adrenergice si colinergice

8/11/2019 Adrenergice Si Colinergice

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Chapter 80B

CHOLINERGIC AGENTS

JOHN H.K. LIU and KRISTINE ERICKSON

INTRODUCTIONCholner!" a!ent# pla$ an %portant role n o"&lar phar%a"olo!$ and to'"olo!$. ()

*nd+, Cholner!" a!on#t# appled top"all$ are -del$ ed n the treat%ent o

!la&"o%a and a""o%%odat/e e#otropa. Top"al "holner!" anta!on#t# are e&l nprod&"n! %$dra## and "$"lople!a or ntrao"&lar da!no## #&r!er$ and treat%ent.

The phar%a"olo!$ o "holner!" a!ent# # 1a#ed on ther a"ton# &pon ne&ral #$nap#e#

and ne&roee"tor# -here the endo!eno ne&rotran#%tter # a"et$l"holne2 a!on#t#%%" the a"ton o a"et$l"holne and anta!on#t# %par the a"ton o a"et$l"holne and

other "holner!" a!on#t#. A 1re re/e- o the a"et$l"holne le "$"le -o&ld help to

&nder#tand the ratonale# o n! "holner!" a!on#t# and anta!on#t#.

SYNTHESIS, ACTION, AND DEGRADATION OF

ACETYLCHOLINENor%all$ a"et$l"holne # #$nthe#3ed ro% "holne and a"et$l "oen3$%e A 1$ the

en3$%e "holne a"et$ltran#era#e n the "$topla#% o #pe"" ner/e# and #tored n the

#$napt" /e#"le# lo"ated at the a'onal ter%nal. 4 There # a -de d#tr1&ton o"holner!" ne&ron# dented 1$ lo"al3aton o "holne a"et$ltran#era#e n 1oth the

"entral ner/o #$#te% 5CNS6 and the perpheral ner/o #$#te%. The net-or7 o

"holner!" ner/e# n the CNS # not a# -ell "hara"ter3ed a# n the perpher$. Ho-e/er

the #$nthe## a"ton and de!radaton o a"et$l"holne n 1oth "entral and perpheralner/o #$#te%# are 1ele/ed to 1e #%lar. A%on! the perpheral lo"aton# all o the

pre!an!lon" 1er# and the para#$%pathet" po#t!an!lon" 1er# o the a&tono%"

ner/o #$#te% are "holner!". So%at" %otor ner/e# are al#o "holner!" 5the$ donot ha/e !an!la n the perpher$6. A##o"ated -th the "holner!" nner/aton there are

%e%1rane re"eptor# at po#t!an!lon" ner/e 1er# po#t9&n"tonal ne&roee"tor# and

ne&ro%"&lar 9&n"ton# that re#pond to a"et$l"holne d&rn! ne&ral tran#%##on. On thepro'%al #de o #$napt" and 9&n"ton "let# pre9&n"tonal "holner!" re"eptor# %a$

al#o e'#t to %od&late #pe"" ne&ral a"t/te#. So%e a"et$l"holne:"ontann! "ell# and

"holner!" re"eptor# are not a##o"ated -th nner/aton. ;or n#tan"e the "ornealepthel&% ha# one o the h!he#t "on"entraton# o a"et$l"holne %ole"&le# %o#t o

-h"h do not re#de n the ne&ron#. 8 < The ph$#olo!" role o the#e non:ne&ral

a"et$l"holne# n the "ornea ha# not 1een "lared. In the 1lood /e##el a #!n"antn&%1er o non:ne&ral "holner!" re"eptor# are o&nd and ther %pa"t on the

phar%a"olo!$ o e'o!eno "holner!" a!ent# # #!n"ant.

D&rn! the re#tn! #ta!e n ne&ral tran#%##on a "ontn&o #%all relea#e o

a"et$l"holne n =&anta 5appro'%atel$ (000 %ole"&le#6 nto the 9&n"tonal "let o""&r#.It prod&"e# a #%all depolar3aton n ele"tr"al potental a"ro## the po#t9&n"tonal

%e%1rane "alled %nat&re end plate potental# 5>E??#6. It # 1ele/ed that >E??#


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#er/e a# a "ontn&o #t%&laton n %antann! a "holner!" tone o the ne&roee"tor

-h"h # %portant n "ertan t##&e# #&"h a# the #7eletal %"le. (0 D&rn! an a"t/e

ne&ral tran#%##on the arr/al o an a"ton potental at the a'onal ter%nal "ae# annl&' o Ca@*pl+ on# that rapdl$ depolar3e# the %e%1rane potental. ;on o

a'onal and /e#"&lar %e%1rane# o""&r# and e'o"$to## o a"et$l"holne ro% #$napt"

/e#"le# ollo-#. One a"ton potental %a$ "ae the relea#e o #e/eral h&ndred =&anta oa"et$l"holne nto the #$napt" or 9&n"tonal "let#. The#e a"et$l"holne %ole"&le# 1nd

-th re"eptor# lo"ated %anl$ on the po#t#$napt" #te aro&nd the "let#. hen #&"ent

a"et$l"holne %ole"&le# rea"t -th po#t#$napt" re"eptor# an e'"tator$ po#t#$napt"potental 5E?S?6 o""&r# o-n! to %e%1rane depolar3aton 1$ an n"rea#e o Na*pl+

per%ea1lt$. S%larl$ an nh1tor$ po#t#$napt" potental 5I?S?6 %a$ o""&r o-n! to

h$perpolar3aton 1$ an n"rea#e o K*pl+ or anon per%ea1lt$. hen the E?S?

e'"eed# the thre#hold potental an a"ton potental !enerate# n the po#t#$napt" ne&ron.In %otor end plate# o %"le 1er# a #%lar a"ton potental # "alled the end plate

potental 5E??6. On the other hand I?S? oppo#e# an e'"tator$ potental !enerated 1$

#&1#e=&ent #t%&l on the #a%e ne&ron. In the ne&roee"tor# the #t%&laton o re"eptor#

1$ a"et$l"holne a"t/ate# %e%1rane:1o&nd G:proten#. The a"t/aton o G:proten# %a$dre"tl$ %od&late on "hannel# or %a$ ntate #pe"" ntra"ell&lar #!nal tran#d&"ton#

and "on#e=&entl$ ae"t on "hannel#. A #&%%aton o the#e "ell&lar e/ent# e/ent&all$"reate# a /aret$ o 1olo!" re#pon#e#.

A"et$l"holne # a le'1le %ole"&le that 1nd# -th /aro %e%1rane re"eptor# to or%

&n=&e "onor%aton#. Cholner!" re"eptor# tradtonall$ are d/ded nto t-o "la##e#%"arn" and n"otn" 1a#ed on the #%lart$ n rea"ton# "aed 1$ t-o protot$pe

#t%&lant# %"arne and n"otne. (( Altho&!h a"et$l"holne # the "o%%on

ne&rotran#%tter or 1oth the %"arn" and n"otn" re"eptor# the "on"entraton o

e'o!eno a"et$l"holne needed to "ae %"arn" and n"otn" re#pon#e# arederent. In !eneral a (000:old h!her do#e o a"et$l"holne # needed to prod&"e

n"otn" re#pon#e# than %"arn" re#pon#e#.

In re"ent $ear# a %ore d/er#ed "la##"aton o "holner!" re"eptor# e%er!ed aterthe d#"o/er$ o %ore #ele"t/e a!ent# or derent %"arn" re"eptor# and 1$ the

re#&lt# ro% %ole"&lar "lonn! o /aro "holner!" re"eptor#. (@ (0 ?re#entl$ /e

#&1t$pe# o %"arn" re"eptor# and t-o #&1t$pe# o n"otn" re"eptor# -h"h ha/ed#tn"t anato%" lo"al3aton# and 1o"he%"al #pe""te# ha/e 1een dented.

