Pharm - Nursing Sedative Hypnotics lecture
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Transcript of Pharm - Nursing Sedative Hypnotics lecture
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LearningObjectives UnderstandtheroleofGABAintheCNS ListdrugsthataffecttheGABAsystemandtheir
physiologicandclinicaleffects
Differentiatemusclerelaxantsthatworkonthemotorendplatevs.centrally-actingagents
Understandthecommonside-effectsofdrugsinthesedative-hypnoticandskeletalmusclerelaxantclass
Definethetermstolerance,dependence,andaddiction
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Sedative-hypnotics Alcohol
Ethanol Benzodiazepines
Alprazolam,clonazepam,diazepam,lorazepam,temazepam Barbiturates
Phenobarbital,secobarbital Newerhypnotics
Zolpidem,zaleplon,eszopliclone Melatoninreceptoragonist
Ramelteon 5-HTreceptoragonist
Buspirone
Skeletalmusclerelaxants Depolarizingneuromuscularblockingagents
Succinylcholine Non-depolarizingneuromuscularblockingagents
d-tubocurarine,cistracurium,rocuronium Centrally-actingspasmolytics
Baclofen,cyclobenzaprine,carisoprodol,metaxalone,methocarbamol,tizanidine
Direct-actingmusclerelaxant Dantrolene
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RecommendedReadingKatzungBG,etal.(eds)BasicandClinicalPharmacology,11thedition
Chapter22:Sedative-hypnoticdrugs Chapter23:Thealcohols Chapter27:Skeletalmusclerelaxants
LehneRA.PharmacologyforNursingCare,7thedition Chapters25,34,&38
Sedative-Hypnotics
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Classification Sedative-hypnoticsaresonamedbecausetheyreduce
anxietyandcausedrowsiness
Sedativesoranxiolyticsexertacalmingeffect Hypnoticsproducedrowsinessandencourageonsetand
maintenanceofsleep
Sometimesreferredtoascentralnervoussystem(CNS)depressants
Depressantactivityisgradedanddose-dependent(seegraphicnextslide)
Mostexerttheirpharmacologiceffectviaactionongamma-aminobutyricacid(GABA)receptorsintheCNS
DrugA:Ethanolorbarbiturates;DrugB:Benzodiazepines
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GABA Majorinhibitory
neurotransmitter GABA-releasingneurons
foundthroughouttheCNS
Twomaintypesofreceptors GABAA&GABAB
Manydifferentsubunits,mediatingdifferentresponses
Sedation,amnesia,anesthesia,anticonvulsant,anti-anxiety,musclerelaxation
ChemicalstructureofGABA
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DrugsthataffectGABAEthanol
Benzodiazepines
Barbiturates
Non-BZsedative-hypnotics
Alcohol Ethylalcohol(ethanol)israpidly
absorbedfromtheGItract Otherformsofalcohol:
Methanol Isoproprylalcohol
HasamarkedeffectontheCNS: Sedation Euphoria,lossofinhibition Slowedreactiontime,impaired
motorfunction
Slurredspeech,ataxia Emesis,stupor Coma Respiratorydepression,death
Chemicalstructureofethanol
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Ethanol TwomajorpharmacologiceffectsintheCNS:
EnhancestheactionofGABAatGABAAreceptors Inhibitstheabilityofglutamatetoopencationchannels
associatedwithNMDAreceptors
Othereffects: Heartdepressionofmyocardialcontractility Smoothmusclevasodilationintheperiphery
Clinicaluses: Self-treatmentofanxiety,depression,essentialtremor
Benzodiazepines Groupofchemically-similarcompoundsusedasanxiolyticsand
hypnotics
BindwithGABAAreceptorstoenhanceGABA-ergicactivity Undergohepaticmetabolism
PhaseI(oxidation) Somehaveactivemetaboliteswithlonghalf-lives
PhaseII(conjugation) Durationofactivitybasedonkinetics:
Short-acting Alprazolam,triazolam
Intermediate-acting Clorazepam,lorazepam
Long-acting Diazepam,flurazepam
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BarbituratesOlderagents,nolongercommonlyusedassedative-hypnotics
Longhalf-livescanleadtoaccumulation
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Non-BZHypnotics Agroupofneweragents
introducedinthepast
decade
BindtoGABAAreceptoratdifferentsitethanBZs
Rapidlyabsorbed,fewmetabolites,short-halflives
Heavilymarketed,commonlyprescribedsleep
aids(Ambien,Sonata,Lunesta)
Flumazenil Antagonistof
benzodiazepines,
eszopiclone,zaleplon,zolpidem
Doesntblockactionsofethanolorbarbiturates
Maybeusedinoverdosemanagement
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OrganLevelEffectsSedative-hypnoticshavevaryinglevelsofactivityandclinicalutilityforthefollowing:
Sedation Hypnosis Anesthesia AnticonvulsanteffectsMusclerelaxation
Effectsonrespiratoryandcardiacfunction
PhysiologicEffectsSedation
