NSAIDs, ACETAMINOPHEN, & DRUGS USED IN GOUT A. Q. Sangalang, MD, FPOGS FACULTY OF PHARMACY UNIVERSITY OF SANTO TOMAS IMMUNE RESPONSE Immunologiall! om"#$#n$ om"#$#n$ #ll% a a$i'a$#( in %"on%# $o )oign o&gani%m% o& an$ig#ni %u*%$an#% Li*#&a$#( (u&ing in)lamma$o&! %"on%# Man! $a$m#n$ %$&a$#gi#% a""li#( $o $+# (u$ion o) in)lamma$ion a $a&g#$#( a$ $+# immun# "&o#%% Ou$om# #n#)iial T+# in'a(ing o&gani%m $o *# "+ago!$o%#( o& n#u$&ali-#( D#l#$#&iou% L#a(% $o +&oni in)lamma$ion No %olu$ion o) $+# un(#&l!ing inu&iou% "&o#%% INFLAMMATION Common non%"#i)i mani)#%$a$ion o) man! (i%#a%#% / )o&m% Au$# C+&oni C+&oni R#l#a%# o) im"o&$an$ m#(ia$o&% $+a$ a no$ "&omin#n$ in au$# %"on%# R+#uma$oi( a&$+&i$i% Con(i$ion% $+a$ %ul$% )&om $+# l#a%# o) $+#%# m#(ia$o&% Pain an( (#%$&u$ion o) *on# an( a&$ilag# $+a$ an l#a( $o %#'# (i%a*ili$! L#u0o!$#% l#a%# l!%o%omal #n-!m#% A&a+i(oni ai( i% li*#&a$#( P&o%$aglan(in 1PG2 i% %!n$+#%i-#( )&om $+# !loo3!g#na%# "a$+4a! C!loo3!g#na%# C!loo3!g#na%# "a$+4a! +a% / i%o)o&m% CO5 67T#n(% 67T#n(% $o *# +om#o%$a$i in )un$ion 7 E3"%%#( in non7in)lamma$o&! #ll% CO5 /7In(u#( (u&ing in)lamma$ion 7 E3"%%#( in a$i'a$#( l!m"+o!$#%, l!m"+o!$#%, PMN%, o$+#& in)lamma$o&! #ll% Li"o3!g#na%# "a$+4a! Yi#l(% l#u0o$&i#n#% C+#mo$a$i #))#$ on #o%ino"+il%, n#u$&o"+il%, an( ma&o"+ag#% P&omo$# *&on+oon%$&i$ion an( al$#&a$ion in 'a%ula& "#&m#a*ili$! 8inin%, n#u&o"#"$i(#% an( +i%$amin# a l#a%#( $og#$+#& 4i$+ om"l#m#n$ om"on#n$% an( !$o0in#% O3!g#n7(#&i'#( )# &a(ial% H!(&og#n "#&o3i(# an( +!(&o3!l &a(ial% P&o(u#( )&om n#u$&o"+il% m#m*&an#% In$#&a$ 4i$+ a&a+i(oni ai( $o g#n#&a$# +#mo$a$i )a$o&% $+a$ "#&"#$ua$# in)lamma$o&! "&o#%%
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THERAPEUTIC STRATEGIES / GOALS 6. R#li#) o) "ain "ain /. Slo4 o& a&%$ $+# $i%%u#7(amaging "&o#%% "&o#%% ASPIRIN AND OTHER NSAIDs NONSTEROIDAL ANTI-INFLAMMATORY DRUG (NSAIDs) A. Chemistr !"# Ph!rm!$%i"eti$s 9#a0 o&gani ai(% #3#"$ Na*um#$on# 1a 0#$on# "&o(&ug m#$a*oli-#( $o a$i'# ai(i (&ug2 9#ll a*%o&*#(, )oo( (o#% no$ +ang# *ioa'aila*ili$! Hig+l! m#$a*oli-#( Som# *! "+a%# I )ollo4#( *! "+a%# II m#+ani%m Som# *! (i$ gluo&oni(a$ion 1"+a%# II alon#2
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R#nal #3$ion i% $+# &ou$# ) o& #limina$ion All un(#&go a (#g# o) *ilia&! #3$ion an( a*%o&"$ion 1#n$#&o+#"a$i i&ula$ion2 Mo%$l! a +ig+l! "&o$#in7*oun( 1:;<2 $o al*umin Som# a &a#mi mi3$u% 1i*u"&o)#n2, %ingl# #nan$iom#& 1na"&o3#n2 an( )#4 +a'# no +i&al #n$#& 1(ilo)#na2 All an *# )oun( in $+# %!no'ial )lui( a)$#& "#a$#( (o%ing D&ug% 4i$+ %+o&$#& +al)7li'#% main in $+# oin$% long#& $+an $+#i& +al)7li'#% D&ug% 4i$+ long#& +al)7li'#% (i%a""#a& a$ a &a$# "&o"o&$iona$# $o $+#i& +al)7li'#% . Ph!rm!$%#"!mi$s An$i7in)lamma$o&! a$i'i$! i% m#(ia$#( +i#)l! $+&oug+ in+i*i$ion o) *io%!n$+#%i% o) PG% A((i$ional m#+ani%m% In+i*i$ion o) +#mo$a3i% Do4n7gula$ion o) in$#&l#u0in76 "&o(u$ion D#a%#( "&o(u$ion o) )# &a(ial% an( %u"#&o3i(# In$#&)#n# 4i$+ alium7m#(ia$#( in$&a#llula& #'#n$% A%"i&in I&'#&%i*l! a#$!la$#% an( *lo0% "la$#l#$ !loo3!g#na%# Non7CO5 %#l#$i'# NSAID% R#'#&%i*l# in+i*i$o&% Hig+l! %#l#$i'# CO5 / in+i*i$o&% Do no$ a))#$ "la$#l#$ )un$ion a$ $+#i& u%ual (o%#% E))ia! #=ual% $+a$ o) ol(#& NSAID% GI %a)#$! ma!*# im"&o'#( Ma! ina%# #(#ma an( +!"#&$#n%ion
