Pharm-Block6CNSMemorizer

8/11/2019 Pharm-Block6CNSMemorizer

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Introduction

Classes ofNeurotransmitters

Amino Acids GABA(aminobutyricacid)

Glutamate

Aspartate(NMDA)

Glycine

Acetylcholine Acetylcholine

Amines Dopamine

NE,E

5hydroxytryptamine(serotonin)

Histamine

Peptides Endorphin family proenkephalinderivatives

proopiomelanocortinderivates

prodynorphinderivatives

Vasotocin family vasopressin

oxytocin

Glucagon family glucagon

vasoactiveintestinalpolypeptide(VIP)

secretin

growthhormonereleasingfactor

Neurokinins

Cholecystokinins

Neuropeptides Y

Others Purines

NO

Arachidonic Acid derived prostaglandins

thromboxanes

leukotrienes

Ligand-gated ion channels Includesreceptorsfor:NicotinicAchR

Mostaminoacidreceptors

GABAAR

mostglutamateR

aspartateR

glycineR

(NOTGABABandsomeglutamateR)

onesubtypeofserotoninR:5HT3

Ionchannelisatetramerorpentamerof4TMsubunits

G-protein coupledreceptors (GPCR)

Includesreceptorsforallothers!

Muscariniccholinergicreceptors

GABABsomeglutamatereceptors

allotherreceptorsforamineand

peptideneurotransmitters

7TMreceptor.Agonistbindstoextracellular

side;Gproteinbindstointracellularside

Gproteincouplesreceptortoeffector:Gproteincomposedof3subunits

:specificforreceptor,bindsGTP

GTPhydrolysisactivateseffector

or dimerregulateeffector:

adenylcyclase

phospholipaseC

inwardrectifyingK+channel

Ca2+channel

PIP3kinase


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Mechanisms oftermination of NT action

AchismetabolizedbyAchE

AmineandaaNTstakenupbyspecifictransportsystemsonpresynapticmembrane

OtherNTsmetabolizedbyenzymes,whichmayormaynotbenearthesynapse

Mechanisms by which amedication can affectneurotransmission

1.agonistorantagonizereceptor

2.bindtositedistinctfromNTbindingsiteandalteraffinityofreceptorforNT

3.inhibitpresynapticreuptakeofNT

4.inhibitsynthesisormetabolismofNT

5.inhibitorpotentiatereleaseofNT

Acetylcholine Cholinergicantagonists:

relativeexcessofAchinparkinsons,

canusemuscarinicantagoniststotreat

relativeexcesscauseEPS;canuse

cholinergicantagoniststotreat

EPScausedbyantipsychotic

drugs(dopaminergicantagonists)

anticholinergicblockadecauses:

antiemetic,sedation,amnesia

Cholinergicagonists:

AlzheimerstreatedwithAchE

inhibitors

ExcessiveAchEdosesproducecentral

cholinergicsyndromeconvulsions

coma,death

Centrallyactingnicotinicagonistsmay

haveanalgesicproperties

Epibatidine Centrallyactingnicotinicagonist.Hasanalgesicactivity.Isolatedfromskinofpoisonous

tricolorfrog.

GABA Inhibitory.

GABAA:ligandgatedClionchannel,hyperpolarizesmembrane

morecommoninCNS

significantheterogeneity:diverseeffectsofmedsmany,manyGABAAsubtypes.

benzodiazepines: (=potentiate)effectofGABAatGABAAreceptor.

Neweranticonvulsants:GABAreuptake

endogenousligandatreceptorfor9THC:GABArelease

GABAB:GPCR.Baclofenactsasanagonist

Gabapentin GABAreleasefromnerveterminals.

Usedasananticonvulsantandinthetreatmentofchronicpain

Baclofen Centrallyactingmusclerelaxant.

UsedtotreatmusclespasmsassociatedwithSCinjuriesandneurodegenerativediseases.

Glycine Inhibitory.ReceptorslocatedprimarilyinbrainstemandSC.

NMDA(Glutamate and aspartate)

Excitatoryneurotransmitter.

Many,manyglutamate/aspartatesubtypes.

Someareligandgatedionchannelsand

someareGPCRs.

NMDA(NmethylDaspartate)receptors:

excessiveactivityassociatedwith

neuronalinjuryanddeath.

NMDAantagonistsproduceanalgesia,dissociativeanesthesia

KetaminePhencyclidine (PCP)AmantadineMemantine

AntagonistsatNMDAreceptors.

KetamineandPCPcausedissociativeanesthesia

AmantadineusedtotreatParkinsondisease

MemantineusedtotreatadvancedAlzheimerdisease


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Dopamine D1,D5:adenylcyclase

D2,D3,D4:adenylcyclase

Dopaminergicneuronsinvolvedinpathways

thataffectbehaviorandmovement.

Prevalentinbasalganglia,nucleus

accumbens,amygdala.

Lossofdopaminergicneuronsinbasal

gangliaParkinsons

Dopamineantagonists:

effectiveintreatingpsychosessuchas

acutemaniaandschizophrenia

maycausedysphoria,catatoniain

normals

DAantagonistsareantiemetic

Dopamineagonists/potentiation:

Cocaineinhibitsreuptakeofdopamine

reinforcingeffectofcocaine

Dopamineagonistsoftencausenausea

NeweranticonvulsantsDArelease

NE Both and adrenoreceptorsinCNS.

1:causesdepolarizationduetoinK+

conductance,activationofadenyl

cyclase,and/orstimulationof

phospholipaseC2:causeshyperpolarizationduetoinward

rectifyingK+conductance.

:adenylcyclase

Alongwithserotonin,NEneuronsregulate

mood.

Depressionassociatedwithcentral

noradrenergicactivity:earlier

antidepressants(tricyclicsandMAOinhibitors)potentiateeffectsatthese

neurons.

ClonidineDexmedetomidine

2agonists.Haveusefulantihypertensiveactivity.Unlikemanyantihypertensives,rarely

causehypotension.

Profoundlysedatingwithoutaffectingventilatorydrive.

Serotonin (5 HT) 5HT1receptorhasatleast5subtypes

(5HT1A5HT1E):allareGPCRslinked

toadenylcyclaseinhibitionortoK+or

Ca++channels.Associatedwithregulationofmoodas

wellaspathogenesisofmigraine

5HT2receptorhasatleast3subtypes

(5HT2A5HT2C):GPCRslinkedto

activationofphospholipaseC.

5HT3receptorisligandgatedionchannel

5HT45HT7areallGPCRs

Manysubtypesofreceptors,butonlya

fewhavespecificagonistsorantagonists.

5HTreceptorsimportantinregulationof

mood.Newerantidepressentsare

inhibitorsofserotonin(


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Enkephalins Pentapeptideswithfouraminoacidsincommon(namedonbasisoffifthaa).

PrimarilyactasNTsreleasedfromsortinterneuronswithinthespinalcard

Alsofoundinadrenalmedullaandincatecholaminecontainingnerveterminals.

Endogenousopioidagonists:Enkephalins(andexogenousopioids)bindto receptorson

nerveterminalscontainingNTslikesubstanceP:InhibitionofsubstancePreleasedmay

beamechanismofopioidanalgesia.

Enkephalinsmetabolizedextremelyrapidlyinvivo:IVadminnotuseful.Stableanalogueshavebeensynthesized,mayfindfutureuseasanalgesics.

Dynorphins Endogenousligandsatthe receptor.Similardistributiontoenkephalins.

opioidreceptormostprevalentopioidreceptorinCNS.

Endorphins Endogenousopioidagonists.

Proopiomelanocortin(POMC)

Containsmanyopioidandnonopioid

peptides.Foundinanteriorpituitaryand

hypothalamus.

Thefinal31aasformendorphin(themost

importantofthehumoralendogenousopioids).endorphinisanimportant

endogenousligandatthereceptor

SelectivecleavageofPOMCyieldsmany

nonopioidhormones:

ACTH

MSH

lipotropins


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Neurodegenerative Diseases

Expirimental or theoreticaletiology of neuronal death

Toxic:6hydroxydopamineofMPTP

Excitotoxicity:ExcessglutamateinvolvingtheNMDAreceptor(mediatesinfluxofcalcium

ionswhichcausesneoronaldeathinexcess)

ROS:

ROScansometimesbegeneratedwhenoxygenbindstoheme

Hb2++O2HbO2(normalrxn)

Hb2++O2Hb3++O2(oxygenreducedtosuperoxideanion)

Normally,superoxideanionismetabolizedbysuperoxidedismutase(SOD):

2O2+2H+H2O2+O2

Andhydrogenperoxide(whichisalsotoxic)ismetabolizedbyglutathioneperoxidase

H2O2+2GSH2H2O+GSSG(GSH=reducedglutathione;GSSG=oxidizedform)

HydrogenperoxideisalsoproducedbyMAOinneurons:

oxidationofamonoamineproducesammoniaandhydrogenperoxide

IfglutathionetodetoxifyH2O2,theVERYreactivehydroxylradicalisproduced:

H2O2+Fe2+OH+OH+Fe3+(Fentonreaction)

Parkinsons:mayreflectlossofabilityofcelltoprotectitselffromoxygenradicals

ALS:MayinvolvedefectinSOD

Management

of

Parkinson

Disease

Parkinson disease Fourcharacteristics:

1)Bradykinesia(slownessofmovement)

2)Rigidity

3)Tremor

4)Balanceimpairment

Typicallybeginsinlatemiddleagewith

restingtremor(tremordisappearswith

voluntarymovement).About1/3

developdementiaiftheylivelong

enough.

