.
Methyldopa: iExtensively imetabolized iby ithe iliver ito iinactive imetabolites, iwith iabout i20% iof ithe iactive
idrug iappearing iin ithe iplasma.
Clonidine: iAbout i50% iof iclonidine idose iis ihepatically imetabolized ito iinactive imetabolites, iand ithe
iremaining i50% iis iexcreted iunchanged iin ithe iurine.
Pharmacotherapeutics: iCautious iuse iis irecommended iin ithe ipresence iof isevere icoronary iinsufficiency, irecent
iMI, iand irenal ifunction iimpairment. iBecause ithey icross ithe iblood ibrain ibarrier, imethyldopa iand iclonidine iare
iused icautiously iin ithe ipresence iof icerebrovascular idisease.
Clonidine: iShould ibe iused iwith icaution iwith ipatients iwho iare iat irisk ifor imental idepression, iand iit ishould
ibe idiscontinued iif idepression ioccurs. iShould ibe iavoided iin ipatients iat irisk ifor ibradycardia. iBecause ithey
iaffect icognitive ifunction, icentrally iacting ialpha2 iagonists ishould ibe iavoided ior iused iwith iextreme icaution
iin ipopulation isuch ias iolder iadults iwhom ithis iadverse iresponse icreates isignificant iproblem.
Preganancy iCategory iC. iCrosses ithe iplacenta iand ino iwell-controlled istudies ihave ibeen idone iin ipregnant
iwomen.
Guanabenz: iPregnancy iCategory iC. iNo iadequate ihuman istudies ihave ibeen idone ion iguanabenz, iand
iskeletal ianomalies iwere ifound iin ithe ioffspring iof imice ithat iwere igiven ithe idrug.
Methyldopa: iPregnancy iCategory iB iin ioral iform. iPregnancy iCategory iC iin iinjectable iform. iAppears iin
ibreast imilk.
i i i i
Chapter 14: Drugs Affecting the Autonomic Nervous System
i i i i ii i i
Adrenergic iAgonists i(p. i174): iBind idirectly ito iorgans ior itissues iand ipromote inorepinephrine irelease ior imimickithe
iaction iof inorepinephrine ior iepinephrine. iTarget ithe iSNS iby idirect ireceptor ibinding ito iorgans ior itissues.
There iare ifour imain ireceptor itypes iinvolved iin ithis iprocess: ialpha1, ialpha2, ibeta1, iand ibeta2.
ht
ps:/
www.
yout
ube
.com/
wat
ch?
v=Kt
mV-
yMDYPI
Alpha1 iReceptors: iMostly iassociated iwith iexcitation ior istimulation iand iare ifound imainly iin ithe ieye, isalivary
iglands, iarterioles, ipostcapillary ivenules, iand iGI iand iGU isphincters.
Alpha2 iReceptors: iMostly iassociated iwith irelaxation ior iwith iinhibition iof inorephinephrine irelease, iand ithe
imajority iare ilocated iin ithe ipresynaptic inerve iterminals iof ismooth imuscles, ithe iislet icells iof ithe ipancreas, isalivary
iglands, iskin, iand imucosa.
Beta1 iReceptors: iFound imostly iin ithe iheart, ibrain, ikidney, iand ilipocytes iare iassociated iwith istimulation iof
iadenylyl icyclase ivia iG5-G-protein-coupled ireceptors ito iincrease icAMP iproduction.
Beta2 iReceptors: iLocated iin ithe ismooth imuscle iof ithe ieye, iarterioles, ivenules, ibronchioles, iliver, ipancreas, iandiGI
iand iGU isystems. iThey istimulate iadenylyl icyclase, iincrease icAMP, iand iactivate icardiac iG1 iunder icertain
iconditions.
Norepinephrine: iStimulates ithe ialpha iand ibeta1 ireceptors.
Epinephrine: iStimulates iall ifour itypes iof ireceptors.
Alpha2 iAgonists iCentral i(p. i174):
Drug iNames:Clonidine i(Catapres), iguanabenz i(Wytensin), iguanfacine i(Tenex), iand imethyldopa.
