Sedatives (Anxiolytic; minor tranquilizers) and Hypnotics
Jin-Chung Chen
Department of Pharmacology and Physiology
Room 664, x 5282
Drug Classifications:
1. Benzodiazepines
2. Barbiturates
3. Alcohol
Symptomsofsevereanxietyaresimilartofear(tachycardia,swea8ng,trembling,palpita8on)whichinvolvesympathe8cac8va8on.Seda%ve-hypno%cdrugsareusedtoinduceseda8on(reliefofanxiety)ortoencouragesleep.Aneffec%veseda8ve(anxioly/c)istopromotethecalmingeffectinanxiouspa%entswithminimaleffectonCNSdepression.Ahypotonicdrugistoproducedrowsinessandencouragetheonsetandmaintenanceofsleep,thuscausepronounceddepressionofCNSfunc%on.
Barbiturate Alcohol
Benzodiazepam
Increasing dose
Coma
anesthesia
Hypnosis
Sedation
Dose-dependent curve for two hypothetical sedative-hypnotics.
Benzodiazepines (BZs)
1. Long-ac8ng(30-80hrs):diazapam(valium),flurazepam,prazepam,quazepam,clorazepate
2. Intermediateac8ng(3-25hrs):lorazepem,temazepam,oxazepam,alprazolam,estazolam
3. Short-term(1-5hr):triazolam
FM2:flunitrizopam2mg
Chemical structure of Benzodiazepines
A.Pharmacology
1. Siteofac%on:poten%ateGABAAreceptor–mediatedinhibi%onviaCl-influxandhyperpolariza8on
2. Majortreatment:an%-anxiety(α2effect),controlofinsomnia(notaffectREMsleep)(α1effect)andproduceseda%veeffect(α1effect);highertherapeu%cindex,thusconsideredtobedrugofchoice.
3. Treatmentofepilepsy(α1effect)
4. Musclerelaxant:highdoseeffectviaincreasingpresynap%cinhibi%oninthespinalcord(α2effect)
5. Pre-medica%onofanesthesia
6. Treatmentforalcoholwithdrawalsyndromes
7. Panicdisorder:alprazolam(quickon-set)
Structure of GABAA receptor (αβγδεπρ subunits)
Most common form of GABA-A receptors:
two α1, two β2, one γ2
BZ binds at the interface of the α and γ2 subunt
B. Pharmacokinetics
1. Absorp8on:Usuallygivenorally.Rateofabsorp%ondependsonlipophilicity.Oralabsorp%onoftriazolam,diazepamandclorazepatearemorerapidthanothers.Plasmabindingdoesnotlimititsbioavailability.
2. Allseda8ve-hypno8cscancrosstheplacentalbarrierduringpregnancyandexistinthebreastmilk.
3. Biotransforma8on:a.Hepa%cmetabolismaccountsfortheclearanceofBZs.MostBZsundergomicrosomaloxida%on(dealkyla%on,hydroxyla%on)followedbyphaseIIglucuronida%on
b.PhaseImetabolitesareusuallyac%ve:wouldcauseunwantedCNSdepressionandday%meseda%on(desmethyldiazepamfromprazepam,diazepam,clorazepate)
c.Oxazepam,lorazepamandalprazolamareshort-livedandforminac%veglucuronides
C. Adverse effects and Drug interaction
1. Comparedtobarbiturates,ithaslesssideeffects.Pa%entsmightcomplainwithprolonged%me.
2. Suicidaltendencywithhighdosage3. Developmentoftolerance(>14days).Dependenceifusefor
morethan6months,i.e.withdrawalsyndromes(insomnia,anxiety,tremor,lossofappe%te,perceptualdisturbance)occurreda_erabruptcessa8on.
