1.

CH1Pharmacokinetics
a. kinetics:whatthebodydoestothedrug.
b. dynamics:Whatthedrugdoestothebody
c. Pharmacokineticproperties:
i.
Absorption
ii.
Distrobution
iii.
Metabolism
iv.
Elimination
d. FactorsaffectingAbsoprtion
i.
pHonabsorption
1. weakacidstransportbestprotinated(HA).Weakbasestransportbestas
unprotinated
(B).
2. pKaisameasureofprotination.
a. pH<pKatheprotinatedformspredominate
b. pH>pKathe
unprotinated
formspredominate
ii.
Pglycoprotein
1. Atransmembraneproteinthatactivelypumpsdrugsoutofcells
a. Liver:transportsintobile
b. kidneys:transportsintourine
c. placenta::transportsintomaternalblood
d. intestines::transportsintointestinallumen(outofcirculation)
e. braincapillaries::transportsintobloodandawayfrombrain
2. ThehighertheexpressionofPglycoproteintheharderthedrugistoabsorb.
iii.
Bioavailability:
1. fractionofadministereddrugthatgetstocirculation
2. Areaundercurveoforal/AreaundercurveofIVadministration
iv.
Bioequivalence
1. twodrugsarebioequivalentifthehavesimilarbioavailabilityandtimestopeak
concentrations
v.
Therapeuticequivalence
1. samesafetyandeffects
e. FactorsonDistribution
i.
Bloodflow
ii.
Capillarypermeability
iii.
Bindingofdrugstoplasmaproteins
1. plasmaproteinsreduceserumconcentrationsofdrugs(malnourishedneedless
drugtogetasimilarserumconcentrationasawellnourished)
2. bindingtotissueproteinssomedrugsaccumulateincertaintissues
iv.
Volumeofdistribution
1. dose/Co=Vd
2. Istheapparentvolumeofwaterthatthedrugwasdistributedinto.Sothetotal
amountofdrugadministered/serumconcentration.attimezero
3. AlargeVdmeansthedrugdistributesintotheplasma,insterstialfluidand
intercellularfluidwell.AsmallVdmeansthedrugstaysintheplasma.
f. FactorsonMetabolism
i.
Zero&firstorderkinetics
1. Atlowdosesdrugsarefirstorder(i.e.therearehalflivesofdrugs)

2. athighdosesdrugsarezeroorder(thereisaconstantamountdropped...10mg
everyhour)
ii.
Drugmetabolism(byliver)
1. lipophilicdrugsneedtobeprocessedtobecomemorehydrophillicbytheliver.
2. phase1:makelipophillictomorepolar
Oxidation,Reduction,Hydrolysis
3. Phase2:
Conjugation
iii.
Drugclearancebykidney
1. decreasedbloodflowtokidneywilldecreasedrugclearanec
2. drugsenterrenaltubulesby
a. glomerularfiltrate
b. activesecretionintoproximaltubule
c. passivereabsorptionbydistaltubule
iv.
Dosing
1. adrugreachesitssteadystateinabout3.3halflives
2. aloadingdosecanreachsteadstateimmediately(Vd*steadystate)/bioavailibity
2. Ch2DrugReceptorInteractionsandPharmacodynamics
a. Signaltransduction:
i.
oftendrugsactonareceptorwhichtriggersmanydownstreameffects
ii.
thesearemediatedbysecondmessagnerswhocarryoutthesedownstreameffects
b. receptorfamilies
i.
Ligandgatedionchannels:changesmembranepotentialorionicconcentrationincell
1. quickestSecondsandlastonlyminutes
ii.
Gproteincoupledreceptors:bindingcausesgproteinchanges
1. Gproteinisathreesubunit(alpha,beta,andgamma)proteinwhosealpha
subunitinterfaceswithGDP.Alphabreaksofffromthebetaandgamma
subunitswhenGTPchargestillitinteractswithsomethingelse
a. adenylylcyclaseisturnedonbyAlphaGTP.Thistheninteractswith
cAMP(cyclcadenosinemonophosphate
iii.
Enzymelinkedreceptors:receptorisanenzyme
iv.
Intracellularreceptors:diffuseintocellinteractwithinternalreceptors
1. typicallytargetRNAandDNA
2. mustbelipophilicandsmalltodiffusethroughmembrane
3. theslowestsincetheyneedtowaitforproteinproduction
c. Signaltransduction
i.
signalamplification
1. oneligandmighthave200Gproteinsinit
ii.
Desnsitization
1. tachyphylaxisrepeatstimulationwillyieldquickdownregulation.
d. Doseresponserelationships
i.
potency:Theconcentrationofdrugneededtoproduceaneffectthatis50%maximum
effect.
ii.
Efficacy:theabilityofadrugtoelicitaneffectwheninteractingwithareceptor.
e. Agonists
i.
Fullagonist:producescompleteactivationofareptor
ii.
partialagonist:produceslessthat100%activationofareceptorevenathigh
concentrations
iii.
Inverseagonist:reducetheintrinsicactivityofareceptor.
f. Antagonists

i.
competiive:bindtothereptorsite
ii.
noncompetetive:bindtoareasotherthanthereceptorsite
iii.
irreversible:removethereceptorfromusepermanently
3. Ch3TheAutonomicNervousSystem
a. CNSisbrainandspinalcord
b. PNSiseverythingelse
i.
afferentPNS:sensoryinput
ii.
effereentPNS:theactionside
1. Somatic:skeletalmusclecontractions
a. singleneuronorigionatinginCNSwithoutganglionicsynapse
2. Autonomic:nonvoluntary
a. sympathetic
i.
thoracolumbarsynapsewithganglionicchain
ii.
shortpregangliaandlongpostganglia
iii.
extensivepregangionicbranching
b. parasympathetic
i.
Craniosacral(CNIII,VII,IX,X)
ii.
gangliaarenearthetargets
iii.
longpregangliaandshortpostganglia
iv.
usuallya1:1ratioofpreandpostganglia
c. enteric
i.
independentofCNS
ii.
gutbrain
iii.
modulatedbybothsympatheticandparasympatheticNS.
c. Chemicalsignalingbetweencells
i.
typesofneurotransmitters
1. acetylcholineisreleasesdbyallpreganglionicandsomaticfiberstonicotinic
receptors(acetylcholinenicotinic)
Cholinergic**
muscarinicreceptorsforpost
ganglionicaceteylcholineofparasympathetic(Muscarinicparasympathetic)
2. norepinephrineisrelasedbypostganglionicsympatheticstoadrenergic
receptors(norepinephrineadrenergic
sympathetic
)
4. Ch4CholinergicAgonists
a. Neurotransmissionatcholinergicneurons
i.
synthesis
1. cholineisalwayschargedandcantdiffuse
2. ratelimitingstepinAChsynthesis
ii.
storage
1. AChisstoredinpresynapticvesicles
2. thereareusuallycotransportersstoredwithAChtomodulateeffectofACh
iii.
release
1. Influxofcalciumcausesvesiclestobindwithcellmembranes
2. botulinumtoxininhibitsthis
3. blackwidowvenomcausesallAChtobereleasedatonce.
iv.
bindingofAChtoreceptor
1. eitheronthepostsynapticcell,orpresynapticcellorotherothertargeted
presynapticreceptors.
v.
degredationinsynapse
1. AcetylCholinesterasecleavesAChintocholineandacetate

vi.

recyclingofcholineandacetate
1. cholineisuptakenbyactivetransportwithsodiumcoupledtransporters.
b. CholinergicReceptors
i.
Muscarinnic
1. Gproteincoupledreceptors
2. 5subclasses(M1throughM5)
a. M1gastricparietalcells
b. M2Cardiacandsmoothmusclecells
c. M3Bladderandsmoothmuscle
ii.
Nicotinic
1. ligandgatedionchannel
2. 2subtypes
a. atneurmuscularjunction(blockedbytubocurarine)
b. others(blockedbyhexamethonium)
iii.
DirectActingCholinergicagents
1. Cholineesters
a. Acetylcholine(charged)
i.
Diffuseeffectsbecauseusedbymanyneurorecptors
ii.
worksonbothmuscarinicandnicotinicrecptors
iii.
decreasesHRandinotropy(likeAChfromvagusn.)
iv.
Indirectlyvasodilates(causesSmoothmuscletoproducenitric
oxide)
v.
causemiosisduetocontractionofcilliarymmuscle
b. Bethanechol(charged)
i.
nothydrolizedbyAChE
ii.
Nonicotinicaction
iii.
worksonsmoothmusclesofbladderandGI
iv.
relaxestrigoneandandsphincterofbladderandcontracts
detrussor
c. Carbachol(charged)
i.
Bothmuscarinicandnicotinic
ii.
nothydrolizedbyAChE
iii.
usedasamitoticagent
2. Alkaloids
a. Pilocarpine
i.
leastpotentdirectactingcholinergicagent,butwillpenetrateCNS
ii.
muscarinicactivity
iii.
usedasamitoticagent
iv.
usedasaprosalivationandprolacrimationagent(Sjogrens
disease)
v.
usedinemergentglaucoma(bothwideandnarrowangle)
iv.
IndirectactinCholinergicagonists(acetylcholineseraseinhibitors)
1. reversibleAChEinhibitorscanbeclassifiedasshortandlongacting
2. Edrophonium(shortactingAChEinhibitor)
a. renalelimination
b. limitedtoperiphery(chargedamine)
c. UsedindiagnosisofMyastheniaGravis(whengivenresultsinrapid
increaseinstrength).MGisantibodiestoNicotinicrecptorsatNMJ