Hig+l! %#l#$i'# CO5 / in+i*i$o&% C#l#o3i*, E$o&io3i* A'aila*l# CO5 / (&ug% in $+# ma&0#$ Ro)#o3i* an( Val(#o3i* 9i$+(&a4n (u# $o ina%# a&(io'a%ula& $+&om*o$i #'#n$% M#lo3iam R#la$#( $o "i&o3iam P)#n$iall! in+i*i$% CO5 / o'#& CO5 6 a$ i$% lo4#%$ $+#&a"#u$i (o%# o) >.? mg F#4#& GI %!m"$om% an( om"lia$ion% In+i*i$% %!n$+#%i% o) $+&om*o3an# A/ *u$ no #))#$ on "la$#l#$ )un$ion A%"i&in, In(om#$+ain, Pi&o3iam an( Sulin(a Mo #))#$i'# in in+i*i$ing CO5 6 I*u"&o)#n an( M#lo)#nama$# In+i*i$ / i%o#n-!m#% #=uall! In$#&)# 4i$+ $+# +om#o%$a$i )un$ion o) PG% R#(u# PG7m#(ia$#( !$o"&o$#$ion in $+# GI $&a$ an( au$ogula$ion o) nal )un$ion D#a%# $+# %#n%i$i'i$! o) '#%%#l% $o *&a(!0inin an( +i%$amin# A))#$ l!m"+o0in# "&o(u$ion R#'#&%# $+# 'a%o(ila$ion o) in)lamma$ion All ga%$&i i&&i$an$% All (&ug% a n#"+&o$o3i (u# in "a&$ $o in$#&)#n# o) au$ogula$ion o) nal *loo( )lo4 H#"a$o$o3ii$! an ou& 4i$+ an! NSAID No #'i(#n# %+o4 $+a$ $+#! al$#& $+# ou&%# o) an a&$+&i$i (i%o&(#& A""#a& $o (u# $+# ini(#n# o) olon an#& 4+#n $a0#n +&oniall! 1inlu(ing a%"i&in2 ?@< (u$ion in la$i'# &i%0 a)$#& ? !#a&% o) in$a0# M#+ani%m )o& "&o$#$i'# m#+ani%m i% unl#a& ASPIRIN A#$!l%ali!li ai( 1ASA2 P&o$o$!"# Ral! u%#( a% an an$i7in)lamma$o&! ag#n$ R#"la#( *! i*u"&o)#n an( na"&o3#n A. Ph!rm!$%i"eti$s $+#&a"#u$i (o%# &ang#%
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Lo4 &ang# 1B @@mg(a!2 E))#$i'# in (uing "la$#l#$ aggga$ion In$#&m#(ia$# (o%# 1@@7/@@ mg(a!2 Ha'# an$i"!$i an( analg#%i #))#
%$Hig+ (o%# 1/@@7@@@ mg(a!2 U%#( )o& $+#i& an$i7in)lamma$o&! #))#$ R#a(il! a*%o&*#( H!(&ol!-#( in *loo( an( $i%%u#% $o a#$a$# an( %ali!li ai( E3$ion i% 'ia $+# 0i(n#! Al0alini-a$ion o) u&in# a))#$% &a$# o) #3$ion
N%"!$et'!te# S!'i$'!tes A. Ph!rm!$%i"eti$s C+olin# %ali!la$#, %o(ium %ali!la$#, %ali!l %ali!la$# R#'#&%i*l# non%#l#$i'# in+i*i$o& o) !loo3!g#na%# E))#$i'# an$i7in)lamma$o&!, l#%% #))#$i'# analg#%i% Do no$ in+i*i$ "la$#l#$ aggga$ion A(mini%$#( in (o%#% u" $o 7 g a (a! Elimina$ion i% )i&%$ o&(#& a$ lo4 (o%#%, 4i$+ a +al)7li)# o) 7? + Elimina$ion *#om#% -#&o o&(#& a$ +ig+ (o%#%, +al)7li)# ina%#% $o 6? + o& mo oun( $o al*umin P)#&( in "a$i#n$% 4i$+ A%$+ma l##(ing $#n(#ni#% R#nal (!%)un$ion Other N%"se'e$tie CO I"hi*it%rs A. Ph!rm!$%i"eti$s 9#ll a*%o&*#( a)$#& o&al in$a0# Dilo)#na P+#n!la#$i ai( (#&i'a$i'# El#'a$ion o) li'#& #n-!m#% i% ommon GI ul#&a$ion l#%% ommon Di)lu%inal D#&i'#( )&om %ali!li ai( Cl#a&an# (#"#n(% on nal an( +#"a$i m#$a*oli%m E))#$i'# )o& an#& "ain in *on# m#$a%$a%#% E$o(ola Ra#mi a#$i ai( (#&i'a$i'# Do#% no$ un(#&go +i&al in'#&%ion in $+# *o(! Gi'#n $o $im#% (ail! Flu&*i"&o)#n P&o"ioni ai( (#&i'a$i'# Mo om"l#3 m#+ani%m o) a$ion IV "" #))#$i'# )o& "#&io"#&a$i'# analg#%ia in mino& %u&g#&! I*u"&o)#n P+#n!l"&o"ioni ai( (#&i'a$i'# /@@ g (ail! i% #=ui'al#n$ $o g a%"i&in in an$i7in)lamma$o&! #))#$ O&al "" in lo4#& (o%#% )o& analg#%i #))#$ E))#$i'# in lo%ing PDA in "$#&m in)an$% Sam# #))ia! an( %a)#$! a% in(om#$+ain O&al an( IV &ou$#% a #=uall! #))#$i'# D#a%# u&in# ou$"u$ l#%% an( au%#% l#%% )lui( $#n$ion $+an in(om#$+ain Conomi$an$ a(mini%$&a$ion 4i$+ a%"i&in An$agoni-#% "la$#l#$ in+i*i$ion in(u#( *! a%"i&in Ma! (#a%# $+# $o$al an$i7in)lamma$o&! #))#$ In(om#$+ain
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In(ol# (#&i'a$i'#, "o$#n$ 4i$+ ina%#( $o3ii$! T+&om*o!$o"#nia an( a"la%$i an#mia Ra "%!+o%i% an( +alluina$ion U%#( $o a#l#&a$# lo%u o) PDA 8#$o"&o)#n P&o"ioni ai( (#&i'a$i'# In+i*i$% *o$+ CO5 1non%#l#$i'#2 an( li"o3!g#na%# No$ %u"#&io& $o o$+#& NSAID% in %"i$# o) (ual #))#$