Parkinsonism:similarsymptomstoParkinsondisease,butusuallyreversible.More

oftenthannot,symptomsarecausedby

medications.i.e.toxiceffectsof

dopamineantagonistsusedtotreat

psychoses.

Diseaseduetolossofdopaminergicneurons

insubstantianigrawhichprojectto

caudateandputamen. Characteristicso

Parkinsonsareseenwhenlossexceeds

80%.Leadstorelativeexcessin

cholinergicneuronalactivitytherapy

involveseitherpotentiatingdopaminergic

activityorinhibitingcholinergicactivityin

thestriatum.

Drugseffectiveintreatmentinclude:

Levodopa(DAprecursor)Dopamineagonists

Cholinergicantagonists

SelectiveMAOinhibitors

COMTinhibitors

NMDAantagonists

Levodopa(given w/Carbidopa)

PrimarymedicationusedtotreatParkinson

disease.DAcannotbeuseddirectly

becausedithasoralbioavailability,

doesnotcrossBBB,andisassociated

withsignificantnausea.

Levodopaisrapidlydecarboxylatedto

dopaminebyaromaticaminoacid

decarboxylase,thereforeitisalmost

alwaysgivenincombinationwithan

inhibitorofthisenzymesuchascarbidopa.

Majorproblem:Patientsbecomerefractoryin

afewyears.

AEs:N&V,hallucinations,orthostatichypo

Ifabruptlystoppedneurolepticmalignant

syndromemayresult.

PK: rapidonset,shortduration

Transportedacrossgutepitheliumand

BBBbyactivetransportsystemfor

aromaticaas.Dietaryaascompete

forbothoftheseprocesses.

Inthebrain,levodopaactivelytakenupbypresynapticterminalsofDA

neurons,decarboxylatedtoDA,and

incorporatedintovesicles

Peakeffects:30min1hr

Durationofaction:46hrs

(severaldosesneededperday)

Widefluctuationsineffect

Justtherightamountisneeded:

toolittlerigidity,bradykinesia

toomuchdyskinesias


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Effects of dopamine excess Dyskinesia:commonlypresentsaschoreiformmovements(rapidlyflowing,nonstereotyped,

involuntarymovementsofbodyunbeknownsttopatient)ordystonia(involuntary

sustainedposture,mayactuallyoccurindopaminergicexcessordeficiency)

Nausea,hallucinations,confusion

antipsychoticandantiemeticmedicationsaredopaminergicantagonists;theyshould

NOTbeusedtotreattoxiceffectsoflevodopainParkinsonpts!

PeripheraleffectsofDA:orthostatichypotension,cardiacarrhythmias.NonselectiveMAO

inhibitorsshouldbestopped2weekspriortostartinglevodopatharapytopreventDA

concentrationsthatcancausehypertensivecrisisormalignantcardiacarrhythmia.

Advantages ofDopaminergic agonistsover Levodopa inParkinsons

Norequirementforenzymaticconversionbyintactneuron

SelectiveforcertainsubtypesofDAreceptors

Longerdurationofaction

NoconverstiontoROS

Bromocriptine Dopaminergicagonistwithlonghistoryof

useinPD.

D2andD3agonistandD1antagonist.

Taken3x/daily.

Sharesbeneficialandtoxiceffectsof

levodopa.

Ergotderivativecancauseretroperitoneal

andpulmonaryfibrosisandvasospasm(avoidonRaynauddzandother

disordersofsmallarteries)

Pergolide Dopaminergicagonist,verysimilartobromocriptineexceptisanagonistatD1.

PramipexoleRopinirole

Dopaminergicagonists.GreateractivityatD3comparedtoD2.

Maynothavecrossrefractivity.

Selegiline SelectiveinhibitorofMAOB(theformofthe

enzymepresentinstriatum).

DAmetabolismandneuronalproduction

ofhydrogenperoxide.NoneedtoavoidtyraminebecauseMAOA

(intheperipheryandgut)isnot

inhibited.

ProducesfewAEsinearlyParkinsonpts.

Asdzprogresses,selegilinemaypotentiate

theadversemotoreffectsoflevodopa.

TrihexyphenidylBenztropineDiphenhydramine

Centrallyactingmuscarinicantagonistsuseful

inparkinsondz.

Diphenhydramine:antihistaminewith

antimuscariniceffects

Primarilyusefulearlyindisease.

TypicalanticholinergicAEs(sedation,dry

mouth,urinaryretention)

Amantadine WeakantagonistatNMDAreceptor,maybeusedinearlyPD.

UsedtopreventinfluenzaA

TolcaponeEntacapone

InhibitorsofcarboxyOmethyltransferase

(COMT).

Actbyperipherallyincreasinghalflifeof

levodopa(similartocarbidopa).

COMTinhibitorslesstoxicthanDAagonists

ormuscarinicantagonists.

Tolcaponemayveryrarelycausehepatic

necrosis:monitorLFTs.

Entacaponeisnothepatotoxic.

Management of diseaseprogression

Noclearconcensusonwhentostarttherapy,orhowtousetherapy.

Asthediseaseprogresses,itbecomesfarmoredifficulttomanage.


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ManagementofAlzheimer Disease

Alzheimer disease Lossofcholinergicneuronsinhippocampusandcortex(notethatamnesiacanbeproducedby

centrallyactinganticholinergicsuchasscopolamine).

TacrineDonepezilRivastigmine

Galantamine

CentrallyactingAchEinhibitors.

Smallbutstatisticallysignificant

improvementsinneuropsychiatrictest

scores.Improvementslastedlessthanayear.

Cholinergicexcess:Nausea,vomiting,

diarrhea

Memantine NMDAantagonists.ApprovedforadvancedAD.

NotethatsomeotherNMDAantagonistsproducedissociateanesthesiaandhallucinations,bu

notthisone.

Coxibs MayriskofdevelopingAD.

Maycauseregressionofplaques.

Notknown:differenceinASAvs.ibuprofenvs.naproxen,orifnewCOX2inhibitorsarealso

effective.

Management

of

ALS

Disease

Riluzole Preventsreleaseofneurotransmitterglutamate.

Barelysignificantprolongationofsurvival(19monthsvs.17months)

ManagementofHuntington Disease

Out of Luck Cantreatparanoia/depressionsymptomsonly

Management of Headache

Tension headaches usuallybilateralandbifrontal/occipitonuchal

Viseclampinghead

Mostcommonformofheadache

Cluster headaches Afewshortlivedattacksofperiorbitalpainperdayforafewmonths

Oftenfollowedbysymptomfreeperiodofmanymonthsbeforenextepisode

80%male

Painbeginswithoutwarningandreachesapeakwithinafewminutes,lastsforanhourortw

Painisalmostalwaysunilateralandhasautonomicfeatures(lacrimation,eyereddening,

stuffiness,nausea,ptosis).

CanbepreciptatedbyingestionofEtOH.

Migraine headches Classicmigraine:migrainewithaura

Commonmigraine:migrainew/oaura,isfarmorecommon

Frontotemporalpay(uni orbilateral),lasts

fromafewhourstodays.

F>M

Manysufferersgrowoutoftheirafflication

aftermiddleage.

Formertheory:intracranialvasodilation.

Basedonobservationthatvasoconstrictorscanalleviatepain.

Theoryisdiscreditedbutthese

medicationsarestillused.

Currenttheory:hereditarydysfunctionof

seritonergicneuraltransmission.Curren

medicationsareagonstsorantagonistsa

specificsubtypesofserotonin(5HT)

receptors.


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Ergot poisoning adrenergicagonismgangrene

uterinestimulationabortion

psychosis5HTagonism

ErgotamineDihydroergotamine

Relativelynonselectiveagonistat

5HT1,5HT2,andadrenergicRs

UsuallygivenwithCaffeine

PO,suppositoryDihydroergotaminemaybegivenIVorIM

formorerapidonset.

Nausea(canbeproblematicasnauseaalmost

alwaysaccompaniesmigraineattack.)

Vasoconstrictioncancause:

ParesthesiasinfingersandtoesAnginapectoris

ShouldNOTbegiventopregnantwomen,

becauseuterinecontractionsmayleadto

miscarriage!

Methysergide 5HT2antagonist

IncontrasttootherErgotconstituents,has

littlevasoconstriveoroxytocicactivity.

Ineffectiveintreatingmigraineattack;only

usedprophylactically.

Retroperitoneal,pleuropulmonary,

pericardia,orendocardialfibrosis(to

minimizerisk,givefornomorethana

fewmonthsatatimewithaseveral

weeklongbreakinbetween)

SumatriptanZolmitrptanNaratriptanRizatriptanEletriptan

Selective5HT1Dagonist.Haslessactivityatother5HT1receptorsandessentiallyno

activityatother5HToradrenergic

receptors.

Probablyactsbypreventing5HTrelease.

The5HT1Dreceptorblocksthereleaseof

serotoninfromserotonergicnervesviaa

presynapticmechanism.Unknownwhy

agonisthererelatestomigrainepain.