3. Physostigmine
a. intermediateactingagent
b. canstimulateCNS
c. AE:convulsions,bradycardia,hypotension.
4. Neostigmine
a. absorbedpoorlyinGItract
b. greatereffectonSkeletalmuscles
c. noCNSeffects
d. Dontuseifbladderobstruction
v.
Indirectactingcholinergicagonists(anticholinesterases
irreversible
)
1. organophosphatescanbeusedasinsectacides
2. Manyweredevelopedasnerveagentsforwar
3. Echothiophate
a. limitedwindowwherePralidoximewillreverseitsbindingtoAChE.
b. causesmiosisandislastlineagentinglaucoma
vi.
ToxicologyofAcetylcholinesesteraseinhibitors
1. PralidoximecantenterCNS
a. cannot
overcomereversibleinhibitorsofAChE
2. atropinereducesmuscariniceffects
3. Diazepamreducesconvulsions
5. Ch5CholinergicAntagonists
a. Workatthecholinoreceptors
b. Antimuscarinicagents
i.
Atropine
1. competitiveinhibitorforAChatmuscarinicreceptors
2. Myadriasis,AntispasmoticinGI,urinaryretention,tachycardia(atlowdose
bradycardia)
3. entersCNS(goodforcholinergicoverdoses)
ii.
Scopolamine
1. goodformotionsickness
2. EntersCSN
3. Amnesiaandsedation
iii.
Ipratropiumandtiotropium
1. bronchodialators
2. donotenterCNS
c. Antinicotinic(ganglionicBlockers)
i.
Nicotine
1. depolarizesautonomicganglia
2. releaseofneurotransmitters
d. NeuromuscularBlockingdrugs
i.
eitheractasantagoniststoatNMJreceptors(nondepolarizing)orantagonists
(depolarizing)
ii.
Nondepolarizing
1. closeiongatedchannelsbyblockingNMJnicotinicreceptors
2. canbeovercomebyincreasingACh
3. Vecuroniumandrocuroniumappearmainlyinbile
4. othersareexcretedinurine.
5. mustbeIV,structureallowsforlittleoralabsorption

iii.

Depolarizingagents
1. Succinylcholine
a. causesopeningofsodiumchanels(phase1)depolarizing(tremors)
b. continuedbindingatNMJcreatesanabsoluterefractoryperiod.(phase2)
c. AE:hyperthermia,apnea,hyperkalemia
6. Ch6AdrenergicAgonists
a. Sendingasinglesignalinvolves:
i.
snythesis:TyrosineisimportedintothecellwhereitsconvertedtoDOPAandfinallyto
dopamine
ii.
storage:Acarrierproteintransportsandstoresdopamine(andreuptakenNORepi).
reesrpine
blocksthisaction.HereDopamineischangedtoNORepi(thentoEPIin
cromaffincellsinadrenalmedulla)
iii.
release:stillrequiresavoltagegatedinfluxofCa2+toreleasepayload(
guanethidine
blocksthispart)
iv.
receptorbinding:bindstocellprotiensthatcanhavemanysecondarymessagners
v.
removal
1. diffuseout
2. bemetabolizedbyCOMT
3. recapturedbyreuptakesystem(inhibitedbySSRI,SNRIandTCAs
vi.
FateofNORepi
1. reused
2. held
3. degradedbyMAO
b. Adrenoceptors
i.
determinedbybindingtoEPI,NORepiandIsoproterenol
1. Alpha1:higherafinityforphenylephrin.
locatedpostsynaptically
workviaG
proteinandinositoltoincreasecytoplasmicCa2+
2. Alpha2:higherafinityforclonidine
Locatedpresynaptically
causesfeedback
inhibitiontostopthereleaseofNORepi.Alsofoundonpresynaptic
parasypatheticneuronsandwillstopthereleaseofACh.Workviainhibitionof
adenylylcyclaseandfallofcAMPlevels
ii.
Betareceptors
1. strongresponseto
isoproterenol
andlesstoepiandNORepibindingtothe
receptorincreasescAMPlevelsincells
2. threesubdivisions:
a. Beta1:equalforepiandnorepi
b. Beta2:epi>thannorepi
c. Beta3:involvedinlypolysis
c. CharacteristicsofAdrenergicagonists:
i.
Catecholamines
1. Epi,NORepi,isoproterenol,dobutamineanddopaminesharehighpotencyfor
activatingalphaandbetareceptors.RapidinactivationbyCOMPTinterneurally
andMAOintraneurally.PoorCNSpenetrationbecausepolar.
ii.
Noncatecholamines
1. lackthe34dihydroxybenzenegroupand
cannot
beinnactivatedbyCOMT.
ThesearealsopoorsubstratesforMAO.nonpolarandthereforehasgreater
penetrationintotheCNS
iii.
Substitutionsonthaminenitrogen

1. Asthegroupsaddedtotheaminenitrogengetbiggertheafinityforbeta
receptorsincreases.
iv.
Sitesofaction
1. Directactingagonists:Directlyactivatesthereceptor
2. Indirectactingagonists:doesnotactdirectlyonhereceptor
3. Mixedactionagonists:haveboth.
d. DirectActingAdrenergicAgonists
i.
Epinephrine
1. synthesiedintheadrenalmedullaandreleasedintothebloodstream.interacts
withbothAlphaandbetareceptors.Atlowdosesthebetaeffectspredominate
(vasodilationonthevascularsystem)athigherdosesthealphaeffectsare
strongestonbloodstream(vasoconstriction).
2. Cardio(
beta1)
:increasedcontractiltyofmyocardium,increasedrate.
3. resp:brochodilation(
beta2
).
4. Hyperglycemia:hashyperglycemiceffectsinceitincreseesglycogenolysisin
liver,releasesglucagon,anddrecreasesinsulin.
5. lypolysis
6. brokendownbyCOMTandMAO
andmetabolytesarefoundinurine\
7. therapeuticuses:
bronchospasm,anaphylacticshck(type1sensitivity),cardiac
arrest,mixedwithanestheticstoinceaselocaleffectsoflido
8. Rapidonsetbutbriefduration.MaybegivenIM,IV,aerosol,subcut(notorally)
9. AE:anxietyfearHA,mayinducecerebralhemorrhage,arrhythmias,pulmonary
oedemea
10. Interactions
:enhancedcardiaceffectsinhyperthyroidism,cocaine,DM,with
BetablockerstheepiwilloverwhealmAlphareceptors,inhaledanesthetics
sensitizethehearttoepi.
ii.
Norepinephrine
1. Attherapeuticdosesthealphaeffectspredominate.
2. CV:increasedvasoconstrictionwithminimaleffectonheart
3. Therapeuticuses:
treatesshock,onlygivenIV
4. AE:similartoEPIwithsloughingofskinalongvein
iii.
Isoproterenol
1. Stimulatesthebetas
2. becauseithaslittleactivityagainstalphasandsolelybetaitcausesahuge
increaseinHR,dialatesskeltalarterioressoyouseeawideningoftheBPand
andadroppingintheSVR
3. Use:
onlyusedtostimulateheartinEmergencysituations.
iv.
Dopamine
1. immediateprecursertoNORepiactivatesbothalphaandbetas.ActsonD1and
D2receptorsthatexistintheperipheralrenalandmesenetericvascularbedsand
producesvasodilation.
2. atlowdosesthebeta1effectspredominate(increaseHRetc)athigherdosesit
startstovasoconstrict.IntherenalvasuclarbedsitcandecreaseVRdueto
dialation
3. Dopaminedialatesrenalandsplanchnicarterioles.
4. DOCforcardiogenicandsepticshock
v.
Fenoldopam
1. AgonistsofD1receptorsandmoderateafinityforalpha2