8#$o&ola P&omo$#( )o& %!%$#mi u%# mainl! a% an analg#%i U%#( %u#%%)ull! $o "la# mo&"+in# in mil( $o mo(#&a$# "o%$%u&gial "ain IV u%# %$&i$#( $o >/ + O&al "" i% a'aila*l# Ri%0 o) GI an( nal (amag# 4i$+ long#& u%# Na*um#$on# Onl! nonai( NSAID P&o(&ug on'#&$#( $o a#$i ai(, %#m*l#% na"&o3#n V#&! #3"#n%i'# Hal)7li)# i% mo $+an / +, on# (ail! L#%% GI (amag# Hig+#& (o%#% a o)$#n n##(#( Na"&o3#n Na"+$+l!"&o"ioni ai( (#&i'a$i'# Onl! NSAID ma&0#$#( a% %ingl# #nan$iom#& Lo4 ini(#n# o) GI *l##(ing *u$ (ou*l# $+a$ o) i*u"&o)#n O3a"&o-in P&o"ioni ai( (#&i'a$i'# V#&! long +al)7li)# o) ?@7@ + U&io%u&i Pi&o3iam A$ +ig+ on#n$&a$ion% al%o in+i*i$% PMN mig&a$ion, (#a%#% O/ &a(ial "&o(u$ion an( l!m"+o!$# )un$ion Long +al)7li)# "#&mi$% on# (ail! (o%ing Sulin(a Sul)o3i(# "&o(&ug Ma! in+i*i$ (#'#lo"m#n$ o) olon, *a%$ an( "&o%$a$# an#& Ma! #l#'a$# li'#& #n-!m#% li0# (ilo)#na Tolm#$in S+o&$ +al)7li)# o) 67/ + an( no$ o)$#n u%#( In#))#$i'# in $+# $a$m#n$ o) gou$ )o& un0no4n a%on A-a"&o"a-on#, Ca&"&o)#n, M#lo)#nama$#, an( T#no3iam Ral! u%#( . Me$h!"ism %+ A$ti%" !"# C'i"i$!' Uses An$i7in)lamma$o&! #))#$% Asiri" Non%#l#$i'# i&'#&%i*l# in+i*i$o& o) *o$+ CO5 i%o#n-!m#% In+i*i$% "la$#l#$ aggga$ion Analg#%i #))#$% Mo%$ #))#$i'# in (uing mil( $o mo(#&a$# "ain $+&u i$% #))#$ on in)lamma$ion An$i"!$i #))#$% M#(ia$#( *! *o$+ CO5 in+i*i$ion in $+# CNS an( in+i*i$ion o) in$#&l#u0in 6 An$i"la$#l#$ #))#$% I&'#&%i*l# in+i*i$ion au%#% $+# an$i"la$#l#$ #))#$ $o la%$ )o& ;76@ (a!% 1li)# %"an o) $+# "la$#l#$2 O$+#& #))#$% D#a%#% $+# ini(#n# o) $&an%i#n$ i%+#mi a$$a0% 1TIA%2, un%$a*l# angina, o&ona&! a&$#&! $+&om*o%i% 4i$+ MI an( $+&om*o%i% a)$#& angio"la%$!
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Other NSAIDs Ta$m#n$ o) mil( $o mo(#&a$# "ain o) in)lamma$ion A&$+&i$i% Gou$ C. T%i$it T+#&a"#u$i an$i7in)lamma$o&! (o%#% o) a%"i&in Ga%$&i u"%#$ i% mo%$ ommon C+&oni u%# Ga%$&i ul#&a$ion%, u""#& GI *l##(ing R#nal #))#$%, inlu(ing au$# )ailu an( in$#&%$i$ial n#"+&i$i% Small (o%#% o) a%"i&in 9i$+ a%"i&in %#n%i$i'i$! 1#%"#iall! a%%oia$#( 4i$+ na%al "ol!"%2 Ma! #3"#&i#n# a%$+ma )&om $+# ina%#( %!n$+#%i% o) l#u0o$&i#n#% Hig+#& (o%#% o) a%"i&in Sali!li%m Vomi$ing, $inni$u%, '#&$igo, (#a%#( +#a&ing R#'#&%i*l# *! (uing $+# (o%# V#&! +ig+ (o%#% o) a%"i&in R#%"i&a$o&! al0alo%i% )ollo4#( *! m#$a*oli ai(o%i% 1%ali!la$# aumula$ion2 R#%"i&a$o&! (#"%%ion, (#+!(&a$ion, +!"#&$+#&mia, olla"%#, oma an( (#a$+ A%"i&in C+il(n 4i$+ 'i&al in)#$ion% a a$ ina%#( &i%0 )o& R#!#% %!n(&om# H#"a$i )a$$! (#g#n#&a$ion an( #n#"+alo"a$+! Ma!*# 'alua*l# in $a$ing "#lam"%ia7#lam"%ia in "gnan! Non%#l#$i'# NSAID% Signi)ian$ GI (i%$u&*an#% Lo4#& ini(#n# $+an a%"i&in Ri%0 o) nal (amag# 4i$+ an! NSAID P+#n!l*u$a-on# No$ u%#( +&oniall! Cau%#% a"la%$i an#mia an( ag&anulo!$o%i% CO57/7%#l#$i'# in+i*i$o&% R#(u#( &i%0 o) GI #))#$% Ga%$&i ul#&% an( GI *l##(ing Do no$ +a'# an$i"la$#l#$ #))#$ No$ a&(io"&o$#$i'# No$ omm#n(#( in nal (!%)un$ion A$i'# in $+# 0i(n#! C#l#o3i* Sul)onami(# Ma! au%# +!"#&%#n%i$i'i$! DISEASE MODIFYING, SLO.-ACTING ANTIRHEUMATIC DRUGS (DMARDS, SAARDS) Di%#a%#7mo(i)!ing (&ug% H#$#&og#nou% g&ou"% o) ag#n$% An$i7in)lamma$o&! a$ion% in %#'#&al onn#$i'# $i%%u# (i%#a%#% Slo4ing o& #'#n '#&%al o) oin$ (amag# E))#$ n#'#& %##n in NSAID% Slo47a$ing 4##0% o& mon$+% )o& *#n#)i$% $o *#om# a""an$ Co&$io%$#&oi(% An$i7in)lamma$o&! (&ug% 4i$+ an in$#&m#(ia$# &a$# o) a$ion Slo4#& $+an NSAID% *u$ )a%$#& $+an $+# o$+#& DMARD% Too $o3i )o& &ou$in# +&oni u%# T#m"o&a&! on$&ol o) %#'# #3a#&*a$ion% an( long $#&m u%# in "a$i#n$% 4i$+ %#'# (i%#a%# no$ on$&oll#( *! o$+#& ag#n$% M#$+o$a$# 6%$ +oi# $o $a$ &+#uma$oi( a&$+&i$i% 1RA2
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U%#( in @< o) "a$i#n$% A$i'# in lo4#& (o%#% $+an $+o%# n##(#( in an#& +#mo$+#&a"!
