the neuropharmacology of benzodiazepines and drugs with … · 2019. 1. 24. · objectives...
TRANSCRIPT
TheNeuropharmacologyofBenzodiazepinesandDrugswithSimilar
MechanismofAction
RobertB.Raffa,PhDProfessorEmeritus,TempleUniv,PhiladelphiaPAAdjunctProfessor,Univ ArizonaCollegeofPharmacy,TucsonAZNEMAResearchGroup,Naples,FL
TheInternationalBenzodiazepineSymposiumBend,ORSeptember16,2017
Disclosures
1986– 1996 Johnson&Johnson,analgesicsdrugdiscovery1996– 2016 TempleUniversitySchoolofPharmacy2016– NEMAResearch;CaRafe DrugInnovation(anon-opioid
analgesicsdrugdiscoverycompany);andaconsultant,AdBoard member,speakeronanalgesicsformultiplepharmaceuticalCompanies
Dr.Raffadeclaresnoconflictofinterest– heisnotawareofanydirect,orindirect,benefitfromthesaleofbenzodiazepinesorrelatedtherapy.
Objectives
1. Describethebasicneurophysiologyofanxietyandanxiolysis2. DevelopthetargetandmechanismofBZDanxiolyticactivity
u describetheassociationanddifferencebetweenGABAA andBZDreceptors
u describewhyBZDand‘Z,E’drugsshareacommonanxiolyticmechanism
3. DescribethebasicneuropharmacologyofBZDandrelateddrugs
4. DescribebasicADME(absorption,distribution,metabolism,elimination)featuresofthesedrugs
5. Describe‘peripheral’BZDreceptors
Underlyingprinciples
• TheCNSrequiresbalanceofexcitatoryandinhibitorya.a.• Inbrain:Glu andGABA• Excessexcitation– seizure;excessinhibition– coma
Glu GABA
Underlyingprinciples
• Anxiety:fearornervousnessaboutwhatmighthappeno productiveforsurvivalo transiento totaleliminationisnotdesirable
• Clinicalanxiety:anabnormal andoverwhelming senseofapprehensionanddread(panic)
o counterproductiveo on-going,physiologicallydrainingo returntobaseline(anxiolysis)desirableo theoptimalapproachmatchesthetreatment(non-
pharmacologicorpharmacologic)tocause
“Benzodiazepine”pharmacology
• Benzodiazepines(BZDs)aredefinedbasedonchemicalstructure(benzenze ringplusdiazepine ring)
• Benzodiazepines(BZDs)producetheirmajoreffectsthrough affinityfor(bindingto)andintrinsicactivity(agonistaction)atbenzodiazepinereceptors(BZD-R)
• Butsubstanceswithnon-benzodiazepinechemicalstructures(e.g.,the“Z”drugs)alsoactatBZD-R
• èThepharmacologiceffectsarethesame• Thus,itismostinformativetospeakofBZD-Rpharmacology
β-Carbolines:Abecarnil,Gedocarnil,SL-651,498,ZK-93423
Others:CGS-20625,CGS-9896,CL-218,872,ELB-139,GBLD-345,L-838,417,NS-2664,NS-2710,Pipequaline,RWJ-51204,SB-205,384,SL-651,498,SX-3228,TP-003,TP-13,TPA-023,Y-23684
N
N
N
N
N
N N N
N
NN
O
OH
BenzodiazepinesImidazopyridines Pyrazolopyrimidines Cyclopyrrolonese.g.,Zolpidem(AMBIEN,etc.)
e.g.,Zaleplon(SONATA,etc.)
e.g.,Eszopiclone(LUNESTA,etc.)Zopiclone(IMOVANE,etc.)
Non-BZDBZD-Ragonists
CentralBZDreceptors• discoveredin19771• autoradiographic demonstrationinhumanbrainin19882• positiveallostericmodulationoftheGABA-Areceptor
PeripheralBZDreceptors• discoveredin19923• Tryptophan-richsensoryprotein(TspO)
(translocator protein)
BZD-Rpharmacology
1MöhlerandOkada(1977)Science198:849-851; SquiresandBraestrup (1977)Nature266:732-734.2Zezulaetal.(1988)Neuroscience25:771-795.3McEneryetal.(1992)PNAS89:3170-3174.