St%&laton# o %"arn" re"eptor ( and , #&1t$pe# a"t/ate a "ell %e%1rane

en3$%e pho#pholpa#e C thro&!h a pert## to'n)*nd+n#en#t/e G:proten. Th#

"on#e=&entl$ "han!e# "ell&lar &tlt$ o no#tol pho#phate# 5%anl$ no#tol:(,:tr#pho#phate6 da"$l!l$"erol "al"&% on and proten 7na#e C. St%&laton o the#e

%"arn" re"eptor #&1t$pe# al#o "ae# the relea#e o ara"hdon" a"d. The#e "ell&lar

"han!e# lead to a /aret$ o ph$#olo!" re#pon#e# n /aro ne&roee"tor#. St%&laton#o %"arn" re"eptor @ and #&1t$pe# a"t/ate #pe"" G:proten# that are pert##

to'n #en#t/e. Th# a"t/ate# pota##&% "hannel# and nh1t# aden$late "$"la#e)

*nd+%edated "ell&lar e/ent#. In %o#t t##&e# #t&ded #e/eral %"arn" re"eptor#&1t$pe# "oe'#t. A""&rate %"arn" re"eptor #&1t$pe# n h&%an o"&lar t##&e# ha/e not

1een deter%ned. There are t-o #&1t$pe# o n"otn" re"eptor#. The ne&ronal n"otn"

re"eptor# are lo"ated at the a&tono%" !an!la the adrenal %ed&lla and n the CNS. The

%"&lar n"otn" re"eptor# are lo"ated at the ne&ro%"&lar 9&n"ton# n #7eletal


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%"le#. St%&laton o the#e n"otn" re"eptor# open# "aton" "hannel# n the

po#t#$napt" ne&ron# to propa!ate a"ton potental# and n the po#t9&n"tonal %"&lar

end plate# to "ontra"t %"le#.>"arn" re"eptor# %a$ "oe'#t -th n"otn" re"eptor#. In #$%pathet" !an!la n

addton to the nor%al E?S? 5-h"h ha# a laten"$ o ( %#e" and a d&raton o (0 to ,0

%#e"6 !enerated 1$ the #t%&laton o n"otn" re"eptor# #t%&laton o po#t#$napt"%"arn" re"eptor #&1t$pe ( !enerate# a #lo- E?S? that ha# a lon!er laten"$ and a

d&raton o (0 #e". ( Th# #lo- E?S? pro1a1l$ part"pate# n a lon!:la#tn!

%od&laton o #$napt" e'"ta1lt$. (Endo!enol$ relea#ed a"et$l"holne # h$drol$3ed rapdl$ 1$ a"et$l"holne#tera#e

lo"ated n "holner!" ner/e# #$nap#e# and ne&roee"tor#. Th# en3$%e ha# an anon"

#te that 1nd# -th the =&aternar$ ntro!en !ro&p o a"et$l"holne and an e#terat" #te

that 1nd# -th the e#ter ln7a!e o a"et$l"holne. The e#ter ln7a!e # 1ro7en do-n r#tto or% a"$l a"et$l"holne#tera#e and "holne. Cholne %o/e# a-a$ ro% the en3$%e and

a -ater %ole"&le %o/e# n and rea"t# -th the a"$l a"et$l"holne#tera#e to ree the

a"etate. The en3$%e # then read$ to rea"t -th another a"et$l"holne %ole"&le. The

h$drol$## pro"e## # /er$ a#t 5le## than ( %#e" n the ne&ro%"&lar 9&n"ton6 n orderto %antan the readne## o ne&ron# and ne&roee"tor# or the ne't -a/e o

a"et$l"holne %ole"&le#. The h$drol$3ed prod&"t# "holne and a"etate ha/e /er$ lttlea"t/t$ on the "holner!" re"eptor. Cholne "an 1e &pta7en nto the pre#$napt" ter%nal#

1$ a"t/e tran#port %e"han#%# or the #$nthe## o a"et$l"holne. Under nor%al

ph$#olo!" "ondton# ter%naton o endo!eno a"et$l"holne 1$ don a-a$ ro%the #$napt" or 9&n"tonal "let# # &n%portant. A"et$l"holne "an al#o 1e h$drol$3ed 1$

1&t$r$l"holne#tera#e o&nd n the pla#%a l/er and other or!an#. Th# non#pe""

en3$%e "an pla$ a #!n"ant role n de!radn! e'o!eno a"et$l"holne.

Alon! th# le "$"le o a"et$l"holne #e/eral #te# %a$ 1e %anp&latedphar%a"olo!"all$ to prod&"e ether a "holner!" or an ant"holner!" 5"holnol$t"6

a"ton. The r#t #te # the ner/e ter%nal -here #$nthe## and relea#e o a"et$l"holne

ta7e# pla"e. Se/eral a!ent# 1elon! to th# "ate!or$ he%"holn&% 1lo"7# the tran#port o"holne a"ro## the "ell %e%1rane o the ner/e ter%nal /e#a%"ol 1lo"7# the tran#port o

a"et$l"holne nto the #$napt" /e#"le 1ot&ln to'n pre/ent# the relea#e o

a"et$l"holne and /eno% o 1la"7 -do- #pder "ae# a tran#ent relea#e oa"et$l"holne 1eore a per%anent 1lo"7ade. Bot&ln to'n ha# an ntere#tn! ophthal%"

appl"aton. In9e"ton o 1ot&ln to'n nto the e'trao"&lar %"le -ea7en# %"le

"ontra"ton or a lon! t%e 1$ 1lo"7n! ne&ral a"et$l"holne relea#e. Thereore 1ol&ln

to'n "an 1e ed a# an alternat/e or #tra1#% #&r!er$. (,An %portant #te or phar%a"olo!" appl"aton# # the %e%1rane re"eptor#. Cholner!"

a!on#t# #t%&late the re"eptor and %%" the a"ton o a"et$l"holne and "holner!"

anta!on#t# rea"t -th the re"eptor and 1lo"7 t# rea"ton -th a"et$l"holne and other"holner!" a!on#t#. The protot$pe# o "holner!" a!on#t# are %"arne and n"otne.

The protot$pe o %"arn" anta!on#t # atropne -h"h rea"t# -th all %"arn"

re"eptor #&1t$pe#. A%on! the /e d#tn"t %"arn" re"eptor #&1t$pe# relat/el$#ele"t/e anta!on#t# or %"arn" re"eptor ( @ and #&1t$pe# ha/e 1een

de/eloped. (4 Ne&ro%"&lar and !an!lon" 1lo"7er# rea"t #pe""all$ -th n"otn"

re"eptor# at ne&ro%"&lar 9&n"ton# and a&tono%" !an!la.


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Another %portant #te or phar%a"olo!" %anp&laton o the "holner!" #$#te% # the

a"et$l"holne#tera#e. B$ nh1tn! or #lo-n! the de!radaton o a"et$l"holne the

=&antt$ o endo!eno a"et$l"holne at the ne&roee"tor# 5%"arn" re"eptor#6 and atne&ro%"&lar 9&n"ton# and #$nap#e# 5n"otn" re"eptor#6 "an 1e n"rea#ed. The poten"$

and d&raton o "holner!" a"ton # thereore enhan"ed and prolon!ed.

A /er$ lar!e n&%1er o "holner!" a!ent# a"tn! on all three #te# ha/e 1een de/eloped.Ho-e/er onl$ a l%ted n&%1er o a!ent# a%ed %anl$ at the latter t-o #te# ha/e

pra"t"al "ln"al appl"aton#. The#e "holner!" a!ent# are "&rrentl$ "la##ed nto o&r

!ro&p# 5(6 a!ent# dre"tl$ #t%&latn! the %"arn" re"eptor 5@6 a"et$l"holne#tera#enh1tor# 56 ant%"arn" a!ent# and 56 a!ent# rea"tn! -th n"otn" re"eptor# at

ne&ro%"&lar 9&n"ton# and a&tono%" !an!la.

DIRECT-ACTING MUSCARINIC AGONISTSThe dre"t:a"tn! %"arn" a!on#t# #t%&late the re"eptor# at ne&roee"tor#

a&tono%" !an!la and other %"arn" re"eptor# not a##o"ated -th nner/aton. The#e%"arn" a!on#t# 5para#$%patho%%et"#6 are d/ded nto t-o !ro&p# 1a#ed on ther

"he%"al #tr&"t&re# 5;!. 80)*nd+(6. The r#t !ro&p "on##t# o a"et$l"holne and

#tr&"t&rall$ related "holne e#ter# #&"h a# "ar1a"hol %etha"holne and 1ethane"hol. The

#e"ond !ro&p "on##t# o nat&ral al7alod# and #$nthet" analo!# n"l&dn! plo"arpne%"arne are"olne and a"e"ldne 5#$nthet"6 -h"h do not po##e## a #tr&"t&ral

#%lart$ -th a"et$l"holne and are not de!raded 1$ "holne#tera#e#.