2. arapidactingvasodilatorforseverehypertension
3. HAflushingdizziness,etcmightbeobserved.
vi.
Dobutamine
1. B1receptoragonist
2. increaseCOanddoesnotelevateO2demandinmyocardium
3. CautioninAtrialfib.ThisincreasesAVconduction,similarAEtoepi.
vii.
Oxymetazoline
1. Alpha1andalpha2receptorsineyeandnoseforvasoconstriction.Usedinany
OTCdecongestantlongtermusecanproducereboundcongestion
viii.
Phenylephrine
1. bindstoalpha1s
2. NotacatecholaminethereforenotdegradedbyCOMTraisesBPsoyouget
reflexbradycardia
ix.
Clonidine
1. alpha2agonist.WorksinCNStolowerBP.Workscentrallytoreduce
sympatheticoutflow(becausealpha2sareinhibitiory)
x.
metaproterenol
1. Similartoisoproterenolbutnotacatecholamine(noCOMTmetabolism).There
arebetterlongeractingB2agonists.
xi.
Albuterolandterbutaline
1. ShortactingB2agonists(bronchodialation).CautionifptisoneMAOisinceit
canproduceunwantedcardiovascularstimulation.
xii.
Salmeterolandformoterol
1. delayedactionB2agonistsbutmuchlongerduration.Greatfornocturnal
asthma.
e. IndirectActingAdrenergicAgonists
i.
AlleithercausereleaseoforinhibitthereuptakeofNORepi
ii.
Amphetamine
1. CNSstimulationandA1agonist(hugeuptickinBP)andbetaeffectsonheart.
BlocksNORepireuptake
iii.
Tyramine
1. Foundinfermentedfoods.OxidizedbyMAO,butifptisonMAOithisactby
causesNORepirelease.
iv.
Cocaine
1. BlockstheNa/KATPaserequiredforreuptakeofNORepi.
2. IncreasesBPbyalpha1andbetastimulation.
f. MixedActionAdrenergicAgonists
i.
InducethereleaseofNORepiandactivateadrenergicreceptors
ii.
EphedrineandPseudophedrine
1. Similaractiontoepinephrine.
2. PoorlymetabolizedbyCOMTandMAO
3. EphedrineentersCNSpseudopedrinepoorlydoes
4. ephedrineiselminiatedbykidney
5. pseudoismetabolizedbyliverthenelminatedbykidney
6. ephedrinecanbeusedforitsalertnessproperties
7. pseudoisusedforitdecongestantproperties
7. AdrenergicAntagonists
a. Alphaadrenergicblockingagents

i.
ii.

HugedecreasestoSVRandthereforecanseereflextachycardiaandhypotension
Phenoxybenzamine
1. HitsbothAlpha1and2s.Irreversibleandnoncompetetive.Mustsynthesizenew
receptors.
2. reflextachycardia.
3. IfEpinephineiscoadministeredtheBeffectswillfurtherthehypotensionsince
epicannotworkonthealphareceptors.
4. Onlyuseisforpheochromocytomaspriortosurgery(whenmanipulationoftissue
couldcauseHTN.
iii.
Pentolamine
1. blocksbothAlpha1and2s
2. canalsocauseepireversal.
3. alsousedforshorttermmanagementofpheochromocytomas
4. usedtopreventdermalnecrosiswithNORepiuse
5. treatsHTNcrisesfromwithdrawalofclonidineandeatingcheesewhenonMAOi
iv.
Prazosin,terazosin,doxazosin,tamsulosisn,alfuzosin
1. pra,teraanddoxacanbeusedfortreatmentofHTN.
2. TAmsulosinandalfuzosinareusedforBPH
3. AllareexcretedinurineexceptDoxazosinwhichisfeces.withminimalchanges
toCO
4. TamsulosinhasleasteffectonBP,sinceselectiveforalpha1sofurethra,but
canhaveretrogradeejaculation
5. NB:
Tamsulosinisselectiveforalpha1sonurethraandcantake24weeksfor
fulleffects.The5alphareductaseinhibitors(finasteridedutasteride)reducethe
sizeoftheprostateandtestosteroneconversionbuttake6monthsforpeak
effect.
v.
Yohimbine
1. selectivecompetittivealpha2blocker.hasCNSeffectstoincreasethe
sympatheticoutflow.canbeusedtocounterRaynaudconstriction.Cautionwith
CardiacandCNSissues.
b. BetaAdrenergicBlockingAgents
i.
Allarecompetitiveangtagonists.NonselectiveincludebothB1andB2.Cardioselective
areB1.TherearenoclinicallyusefulB2blockers.Lessposturalhypotensionbecause
alphblockersareintact.
ii.
Propranolol:AnonselectiveBetaantagonist
1. Blocksbeta1andbetaequally.Sustainedreleasearegoodforonceaday
dosing.
2. negativeinotropicandchronotropiceffects.
3. DirectlydepressesSAandAVnodes
4. stopsB2vasodilation
5. causesbronchoconstriction(
notusedinCOPDorAsthma)
6. IncreasesNaretentionduetodecreasedperfusionofkidneys
7. Canattenuatenormalresponsestohypoglycemia
8. Blockstheactionofpropranolol.
9. 100%oralabsorption.largeVolumeofdistrobution,crossesbloodbrainbarrier.
10. USE:
a. HTN:willreducebpbutnotinnormotensivepeople.
b. Migrain:canbeusedprophylacticallyformigraines

c. Hyperthyroidism:bluntsthesympatheticstimulationinhyperthyroidism
d. GreatfordecreasingO2needsduringangina.
e. MI:protectiveeffectonmyocardium.
11. AEs:
a. Bronchoconstrition
b. Arrhythmias:thisdrugcannotbeD/Cimmediately
musttaperoff
c. Sexualdysfunction
d. Metabolicdistubances:hypoglycemia,blockssymptomsofhypoglycemia
e. CNSeffectslikedepression,hallucinations,insomnia
f. manydrugschangethemetabolismofpropranolol
iii.
Timololandnadolol:nonselectiveBetaantagonists
1. Morepotentthanpropranolol.
2. Nadololhasverylongduration
3. timololreducesaquaeoushumorproductionineyes.(Txforopenangle
glaucoma).
4. glaucoma
a. Bblockersaregoodforchronictx
b. PilocarpineisDOCforAcuteglaucoma
iv.
Acebutolol,atenolol,metoprolol,bisoprolol,betaxolol,nebivolol,andesmolol:selective
B1antagonists
1. cardioselectivityismostpronouncedatlowdoses,butlostathighdoses.
v.
Pindololandacebutolol:Antagonistswithpartialagonistsactivity
1. aceisselectiveandpinisnot.
2. mixedbecausetheystimulateB1andB2asagonists,butonlyweaklyso(less
antagonismthanafullantagonist
vi.
Labetalolandcarvedilol:AntagonismofbothAlphaandbetaadrenoceptors
1. blockalpha1sotheseareusefulinpatientforwhomwedonotwant
vasoconstriction(inceaseinSVR)
c. DrugsaffectingNeurotransmitterreleaseoruptake
i.
Reserpine
1. blocksMg/ATPtransportofamines,NORepiandDopamine,andserotoninfrom
cytosoltovesciclesinadrenergicnerves.Theseisadecreasedstorageof
NORepiandthereforeadecreasedrelease.
ii.
Guanethidine
1. blocksthereleaseofstoredNORepifromvesciles.
iii.
Cocaine
1. blockaideofreuptakeofNORepi,epi,sero,dopa).
2. cancreatecycleofdepression(duetodecreaseddopastores)thatisonly
releavedbycocaineuse.
8. NeurodegenerativeDiseases
a. NeurotransmittersintheCNS
i.
UnlikethePNS,theCNShaspowerfulinhibitoryneurons.Usesasmanyas50
neurotransmitters.
b. SynapticPotentials
i.
Mostrecptorscontroliongatedchannels
ii.
Excitatoryreceptorscreatedepolarization
iii.
inhibitoryreceptorscreatehyperpolarization
c. OverviewofParkinsonDisease

i.
ii.
iii.
iv.