Mostagentsreduceanxietyatlowdoses
Beyondsimplycausingdrowsiness
Depressanteffectsoncognitivefunctions
Anterogradeamnesia
Hypnosis
Willinducesleepathigherdoses
Decreasesleeplatency Increasestage2NREM DecreaseREMsleep Decreasestage4NREM
SignificanceofeffectsonREMstillunclear
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PhysiologicEffectsAnesthesia
Highdosesofsedative-hypnoticscandepress
theCNStothepointofgeneralanesthesia
Barbiturateshavefavorablecharacteristics
BZsareusedIVincombowithotheragents
Anticonvulsant
BothBZsandbarbituratesinhibitthe
spreadofepileptiformelectricalactivity
Agentsused: Phenobarbital Clonazepam Diazepam Lorazepam
PhysiologicEffectsMuscleRelaxation
BZsandmeprobamatehaveinhibitoryeffectsonpolysynapticreflexes
Mayalsodepresstransmissionatskeletalneuromuscularjunctions
Agents: Clonazepam Diazepam
Respiratory/Cardiac
Effects Athypnoticdoses,these
agentsproduceeffectsonrespirationsimilartonaturalsleep
Athigherdosesorinrespiratory/cardiac
compromisedpatientsmayinduce:
Respiratorydepression Circulatorycollapse
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AbusePotential Mostsedative-hypnoticscanbemisusedandmaybe
compulsivelyabused
Importantdefinitions: Tolerance:theneedforhigherdosestoproduceresponse Physicaldependence:withdrawalsymptomselicitedupon
discontinuation
Addiction:usedespiteharm;psychologicalcravinganddisplayofaddictivebehaviors
TheBZs,barbiturates,andnon-BZagents(i.e.zolpidem)areScheduleIVControlledSubstancesintheUS
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OtherAgents Ramelteon(Rozerem)
AgonistatMT1andMT2(melatoninreceptors)
NodirecteffectsonGABA Reducessleeplatency,but
doesnotappeartoaffectotheraspectsofsleep
architecture
Maydecreasetestosteroneandincreaseprolactin
levels
Notacontrolledsubstance
Buspirone(Buspar) Reducesanxietywithout
causingmarkedsedationor
euphoria
Actsviaserotoninanddopaminereceptors;nodirectGABAactivity
Notappropriateforacuteanxietystates
Doesnotpotentiateimpairmentcausedbyothersedative-hypnotics
OtherClasses(non-GABA) Antihistamines
Diphenhydramine(Benadryl) Hydroxyzine(Atarax) Promethazine(Phenergan)
Antidepressants Tricyclicantidepressants:amitriptyline(Elavil) Trazodone(Desyrel) SSRIs:fluoxetine(Prozac),sertraline(Zoloft)
Antipsychotics Quetiapine
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SkeletalMuscleRelaxants Drugsthataffectskeletalmusclemayactvialocalor
centralmeans
Heterogeneousgroupofdrugs Neuromuscularblockingagents
Non-depolarizing:pancuronium Depolarizing:succinylcholine
Centrally-actingrelaxants
Benzodiazepines Baclofen,Cyclobenzaprine,Carisoprodol,Methocarbamol
Direct-actingskeletalmusclerelaxant Dantrolene
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Neuromuscular
BlockingAgents
History Curareisapoisonderived
fromSouthAmericanplants
Nativesuseditasarrowpoisoninhunting
Producesskeletalandrespiratorymuscleparalysis
Activecompoundisd-tubocurarine
Helpedinourunderstandingofneuromuscularfunction
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NeuromuscularFunction
BlockadeofEndPlate Twomainmechanisms:
Non-depolarizingneuromuscularblockers: AntagonismofacetylcholineactivitybyblockingAChbindingto
nicotinicreceptors
Preventsdepolarizationandpropagationoftheactionpotential Examples:pancuronium,vecuronium,rocuronium
Depolarizingneuromuscularblocker: Paradoxically,toomuchdepolarizingagonistalsostopsthe
propagationoftheactionpotential PersistentdepolarizationmakethemusclefiberresistanttoACh
Example:succinylcholine
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BotulinumToxin BlockadeofAChactivity
atthemotorendplate
mayalsooccurifAChisnotreleasedpre-
synaptically
Resultisparalysis Botulism BoToxCosmetic
Otheruses
ClinicalUseofNeuromuscular
BlockingDrugs Surgicalrelaxation
Facilitatesvarioustypesofsurgery Trachealintubation
Viarelaxationofpharyngealandlaryngealmusclesallowsforplacementoftrachealtubes
Controlofventilation AdministeredinICUtopatientswithventilatoryfailure Allowsforadequategasexchange
Treatmentofconvulsions Occasionallyusedforattenuateperipheralmanifestationsof
seizureactivity
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SpasmolyticDrugsTwomajorclinicalclassifications:
Drugsforthetreatmentofspasticity
Drugsforthetreatmentofmusclespasms
SpasticityCharacterizedbyexaggeratedmusclestretch
reflex