MaybegivenSubQ:onsetin10min.

Orally:onsetin30min.

Naratriptan:sloweronsetandlonger

duration,fewerrecurrences

Zolmitriptan/Rizatriptan:fasteronsetafter

oraladminthanSumitriptan,availablein

orallydisintegratingtables

Otherdevelopments:Nasalspray

ShouldNOTbegivenIV!CancauseMIanddeath.

Contraindicatedinptswithvasospastic

disease(Prinzmetalangina,Raynaud)

UsecautiouslywithCAD.

Mayexperiencegeneralwarmthortingling

Noneofthetriptanagentsshouldbegiven

withinadayofanergotdrugorwithin2

weeksofaMAOinhibitor.

Management of headache Tensionheadaches:NonopioidanalgesicssuchasASA,APAP,ibuprofen.Treatanxietyor

depressionasappropriate.

Clusterheadaches:triptans,ergotamine,methysergide.Oftenrespondtomedsineffectivein

treatingmigraines,suchaslithium,prednisone,verapamil.

Episodicmigraine:Mosteffective:parenteralsumatriptan.Ifunresponsivetotriptans,maytry

ergotamine.

Prophylaxisofmigraine:blockers,valproicacid(antivonvulsant),verapamil,tricyclics,

methysergide(inprogressionfromleastmosttoxic).


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Psychopharmacology: Antipsychotic, Antianxiety, Antidepressants & Mood-Stabilizing Agents

Psychosis Impairmentofbehaviorandinabilitytothink

coherently,comprehendreality,orhave

insightintothepresenceofthese

abnormalities.

Schizophreniaisthemostcommonpsychosis:

chronicallydisorderedthinking

emotionalwithdrawal

delusions,auditoryhallucinations

Commonsymptoms:

Delusions(falsebeliefs)

Hallucinations(abnormalsensations)

Major depressionBipolar disorder

MajorDepression

Approximately10%ofthepopulationwillatsomepointbeaffectedbymajordepression

Sadnessanddespair,mentalslowing,lossofconcentration,insomniaorhypersomnia,

Anorexiaorovereating;~15%ofaffectedpatientswillattemptsuicide

Bipolarismuchlesscommon.Alternatingmaniaanddepression.

Anxiety disorders Severeanddisablingsymptoms,butcanstillcomprehendreality.

Canhavelargebenefitwithcombinationofpsychotherapyanddrugtherapy

Cognitive Disorders Usuallyassociatedwithspecificneuropathological,metabolic,ortoxicchanges.

Usuallynotamenabletosuccessfulpharmacologicalintervention.

Personality disorders Lifelongconditionscharacterizedbycertainpersonalitystyles:Drugsusuallynoteffective

(avoidant,withdrawn,paranoid,dependent).

Canalsohavebehavioralpatterns(substanceabuse,abnormaleating,hypochondriasis)

Antipsychotics

Overview of Antipsychotics Phenothiazines:chlorpromazine

Butyrophenones:haloperidol

Atypical:olanzapine

Neuroleptic(goodsynonym)

Majortranquilizer(badsynonym)

Chlorpromazine Prototypicalantipsychotic.Phenothiazine.

Verydirtydrug:competitiveantagonistat:D2(primaryantipsychoticeffect)

Muscarinic

H1

adrenergic

5HT2

Whengiventopsychoticpt:

improvementinthoughtdisorder,

fewerhallucinations&delusions,reality

perceptionimproves

Whengiventonormalpt:

diminishedbehavior,caninducecatatonicstatew/preservedmemoryand

consciousness.

AntiemeticeffectbyblockingDAreceptorsin

chemoreceptortriggerzone.

MaybegivenIM,butshouldrarelybegiven

IVduetoprofoundvasodilation.

anticholinergicAEs

drymouth,blurryvision, sedation,urinaryretention

blockade:

orthostatichypotension

nasalstuffiness

DAblackadeinbasalgangliaEPS

Akathisia(cantsitstill)

Dystonia(contractionsofface/neck)

Rigidity(parkinsonism)

Tardivedyskinesia

(permanentstereotypedmovements,

maybeparadoxicallysuppressedw/chlorpromazine)

Neurolepticmalignantsyndrome:

hyperthermia(musclecontractures)

resemblesmalignanthyperthermia

stupor

CK,myoglobinemia

seizurethreshold

PRLsecretion(DAisreleasedbyhypothal

toinhibitprolactinsecretionbypituitary

Cholestaticjaundice


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ThioridazineTrifluoperazineFluphenazine

Phenothiazines.

Thioridazine:

anticholinergic,blockade

Trifluoperazine,Fluphenazine:

anticholinergic,DAblockade

Fluphenazine:Availableasfattyacidesters

dissolvedinoil(fornoncompliant

patientIMinjectioneveryfewweeks).

Thioridazine:greatersedatingand

hypotensiveeffectsvs.chlorpromazine,

causeslessEPS.

Trifluoperazineandfluphenazineless

sedating,causefewerhypotensive

effects,moreEPS.

TrifluoperazinemayprolongQT.

Haloperidol PrototypeButyrophenone.

MaybegivenIVorIM

Availableasfattyacidestersdissolvedinoil

(fornoncompliantpatientIMinjection

everyfewweeks).

Causeslittlesedationorhypotension

CommonEPS

ClozapineOlanzapineQuetiapineRisperidoneAripiprazole

Ziprasidone

Atypicalantipsychotics.Atypicalbecause

theyhaveDAorcholinergic

antagonism.Antipsychoticactivitydue

to5HT2blockade.

Aripiprazole:partialagonistatbothD2and5HT1Areceptors

Goodantagonists:orthostatichypotension

common

Somemaycausesignificantweightgain

Effectiveness:

clozapine>risperidone/olanzapine

clozapineismosttoxic

risp/olaarebetterthan

phenothiazines &butyrophenones

Allareorallyeffective.

ZiprasidoneandolanzapinemaybegivenIM

Risperidone:Availableasfattyacidesters

dissolvedinoil(fornoncompliant

patientIMinjectioneveryfewweeks).

Potentblockersorthostatichypotension

RareEPS

Clozapine:maycause

weightgain

diabetesseizures

agranulocytosis(monitorWBCs)

Olanzapine(closelyrelatedtoClozapine):

NOseizures

NOagranulocytosis

weightgain

diabetes

Risperidone:

EPS@doses

weightgain

Ziprasidone:rarelyEPS

QT

Quetiapine,ziprasidone,aripiprazole:

Noweightgain

Choice of antipsychotic Emergencyuse

haloperidol,chlorpromazine,ziprasidone

Depotformulations

haloperidol,fluphenazine,risperidone

Chronicuse

choicebasedonadverseeffects,efficacy

ProchlorperazineDroperidol

Classicalantipsychoticsmarketedas

antiemetics.

Prochlorperazineisverysimilarto

chlorpromazine.Availableintablets,

liquid,suppository,andIM,NOTIV.

Droperidolisverysimilartohaloperidol.

Excellentantiemeticatdosesbelowthose

thatcausesedation.AvilableIMorIV

injection.

Droperidol:

muchlesslikelythanprochlorperazine

tocauseorthostatichypotension.

RareEPSatnonsedatingdoses.


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Antianxietyagents

Diazepam(Valium

)Chlordiazepoxide

(diazepam pro-drug)LorazepamOxazepam

(diazepam active

metabolite)AlprazolamClonazepam

Prototypicalantianxietyagent.

Benzodiazepine.

PotentiatestheeffectsofGABA(inhibitory

neurotransmitter).

Notethatbarbituratesandgeneralanesthetics

doNOThaveanantianxietyeffectdespitealsobeingabletopotentiatethe

effectsofGABA.

DiazepambindstobenzodiazepineRthatthis

locatedclosetotheGABAreceptorand

increasestheaffinityoftheGABARfor

GABA:

GABAbindingClconductance

hyperpolarization

Causespleasantsedation(incontrastto

unpleasantsedatioonproducedby

antipsychoticmedications).Excellentanticonvulsant

Pharmacokinetics:

rapidlyabsorbed

90%proteinbound

largeVd,smallclearance

longhalflife(20hr)

nordazepam(activemetabolite):

100hrhalflife

notwatersoluble(IVpreparation

containspropyleneglycol)

notreliablyabsorbedfromIM

Anterogradeamnesticeffectthatoccurseven

whenpatientdoesnotappearvery

sleepy.

Anterogradeamnesia:amnesticforevents

occurringafterdrugadministration.

Retrograde

administration:

No

drug

can

reliably

causethis.

Causesventilatorydepressionbutrarely

apnea(butcanbepotentiatedbyother

ventilatorydepressantssuchasopioids

orEtOH).

Dontwithdrawtooquickly,oryoumayget

seizures.Itmaytakeafewdaystosee

withdrawalsymptomsbecauseactive

metabolitehaslonghalflife.

Cancausedisinhibition.

Continuedtherapy:sedativeeffect,but

anxiolyticeffectispreserved.

DoesNOTREMsleep(incontrastto

barbituratesandEtOH),butitdoes

stage4sleepandoverallsleeptime.

AEs:mostlyextensionofeffects,rarelyfatal

sedation

ataxia

ventilatorydepression

Alprazolam (Xanax

) Hasfourringsincontrasttotypicalbenzodiazepinesthreerings.

