Rang and Dale Pharmacology Flashcards.pdf

R&D 7eCh24,p37C4D&,40;e42H&0pH 4H548Dh&.g hn dhGw toAsc‚
R&D 7&eCh2h&4,p4D2302 4&;2 4H584-20p3D2 Cp& 5Cp-2H329p4&;
R&D 7eChCh24,p3240
;
lgiwghtofnccn(tyohk),gcy togv
.gv)godtoG
oyindigogiGt)
to,tIt(tyo
.gv)godtoG
vgiy(yogiGt)k
go gT,nutogiGt)
to,tIt(tyo
lgxiyTn(,t)hTnto
zux(ncn(gk
vxIv(no)ghp
piyv(nGunodtov
•,R,
go gT,nuto
•Ttonuh)yid
R&DCh
pgitT,gis

R&D 7e7C&h24&CD,Cp3
R&D 7e7C&h24&CD,Cp3
0&D ,e;C&h
H5;H;8pH &C&
0&D ,e;C&h
H5;H;8pH &C&
-5,9,e;3
-5,9,e;3
H5;4&C
)bpmwmti 0;5H 7C&h2e7,9;5H 7C&h
yklgitmgldstioa,m isti
vit.mgea,mgniw
fdbpbck.
BGI
)Tr
fs..kia bcbui
)m,s,ilnsxiazamgaGaB
lbstab•igitn
vlstmndbpbcs,angb,n
tikgmt
(tnigtikgmtast
mg.bpadmgt
rmgldstioa sbcmgldstio
yklgitmgldstioa,m isti
Bindisi toaht
•m,k.a,igkpik.

ReaoftFrtiidea pitf (.r etpr.Fdahon Fdoe )Aoloudr frpcg e.raroFa-uoetmy(t dtu bFtio
Reductuioun furupa hude.uatuiounafuru(F
Reduction of neuropathic pain. (For antidepressant action see set 24).Reducti
Analgesic action of antidepressants is mainly due to inhibition of the opening of neuronal
voltage-gated Na
+
channels (Na
v
1.7 subtype) rather than to inhibition of monoamine reuptake. Na
+

channel block reduces pain transmission from site of nerve injury.
onR
Postherpetic neuralgia, diabetic peripheral neuropathy, neuropathic cancer pain. futuerfpaih
Sedation (antihistamine action, less with nortriptyline). Blurred vision, dry mouth, constipation,
urinary retention (antimuscarinic action). Postural hypotension (R
1
-adrenoceptor antagonism).
Overdose potentially fatal due to cardiac dysrhythmia, severe hypotension, seizure and CNS
depression. Increased risk of suicide in young patients.
R.(hFihphshedi
Oral administration. Hepatic P450 metabolism (nortriptyline is a metabolite of amitriptyline).
T
0.5
12–24h.
R2i4)uidF24Aful

R&D 7eCh24,p37C4D&,40;e42H&0pH 4H548Dh&Goboh,nfdnAscƒ
R&D 7&eCh2h&4,p4D2302 4&;2 4H584-20p3D2 Cp& 5Cp-2H329p4&;
R&D 7eChCh24,p3240
;
prexrfn,TtmmtInb,fuNcrmbdn,rS
srSNr,hn,A
,bether,reAnN
n,cnGnInb,
srSNr,hn,A
SrebIb,reAnNu
r,drRctgn,reAnN
n,cnGnInb,
prvebRtIcnNfRtn,
CgvItmtIru
SvGSIt,Nrfl
lebSItAgt,hn,S
•,R,
r,drRctgn,
fRn,tgfNbeh
R&DCh
lrenRcrei

Pethidine, fentanyl
Pethidine, fentanyl
Methadone,
propoxyphene
Methadone,
propoxyphene
Tramadol
Tramadol
Ibuprofen
Naloxone Morphine, diamorphine,
buprenorphine, codeine
Sensory cortex
Thalamus
PAG
NRM
Tissue damage
Nociceptive C or A B
pain aferent
Spinothalamic tract
neuron
Interneuron in
dorsal horn
Morphine, diamorphine,
buprenorphine, codeine
Amitriptyline
Carbamazepine
Locus ceruleus

G-protrerinNCiN5pt n5b5ordtgdwastbim5lrpr5ei1G-prot-ei
G-protreirnNCr55rHNT HNbdrp-grNtreirnnCr5rwaa
G-prpoteitnpiN-CN5H5tTCoiC iop-rpi5btTCoiNCtpotT5degiwdCbaeies5ddmlT5sptp-iN5Toi12-pei5tidC3p-
bCobpot-5tTCoitn5oid5-Hpi12-peg
G-prote
4epmlpNpolpoti2dCbaiC irCdt5HpmH5tpli65
7
ibn5oopdei -CsiToeTlp

????
??
???
inG
? ??
?? ?
???????? ?
? ?? ????
NCrtr-5CHTe
? ????
??

Gbd ge H w -pe
???
?? ??
??????
?
?
GaesmrepgaslCr1
? ?
?
7
? ?
?
7
?
7
?
7
?
7
α
β β

To

G-protrerinNCiN5pnHT -btot-eiG-pH2
G-protrerinNCiN5pntHrTt itrbH5e5nNidibt5etrtgrd5iNTt-wtarTntN-tdibspitNCitNdrenH5nn5-et-wtmr5etN-tNCitl123
G-prote
oioenNCen5o
GH5ioT
oioenNCen5o
epNebpo
d-pogwoNep
apotCis5mgwoNep
li1TNpoN5si
oioenNCen5o
G-prot-einNC5GH
G-prot-ei G-prot-ei G-prot-ei
G-prot-ei
Geinsp2
iep3e
4ep3e
bTst6
7H5m-poT
oioenNCen5o

G-protrerinNCiN5pt 35b5ordtgdwastoil-4wm5lrpr5ei6td-m5lrpr5ei1HT -btot-ei
G-protreirnNCr55rHNT HNbdrp-grNtreirnnCr5rwaa
G-prpoteitnpiN-CN5H5tTCoiC iop-rpi5btTCoiNCtpotT5degiwdCbaeies5ddmlT5sptp-iN5Toi12-pei5tidC3p-
bCobpot-5tTCoitn5oid5-Hpi12-peg
G-prote
4epmlpNpolpoti2dCbaiC irCdt5HpmH5tpli65
b
ibn5oopdei -CsiToeTlp
ffmm)uffmm)f/RfT)fx
T/mu••(u•••m/TxP
tnpidC3p-iN•iTob-p5epeiTCoTe5tTCoiC itnpi3p5ad i25eTbidCb5d
5o5petnptTbi••-•g
inG

NCrtr-5CHTe

-CNTr5b5Topidpeeib5-lTCtC…Tbg•
Gbd ge H w -pe

‰gˆ
iŠ‹Œng
GaesmrepgaslCr1

7

wi7i•
7
iiiiiw•
7
wi7i•
7
iiiiiw•
7
α
β β

To

SvailtP3– ehmikMv eyphpccpyvtympathmeiptcvt0eymvbrpMpctivPik0nvtM phpccpy)n Mbeiettem
Sympatphepicvp0p–6a+pmy3p6tphepMavp00pbcarbcn
Sympathmheyicvh0pat–ata6v+hp3vmaiiv+yiiv6M0p3a6h6vh0vehbheh0rvnympathy Sympath
Sh0e6vpovy0evh03hnhp6vp3ava0lM(avp3ypvmto66Vih0)6vp3av4a4pheavm3yh0vo–vp3av0a+iMv–ot(aevPnkhieh0rv
niom)6dvpovp3av4a4pheoriMmy0vmaiiv+yiivnym)no0a vv
eiS
sty(V0aryphbavnympathyvy6v+aiivy6v6pta4pomommyiFvro0omommyiFv(a0h0romommyivh0–ampho06Fvy0p3ty2Fv
eh4p3p3athyFvry6vry0rta0a v
cvptpy0v–6h+
uM4at6a06hphbhpMvtaympho06v1ty63a6FvktphmythyFvy0rhoaea(yFv–abatFvytp3tyirhyFvy0y43Miy2h6Rcvs• v
eh6pktny0ma6cvtytaiMvmoihph6 v
S3M+bh+–+r+ymh
shba0vh ( votvh b votvnMv6io+vh b vh0–k6ho0 v-y66a6vh0povyiivnoeMv€khe6cva2mtapaevh0vp3avkth0av1niom)aevnMv
4tona0amheR v‚(4hmhiih0vh6vrhba0vh b v
Snh ophmbn lvp(
V+hphm0ty+ƒopva„amphbavyryh06pv6py43Miomommhv1ekavpovSViympy(y6aRvy0evpov6pta4pomommhv+3hm3v3ybavh(4yhtaev
SViympy(vnh0eh0rvekavpov(kpypho0vo–vp3avpty064a4phey6ava0lM(a
)4+yp0v–4aptmh•0ymphbypaevnMvnympathyivSViympy(y6a6cvk6kyiiMvrhba0v+hp3vmiybkiy0hmvymhev+3hm3vh03hnhp6v SViympy(y6a6 v