MOA •
In+i*i$ion o) aminoimi(a-ol#a&*o3i(# &i*onul#o$i(# 1AICAR2 $&an%)o&m!la%# an( $+!mi(!la$# %!n$+#$a%# 4i$+ %#on(a&! #))#$% on "ol!mo&"+onul#a& +#mo$a3i%
Ph!rm!$%i"eti$s >@< a*%o&*#( a)$#& o&al a(mini%$&a$ion M#$a*oli-#( $o l#%% a$i'# +!(&o3!la$#( m#$a*oli$# Hal)7li)# 7: +, ma! %$a! a% long a% / + Con#n$&a$ion i% ina%#( in $+# "%#n# o) +!(&o3!+lo&o=uin# P&ini"all! #3$#( in $+# u&in#, @< in $+# *il# 6?7/? mg 4##0l!7@7? mg 4##0l! D#a%#% $+# a""#a&an# o) n#4 l#%ion% A#erse e++e$ts Nau%#a an( muo%al ul#&% a mo%$ ommon P&og%%i'# (o%# la$#( +#"a$o$o3ii$! 1#n-!m# #l#'a$ion2, i&&+o%i% i% &a Ra +!"#&%#n%i$i'i$! a$ion lung a$ion 4i$+ au$# %+o&$n#%% o) *a$+ Ini(#n# o) GI an( li'#& )un$ion a*no&mali$i#% an *# (u#( 4i$+ $+# u%# o) l#uo'o&in / + a)$#& #a+ 4##0l! (o%# o& *! $+# u%# o) (ail! )oli ai( CI in "gnan! C+lo&am*uil MOA !"# h!rm!$%i"eti$s T+&oug+ i$% m#$a*oli$#, "+#n!la#$i ai( mu%$a&(, &o%%7lin0% DNA "'#n$ing #ll "lia$ion >@< *ioa'aila*ili$! Com"l#$#l! m#$a*oli-#( 4i$+ #3$ion om"l#$#( in / + A#erse e++e$ts Do%# la$#( *on# ma&&o4 %u""%%ion i% mo%$ ommon In)#&$ili$! 4i$+ a-oo%"#&mia an( am#no&&+#a Ri%0 on n#o"la%ia i% ina%#(, $#n)ol( )o& l#u0#mia a)$#& !#a&% o) u%# C!lo"+o%"+ami(# MOA Mao& a$i'# m#$a*oli$# "+o%"+o&ami(# mu%$a&(, &o%%7lin0% DNA $o "'#n$ #ll "lia$ion A$i'# again%$ RA 4+#n gi'#n o&all! a$ /mg0g( A#erse e++e$ts Do%# la$#( in)#&$ili$! in *o$+ m#n an( 4om#n on# ma&&o4 %u""%%ion Alo"#ia H#mo&&+agi !%$i$i%, &al! *la((#& CA C!lo%"o&in# MOA In+i*i$% IL76 an( IL7/ #"$o& "&o(u$ion an( %#on(a&il! in+i*i$% ma&o"+ag#7T #ll in$#&a$ion an( T #ll %"on%i'#n#%% Ph!rm!$%i"eti$s A*%o&"$ion i% inom"l#$# an( #&&a$i G&a"#)&ui$ ui# ina%#% i$% *ioa'aila*ili$! *! /< M#$a*oli-#( *! CYPA an( %u*#$#( $o a lo$ o) (&ug in$#&a$ion% 1DI2 R#$a&(% )o&ma$ion o) n#4 *on! #&o%ion% A#erse e++e$ts N#"+&o$o3i To3ii$! i% ina%#( *! DI 4i$+ (il$ia-#m, "o$a%%ium7%"a&ing (iu$i% H!"#&$#n%ion, +!"#&0al#mia, +#"a$o$o3ii$!, gingi'al +!"#&"la%ia, +i&%u$i%m A-a$+io"&in# MOA Mao& m#$a*oli$# 7$+ioguanin# %u""%%#% ino%ini ai( %!n$+#%i%, an( T #ll )un$ion, immunoglo*ulin "&o(u$ion an( IL7/ %#$ion Ph!rm!$%i"eti$s Ra"i( m#$a*oli-#&% l#a& $+# (&ug $im#% mo &a"i(l! $+an %lo4 m#$a*oli-#&% A#erse e++e$ts
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on# ma&&o4 %u""%%ion GI (i%$u&*an#% Ina%# in in)#$ion &i%0 L!m"+oma% ma! ina%# F#'#&, &a%+, +#"a$o$o3ii$! %ignal all#&gi a$ion
M!o"+#nola$# mo)#$il No 4#ll on$&oll#( (a$a ga&(ing i$% #))ia! in RA C+lo&o=uin# an( +!(&o3!+lo&o=uin# MOA U%#( mainl! in mala&ia an( in &+#uma$i (i%#a%# M#+ani%m in RA i% unl#a& Su""%%ion o) T l!m"+o!$# %"on%#% $o mi$og#n D#a%#( l#u0o!$# +#mo$a3i% S$a*ili-a$ion o) l!%o%omal #n-!m#% In+i*i$ion o) RNA an( DNA %!n$+#%i% T&a""ing o) )# &a(ial% Ph!rm!$%i"eti$s Ra"i(l! a*%o&*#(, ?@< "&o$#in7*oun( E3$#n%i'#l! $i%%u# *oun( "a&$iula&l! in m#lanin7on$aining $i%%u# li0# $+# #!#% D#amina$#( in $+# li'#& Hal)7li)# o) u" $o ? (a!% I"#i$!ti%"s A""&o'#( )o& RA *u$ a no$ '#&! #))iaiou% No #'i(#n# %+o4 $+a$ $+#! im"&o'# *on! (amag# U%uall! $a0#% 7 mon$+% $o o*$ain %ul$% A#erse e++e$ts Oula& $o3ii$! ma! ou& a$ (o%#% ga$#& $+an /?