Pharmacodynamics: iActivation iof icentral ialpha2 ireceptors iresults iin iinhibition iof icardio iacceleration iand
ivasoconstriction icenters iin ithe ibrain i(The imedulla). iThis ileads ito ia idecrease iin iperipheral ioutflow iof
inorepinephrine, ileading ito ia idecrease iin iperipheral iresistance, irenal ivascular iresistance, iheart irate, iand iblood
ipressure. iThey ican iproduce icompensatory ieffects ion iblood ipressure iresulting iin iretention iof isodium iand
iexpansion iof iblood ivolume ithrough imechanisms ithat iare inot idependent ion iadrenergic inerves. iFor ithis ireason,
ithey imay ibe igiven iin icombination iwith ia idiuretic.
Hypertension: iUsually iused ias isecond iline ior ithird iline idrugs iin ithe itreatment iof imild ito imoderate
ihypertension.
Elderly: iDrugs iin ithis iclass imay ibe iinappropriate ifor iuse iin igeriatric ipatients.
, Tapering ithe iDrug: iThese idrugs ishould inot ibe istopped iabruptly ibecause ithe irelative i“lack” iof ialpha2
ireceptors iimpair ithe ihomeostatic ibalance ithat iregulates iSNS iaction. iThe iprescriber ishould igradually
taper ithe idose iwhen idiscontinuing ithe imedication iover i4 idays.
i
Pharmacokinetics:
Absorption iand iDistribution: iAbsorption ifollowing ioral iadministration ivaries iamong ithe idrugs iin ithis
iclass. iClonidine iis ieasily iabsorbed ifrom ithe iGI itract iand ithe iskin iand iis ilipid-soluble, iallowing iit ito
irapidly ienter ithe ibrain iform ithe icirculation. iGuanabenz iand iguanfacine iare ialso iwell iabsorbed. iAll iof ithe
idrugs iare iwidely idistributed iin ibody itissues. iBoth iclonidine iand imethyldopa icross ithe iplacenta iand iare
ifound iin ibreast imilk. iMethyldopa iis inot icompletely iabsorbed iin ithe igut iand iis iabsorbed ivia ian iaromatic
iamino iacid itransport isystem.
Metabolism iand iExcretion: iThe iliver, iin ivarying idegrees, imetabolizes ieach iof ithese idrugs. iThe ikidney iis
ithe iorgan iof iexcretion ifor ieach iof ithese idrugs. iPatients iwith irenal ifailure iwill iexperience iincreased
iadverse ieffects ias imethyldopa iand iits imetabolites iaccumulate, iresulting iin iprolonged ihypotensive iaction.
Guanfacine: iHas ia isignificant ifirst-pass ieffect. iThe idrug iis imetabolized iby iCYP3A4 iwith iabout i50% iofithe
ioral idose imetabolized ito iinactive isulfate imetabolites iand i50% ieliminated iunchanged iin ithe iurine.
Methyldopa: iExtensively imetabolized iby ithe iliver ito iinactive imetabolites, iwith iabout i20% iof ithe iactive
idrug iappearing iin ithe iplasma.
Clonidine: iAbout i50% iof iclonidine idose iis ihepatically imetabolized ito iinactive imetabolites, iand ithe
iremaining i50% iis iexcreted iunchanged iin ithe iurine.
Pharmacotherapeutics: iCautious iuse iis irecommended iin ithe ipresence iof isevere icoronary iinsufficiency, irecent
iMI, iand irenal ifunction iimpairment. iBecause ithey icross ithe iblood ibrain ibarrier, imethyldopa iand iclonidine iare
iused icautiously iin ithe ipresence iof icerebrovascular idisease.
Clonidine: iShould ibe iused iwith icaution iwith ipatients iwho iare iat irisk ifor imental idepression, iand iit ishould
ibe idiscontinued iif idepression ioccurs. iShould ibe iavoided iin ipatients iat irisk ifor ibradycardia. iBecause ithey
iaffect icognitive ifunction, icentrally iacting ialpha2 iagonists ishould ibe iavoided ior iused iwith iextreme icaution
iin ipopulation isuch ias iolder iadults iwhom ithis iadverse iresponse icreates isignificant iproblem.
Preganancy iCategory iC. iCrosses ithe iplacenta iand ino iwell-controlled istudies ihave ibeen idone iin ipregnant
iwomen.
Guanabenz: iPregnancy iCategory iC. iNo iadequate ihuman istudies ihave ibeen idone ion iguanabenz, iand
iskeletal ianomalies iwere ifound iin ithe ioffspring iof imice ithat iwere igiven ithe idrug.
Methyldopa: iPregnancy iCategory iB iin ioral iform. iPregnancy iCategory iC iin iinjectable iform. iAppears iin
ibreast imilk.
