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ver|alax|re

Vecrar|sr ol acl|or
ver|alax|re |s a o|cyc||c arl|depressarl, ard |s usua||y calegor|zed as a serolor|r-rorep|reprr|re reupla|e
|rr|o|lor (3NRl), oul |l ras oeer relerred lo as a serolor|r-rorep|reprr|re-dopar|re reupla|e
|rr|o|lor (3N0Rl).
[58|[59|
ll Wor|s oy o|oc||rg lre lrarsporler reupla|e prole|rs lor |ey reurolrarsr|llers allecl|rg
rood, lrereoy |eav|rg rore acl|ve reurolrarsr|llers |r lre syrapse. Tre reurolrarsr|llers allecled
are serolor|r ard rorep|reprr|re. Add|l|ora||y, |r r|gr doses |l Wea||y |rr|o|ls lre reupla|e ol dopar|re,
[0|
W|lr
recerl ev|derce sroW|rg lral lre rorep|reprr|re lrarsporlera|so lrarsporls sore dopar|re as We||, s|rce dopar|re
|s |racl|valed oy rorep|reprr|re reupla|e |r lre lrorla| corlex, Wr|cr |arge|y |ac|s dopar|re lrarsporlers, lrerelore
ver|alax|re car |rcrease dopar|re reurolrarsr|ss|or |r lr|s parl ol lre ora|r.
[1|[2|
ver|alax|re |rleracls W|lr op|o|d
receplors (ru-, |appa1- |appa3- ard de|la-op|o|d receplor suolypes) as We|| as a|pra2-adrererg|c receplor, ard Was
sroWr lo |rcrease pa|r lrresro|d |r r|ce. wrer r|ce Were lesled W|lr a rolp|ale ara|ges|a reler, oolr ver|alax|re
ard r|rlazap|re |rduced a dose-deperderl, ra|oxore-revers|o|e arl|roc|cepl|ve ellecl lo||oW|rg |p adr|r|slral|or.
Trese l|rd|rgs suggesl ver|alax|re's seer|rg|y super|or ell|cacy |r severe depress|or.

2. Levol|oxac|r
Vecrar|sr ol acl|or
Levol|oxac|r |s a oroad-speclrur arl|o|ol|c lral |s acl|ve aga|rsl oolr 0rar-pos|l|ve ard 0rar-regal|ve oacler|a. ll
lurcl|ors oy |rr|o|l|rg 0NA gyrase, a lype ll lopo|sorerase, ard lopo|sorerase |v,
[9Z|
Wr|cr |s ar erzyre recessary
lo separale rep||caled 0NA, lrereoy |rr|o|l|rg ce|| d|v|s|or.
Tre l|uoroqu|ro|ores |rlerlere W|lr 0NA rep||cal|or oy |rr|o|l|rg ar erzyre corp|ex ca||ed 0NA gyrase. Tr|s car
a|so allecl rarra||ar ce|| rep||cal|or. lr parl|cu|ar, sore corgerers ol lr|s drug lar||y d|sp|ay r|gr acl|v|ly rol or|y
aga|rsl oacler|a| lopo|sorerases oul a|so aga|rsl eu|aryol|c lopo|sorerases, ard are lox|c lo cu|lured rarra||ar
ce||s ard |n v|vo luror rode|s. A|lrougr lre qu|ro|ore |s r|gr|y lox|c lo rarra||ar ce||s |r cu|lure, |ls recrar|sr ol
cylolox|c acl|or |s rol |roWr. 0u|ro|ore-|rduced 0NA darage Was l|rsl reporled |r 198.
Recerl slud|es rave derorslraled a corre|al|or oelWeer rarra||ar ce|| cylolox|c|ly ol lre qu|ro|ores ard lre
|rducl|or ol r|croruc|e|. As sucr sore l|uoroqu|ro|ores ray cause |rjury lo lre crrorosore ol eu|aryol|c ce||s.
Trere corl|rues lo oe deoale as lo Wrelrer or rol lr|s 0NA darage |s lo oe cors|dered ore ol lre recrar|srs ol
acl|or corcerr|rg lre severe ard ror-aoal|rg adverse reacl|ors exper|erced oy sore pal|erls lo||oW|rg
l|uoroqu|ro|ore lrerapy