O-n! to the -de d#tr1&ton o %"arn" re"eptor# the #$#te%" ad%n#traton o%"arn" a!on#t# "ae# /er$ 1road rea"ton# thro&!ho&t the -hole 1od$. ( hen

appled to the e$e the %"arn" a!on#t "ae# %o## 1$ "ontra"ton o the p&pllar$

#phn"ter %"le. Th# a"ton -h"h p&ll# the perpheral r# a-a$ ro% the %e#h-or7 #

1ene"al n an!le:"lo#&re !la&"o%a. St%&laton o %"arn" re"eptor# n the "lar$%"le "ae# a""o%%odat/e %$opa. Intrao"&lar pre##&re 5IO?6 all# o-n! to the

a"ltaton o a=&eo h&%or o&tlo-. Th# # pro1a1l$ a re#&lt o the "lar$ %"le

"ontra"ton "an! tra"ton o the #"leral #p&r and -denn! o the #pa"e# n thetra1e"&lar %e#h-or7. (8 It appear# that %"arn" #t%&laton ha# no #!n"ant

ee"t on the prod&"ton o a=&eo h&%or. La"r%al #e"reton n"rea#e# a# a re#&lt o the

#t%&laton o %"arn" re"eptor#. (


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needed d&rn! ntrao"&lar #&r!er$ "ar1a"hol "an repla"e a"et$l"holne. Ho-e/er o-n!

to the #tr&"t&ral %od"aton "ar1a"hol a"=&re# #!n"ant n"otn" a"t/t$ at the

a&tono%" !an!la and t %a$ al#o relea#e a"et$l"holne ro% the "holner!" ner/e#.The n"otn" a"t/t$ o a"et$l"holne "an 1e red&"ed 1$ the addton o a %eth$l !ro&p

at the 1*1eta+:"ar1on. >etha"holne and 1ethane"hol 1oth ha/n! a %eth$l !ro&p at

ther 1*1eta+:"ar1on prod&"e pr%arl$ %"arn" a"ton. A #ele"t/t$ to-ard%"arn" a"ton # de#red "ln"all$ 1e"ae -th the#e a!ent# onl$ the para#$%pathet"

ne&roee"tor# not #7eletal %"le# and a&tono%" !an!la -o&ld 1e #t%&lated.

>"arne the protot$pe %"arn" a!on#t # #tr&"t&rall$ #o%e-hat #%lar to%etha"holne 1&t # not readl$ h$drol$3ed 1$ e#tera#e# 1e"ae t ha# no e#ter ln7a!e.

The addton o a %eth$l !ro&p at the a*alpha+:"ar1on o a"et$l"holne red&"e# the

%"arn" a"t/t$ that # not de#red or "ln"al appl"aton#. The ee"t o a"et$l"holne

and %etha"holne "an 1e #!n"antl$ enhan"ed 1$ the ad%n#traton oant"holne#tera#e# that #lo- do-n the de!radaton o the#e "o%po&nd#. th the #a%e

ratonale the ee"t o "ar1a"hol and 1ethane"hol # onl$ addt/e -th the ee"t o

ant"holne#tera#e#.

A%on! the three %a9or "holner!" al7alod# %"arne a"t# onl$ at the %"arn"re"eptor#. Are"olne ha# an addtonal ee"t at the n"otn" re"eptor#. ?lo"arpne -or7#

predo%nantl$ at the %"arn" re"eptor# 1&t ha# #&1#tantal n"otn" a"t/t$. Sn"ethe#e al7alod# ad%n#tered #$#te%"all$ "ae lon! and 1road "holner!" a"t/te# the

#$#te%" a!e o the#e al7alod# # al#o l%ted. The#e nat&ral al7alod# ho-e/er ha/e

%portant ophthal%" a!e. ?lo"arpne # one o the olde#t and %o#t -del$ edant!la&"o%a %ed"ne#. hen appled to the e$e plo"arpne "ae# t$p"al "holner!"

re#pon#e# %o## #pa#% o a""o%%odaton and a tran#ent o"&lar h$perten#on

ollo-ed 1$ a prolon!ed de"rea#e n IO?. It appear# that %"arn" re"eptor# n the r#

#phn"ter %"le are %ore #en#t/e than re"eptor# n the "lar$ %"le. >o## o""&r#1eore the ee"t on a""o%%odaton and the d&raton o %o## # lon!er than the "han!e

n a""o%%odaton. Intere#tn!l$ la1orator$ data nd"ate that the ee"t# o a"e"ldne an

analo! o are"olne on the o&tlo- a"lt$ o a=&eo h&%or and on a""o%%odaton "an&rther 1e d##o"ated altho&!h 1oth a"ton# o""&r /a %"arn" re"eptor# n the "lar$

%"le. @ Contra"ton o the "lar$ %"le %a$ "ae rare pre"ptaton o retnal

deta"h%ent. @ O-n! to t# lon!:ter% ee"t on IO? plo"arpne n /aro preparaton## ed n the treat%ent o !la&"o%a. @, In hea/l$ p!%ented e$e h!her "on"entraton

o plo"arpne %a$ 1e needed to lo-er IO? a# n the l!htl$ p!%ented e$e. @4 The

%ot" ee"t o plo"arpne # e&l to "o&ntera"t the %$dra## "aed 1$ atropne. A

pro"ed&re o n! alternat/el$ plo"arpne and a %$drat" "an 1rea7 adhe#on# 1et-eenthe r# and len#.

ANTICHOLINESTERASE AGENTSA"et$l"holne#tera#e h$drol$3e# a"et$l"holne at ne&roee"tor 9&n"ton# and ne&ral

#$nap#e#. The appl"aton o the ant"holne#tera#e a!ent allo-# the a""&%&laton o

endo!eno a"et$l"holne n the 9&n"tonal and #$napt" "let# to nd&"e %"arn" andn"otn" re#pon#e#. Thereore the phar%a"olo!" a"ton# o ant"holne#tera#e# are

#%lar to tho#e o a"et$l"holne e'"ept the %e"han#% # ndre"t. In !eneral the


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ophthal%" ee"t# o ant"holne#tera#e# are #%lar to tho#e o dre"t "holner!"

a!on#t#. ?h$#o#t!%ne a nat&ral ant"holne#tera#e ha# 1een ed to treat !la&"o%a or

o/er a "ent&r$. In the earler $ear# o orld ar II #$nthet" ant"holne#tera#e# theor!anopho#phate# -ere de/eloped. The or!anopho#phate# are -del$ ed a# a!r"&lt&ral

n#e"t"de# a# -ell a# n "he%"al -arare. A""ordn! to the %ode and d&raton o a"ton

ant"holne#tera#e# "an 1e "la##ed nto three "la##e# 5or ther #tr&"t&ral or%&la# #ee;!. 80)*nd+@6.

UltraShort-Acting, R!r"i#l Anticholin"tra"

Edrophon&% nh1t# a"et$l"holne#tera#e 1$ an ntera"ton 1et-een t# =&aternar$ntro!en and the anon" #te o a"et$l"holne#tera#e. The nh1ton o

a"et$l"holne#tera#e # /er$ #hort and re/er#1le 1e"ae o the or%aton o onl$ an on"

1ond and the rapd renal el%naton o edrophon&%. Th# a!ent # ed n the da!no##

o %$a#thena !ra/# that "ae# pto## and e'trao"&lar %"le pal#$. The te#t #peror%ed 1$ an ntra/eno n9e"ton o edrophon&% ollo-ed 1$ an addtonal

n9e"ton no re#pon#e o""&r# n , #e". S$#te%" ad%n#traton o atropne # ed to

"o&ntera"t #e/ere "holner!" re#pon#e#.

Short-Acting, R!r"i#l Anticholin"tra"A!ent# #&"h a# de%e"ar&% ph$#o#t!%ne and neo#t!%ne ha/e "ar1a%$l e#ter

ln7a!e# that or% a "o/alent 1ond -th the e#terat" #te o a"et$l"holne#tera#e. The#ea!ent# #er/e a# an alternate #&1#trate or a"et$l"holne#tera#e. The al"ohol %oet$ o

the#e a!ent# # "lea/ed a-a$ 1$ the en3$%e to or% a "ar1a%o$l a"et$l"holne#tera#e

"o%ple' that # %ore #ta1le than the a"$l a"et$l"holne#tera#e "o%ple' -hen the#&1#trate # a"et$l"holne. The or%aton o a "ar1a%o$l a"et$l"holne#tera#e "o%ple'

la#t# or ho&r#. Thereore ater a treat%ent -th the#e ant"holne#tera#e# le## ree

a"et$l"holne#tera#e # a/ala1le and endo!eno a"et$l"holne # h$drol$3ed at a %&"h

#lo-er rate.