M

M

Excretion valutengseiDhxiolvg
eocgtedBeasuot
utnBr
Excd
Excretion via lungs
Excretiecion ovtirtar rlnugrviroxcrstlDrvhrnclueclrcvoxcnrsDrvohrdco stBvhdrtnrsDrvohrcyencovtiruiex igcl
Drug in exhaled air
B
i
l
ia
r
y
e
xcrExcre
tion vExalrucxE EgsiExcre lD hcdeED
BesyaenEd dion EgsiExcr
e
l
D
h
c
d
e
E
D
BesyaenEd dion ri
vExalrucxE ce oiceE
tion ri vExalrucxE
ce aEsE
tion vExalrucxE
ce lrdD
cucaiD EgsiExcre
tion ce lrdD
ya E
ya E
Dx
Edosxcre
•DdiruD c
Excr
etion va
Excr
etleuegsva
•gcdaxcre
re•onaxcre

↓

R&D 7e Ch 35 , pp34p;pH D&2 Ch 75 , ;1
R&D 7eCh7h35Ch h,7p4 &7 ;h7HCp4h27hp ;hC7p47e47H45;e41h,7-&C7&C7eD7e7h e&p h7
6Chh7Ch3e7C&9hDDhD7eCh7p3&h,
R&D 7eC&he
3&5eh5,Dp
R&D 7eCh37&5 ,ph ,47DC,7;5Cp,e7DpC5447H2,73 5&,Ch DC7&,&1CD-,717H2,7C,44hC,7-7H2,7C,-D
↓↓↓↓↓ ↓↓↓↑↓
↓↑↓
4C;C&he
H72e75,Dp
↑↓↓↓↓↑↓
↓↓↓↓↓↓↓
•↑↑↓•••↑↓
↓↓↓↓↓•↑↓
↓•↓
4C;C&he
e7h;HDe15,Dp
↓↓↑↓↓↓
-↓↓€↓↓↑↑↓↓
↓↓↓‚&C9h,7eep3h7,p;ChDpD7;H,793D;97967Dpep
eCh237,273D p D;,737pC,D3,e7397C,ehp27C,D39C;97De7pC,D327p ,DCDp,7•ƒD7,7h3,6h
7eCh279,Ce93,•

???

?

?

?????

?

?

???????

???????

?

TyrosrinireNADOronPpNPPNyn Py,euva2.a?
TyrosineNroniArDoOoDiPparomeMaivromsovmNOtNrvrNnicoMNOvDPiDDimv
Tyrosine
Ty
Noradrenergic
varicosity
Ty
NA
α
r
Ty
β
r
α
o
β
o
DOPA
Dopamine
Dopa decarboxylase
Dopamine
Movement
Acts on, causes,
gives rise to
s
s
s
s
s
Tyrosine
Tyrosine
Salbutamol,
terbutaline,
salmeterol
s
s
Atenolol, metoprolol, propranolol, oxprenolol
i
Propranolol, oxprenolol
Noradoenrad gicndaivrads
i
Uptake 1
s
s

R&D 7eCh24,p37C4D&,40;e42H&0pH 4H548Dh&.g hn dhGw toAsc‚
R&D 7&eCh2h&4,p4D2302 4&;2 4H584-20p3D2 Cp& 5Cp-2H329p4&;
R&D 7eChCh24,p3240
;
lgiwghtofnccn(tyohk),gcy togv
.gv)godtoG
oyindigogiGt)
to,tIt(tyo
.gv)godtoG
vgiy(yogiGt)k
go gT,nutogiGt)
to,tIt(tyo
lgxiyTn(,t)hTnto
zux(ncn(gk
vxIv(no)ghp
piyv(nGunodtov
•,R,
go gT,nuto
•Ttonuh)yid
R&DCh
pgitT,gis

R&D 7e7C&h24&CD,Cp3
R&D 7e7C&h24&CD,Cp3
0&D ,e;C&h
H5;H;8pH &C&
0&D ,e;C&h
H5;H;8pH &C&
-5,9,e;3
-5,9,e;3
H5;4&C
)bpmwmti 0;5H 7C&h2e7,9;5H 7C&h
yklgitmgldstioa,m isti
vit.mgea,mgniw
fdbpbck.
BGI
)Tr
fs..kia bcbui
)m,s,ilnsxiazamgaGaB
lbstab•igitn
vlstmndbpbcs,angb,n
tikgmt
(tnigtikgmtast
mg.bpadmgt
rmgldstioa sbcmgldstio
yklgitmgldstioa,m isti
Bindisi toaht
•m,k.a,igkpik.

ReaoftFrtiidea pitf (.r etpr.Fdahon Fdoe )Aoloudr frpcg e.raroFa-uoetmy(t dtu bFtio
Reductuioun furupa hude.uatuiounafuru(F
Reduction of neuropathic pain. (For antidepressant action see set 24).Reducti
Analgesic action of antidepressants is mainly due to inhibition of the opening of neuronal
voltage-gated Na
+
channels (Na
v
1.7 subtype) rather than to inhibition of monoamine reuptake. Na
+

channel block reduces pain transmission from site of nerve injury.
onR
Postherpetic neuralgia, diabetic peripheral neuropathy, neuropathic cancer pain. futuerfpaih
Sedation (antihistamine action, less with nortriptyline). Blurred vision, dry mouth, constipation,
urinary retention (antimuscarinic action). Postural hypotension (R
1
-adrenoceptor antagonism).
Overdose potentially fatal due to cardiac dysrhythmia, severe hypotension, seizure and CNS
depression. Increased risk of suicide in young patients.
R.(hFihphshedi
Oral administration. Hepatic P450 metabolism (nortriptyline is a metabolite of amitriptyline).
T
0.5
12–24h.
R2i4)uidF24Aful

R&D 7eCh24,p37C4D&,40;e42H&0pH 4H548Dh&Goboh,nfdnAscƒ
R&D 7&eCh2h&4,p4D2302 4&;2 4H584-20p3D2 Cp& 5Cp-2H329p4&;
R&D 7eChCh24,p3240
;
prexrfn,TtmmtInb,fuNcrmbdn,rS
srSNr,hn,A
,bether,reAnN
n,cnGnInb,
srSNr,hn,A
SrebIb,reAnNu
r,drRctgn,reAnN
n,cnGnInb,
prvebRtIcnNfRtn,
CgvItmtIru
SvGSIt,Nrfl
lebSItAgt,hn,S
•,R,
r,drRctgn,
fRn,tgfNbeh
R&DCh
lrenRcrei

Pethidine, fentanyl
Pethidine, fentanyl
Methadone,
propoxyphene
Methadone,
propoxyphene
Tramadol
Tramadol
Ibuprofen
Naloxone Morphine, diamorphine,
buprenorphine, codeine
Sensory cortex
Thalamus
PAG
NRM
Tissue damage
Nociceptive C or A B
pain aferent
Spinothalamic tract
neuron
Interneuron in
dorsal horn
Morphine, diamorphine,
buprenorphine, codeine
Amitriptyline
Carbamazepine
Locus ceruleus

G-protrerinNCiN5pt n5b5ordtgdwastbim5lrpr5ei1G-prot-ei
G-protreirnNCr55rHNT HNbdrp-grNtreirnnCr5rwaa
G-prpoteitnpiN-CN5H5tTCoiC iop-rpi5btTCoiNCtpotT5degiwdCbaeies5ddmlT5sptp-iN5Toi12-pei5tidC3p-
bCobpot-5tTCoitn5oid5-Hpi12-peg
G-prote
4epmlpNpolpoti2dCbaiC irCdt5HpmH5tpli65
7
ibn5oopdei -CsiToeTlp

????
??
???
inG
? ??
?? ?
???????? ?
? ?? ????
NCrtr-5CHTe
? ????
??