Abnormalreflexactivityisvelocitydependent,withrapidlengtheningofthemusclecausingastrong
contractioninthestretchedmuscle
Occurswhensupra-spinalcontrolislostbecauseofdamagetooralesiononthespinalcord/brain
Causesinclude:Cerebrovascularaccident(CVA),cerebralpalsy(CP),multiple
sclerosis(MS),orspinal/headtrauma
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Spasticity Oftencomposedofthe
followingtriad:
Painfulmassmusclespasms
Rigidposturingoflimbs Increasedreflexes
Anycomponentofthetriadcanoccurinvaryingseverity
http://www.comawakening.com/spasticity.html
MuscleSpasms Increasedtensioninskeletalmusclefollowingcertain
musculoskeletalinjuriesand/orinflammation,suchaswithmusclestrains
Muscletensionisinvoluntary,sothepatientisunabletorelaxthemuscle
Aloopiscreatedbetweennociceptiveinputfromdamagedtissueandmotorneuronscontrollingthemuscle
Resultsinpainful,toniccontractionofthemuscle UppermotorneuronsareNOTinvolved Mayoccurinpatientswithchroniclowbackpain
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SkeletalMuscleRelaxants Maybedividedintotwogroups:
Spasticityindications Musclespasmindications
Adverseeffectsingeneralinclude: Drowsiness Dizziness Ataxia Fatigueandvaryingdegreeofmuscleweakness
Mostrecommendationssupporttheshort-term(
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Baclofen Brandname:Lioresal
(genericavailable) Structuralanalogof
gamma-aminobutyricacid(GABA)
ActsviaGABABreceptors Resultsin
hyperpolarizationandreducedcalciuminflux
Chemicalstructureofbaclofen
IntrathecalBaclofen Mostoftendosedorally,but
maybedelivereddirectlyintothesubarachnoidspaceatdifferentlevelsofthespinalcord Patientswithsevere,
intractablespasticity
Catheterisusuallyimplantedsurgicallyandattachedtoaprogrammablepump
PumpmayalsobeimplantedSQhttp://cuidatucorazon.com
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Tizanidine Brandname:Zanaflex Classifiedasanalpha-2adrenergicagonist Pharmacologicstudiesindicate1/10to1/50thepotencyof
clonidineinbloodpressureloweringability
Useforspasticityfrom: Multiplesclerosis Spinalcordlesions PostCVA
Maybeusedformusclespasms
DantroleneSodium Brandname:Dantrium TheonlySMRthatexerts
itseffectsdirectlyontheskeletalmusclecell
Impairsthereleaseofcalciumfromthesarcoplasmicreticulumduringexcitation
Attenuatesmusclecontractionand
enhancesrelaxation
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Dantrolene Usedforseverespasticityresultingfrom:
Traumaticspinalcordinjury AdvancedMS Cerebralpalsy Stroke
Preoperativepreventionofmalignanthyperthermiainsusceptiblepatientsrequiringanesthesia/surgery
IVduringcrisis,orallyafterwardstopreventrecurrence
NeurolepticMalignantSyndrome Mainsideeffect:generalizedmuscleweakness
AgentsforMuscleSpasms Agents: Carisoprodol(Soma) Chlorzoxazone(ParafonForte) Cyclobenzaprine(Flexeril) Metaxalone(Skelaxin) Methocarbamol(Robaxin) Orphenadrine(Norflex) Tizanidine(Zanaflex)alsoforspasticity
Mechanismofaction:probablyblocksinterneuronalactivityinthedescendingreticularformationandspinalcord
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CarisoprodolToxicity Afteroraladministration,carisoprodolismetabolizedinthe
livertoseveralbiologicallyactivemetabolites,includingmeprobamate
Meprobamatealoneisasedative-hypnoticformerlyavailableunderthetradenamesMiltownorEquanil
Inthe1960s,meprobamatehadastreetvalueandwassoldasUncleMiltiesorBams
Pharmacologically,meprobamateisrelatedtothebarbituratesandisascheduleIVcontrolledsubstance
Abusersofcarisoprodoldemonstratesignsoftoleranceandreportedlysufferwithdrawalsymptomsofanxiety,tremors,andin
somecases,hallucinationsorseizures AcuteoverdosemayresultinCNSdepression,respiratory
depression,comaanddeath
Cyclobenzaprine Brandname:Flexeril(genericavailable) MostcommonlyprescribedSMRwithsimilarindicationsand
mechanismofactionasothermembersofitsclass
Structurallyrelatedtotricyclicantidepressants(TCAs)
Cyclobenzaprine Amitriptyline
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Summary Sedative-hypnoticsincludemedicationssuchas
benzodiazepines,barbiturates,andnon-BZGABAergic
agents
Usedforanxiety,sleep,convulsions,ormusclerelaxants BZsdifferinhalf-life&activemetabolites Non-BZsusedforsleep(zolpidem,zaleplon)
Skeletalmusclerelaxantsareagroupofdrugsthatincludeneuromuscularblockers(actatmotorendplate),centrally
actingagents(workatspinalcordorbrainstem),anddantrolene(directlyonskeletalmuscle)
Usedforspasticityormusclespasms