Characterizedbymusclerigidityandbradykinesia
CorrelatedwithDopaminergicneuronsinthesubstantianigra
notlikelygenetics
Subtantianigraextrapyramidalsourceofdopaminergicneruonsandfiretonically
NeostriatumconnectedtosubstantianigraandemitinhibitaryGABA.AndtheSNemits
dopaminewhichisinhibatorytoNeo.BetweenthetwothereisaAChstimulatingneuron
thatisinhibitiedbyDAandemitsAChtostimulateGABA.InParkinsonsThereisnoDA
fromtheSN,thereisanincreaseinAChandthenanincreseinGABA.
v.
TherapyiseithertorestorDAorantagonizetheexcessiveACh
d. DrugsusedinParkinsonDisease
i.
LevopaandCarbidopa
1. levodopaisaprecursertoDAandcanbeconvertedbytheremaining
dopaminergicneuronsintheSN.Earlyonindiseaseitworks,butasthenumber
ofdopaminergiccellsdecreasestheeffectswearoff.
2. Carbidopaisdopdecrboxylaseinibitorthatdosenotcrossthebloodbrain
barrier
3. MOA
a. DAdoesnotcrosstheBBB,buttheprecurserLevodopacan.Large
dosesoflevodopaareconvertedintheperipheryandcanresultinnusea
vomitingcardiacarrhythmiasandhypotension.
b. CarbidopademinishesthemetabolismoflevodopaintheGIand
peripheraltissues.LowersthedoseofLevodopaneded.
4. Thesemustbetakenbeforemealsinceproteinscompetewithlevodopafor
absorptionsites.
5. AE
a. anorexia,nuaseavomiting.CardiaceffectsduetoDAinperiphery
b. CNS:hallucinations,psychosis
6. Interactions
a. VitaminB6breaksdownlevodopa
b. MAOiwillcausehypertensivecrisisduetoincreasedcatecholamines
c. cautioninpsychoticpatients(mayexacerbatesymptoms
d. CAincardiacPTsmaycausearrhthmias
ii.
SelegilineandRasagiline
1. SelegilineinhibitisMAOtypeB(whichmetabolizesDA).
a. metabolizedtoamphetamineandmaycuaseinsomnia
2. Rasagilineis
5xaspotentasselegiline
.irreversibleinhibitionofMAOtypeB.
a. NOTmetabolizedtoamphetamine
iii.
CatecholOmethyltransferaseinhibitors
1. whenCarbidopinhibitslevodopaperipherallyCOMTwillmaketoomuch
3OMethyldopa,whichcompeteswithlevodopaforabsorptionintotheCNS.
2. entacapone/tolcaponeinhibitsCOMTfrommaking3Omethyldopa
3. Maybetakenwithfood.
4. Highlyproteinbound.
5. TolcaponecrossestheBBB
6. AE:
a. Diarrhea,nausea,anorexia,hallucinations
b. hepaticnecrosiswithTolcapone
iv.
DopaminereceptorAgonists
1. Thesearenoteffectiveinpatientswhohavenotrespondedtolevodop

2. Bromocriptineanergotwithmanysideeffects.caridiacproblems,vasospasm,
ulcersandpulmonaryfibrosis
3. Apomorphine,pramipexole,ropinirole,rotigotine
a. nonergot
b. Apomorphineisuesddurringofftimes
c. novasospasm,nofibrosis
d. AE:hypotension
e. pramipexoleisdependentonrenalfunction
f. RopinirolehasahugeVdandthereforelargerdoses
v.
Amantadine
1. increasesdopaine,isnanticholinergic,NMDAinhibition
2. lesssideeffectsthanlevodopa,butwillburnoutsooner.
vi.
Antimuscarinicagents
1. Onlyadjuvants.
2. contraindicatedinglaucoma,BPH,pyloricstenosis.
e. DrugsusedinAlzheimerDisease
i.
Onlypalliative
ii.
Alzheimerscharacterizedbybetaamyloidplaques,formationofneurofibrillarytangles,
lossofcorticalneurons(chollingericones).
iii.
AChEinhibitors
1. donepezil,galantamine,rivastigmine,tacrine
2. galantamineistheonlycompetetiveinhibitorofAChE
3. rivastigminehasnotCYPmetabolism
4. tacrineishepatotoxic
5. AE:N,V,D,anorexia,tremors,brdycadia
iv.
NMDAreceptorantagonist
1. stimulationofglutamatereceptorsisneededformemoryformation.Antagonism
ofNMDAwillpreventneuronalapoptosis
2. MemantineblockstheNMDAionchannel
3. confusionisAE
f. DrugsusedinMultipleSclerosis
i.
AutoimmuneinflammatorydemyelinatingdiseaseofCNS.
ii.
corticosteroidsareusedinacuteattacks
iii.
Otheragentsusedarechemotherapeutic
iv.
InterferonB1aandbareimmunomodulatorsoftheThelpercells.
v.
Mitoxantrone:KillsTcells.AE:depression,infusionrections,hepaticenzymeincreases,
flusymptomsandleukopenia
vi.
Fingolimod:alterslymphocytemigrtion.keepstheminlymphnodes.AE:ofinfections
vii.
Dalfampridine:Kchannelblocker.Improeswalkingspeeds.
viii.
Glatiramer:syntheticmyelinprotein.Mightactasdecoy.
ix.
natalizumab(monoclonal)forMSthathasfailedothertherapies.
g. Drugsinamyotrophiclateralsclerosis
i.
RiluzoleisaNMDAreceptorantagonist.itmightdelayventilatortime.
9. AnxiolyticandHypnoticDrugs
a. Benzodiazepines
i.
MOA
1. BindtoGABAreceptorsandopenofachloridechannel.Bindingwillcause
increasedaffinityforbenzosandGABA

ii.

Action:
1. NOANTIPSYCHOTIC,ANALGESIC,orAUTONOMICactivity
2. Reductionofanxiety.EnhancesGABAergictransmission
3. Sedativeandhypnoticactions
4. Anterogradeamnesia
5. Anticonvulsant
6. Musclerelaxant:increasespresynapticinhibitionbyGABAatspinalcord.
Baclofen
isthoughttoworkatthelevelofthespinalcord.
iii.
TherapeuticUse
1. Anxietydisorders:reservedforcontinuedandseverestrees.ONlyinshortbursts
sincetheyareaddictive.Longactingagents(clonazepam,lorazepamand
diazepam)arepreferredforlongtermuse.
Alprazolam
isprefferedforthose
withpanicdisorders
2. Musculardisorders:Diazepamforskeletalmusclespasm.
3. Amnesia:Usedbeforeanxietyinducingprocedures
Midazolam
isprefererred.
4. Seizures:
lorazepamispreffered
foracuteterminationofstatusepilepticus
5. Sleepdisorders:Needtobalancethesedativeeffectsandthepostusage
hangovereffectsofdrugusage.
a. Flurazepam:longacting,canbeusedforupto4weeks
b. Temazepam:goodforpeoplewhoexperiencemidsleepawakeningtake
12hrsbeforeHS.
c. Triazolam:causesreboudinsomniadoesntworkdailywyuseit.
iv.
Pharmacokinetics
1. Absorptionanddistribution:lipophillic,rapidandcompleteoralabsorption.Large
distributedthroughoutthebody.
2. Duration:short,intermediateandlongactingdurations.Thepharmdurations
andclincialdurationsdonotalwaysmatch.
3. Hepaticmetabolism
,excretedinurine,crossplacentalbarrierandpresentin
breastmilk.
v.
Dependence
1. Highdoses,prolongedperiodsoftime.AbruptdiscontinuationofBenzoswill
givewithdrawal,confustionanxietyLongdurationBZDwillcauseslow
withdrawal.Shortwillcausestrongwithdrawalsymptoms
vi.
Adverseeffects
1. Drowsinessandconfusion
2. Precautionswithliverdisease,
narrowangleglaucoma
,
b. Benzodiazepineantagonist
i.
Flumazenil:Gabareceptorantagonis.canpercipitatewithdrawalandseizures.
c. OtherAnxiolyticAgents
i.
Antidepressant:SSRIandSNRIhavebeenshowntobeeffectiveforGAD.Maytake4
weeksformedicationtowork.MostlikelyaclasseffectandnotaFDAapprovaleffect.
ii.
Buspirone:NotgoodforacuteorPRNusage,butgoodforchronicmanagement.Some
affinityforSerotoninandDAreceptors.
Noanticonvulsantormusclerrelaxant
properties,minimalsedation
lowdependence,slowonsetofaction.Goodfor
geriatrics,andalcoholicssinceitdoesnotpotentiatewithalcohol.
d. Barbiturates
i.
FormerlyTxforanxiety,buthadtoleranceandcoma.
ii.
MechanismofAction:GABAergic.Also
blockglutamate

iii.