BZDsandotherBZDReceptorAgonists
BZDreceptor-mediatedeffects “Off-target”effects
BZD-Rpharmacology
https://upload.wikimedia.org/wikipedia/commons/4/46/NAchR_2BG9.pnghttps://upload.wikimedia.org/wikipedia/commons/0/06/GABAA_receptor_schematic.png
GABAA ionotropic receptor
https://upload.wikimedia.org/wikipedia/commons/4/46/NAchR_2BG9.pnghttps://commons.wikimedia.org/wiki/File:GABAA-receptor-protein-example.pnghttps://upload.wikimedia.org/wikipedia/commons/0/0e/Cell_GABA_Receptor.png
CentralBZDreceptor
GABABZD
BZDMoA:summary
• SelectivebindingtoBZDreceptorsiteonGABAA complex• NoeffectonGABAA bindingsite• PositiveallostericmodulationofGABA-inducedCl– influx• BZDeffectisattenuatedbyBZD-Rantagonist(flumazenil)• BZD-RantagonisthasnodirecteffectonGABA
0""
mV""
–60""
–70""
–80" Time""
Threshold ReTrPotlΔ
E " " " """""E"I"
GABA$BZD$
https://upload.wikimedia.org/wikipedia/commons/0/0e/Cell_GABA_Receptor.png
EffectofGABAA agonistbinding
https://upload.wikimedia.org/wikipedia/commons/0/0e/Cell_GABA_Receptor.png
EffectofBZD-Ragonistbinding
GABA$
Cl– $con
ductance$
Log$[GABA]$
GABA$BZD$
GABA$BZD$
0""
mV""
–60""
–70""
–80" Time""
Threshold ReTrPotlΔ
E " " " """""E"I"
https://upload.wikimedia.org/wikipedia/commons/0/0e/Cell_GABA_Receptor.png
EffectofBZD-Rantagonistbinding
http://ibmmsrvlakitu.unibe.ch/sigel/video.mp4Middendorp etal.(2014)Chem Biol 9:1854-1859
Non-BZD-Ragonists
Apharmacophore modelofthebenzodiazepinebindingsiteontheGABAAreceptor.[159]Whitesticksrepresentthecarbonatomsofthebenzodiazepinediazepam,whilegreenrepresentscarbonatomsofthenonbenzodiazepine CGS-9896.Redandbluesticksareoxygenandnitrogenatomsthatarepresentinbothstructures.TheredsphereslabeledH1andH2/A3are,respectively,hydrogenbonddonatingandacceptingsitesinthereceptor,whileL1,L2,andL3denotelipophilicbindingsites.
Samereceptor–>sameeffects(individualdifferencesinPK,off-targetEs)
BZD-R:phylogenetically old
KristinFinno,TUundergrad;TJUPharmacy
0102030405060708090
100110120130140150160170
0 1 2 3 4 5 6 7 8 9 1011
LMA
(grid
lines
cro
ssed
)
Time (min)
BZD-Rinplanarians
• BZDs(clorazepate,midazolam)producedose-relatedeffects(alterbehavior)
• TheBZD-inducedeffectsaredose-relatedlyattenuatedbyaBZD-R-selectiveantagonist(flumazenil)
• Thenon-BZDBZD-Ragonist(zolpidem)dose-relatedlyproducesthesameeffectsastheBZDs
• Thenon-BZD-inducedeffectsareattenuatedbyaBZD-R-selectiveantagonist(flumazenil)
Raffaetal.(2007)Eur JPharmacol 564:88-93
BZD-Rinhumanbrain
Receptorautoradiographyusing[3H]Flunitrazepam1
• Highestdensitieslocalizedincorticalandlimbicregions(hippocampus,nu.accumbens,amygdala,andmammillarybodies)
• Intermediatedensitiesinbasalgangliaandthalamicandhypothalamicnuclei
• Lowdensitiesinbrainstem• Verylowdensitiesinwhitematter
1Zezulaetal.(1988)Neuroscience.25:771-795.
WhyaBZD-R?
IsthereanendogenousBZD-Ragonist?anendozepine?thebrain’sValium?