Gbd ge H w -pe
???
?? ??
??????
?
?
GaesmrepgaslCr1
? ?
?
7
? ?
?
7
?
7
?
7
?
7
α
β β

To

G-protrerinNCiN5pnHT -btot-eiG-pH2
G-protrerinNCiN5pntHrTt itrbH5e5nNidibt5etrtgrd5iNTt-wtarTntN-tdibspitNCitNdrenH5nn5-et-wtmr5etN-tNCitl123
G-prote
oioenNCen5o
GH5ioT
oioenNCen5o
epNebpo
d-pogwoNep
apotCis5mgwoNep
li1TNpoN5si
oioenNCen5o
G-prot-einNC5GH
G-prot-ei G-prot-ei G-prot-ei
G-prot-ei
Geinsp2
iep3e
4ep3e
bTst6
7H5m-poT
oioenNCen5o

G-protrerinNCiN5pt 35b5ordtgdwastoil-4wm5lrpr5ei6td-m5lrpr5ei1HT -btot-ei
G-protreirnNCr55rHNT HNbdrp-grNtreirnnCr5rwaa
G-prpoteitnpiN-CN5H5tTCoiC iop-rpi5btTCoiNCtpotT5degiwdCbaeies5ddmlT5sptp-iN5Toi12-pei5tidC3p-
bCobpot-5tTCoitn5oid5-Hpi12-peg
G-prote
4epmlpNpolpoti2dCbaiC irCdt5HpmH5tpli65
b
ibn5oopdei -CsiToeTlp
ffmm)uffmm)f/RfT)fx
T/mu••(u•••m/TxP
tnpidC3p-iN•iTob-p5epeiTCoTe5tTCoiC itnpi3p5ad i25eTbidCb5d
5o5petnptTbi••-•g
inG

NCrtr-5CHTe

-CNTr5b5Topidpeeib5-lTCtC…Tbg•
Gbd ge H w -pe

‰gˆ
iŠ‹Œng
GaesmrepgaslCr1

7

wi7i•
7
iiiiiw•
7
wi7i•
7
iiiiiw•
7
α
β β

To

FPouGuGplmuGmyh9LŽ‘iLaglatGgmhlh9Luagga•mgGmyhtyPLaOloySLHLySrn
R&D 7e Ch 29, p 367; D&H 2e Ch 27, p 67
FSHLySpoLthaSMA, monaieDdemopnAiApn,em,pnDoenaeoDpeAapmNrna Al5e-nH elDaAaeTaAledDheomTaAmemoleyDinpnoHeDd
, AiDp AhmxteOAax5e,naxrmpnos5ecAoAhmrrteTaAlenoe,DiNnompnDoeunp eDp AhemopnAiApn,a5e
lLaaLmuahustf,pnDoeynmeb/
g
ehA,AxpDha5evaAledDheomTaAmemoleyDinpnoHemaaD,nmpAleunp e,mo,Ahe, AiDp Ahmxt5e
ShDomNnoDrenaep Aeimnoem,pnyAenoHhAlnAopeOpAphm tlhD,moomNnoDrseDde,moomNnaReomNnrDoAenaemeatop Apn,
momrDHTA5eMmte,mTaAelAxAolAo,A5ewmNnrDoAenaeem,pnyAeNteiDTp Ref
5-
e€ 5
PSerhiuaua
rS SOphr
LapLghautpt
‚5H5emxhAxnpmopeNrD,ƒaeaTNapmo,Ae„ehA,AxpDhaenoep AeyDinpnoHe,AophA5efl…To,pedDhephAmpiAopeDd
, AiDp Ahmxt†nolT,AleemolexDap†DxAhmpnyAeomTaAmemoleyDinpnoH5e‡hmrrtem,pnyA5
MApmNDrnaAleNte,tpD, hDiAe„ˆ- eatapAienoernyAh5ef
5-
eg€ 5

Diagrm of ’•h• gi aP shrgDiap•
Diaggrm a omfthieahimf
nfsg at cdupicdymPp,
nfsg at cde githaPtit
cps cdupicd dtmPictdymPp,
D sg at cde githaPtitdthatit
agat,eahr hisd d fh gisdf gymptdtth ,
igpt td dash giadasph
miftd •••dormP gadhmif
•Ppicdt sg himf
•aPatmgehimf
Dgp•dtic d • shtd
•••dmeimict•dafhisrmPif g•ist
fc gPif•dcit at •dafi h
-fhiash giaPt
€t,mhisdPmac

“ogfƒ‹bmvof,ffgbhoggfE••D.oD.E
fbu

fb
ufpfkoL
D.LLkLgL

R&D 7eCh24,p37C4D&,40;e42H&0pH 4H548Dh&.g hn dhGw toAsc‚
R&D 7&eCh2h&4,p4D2302 4&;2 4H584-20p3D2 Cp& 5Cp-2H329p4&;
R&D 7eChCh24,p3240
;
lgiwghtofnccn(tyohk),gcy togv
.gv)godtoG
oyindigogiGt)
to,tIt(tyo
.gv)godtoG
vgiy(yogiGt)k
go gT,nutogiGt)
to,tIt(tyo
lgxiyTn(,t)hTnto
zux(ncn(gk
vxIv(no)ghp
piyv(nGunodtov
•,R,
go gT,nuto
•Ttonuh)yid
R&DCh
pgitT,gis

R&D 7e7C&h24&CD,Cp3
R&D 7e7C&h24&CD,Cp3
0&D ,e;C&h
H5;H;8pH &C&
0&D ,e;C&h
H5;H;8pH &C&
-5,9,e;3
-5,9,e;3
H5;4&C
)bpmwmti 0;5H 7C&h2e7,9;5H 7C&h
yklgitmgldstioa,m isti
vit.mgea,mgniw
fdbpbck.
BGI
)Tr
fs..kia bcbui
)m,s,ilnsxiazamgaGaB
lbstab•igitn
vlstmndbpbcs,angb,n
tikgmt
(tnigtikgmtast
mg.bpadmgt
rmgldstioa sbcmgldstio
yklgitmgldstioa,m isti
Bindisi toaht
•m,k.a,igkpik.

ReaoftFrtiidea pitf (.r etpr.Fdahon Fdoe )Aoloudr frpcg e.raroFa-uoetmy(t dtu bFtio
Reductuioun furupa hude.uatuiounafuru(F
Reduction of neuropathic pain. (For antidepressant action see set 24).Reducti
Analgesic action of antidepressants is mainly due to inhibition of the opening of neuronal
voltage-gated Na
+
channels (Na
v
1.7 subtype) rather than to inhibition of monoamine reuptake. Na
+

channel block reduces pain transmission from site of nerve injury.
onR
Postherpetic neuralgia, diabetic peripheral neuropathy, neuropathic cancer pain. futuerfpaih
Sedation (antihistamine action, less with nortriptyline). Blurred vision, dry mouth, constipation,
urinary retention (antimuscarinic action). Postural hypotension (R
1
-adrenoceptor antagonism).
Overdose potentially fatal due to cardiac dysrhythmia, severe hypotension, seizure and CNS
depression. Increased risk of suicide in young patients.
R.(hFihphshedi
Oral administration. Hepatic P450 metabolism (nortriptyline is a metabolite of amitriptyline).
T
0.5
12–24h.
R2i4)uidF24Aful

R&D 7eCh24,p37C4D&,40;e42H&0pH 4H548Dh&Goboh,nfdnAscƒ
R&D 7&eCh2h&4,p4D2302 4&;2 4H584-20p3D2 Cp& 5Cp-2H329p4&;
R&D 7eChCh24,p3240
;
prexrfn,TtmmtInb,fuNcrmbdn,rS
srSNr,hn,A
,bether,reAnN
n,cnGnInb,
srSNr,hn,A
SrebIb,reAnNu
r,drRctgn,reAnN
n,cnGnInb,
prvebRtIcnNfRtn,
CgvItmtIru
SvGSIt,Nrfl
lebSItAgt,hn,S
•,R,
r,drRctgn,
fRn,tgfNbeh
R&DCh
lrenRcrei

Pethidine, fentanyl
Pethidine, fentanyl
Methadone,
propoxyphene
Methadone,
propoxyphene
Tramadol
Tramadol
Ibuprofen
Naloxone Morphine, diamorphine,
buprenorphine, codeine
Sensory cortex
Thalamus
PAG
NRM
Tissue damage
Nociceptive C or A B
pain aferent
Spinothalamic tract
neuron
Interneuron in
dorsal horn
Morphine, diamorphine,
buprenorphine, codeine
Amitriptyline
Carbamazepine
Locus ceruleus

?

?

+–disdplpdace NdilA2cAAc–l2.