3. Alorvaslal|r

Vecrar|sr ol acl|or
Va|n arr|o|e. $rar|n
As W|lr olrer slal|rs, alorvaslal|r |s a corpel|l|ve |rr|o|lor ol lV0-CoA reduclase. ur|||e rosl olrers, roWever, |l |s
a corp|ele|y syrlrel|c corpourd. lV0-CoA reduclase cala|yzes lre reducl|or ol3-rydroxy-3-relry|g|ulary|-
coerzyre A (lV0-CoA) lo reva|orale, Wr|cr |s lre rale-||r|l|rg slep |r repal|c cro|eslero| o|osyrlres|s. lrr|o|l|or
ol lre erzyre decreases oe novo cro|eslero| syrlres|s, |rcreas|rg express|or ol |oW-ders|ly ||poprole|r receplors
(L0L receplors) or repalocyles. Tr|s |rcreases L0L upla|e oy lre repalocyles, decreas|rg lre arourl ol L0L-
cro|eslero| |r lre o|ood. L||e olrer slal|rs, alorvaslal|r a|so reduces o|ood |eve|s ol lr|g|ycer|des ard s||grl|y
|rcreases |eve|s ol l0L-cro|eslero|.
lr c||r|ca| lr|a|s, drugs lral o|oc| cro|eslero| upla|e |||e ezel|r|oe coro|re W|lr ard corp|ererl lrose lral o|oc|
o|osyrlres|s |||e alorvaslal|r or s|rvaslal|r |r |oWer|rg cro|eslero| or largel|rg |eve|s ol L0L.
1. Ar|od|p|re
Vecrar|sr ol acl|or
Ar|od|p|re |s a d|rydropyr|d|re ca|c|ur arlagor|sl (ca|c|ur |or arlagor|sl or s|oW-crarre| o|oc|er) lral |rr|o|ls lre
lrarsrerorare |rl|ux ol ca|c|ur |ors |rlo vascu|ar sroolr rusc|e ard card|ac rusc|e. Exper|rerla| dala suggesl
lral ar|od|p|re o|rds lo oolr d|rydropyr|d|re ard rord|rydropyr|d|re o|rd|rg s|les. Tre corlracl||e processes ol
card|ac rusc|e ard vascu|ar sroolr rusc|e are deperderl upor lre rovererl ol exlrace||u|ar ca|c|ur |ors |rlo
lrese ce||s lrrougr spec|l|c |or crarre|s. Ar|od|p|re |rr|o|ls ca|c|ur |or |rl|ux across ce|| rerorares se|ecl|ve|y,
W|lr a grealer ellecl or vascu|ar sroolr rusc|e ce||s lrar or card|ac rusc|e ce||s. Negal|ve |rolrop|c ellecls car oe
delecled |r v|lro oul sucr ellecls rave rol oeer seer |r |rlacl ar|ra|s al lrerapeul|c doses. 3erur ca|c|ur
corcerlral|or |s rol allecled oy ar|od|p|re. w|lr|r lre prys|o|og|c pl rarge, ar|od|p|re |s ar |or|zed corpourd
(pKa=8.), ard |ls ||rel|c |rleracl|or W|lr lre ca|c|ur crarre| receplor |s craracler|zed oy a gradua| rale ol
assoc|al|or ard d|ssoc|al|or W|lr lre receplor o|rd|rg s|le, resu|l|rg |r a gradua| orsel ol ellecl.
Ar|od|p|re |s a per|prera| arler|a| vasod||alor lral acls d|recl|y or vascu|ar sroolr rusc|e lo cause a reducl|or |r
per|prera| vascu|ar res|slarce ard reducl|or |r o|ood pressure.
Tre prec|se recrar|srs oy Wr|cr ar|od|p|re re||eves arg|ra rave rol oeer lu||y de||realed, oul are lrougrl lo
|rc|ude lre lo||oW|rg:
Exerl|ora| arg|ra
lr pal|erls W|lr exerl|ora| arg|ra, ar|od|p|re reduces lre lola| per|prera| res|slarce (aller|oad) aga|rsl
Wr|cr lre rearl Wor|s ard reduces lre rale pressure producl, ard lrus |oWers ryocard|a| oxyger derard,
al ary g|ver |eve| ol exerc|se.
vasospasl|c arg|ra
Ar|od|p|re ras oeer derorslraled lo o|oc| corslr|cl|or ard reslore o|ood l|oW |r cororary arler|es ard
arler|o|es |r resporse lo ca|c|ur, polass|ur ep|reprr|re, serolor|r, ard lrrorooxare A2 ara|og |r
exper|rerla| ar|ra| rode|s ard |r rurar cororary vesse|s |r v|lro. Tr|s |rr|o|l|or ol cororary spasr |s
respors|o|e lor lre ellecl|veress ol ar|od|p|re |r vasospasl|c (Pr|rzrela|'s or var|arl) arg|ra.