Usefulinpanicdisorderandagoraphobia

Clonezepam (Klonopin

) Primarilyusedasanticonvulsant

Alsousefulinpanicdisorder

Leastlikelytoresultinbreakthroughanxietybetweendoses,onlyneedstobetaken2x/day

Lessofaddictiverushassociatedwithdiazepam.

Buspirone(Buspar

) 5HT1Apartialagonist,littleactivityatDAorGABAreceptors.Notabenzodiazepine.

Doesnotcausesedationorhaveanticonvulsanteffect.Notolerance:nocrosstolerancewithbenzodiazepinesorotherCNSdepressents

Lessanxiolyticeffectthandiazepam,noteffectiveinpanicattacks

Usefulinpeoplewhohaveabusedbenzodiazepineslittleabusepotential

Flumazenil (Romazicon

) Competitiveantagoninstofbenzodiazepines,

usedtotreatoverdoses.

Notwithoutitsownproblems,onlyusein

UNSAFEbenzodiazepineoverdose.

Shorteractingthanbenzodiazepines,may

needrepeateddosingtoreversebenzos.

Mayproduceastateofextremeagitation.


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Mood-Disorders

Tricyclic Antidepressants inhibitNEreuptake

Tertiary:amitryptylineisprototype;verysedating,significantanticholinergiceffects

Secondary:desipramineisprototype;lesssedating;feweranticholinergiceffects

Amitryptyline (Elavil

)Imipramine(Tofranil

)

Clomipramine (Anafranil

)

Doxepin(Sinequan

)

Prototypicaltertiarytricyclicantidepressent.

InhibitsthereuptakeofNEandSerotonin

Hasbothcentralandperipheral

anticholinergiceffects.

Whengiventonormalpeople,noin

mood.

Whengiventopersonwithdepression,

moodafterafewweeks(lagtime)

Tolerancedevelopstosedatingeffects,butnot

toantidepressanteffects.

Facilitatesbothfallingandstayingasleep

(insomniaandearlyawakingare

symptomsofdepression).

Sleepislessphysiological:stage4sleep,REMsleep

Fataldoseis12weekssupply

(manydepressedpeoplehavekilled

themselvesthisway:4thleadingcauseof

druginduceddeath)

Sedation,difficultyconcentrating

(unpleasant).

Prominentanticholinergiceffects:drymouth

&blurredvision.

Orthostatichypotension(blockade)

seizurethreshold,mayfreqofseizuresin

epileptics,butlittledangerinnon

epileptics

Somedepressedpationswillgobeyond

normalandbecomemanic(morelikely

w/bipolar)

Weightgain

ECGs:

HR(atropinelikeeffect)conductiontime;contractility

flatteningorinversionofTwaves

bewareinptsonClassI

antiarrhythmics!

overdosingisoftenfatal!

ventriculararrhythmias!

largerdoseslowerabsorption

Lidocaineisantiarrhythmicofchoice

Desipramine (Norpramin

)

Nortriptyline(Pamelor

)

Desipramine:prototypicalsecondarytricyclic

Similareffectsoncardiacconductionandmay

belethalinoverdose

Causesmuchlesssedationthanamitriptyline

aswellasfeweranticholinergicAEsand

lessweightgain

Trazodone (Desyrel

)

Nefazodone(Serzone

)

Atypicalantidepressants.

Donothavetypicaltricyclicstructure.

Verysedatingbuthavelittleanticholinergic

activityandminimaleffectsoncardiac

conduction

Bupropion (Wellbutrin

)

Zyban

(controlled release)

Atypicalantidepressant.

Usefulindiminishingsymptomsofnicotine

withdrawal.

Lackofsedative,anticholinergic,orthostatic,

andcardiacconductioneffects

seizurethresholdmorethananyother

antidepressant.

Fluoxetine(Prozac

)Citalopram(Celexa

)

Escitalopram (Lexapro)

Paroxetine (Paxil)

Venlafaxine (Effexor)

Sertraline(Zoloft)

Fluvoxamine(Luvox

)

Selectiveserotoninreuptakeinhibitors(SSRI)

Verysafe,lackoftypicalantidepressantadverseeffects,verysafeeveninOD.

Sometimesprescribedtonormals

Escitalopramisactiveisomerofcitalopram.

Fluoxetine,paroxetine,sertralinealsousedto

treatpanicattacksandOCD

FluvoxamineisusedprimarilyforOCD

FluoxetineonlySSRIapprovedforusein

children(depression&OCD)

Causenosedation,anticholinergic,orthostatic,or

cardiacconductioneffects

Donotpromoteweightgain

Donotaffectseizurethreshold

MildAEs:headache,nausea,nervousness,

insomnia,fatigue,impotence.EPSmay

occur(TDveryrare).MostinhibitP450.

Questionsaboutsuiciderisk.Mayshow2x

increaseinriskofattempt.Controversia

Maycausemania

(probablyunderlyingbipolar)


13/30

Isocarboxazid (Marplan

)

Phenelzine (Nardil

)Tranylcypromine

(Parnate

)

(mustknowtradenames

duetoriskofdrug

interactions)

Monoamineoxidaseinhibitors(MAOI).

Nonspecific:inhibitboth

MAOA(gut)&MAOB(brain)

Firstclassofmedicationsusedtotreat

depression

Todaynotusedasfirstlinetherapy(reserved

forptswhodonotrespondtoothermeds).

NotethattheselectiveMAOBinhibitor

Selegilinefarlesslikelytobeinvolvedin

significantdruginteractions.

Potentiallydangerousbecauseoflarge

numberofdruginteractionsand

potentialformanyoftheseinteractions

tobefatal.

Mustavoidtyraminehypertensivecrisis

MustavoidtheopioidMeperidine(Libby

Zion):IfMAOisinhibited,meperidine

metabolitemaycausehyperpyrexia&

seizures.

LithiumLithium carbonate

(Eskalith CR

Lihobid

)Lithium citrate syrup

Primarymedicationusedinbipolardisorder.

Alkalimetal,similarchemistrytoNa+andK+.

Noknownphysiologicalfunction.

Attherapeuticconcentrations,Li+

releaseofNEandDA(butnot

Serotonin)fromnerveterminalsin

responsetoAP.

Notethatpersonswithbilopardisorder

usuallymanageddifferentlythanthose

personswhoseillnessismanifestedby

depressivesymptoms.

PK:

WellabsorbedfromGItract

notboundtoplasmaproteins

distributedthroughttotalbodywater

completelyexcretedinurine

terminalhalflifeabout1day

hyponatremiamarkedlyLi+excretion

(prolongedeffectw/renalimpairment)

Significanttoxicity@2xtherapeutic

concentration:mustcloselymonitor

plasmaLiionconcentraion.

Therapeuticdosescausethirst,weightgain,

drowsiness,Twaveflattening

Mildtoxicity:nausea,vomiting,abdominal

painanddiarrheasedation,tremor.

Severetoxicity:hyperreflexicw/CNand

otherfocalneurologicalsigns.,

NephrogenicDI,cancausepermanent

renaldamage.

Deadlyintoxication:seizures,coma,death.If

ptsurvives,maybefollowedby

permanentneurologicalimpairment.

Lithiumintoxicationtreatedwithdialysis.

Watchfordruginteractions:Anythingthat

changesurinefloworionconcentrationscaninteractwithlithium!

Management of acutemania and bipolardisorder

Acutemania:

neurolepticand/orsedative

Severaldaysarerequiredforachievingastableplasmalithiumconcentration

Chronicbipolardisorder

AnticonvulsantincombinationwithlithiumlowerdosesofLi+required.

carbamazepineORvalproicacid

Lithium

Somepatients,whosebipolardisorderisPRIMARILYdepressive,mayrespondbestto

antidepressant(eventhoughlabelsaysnottouseinbipolardisorder).Morerecently,somepsychiatristshaveusedcarbamazepineorvalproicacidasfirstline

therapyinbipolardisorder:Li+rarelyusedthesedaysassolemedinbipolar.

Afterafirstmanicepisode,drugtherapyusuallycontinuedfor612moafternormalizationof

mood.


14/30

Sedatives and Hyptontics

Sedative Amedicationtoproducesleepness.Mosthaveotherfeatures.

Benzodiazepinescommonlyusedaspreoperativesedativesbecausetheyanxietyand

produceamnesia

Opioidscommonlyusedassedativesduringnoxiousproceduresbecausetheyproduce

analgesia+sedation.

Characteristicsofanidealmedicationusedtofacilitatesleep:

rapidonsetofactiondurationlongenoughtopermitanormalnightsrest

nottoolongadurationtocausehangover

causeminimalsinpatternofvariousstagesofsleep

producenotolerancenorphysicaldependence

besafeinlargeoverdose

producenoadversepsychologicaleffects(likeamnesia)

Hypnotic Medicationtoproduceunconsciousness(orastateresemblingsleepfromwhichthepatient

cannotbearoused).

Oftenasinglemedisbothsedativeandhypnoticdependingonthedose(doseforsedative).

Manysedative/hypnoticshaveotherfunctionality.

benzodiazepines:antianxietry,anticonvulsantbarbiturates:anticonvulsants,generalanestheticagents

H1antagonistsusedtotreatallergicdisorders

Triazolam (Halcion

)

Oxazepam(Serax

)

Estazolam (ProSom

)

Midazolam(Versed

)

Benodiazepines.Relativelysafesedatives.