Actions:durations(long,shortandultrashort)
1. DepressionofCNS:fromsedationofhypnosis,coma,death
2. Respiratorydepression:depressCO2response
3. EnzymeInduction:turnsonCYP450
iv.
TherapeuticUses:
1. Anesthesia
2. Anticonvulsant:
phenobarbitalisDOCforrecurrentpediatricfevers.
3. Anxiety:mosthavebeenrelpacedbybenzos.
v.
Pharmacokinetics:oral,andwidedistrobutionstartsatbrainandendsinfat.Cross
placenta,metabolizedinliver,andexcretedinurine.
vi.
Adverseeffects
1. CNS:drowsinessconcentrationandsluggishness
syngerizeswithEtOH
2. Drughangover:
3. Precautions:makeincreaseporphyrinsynthesisandshouldbeusedcautiouslyin
patientswithintermittentporphyria(onandoffabpainwithcompleterevoery)
4. Physicaldependence:moreseverethanopiates
5. Poisoning:respiratorydepressionleadstodeath.Nospecificantagonist.
Intubate,alkinizeurine,andhemodialysis.
e. OtherHypnoticAgents
i.
Zolpidem:NotaBNZbutactsasasubset.
lacksanticonvulsantormusclerelaxing
properties
Minimalreboundortolerance.
hepaticmetabolism
rifampininteracts.AE:
Nightmares,HA.Noalterationofsleepcycleslikebenzos(whichmakeyoufallasleep
butnotnecessarilygetgoodsleep)
ii.
Zaleplon:fewereffectsonpsychomotor.Betterforelderly??
iii.
Eszopiclone:goodforupto6mo.Metabolizedbyliverexcretedbyurine.
iv.
Ramelteon:Melatoninagonist.Mayincreaseprolactinlevels.
v.
Antihistamines:onlygoodformildestformsofinsomnia.AE:includeanticholinergic
effects.
vi.
Ethanol:toxicpotientialoutweighsbenefits
f. DrugstotreatAlcoholdependence
i.
Disulfiram:blocksoxidationofaldehydetoaceticacid.
ii.
Naltrexone:reducesthedesireforEtOH
iii.
Acamprostate:poorlyunderstooddrug
10. CNSStimulants
a. PsychomotorStimulants
i.
Methylxanthines
1. Caffeine(coffee),Theobromine(chocolate),Theyophylline(tea)
2. MOA:Probableblockadeofadenosinereceptors
3. Actions:
a. CNS:Caffeine12cupsgivesawakefullness,1215tremrorsananxiety.
b. Cardiovascularsystem:+inotropicandchronotropiceffects,PVCs
c. Dirueticeffects
d. Increasedacidproductionbygastricmucosa
4. Therapeuticuses:previouslywereusedtorelaxbronchioles
5. Pharmacokinetics:distrobutethroughbodyandbrain,placentaandbreastmilk
6. AE:withdrawalHA
ii.
Nicotine
1. MOA:ganglionicstimulation,athighdoses,respiratorydepression.

iii.

iv.

v.

vi.

2. Action:
a. CNS:euphoriaandrelaxation,
b. Peripheraleffects:increasedbpandhr.
3. Pharmacokinetics:crossesmucosaandlungs,GIandskin.metabolizedinlung,
liver.
4. AE:irritability,tremors,cramps,diarrhea.increasedmetabolismofotherdrugs
Varenicline
1. Partialnicotinicagonist.Usedtoaugmentnicotinequitting.Monitorfor
nightmaresandmoodchanges.
Cocaine
1. MOA:blocksreuptakeofNORepi,serotonin,andDAbyinhibitionofMOA
reuptake.ChronicusecandepleteDAandleadtostrongcravings.
2. Actions:
a. CNS:stimulationsofcortexandbrainstem.Euphoriatotremorsathigh
doses
b. Sympatheticnervoussystem:peripherallypotentiatesactionofNORepi
c. Hyperthermia:evenseeninsmallnasaldoses.
3. Therapeuticuse:EENTsurgeryastopicalanaesthetic.Onlylocalanestheticto
producevasoconstrition(andseptalnecrosis)
4. Pharmacokinetics:highlasts1.5hours.canbedetectedinurine.
5. Adverseeffects:
a. Anxiety:HTN,tachycardia,paranoia
b. Depression:stimulantthatisfollowedbyCNSdepression
c. toxiceffects:caninduceseizuresandarrhythmias.NomarkersforMI
riskwhentakingcocaine(youneverknow)unrelatedtodose.
Amphetamine
1. MOA:likecocaineitsindirectlyelevatescatecholamines.Amphetaminecauses
areleaseofallcatecholaminestores.
2. Action:
a. CNS:alertness,depressedappetite,insomnia.
b. Sympatheticneroussystem:indirectlystimulatesadrenergicsystem
3. Therapeuticuses:
a. ADHD:usedtostimulatetheCNStofocusmore.Lisdexamfetamineis
theprodrugofdextroamphetamine.Atomoxetineisanonstimulatentthat
canbeused(notforthoseonMAOi)MethylphenidateblocksDA
reuptake,atomoxetineblocksNORepireuptake(nothabitforming)
b. Narcolepsy:stimulantsormodafinilwhichpromoteswakefulness(by
adrenergicanddopaminergicsystems.Hepaticmetabolism
4. Pharmacokinetics:100%absorptioninGI,metabolizedbyliverandexcretedin
urine.
5. AE:
a. CNS:ninsomnia,confusion,ODsaretreatedwithchlorpromazineor
haloperidol.
b. CV:palpitations
c. GI:anorexia,nausa,vomiting,diarrhea.
d. ContraindicatedwithHTN,CVhyperthyroidismorglaucoma.
Methylphenidate

1. MOA:ADHDmightproduceweakDAsignals.MethylphenidateDAtransport
inhibitor.
2. TherapeuticUse:ADHD616.
3. Pharmacokinetics:oralabsorptionisgood.excretedinurine
4. AE:GI,abdominalpain,nausea,fever,seizuresifwithantidepressant.
b. Hallucinogens
i.
Lysergicaciddiethylamide
1. 5HTagonistatpresynapticmidbrain,and5HTrecepotragonist.Haloperidol
abortshallucinations.
ii.
Tetrahydrocannabinol
1. THCrepceptorsfoundoncabanoidreceptors.lipophillic,elminiationviabiliary
route.
iii.
Phencyclidine
1. inhibitsreuptakeofDA,5HTandNorepi.anticholingricactibity,butcauses
hypersalivation.
11. Anesthetics
a. Anesthesiais:
i.
Sedationandreductionofanxiety
ii.
Lackofawarenessandamnesia
iii.
Skeletalmusclerelaxation(facilitateintubation)
iv.
Suppressionofundesireablereflexes
v.
Analgesia
b. Nosingleagentprovidesalloftheabove,soyouhavetousemultiples.
c. Patientfactorsinselectionofanesthesia
i.
Statusoforgansystems
1. CV:halothanemaysensitizehearttoanrrhythmogeniceffectsof
sympathomimeticagents.
2. Lung:Inhaledanestheticsdepresstherespiratorystystemandactas
bronchodialators.
3. Liverandkidney:NeedtoevaluateforL/Kdiseasetohandlemetabolites
4. Nerous:neurodisorderscanchangeourselectionorwatchformalignant
hyperthermia
5. Pregnancy:earlypregnancyisaconcern.
Nitrousoxidecancauseaplastic
anemiainunborn.Benzoscausecleftpalet.
ii.
Concomitatntuseofdrugs
1. Multipleadjuctagents:
a. H2blockertoreduceacidity
b. BZD:foranxiolytic
c. opioids:analgesia
d. antihistamines:preventallergicreations
e. antiemetics:antinausea
f. anticholinergics(
glycopyrrolate)
topreventbradycardia.
2. Concomitantuseofadditionalnonanestheticdrugs:EtOHusersmighthave
eleveatedhepaticenzymefx.
iii.
Stagesanddepthofanesthesia
1. Stages
a. Induction:administrationtosurgicalanesthesia.
i.
oftenpropofolandskeletalmusclerelaxants.

iv.

b. Maintence:sustainedanesthesia
i.
inhaledanestheticsareusedoftenwithopioidsforpaincontrol
c. Recovery:discontinuationtoreturnofconsciousness
i.
sometimesreversalagentsareused,othertimeswewaitforthem
towashout.
2. Depthofanesthesia
a. 4sequentialstages
i.
Analgesia:interferencewithsensorytransmitioninsipinothalamic
tract.
ii.
Excitement:delirium,combativebehavior.irregularBP,
laryngospasm.
Propofolisusedtoeliminateorshortenthis
stage.
iii.
Surgicalanesthesia:lossofspontaneousmovement.
iv.
Medullaryparalysis:inhibitionofthesecenterstomaintainbpand
hr.
InhalationAnesthetics
1. usedformaintenanceofanesthesiapostIVuse.Steepdoseresponsecurves
andnarrowtherapueticindexs.Mostpassthroughrecirculatingsystemstoscrub
andreuseanywastedanesthetic
2. Commonfeaturesofinhalationanesthetic
a. therearebothvolitileandnonvolitlieanesthetics.
b. Decreasecerebrovascularresistanceandincreaseperfusiontobrain.
c. bronchodilation,andreducepulmonaryvascularresistence.
3. Potency
a. MinimumAlveolarConcentration(MAC)endtidalvonventrationof
anestheticgasneededtoeliminatemovmentin50%ofpatients.
i.
AhighMAC%=lowpoentency.
ii.
FactorsincreasingMAC:
1. hyperthermia
2. drugsthatincreaseCNScatecholamines
3. Chronicethanolabuse
iii.
FactorsdecreasingMAC
1. age
2. hypothermia
3. pregnancysepsis
4. acuteethanolintoxication
5. IVanesthetics
6. alpha2adrenergicreceptoragonists(clonidineand
dexmedetomidine
4. Uptakeanddistributionofinhalationanesthetics
a. Alveolarwashin:replacementofNLlunggaseswithinspiredanesthetics.
b. Anestheticuptake:
i.
Solubilityinblood:theratioofanestheticinbloodtoanestheticin
alveoli.Ahighernumberequalsmoreinblood.
1. anestheticswithhighsolubilitytakelongertoinduceand
longertowashout(sincebloodjustspongesthemup).
2. Lowersolubilitydrugstakelesstimetoinduceandless
timetowashout,butyoumightnotbeabletogetasdeep

5.