5. ver|alax|re
Vecrar|sr ol acl|or
ver|alax|re |s a o|cyc||c arl|depressarl, ard |s usua||y calegor|zed as a serolor|r-rorep|reprr|re reupla|e
|rr|o|lor (3NRl), oul |l ras oeer relerred lo as a serolor|r-rorep|reprr|re-dopar|re reupla|e
|rr|o|lor (3N0Rl).
[58|[59|
ll Wor|s oy o|oc||rg lre lrarsporler reupla|e prole|rs lor |ey reurolrarsr|llers allecl|rg
rood, lrereoy |eav|rg rore acl|ve reurolrarsr|llers |r lre syrapse. Tre reurolrarsr|llers allecled
are serolor|r ard rorep|reprr|re. Add|l|ora||y, |r r|gr doses |l Wea||y |rr|o|ls lre reupla|e ol dopar|re,
[0|
W|lr
recerl ev|derce sroW|rg lral lre rorep|reprr|re lrarsporlera|so lrarsporls sore dopar|re as We||, s|rce dopar|re
|s |racl|valed oy rorep|reprr|re reupla|e |r lre lrorla| corlex, Wr|cr |arge|y |ac|s dopar|re lrarsporlers, lrerelore
ver|alax|re car |rcrease dopar|re reurolrarsr|ss|or |r lr|s parl ol lre ora|r.
[1|[2|
ver|alax|re |rleracls W|lr op|o|d
receplors (ru-, |appa1- |appa3- ard de|la-op|o|d receplor suolypes) as We|| as a|pra2-adrererg|c receplor, ard Was
sroWr lo |rcrease pa|r lrresro|d |r r|ce. wrer r|ce Were lesled W|lr a rolp|ale ara|ges|a reler, oolr ver|alax|re
ard r|rlazap|re |rduced a dose-deperderl, ra|oxore-revers|o|e arl|roc|cepl|ve ellecl lo||oW|rg |p adr|r|slral|or.
Trese l|rd|rgs suggesl ver|alax|re's seer|rg|y super|or ell|cacy |r severe depress|or.
[3|


. Eroxapar|r sod|ur
Vecrar|sr ol acl|or
Eroxapar|r o|rds lo ard acce|erales lre acl|v|ly ol arl|lrroro|r lll. 8y acl|val|rg arl|lrroro|r lll, eroxapar|r
prelererl|a||y polerl|ales lre |rr|o|l|or ol coagu|al|or laclors Xa ard lla. Tre arl|coagu|arl ellecl ol eroxapar|r car
oe d|recl|y corre|aled lo |ls ao|||ly lo |rr|o|l laclor Xa. Faclor Xa cala|yzes lre corvers|or ol prolrroro|r lo lrroro|r,
so eroxapar|r's |rr|o|l|or ol lr|s process resu|ls |r decreased lrroro|r ard u|l|rale|y lre preverl|or ol l|or|r c|ol
lorral|or.