Thesebenzodiazepineshaverapidonset,

shortduration,andnoactivemets

suitableforuseassleepaids.

Characteristicsofbenzodiazepinesleep:

stage0sleep(timerequiredtofall

asleep=latency)

timespentinstages3and4

timespentinstage2

timeinREM,but#REMcycles

overall,thesealterationsinpatternof

sleeparenotdisruptive.Personsusually

awakenrefreshed.Prettyphysiologic.

Midazolamistheonlywatersoluble

benzodiazepineavailableasIM.Very

shortdurationofaction,nometabolites.

usedfornoxiousprocedures&

preoperativesedation

Toleranceanddependencedevelop

Amnesiaisprominentsideeffect

Agentchosenonbasisofkinetics

Notethatsomebenzodiazepinesthatare

FDAapprovedfornighttimesedation

aretooslowinonsetandtoolongin

durationtobeuseful:Flurazepam(Dalmane)

Quazepam(Doral)

Midazolam:significantventilatorydepressio

incombinationwithopioids!

Zolpidem (Ambien)Zaleplon (Sonata

)

Eszopiclone (Lunesta

)

Benzodiazepineagoniststhatareusedfornighttimesedation.EXPENSIVE!Notstructurallyinbenzodiazepineclass.Bindnearbenzodiazepinereceptor.

Similarpharmacologicaleffectstotriazolam,butproducelesstolerance,lessamnesia.

Triazolamandoxezepamavailableasgenerics(muchlessexpensivethanzolpidem,zaleplon,

eszopiclone).

Eszopicloneisapprovedforlongtermtreatmentofinsomnia.

Dose-dependent kineticsof benzodiazepines andbenzodiazepine agonists

Withdose(morerapid)onset,(longer)duration

Ifdoseistoolow,ptmayawakenearlyandhavedaytimeanxietythefollowingday&

reboundinsomniathefollowingnight

Ifdoseistoohigh,ptmayhavedaytimesedation&motorimpairment.


15/30

Thiopental (Pentothal

)

Methohexital (Brevital

)

Shortactingbarbiturates.Usedprimarilyasgeneralanesthetics

Phenobarbital (Luminal

) Longactingbarbiturate,usedprimarilyasanticonvulsant.

Pentobarbital(Nembutal

)

Secobarbital (Seconal

)

Intermediateactingbarbiturates.Beforethe

introductionofthebenzodiazepines,

wereusedasnighttimesedatives.

Rarelyusedthesedaysforthatreasondueto

excessivedurationofaction,REM,

anddangerofoverdose.

Butmaybeusedinpregnantwomen:

50yearsafetyrecord

Diphenhydramine

(Benadryl

)

(Sominex

)

Antihistimines(H1agonists)areverysafesedatives,availablewithoutaprescription.

REMsleep

DoesNOTproduceventilatorydepression

Donotproducephysiologicsleep.

Ethanol Lousysedative.

RapidonsetofCNSdepressionfollowedby

CNSexcitation

Rapidonsetofsleepveryearlyawakening

REM


16/30

Anticonvulsants

Partial seizures Beginsindiscretesiteincortex.Threetypes.

1)Simplepartial:preservationofconsciousness,rhythmiccontractionofmuscle(s)

2)Complexpartial:impairmentofconsciousness,rhythmiccontractionofmuscle(s)or

complexbehavior.Alsocalledpsychomotorortemporallobeepilepsy.

3)Partialwithgeneralizedtonicclonic:beginassimpleorcomplexpartialandevolveinto

generalizedtonicclonic

Generalized seizures Beginsinbothcerebralhemispheresfromtheoutset.Threetypes.

1)Absence

2)Myoclonic:brief,joltlikecontractionofmuscleormanymuscles.Consciousnesspreserved.

3)Tonicclonic(grandmal):lossofconsciousness;alternatingperiodofsustainedmuscle

contractions(muscletone)andclonus(alternatingcontractionandrelaxationof

muscles).Postictalphaselastsminuteshours.

Phenobarbital (Luminal

) Barbiturate.Highestratioofanticonvulsant

efficacytosedation.Tolerancedevelops

tosedatingeffectbutnotto

anticonvulsanteffect.Oftenusedlessin

children(irritability&hyperactivityinyoungerpatients).

Firstmedicationtobeusedinseizures,stillin

usetoday

PK:Slowonsetafteroraladministrationand

longhalflifeofseveraldays.

Effectiveingeneralizedtonicclonicseizures

andpartialseizures.

Inducessynthesisofmicrosomalenzymes

(P450andglucuronyltransferase)

metabolismofmanydrugs

Inducessynthesisofhemebiosynthesis

contraindicatedinporphyria

Phenytoin (Dilantin

) Doesnotproducegeneralizeddepressionof

CNS(asdoesphenobarbital);isnot

sedating.

Givenforseizureprophylaxis,notforacute

seizures.

Causesaslowingintherateofrecoveryof

Na+channels.

PK: Oraladministration.

Slowandvariableabsorption.

Differencesinbioavailabilityin

preparationsfromdifferent

manufacturers.

ShouldnotbegivenIMorSubQ

precipitatesininterstitialfluid.

Halflifeofonetoafewdays

extensivelymetabolizedtoinactive

products

Extensivelyboundtoplasmaproteins

druginteractionsifdisplacedfrom

albumin

Effectiveingeneralizedtonicclonicseizures

andpartialseizures.

Alsousefulinchronicpainsyndromesandas

antiarrhythmic(ClassIb)

IfgivenIV,mustbegivenslowlybecause

highbloodconcentrationscausecardiac

arrhythmiasCVcollapse.

Acuteoverdose:arrhythmias,hypotension,

CNSdepression

Chronictherapy:

ataxia

gingivalhyperplasia

hirsutisminfemales

BMsuppression

Smalltherapeuticindex

MANYDRUGINTERACTIONS

Caninterferewithfolateabsorption

macrocyticanemia


17/30

Primidone (Mysoline

) Prodrugmetabolizedtophenobarbital,butmorerapidlyandcompletelyabsorbedafteroral

administration.

Carbamezepine(Tegretol

) Chemicallysimilartotricyclic

antidepressants,buthasaneffectonNa+

channelslikephenytoin.Metabolizedby

P450epoxidationofcentralringandthis

epoxidemetaboliteisbothstableandasactiveastheparentdrug.

PK: Oraladministration.

Slowandvariableabsorption

inchronictherapy,halflife16hrs

inducesitsownmetabolism

Usefulingeneralizedtonicclonicseizures

andsimpleandcomplexpartialseizures.

Alsousedinneuropathicpain(trigeminal

neuralgiaandpainoftabesdorsales)

Usefulinbipolardisorder,especiallyin

personsunresponsivetoLi+.

Sedation,ataxia,vertigo,blurredvision

(tolerancedevelopstotheseeffects)

Occasionally:

inreleaseofADH

BMsuppressionStevensJohnsonsyndrome

immunemediatedskinexfoliation;

mustbemanagedas3rddegreeburn

Hepaticfailure

Acuteoverdose:comaandventilatory

depression.

Oxcarbazepine (Trileptal

) Similartocarbamazepin,butfeweradverse

effects.

Approvedassingleagenttherapyandin

additiontoothermedsforpartial

seizures.Butcanprobablyreplace

Carbamezepine.

NocasesofStevensJohnsonsyndrome,BM

suppression,norhepaticfailurehave

beenreported

Ethosuximide (Zarontin

) Narrowspectrum:Selectiveforabsence

seizures(drugofchoice)

Commonlyusedinchildren.

AnticonvulsantactionduetoantagonismoflowthresholdCa2+currentsinthalamus.

PK: wellabsorbedafteroraladministration

halflifeabout35days

CNS(sedation,dizziness,headache)

tolerancedevelopstotheseAEs

GI(nausea,vomiting,anorexia)

Hypersentivity(urticaria,*StevensJohnson,SLE,*BMsuppression)

*veryrare

Valproic acid(Depakene

) Simplemoleculeaccidentallydiscoveredto

haveanticonvulsantproperties.

Originallyusedassolubilizingvehicle

forotheranticonvulsants

EffectsonNa+channelssimilartophenytoin

EffectsonCa2+channelssimilarto

ethosuximide.PK: oraladministration

rapidandcompleteabsorption

metabolizedbyglucuronidationand

FAhydroxylasesinmitochondria

Effectiveagainstalltypesofseizures:

Broadestspectrum

Veryeffectiveinbipolardisorder.Many

psychiatristspreferittoLi+asfirstline

drug.

Alsoapprovedforprophylaxisofmigraine

Hepatotoxicity!(upto50%willhave

asymptomaticLFTs)

1/10,0000fulminanthepaticnecrosis:babies

andyoungchildrentakingmutiplemed

areatgreatestrisk

Nausea,anorexia,occasionallysedationand

ataxia.


18/30

Clonazepam(Klonopin

) Benzodiazepine.Effectiveagainstmanytypesofseizuresexceptgeneralizedtonicclonic

seizures:simplepartial,complexpartial,absence,myoclonic.

Incontrasttootheranticonvulsants,astolerancedevelopstosedatingandataxiceffectsof

clonazepam,anticonvulsantefficacyalsodecreases(over6months).