@ mg( +lo&o=uin# an( . mg0g( )o& +!(&o3!+lo&o=uin# O"+$+almi moni$o&ing #'#&! 76/ mon$+% D!%"#"%ia, nau%#a, 'omi$ing, a*(ominal "ain, &a%+#% an( nig+$ma% Sa)# in "gnan! Gol( U%#( in $+# 6:@%, *u$ *#au%# o) $+#i& $o3ii$!, $+#! a in)=u#n$l! u%#( $o(a! In$&amu%ula& )o&mula$ion% 1on$ain% ?@< gol(2 Au&o$+iomala$# Au&o$+iogluo%# O&al )o&mula$ion 1on$ain% /:< gol(2 Au&ano)in MOA Main MOA Al$#&% $+# mo&"+olog! an( )un$ional a"a*ili$i#% o) +uman ma&o"+ag#% %ul$ing $o mono!$# +#mo$a$i )a$o&76, IL7; IL76*#$a an( 'a%ula& #n(o$+#lial g&o4$+ )a$o& a in+i*i$#( IM gol( om"oun(% Al$#& l!%o%omal #n-!m# a$i'i$!, (u# +i%$amin# l#a%#, ina$i'a$# om"l#m#n$ 6 an( %u""%% "+ago!$i a$i'i$! o) PMN O&al gol( om"oun(% In+i*i$ l#a%# o) "&o%$aglan(in E/ an( l#u0o$&i#n# Ph!rm!$%i"eti$s Hig+ *ioa'aila*ili$! a)$#& IM a(mini%$&a$ion Con#n$&a$#% in $+# %!no'ial m#m*&an#%, li'#&, 0i(n#!, %"l##n, l!m"+ no(#%, an( *on# ma&&o4 On# mon$+ a)$#& IM in#$ion, >?7;@< o) $+# (&ug i% #limina$#( )&om $+# %#&um To$al *o(! +al)7li)# i% a""&o3ima$#l! 6 !#a& O&al gol( om"oun( i% /?< *ioa'aila*l# E3$#( < in $+# u&in# an( < 'ia $+# )##% No o&la$ion *#$4##n %#&um gol( on#n$&a$ion an( #i$+#& #))ia! an( $o3ii$! E))#$i'# )o& a$i'# &+#uma$oi( a&$+&i$i% Slo4% &a(iologi "&og%%ion o) $+# (i%#a%#
7
In$&amu%ula& gol( i% gi'#n a% $#%$ (o%# o) ?7/? mg $+#n a% ?@ mg 4##0l! )o& /@ 4##0% A#erse e++e$ts P&u&i$i %0in &a%+#% in 6?7/@< 4i$+ #o%ino"+ilia S$oma$i$i% an( m#$alli $a%$# in $+# mou$+ i% ommon T+&om*o!$o"#nia, l#uo"#nia an( "an!$o"#nia in 676@< A"la%$i an#mia i% &a *u$ )a$al @7@< (i%on$inu# $+#&a"! in a !#a& P#niillamin# M#$a*oli$# o) "#niillin D i%om#& i% u%#( $o $a$ RA Ral! u%#( $o(a! *#au%# o) $o3ii$! Sul)a%ala-in# MOA M#$a*oli-#( $o %ul)a"!&i(in# an( ?7amino%ali!li ai( Sul)a"!&i(in# i% $+# a$i'# moi#$! in $a$ing RA Ph!rm!$%i"eti$s 6@7/@< i% a*%o&*#( a)$#& o&al a(mini%$&a$ion F&a$ion un(#&go#% #n$#&o+#"a$i i&ula$ion 4+#n in$#%$inal )lo&a li*#&a$#% i$% m#$a*oli$#% Hal)7li)# o) 76> + Ini$iall! u%#( )o& in)lamma$o&! *o4#l (i%#a%# E))#$i'# )o& a$i'# &+#uma$oi( a&$+&i$i% Slo4% &a(iologi "&og%%ion o) $+# (i%#a%# A#erse e++e$ts Nau%#a, 'omi$ing, +#a(a+# an( &a%+ a ommon H#mol!$i an#mia an( m#$+#moglo*in#mia i% &a Pulmona&! $o3ii$! R#'#&%i*l# in)#&$ili$! in mal#% No$ $#&a$og#ni TNF77lo0ing Ag#n$% C!$o0in#% C#n$&al &ol# in immun# %"on%# an( RA TNF7 a""#a&% $o *# $+# +#a&$ o) $+# in)lamma$o&! "&o#%% A))#$% #llula& )un$ion 'ia a$i'a$ion o) TNF #"$o&% A(mini%$#( %olu*l# TNF #"$o&% *! om*ining 4i$+ %olu*l# TNF7 an in+i*i$ #))#$% o) #n(og#nou% !$o0in#% (&ug% in$#&)#&ing 4i$+ TNF7 a a""&o'#( )o& $a$m#n$ o) RA 6. A(alimuma* Full! +uman IgG6 an$i7TNF monolonal an$i*o(! Do4n gula$#% ma&o"+ag# an( T #ll )un$ion Gi'#n %u*u$an#ou%l!, +al)7li)# o) 6@7/@ (a!% E))#$i'# a% mono$+#&a"! an( in om*ina$ion 4i$+ m#$+o$a$# an( o$+#& DMARDS Cl#a&an# i% (#a%#( *! @< in $+# "%#n# o) m#$+o$a$# Ri%0 o) ma&o"+ag#7(#"#n(#n$ in)#$ion 1T an( o$+#& o""o&$uni%$i in)#$ion%2 i% ina%#( No ina%#( ini(#n# o) %oli( malignani#% /. In)li3ima* C+im#&i 1 /?