6.

7.

8.

9.

ofanthesthisasincethereslessabliltytorampupthegas
concentrationsinblood.
3. Bloodsolubilityisrankedasfollows:halothane>isoflurane
>sevoflurante>nitrousoxide>desflurane
ii.
CardiacOutput:
1. higherCOremovesanesthetictoperipheraltissues(where
ithasnoeffect.Itwilltakelongertogetdrugtoalveolar
steadystate.
iii.
Alveolartovenouspartialpressuregradientoftheanesthetic
1. Venouspartialpressureincreases,thegaswilredistribute
backtoalveolae.
c. Effectofdifferenttissuetypesonanestheticuptake
i.
Brainheartliverkidneyandendocrineglands:perfusedand
rapidlyattainasteadystate
ii.
Skeletalmuscle:poorlyperfusedduringanesthetisa,largevolume
andrequirealongtimetoreachsteadystate.
iii.
Fat:poorlyperfused,buthighlylipophillic.verylongtimetoreach
steadystate
iv.
Bone,ligamentandcartilage:lowcapacitytostoreanesthetic
d. Washout:
i.
gaseswithlowaffinityforbloodpassintoalveolifastest.Drugs
thattaketheleasttowashin,taketheleasttowashout.
MechanismofAction
a. Thereisnospecificmechanismidentified,butprobablysomesortof
affinityformanyreceptors.
Halothane
a. Prototypetowhichneweranestheticsarecompared.
b. anestheticstatequicklyandrapidwashout.
c. Therapeuticuse:weakanalgesic.Potentbronchodialator.
not
hepatotoxicinpeds,butisinadults
.Inducesuterinerelaxation.
d. Pharmacokinetics:Femalescanhavereationstotoxicmetabolities(fever,
anorexia,nausea,vomiting,hepatitis.Incedenceislow,but50%die.
e. Adverseeffects:
i.
cardiac:vagomimeticatropinesensitivebradycardia.Canproduce
hypotension.Counterwithdirectactingvasoconstrictor
phenylephrine.
ii.
Malignanthyperthermia:increaseinskeletalmuscleoxidative
metabolism.
Isoflurane
a. Stable,nontoxictoliverorkidneys.Nonarryhtmogenic.Canproduce
hypotension.Pungentodorandcannotbeusedforinhaledinduction.
Typicallyreplacedbysevo.ordes.,sinceisohavehigherbloodsolubility
andthereforetakeslongertoinduceandwashout.
Desflurane
a. rapidonsetandrecoverybecauseoflowerbloodsolubility.Lowvolitility
andneedtouseaheatedvaporizer.Veryexpensivesonotusedfor
maintenceanesthesia.
Sevoflurane

a. Lowpungencygoodforinhalationinductionandpeds.rapidonsetand
recovery(lowbloodsolubility).
metabolizedbyliver
.Compoundsformed
byanesthesiacanbe
nephrotoxic
.
10. Nitrousoxide
a. Potentanalgesic,butweakgeneral.Becauseithassuchfastuptakeit
canconcentratehalogenatedgasesinthealveoli.Canincreaseinclosed
bodycampartments
b. ThespeedofitsmovmentslowsO2uptakeduringrecovery.Mustmakes
recoverwithHighconcnetrationO2
d. IntravenousAnesthetics
i.
Veryrapidinductionofanesthesia,whichisthenmaintainedbyinhalationanesthetics.
ii.
Induction:Pecentageisboundtoplasmaproteinsbutrestisfree.Since70%ofCOgoes
tobrain,liverandkidneyalargepartreachesthebrain.
Unbound,lipidsoluble,
nonionizing,moleculecrosstheBBBeasiest
.
iii.
Recovery:Laterdrugdiffusesouttoothertissuesandreducesplasmaconcentration.
Drugflowsoutduetoconcentrationgradient.
Adiposetakeslittleofinduction,but
withmaintencebecomesalargeresovoirofdrug.
iv.
EffectofreducedCO:whencardiaccompromisebloodisshuntedtobrainand
prolongedcirculationtime.ThereforelessdrugisneededinreducedCOsituationsto
induceandthedrugwillbealonglonger(lessisneededformaintence.
v.
Propofol
1. Firstchoiceforanesthesia
2. Onset:3040secondsafteradministration.prolongedmetabolismbyliverand
kidney,butnottoomuchchangeuntillseverimparement.
3. Action:CNSdepression,littleanalgesia.Hypotensionwithouteffecton
myocardium
vi.
Fospropofol:watersolubledrugonlyforsedation.takesabout4mintolose
consciousness.
vii.
Barbituruates:Thiopentalultrashortactingbarbiturate.rapiddistrobutiontoCNSand
thenrapidout.
Cancausebronchospasm
.Dontusein
porphyrias
viii.
Benzodiazepines:sedation,metabolismbyliver.
ix.
Opioids:Canbeusedinmanywaystoinduceorprolonganalgesia.
x.
Etomidate:hypnotic,butnonanalgesic.rapidbutshortacting.Goodforcardiac
compromisedpatients.metabolizedbyliver.
Notformaintenencesinceitsuppresses
cortisolandaldosterone.
xi.
Ketamine:shortacting,nonbarbiturateanesthetic.Dissociatedstates,nopain.
NmethylDaspartatereceptor.Increasessympatheticoutflow.Goodwhen
hypovolemicorshocky.metabolizedinliver,mainlyinchildrenandelderyforshort
procedures.causeshallucinationsinadults
xii.
Dexmedetomidine:ICUandanesthesiologists.sedationwithoutrespiratorycompromise.
LIkeclonidineAlpha2receportagonist
e. Paralytics/Neuromuscularblockers:abolishreflexesandfacilitateintubation.block
nicotinic
acetylcholine
Cisatracurium,pancuronum,rocuronium,succinylcholine,vecuronium.
f. LocalAnesthetics
i.
blocksensorytrasmission.Eachhasanamideoresterlinkage.Bupivacainehas
cardiotoxicity,mepivavatineshouldntbeusedinOBbecausetoxictoneonates.
ii.
Metabolism:Amidesaremetabolizedinliver.Prilocaineismetabolisedinplasmaand
kidneys.Estersaredoneintheplasma.

iii.
iv.
v.

Onsetandduration:Varriesbydrugandlocation.AspHdrops(ie.puss)theyworkless.
Actions:vasodialation,oftenmixedwithepitopreventthis.
Allergy:oneesterallergyrulesoutotheresters,butoneamideallergydoesnotruleout
otheramides.
vi.
Administrationtochildrenandelderly:calculatemaxiumdoestopreventlocaltoxicity.
vii.
Systemiclocalanesthetictoxicity:aspirationbeforeinjectionisneededtoprevent
systemicspread.20%lipidemulsionmightbereversaltherapyforlocals
viii.
Esters:Procaine,tetracaine,cocaine,chloroprocaine.
ix.
Amides:Lidocaine,mepivacaine,bupivacaine,prilocaine,rapivacaine.
12. Antidepressants
a. Mechanismofantidepressantdrugs
i.
Potentiateactionsof5HTornorepiinbrain
b. SelectiveSerotoninReuptakeinhibitors
i.
inhibitserotoninreuptakeinsteadofTCAswhichhavenoselectivityfor5THorNORepi
reuptakechannels.
ii.
LittleblockingofDAreuptake,muscarinicAadrenergic,histaminereceptors(sono
drymouthorsedationlikeTCAs)
iii.
Actions:Take28weekstowork.~40%ofpatientsdonotrespondtofirstagents,but
nearlyallwillrespondtoatleastone.
iv.
Therapueticuse:Depression,OCD,PTSD,Socialanxietydisorder,premenstrual
dysphoricdisorder,bulimanervosa
v.
Pharmacokinetics
1. Foodhaslittleeffect
exceptforsertraline:foodincreasesabsorption
2. SertralineONLYhasfirstpassmetabolism
.CYP450dependent
3. Fluoxetine
muchlongerhalflife
andavailableinonceweeklydosing.Metabolite
Snorfluoxetineisaspotentasparentdrug.
4. FluoxetineandparoxetineareinhibitorsofCYP2D6(~7%ofcaucasianslackthis
enzyme).
5. Excretionisviakidneysexcept
paroxetineadnsertraline
(fecal)\
vi.
Adverseefects
1. Sleepdisturbances
a. Paroxetineandfluvoxaminearesedating
b. Fluoxetineandsertralineareactivating
2. Sexualdysfunction
a. bupropionandmirtazapinehavefewersexualsideeffects.
b. Txwithviagraectmightwork
3. Useinkids
a. 1in50kidsreportsuicidalideationatstart.Fluoxetineisapprovedto
treatpediatricdepression.
4. Seizures
a. Lowersthershholdforseizures.Riskofserotoninsyndrome.Givelong
washoutperiodwhenswitchingmeds.
5. Discontinuationsyndrome:
a. shorterhalflivesriskofwithdrawalafterabruptstop
c. Serotonin/Norepinephrinereuptakeinhibitors
i.
MightbehelpfulifpatientisSSRIresistant.Andmightbegoodforptswithchronicpain
(SSRIwontworkhere).
Goodwhenchronicpainanddepressionaretogeth
er.
ii.
Venlafaxineanddesvenlafaxine