Smoth us
βα
Smotho u oscl
idce–NcA2
βα
cl
β
↑
βα
NAe

Smoth ushmcltetsh
NA2 is1Ai sdp
+
+
+
+
1piAl
1piAl
Smoth musoc
pe isp–dNAec
2–dlepe ad
+
+
1peAadadc
–

1lep–lNAec displace NA
Smoth u

–
+

+
dc s
+
+
p–l2sda2NA
–
β
2
α
1
β
1
Smooth muscle cell S SS
↑β
↑

+
–
–
–

Smoth uscl

Surrfactn wa ifafh emlmcSurfacuSursy
Surfactnf wihreerefmrlrwatntnsfygiimfsgohierfhinhrnlwcltine
Glycogenolysis in
muscle and liver
Absorption of
glucose from GIT
Gluconeogenesis
in liver
Uptake and utilisation
of glucose by tissues
Glycogen synthesis in
muscle and liver
Blood glucose

G-protrerinNCiN5pt n5b5ordtgdwastbim5lrpr5ei1G-prot-ei
G-protreirnNCr55rHNT HNbdrp-grNtreirnnCr5rwaa
G-prpoteitnpiN-CN5H5tTCoiC iop-rpi5btTCoiNCtpotT5degiwdCbaeies5ddmlT5sptp-iN5Toi12-pei5tidC3p-
bCobpot-5tTCoitn5oid5-Hpi12-peg
G-prote
4epmlpNpolpoti2dCbaiC irCdt5HpmH5tpli65
7
ibn5oopdei -CsiToeTlp

????
??
???
inG
? ??
?? ?
???????? ?
? ?? ????
NCrtr-5CHTe
? ????
??

Gbd ge H w -pe
???
?? ??
??????
?
?
GaesmrepgaslCr1
? ?
?
7
? ?
?
7
?
7
?
7
?
7
α
β β

To

G-protrerinNCiN5pnHT -btot-eiG-pH2
G-protrerinNCiN5pntHrTt itrbH5e5nNidibt5etrtgrd5iNTt-wtarTntN-tdibspitNCitNdrenH5nn5-et-wtmr5etN-tNCitl123
G-prote
oioenNCen5o
GH5ioT
oioenNCen5o
epNebpo
d-pogwoNep
apotCis5mgwoNep
li1TNpoN5si
oioenNCen5o
G-prot-einNC5GH
G-prot-ei G-prot-ei G-prot-ei
G-prot-ei
Geinsp2
iep3e
4ep3e
bTst6
7H5m-poT
oioenNCen5o

G-protrerinNCiN5pt 35b5ordtgdwastoil-4wm5lrpr5ei6td-m5lrpr5ei1HT -btot-ei
G-protreirnNCr55rHNT HNbdrp-grNtreirnnCr5rwaa
G-prpoteitnpiN-CN5H5tTCoiC iop-rpi5btTCoiNCtpotT5degiwdCbaeies5ddmlT5sptp-iN5Toi12-pei5tidC3p-
bCobpot-5tTCoitn5oid5-Hpi12-peg
G-prote
4epmlpNpolpoti2dCbaiC irCdt5HpmH5tpli65
b
ibn5oopdei -CsiToeTlp
ffmm)uffmm)f/RfT)fx
T/mu••(u•••m/TxP
tnpidC3p-iN•iTob-p5epeiTCoTe5tTCoiC itnpi3p5ad i25eTbidCb5d
5o5petnptTbi••-•g
inG

NCrtr-5CHTe

-CNTr5b5Topidpeeib5-lTCtC…Tbg•
Gbd ge H w -pe

‰gˆ
iŠ‹Œng
GaesmrepgaslCr1

7

wi7i•
7
iiiiiw•
7
wi7i•
7
iiiiiw•
7
α
β β

To

DbDfDfE
//fDfDfS
g•

mfE
ff•••fS
g•
mfE
mD•/fE
DbDfDfE
Db/f•S
••
•
•
-
Db/f•S
DbDfDfE
DmD
/fS
•€
-
••
-
•D
m
g

mfEb•DE
ff•••fS

? aP2 cihL
IL-2Pl2as2m c2ee2mPAnmPPt2-Li2gl2as2gpc2e2Ar
IL-2Pl-asmL  cseLAn a-sn tn-tliPlg tpsrtni-Pa-asiPl-sPtcsT in-s Ts=-Pilsn tliPnlg tpIL-2Pla
,LAnPe tsPnlg2Pl-asPc-thLPl-snhnLPa-smhsPnlgtes ts,B1i l-gtsn A1L-csi-n-1l iasLgt-csl s,
a
psrla
Pnlg tasl=Aasggnsl= a-s TsPci-tPLgt-sPnlg2PlgtesIBPci-t n-1l iapsrls-L-2Pl-asmL  cseLAn a-smh
algALPlgtes=-1PlgnseLAn t- e-t-agasPtcseLhn e-t LhagasPtcsmhsgt=gmglgteseLhn e-tsahtl=-agap
smI
I-ie-tnhsli-Pl-tls Ts=h1 eLhnP-gns--ie-tnhsnPAa-csmhsgtaALgts 2-ic a-s=-ts iPLs isgp2p
eLAn a-sPcgtgaliPlg tsgast ls1 aagmL-ps•La sAa-csl sli-Pls=-PilssTPgLAi-s1i-ng1glPl-csmhs
IBPci-t n-1l isPtlPe tgalap
c2l2LecAnat
,LAnPe tsgasPs1-1lgc-s= i t-s=gn=sAalsm-seg2-tsmhsgt•-nlg tps•LPaPs=PLTBLgT-s•gtpIiagp2a-rigTc2=
??IBmL n-ias isgl=s1=P- n=i  nhl PpI,htrat
tBtL-a

Thee diagrmdrs d orwc-ciy oosfnThe?
The diahgremdsowhece-emds
tdcgwheiemdsoigndwheiemdThe diag fiu,hei
The diag
Fagt lud
fiu,hei
pdnbltrei vluewheng-lidsocelwheng-lid
ThOalwdilhOueuoei
r,uahdogimohexdt
F ultcneliolb
wh,aludobtlroTfy
Th,aludoeioeinduneid
Th,alidlwdidueu
eiohexdt
bmynWahncwh.yruronyrpc
lbowh,aludo Ooneuu,du
Suvtpeachovcy-aorohrc
r,uahdogimohexdt
•hllmowh,alud
•lrchd•
tnsfp-vwsnyaohrchdppw
vluewheng-lidsocelwheng-lid
fiu,heiotdhdgudobtlr
•oadhhuoeiocgiatdguo
Surfactnf wihreerefmrlrwatntnsfygiimfsgohierfhinhrnlwcltine

?

DbDfDfE
//fDfDfS
g•

mfE
ff•••fS
g•
mfE
mD•/fE
DbDfDfE
Db/f•S
••
•
•
-
Db/f•S
DbDfDfE
DmD
/fS
•€
-
••
-
•D
m
g

mfEb•DE
ff•••fS

SvailtP3– ehmikMv eyphpccpyvtympathmeiptcvt0eymvbrpMpctivPik0nvtM phpccpy)n Mbeiettem
Sympatphepicvp0p–6a+pmy3p6tphepMavp00pbcarbcn
Sympathmheyicvh0pat–ata6v+hp3vmaiiv+yiiv6M0p3a6h6vh0vehbheh0rvnympathy Sympath
Sh0e6vpovy0evh03hnhp6vp3ava0lM(avp3ypvmto66Vih0)6vp3av4a4pheavm3yh0vo–vp3av0a+iMv–ot(aevPnkhieh0rv
niom)6dvpovp3av4a4pheoriMmy0vmaiiv+yiivnym)no0a vv
eiS
sty(V0aryphbavnympathyvy6v+aiivy6v6pta4pomommyiFvro0omommyiFv(a0h0romommyivh0–ampho06Fvy0p3ty2Fv
eh4p3p3athyFvry6vry0rta0a v
cvptpy0v–6h+
uM4at6a06hphbhpMvtaympho06v1ty63a6FvktphmythyFvy0rhoaea(yFv–abatFvytp3tyirhyFvy0y43Miy2h6Rcvs• v
eh6pktny0ma6cvtytaiMvmoihph6 v
S3M+bh+–+r+ymh
shba0vh ( votvh b votvnMv6io+vh b vh0–k6ho0 v-y66a6vh0povyiivnoeMv€khe6cva2mtapaevh0vp3avkth0av1niom)aevnMv
4tona0amheR v‚(4hmhiih0vh6vrhba0vh b v
Snh ophmbn lvp(
V+hphm0ty+ƒopva„amphbavyryh06pv6py43Miomommhv1ekavpovSViympy(y6aRvy0evpov6pta4pomommhv+3hm3v3ybavh(4yhtaev
SViympy(vnh0eh0rvekavpov(kpypho0vo–vp3avpty064a4phey6ava0lM(a
)4+yp0v–4aptmh•0ymphbypaevnMvnympathyivSViympy(y6a6cvk6kyiiMvrhba0v+hp3vmiybkiy0hmvymhev+3hm3vh03hnhp6v SViympy(y6a6 v