Long-Acting, Irr!r"i#l Anticholin"tra"

The#e are or!anopho#phor "o%po&nd# that 1nd -th the e#terat" #te o

a"et$l"holne#tera#e rre/er#1l$. The #&1#trate:en3$%e "o%ple' # e'tre%el$ #ta1le andla#t# or da$# to -ee7#. Ret&rn o the en3$%e a"t/t$ n de!radn! a"et$l"holne depend#

on the #$nthe## o ne- a"et$l"holne#tera#e. E"hothophate and #ol&rophate are e&l

lon!:a"tn! ant"holne#tera#e# n "ln"al ophthal%olo!$.In addton to ther ee"t# on a"et$l"holne#tera#e ph$#o#t!%ne and =&aternar$

a%%on&% ant"holne#tera#e# ha/e dre"t a"ton# at #o%e "holner!" re"eptor# ether a#

a!on#t# or anta!on#t#. The phar%a"olo!" 1a## o ant"holne#tera#e a!ent# #

ne/erthele## the pre/enton o the h$drol$## o a"et$l"holne. ?reparaton# oant"holne#tera#e# are ed n "ln"al "ondton# n the e$e !a#tronte#tnal tra"t and

#7eletal %"le. Ele/ated IO? n !la&"o%a patent# "an 1e red&"ed -th ph$#o#t!%ne

de%e"ar&% e"hothophate or #ol&rophate. hen appled to the e$eant"holne#tera#e# "ae "on9&n"t/al h$pere%a %o## and a 1lo"7 o a""o%%odaton.

Lon!:ter% therap$ -th lon!:a"tn! ant"holne#tera#e# %a$ "ae "atara"t

de/elop%ent @ @8 o-n! to the nh1ton o "holne#tera#e n the len#. @< Lon!:a"tn! ant"holne#tera#e# are al#o re=&entl$ %#ed or ho%"dal and #&"dal

p&rpo#e#.

An o/erdo#e o ant"holne#tera#e %a$ prod&"e e'"e##/e #t%&laton o "holner!"

re"eptor# thro&!ho&t the 1od$. S$%pto%# n"l&de %"le -ea7ne## h$per#al/aton


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#-eatn! naea /o%tn! a1do%nal pan &rnar$ n"ontnen"e darrhea 1rad$"arda

#e/ere h$poten#on and 1ron"ho#pa#%. >"arn" anta!on#t# #&"h a# atropne "an 1e

ed or #$%pto%at" treat%ent. Into'"aton 1$ or!anopho#phor "o%po&nd# # lon!:la#tn! and #ho&ld 1e treated %%edatel$ -th praldo'%e. ?raldo'%e rea"t/ate# the

1o&nd a"et$l"holne#tera#e and na"t/ate# ree or!anopho#phor "o%po&nd# n the

pla#%a. Or!anopho#phor "o%po&nd# al#o prod&"e "hron" a'onal de!eneraton andde%$elnaton o-n! to the nh1ton o ne&roto'" e#tera#e -h"h # /er$ d"&lt to

treat. 0

>USCARINIC CHOLINERGIC ANTAGONISTSCholner!" anta!on#t# -or7 at re"eptor# to "o&ntera"t the ee"t o a"et$l"holne or

other "holner!" a!on#t#. The anta!on#% %a$ o""&r at the %"arn" re"eptor# o

ne&roee"tor# or n"otn" re"eptor# o ne&ro%"&lar 9&n"ton# and a&tono%" !an!la.

The ee"t# o "holner!" anta!on#t# "an 1e o/er"o%e 1$ n"rea#n! the "on"entraton oa"et$l"holne or a!on#t# at the re"eptor#. In pra"t"e the ter% "holner!" anta!on#t

!enerall$ reer# to %"arn" anta!on#t onl$ #n"e antn"otn" a!ent# "an 1e reerred

to a# ne&ro%"&lar 1lo"7er# or !an!lon" 1lo"7er#. E'"ept n /er$ h!h "on"entraton#

ant%"arn" 5para#$%pathol$t"6 a!ent# ha/e lttle a"ton# at the ne&ro%"&lar9&n"ton. In #$%pathet" !an!la -h"h "ontan the %"arn" re"eptor #&1t$pe (

ant%"arn" a"ton# %!ht "ae #!n"ant ee"t#.Certan nat&ral 1elladonna al7alod# atropne and #"opola%ne 5;!. 80)*nd+6 are

ant%"arn" a!ent#. The#e a!ent# are tertar$ a%%on&% "o%po&nd# that penetrate the

1lood:1ran 1arrer -ell and "an "ae #!n"ant CNS a"ton#. In therape&t" do#e#atropne "ae# le## CNS ee"t# than #"opola%ne. B$ addn! a %eth$l !ro&p at the

ntro!en o tho#e 1elladonna al7alod# %oded =&aternar$ a%%on&% "o%po&nd#

5%eth$latropne and %eth$l#"opola%ne6 red&"e the per%ea1lt$ a"ro## the 1lood:1ran

1arrer and thereore "ae le## CNS ee"t#. Ho-e/er the#e =&aternar$ a%%on&%"o%po&nd# a"=&re #!n"ant n"otn":1lo"7n! a"t/te#. Ho%atropne # a

#e%#$nthet" ant%"arn" a!ent. S$nthet" ant%"arn" a!ent# "$"lopentolate and

trop"a%de are #tr&"t&rall$ /er$ derent ro% 1elladonna al7alod# 5;!. 80)*nd+6.S$nthet" ant%"arn" a!ent# are de#!ned or #pe"" p&rpo#e# #&"h a# ha/n! a #hort

d&raton o a"ton or ophthal%" da!no##.

Ant%"arn" a!ent# ha/e 1een ed n a -de /aret$ o "ln"al "ondton#. Sn"e the#ea!ent# are not #pe"" or #ele"t/e %"arn" re"eptor #&1t$pe# the #$#te%" e o

ant%"arn" a!ent# # al-a$# a""o%paned 1$ #de ee"t#. ?atent "o%plan"e # poor

d&rn! lon!:ter% therap$. Ant%"arn" a!ent# are ed top"all$ a# an ad n rera"ton

nternal e$e e'a%naton and other da!no#t" pro"ed&re#2 to prod&"e %$dra## and"$"lople!a 1eore d&rn! and ater ntrao"&lar #&r!er$2 and to treat anteror &/et# and

#o%e #e"ondar$ !la&"o%a#. Ant%"arn" a!ent# "ae %$dra## o-n! to the

paral$## o the #phn"ter %"le o the r#. The p&pllar$ l!ht rele' d#appear#. The-de p&pllar$ dlaton %a$ "ae photopho1a. C$"lople!a o""&r# o-n! to the

paral$## o the "lar$ %"le. >$dra## !enerall$ o""&r# %ore rapdl$ than "$"lople!a

per##t# lon!er and "an 1e o1taned -th lo-er dr&! "on"entraton. The %$drat" ee"to atropne der# ro% the %$dra## "aed 1$ #$%pathet" a!on#t# -h"h do not

"ae "$"lople!a.

The nor%al #$#te%" do#e o atropne 50.4 %!6 ha# /er$ lttle o"&lar ee"t#. B&t an e=&al

do#e o #"opola%ne "ae# %o## and "$"lople!a. Atropne and #"opola%ne appled


8/30

top"all$ "ae %$dra## and "$"lople!a or a lon! perod o t%e. A""o%%odaton and

p&pllar$ rele' %a$ not re"o/er or #e/eral da$# &p to @ -ee7#. Ho%atropne

"$"lopentolate and trop"a%de "ae a #horter %$dra## and "$"lople!a. I a "o%pleteprolon!ed "$"lople!a # needed atropne and #"opola%ne are preerred rather than the

#$nthet" "o%po&nd#. hen onl$ %$dra## # de#red -ea7er "o%po&nd# #&"h a#

"$"lopentolate and trop"a%de are preerred. >$dra## 1$ the #hort:a"tn!ant%"arn" a!ent# "an 1e "o&ntera"ted 1$ plo"arpne. B&t %$dra## d&e to atropne

and #"opola%ne "an 1e onl$ partall$ re/er#ed 1$ plo"arpne or 1$ ant"holne#tera#e#.