1. atlowerdosesactsasSSRI,mediumandhigherdosesinhibitsNorepiandDA
ruptake
2. minimalCYP450inhibition.
iii.
Duloxetine
1. S
NRIatalldoesemetabolized
byliverextensively(notfor
liverd
z)excretedin
urine(notfo
rrenaldzeithe
r).
2. fooddelaysabsorption.
3. sexualdysfunction.
4. moderateinhibitorofCYP2D6and3A4
d. AtypicalAntidepressants
i.
Bupropion
1. WeakDAandNORepireuptakeinhibitor.
2. willrequireQDdosing.
3. Goodtostopnicotinecravings
4. lowincidentofsexualdysfunction.
5. notforptswithseizuresorbulimia
ii.
Mirtazapine
1. Enhances5HTandNORepitransmission.
2. sedativeduetoantihistaminicactivity(butnoantimuscariniceffects)nosexual
dysfunction.
3. Weightgain
iii.
Nefazodoneandtrazodone
1. 5HTruptakeinhibitor.
2. sedatingduetoH1blocking
3. priapismwithtrazodone
4. nefazodonehashepatotoxicity.
5. orthostasisandtacycardia
e. TricyclicAntidepressants
i.
TCAsaresecondaryandtertiaryaminesthatblockthereuptakeof5HTandNORepi
ii.
MOA
1. Blockthereuptakeof5HTandNORepi.
Maprotilineanddesipramineare
realtivelyselectiveforNORepi.
2. Alsoblockserotonergic,alphaadrengeric,histaminicadnmuscarinicreceptors.
Amoxapineblocks5HT2andD2receptors
iii.
Action:workin5070%ofpatientswithMDD.Donotcommonlyproducemood
elevation.Withdrawalwithabruptdiscontinuation.
iv.
Therapeuticuses
1. Formoderatetoseveredepression
2. Imipramine
forbedwettingchildren
3. Amitriptylineusedforheadachesandchronicpain.
v.
Pharmacokinetics
1. wellabsorbedduetolipophillicnature
2. Varriablelife.duetofirstpassmetabolismlowbioavailability.
3. Hepaticmetabolism
4. renalexcretion.
vi.
Adverseeffects
1. muscarinicblockade:blurriedvision,xerostomia,urinaryretention,tachycardia,
constipation,narrowangleglaucoma

2. Alphaadrenergicblockade:orthostatichypotension,hypotension.
3. imipraminemostlikelytocauseorthostaticHypo,nortriptylineleastlikely.
4. Precautions:inbipolarpateintscautionusageofTCAssincewhenswitchingto
manictheyllbesupercrazy.
f. MonoamineOxdaseInhibitors
i.
MAOinactivatesexcess5HT,NORepi,DA.MAOisinmitochondriainpresynaptic
fibers.
ii.
4onthemarketnow:selegiline,phenelzine,tranylcypromine,isocarboxazid.
iii.
Limiteduseduetocomplexdietaryrestrictions.
iv.
MOA
1. formesstablecomplexeswithMAOtopreventoxidationofcatecholamines
2. becauseMAOeatsalotoftoxins(liketyramine)thatareinalotoffoods.
v.
Action:MAOisfullyinhibitedafter35daysoftreatment,butstillrequires48weeksto
beforeantidepressanteffectsareseen.
Selegilineandtranylcypromineare
stimulating
vi.
Therapeuticuse:MAOiaregoodforpatientsdontdowellonTCAs.Goodforphobias.
Mightbebetterforatypicaldepressio(labilemood,rejectionsensitivitiy,appetite
disorder).Lastlineagents.
vii.
Pharmacokinetics:Goodoralabsorption,severalweeksofMAOregenerationafter
D/Cingdrug.MAOiaremetabolizedandexcretedbykidney
viii.
Adverseeffects:drugdrug,drugfoodinteractions.Unmetabolizedtyramine(duetono
MAO)cancausecatecholaminerelease==>Hypertensivecrisis(phentolamineand
prazosinaregoodtouseforHTNcrisis).
g. TreatmentofManiaandBipolarDisorder
i.
Lithium:prophylaxisformanicdepressivepatients.UnknownMOA.Excretedbykidney.
Assafeasdigoxin.HA,drymouth,diz/fatigue.ataxiatremorscansuggestOD.Monitor
Thyroid.
ii.
Benzosusedinacute.antiepilepticsforprophylaxis.
13. AntipsychoticDrugs
a. Schizophrenia:delusions,hallucinations,thoughtandspeechdistrubances.
b. AntipsychoticDrugs
i.
FirstGenerationAntipsychotics
1. competitiveinhibitorsbyblockingD2receptors.Mostlikelytohavemovement
disordersofthestrong1stgenantipsychotics(Fluphenazine,haloperidol,
pimozide,thiothixene).
ii.
SecondGenerationantipsychotics
1. fewextrapyramidalissues,buthigherriskofmetabolicissues(DM,dyslipidemia,
weightgain).Block5HT,DAandothers
2. Drugselection:Notinterchangeable.Eachistailorcraftedbasedonparticular
needs
3. Refractorypatients:20%arerefractorytoboth1stand2ndgen.Clozapineis
besthere,duetoserioussideeffects.(clozapineaes:marrowsuppression,
seizure,CVsideffects,agranulocytosis).
iii.
MOA:
1. DAreceptorblockingactivityinbrain
2. 5HTreceptorblockingactivityinbrain:most2ndgenalsoblock5HT.
iv.
Actions:

v.

vi.

vii.

1. Mostalleviatepostivesymptoms(halluctions,delusions),butdontdomuchfor
negativesymtpom(anhedonia,bluntedaffect,apathy,impairedattention,
cognitiveimpairment)especiallynotthe1stgens.Donotdepressintellectual
functioninglikeabarbituate
2. Extrapyramidaleffects:probablycausedbyblockingDA
3. Antiemeticeffects:otherthanaripiprazoleantiemeticeffectsaremediatedby
D2antagonism
4. Anticholinergiceffects:blurredvision,drymout.
5. Orhtostatichypotension,hypotension,changesinprolacting.
Therapeuticuse:
1. Treatmentofschizophrenia:Firstgentreatpositvesymptoms,secondget
negative.
2. treatmentofpowerfulnausea(prochlorperazine.
Absorptionandmetabolism
1. varriableabsorption
2. unaffectedbyfood(
ziprasidoneandpaliperidoneareincreasedwithfood)
3. metabolizedbyCYP2D6,1A2,3A4.
4. somelongactingversionsusedoveraweek.
Adverseeffects
1. Extrapyramidal:becomemorepermanentwithtime
2. ifanticholinergicsareused,movementsarereduced.
3. TardiveDyskinesia:canbeirreversible
4. Antipsychoticmalignantsyndrome:feverAMSstupor,dantroleneor
bromocriptinemightbehelpful.
5. Drowsiness,confusion,weightgain,galactorrhea

14. Opioids
a. neurologicpainrespondsbesttoanticonvulsantsTCA,SNRI
b. arthriticpainrespondsbesttoNSAIDS
c. Acute/Chronicpainrepsondstoopiods
d. Opioidreceptors
i.
majoreffectsaremediatedby3mainreceptorsMu,kappa,delta.
ii.
Muismainlytheanalgesicproperties
iii.
kappahassomeanalgesiceffect(nalbuphineandbutorphanol)
iv.
Allimpedeneuronfiringbyhyperpolarization(increasedKeffluxandreducedCainflux).
e. StrongAgonists
i.
Morphine
1. istheopioidprototype
2. Actions
a. Reducessensationofpain
b. Euphoria
c. Respiratorydepression:tolerancearrivesquickly
d. Depressionofcough
e. Miosis:Causedbyuseofmorphine
f. Emesis:candirectlystimulatevomitingcenters
g. GI:decreasesmotility,increasessphincterofOdiicontractionsforbiliary
stasis
h. Histaminerelease:causesitching,urticaria,sweating,vaodilation,
bronchoconstriction

ii.

iii.

iv.

v.
vi.
vii.
viii.