< mou%#, >?< +uman2 Sam# MOA a% a(alimuma* Gi'#n IV, la$ion%+i" *#$4##n %#&um on#n$&a$ion an( #))#$ Hal)7li)# o) :76/ (a!% Conu&n$ $+#&a"! 4i$+ m#$+o$a$# R#(u#% $+# "'al#n# o) an$i+im#&i an$i*o(i#% D#a%#% $+# &a$# o) )o&ma$ion o) n#4 #&o%ion% mo $+an m#$+o$a$# alon# U""#& %"i&a$o&! $&a$ in)#$ion, nau%#a, +#a(a+#, %inu%i$i% &a%+ an( oug+ a ommon Ri%0 o) ma&o"+ag#7(#"#n(#n$ in)#$ion 1T an( o$+#& o""o&$uni%$i in)#$ion%2 i% ina%#( No ina%#( ini(#n# o) %oli( malignani#% . E$an#&#"$ R#om*inan$ )u%ion "&o$#in om"&i%ing /TNF #"$o&% lin0#( $o immunoglo*ulin A$% a% a (#o! (#a%ing $+# #llula& a$ion% o) TNF7
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Gi'#n %u*u$an#ou%l!, a*%o&*#( %lo4l! 4i$+ "#a0 on#n$&a$ion a)$#& >/ +, +al)7li)# o) .? (a!% Ini(#n# o) a$i'a$ion o) la$#n$ T i% num#&iall! *u$ no$ %$a$i%$iall! lo4#& No ina%#( ini(#n# o) %oli( malignani#% A*a$a#"$ Co%$imula$ion mo(ula$o& $+a$ in+i*i$% a$i'a$ion o) T #ll% Gi'#n a% IV in)u%ion in "a$i#n$% 4+o +a'# +a( an ina(#=ua$# %"on%# $o DMARDS o& TNF an$agoni%$% Ina%#( u""#& %"i&a$o&! $&a$ in)#$ion No$ u%#( in om*ina$ion 4i$+ TNF an$agoni%$ Ri$u3ima* C+im#&i monolonal an$i*o(! $a&g#$ing #ll% U%#( )o& RA )&a$o&! $o an$iTNF ag#n$% Gi'#n a% IV in)u%ion, an *# om*in#( 4i$+ m#$+o$a$# L#)lunomi(# P&o(&ug $+a$ i% &a"i(l! m#$a*oli-#( $o a om"oun( $+a$ in+i*i$% (i+!(&oo&o$a$# (#+!(&og#na%# En-!m# =ui( *! a$i'a$#( l!m"+o!$#% )o& $+# %!n$+#%i% o) "!&imi(in#% $+a$ a n##(#( )o& RNA %!n$+#%i% R#%ul$% in #ll !l# a&%$ C+ol#%$!&amin# ina%#% l#a&an# o) $+# (&ug *! ?@< A% #))#$i'# a% m#$+o$a$# in RA Com*in#( 4i$+ m#$+o$a$#
A('#&%# #))#$% Dia&&+#a ou& in /?< El#'a$ion o) li'#& #n-!m#% Mil( alo"#ia, 4#ig+$ gain an( ina%# P ALL (i%#a%#7mo(i)!ing ag#n$% an au%# %#'# o& )a$al $o3ii$i#% Ca)ul moni$o&ing o) "a$i#n$% 4+o $a0# $+#%# (&ug% i% man(a$o&!
OTHER ANALGESICS A#$amino"+#n A. Cla%%i)ia$ion an( "&o$o$!"# Onl! o'#&7$+#7oun$#& non7an$i7in)lamma$o&! analg#%i ommonl! a'aila*l# in $+# Uni$#( S$a$#% P+#na#$in To3i "&o(&ug M#$a*oli-#( $o a#$amino"+#n 1%"on%i*l# )o& analg#%i #))#$2 S$ill a'aila*l# in %om# o$+#& oun$&i#% . M#+ani%m o) a$ion A$i'# m#$a*oli$# o) "+#na#$in 9#a0 CO576 an( CO57/ in+i*i$o& in "#&i"+#&al $i%%u#% Aoun$% )o& i$% la0 o) an$i7in)lamma$o&! #))#$ Ma! in+i*i$ a $+i&( #n-!m#, CO57, in $+# CNS C. E))#$% Analg#%i an( an$i"!$i ag#n$ la0ing an$i7in)lamma$o&! o& an$i"la$#l#$ #))#$% D. P+a&mao0in#$i% an( linial u%# E))#$i'# )o& $+# %am# in(ia$ion% a% in$#&m#(ia$#7(o%# a%"i&in Pa&$iall! m#$a*oli-#( *! $+# li'#& $o ina$i'# %ul)a$# an( gluo&oni(# N-a#$!l7 p7*#n-o=uinon# Mino& *u$ +ig+l! a$i'# m#$a*oli$# To3i $o *o$+ li'#& an( 0i(n#! in +ig+ (o%#% A%"i&in %u*%$i$u$# C+il(n 4i$+ 'i&al in)#$ion% A%"i&in in$ol#&an# 9#ll a*%o&*#( o&all! Hal)7li)# i% /7+ Una))#$#( *! nal )un$ion La0% an$i7in)lamma$o&! #))#$% Do#% no$ a))#$ u&i ai( l#'#l%
9
