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.