Ater a #hort:ter% #$#te%" treat%ent o ant%"arn" a!ent# n !la&"o%a patent# anntereren"e o a=&eo h&%or o&tlo- and an n"rea#e o IO? rarel$ o""&r o-n! to the

rela'aton o the "lar$ %"le. ( Ho-e/er top"al treat%ent or lon!:ter% #$#te%"

treat%ent %a$ n"rea#e IO? n "ertan patent# -th open:an!le !la&"o%a. @ In patent#

-th narro-:an!le !la&"o%a treated -th top"al ant%"arn" a!ent# rela'aton o the#phn"ter %"le %a$ &rther de"rea#e the an!le and "ae an a"&te !la&"o%a atta"7.

The 1elladonna al7alod# are ea#l$ a1#or1ed thro&!h the !a#tronte#tnal tra"t. Top"al

appl"aton o the#e al7alod# or ophthal%" e'a%naton "an al#o "ae #!n"ant

#$#te%" a1#orpton /a the na#ola"r%al d&"t. Inant# and "hldren are %ore /&lnera1leto atropne nto'"aton ater top"al appl"aton. The =&aternar$ a%%on&% der/at/e#

o 1elladonna al7alod# are poorl$ a1#or1ed thro&!h the !a#tronte#tnal ro&te 1&t are #tll#!n"antl$ a1#or1ed ater o"&lar appl"aton#. So%e anth#ta%ne a!ent# %a$ "ae a

#%lar nto'"aton o-n! to ther ant%"arn" a"t/te#.

CHOLINERGIC AGENTS ORKING AT NEURO>USCULAR JUNCTIONS ANDGANGLIA

N"otn" re"eptor #&1t$pe# at the ne&ro%"&lar 9&n"ton# and a&tono%" !an!la "an 1e

d#tn!hed 1$ #ele"t/e phar%a"olo!" a!ent#. Ne&ro%"&lar 1lo"7er# 5;!. 80)

*nd+6 rea"t -th n"otn" re"eptor# at the ne&ro%"&lar 9&n"ton and the$ are"la##ed nto t-o "ate!ore# 5(6 Nondepolar3n! 1lo"7er# #&"h a# d:t&1o"&rarne.

The#e a!ent# "o%pete -th endo!eno a"et$l"holne or re"eptor#. The nor%al

ne&ro%"&lar tran#%##on 1$ a"et$l"holne # 1lo"7ed -tho&t %e%1ranedepolar3aton. 5@6 Depolar3n! 1lo"7er# #&"h a# #&""n$l"holne and de"a%ethon&%.

The#e a!ent# 1nd -th n"otn" re"eptor# and then open the Na*pl+ "hannel -h"h

"ae# a %e%1rane depolar3aton and a de#en#t3aton o %e%1rane to ne&raltran#%##on. The %e"han#% o a"ton o ne&ro%"&lar 1lo"7er# # derent ro% that

o 1ot&ln to'n. In9e"ton o 1ot&ln to'n nto the e'trao"&lar %"le# to treat

#tra1#% # 1a#ed on the 1lo"7ade o a"et$l"holne relea#e at ne&ro%"&lar 9&n"ton#.

The %a9or "ln"al appl"aton o ne&ro%"&lar 1lo"7er# # a# an ad9&/ant n #&r!"alane#the#a. Ne&ro%"&lar 1lo"7er# rela' #7eletal %"le# n"l&dn! the e'trao"&lar

%"le#. Rapdl$ %o/n! %"le -th a h!h de!ree o nner/aton # %ore ea#l$

ae"ted 1$ the#e a!ent#. Thereore the ee"t o #$#te%" ne&ro%"&lar 1lo"7er# -o&ld1e o1#er/ed n th# #e=&en"e e$eld a"al %"le ne"7 %"le e'tre%te# tr&n7 and

daphra!%. The to'" #$%pto%# prod&"ed 1$ ne&ro%"&lar 1lo"7er# are !eneral %"le

paral$## and re#prator$ al&re. I nto'"aton o""&r# ater the ad%n#traton o thenondepolar3n! ne&ro%"&lar 1lo"7er# ant"holne#tera#e 5#&"h a# neo#t!%ne6 "an 1e

ed a# an ee"t/e antdote. It #ho&ld 1e noted that #er&% "holne#tera#e# are

re#pon#1le or the de!radaton o another ne&ro%"&lar 1lo"7er #&""n$l"holne. The


9/30

ee"t o #&""n$l"holne n paral$3n! #7eletal %"le# %a$ 1e enhan"ed -th a top"al

ad%n#traton o ant"holne#tera#e#.

T-o t$pe# o a!ent# "an #t%&late "holner!" re"eptor# at the a&tono%" !an!la. Ther#t t$pe o a!ent# #t%&late the %"arn" re"eptor# at a&tono%" !an!la and ther

ee"t# "an 1e 1lo"7ed 1$ atropne:l7e ant%"arn" a!ent#. The #e"ond t$pe o a!ent#

#&"h a# n"otne 5;!. 80)*nd+,6 #t%&late n"otn" re"eptor# at the !an!la. Theree"t# "an 1e 1lo"7ed 1$ nondepolar3n! !an!lon" 1lo"7er# that "o%pete -th

#t%&lator# or the n"otn" re"eptor#. Gan!lon" n"otn" #t%&lator# are e&l tool# n

re#ear"h 1&t ha/e no "ln"al appl"aton. There are t-o t$pe# o "ln"all$ e&l!an!lon" 1lo"7er#. The r#t t$pe o 1lo"7er# #&"h a# he'a%ethon&% and tr%ethaphan

5;!. 80)*nd+,6 "ae no !an!lon" #t%&laton and no %e%1rane potental "han!e.

The$ ether "o%pete -th a"et$l"holne or n"otn" re"eptor# or 1lo"7 the opened on

"hannel#. The #e"ond t$pe o 1lo"7er# %par ne&ral tran#%##on -th ntal #t%&latono the n"otn" re"eptor# and then 1lo"7ade 1$ a per##tent depolar3aton. A prolon!ed

appl"aton o n"otne %a$ re#&lt n de#en#t3aton o the n"otn" re"eptor# 1$ th#

%e"han#%.

The %a9or "ln"al e o !an!lon" 1lo"7er# # n the "ontrol o "ertan #$#te%"h$perten#on# and a&tono%" h$perrele'a. Th# therap$ %a$ 1e a""o%paned 1$ #ero

#de ee"t# #n"e a lar!e n&%1er o a&tono%" !an!la are ae"ted. Ater #$#te%"ad%n#traton o !an!lon" 1lo"7er# %$dra## and "$"lople!a %a$ appear 1e"ae the

predo%nant a&tono%" tone at the r# and "lar$ %"le are para#$%pathet". There #

no #pe"" appl"aton o !an!lon" 1lo"7er# n "ln"al ophthal%olo!$.

Chapter 8(B

ADRENERGIC AGENTS

STE?HEN ?. BARTELS

DIRECT:ACTING ADRENERGIC AGENTSDentonAdrener!" a!on#t# a"t 1$ 1ndn! to adrener!" re"eptor# and a"t/atn! !&anne

n&"leotde:1ndn! re!&lator$ proten# 5G:proten#6 that are "o&pled to en3$%at" ee"tor

#$#te%# 5e.!. pho#pholpa#e C or aden$l "$"la#e6. Th the$ are operatonall$ derentro% other "la##e# o re"eptor# l7e #ol&1le "$topla#%" DNA:1ndn! re"eptor# 5e.!.

#terod# retnod# /ta%n D6 peptde:1ndn! t$ro#ne 7na#e:"o&pled re"eptor# 5e.!.n#&ln epder%al: or platelet:der/ed !ro-th a"tor#6 and on "hannel)*nd+"o&pledre"eptor# 5e.!. n"otn" "holner!" !l&ta%ate and a#partate re"eptor#6. Ho-e/er the$

do #hare "on#dera1le ho%olo!$ -th other G:proten)*nd+"o&pled re"eptor# 5e.!.

%"arn" "holner!" and rhodop#n6.Re"eptor#

Adrener!" re"eptor# are ph$#olo!" %a"ro%ole"&le# -ho#e nor%al &n"ton # to #er/e

a# a""e##1le re"o!nton #te# or #pe"" e'tra"ell&lar #!nal#. The$ 1nd endo!eno


10/30

%e##en!er# 5norepnephrne ro% ner/e# and epnephrne ro% the adrenal %ed&lla6 and

tran#%t the e'tra"ell&lar %e##a!e to the tar!et "ell. The$ are #t&ated n the pla#%a

%e%1rane at the ntera"e 1et-een the e'tra: and ntra"ell&lar %le and ther proten#tr&"t&re rele"t# t-o pr%ar$ &n"ton#F*%d+l!and 1ndn! and #!nal propa!aton.