Can *# u%#( 4i$+ "&o*#n#i( La0% "la$#l#$7in+i*i$ing "&o"#&$i#% U%#)ul )o& mil( $o mo(#&a$# "ain E. To3ii$! N#gligi*l# $o3ii$! Dang#&ou% +#"a$o$o3in 4+#n $a0#n in o'#&(o%# o& *! "a$i#n$% 4i$+ li'#& im"ai&m#n$ P#o"l# 4+o gula&l! on%um# o& mo alo+oli (&in0% "#& (a! a a$ ina%#( &i%0 )o& a#$amino"+#n7in(u#( +#"a$o$o3ii$! R#=ui% o3i(a$ion $o !$o$o3i in$#&m#(ia$#% *! "+a%# I !$o+&om# P?@ #n-!m#% Ou&% i) %u*%$&a$#% )o& "+a%# II onuga$ion a$ion% 1a#$a$# an( gluu&oni(#2 a la0ing. A#$!l!%$#in# Sul)+!(&!l (ono&, ma! *# li)#%a'ing a)$#& an o'#&(o%#
DRUGS USED IN GOUT Gou$ A%%oia$#( 4i$+ ina%#( %#&um on#n$&a$ion% o) u&i ai( Au$# a$$a0% in'ol'# oin$ in)lamma$ion ini$ia$#( *! "i"i$a$ion o) u&i ai( &!%$al% A. Cla%%i)ia$ion an( "&o$o$!"# Ta$m#n$ %$&a$#gi#% R#(uing in)lamma$ion (u&ing au$# a$$a0% Col+iin#%, NSAID%, o& gluoo&$ioi(% A#l#&a$ing nal #3$ion o) u&i ai( 4i$+ u&io%u&i (&ug% P&o*#n#i( o& %ul)in"!&a-on# R#(uing $+# on'#&%ion o) "u&in#% $o u&i ai( *! 3an$+in# o3i(a%# Allo"u&inol . An$i7in)lamma$o&! (&ug% u%#( )o& gou$ In(om#$+ain 6. M#+ani%m E))#$i'# in in+i*i$ing $+# in)lamma$ion o) au$# gou$! a&$+&i$i% R#(u$ion o) "&o%$aglan(in )o&ma$ion an( $+# in+i*i$ion o) &!%$al "+ago!$o%i% *! ma&o"+ag#% In(om#$+ain an( gluoo&$ioi(% /. E))#$% R#(u# $+# %!n$+#%i% o) m#(ia$o&% o) in)lamma$ion *! in)lamma$o&! #ll% in $+# gou$! oin$ . P+a&mao0in#$i% an( linial u%# P)#&( )o& $+# $a$m#n$ o) au$# gou$! a&$+&i$i% O&al "" )o& in(om#$+ain Gluoo&$ioi(% O&al 1"(ni%on#2 IV 1$&iaminolon# a#$oni(#2 . To3ii$! In(om#$+ain R#nal (amag# o& *on# ma&&o4 (#"%%ion S+o&$ ou&%#% o) gluoo&$ioi(% Can au%# *#+a'io&al +ang#% an( im"ai( gluo%# on$&ol Col+iin# 6. M#+ani%m S#l#$i'# in+i*i$o& o) mi&o$u*ul# a%%#m*l! R#(u#% l#u0o!$# mig&a$ion an( "+ago!$o%i% Ma! al%o (u# "&o(u$ion o) l#u0o$&i#n# an( (#a%# )# &a(ial )o&ma$ion /. E))#$% R#a$% 4i$+ $u*ulin an( in$#&)#% 4i$+ mi&o$u*ul# a%%#m*l! Mi$o$i "oi%on . P+a&mao0in#$i% an( linial u%# Mo %"#i)i *u$ "la#( *! NSAID% in $+# $a$m#n$ o) au$# gou$ *#au%# o) (ia&&+#a Lo4#& (o%#% P&o"+!la3i% o) u&n$ #"i%o(#% o) gou$ Manag#m#n$ o) M#(i$#&&an#an )#'#& Di%#a%# o) un0no4n au%#
10
F#'#&, +#"a$i$i%, "#&i$oni$i%, "l#u&i$i%, a&$+&i$i%, an( oa%ionall! am!loi(o%i% A*%o&*#( a(il! a)$#& o&al a(mini%$&a$ion Pan$#&al ""a&a$ion i% no$ omm#n(#( A% li$$l# a% ; mg in / + ma!*# )a$al
.
To3ii$! T&ou*l#%om# (ia&&+#a Can %#'#l! (amag# $+# li'#& an( 0i(n#! Do%ag# mu%$ *# a)ull! limi$#( an( moni$o( O'#&(o%# i% o)$#n )a$al C. U&io%u&i ag#n$% 6. M#+ani%m P&o*#n#i(, %ul)in"!&a-on# O&gani 4#a0 ai(% Com"#$# 4i$+ u&i ai( )o& a*%o&"$ion *! $+# 4#a0 ai( $&an%"o&$ m#+ani%m in $+# "&o3imal $u*ul#% o) $+# 0i(n#! Ma! al%o om"#$# 4i$+ u&i ai( )o& %#$ion *! $+# $u*ul# a$ lo4 (o%#% /. P+a&mao(!nami% A%"i&in in (o%#% o) l#%% $+an /. g (ail! %+oul( no$ *# u%#( )o& analg#%ia in "a$i#n$% 4i$+ gou$ Cau%#% $#n$ion o) u&i ai( *! in+i*i$ing $+# %#$o&! $&an%"o&$#& . E))#$% A$ "&ima&il! in $+# 0i(n#! In+i*i$ $+# %#$ion o) a la&g# num*#& o) o$+#& 4#a0 ai(% 1#.g., "#niillin, m#$+o$a$#2 in a((i$ion $o in+i*i$ing $+# a*%o&"$ion o) $+# u&i ai( . P+a&mao0in#$i% an( linial u%# C+&oni gou$ i% $a$#( o&all! 4i$+ a u&io%u&i ag#n$ o& allo"u&inol A o) no 'alu# in au$# gou$! a&$+&i$i% #%$ 4i$++#l( )o& 67/ 4##0% a)$#& an au$# #"i%o(#
?.