Z. lral|r|o
Vecrar|sr ol acl|or

lral|r|o |s a 2-prery|ar|ropyr|r|d|re der|val|ve lral lurcl|ors as a spec|l|c |rr|o|lor ol a ruroer ol lyros|re ||rase
erzyres. ll occup|es lre % acl|ve s|le, |ead|rg lo a decrease |r acl|v|ly.
Trere are a |arge ruroer ol % erzyres |r lre oody, |rc|ud|rg lre |rsu||r receplor. lral|r|o |s spec|l|c lor
lre % dora|r |rao| (lre Aoe|sor prolo-orcogere), c-||l ard P00F-R (p|ale|el-der|ved groWlr laclor receplor).
lr crror|c rye|ogerous |eu|er|a, lre Pr||ade|pr|a crrorosore |eads lo a lus|or prole|r ol ao| W|lr oor (oreakpo|nr
o|usrer re|on), lerred oor-ao|. As lr|s |s roW a corsl|lul|ve|y acl|ve lyros|re ||rase, |ral|r|o |s used lo decrease oor-
ao| acl|v|ly.
Tre acl|ve s|les ol lyros|re ||rases eacr rave a o|rd|rg s|le lor ATP. Tre erzyral|c acl|v|ly cala|yzed oy a lyros|re
||rase |s lre lrarsler ol lre lerr|ra| prosprale lror ATP lo lyros|re res|dues or |ls suoslrales, a process |roWr as
prole|r lyros|re prosprory|al|or. lral|r|o Wor|s oy o|rd|rg c|ose lo lre ATP o|rd|rg s|le ol oor-ao|, |oc||rg |l |r a
c|osed or se|l-|rr|o|led corlorral|or, ard lrerelore |rr|o|l|rg lre erzyre acl|v|ly ol lre prole|r ser|-
corpel|l|ve|y.
[22|
Tr|s lacl exp|a|rs Wry rary 8CR-A8L rulal|ors car cause res|slarce lo |ral|r|o oy sr|ll|rg |ls
equ|||or|ur loWard lre oper or acl|ve corlorral|or.
[23|

lral|r|o |s qu|le se|ecl|ve lor oor-ao| - |l does a|so |rr|o|l olrer largels rerl|ored aoove (c-||l ard P00F-R), oul ro
olrer |roWr lyros|re ||rases. lral|r|o a|so |rr|o|ls lre ao| prole|r ol ror-carcer ce||s oul ce||s rorra||y rave
add|l|ora| redurdarl lyros|re ||rases Wr|cr a||oW lrer lo corl|rue lo lurcl|or ever |l ao| lyros|re ||rase |s |rr|o|led.
3ore luror ce||s, roWever, rave a deperderce or oor-ao|.
[5|
lrr|o|l|or ol lre oor-ao| lyros|re ||rase a|so sl|ru|ales
|ls erlry |r lo lre ruc|eus, Wrere |l |s urao|e lo perlorr ary ol |ls rorra| arl|-apoplop|c lurcl|ors.
[21|


8. o|p|der
Vecrar|sr ol acl|or
0ue lo |ls se|ecl|ve o|rd|rg, o|p|der ras very Wea| arx|o|yl|c, ryore|axarl, ard arl|corvu|sarl properl|es
oul very slrorg ryprol|c properl|es.
[11|
o|p|der o|rds W|lr r|gr all|r|ly ard acls as a lu|| agor|sl al lre d1-
corla|r|rg 0A8AA receplors, aooul 10-lo|d |oWer all|r|ly lor lrose corla|r|rg lre d2- ard d3-
0A8AA receplorsuour|ls, ard W|lr ro apprec|ao|e all|r|ly lor d5 suour|l-corla|r|rg receplors.
[15|[1|
1 lype
0A8AA receplors are lre d1-corla|r|rg 0A8AA receplors ard 20A8AA receplors are lre d2-, d3-, d1-, d5-,
ard d-corla|r|rg 0A8AA receplors. 1 0A8AA receplors are lourd pr|rar||y |r lre ora|r, Wrereas
2 receplors are lourd pr|rar||y |r lre sp|re. Trus, zo|p|der ras a prelererl|a| o|rd|rg lor lre 0A8AA-
oerzod|azep|re receplor corp|ex |r lre ora|r oul a |oW all|r|ly lor lre 0A8AA-oerzod|azep|re receplor
corp|ex |r lre sp|re.
[1Z|