Adrener!" re"eptor# ha/e e'tra"ell&lar do%an# h$dropho1" %e%1rane:#pannn!

do%an# -th #e/en a*alpha+:hel"al #e!%ent# %ade &p o @0 to @8 h$dropho1" a%noa"d# that tra/er#e 1a"7 and orth a"ro## the %e%1rane and ntra"ell&lar "ar1o'$:

ter%nal do%an# 5;!. 8()*nd+(6. ()*nd+ It # the tertar$ #tr&"t&re o the#e

%e%1rane:#pannn! #e!%ent# that or%# the l!and:1ndn! #te. Intra"ell&larl$adrener!" re"eptor proten# ha/e h$drophl" do%an# that ntera"t -th G:proten#.

At lea#t o&r derent t$pe# o adrener!" re"eptor# are no- !enerall$ a""epted

5a*alpha+( a*alpha+@ 1*1eta+( 1*1eta+@62 ho-e/er there appear to 1e #&1d/#on#

5e.!. a*alpha+(a a*alpha+(1 a*alpha+@a and a*alpha+@16 and there %a$ 1e a 1*1eta+t$pe that re#pond# to anta!on#t# l7e pndolol a# partal a!on#t#. Deren"e# 1et-een

re"eptor t$pe# are "hara"ter3ed 1a#ed on #tr&"t&re:a"t/t$ relaton#hp#. ?ror to the

a/ala1lt$ o radola1eled l!and# the #pe""t$ o l!and:re"eptor ntera"ton# -a#

deter%ned 1$ %ea#&rn! the 1olo!" re#pon#e# to derent #tr&"t&ral analo!#. ;orn#tan"e Al=t ed #' analo!# 5norepnephrne l:epnephrne dl:epnephrne

%eth$lepnephrne %eth$lnorepnephrne and #oproterenol6 and n/e#t!ated /aroee"t# 5/a#"&lar %$o"ardal and &terne a"t/t$2 "ontra"tlt$ o the le&% &reter and

n"ttatn! %e%1rane2 and p&pllar$ dlaton6 to d#"r%nate 1et-een a*alpha+: and

1*1eta+:adrener!" re"eptor#. , Land# et al. ed (0 "o%po&nd# and %ea#&red att$ a"d%o1l3aton ro% adpo#e t##&e or"e o %$o"ardal "ontra"ton 1ron"hodlaton and

/a#odlaton to d#"r%nate 1et-een 1*1eta+(: and 1*1eta+@:adrener!" re"eptor#. 4 A#

radola1eled l!and# 1e"a%e a/ala1le the$ -ere ed to #t&d$ /aro re"eptor#. (@, I:

Adreno"ort"otropn and (@, I:an!oten#n -ere the radola1eled l!and# r#t#&""e##&ll$ ed to #t&d$ #pe"" %e%1rane:1ndn! #te#. 8 D&rn! the %d (


11/30

Adrener!" re"eptor# are "o&pled to "ell&lar ee"tor #$#te%# 1$ tran#d&"ton %ole"&le#

the G:proten#. G:proten# "on#tt&te a a%l$ o proten# that are n/ol/ed n a n&%1er o

ph$#olo!" &n"ton#. E/en tho&!h the dr&!:a"t/ated #!nal tran#d&"ton path-a$#%edated /a adrener!" re"eptor:"o&pled G:proten# are 1en! e%pha#3ed here other G:

proten# 5e.!. pol$peptde elon!aton a"tor# and the ra# proten# and ther !ene#6 e'#t

and ha/e 1een the #&19e"t# o nten#e re#ear"h ntere#t. ()*nd+(? "ae# a"t/aton o "A>?:dependent proten 7na#e 5proten

7na#e A6. Tar!et proten# pho#phor$lated 1$ proten 7na#e A then el"t the t##&e

re#pon#e to the 1*1eta+:adrener!""A>?)*nd+dependent #t%&laton.Aden$l "$"la#e # a relat/el$ #"ar"e la1le !l$"oproten 5((, to (,0 7D6 o&nd

prn"pall$ n %e%1rane# 5;!. 8()*nd+6. )*nd+< There are %&ltple or%# o the

en3$%e e.!. "al"&%"al%od&ln #en#t/e and n#en#t/e. 0)*nd+ B$ n!or#7oln a dterpene that 1nd# #pe""all$ aden$l "$"la#e ha# 1een p&red to

ho%o!enet$ and "an 1e re"on#tt&ted nto pho#pholpd /e#"le# -th 1*1eta+:adrener!"

re"eptor# and G:proten to re:or% a &n"tonal "A>? #$nthet" #$#te%. ,)*nd+ It#relat/el$ lar!e #3e t# a1lt$ to 1nd -heat !er% a!!l&tnn and the pre#en"e o t-o

lar!e h$dropho1" do%an# ea"h apparentl$ "ontann! #' tran#%e%1rane #pan# #&!!e#t#

that porton# o aden$l "$"la#e %a$ 1e e'po#ed to the o&t#de o the "ell. < In

addton the #en#t/t$ o aden$l "$"la#e to 1oth e'tra"ell&lar a!on#t# and ntra"ell&lar"al"&%"al%od&ln pre#ent# the po##1lt$ that t too "an a"t a# a te%poral nte!rator n

the #!nal tran#d&"ton pro"e##.

Se"ond >e##en!er)Re!&lated S$#te%#I?:CALCIU>

St%&laton o a*alpha+(:adrener!" re"eptor# lead# to G:proten)*nd+%edated

a"t/aton o pho#pholpa#e C ?I?@ h$drol$## and I? or%aton. T$p"all$ the"on"entraton o "$topla#%" "al"&% # 7ept /er$ lo- 50.( %*%&+>6 1e"ae

ntra"ell&lar pho#phate e#ter# are "o%%on 5e.!. n&"leotde# and pho#pho!l$"erde#6 and

the or%aton o "al"&% pho#phate #alt# that are n#ol&1le 5e.!. "al"&l and 1one6 #

ph$#olo!"all$ &nde#ra1le. @< The pho#pholpa#e C?I?@ h$drol$## #$#te% pro/de# a


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%e"han#% to "ae tran#ent n"rea#e# n "$topla#%" "al"&%. The lar!e "on"entraton

!radent 1et-een the "$topla#% and the e'tra"ell&lar l&d the endopla#%" ret"&l&% or

#ar"opla#%" ret"&l&% # ed or a rapd #!nal tran#d&"ton #$#te% that # re!&lated 1$a !atn! %e"han#% that "ontrol# on" %o/e%ent. Cal"&% "hannel# open n re#pon#e to

the n"rea#ed le/el# o I? and "ae the ntra"ell&lar "on"entraton o "al"&% to

n"rea#e a1r&ptl$. In #%ooth %"le or e'a%ple "al"&% then 1nd# to "al%od&ln"an! "onor%atonal "han!e# that a"t/ate %$o#n l!ht "han 7na#e. Th# "al"&%:

dependent pho#phor$laton o %$o#n l!ht "han then "ae# "ontra"ton. @,

?ho#phata#e# depho#phor$late and "ae rela'aton.DAG)?ROTEIN KINASE C

Co%ple%entar$ or%aton o DAG o""&r# ollo-n! #t%&laton o a*alpha+(:adrener!"

re"eptor# and ?I?@ h$drol$##. Da"$l!l$"erol # the ph$#olo!" a"t/ator o "al"&%:

pho#pholpd)*nd+dependent proten 7na#e 5?KC6. ?roten 7na#e C -a# d#"o/ered nthe late (


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?ROTEIN KINASE A

Epnephrne and norepnephrne #t%&late 1*1eta+:adrener!" re"eptor# -h"h lead# to

G:proten)*nd+%edated a"t/aton o aden$l "$"la#e and "A>? or%aton. In"rea#edle/el# o "A>? a"t/ate proten 7na#e A. The$ are 9t t-o o %an$ hor%one# -ho#e

re"eptor:#pe"" #!nal # tran#d&"ed /a "A>?:dependent proten 7na#e# 5?KA6. ;or

e'a%ple /a#opre##n -h"h # prod&"ed n the ne&roh$poph$#eal #&praopt" andpara/entr"&lar n&"le %antan# pla#%a o#%olart$ /a a "A>? path-a$ that enhan"e#