M

M

? aP2 cihL
IL-2Pl2as2m c2ee2mPAnmPPt2-Li2gl2as2gpc2e2Ar
IL-2Pl-asmL  cseLAn a-sn tn-tliPlg tpsrtni-Pa-asiPl-sPtcsT in-s Ts=-Pilsn tliPnlg tpIL-2Pla
,LAnPe tsPnlg2Pl-asPc-thLPl-snhnLPa-smhsPnlgtes ts,B1i l-gtsn A1L-csi-n-1l iasLgt-csl s,
a
psrla
Pnlg tasl=Aasggnsl= a-s TsPci-tPLgt-sPnlg2PlgtesIBPci-t n-1l iapsrls-L-2Pl-asmL  cseLAn a-smh
algALPlgtes=-1PlgnseLAn t- e-t-agasPtcseLhn e-t LhagasPtcsmhsgt=gmglgteseLhn e-tsahtl=-agap
smI
I-ie-tnhsli-Pl-tls Ts=h1 eLhnP-gns--ie-tnhsnPAa-csmhsgtaALgts 2-ic a-s=-ts iPLs isgp2p
eLAn a-sPcgtgaliPlg tsgast ls1 aagmL-ps•La sAa-csl sli-Pls=-PilssTPgLAi-s1i-ng1glPl-csmhs
IBPci-t n-1l isPtlPe tgalap
c2l2LecAnat
,LAnPe tsgasPs1-1lgc-s= i t-s=gn=sAalsm-seg2-tsmhsgt•-nlg tps•LPaPs=PLTBLgT-s•gtpIiagp2a-rigTc2=
??IBmL n-ias isgl=s1=P- n=i  nhl PpI,htrat
tBtL-a

Thee diagrmdrs d orwc-ciy oosfnThe?
The diahgremdsowhece-emds
tdcgwheiemdsoigndwheiemdThe diag fiu,hei
The diag
Fagt lud
fiu,hei
pdnbltrei vluewheng-lidsocelwheng-lid
ThOalwdilhOueuoei
r,uahdogimohexdt
F ultcneliolb
wh,aludobtlroTfy
Th,aludoeioeinduneid
Th,alidlwdidueu
eiohexdt
bmynWahncwh.yruronyrpc
lbowh,aludo Ooneuu,du
Suvtpeachovcy-aorohrc
r,uahdogimohexdt
•hllmowh,alud
•lrchd•
tnsfp-vwsnyaohrchdppw
vluewheng-lidsocelwheng-lid
fiu,heiotdhdgudobtlr
•oadhhuoeiocgiatdguo
Surfactnf wihreerefmrlrwatntnsfygiimfsgohierfhinhrnlwcltine

?

SvailtP3– ehmikMv eyphpccpyvtympathmeiptcvt0eymvbrpMpctivPik0nvtM phpccpy)n Mbeiettem
Sympatphepicvp0p–6a+pmy3p6tphepMavp00pbcarbcn
Sympathmheyicvh0pat–ata6v+hp3vmaiiv+yiiv6M0p3a6h6vh0vehbheh0rvnympathy Sympath
Sh0e6vpovy0evh03hnhp6vp3ava0lM(avp3ypvmto66Vih0)6vp3av4a4pheavm3yh0vo–vp3av0a+iMv–ot(aevPnkhieh0rv
niom)6dvpovp3av4a4pheoriMmy0vmaiiv+yiivnym)no0a vv
eiS
sty(V0aryphbavnympathyvy6v+aiivy6v6pta4pomommyiFvro0omommyiFv(a0h0romommyivh0–ampho06Fvy0p3ty2Fv
eh4p3p3athyFvry6vry0rta0a v
cvptpy0v–6h+
uM4at6a06hphbhpMvtaympho06v1ty63a6FvktphmythyFvy0rhoaea(yFv–abatFvytp3tyirhyFvy0y43Miy2h6Rcvs• v
eh6pktny0ma6cvtytaiMvmoihph6 v
S3M+bh+–+r+ymh
shba0vh ( votvh b votvnMv6io+vh b vh0–k6ho0 v-y66a6vh0povyiivnoeMv€khe6cva2mtapaevh0vp3avkth0av1niom)aevnMv
4tona0amheR v‚(4hmhiih0vh6vrhba0vh b v
Snh ophmbn lvp(
V+hphm0ty+ƒopva„amphbavyryh06pv6py43Miomommhv1ekavpovSViympy(y6aRvy0evpov6pta4pomommhv+3hm3v3ybavh(4yhtaev
SViympy(vnh0eh0rvekavpov(kpypho0vo–vp3avpty064a4phey6ava0lM(a
)4+yp0v–4aptmh•0ymphbypaevnMvnympathyivSViympy(y6a6cvk6kyiiMvrhba0v+hp3vmiybkiy0hmvymhev+3hm3vh03hnhp6v SViympy(y6a6 v

M

M

????????
R&D 7e Ch 24, p 304- D&5 ;e Ch 2H, p 08
R&D 7eC
h2R
R4C,p CD3 4,0- 5
;- e &H-89C
D.LLkLgL
R&D 7eCh &24& e&,

;C3537D4C2

?
???
??
??????
??
???

?

? ?

??

SvailtP3– ehmikMv eyphpccpyvtympathmeiptcvt0eymvbrpMpctivPik0nvtM phpccpy)n Mbeiettem
Sympatphepicvp0p–6a+pmy3p6tphepMavp00pbcarbcn
Sympathmheyicvh0pat–ata6v+hp3vmaiiv+yiiv6M0p3a6h6vh0vehbheh0rvnympathy Sympath
Sh0e6vpovy0evh03hnhp6vp3ava0lM(avp3ypvmto66Vih0)6vp3av4a4pheavm3yh0vo–vp3av0a+iMv–ot(aevPnkhieh0rv
niom)6dvpovp3av4a4pheoriMmy0vmaiiv+yiivnym)no0a vv
eiS
sty(V0aryphbavnympathyvy6v+aiivy6v6pta4pomommyiFvro0omommyiFv(a0h0romommyivh0–ampho06Fvy0p3ty2Fv
eh4p3p3athyFvry6vry0rta0a v
cvptpy0v–6h+
uM4at6a06hphbhpMvtaympho06v1ty63a6FvktphmythyFvy0rhoaea(yFv–abatFvytp3tyirhyFvy0y43Miy2h6Rcvs• v
eh6pktny0ma6cvtytaiMvmoihph6 v
S3M+bh+–+r+ymh
shba0vh ( votvh b votvnMv6io+vh b vh0–k6ho0 v-y66a6vh0povyiivnoeMv€khe6cva2mtapaevh0vp3avkth0av1niom)aevnMv
4tona0amheR v‚(4hmhiih0vh6vrhba0vh b v
Snh ophmbn lvp(
V+hphm0ty+ƒopva„amphbavyryh06pv6py43Miomommhv1ekavpovSViympy(y6aRvy0evpov6pta4pomommhv+3hm3v3ybavh(4yhtaev
SViympy(vnh0eh0rvekavpov(kpypho0vo–vp3avpty064a4phey6ava0lM(a
)4+yp0v–4aptmh•0ymphbypaevnMvnympathyivSViympy(y6a6cvk6kyiiMvrhba0v+hp3vmiybkiy0hmvymhev+3hm3vh03hnhp6v SViympy(y6a6 v

R&D 7eCh24,p37C4D&,40;e42H&0pH 4H548Dh&.g hn dhGw toAsc‚
R&D 7&eCh2h&4,p4D2302 4&;2 4H584-20p3D2 Cp& 5Cp-2H329p4&;
R&D 7eChCh24,p3240
;
lgiwghtofnccn(tyohk),gcy togv
.gv)godtoG
oyindigogiGt)
to,tIt(tyo
.gv)godtoG
vgiy(yogiGt)k
go gT,nutogiGt)
to,tIt(tyo
lgxiyTn(,t)hTnto
zux(ncn(gk
vxIv(no)ghp
piyv(nGunodtov
•,R,
go gT,nuto
•Ttonuh)yid
R&DCh
pgitT,gis

R&D 7e7C&h24&CD,Cp3
R&D 7e7C&h24&CD,Cp3
0&D ,e;C&h
H5;H;8pH &C&
0&D ,e;C&h
H5;H;8pH &C&
-5,9,e;3
-5,9,e;3
H5;4&C
)bpmwmti 0;5H 7C&h2e7,9;5H 7C&h
yklgitmgldstioa,m isti
vit.mgea,mgniw
fdbpbck.
BGI
)Tr
fs..kia bcbui
)m,s,ilnsxiazamgaGaB
lbstab•igitn
vlstmndbpbcs,angb,n
tikgmt
(tnigtikgmtast
mg.bpadmgt
rmgldstioa sbcmgldstio
yklgitmgldstioa,m isti
Bindisi toaht
•m,k.a,igkpik.