Oneofthemosteffectivetreatmentsforpanicdisorder.

Diazepam oneofthedrugsofchoiceforstatusepilepticus

Gabapentin (Neurontin) DerivativeofGABA,designedasGABAagonist;doesnotbindtoGABArceptors.

releaseofGABAfromnerveterminals

PK: Rapidlyabsorbedafteroraladmin

excretedunchanged

shorthalflifeof7hours

Partialseizures(onlyapprovedw/others)

Alsousefulinneuropathicpainsyndromes.

Minimaltoxicity,noimportantinteractions.Sedationorataxia,buttolerancetothese

effectsdevelopsoverafewweeks

Other Anticonvulsants Justknowthattheyareusedforpartialseizuresw/othermeds.Maybeknowwhatsinbold.

Primarilysecondlinetherapy.

Lamotrigine (Lamictal

) InhibitsNa+channels

like

phenytoin.

Wellabsorbedafteroraladmin,halflifeabout

aday

sedation,dizziness,ataxia

Topiramate (Topamax

)InhibitsNa+channelsandpotentiatesGABA

atitsreceptor

Alsoapprovedforprophylaxisofmigraine&

chronicpain

Cognitiveimpairment

Tiagabine (Gabitril

)InhibitsGABAreuptake sedation,ataxia,cognitiveimpairment

Levetiracetam(Keppra

)

Unique/obscureMOA Sedation,ataxia

Agitation,depression,psychosis

Zonisamide(Zonegran

) BlocksNa+channelsand Ca++channelsand

releaseofDAandSerotonin

Inhibitscarbonicanhydraseriskofstones

Sedation,ataxia,nausea,anorexia,cognitive

impairment,psychosis

Renalstones

Management of Epilepsy Initially,begintherapywithasingledrugandsearchforstructurallesion.Slowlyincrease

dose.Ifdrugdoesntwork,switchtodifferentdrug.

Plasmaconcentrationdoesntnecessarilycorrelatewitheffectiveness,butitdoesrelateto

toxicity.

Drugsshouldbetaperedtoavoidstatusepilepticus

Mostcommoncauseofdrugfailure:noncomplianceRiskfactorsforrecurrenceofseizures:

positiveFHx

requirementformorethanonemed

postchildhoodonsetofepilepsy

EEGabnormalitiesduringtherapy

Mostanticonvulsantsareteratogenicinanimals.Recurrentseizuresarealsoharmfultoboth

motherandfetus.

Thetherapeuticgoalofstatusepilepticusistoendabnormalelectricalactivityasquicklyas

possible:medicalemergency,canhavepermanentinjury

diazepamorthiopentalIVoftencausesapnea,hypotension


19/30

Opioids

Definition of Opioiod Naturalorsyntheticcompoundthathasagonistorantagonistactivityatthereceptorstowhich

morphinebinds

Opioid Receptor giveenoughfull agonistandyoucanmake

anyoneapneic

1:supraspinalanalgesia,sedation

2:spinalanalgesia,ventilatorydepression

Opioid Receptor agoniststendtoproduceanalgesianotas

highinefficacyas agonists,andevena

largeODwontcauseapnea

1:spinalanalgesia

3:supraspinalanalgesia,ventilatory

depression,sedation

Opioid Receptor nodrugsyet :spinalanalgesia

Opioid ReceptorAgonists:dysphoric&hallucinogenic:

pentazocine,ketamine,PCP

Bettertocallitphencyclidinereceptor

phencyclidine=PCP

Opioid Effects Analgesia

SCtransmissionofpain

cortexresponsetopain

fullagonistsVERYeffective(butatcostofsevereventilatorydepression)

constant,prolongedpainbetterrelievedthansharp,intermittentpain

neuropathicpaindoesntrespondwell

Sedation

pleasantdrowsiness,concentration,littleamnesia

anxiolysisonlyifetiologyofanxietyispainorfearofpain

occasionaldysphoria

VentilatoryDepressionPRODUCEDBYALLAGONISTS

responsetoCO2inmedulla

setpointtoCO2increased

dontmeasureventilatoryRATEtocheckforventilatorydepressionmeasurePO2

Doseresponse:

lowdose:RR+/ TV; highdose:TV; highestdose:apnea

effectpotentiatedbyotherCNSdepressantsdepthofsedationpoorindicatorofventilatorydrive

equianalgesicdosesofagonistsproduceequivalentdegreesofventilatorydepression

Tolerance

inapparentdurationandintensityofeffect,canbeovercomebydose

crosstolerancetootheropioids

developsprimarytodepressenteffects(analgesia,ventdepression,euphoria)

little/notolerancetostimulanteffects(miosis,GImotility,GIsphincter)

physicaldependence,withdrawalsyndrome

uncomfortable,NOTlifethreatening;withdrawaldoesNOTinvolveseizures

Otheropioideffects

coughsuppression:dextromethorphanistheDisomerofmorphine;NOTanalgesicmiosis:[email protected].

nausea,vomiting,bradycardia,vasodilation

GIsmoothmusclespasm(CONSTIPATION),histaminerelease(NOTallergic!)

Morphine slowonset,longduration.ItsactuallypumpedoutofCNS(nearly)asfastasitcomesin.

oralbioavailablity,firstpasseffect

metabolizedto3 and6glucuronides

Morphine6glucuronideisactiveandmorepotentthanparentcompound

Significanthistaminerelease


20/30

Codeine Inactiveprodrugofmorphine

requires3Odemethylationby2D6

2D6hasthegreatestdegreeofpolymorphismofanyCYPenzymes:

about10%ofcaucasians2D6deficient

usuallygivenorallyincombinationwithacetaminophen

Meperidine Dontuseit,therearealmostalwaysbetter

alternatives(butusefulforshivering)

muchfasteronsetthanmorphineafterinjection

shorterdurationthanmorphine

metabolizedtonormeperidine,aCNS

stimulant

NORmeperidinetoxicitylikely

(normeperidinehasaslowerhalflife,so

eventhoughmeperidinelevelscouldbeOK,normeperidinelevelswouldkeep

rising)

MAOItherapy

renalfailure

chronic,highdosetherapy

Methadone oralbioavailability

firstdose:kineticssimilartomorphine.Butrepeateddosesresultinlongerhalflife

steadystate:longduration,possiblyoncedailydosing

minimaleuphoria,rush

oftenusedforwithdrawalprophylaxis

Hydromorphone 2advantagesovermorphine:

fasteronsetthanmorphine

nohistaminerelease

Commonlyusedasmorphinesubstitute

Beware:8xmorepotentthanmorphine:FAR

tooeasytoODapatient

Oxycodone highoralbioavailablity

oftengivenincombinationwithacetaminophen

longactingoralpreparationforchronicpain

Fentanyl veryrapidonsetafterinjection

shortdurationduetoredistribution

usedforacutepainornoxiousprocedures

patchavailableforchronicpain:butDONOTUSEpatchforacutepain,sinceittakes4or5

daystoreachstablehalflifebythentheacutepainmaybegoneandyougetan

imbalanceinthepain:ventilatorydepressionratio.

NalbuphineButorphanol

antagonists, partialagonists

verysedating

ceilingeffectforanalgesia&ventilatory

depression:evenlargedosesdontcause

apneaorsignificantpainrelief

canbeusedforanalgesiainlabor

Maycausewithdrawalintolerantpersons

littleabusepotential

Buprenorphine Usedinchronicmanagementofprevious

abusers.

opioidpartialagonist

tightbiding,slowdissociationtherefore

norushifheroinisinjected

Maycausewithdrawalintolerantpersons

only(butnotinnontolerantpeople)

littleabusepotential

Naloxone ANTAGONISTat,, receptors

Competitiveantagonist(surmountable)

Rapidonset,shortduration

Almostnoeffectinpeoplewithnopainand

noopiatesinblood

CanresultinseverepainandHRina

personwithpain


21/30

Local Anesthetics (starred drugs (*) = one of the big three)

Old axon research charged(R3N+H)formactive uncharged(R3N)formcrossesmembrane

Local Anesthetic Blockade Na+channelisatetramer(4subunits).

LocalanestheticsbindtoNa+channelinopenstate(all4subunitsrotatedtoopenposition).

Blockagebymorepositiverestingpotentialorhigherstimulationfrequency

(activenerveblockedmorereadilyinpracticethisisjusttheoreticalsincepatientskeep

theirlimb/whateverstill).

Ingeneral,smallerfiberseasiertoblockthanlargerones.

Myelinatedareeasiertoblockthanunmyelinated(onlynodeofRanvierneedstobeblocked)

Smallunmyelinatedfibers(C)overallareeasiertoblockthanlargemyelinatedfibers(A).

Orderofonsetofblockade:

first:sympatheticsvasodilation(canblockwithjustlowconcentrationofanesthetic)

second:pain,temperature(canblockwithintermediateconcentrationofanesthetic)

last:motor,proprioception(needhighconcentrationofanesthetictoblock)

Offsetinreverseorder

Procaine Esterclassoflocalanesthetics MetabolizedtoPABA(canbeallergenic)

* Lidocaine Essentiallynooneisallergic(2documentedcasesinhistoryofmankind)

mostcommonlyusedlocalanesthetic

fastonset,shortduration

lowtoxicity:relativelysafeevenwithaccidentalIVadmin

versatile

* Bupivacaine amidelocalanesthetic

relativelylipidsoluble

toxicity

longduration,slowonset

noonehasyetseparatedtoxicity

fromlongduration

veryslowdissociationfromsodiumchannel

versatile

localinfiltration

nerve,plexusblock

spinal,epiduralblock

Toxic!

