pharm - nursing sedative hypnotics lecture

7/31/2019 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

pharm - nursing sedative hypnotics lecture

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