ReaoftFrtiidea pitf (.r etpr.Fdahon Fdoe )Aoloudr frpcg e.raroFa-uoetmy(t dtu bFtio
Reductuioun furupa hude.uatuiounafuru(F
Reduction of neuropathic pain. (For antidepressant action see set 24).Reducti
Analgesic action of antidepressants is mainly due to inhibition of the opening of neuronal
voltage-gated Na
+
channels (Na
v
1.7 subtype) rather than to inhibition of monoamine reuptake. Na
+

channel block reduces pain transmission from site of nerve injury.
onR
Postherpetic neuralgia, diabetic peripheral neuropathy, neuropathic cancer pain. futuerfpaih
Sedation (antihistamine action, less with nortriptyline). Blurred vision, dry mouth, constipation,
urinary retention (antimuscarinic action). Postural hypotension (R
1
-adrenoceptor antagonism).
Overdose potentially fatal due to cardiac dysrhythmia, severe hypotension, seizure and CNS
depression. Increased risk of suicide in young patients.
R.(hFihphshedi
Oral administration. Hepatic P450 metabolism (nortriptyline is a metabolite of amitriptyline).
T
0.5
12–24h.
R2i4)uidF24Aful

R&D 7eCh24,p37C4D&,40;e42H&0pH 4H548Dh&Goboh,nfdnAscƒ
R&D 7&eCh2h&4,p4D2302 4&;2 4H584-20p3D2 Cp& 5Cp-2H329p4&;
R&D 7eChCh24,p3240
;
prexrfn,TtmmtInb,fuNcrmbdn,rS
srSNr,hn,A
,bether,reAnN
n,cnGnInb,
srSNr,hn,A
SrebIb,reAnNu
r,drRctgn,reAnN
n,cnGnInb,
prvebRtIcnNfRtn,
CgvItmtIru
SvGSIt,Nrfl
lebSItAgt,hn,S
•,R,
r,drRctgn,
fRn,tgfNbeh
R&DCh
lrenRcrei

Pethidine, fentanyl
Pethidine, fentanyl
Methadone,
propoxyphene
Methadone,
propoxyphene
Tramadol
Tramadol
Ibuprofen
Naloxone Morphine, diamorphine,
buprenorphine, codeine
Sensory cortex
Thalamus
PAG
NRM
Tissue damage
Nociceptive C or A B
pain aferent
Spinothalamic tract
neuron
Interneuron in
dorsal horn
Morphine, diamorphine,
buprenorphine, codeine
Amitriptyline
Carbamazepine
Locus ceruleus

G-protrerinNCiN5pt n5b5ordtgdwastbim5lrpr5ei1G-prot-ei
G-protreirnNCr55rHNT HNbdrp-grNtreirnnCr5rwaa
G-prpoteitnpiN-CN5H5tTCoiC iop-rpi5btTCoiNCtpotT5degiwdCbaeies5ddmlT5sptp-iN5Toi12-pei5tidC3p-
bCobpot-5tTCoitn5oid5-Hpi12-peg
G-prote
4epmlpNpolpoti2dCbaiC irCdt5HpmH5tpli65
7
ibn5oopdei -CsiToeTlp

????
??
???
inG
? ??
?? ?
???????? ?
? ?? ????
NCrtr-5CHTe
? ????
??

Gbd ge H w -pe
???
?? ??
??????
?
?
GaesmrepgaslCr1
? ?
?
7
? ?
?
7
?
7
?
7
?
7
α
β β

To

G-protrerinNCiN5pnHT -btot-eiG-pH2
G-protrerinNCiN5pntHrTt itrbH5e5nNidibt5etrtgrd5iNTt-wtarTntN-tdibspitNCitNdrenH5nn5-et-wtmr5etN-tNCitl123
G-prote
oioenNCen5o
GH5ioT
oioenNCen5o
epNebpo
d-pogwoNep
apotCis5mgwoNep
li1TNpoN5si
oioenNCen5o
G-prot-einNC5GH
G-prot-ei G-prot-ei G-prot-ei
G-prot-ei
Geinsp2
iep3e
4ep3e
bTst6
7H5m-poT
oioenNCen5o

G-protrerinNCiN5pt 35b5ordtgdwastoil-4wm5lrpr5ei6td-m5lrpr5ei1HT -btot-ei
G-protreirnNCr55rHNT HNbdrp-grNtreirnnCr5rwaa
G-prpoteitnpiN-CN5H5tTCoiC iop-rpi5btTCoiNCtpotT5degiwdCbaeies5ddmlT5sptp-iN5Toi12-pei5tidC3p-
bCobpot-5tTCoitn5oid5-Hpi12-peg
G-prote
4epmlpNpolpoti2dCbaiC irCdt5HpmH5tpli65
b
ibn5oopdei -CsiToeTlp
ffmm)uffmm)f/RfT)fx
T/mu••(u•••m/TxP
tnpidC3p-iN•iTob-p5epeiTCoTe5tTCoiC itnpi3p5ad i25eTbidCb5d
5o5petnptTbi••-•g
inG

NCrtr-5CHTe

-CNTr5b5Topidpeeib5-lTCtC…Tbg•
Gbd ge H w -pe

‰gˆ
iŠ‹Œng
GaesmrepgaslCr1

7

wi7i•
7
iiiiiw•
7
wi7i•
7
iiiiiw•
7
α
β β

To

Fre ff atyrc ric ratdtre ff aysCcisELpcT ratLyEac LVrapm2HHe D73heHR&HH
Fre fatye cridc sre fCEL pesEoiLnl VEsrdED nC sre VyiTtlsniC iG tynl ElnT
R&D 7Fre faetyetcaeyiadsdy fCtFyEeyLefdFCepCF
oap FEnetyepdtcdFtFre faetye asyrFtFyEeyLefdpta
CdlrtporeFEetcaeVyFEtrDeTcpnyCltareaEnfoLetca
CdlrtporepE edaoapraeFEGp>>ptydle>a FptydrDe
ehmTHbvA(hwA)
bvA(hwA)
>ynl ElnT
bpEtcFEaeyuF pra
bpEtcFEaeyuF pra

FPouGuGplmuGmyh9LŽ‘iLaglatGgmhlh9Luagga•mgGmyhtyPLaOloySLHLySrn
R&D 7e Ch 29, p 367; D&H 2e Ch 27, p 67
FSHLySpoLthaSMA, monaieDdemopnAiApn,em,pnDoenaeoDpeAapmNrna Al5e-nH elDaAaeTaAledDheomTaAmemoleyDinpnoHeDd
, AiDp AhmxteOAax5e,naxrmpnos5ecAoAhmrrteTaAlenoe,DiNnompnDoeunp eDp AhemopnAiApn,a5e
lLaaLmuahustf,pnDoeynmeb/
g
ehA,AxpDha5evaAledDheomTaAmemoleyDinpnoHemaaD,nmpAleunp e,mo,Ahe, AiDp Ahmxt5e
ShDomNnoDrenaep Aeimnoem,pnyAenoHhAlnAopeOpAphm tlhD,moomNnoDrseDde,moomNnaReomNnrDoAenaemeatop Apn,
momrDHTA5eMmte,mTaAelAxAolAo,A5ewmNnrDoAenaeem,pnyAeNteiDTp Ref
5-
e€ 5
PSerhiuaua
rS SOphr
LapLghautpt
‚5H5emxhAxnpmopeNrD,ƒaeaTNapmo,Ae„ehA,AxpDhaenoep AeyDinpnoHe,AophA5efl…To,pedDhephAmpiAopeDd
, AiDp Ahmxt†nolT,AleemolexDap†DxAhmpnyAeomTaAmemoleyDinpnoH5e‡hmrrtem,pnyA5
MApmNDrnaAleNte,tpD, hDiAe„ˆ- eatapAienoernyAh5ef
5-
eg€ 5

R&D 7eCh24,p37C4D&,40;e42H&0pH 4H548Dh&.g hn dhGw toAsc‚
R&D 7&eCh2h&4,p4D2302 4&;2 4H584-20p3D2 Cp& 5Cp-2H329p4&;
R&D 7eChCh24,p3240
;
lgiwghtofnccn(tyohk),gcy togv
.gv)godtoG
oyindigogiGt)
to,tIt(tyo
.gv)godtoG
vgiy(yogiGt)k
go gT,nutogiGt)
to,tIt(tyo
lgxiyTn(,t)hTnto
zux(ncn(gk
vxIv(no)ghp
piyv(nGunodtov
•,R,
go gT,nuto
•Ttonuh)yid
R&DCh
pgitT,gis

R&D 7e7C&h24&CD,Cp3
R&D 7e7C&h24&CD,Cp3
0&D ,e;C&h
H5;H;8pH &C&
0&D ,e;C&h
H5;H;8pH &C&
-5,9,e;3
-5,9,e;3
H5;4&C
)bpmwmti 0;5H 7C&h2e7,9;5H 7C&h
yklgitmgldstioa,m isti
vit.mgea,mgniw
fdbpbck.
BGI
)Tr
fs..kia bcbui
)m,s,ilnsxiazamgaGaB
lbstab•igitn
vlstmndbpbcs,angb,n
tikgmt
(tnigtikgmtast
mg.bpadmgt
rmgldstioa sbcmgldstio
yklgitmgldstioa,m isti
Bindisi toaht
•m,k.a,igkpik.