L||e lre vasl rajor|ly ol oerzod|azep|re-|||e ro|ecu|es, zo|p|der ras ro all|r|ly lor d1 ard d suour|l-
corla|r|rg receplors.
[18|
o|p|der pos|l|ve|y rodu|ales 0A8AAreceplors, |l |s presured oy |rcreas|rg lre
0A8AA receplor corp|exes apparerl all|r|ly lor 0A8A, W|lroul allecl|rg desers|l|zal|or or pea|
currerl.
[19|
o|p|der |rcreases s|oW Wave s|eep ard caused ro ellecl or slage 2 s|eep |r |aooralory lesls.
[50|

A rela-ara|ys|s ol lre rardor|sed corlro||ed c||r|ca| lr|a|s lral corpared oerzod|azep|res aga|rsl -
orus sucr as zo|p|der ras sroWr lral lrere are leW cors|slerl d|llererces oelWeer zo|p|der
ard oerzod|azep|res |r lerrs ol s|eep orsel |alercy, lola| s|eep dural|or, ruroer ol aWa|er|rgs, qua||ly ol
s|eep, adverse everls, lo|erarce, reoourd |rsorr|a, ard dayl|re a|erlress.
[51|


0xa||p|al|r
Vecrar|sr ol acl|or
Tre cylolox|c|ly ol p|al|rur corpourds |s lrougrl lo resu|l lror |rr|o|l|or ol 0NA syrlres|s |r carcer ce||s. lr v|vo
slud|es sroWed lral 0xa||p|al|r ras arl|-luror acl|v|ly aga|rsl co|or carc|rora lrrougr |ls (ror-
largeled) cylolox|c ellecls.
8uprop|or
Vecrar|sr ol acl|or
8uprop|or |s a dopar|re ard rorep|reprr|re reupla|e |rr|o|lor ard re|easer.
[125|
ll |s aooul lW|ce as polerl ar
|rr|o|lor ol dopar|re reupla|e lrar ol rorep|reprr|re reupla|e.
[12|
As ouprop|or |s rap|d|y corverled |r lre oody |rlo
severa| relaoo||les W|lr d|ller|rg acl|v|ly, |ls acl|or carrol oe urderslood W|lroul relererce lo |ls relaoo||sr. Tre
occuparcy ol dopar|re lrarsporler (0AT) oy ouprop|or ard |ls relaoo||les |r lre rurar ora|r as reasured
oy pos|lror er|ss|or lorograpry Was -22 |r ar |rdeperderl sludy
[12Z|
ard 12-35 accord|rg lo 0|axo3r|lrK||re
researcrers.
[128|
8ased or ara|ogy W|lr serolor|r reupla|e |rr|o|lors, r|grer lrar 50 |rr|o|l|or ol 0AT Wou|d oe
reeded lor lre dopar|re reupla|e recrar|sr lo oe a rajor recrar|sr ol lre drug's acl|or. 8y corlrasl,
approx|rale|y 5 occuparcy or grealer ol 0AT |s requ|red lo acr|eve eupror|a ard reacr aouse
polerl|a|.
[129|
loWever recerl researcr |rd|cales lral dopar|re |s |racl|valed oy rorep|reprr|re reupla|e |r lre
lrorla| corlex, Wr|cr |arge|y |ac|s dopar|re lrarsporlers, lrerelore ouprop|or car |rcrease dopar|re
reurolrarsr|ss|or |r lr|s parl ol lre ora|r, ard lr|s ray oe ore poss|o|e exp|aral|or lor ary add|l|ora| dopar|rerg|c
ellecls.
[130|
8uprop|or does rol |rr|o|l roroar|re ox|dase or serolor|r reupla|e. loWever, |l ras oeer sroWr lo
|rd|recl|y errarce lre l|r|rg ol serolorerg|c reurors, v|a acl|val|or ol doWrslrear rorep|reprr|re l|oW. 8uprop|or
ras a|so oeer sroWr lo acl as a rorcorpel|l|ve r|col|r|c arlagor|sl.
[125|
Tre degree ol |rr|o|l|or ol d3p1 receplors
corre|ales We|| W|lr lre decrease |r se|l-adr|r|slral|or ol rorpr|re ard relrarprelar|re |r rals,
[131|
ard ray oe
re|evarl lo lre ellecl ol ouprop|or or r|col|re add|cl|or. Tre drug |s supp||ed as aracer|c r|xlure, ard lre acl|v|l|es
ol lre |rd|v|dua| erarl|orers Were rol lourd lo d|ller.
[132|