#alt rea1#orpton n renal %ed&llar$ t&1&le# and a&!%ent# -ater tran#port n "olle"tn!

d&"t#. , ?arath$rod hor%one -h"h # prod&"ed 1$ "he "ell# n the parath$rod!land 1nd# #pe"" re"eptor# n pro'%al and d#tal "ort"al t&1&le# and a"t/ate# aden$l

"$"la#e lo"al3ed n ther 1a#olateral %e%1rane#. The n"rea#ed "A>? or%aton lead# to

a"t/aton o ap"all$ lo"al3ed ?KA pho#phor$laton o proten# n the 1rh 1order

l&%nal %e%1rane and enhan"ed pho#phate e'"reton. ,, Cal"tonn -h"h #prod&"ed 1$ the paraoll"&lar "ell# n the th$rod !land lo-er# #er&% "al"&% 1$ a

"A>?:%edated nh1ton o 1one re#orpton 1$ o#teo"la#t#. ,, Other #&"h hor%one#

n"l&de !l&"a!on "horon" !onadotropn l&ten3n! hor%one "ort"otropn and

oll"le: th$rod: and %elano"$te:#t%&latn! hor%one#. @


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e'pre##ed n the /aro t##&e# o the e$e "o&ld 1e /er$ e&l or the de/elop%ent o

#pe"" nh1tor#.

Mo()lator% Mchani"&"DESENSITIMATION AND DONREGULATION

The %a!nt&de o the re#pon#e that an a!on#t" dr&! "an ntate n a !/en "ell -lldepend on a n&%1er o a"tor# #&"h a# the den#t$ o re"eptor# ther ant$ or an$

#pe"" dr&! and ther #en#t/t$ to the dr&!. Chron" e'po#&re o t##&e# to a dr&! "an

1e e'pe"ted to ae"t #en#t/t$ to the dr&!. Be"ae o t# deal nat&re a# a %odel#$#te% the 1*1eta+:adrener!" re"eptor)*nd+aden$l "$"la#e #$#te% ha# 1een #t&ded

e'ten#/el$. Ater prolon!ed e'po#&re to adrener!" a!on#t# "A>?:%edated "ell&lar

re#pon#e# 1e"o%e de#en#t3ed. 4()*nd+4 The or%# o de#en#t3aton ha/e 1een"hara"ter3ed pheno%enolo!"all$ a# ho%olo!o and heterolo!o. Ho%olo!o

de#en#t3aton reer# to the atten&aton o onl$ the #&1#e=&ent re#pon#e to the #pe""

a!on#t that "aed the de#en#t3aton. ;or e'a%ple a!on#t:#pe"" pho#phor$laton o

1*1eta+:adrener!" re"eptor# "an o""&r 1$ a 1*1eta+:adrener!" re"eptor 7na#e

51*1eta+ARK6 that pho#phor$late# onl$ the a!on#t:o""&ped re"eptor. 4 The1*1eta+ARK # a "$to#ol" en3$%e that !et# tran#ported to the re"eptor# n the pla#%a

%e%1rane -hen a "ell # #t%&lated 1$ a 1*1eta+:adrener!" a!on#t. Heterolo!ode#en#t3aton reer# to the atten&aton o the #&1#e=&ent re#pon#e to other derent

a!on#t# operatn! /a re"eptor# d#tn"t ro% tho#e that "aed the de#ent3aton. ;or

e'a%ple hor%onal a"t/aton o "A>?:dependent ?KA "an "ae de#en#t3aton o1*1eta+:adrener!" re"eptor# and a*alpha+(:adrener!" a"t/aton o ?KC "an "ae

pho#phor$laton and heterolo!o de#en#t3aton o 1*1eta+:adrener!" re"eptor#. The

%a9or %e"han#% n/ol/ed n de#en#t3n! adrener!" "A>?)*nd+%edated re#pon#e# #%od&laton o 1*1eta+:adrener!" re"eptorG:proten ntera"ton. S&1#e=&ent to a!on#t

o""&pan"$ 1*1eta+:adrener!" re"eptor# 1e"o%e pho#phor$lated and th# "ae#

&n"tonal &n"o&pln! ro% aden$l "$"la#e. ?ho#phor$laton o one or t-o "on#en##e=&en"e# n the thrd "$topla#%" loop and the pro'%al porton o the "ar1o'$:ter%nal"$topla#%" tal o the 1*1eta+:adrener!" re"eptor 1$ ?KA appear# to 1e the %an

%e"han#% or de#en#t3aton at lo- 5n>6 a!on#t "on"entraton# 4 -herea# at h!h

5%*%&+>6 "on"entraton# 1*1eta+ARK # al#o a"t/ated and "ae# pho#phor$laton onthe "ar1o'$:ter%nal tal 1&t at #te# derent ro% tho#e o ?KA:%edated

pho#phor$laton. 4 The 1*1eta+ARK:%edated pho#phor$laton # 1ele/ed to "ae a

"onor%atonal "han!e n the re"eptor. Re"eptor &n"o&pln! o""&r# -thn %n&te#.thn a #%lar t%e ra%e the re"eptor# are tran#entl$ re%o/ed ro% the pla#%a

%e%1rane and #e=&e#tered ntra"ell&larl$ n lo-:den#t$ %e%1rane /e#"le# -here

depho#phor$laton and re"$"ln! o""&r#. O/er a lon! t%e ra%e 5ho&r#6 do-nre!&laton

o""&r# n/ol/n! ether the de!radaton o re"eptor# or the red&"ton o re"eptor#$nthe##. Other %e"han#%# that %a$ pla$ #o%e role are %pared &n"tonalt$ o the

G#:proten #tr&"t&ral and &n"tonal alteraton# n aden$l "$"la#e enhan"ed de!radaton

or n"rea#ed lo## o "A>? ro% the "ell. 4(Be"ae the #en#t/t$ o a t##&e to a dr&! # !enerall$ related to the d&raton o t%e

that t # e'po#ed to the dr&! dal$ treat%ent -th an a!on#t "an 1e e'pe"ted to "ae a

red&"ton n #en#t/t$. The prn"pal dre"t:a"tn! adrener!" a!on#t# ed "ln"all$.e. epnephrne 5E?I6 dp/al$l epnephrne 5D?E6 and phen$lephrne all penetrate the


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e$e -ell and !an read$ a""e## to the adrener!" re"eptor# n the anteror #e!%ent o the

e$e. Epnephrne and D?E are &all$ ed "hron"all$ or the treat%ent o !la&"o%a.

Th t # rea#ona1le to e'pe"t that the "A>?:%edated "ell&lar re#pon#e# do 1e"o%ede#en#t3ed d&rn! th# treat%ent re!%e.

Bre H#tor$ o the U#e o Dre"t:A"tn! Adrener!" A!on#t# n Ophthal%olo!$

Epnephrne a "o%1ned a*alpha+: and 1*1eta+:adrener!" a!on#t # the r#t dre"ta"tn! adrener!" dr&! ed n ophthal%olo!$. 4, It re%an# "ln"all$ e&l to "ontrol

1leedn! 1lan"h the "on9&n"t/a and de"rea#e ntrao"&lar pre##&re n patent# -th

!la&"o%a. Ho-e/er patent toleran"e to "hron" top"al epnephrne # #o%et%e# l%ted1e"ae o t# #de ee"t# 5e.!. rea"t/e h$pere%a 1lephart# t"hn! and p!%ent

depo#t# n the "on9&n"t/a6. Th# led to the ntrod&"ton o the prodr&! dp/al$l

epnephrne 5?ropne6 n the late (


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ene#trated "apllare# and enter# the !eneral "r"&laton /a the adrenal /en. >o#t t##&e#

n the 1od$ re#pond to epnephrne.

T$ro#ne h$dro'$la#e "atal$3e# the "on/er#on o the a%no a"d t$ro#ne to L:dopa

-h"h # then "on/erted to dopa%ne 1$ dopa de"ar1o'$la#e. The 1*1eta+:"ar1on odopa%ne # h$dro'$lated and "on/erted to norepnephrne 1$ dopa%ne h$dro'$la#e.