* Mepivacaine fastonset(asfastaslidocaine)

intermediateduration

lowtoxicity(likelidocaine)

uses

localinfiltration

nerve,plexusblock

epiduralblock(notspinal)

Tetracaine slowonset,verylongduration

onlyusedinspinalanesthesia

systemictoxicityraresincespinaldosesare

small

MOSTTOXIC


22/30

Comparison of Duration &Toxicity of lidocaine,mepivacaine, bupivicaine,tetracaine

Duration:

lidocaine(quickest)


23/30

Technique: Plexus block Similartoperipheralnerveblock

brachialorlumbarplexusblockedproximaltoseparationofperipheralnerves

Durationislongerthanblockofperipheralnerve

Technique: Spinalanesthetic

injectionoflocalanestheticsolutionintoCSFafterperforminglumbarpuncture

physiologicallytransectsspinalcord:temporaryparaplegia:NUMB&PARALYZED

sympathetic,sensory,andmotorblockade:differentialblockNOTpossible

EventhoughalwaysinjectedintoL3/L4,cancontrolspreadofblockbymodifyingspecific

gravity(addsugar)andpatientpositioncanthereforebeusedforabdominalsurgery

Technique: Epiduralanesthetic

injectionoflocalanestheticsolutionintoepiduralspace,usuallyviacatheter

segmentalblock

densityofblockreadilyadjusted(analgesiavs.anesthesia)

Technique: Bier block(intravenous regional)

IVcatheterinserteddistallyinextremity

extremitywrappedinbandagetoexsanguinatethelimb(squishoutalltheblood)

pneumatictourniquet(BPcuff)onproximallimb,inflatedto~2xsystolicBPsonobloodcan

getintoarm

dilutesolutionoflidocaineinjected

foranesthesiaofarm(rarelyleg)

durationlimitedbytoleranceoftourniquet(1.52hr)

simpletoperform,anesthesiareliable

Technique: Topicalanesthesia

Mucousmembraneseasytoanesthetize:pharynx,nares,trachea,esophagus,urethra

mostcommonlyusedforendoscopy

systemicabsorptionveryefficient

skinmuchhardertoanesthetizetopically;veryslowonset


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General Anesthesia

General Anesthesia Unconsciousness

Analgesia=nosympatheticresponsetonoxiousstimulus.Notethatunconsciousnessdoesnt

necessarymeananalgesia.

Musclerelaxation(sometimesrequired,sometimesnot)

Reflexablation(i.e.coughreflex)

Stages of General

Anesthesia

I:Analgesia

II:Delirium

III:Surgicalanesthesia

(fourplanesofonlyhistoricsignificance)

IV:Cardiorespiratorycollapse

Morehistorical,appliesto

diethylether.WithmodernIVanesthetics,transition

fromawaketoasleepistoo

quicktonoticestages.

Factors affectingonset of inhalationalanesthetic

Thesefactorsspeedofonsetandspeedofoffset:

inspiredconcentration(obvious)

alveolarventilation(obvious)

flowofgas=freshgasflow(obvious)FRC(cantexhalethegasquickly)

importantinpregnancy

(FRCveryrapidonset/offsetin@term)

importantinascites(FRC)

Thesefactorsspeedofonsetandspeedofoffset:

solubility(seegraphaboveHalothaneismostsoluble

andthereforetheslowest)

cardiacoutput(counterintuitive:withCO,moregasis

pumpedAWAYfromlungs)

FA=fractionofgasinalveoli

FI=fractionofgasinhaled

DrugswithahighermaxFA/FI

(i.e.nitrousoxide)have:

tissuesolubility

(faster)onset

Minimum alveolarconcentration (MAC)

Alveolarconcentrationofgasatwhich50%ofindividualsdo

notmoveinresponsetoaskinincision.

tissuesolubilityMAC(ifagasisverytissuesoluble,

youonlyneedalittlebitofitforastrongeffect)

CanlinearlyaddMACsifyouremixinggasanesthetics

MACisbyCNSdepressants(youneedlessofgas)

AdvangedageMACabout7%perdecade(needlessgas)

Usedasasurrogateforbrain

concentration(whichcantbemeasured)

AgaswithaverylowMAC

(highpotency)willbe

slowerinkinetics(slowerin

onsetandslowerinoffset).

Nitrous Oxide Leastsolubleinhalationalanesthetic(highestMAC=110%!!)

colorloess,odorless,tasteless

minimalcardiovasculareffects

OnlygasanestheticthatNEVER

triggersmalignant

hyperthermia!


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Halothane LowestMAC=0.75%

Olderhalogenated,nonflammablevolatilealkaneanesthetic

Doesntsmelltoobad

Bronchodilator

Notmuchofavasodilator

CO(contractilityBP)

Rare,oftenfatalhepaticfailure

(notusedmuchanymore

becauseofthis)

IsofluraneEnflurane

Mostcommonlyusedvolatileanesthetic.Ether.

MAC1.15%

Doesntsmelltoogoodnotagoodchoiceforinhalationalinduction

Bronchodilator

SVR(incontrasttoHalothane)likeallethers

littleeffectonCO(incontrasttoHalothane)

Enflurane:isomerofisoflurane,lessfrequentlyused.COandSVR.Skeletalmusclerelaxation.

Desflurane Leastsolublevolatile(comesinaliquid)agent

MAC6.0%veryrapidonset/offset

Majoradvantage:allowsrapidwakingup

SVRlikeallethers

Bronchoconstrictor,pretty

irritating

Sevoflurane Doesntsmelltoobad

Bronchodilator

MAC2.0%:morerapidthanisoflurane,slowerthandesflurane

Significantlymetabolized,butnottoanythingtoxic

SVRlikeallethers

Usefulforinhalationalinduction,especiallyforchildren(sincetheydontliketogetIVs)

IVInductionAgents

Thiopental Shortestactingbarbiturate.Rarelyusedtoday(hangover)

RapidonsetofhypnosisafterIVinjection:fallasleepin1min!

brainmetabolicandelectricalactivitySVRandCO

ventilatorydrive

contraindicatedinporphyria(likeallbarbiturates)

Rapidoffsetofeffectduetoredistribution:metabolism/elimination notasimportant

Propofol Mostcommonlyusedinductionagent

Morerapidrecoverythanw/thiopental

lesshangover,nausea,vomiting

BPcomparedtothiopental(little inHR)

Antiemetic

Euphoriceffectabusedbyanesthesiologists

Painoninjectionfrequent:

majordownside

Relatedtokallikrein.

Etomidate Majoradvantage:leasteffectsonSVR,CO:onlyreallyusedin

peoplewhereSVRandCOnotacceptable

Mostemetogenic:lotsof

barfing

Inhibitscortisolsynthesisfor

~8hrs.Imidazole(slightly

antifungal).BindstoP450

(butnodruginteractions).

Inhibits11OHP450

stopscortisolsynthesis

possibleaddisoniancrisi


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Ketamine Dissociativeanesthetic:eyesopen,butdontrespondtopain

SNSHR,CO,BP

ICPdontusew/intracranialmass!

longerdurationthatotherIVagents

emergencedeliriumandhallucinations(coadministerwithbenzodiazepinetoprevent)

MaybegivenIM(onlyinductionagentwiththisproperty)

Opioidscommonlyusedduringgeneralanesthesia

GeneralCharacteristics ofOpioids

Analgesia

MAC

Ventilatorydepression(allanestheticsexceptnitrousoxidecauseVD)

GImotilitypostoperativeileus

Opioids usuallygiven by Bolus

Morphine

histaminereleaseBPandreflextachycardia

slowonsetofeffect(~90minpeak)

Meperidine

shouldNOTbeusedanymore

histaminereleaseonsetmorerapidthanmorphine

severeinteractionw/MAOinhibitors

Fentanyl,Sufentanil

veryhighpotency

rapidonset

effectterminatedbyredistribution(likethiopental)

Opioids usuallygiven by Infusion

(torapidlytitrate

opioideffect)

Alfentanil,Sufentanil

rapidonset

effectterminatedbyredistribution

sufentanilisshorteracting

Remifentanil:Dr.Dershwitzsfavoriteopioidrapidonset

effectterminatedbyrapidnonspecificesterasemetabolismunique!

shortestactingdruginanesthesia:veryclosetoanon/offswitch

idealforasurgerywithextremeoperativepainthathaslittleresidualpostoperativepain

(i.e.bronchoscopy)

Naloxone Opioidantagonist

ReversesopioidinducedventilatorydepressionAND

analgesiausecarefullyoritcancauseextremepain

Shorteractingthantheopioidsitisusedtoreverse

(exceptremifentanil)

Morphine+naloxonewater

Adjuntagents(anxiolysis&antiemetics)

Midazolam Watersolubleinjectablebenzodiazipineforanxiolysis&sedation

Droperidol Antiemetic.

DAblocker,doesntcausedysphoria

Ondansetron 5HT3blocker.Antiemetic.