To3ii$! Ma! "i"i$a$# an a$$a0 o) au$# gou$! a&$+&i$i% (u&ing $+# #a&l! "+a%# o) $+#i& a$ion A'oi(#( *! %imul$an#ou%l! a(mini%$#&ing ol+iin#% o& in(om#$+ain Ma! %+a all#&g#nii$! 4i$+ %ul)onami(# (&ug% Diu$i%, an$imi&o*ial%, o&al +!"ogl!#mi (&ug% 9i$+ $+# #n%uing ina%# in u&i ai( #3$ion P(i%"o%i$ion $o )o&ma$ion o) nal %$on#% U&in# 'olum# %+oul( *# main$ain#( a$ +ig+ l#'#l U&in# "H main$ain#( a$ .@ #a&l! in $+# $a$m#n$ *! a(mini%$&a$ion o) an al0ali D. Allo"u&inol Pu&in#% Fo&m#( )&om amino ai(%, )o&ma$# an( a&*on (io3i(# in $+# *o(! $+a$ a no$ ino&"o&a$#( in$o nul#i ai(% Con'#&$#( $o 3an$+in# o& +!"o3an$+in# O3i(i-#( $o u&i ai( 6. M#+ani%m P)#&( an( %$an(a&(7o)7a $+#&a"! )o& gou$ in $+# in$#&&i$ial "#&io( 1*#$4##n au$# #"i%o(#%2 R#(u#% $o$al u&i ai( *o(! *u&(#n *! in+i*i$ing 3an$+in# o3i(a%# /. E))#$% In+i*i$ion o) 3an$+in# o3i(a%# Ina%#% $+# on#n$&a$ion o) $+# mo %olu*l# +!"o3an$+in# an( 3an$+in# D#a%#% $+# on#n$&a$ion o) $+# l#%% %olu*l# u&i ai( L#%% li0#li+oo( o) "i"i$a$ion o) u&i ai( &!%$al% in oin$% an( $i%%u#% . P+a&mao0in#$i% an( linial u%# M#$a*oli-#( *! 3an$+in# o3i(a%# $o allo3an$+in# *u$ $ain% i$% a"ai$! $o in+i*i$ $+# #n-!m# Gi'#n o&al on# (ail! )o& +&oni gou$ A(un$ $o an#& +#mo$+#&a"! Slo4% $+# )o&ma$ion o) u&i ai( )&om "u&in#% l#a%#( *! $+# (#a$+ o) la&g# num*#&% o) n#o"la%$i #ll% . To3ii$! an( (&ug in$#&a$ion% 9i$++#l( 67/ 4##0% a)$#& an au$# #"i%o(# o) gou$! a&$+&i$i%
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Can "i"i$a$# au$# a$$a0% o) gou$ (u&ing $+# #a&l! "+a%# o) $a$m#n$ GI u"%#$, &a%+, an( &al!, "#&i"+#&al n#u&i$i%, 'a%uli$i%, o& *on# ma&&o4 (!%)un$ion, inlu(ing a"la%$i an#mia In+i*i$% $+# m#$a*oli%m o) m#&a"$o"u&in# an( a-a$+io"&in# D&ug% $+a$ (#"#n( on 3an$+in# o3i(a%# )o& #limina$ion E. F#*u3o%$a$ Fi&%$ non"u&in# in+i*i$o& o) 3an$+in# o3i(a%# ;@< a*%o&*#( a)$#& o&al a(mini%$&a$ion All (&ug% an( m#$a*oli$#% a""#a& in $+# u&in# No (o%ag# a(u%$m#n$ =ui( )o& "a$i#n$% 4i$+ nal im"ai&m#n$ Po$#n$ an( %#l#$i'# in+i*i$o& $+a$ (u#% $+# )o&ma$ion o) 3an$+in# an( u&i ai( No o$+#& #n-!m#% in'ol'#( in "u&in# an( "!&imi(in#% m#$a*oli%m i% in+i*i$#( Mo #))#$i'# a$ ;@ o& 6/@ mg $+an $+# %$an(a&( @@ mg (o%# o) allo"u&inol P&o"+!la$i $a$m#n$ 4i$+ ol+iin# o& NSAID% %+oul( %$a&$ a$ $+# *#ginning o) $a$m#n$ $o a'oi( gou$ )la% To3ii$! inlu(#% li'#& )un$ion a*no&mali$i#%, (ia&&+#a, +#a(a+# an( nau%#a 9#ll $ol#&a$#( in "a$i#n$% 4i$+ +i%$o&! o) allo"u&inol in$ol#&an#
F. P#glo$ia%# N#4#%$ u&a$#7lo4#&ing $+#&a"! a""&o'#( )o& $+# $a$m#n$ o) )&a$o&! +&oni gou$ R#om*inan$ mammalian u&ia%# Ra"i(l! a$ing IV (&ug A+i#'#% "#a0 (#lin# o) u&i ai( 4i$+in /7>/+ Hal)7li)# .76.; (a!% U&a$# o3i(a%# on'#&$% u&i ai( $o allan$oin $+a$ an *# #a%il! #3$#( in $+# 0i(n#!% A*%#n$ in +uman% an( %om# +ig+#& "&ima$#% A*l# $o main$ain lo4 u&a$# l#'#l% )o& u" $o /6 (a!% a$ (o%#% 76/ mg IV (o%ing #'#&! / 4##0% A('#&%# #))#$% In)u%ion a$ion an( gou$ )la 1mo%$ ommon2 o N#"+&oli$+ia%i% An#mia o A$+&algia Mu%l# %"a%m o H#a(a+# P#&i"+#&al #(#ma o Nau%#a Dia&&+#a o URTI UTI o H#mol!$i an#mia • • • • • • • • • •
o o
Pa$i#n$% 4i$+ GPD Fo&ma$ion o) +!(&og#n "#&o3i(# *! u&ia%#
An$i*o(! )o&ma$ion o o o
S+o&$#ning o) i&ula$ing +al)7li)# Lo%% o) %"on%# Moni$o& u&i ai( l#'#l%
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