Upon %eth$laton o the a%no !ro&p o the eth$la%ne #de "han 1$ tran#%eth$la#e

norepnephrne # "on/erted to epnephrne.I%portant !eneral #tr&"t&re:a"t/t$ relaton#hp# a%on! /aro adrener!" "o%po&nd#

are de#"r1ed n detal n other e'"ellent #o&r"e#. < So%e eat&re# that relate to

adrener!" dr&!# %portant to ophthal%olo!$ are d#"#ed here. H$dro'$laton o the

1en3ene rn! # %portant or 1oth a*alpha+: and 1*1eta+:adrener!" a"t/t$ the "on!&raton "onerrn! %a'%al poten"$. The l!and:1ndn! do%an# o adrener!"

re"eptor# appear to 1e a%on! the #e/en tran#%e%1rane h$dropho1" hel"al loop# that

are alternat/el$ ln7ed -th the h$drophl" do%an#. U#n! ol!on&"leotde:dre"ted

%&ta!ene## te"hn=&e# the #pe"" %ole"&lar ntera"ton# 1et-een a!on#t# andadrener!" re"eptor# ha/e 1een n/e#t!ated re"entl$. 80 8( The t-o #erne re#d&e# at

po#ton# @0 and @0 n the th h$dropho1" do%an apparentl$ ntera"t -th the and h$dro'$l !ro&p# o the "ate"hol rn! re#pe"t/el$ 5;!. 8()*nd+6. 8( The a%ne

!ro&p at the end o the eth$l #de "han apparentl$ ntera"t# -th the "ar1o'$lated #de

"han o the a#partate at po#ton (( n the thrd h$dropho1" do%an o the re"eptor. 80?hen$lephrne # ee"t/e a# an a*alpha+(:adrener!" a!on#t. It# 1en3ene rn! #

h$dro'$lated at onl$ the po#ton and ha# lttle 1*1eta+:adrener!" a"t/t$ e/en tho&!h

t# a%ne !ro&p # %eth$lated. It# poten"$ at a*alpha+:adrener!" re"eptor# # lo-er than

that o epnephrne.

A# a !eneral r&le n"rea#n! the al7$l #&1#tt&ton n the a%no !ro&p n"rea#e#

#ele"t/t$ or 1*1eta+:adrener!" re"eptor# 5e.!. #oproterenol # d%eth$lated and

ter1&talne # tr%eth$lated6. The N:%eth$lated pr%ar$ a%ne #tr&"t&re o epnephrnea""o&nt# or t# relat/el$ #tron! a"t/t$ at 1*1eta+:adrener!" re"eptor# and the

relat/el$ -ea7 a"t/t$ o norepnephrne. Th# one deren"e 1et-een epnephrne and

norepnephrne al#o n"rea#e# t# poten"$ at a*alpha+:adrener!" re"eptor# o/er

norepnephrne.Dp/al$l epnephrne # a #$nthet" pro:dr&! analo! o epnephrne. T-o p/al" a"d

!ro&p# ha/e 1een added to h$dro'$l !ro&p# on the "ate"hol rn!. Endo!eno e#tera#e#

"lea/e the p/al" !ro&p# &pon dr&! penetraton nto the e$e. The 1otran#or%aton or%#epnephrne. Th th# #tr&"t&ral %od"aton doe# not "han!e the a"t/t$ o the dr&! at

the re"eptor rather t %pro/e# penetraton and red&"e# #de ee"t#. O-n! to t# !reater

lpophl"t$ !reater a%o&nt# o D?E are a1#or1ed "o%pared -th E?I. A1o&t t-"e a#%&"h epnephrne -a# o&nd n h&%an a=&eo h&%or @ hr ater top"al ad%n#traton o

0., per"ent D?E a# -a# o&nd ater @ per"ent E?I. 4< hen ,0 %*%&+l o ether 0.0,

per"ent ( C:D?E or 0.0, per"ent ( C:E?I -ere appled to the ra11t e$e !reater

total a%o&nt# per e$e o D?E -ere a1#or1ed 5D?EE?I rato 8., at 0 %n


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. at hr and . at 4 hr6. 48 th re!ard to #$#te%" a1#orpton 0 %n ater top"al

n#tllaton o the ( C:E?I onl$ 0. per"ent o the total radoa"t/t$ the %a'%al

a%o&nt -a# o&nd n the treated e$e2 analo!ol$ 40 %n ater top"al n#tllaton o the ( C:D?E onl$ .8< per"ent -a# o&nd. The re#t o the top"al %ed"aton -a# ether

lo#t o&t o the e$e or a1#or1ed #$#te%"all$. S!n"ant le/el# o radoa"t/t$ -ere

dete"ted n the "ontralateral &ntreated e$e# a# earl$ a# 0 %n ater E?I and 40 %n aterD?E ad%n#traton nd"atn! #$#te%" a1#orpton altho&!h the #%all 1od$ -e!ht o

ra11t# "ertanl$ %t 1e "on#dered.

I%da3olne der/at/e# 5apra"londne napha3olne tetrah$dro3olne and

o'$%eta3olne6 ha/e #!n"ant a*alpha+:adrener!" a"t/t$. Str&"t&rall$ the$ are =&te

derent ro% the 1oa%ne# n that the "ate"hol rn! # repla"ed 1$ derent &n#at&ratedrn!# and the eth$la%ne #de "han # repla"ed 1$ the %da3olne !ro&p. The

repla"e%ent o the "ate"hol rn! red&"e# 1*1eta+:adrener!" a"t/t$ to a !reater e'tent

than a*alpha+:adrener!" a"t/t$. e"han#% o A"ton Ste o A"t/t$ and Ophthal%" Ind"aton#

MECHANISM OF ACTIONA# de#"r1ed a1o/e #t%&laton o a*alpha+(:adrener!" re"eptor# lead# to G:proten)

*nd+%edated a"t/aton o pho#pholpa#e C #e"ond:%e##en!er l1eraton 5I? and

DAG6 and an$ n&%1er o t##&e:#pe"" re#pon#e#. St%&laton o a*alpha+@:adrener!"re"eptor# lead# to G:proten)*nd+%edated nh1ton o aden$l "$"la#e and a red&"ton

n #e"ond %e##en!er 5"A>?6 prod&"ton. St%&laton o 1*1eta+:adrener!" re"eptor#

lead# to G:proten)*nd+%edated a"t/aton o aden$l "$"la#e n"rea#ed "A>? #$nthe##

and a"t/aton o a n&%1er o t##&e:#pe"" re#pon#e#.

SITES OF ACTI*ITYCon+)ncti!a

Con9&n"t/al /e##el# are readl$ a""e##1le to top"al %ed"ne# and are "ertanl$

re#pon#/e to adrener!" a!ent#. >o#t o the "o%%onl$ ed top"al dre"t adrener!"a!on#t# 5e.!. phen$lephrne epnephrne apra"londne napha3olne tetrah$dro3olne6

ha/e a*alpha+(:adrener!" a"t/t$. The %%edate ee"t o the#e dr&!# # on /a#"&lar

#%ooth %"le and "ae# /a#o"on#tr"ton and -htenn! o the e$e.

Cornal Eithli)&

The "orneal epthel&% # #%larl$ a""e##1le to top"al dr&!# and re#ear"h nd"ate# thatthere are "ell&lar &n"ton# related to "hlorde tran#port that are re!&lated 1$ 1*1eta+:

adrener!" pro"e##e# and %a$ "ontr1&te to the "ontrol o #tro%al h$draton. 8@ A den#e1a#al ple' o t$ro#ne h$dro'$la#e)*nd+po#t/e ner/e# ha# 1een de#"r1ed n h&%an

"orneal epthel&% that nd"ate# that t # "ate"hola%ner!"all$ nner/ated. 8 1*1eta+:

Adrener!" re"eptor# are pre#ent n ra11t "orneal epthel&%. 8 8, In pr%ate andh&%an "ornea and n #olated pr%ate "orneal epthel&% epnephrne #t%&late# lar!e

n"rea#e# n "A>? nd"atn! the pre#en"e o 1*1eta+:adrener!" re"eptor# n h&%an


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"orneal epthel&%. 84 In /tro the a"t/e tran#port o "hlorde ro% the #tro%al #de o

the "orneal epthel&% to the tear #de # #t%&lated 1$ epnephrne /a a 1*1eta+:

adrener!" %e"han#% n ra11t# and h&%an#. 8)*nd+?:%edated %e"han#%# "o&ld

1e n/ol/ed n the re!&laton o t##&e h$draton or 1a#e%ent %e%1rane "olla!en

prod&"ton ha# 1een #&!!e#ted.


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#t%&lated 5/a "al"&%:"al%od&ln6 and pho#phor$late# rela'ed %$o#n pro%otn!

"ontra"ton. @, @

adrenergice si colinergice

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