DbDfDfE
//fDfDfS
g•

mfE
ff•••fS
g•
mfE
mD•/fE
DbDfDfE
Db/f•S
••
•
•
-
Db/f•S
DbDfDfE
DmD
/fS
•€
-
••
-
•D
m
g

mfEb•DE
ff•••fS

Excretion valutengseiDhxiolvg
eocgtedBeasuot
utnBr
Excd
Excretion via lungs
Excretiecion ovtirtar rlnugrviroxcrstlDrvhrnclueclrcvoxcnrsDrvohrdco stBvhdrtnrsDrvohrcyencovtiruiex igcl
Drug in exhaled air
B
i
l
ia
r
y
e
xcrExcre
tion vExalrucxE EgsiExcre lD hcdeED
BesyaenEd dion EgsiExcr
e
l
D
h
c
d
e
E
D
BesyaenEd dion ri
vExalrucxE ce oiceE
tion ri vExalrucxE
ce aEsE
tion vExalrucxE
ce lrdD
cucaiD EgsiExcre
tion ce lrdD
ya E
ya E
Dx
Edosxcre
•DdiruD c
Excr
etion va
Excr
etleuegsva
•gcdaxcre
re•onaxcre

5r.my3.avry 2tA3r1eUENh.eAth
Fungalg igfecgttgeoaseok,gnuhgolg igfocgtgaa
1. AtacAhmAenmtn2aEnrmyAntyhdmNahmwah.c. hAtvcA.tmacAv. d1. Atac
i.Amy rnthA..romsa3macAmUatA23m. m1gartn .cnUA.th4mUatA23m. mTgNfmtncnUA.thdhm1
f.mAtnaAmU.hAgUatAysmeans.ttealndenAaA.2nErcy
DufmrvhAyt5a cnhomv ctnahnmv mV•ma rmv mh.snmcahnhma lv am•rynmA.mwah.c. hAtvcAv. •o
enaracen4mrv••v nhhomr3hte3Aesvahd
1dNywcyEyvy. c
Dvwn m.ta2234mvdsdm.tmvdwdm aUvrm. hnAm.-macAv. dmBytaAv. pmIf…ed1icosAc wio3nAU

???

?

?

?????

?

?

???????

???????

?

wygnyayirsiegpgnaicrpeEoxaoythvPadracg’rpaioaoh--vrsrpeEoxaeta-)rcpipeaAtsrpaipPaAy kngc‘ipisclst-uaulc‘-FFi(b
Firrst-g-tenaoi
Firrst-srge-nFi
ao
-ie(ir‘-(Ti-ygpc-se-(Ti-
psi(l-s‘-tge’ir(ip-se-(Ti-u)S-se(g-dirrgA‘-
srge-nFi
+o l-vTstT-s‘-my‘gryip-se(g-(Ti-
fAtg‘mh-tihh‘-yc-mt(s’i-(rme‘zgr(-mep-
drgf-(Tieti-se(g-(Ti-zhm‘fm--
)e-(Ti-zhm‘fml-srge-s‘-ygAep-(g-
(rme‘dirrse-mep-fg‘(-s‘-A‘ip--
se-ryt-,ieirm(sge-se-(Ti-
-ygei-fmrrgv
awf,
awf,
)rge-s‘-‘(grip-m‘-dirrs(se-gr-Tmifg‘spirsel-fmsehc-se-fgegeAthimr-zTm,gtc(i‘-nfez -mep-hs’ir
+Ef,+Ef,
STi-ygpc-tmeeg(-ixtri(i-srge-yA(-Pf,-zir-pmc-s‘-hg‘(-fmsehc-
(TrgA,T-‘hgA,Tse,-gd-dirrs(sektge(msese,-u)S-fAtg‘mh-tihh‘
bf,
Dgei-fmrrgv2----------------
se-ryt-zritAr‘gr‘-
nPﬀwf,
Lowerwso wbldddguc
ƒan w(ce bsebsM i
HTms(owsik.
‚Tm
AennPonslH‚)Tmu
„c wonsebssTb(
slH)))Tmuss
…2knTkslfTmu
lyw bsens(wonobcsebsT. m2 aebIsebsr.c rtw Tonskbis ctowsob†.Tonu
-o

p017 5hH• D0
R&D 7e Ch 50, p 663; D&H 2e Ch 34, p 116
R&DD 7eCh750e&Dh7,0p5 70,7R&D 7eCh 50,pDe63D,; 6R&D 7eC
h5R

0, e &p,63C;
H;; p,e& 663

RH2;4C;6;1;&DC

7‚C673&4&1H0Dh7C1 7D042hp71 e&0467

Patien srd srdonoatien s ih-c
uamesa.-ehdTesmemdT
ktamesesmeldy
Antgf
Patien srdsto shrnt-riscngschternbsrdstol-regsor-urn sblbt u
Patienie asrdioho-csrg
aeiberoluPm.T
kiensiohsr
yrnoiseil sn‘sn-it
Patienie asr
mol-reg
P
u
P
–
Ppon-Sehscble1lI-iSeatfi-noc,l
ienosrc,l1-n2lPS-c-hlbon-SehsIli-no
.t ena-h-b‘c
Patiesf
laeiberoc
. Trtol-rken
-Incler
ioho-coc
sclioho-cof
unasIqoilhsroclbo-r
gio-noil4‘-rnsntT
(-iSsb-)eho

R&D 7eCh24,p37C4D&,40;e42H&0pH 4H548Dh&MLCKa2+GAsc
R&D 7&eCh2h&4,p4D2302 4&;2 4H584-20p3D2 Cp& 5Cp-2H329p4&;
R&D 7eChCh13,p6138
-
lgiwghtofnccn(tyohk),gcy togv
.gv)godtoG
oyindigogiGt)
to,tIt(tyo
.gv)godtoG
vgiy(yogiGt)k
go gT,nutogiGt)
to,tIt(tyo
lgxiyTn(,t)hTnto
zux(ncn(gk
vxIv(no)ghp
piyv(nGunodtov
•,R,
go gT,nuto
•Ttonuh)yid
R&DCh
pgitT,gis
•govyish)yi(g•
e,nuncxv
6,•
0••
etvvxghdncnGg
ly)t)gT(twgh hyihbhB
Tntohn-gigo(
•Ttoy(,nunct)h(in)(
h;•&h
€h;&h;•&h3Ch
dyivnuh,yio
‚y)xvh)gixugxv

•LLLoL•€g•kkokv D.gkmoLkk,LL
fbupbko
fbu
pkobLkD.DfbgLDbDbbLumDvooD,D.hCvv
bLvfbD,gLulD,gLLDbvvv,DDD,
LL.DvbDLDD.vfbEouhbDk,oDbvD
•u.uD.D•u•••u
fb•kDuku g-•DulD,DoLDDfbvbbD• DD
DD•DvL€vbv,fDbDkD,LD,DDfDbDu
ufpfkoLmD.DDv‚,bvDfoDƒLk,fb„D.Df.D,
,bvDbkDDuCbffDv••bffD,LbD.
DbDbfu
D.LLkLgL…D†bof,vDu

?

?

+–disdplpdace NdilA2cAAc–l2.

Smoth us
βα
Smotho u oscl
idce–NcA2
βα
cl
β
↑
βα
NAe

Smoth ushmcltetsh
NA2 is1Ai sdp
+
+
+
+
1piAl
1piAl
Smoth musoc
pe isp–dNAec
2–dlepe ad
+
+
1peAadadc
–

1lep–lNAec displace NA
Smoth u

–
+

+
dc s
+
+
p–l2sda2NA
–
β
2
α
1
β
1
Smooth muscle cell S SS
↑β
↑

+
–
–
–

Smoth uscl

R&,5&D 505e 50,pe63,Ch5h50
R&D 7eCh&570,pR&D 7eCDh50, p&6 3;,H&26&2;40h1C7

6 ,750p

3;6
R&D 7eCh570,p

HC707 eCh2pD

641DpDhDD ,p

‚ ;

???

fb
ufpfkoL
D.LLkLgL

fbuuubpkboLDbb.
gbfmbbmbmbmofmbLbmfbmvLf,fLbfbmfmbfL
vLmfbbpfLbhbmfmbmbmCfLbvmLbLfLmbfLboLDblf
gbfmbf

????