i. Mayincreaseurinaryretentionandprolonglabortimes
3. TherapeuticUse
a. Analgesia:producesgoodpaincontrolwithhypnoticeffects
b. tinctureofopiumfordiarrhea
c. coughsupression
d. treatmentofpulmonaryedema,possiblybyvasodilatoryeffects
4. Pharmacokinetics
a. Significantfirstpassmetabolism.
b. Quicklypassesintoalltissues.
c. Conjugatedbyliverofmetabolitesareactive
5. Adverseeffects
a. respiratoryexchangedecrease,ICP,
6. Tolerance:tendstodevelop
7. druginteractionsenhancedbyhypnotics,MAOi,decreasedbyTCAsand
atnipsychotics
Meperidine
1. Syntheticopioidworksonmuandkappa
2. Actions:Depressesrespiratorydrive,butnoCardiovasculareffectswhengiven
orally.IVdecreasesPVR.
doesnotcausepinpointpupils,causesdialation
duetoanticholinergiceffects
3. Therapeuticuses:Notusedlongtermsincemetabolitesareneurotoxic.Not
usefulfortxofdiarrheaorcough.
4. GoodGIabsorption.Shorterdurationthanmorphine.metabolizedinliverand
excretedinurine
5. Adverseeffects:anticholinergiceffects,withantipsychoticsitcanpercipitate
depression.CautioninMAOi.Notgoodforrenalpatients.
Methadone
1. Methadonelongdurationandlesseuphoria
2. MOA:muandNMDArecptors,andneurogenicpain
3. Action:greatoralabsorptionIncreasesbiliarypressurebutlessthanmorphine
4. Therapeuticuses:goodfornociepticandneurgogenicpain.greatoralabsorption.
Goodfortreatingwithdrawalsymptoms.
5. Pharmacokinetics:transformedinliverandexcretedentirelyinfeces.
Accumulatesinfat,andslowrelease.
6. Adverseeffects:cancausestorsades,longhalfliferequirespropertitration
guidelines
Fetanyl
1. Verypotent.ShortIVduration,longdurationofactionindermpreps.Usedin
cardiacsinceithaslittleCVeffects.Renalelimination.
Causespupilary
constriction
.
Sufentanil,alfentanilandremifentanil:Potency:Sufentanil>fentanyl>alfetanil>
remifentanilpotency.
Heroin:betterlipophilicitycrossesBBBfasterthanmorphine.euphoria.
Oxycodoneandoxymorphone:metabolizedbyCP4502d6and3A4.excretionisvia
kidney.
Hydromorphoneandhydrocodone:hydromorphoneismorepotentthanmorphine.
Goodforrenaldzsincelessmetabolites.Hydrocodone:muchweakerthan
hydromorphone(~asstrongasmorphine)Hydrocodoneismetabolizedinliver.

f.

Moderate/Lowagonist
i.
Codeine:Weakerthanmorphine(~30%),hasantitussiveeffects.Typicallyreplacedby
detromethorphanthejustsupressescough.
g. Mixedagonistsantagonistandpartialagonists
i.
Effectsdependonprioropiodexposure,innaivepatientstheyareanalgesics.Inopioid
dependentthesecanpercipitatewithdrawal.
ii.
Pentazocine:agonistatkappaandweakantagonistatmuanddelta.lesseuphoriathan
morphine,increasesstressonheartanddecreasesplasmaflow.Littleeffecton
respiratorysystem.Cautioninopioidabuse.
iii.
Buprenorphine:agonistatmu.goodforopiatedetoxification.lessseverewithdrawal
comparedtomethadone.mixedwithnaloxoneorallytopreventIVabuse.metabolized
inliverandexcretedinbileandurine.respiratorydepressionthatcannotbereversed
withnaloxone.
iv.
Nalbuphineandbutorphanol:IVonly,psychomimetic.Nalbuphinedoesnotcause
changeinheart.
h. OtherAnalgesics
i.
Tramadol:centrallyactingmureceptoragonist.aweakSNRI.anaphylaxisandSSRI
toxicity.DonotuseifonMAOi
ii.
Tapentadol:centrallyactingmagonist.drugdruginteractions.notgoodinmildrenal
impairment.NOifonMAOi.
i. Antagonist
i.
Antagonismofopioidscanreversetherespiratorydepressioneffects.
1. Naloxone:rapidlydisplacesallreceptorboundopioids.Competativeantagonist
atmu,kappaanddeltareceptors.Noeffetinnormalfolk,butwillcause
withdrawalinopioidabusers.
2. Naltrexone:longerdurationofactionthannaloxone,canbecombinedwith
clonidineforrapidopioiddetoxification.Mightbehelpfulintreatingchronic
alcoholism.Canleadtohepatotoxicity.
15. Epilepsy
a. Idiopathyandsymptomaticseizres
i.
Idiopathyepilepsy:noanatomiccause,orneoplasmnoted.
mostcases
ii.
Symptomaticpilepsy:drugs,tumor,injury,hypoglycemia,infectionwithdrawal.Oncetwo
ormorethepthassecondaryepilepsy.
b. Classificationofseizures
i.
Partial:
1. lossofonlyaportionofthebrainsfuctioningConsciousnessispresevrved.May
progresstobecometonicclonic
2. Simplepartial:
hyperactiveneuronsconfinedtoasinglelocationinthebrain.
anddonotspread.
3. Complexparitial
:partialseizuresthatmayspreadtobecomegeneralized.
ii.
Generalized
1. Consciousnessislost
2. Tonicclonic
:Classicarchingandshakingseizures.
3. Absence:
35y/oandlasttypicallyuntillpuberty.stares,eyeblinking,spacing
out.
4. Myoclonic
:musclecontractionsthatmayreoccurreforseveralminutes.
5. Febrileseizure
:familial,shortdurationoftonicclonic.

iii.
iv.

v.

vi.
vii.
viii.
16. HeartFailure
a.

6. Statusepilepticus:
twoormoreseizuresinarowwithoutrecoveryoffull
consciousnessbetween.
Mechanismofactionofantiepilepticdrugs
1. blockingNaorCachannels,enhancingGABA,orinterfereringwithGABA.
DrugChoice
1. Goalistobeseizurefreeandonmontherapysincesideeffectsgreatlyincrease
withmultiple.
Primaryantiepilepticdrugs
1. Benzodiazepines:Reallyonlyusedforemergentpresentations
2. Carbamazepine:blocksNachannels,
partial,general
.Canbeusedfor
Trigeminalneuralgiaandbipolar.Autoinductionfor3A4,cautionwithUGT
inhibitingdrug,notgoodforelderly,
Hyponatremia,
Rash,
avoidinabsence
seizures
.Finickyoralabsorptionandbetweengenerics
3. Ethosuximide:inhibitionofTtypeCachannels.Goodforabsenceseizures.
Narrowspectrumofeffectiveness.
4. FElbamate:Nachannelblock,NDMAcompetetion,Cachannelblock,andGABA
induction.2C19metabolism,and3A4induction
aplasticanemia,hepaticfailure
5. Gabapentin:analogofGABA,adjuctfor
partialseizures
,noplasmaprotein
binding,andexcretedunchangedbykidney.littledruginteractions.
6. Lacosamide:Nachannels,
abjunctivetxforpartialseizures
,euphoria.
7. Lamotrigine:Goodforalltypesofseizures,metabolismismetabolismcanbe
inducedwithdrugslikecarbamazepineandphenytoinandinhibitedwith
valproate.,lowandslowtitration.
8. Levetiracetam:adjunctivetxofpartial,myoclonicandgenearlizedseuzures.
9. Oxcarbazepine:lesspotentinducerthancarbamazepine
10. Phenobarbital:increasesGABAbiggun
11. Phenytoinandfosphenytoin:Nachannelblockaid(Caathighconcentrations),
smallincreasescancausehughechangesininconcentrations.Fos:isthe
prodrugmetabolizedinblood.
gingivalhyperplasia
12. Pregabalin:renalelimination
13. Rufinamide:actsatNachannel,foodincreasesabsorption,QTshorteningcheck
forfamilialshortenedQT.
14. Tiagabine:GABAreuptakeinhibitor,partial,bindstoalbumin,
15. Topiramate:Nachannelblock,Clchannelopening,decreasedCachannels,
eleminatedrenally,cautionwithOBCPs,renalstones,
16. Valproicacidanddivalproex:bothconvertedtovalproateinGI,increasedGABA
concentrationsbyGABAtrasaminaseblockade,Cachannel.Highlyboundto
albumin,interactswithotherproteinbounddrugs,hepatictoxicity(mustmonitor),
teratogenicity
17. Vigabatrin:reducesgabametabolism,visalfieldcanges.Mustberegisteredto
prescibe.
18. Zonisaminde:NaandCachannelblockaide,approvedforpartialepilepsy,
renal
stones
VagalNerveStimulation:Goodforsevererefractoryseisures
DeepBrainstimulation:canaslotreatParkinsonandessentialtremor
EpilepsyinPregnancy:Mustplannpregnancy,Novalproicorbarbituates.