• flumazinil doesnotbindtoGABAA-R,butcaninducepanicattacksinpatientswithpanicdisorder(butnothealthycontrols)
• BZDsarefoundinbraintissue– butalsoinplants• oleamides,inosine,hypoxanthine,nicotimide:onlylowaffinityfor
BZD-R;DBI(diazepam-bindinginhibitor)actuallyacyl-CoA-bindingprotein
• thequestionremainsunanswered
Farzampour etal.(2015)Adv Pharmacol 72:147-164
MultipleGABA-Areceptors
• 6differentαsubunits• 4differentβsubunits• 3differentγ subunits• mostcommonmammalian:(α1)2(β2)2(γ2)1
Neuronalsystemeffects
Inhibition Governor Disinhibition
inhibitoryexcitatory
sedation –– Beneficial calming–– Also used to denote an AE
anxiolytic –– Reduces anxiety without impairment of alertness
hypnotic –– Produces drowsiness and (normal) sleep
Anxiolyticeffect
‘Normal’anxiety• normalresponseof‘fightorflight’• normallyresolvesw/omedication• but,sensitizationtorepeatedstresscandisrupt
normalphysiology
‘Clinical’anxiety• panicattacks,phobias,OCD,possiblyPTSD• clinicallysignificantin~10%ofthepopulation• endogenouscause,orconsequence
Anxiolyticeffect
• majorinhibitoryNTinCNS(primarilybrain)• balancewithexcitatoryaminoacids• NTatabout30%ofallCNSsynapses• allCNSneuronsandglialcellsaresensitivetoGABA
GABA
• Psychotherapeutic,cognitive,behavioral,and• Pharmacologic(onlyifappropriate)
o acuteattackso chronicuse=4-8weekso BZDsbetterTE/AEratiothanbarbiturates
o newerdrugshavebetterTE/AEratiothanBZDs
More specific to anxiety & Fewer AE�s
Placeintherapeutichistory
barbiturates, ethanolDeath
Coma
Anesthesia
Hypnosis
Sedation
DOSE
benzodiazepines
AEsofBZDslessthanthoseofbarbiturates:• CNSdepression• respiratorydepression• psychomotorfunction• daytimesleepiness• effectsonREMsleep• EtOH interaction• hepaticenzymeinduction• DDIs
Placeintherapeutichistory
BZDADME:A,DandE
• mostarereadilyabsorbedfromGItract• drug-specificextentof1st-passeffect• availableinmultipledosageforms• manyarelipidsoluble
o passBBBo mostreadilypassplacentao redistributionto/fromfattytissueo extendeddurationofeffect
• mostBZDsareeliminatedvia urinaryexcretion
BZDADME:metabolism
• hepaticvia Phase1(CYP450andother)andPhase2(glucuronide conjugation),commonlyinsequenceandparallel
• manyPhase1BZDmetabolitesactive(clorazepate aprodrug tooxazepam)
• oxazepam isalsoametaboliteofchlordiazepoxide,diazepam,andprazepam
• alprazolam,flurazepam,lorazepam,triazolam:directglucuronidation
• eszopiclone andzolpidem viaCYP3A4• zaleplon via aldehydeoxidase
• ethanol,barbiturates,andneurosteroids• additiveorsupra-additiveCNSdepression
DDIs:PD– otherGABAA-Rmodulators
https://upload.wikimedia.org/wikipedia/commons/0/0e/Cell_GABA_Receptor.png
GABABZD
EtOH (α)barbiturates(β)propofol (β)neurosteroids (β)
DDIs:PK– metabolic
https://upload.wikimedia.org/wikipedia/commons/9/98/PropDrugsMetabCYP.png
Adverseeffects
Glu GABA
BZD
Tolerance
• Normalphysiologicprocess• Developstomostdrugs• Candevelopatdifferentratesfordifferenteffects
Ø TIcandecreasewithtreatmentduration
Dose
Effect
Dose
Effect
Physicaldependence/withdrawal
• Physicaldependenceisanormalphysiologicprocess• Developstomostdrugs• Usuallycompensatoryoppositetodrug-inducedeffect• Revealedduringwithdrawal(unopposed)• MostseriousforBZDsisexcessexcitation
• BZDsalsobindtootherreceptors,locatedmainlyinperipheraltissuesandglialcellsinthebrain
• Originallytermed‘peripheralBZD-R’,alsoknownastranslocator protein(TSPO)
• Functionsnotfullyknown,butmightinvolvesteroidbiochemistry/transport,cellproliferation/apoptosis,andimmunomodulation
• TSPOnull(Tspo–/–)miceareviable1
1Tuetal.(2014)JBiol Chem 289:27444-27454
OtherBZDbindingsites
PeripheralBZD /TSPOdistribution
• 6healthycontrolsubjects (3men,3women)• 11C-DPA-713,aspecificPETligandfortheassessmentofTSPO• whole-bodyPET/CT(PositronEmissionTomography– ComputedTomography)• absorbeddosehighestinthelungs,spleen,kidney,andpancreas
Radia%on(Dosimetry(and(Biodistribu%on(of(the(TSPO(Ligand(11C=DPA=713(in(Humans(Endres(et#al.#(2012)(J(Nuclear(Med(53:330=335((
http://jnm.snmjournals.org/content/53/2/330
Recap
1. Perspectiveonanxietyandanxiolysis2. Developafundamentalandworkingknowledgeofthe
targetandmechanismofBZDanxiolyticactivityu reviewtheassociationanddifferencebetweenGABAA andBZD
receptorsu developanunderstandingofwhyBZDand‘Z,E’drugssharea
commonanxiolyticmechanism3. Reviewbasicneuropharmacol ofBZDandrelateddrugs4. DiscusssomeADMEfeaturesofthesedrugs5. Broadlydiscuss‘peripheral’BZDreceptors