Other antiemetics Antihistamines,transdermalscopolamine,dexamethasone Itsamystery:dexamethasoneis

antiemetic.


27/30

Receptors inchemoreceptortrigger zone

DA,5HT,cholinergic Ifyoublockthesereceptors

antiemetic

Atypicalgeneralanesthetic

Interviewpatient,insertIV

Midazolamforsedation&anxiolysis

propofolforinductionanalgesia

musclerelaxantfortrachealintubation

nitrousoxide+volatileagent

mechanicalventilation

musclerelaxant,opioidasneeded

stopvolatileagentwellinadvanceofcaseend

durationofanesthesiadependentondurationofdose

longdoselongfadetime

reverseneuromusclarblockade(cholinesteraseinhibitor)

StopN2O,give100%O2

Extubatewhenawakeandbreathing

MalignantHyperthermia

ThescariestthingthatcanhappenintheOR

Apharmacogeneticdisorder

triggeredbyvolatileanestheticsorsuccinylcholine

sustainedcontractureofskeletalmuscleswithoutrelaxation

hypermetabolicstatehypercarbia,metabolicacidosis

treatwithdantroleneactsintracellularlytoinhibit

excitation:contractioncoupling

Thesedays,theonlypeoplewho

dieofMHarethoseina

settingwithnodantrolene.


28/30

Toxicology

Minimizing ingestedpoison absorption

Inductionofvomiting.Contraindicatedif:

ptisunconscious

sustanceiscaustic(canburnesophagus)

substanceisvolatile(absorbtionthroughlungs)

veryrapid(wastestime)

Gastriclavage.Risksof:

esophagealperforation

aspiration

Activatedcharcoal:adsorbsorganiclipidsolublecompounds,butNOTions(Li+,Fl,CN)

Bowelcleansing:produceprofusewaterydiarrhea

clearance rate ofpoison

Alkalinizeurinetoexcretionofacidiccompounds(unchargedcompoundsarereabsorbed)

NaHCO3,acetazolamide

canbeusedforbarbiturates,salicylates(acidiccompounds)

Acidifyurinetoexcretionofbasiccompounds(amphetamines)

NH4Cl

Dialysistoexcretewatersoluble,lowMW,notproteinboundsubstances(i.e.ASA)

Carbon MonoxidePoisoning

Characteristics

200xaffinityforHb2+comparedtoO2

DisplacesO2canmeasurecarboxyhemoglobin

ShiftsO2curvetoL

Bindscytochromeoxidase

VariablehalflifedependingoninspiredO2

46hrsinroomair;~60minw/100%O2;~20minw/w/100%O2@3ATM

Symptomsdependon%HbwithboundCO.Onlyafew%ofinspiredCOcankillyou

10%mildheadache,vasodilation.Aheavysmokerwillhaveavalueof~8%

20%throbbingheadache

30%visuals,dizziness,severeheadache

40%unconsciousness,reflexSNSdischargeHR,RR

50%intermittentseizures

60%hypotension,ventilatorydepression

70%gameover,man,gameover!

Treatment

EliminatesourceofCO(sometimesyoudonthavetobeagenius)

Give100%O2ASAP

considermechanicalventilation,paralysis(O2utilizationbyskeletalmuscle)

considerhyperbarictherapy

considerbarbituratecoma(O2utilizationbybrain)

ASA Poisoning Uncouplesoxidativephosphorylation.Lethaldose 1030g

Initiallyrespalkalosis(compensatorymetacidosis);latercombinedmet+respacidosisTreatment:

Mostimportant:inducevomiting

absorption(vomiting,charcoal)

elimination:urinarypH(itsaweakacid)

correctacidbase

considermechanicalventilation

considerdialysis:ASAdialyzeswellbecauseitsentirelycharged@physiologicalpH


29/30

AcetaminophenPoisoning

Management:similartoASAoverdose

absorption(vomiting,charcoal)

Nacetylcysteine(haveabouta36hourtherapeuticwindow)

Cyanide Poisoning Sources:HCNaspesticide,CNinphotography,metallurgy,oreextraction,fruitpits(apricots)

Chemistry:BindstightlytoFe3+(Methemoglobin)

Majortarget:cytochromeoxidase(alsoinhibitedbyCO)

Createslacticacidosis(cantdoaerobicmetabolism)Lethaldose: 200mgKCNor50mgHCN

Mostpopularsuicidemethodforchemistrygradstudents

Intrinsicdetoxificationformillimolarquantitiesofcyanideindiet:rhodanase

CN(cyanide)+S2O32(thiosulfate)(rhodanaseenzyme)SCN(thiocyanate)+SO32(sulfate)

thiocyanateismuchlesstoxicthancyanide,isexcretedinurine

Management:onlylowexposureaccidentalexposurescanbetreatedsincetoxicdoseissolow

Intentionallyinducemethemoglobin: convertHb2+toHb3+

amylnitrite(inhaled),sodiumnitrite(IV)

Hb3+becomessinkforCNtobindtoformsirreversiblecomplexw/cyanide

Sodiumthiosulfate(IV)toresupplyrhodonasereaction

100%O2Considergastriclavage.NotinitialstepbecausethereisverylikelynoneleftinGItract.

Veryoftenfatal

Methanol Poisoning AlcoholMetabolism:

ethanol(ADH)acetaldehyde(aldehydedehydrogenase)aceticacid

Methanolmetabolism:

methanol(ADH)formaldehyde(aldehydedehydrogenase)formicacid

Formicacidisextremelytoxictotheretina:justafewteaspoons(15mL)requiredforblindness

Ethanolcanpreventmethanolconversiontoformicacid

Pesticide Poisoning Organophosphates:morespecificforinsect

cholinesterases,buthighdosesessentiallylooklikechemicalwarfareagentpoisoning.

malathion,parathion,diazinon

Carbamates:lesstoxic,potentiallyreversible

carbaryl,aldicarb,baygon,ficam

Managementofpesticidetoxicity:

sameaschemicalwarfareagents

preventadditionalabsorption

skin:bathing

GI:gastriclavage,charcoal

atropinetodrysecretions

Pralidoximetoreactivatecholinesterase

Pesticidetoxicity:

Muscariniceffects:nausea,vomiting

pulmonarysecretions

sweating,salivation

miosis

bradycardia

Nicotiniceffects:

HTN

muscleweakness,twitching

CNSeffects:

anxiety,restlessness

seizures,coma

Arsenic Arsenic

Usuallyingestedindrinkingwater

Naturalconstituentofgroundwater

groundwatercontaminationfromagriculturalrunoff

veryoccasionallyusedinmedicines(e.g.Trypanosomiasis)

Treatmentofarsenicpoisoning

initially:dimercaprol

chronictherapy:penicillamine, succimer(notapproved)


30/30

Lead Poisoning Environmentalsourcesoflead

Leadsaltsusedaspaintpigmentsuntil1978;inhousedust

Tetraethylleadusedasgasolineadditivethrough1970s; indirt

Absorbedfromdirtbyacidicfruits(tomatoes)

Leadpipes,leadsoldertojoincopperpipes:acidicpHcausesPbtoleakout

Industry:batteries,radiators

LeadKinetics

afterGIabsorption,circulatesboundtoHb;halflifeincirculation 2months

redistributestobone;halflifeinbone 30years

LeadToxicityinAdults:hardtodiagnosewithvaguesymptoms

GI(vague):anorexia,constipation,metallictaste.Laterpainfulintestinalspasms

Renal:proteinuria,hematuria,cellcasts

Heme:microcytic,hypochromicanemia

Neuro:peripheralneuropathy,HTN

LeadToxicityinChildren

CNS:headache,irritability,ataxia,IQ,behavioralproblems

Abdominalpain,anemia

Routinescreeningrecommended:

[Pb]>10g/dL environment

[Pb]>25g/dLchelationtherapy

Treatment:Chelationtherapy:

EDTA(ethylendiaminetetraaceticacid)

Na2EDTA[Ca2+]eventhoughitsnotusedclinicallyforthiseffect

Ca2EDTAusedintherapyPbdisplacesCafromCa2EDTA

MustbegivenIVorIM

Causesproximaltubuledamage

Alsochelatesessentialmetals:Cu,Zn,Fe

Dimercaprol

usedincombinationwithEDTAinPbpoisoning

solutioninpeanutoil

mustbegivenIM

HR,BP

Requiresalkalineurine

Penicillamine:metaboliteofpenicillin

effectiveorallyusefulinlongtermoutpatientmanagementofPbpoisoning

AlsousedinWilsondisease

Toxicity:autoimmunephenomena(canalsotriggerSLElikesyndrome)

Succimer:Newestchelatingagent

effectiveorally

lesstoxicthandimercaprol,penicillamine

doesnotchelateessentialheavymetals(Cu,Zn,Fe)OnlyapprovedinPbpoisoning

Toxicity:chemicalhepatitis

Mercury ElementalHg:vaporatroomtemp

Hgsalts:usedinmedicinethrough1970s

alsousedinmanyindustries

convertedtomethylmercurybybacteriapoisonssulfhydrylenzymes,risesinfoodchain

Mercurypoisoning:primarilyCNSsymptonsandsignsvisualandhearingloss,ataxia

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Pharm-Block6CNSMemorizer