4. Anterogradeamnesia:temporaryimpairment(α1effect)
5. Cross-tolerancewithalcoholandbarbiturates,shouldbecarefulwhenmul%ple-druginterac%on
Benzodiazepam antagonist
1. Flumazenil:blocktheac%onofBZs,butnototherseda%ve-hypno%csorethanol.
2. ReverseCNSdepressanteffectofBZover-dosage(availableonlythroughIV)
3. ShortT1/2(0.7-1.3hr):requiresrepeatedadministra%onstoovercomethelong-dura%onofBZ
4. Adverseeffect:agita%on,confusion,dizziness,nausea.PrecipitatedwithdrawalsyndromesinBZdependentpa%ents
Barbiturates
A. Classifications: 1. Longac%ng:8h,e.g.phenobarbital(sleepingdisorder)2. Intermediate:6-8h,e.g.amobarbital(insomnia)3. Shortac%ng:3-6h,e.g.secobarbital;pentobarbital(seda8ves)4. Ultra-shortac%ng:15-45min,e.g.thiopental(shortanesthesia)
B. Pharmacology:
1. Siteofac%on:poten%ateGABAAreceptor-mediatedinhibi%on;alsoinhibitglutamatereceptorandhighfrequencysodiumchannels
2. Controlofinsomnia(butreduceREMsleep,socausehangover-likesymptomthefollowingday)
3. Havean%-convulsionability
4. Asanintravenousinduc%onofanesthe%c,e.g.thiopental
Chemical structure of barbiturates
BZsincreasethefrequencyofinhibi%on;barbituratesenhancethedura/onofinhibi%on
C.Pharmacokine8cs1. Oral:on-setisapproximately10-60mindependentonfas%ng2. i.v.injec%onforshort-ac%ngmethohexitalandthiopental3. Metabolizedviamicrosomalenzymesystembyoxida%on,
hydroxyla%on,desulfura%onorglucuronida%onandeliminatedviakidney(usuallyinac%vemetabolites)
4. Quickdevelopdrugtoleranceduetoinduc%onofmicrosomalP450enzymetodrugself(metabolictolerance)
D.Adverseeffectsanddruginterac8on1. Lowtherapeu8cindex:athighdose,barbituratescouldstop
respira8onandheartbeat2. Moreseveretoleranceandwithdrawalsyndromesthan
benzodiazepams;causecomaintoxicdoses.3. Interac%onwithprofoundlivermicrosomalenzymesystem,
thusinterferemetabolismofotherdrugs4. Cross-tolerancewithalcoholandBZs
Non-BZ/-barbiturate Anxiolytic/Hypnotics A. Buspirone
Newanxiely%chaslessseda%ve-effect,euphoriaanddrugdependence.Italsohaslessinterac%onwithotherdrugs.Duetoslowon-set,itisnotappropriateforacutepa%ent
Molecularmechanism:5-HT1Areceptorpar%alagonistandblockD2dopaminereceptor;lacksan%convulsantandmuscle-relaxantproper%esofBZ
Sideeffects:minimalseda%on;tachycardia,headache,nervousness,GIdistress,palpita%ons
Metabolism:byCYP3A4(lengthenediftakenwitherythromycin;shortenediftakenwithrifampin)
B.Zolpidem(S/lnox)andZaleplon1. ActsonasubsetofBZreceptorfamily,BZ1(α1-GABAA).
2. Noan%convulsantormuscle-relaxingproper%es.
3. Nowithdrawaleffects,minimalreboundinsomniaandlihletolerancewithprolongeduse
4. Rapidonsetandshort-ac%ngT1/2(2-3hr)totreatinsomnia
C.Chloralhydrate1. Atrichlorinatedderiva%veofacetaldehyde.
2.Effec%veseda%veandhypno%cthatinducessleepbetween30minto6hours.
3.Sideeffects:GIirrita%ng,epigastricdistress,unpleasanttastesensa%on
2.DiphenhydramineandDoxylaminea.carryseda%veproper%esandareeffec%vein
trea%ngmildinsomnia
b.Over-the-counternonprescrip%ondrugs
1.Hydroxyzinea.Anan%histaminewithan%-eme%cac%vityb.Lowtendencyforhabitua%on;sideeffectofdrowsinessc.Applica%on:seda%onpriortosurgeryanddentalprocedure
D.An8histamines
Alcohol(ethanol,EtOH,C2H5OH)
Socialdrugmorethanasatherapeu%cagent,thedose-responserela%onshipevaluatedbybloodalcoholconcentra/on(BAC):
1) BACof0.05g/dl(0.05%):euphoria2) BACof0.1-0.2g/dl:motorincoordina8on,errorjudgment,loud
voiceandaggressivebehaviors3) BACof0.2-0.3g/dl:amnesiaandanesthesia4) BACof0.3-0.4g/dl:coma
5) BACof0.4-0.5g/dl:fataldoseduetomedullasuppression
A. Pharmacology
1. Treatmentofmethanolandethyleneglycolpoisoning[completewithalcoholdehydrogenase(ADH),thusdecreasetoxicformaldehydeandformicacid]
2. An8sep8c(70%)3. Reducebodytemperature
4. Siteofac8on:a.Decreasesynap%ctransmissionduetolipidsolubilityb.Non-selec%veeffectonmembranereceptors:GABAA,nico%niccholinergic,glutamatereceptorandvoltage-dependentcalciumchannel
B. Pharmacokinetics
1. Morethan90%ismetabolizedbyADHfollowedbyaldehydedehydrogenase(ALDH)inliver
2. First-passmetabolism:ADHac%vityinstomachofwomanisonly50%ofmen.Thus,highincidenceofacutealcoholintoxica%onamongwoman
50%orientalmissac%veALDHwhichresultinflushingbody.Thisenzymeisinhibitedbydisulfiramwhichisusedtotreatalcoholaddic%on(accumula%onofacetaldehydeinthebloodwillcausingflushing,tachycardia,nauseaandhyperven%la%oncondi:onedavoidanceresponse)
Metabolism of ethanol by ADH and ALDH
C. Adverse effects and drug interaction
1. Liver:cirrhosis,hepatoma
2. CNS:Wernicke-Korsakoff’ssyndrome(duetovitaminB1thiaminedeficiency):alcoholamnesicdisorderwithcerebellardegenera%onandataxia
3. Fetalalcoholsyndromes:growthretarda%on,alteredmorphogenesis(microcephalyandflahernface),hyperac%vityandlowIQ
4. Gastrointes8naltract:gastri%s,pep%culcer,gastriccancer,pancrea%%s,pancreasecancer
5. Cardiovascular:cardiomyopathy,portalhypotension,cardiacdyshymias.
Top Related