Simple dpagraogodm ldif dpagpbgolfsmyi f‘fidfgidiroSimtW
Simple diagram of absorption and distribution of a drug
What is meant by the term ‘bioavailability’?
Passage across the
blood–brain barrier
Absorption across the
mucosa of the intestine
Passive reabsorption
from the renal tubules
Penetration
into cells
Drug administration Drug eliminationDrug in plasma
Drug in peripheral
tissues
Drug in brain
Lipid solubility
and ionisation
Routes of
administration
Lipid solubility
and ionisation

•

f••••••
•••f•• •

• •
-•f• •€‚
ƒ„…†

G-protrerinNCiN5pt n5b5ordtgdwastbim5lrpr5ei1G-prot-ei
G-protreirnNCr55rHNT HNbdrp-grNtreirnnCr5rwaa
G-prpoteitnpiN-CN5H5tTCoiC iop-rpi5btTCoiNCtpotT5degiwdCbaeies5ddmlT5sptp-iN5Toi12-pei5tidC3p-
bCobpot-5tTCoitn5oid5-Hpi12-peg
G-prote
4epmlpNpolpoti2dCbaiC irCdt5HpmH5tpli65
7
ibn5oopdei -CsiToeTlp

????
??
???
inG
? ??
?? ?
???????? ?
? ?? ????
NCrtr-5CHTe
? ????
??

Gbd ge H w -pe
???
?? ??
??????
?
?
GaesmrepgaslCr1
? ?
?
7
? ?
?
7
?
7
?
7
?
7
α
β β

To

G-protrerinNCiN5pnHT -btot-eiG-pH2
G-protrerinNCiN5pntHrTt itrbH5e5nNidibt5etrtgrd5iNTt-wtarTntN-tdibspitNCitNdrenH5nn5-et-wtmr5etN-tNCitl123
G-prote
oioenNCen5o
GH5ioT
oioenNCen5o
epNebpo
d-pogwoNep
apotCis5mgwoNep
li1TNpoN5si
oioenNCen5o
G-prot-einNC5GH
G-prot-ei G-prot-ei G-prot-ei
G-prot-ei
Geinsp2
iep3e
4ep3e
bTst6
7H5m-poT
oioenNCen5o

G-protrerinNCiN5pt 35b5ordtgdwastoil-4wm5lrpr5ei6td-m5lrpr5ei1HT -btot-ei
G-protreirnNCr55rHNT HNbdrp-grNtreirnnCr5rwaa
G-prpoteitnpiN-CN5H5tTCoiC iop-rpi5btTCoiNCtpotT5degiwdCbaeies5ddmlT5sptp-iN5Toi12-pei5tidC3p-
bCobpot-5tTCoitn5oid5-Hpi12-peg
G-prote
4epmlpNpolpoti2dCbaiC irCdt5HpmH5tpli65
b
ibn5oopdei -CsiToeTlp
ffmm)uffmm)f/RfT)fx
T/mu••(u•••m/TxP
tnpidC3p-iN•iTob-p5epeiTCoTe5tTCoiC itnpi3p5ad i25eTbidCb5d
5o5petnptTbi••-•g
inG

NCrtr-5CHTe

-CNTr5b5Topidpeeib5-lTCtC…Tbg•
Gbd ge H w -pe

‰gˆ
iŠ‹Œng
GaesmrepgaslCr1

7

wi7i•
7
iiiiiw•
7
wi7i•
7
iiiiiw•
7
α
β β

To

G-protrerinNCiN5pnHT -btot-eiG-pH2
G-protrerinNCiN5pntHrTt itrbH5e5nNidibt5etrtgrd5iNTt-wtarTntN-tdibspitNCitNdrenH5nn5-et-wtmr5etN-tNCitl123
G-prote
oioenNCen5o
GH5ioT
oioenNCen5o
epNebpo
d-pogwoNep
apotCis5mgwoNep
li1TNpoN5si
oioenNCen5o
G-prot-einNC5GH
G-prot-ei G-prot-ei G-prot-ei
G-prot-ei
Geinsp2
iep3e
4ep3e
bTst6
7H5m-poT
oioenNCen5o

DbDfDfE
//fDfDfS
g•

mfE
ff•••fS
g•
mfE
mD•/fE
DbDfDfE
Db/f•S
••
•
•
-
Db/f•S
DbDfDfE
DmD
/fS
•€
-
••
-
•D
m
g

mfEb•DE
ff•••fS

phsfrfhtffhthld
The mo st uf l dfun ehi st ‘f ll ’f.’d
The most useful defnition is ‘Se cardadrS1d6cd.cSe c02i161bS r 2c2db cSe0Scr 0ue bcSe cbpbS i1ucu1ruof0S1d6’.
Incomplete release from the dosage form, destruction within the gut, poor absorption and frst-pass elimination
are important causes of low bioavailability. For drugs with a low therapeutic index it is important that repeat
prescriptions provide medicines of equivalent bioavailability (bioequivalence).
n0rS10fc0,bdraS1d6
-Low lipid solubility.
-Ionisation.
-Complexation with
gut contents (e.g.
tetracycline/Ca
2+ salts)
-Rapid loss from gut
(diarrhoea).
s bSrouS1d6c16ctoSm
Peptides and proteins
subject to proteolytic
enzymes. Some drugs
acid labile.
l S0,df1bic,pctoScioudb0
drcf1C rc16cxhrbSca0bb:T
90% or more of a drug
dose may be metabolised
during its frst passage
through the liver.
Only a fraction of
dose may reach
general circulation
srotc.driof0S1d6: the
main factor determining
diferences between
preparations.
Drug in solution
in the gut
Disintegration and
dissolution of tablet
s10tr0icbedX16tc.0uSdrbc16Ao 6u16tc,1d0C01f0,1f1Sp

?

R&D 7eCh24,p37C4D&,40;e42H&0pH 4H548Dh&Goboh,nfdnAscƒ
R&D 7&eCh2h&4,p4D2302 4&;2 4H584-20p3D2 Cp& 5Cp-2H329p4&;
R&D 7eChCh24,p3240
;
prexrfn,TtmmtInb,fuNcrmbdn,rS
srSNr,hn,A
,bether,reAnN
n,cnGnInb,
srSNr,hn,A
SrebIb,reAnNu
r,drRctgn,reAnN
n,cnGnInb,
prvebRtIcnNfRtn,
CgvItmtIru
SvGSIt,Nrfl
lebSItAgt,hn,S
•,R,
r,drRctgn,
fRn,tgfNbeh
R&DCh
lrenRcrei

Pethidine, fentanyl
Pethidine, fentanyl
Methadone,
propoxyphene
Methadone,
propoxyphene
Tramadol
Tramadol
Ibuprofen
Naloxone Morphine, diamorphine,
buprenorphine, codeine
Sensory cortex
Thalamus
PAG
NRM
Tissue damage
Nociceptive C or A B
pain aferent
Spinothalamic tract
neuron
Interneuron in
dorsal horn
Morphine, diamorphine,
buprenorphine, codeine
Amitriptyline
Carbamazepine
Locus ceruleus

R&D 7 eCh5C,p&D6pC0&0 7&,R&D?
R&D 7eCh5, &p,h68hC&1;&H,82D&,4;e 5,14&1;&h&ChCCh0,h4& e00
R&D 77eCh5,p7
6&D8p71;
D epHD&&&D

?
eCHD;p7h,
?
;p7h,D
?
?
?????
???????
???????
??????
?????
??????
?D?????
?D?????
??D?????
?????
R , 01H,8D ˆ-•‰

+Acts Ason,anueg sos umgegv+Aci
+Actsc on,oaueo cAgoacsteaio,nsocgaAvcgvesorsMtoauescm–o
+Actst ton,aAouenata
gtivorMmnvut na
–nvActivorMmnvut na
oAsna
+rcton,aAouenata
–
ucoanc,snaanonc,ctivavsm
g
+cvuntoa gnMnuvca
•tMcvurirmna
•tamuto,Mcvaa•
mto•a,– ,auco a
–vnmunimuc Are
touncMmuna,•,Mcvaa•mto•a
•mnvsAMto
sna,–
mrvcvrcMtm,toetitua
-•+,aAouenata
+nouvauuto
sncMuvrcton
toetitu,rcton,•,ctiv•
orMmnvut n,aAouenata
•nuevucnun
toetitua,rcton,aAouenata,
o , -•+,aAouenata
•Auciton
toetitua,– ,aAouenata