TWo 3AR slud|es dale lror 2009
[133|
ard 2010.
[131|

Larolr|g|re
Vecrar|sr ol acl|or
Larolr|g|re |s a reroer ol lre sod|ur crarre| o|oc||rg c|ass ol arl|ep||epl|c drugs.
[18|
Ear|y slud|es ol |arolr|g|re's
recrar|sr ol acl|or exar|red |ls ellecls or lre re|ease ol erdogerous ar|ro ac|ds lror ral cereora| corlex s||ces |r
v|lro. As |s lre case lor arl|ep||epl|c drugs lral acl or vo|lage-deperderl sod|ur crarre|s, |arolr|g|re |rr|o|led lre
re|ease ol g|ularale ard asparlale evo|ed oy lre sod|ur-crarre| acl|valor veralr|re ard Was |ess ellecl|ve |r lre
|rr|o|l|or ol acely|cro||re or 0A8A re|ease. Al r|gr corcerlral|ors, |l rad ro ellecl or sporlareous or polass|ur
evo|ed ar|ro ac|d re|ease. Trese slud|es suggesled lral |arolr|g|re acls presyrapl|ca||y or vo|lage-galed sod|ur
crarre|s lo decrease g|ularale re|ease. 3evera| e|eclroprys|o|og|ca| slud|es rave |rvesl|galed lre ellecls ol
|arolr|g|re or vo|lage-deperderl sod|ur crarre|s. For exarp|e, |arolr|g|re o|oc|ed susla|red repel|l|ve l|r|rg |r
cu|lured rouse sp|ra| cord reurors |r a corcerlral|or-deperderl rarrer al corcerlral|ors lrerapeul|c |r lre
lrealrerl ol rurar se|zures. lr cu|lured r|ppocarpa| reurors, |arolr|g|re reduced sod|ur currerls |r a vo|lage-
deperderl rarrer, ard al depo|ar|zed polerl|a|s sroWed a sra|| lrequercy-deperderl |rr|o|l|or. Trese ard a
var|ely ol olrer resu|ls |rd|cale lral lre arl|ep||epl|c ellecl ol |arolr|g|re, |||e lral ol prerylo|r ard caroarazep|re, |s
al |easl |r parl due lo use- ard vo|lage-deperderl rodu|al|or ol lasl vo|lage-deperderl sod|ur currerls. loWever,
|arolr|g|re ras a oroader c||r|ca| speclrur ol acl|v|ly lrar prerylo|r ard caroarazep|re ard |s recogr|zed lo oe
prolecl|ve aga|rsl gerera||zed aoserce ep||epsy ard olrer gerera||zed ep||epsy syrdrores, |rc|ud|rg pr|rary
gerera||zed lor|c-c|or|c se|zures, juver||e ryoc|or|c ep||epsy, ard Lerrox-0aslaul syrdrore. Tre oas|s lor lre
oroader speclrur ol acl|v|ly ol |arolr|g|re |s ur|roWr, oul cou|d re|ale lo acl|ors ol lre drug or vo|lage-acl|valed
ca|c|ur crarre|s. Larolr|g|re o|oc|s T-lype ca|c|ur crarre|s Wea||y, |l al a||. loWever, |l does |rr|o|l ral|ve ard
recoro|rarl r|gr-vo|lage-acl|valed ca|c|ur crarre|s (N- ard P/0/R-lypes) al lrerapeul|c corcerlral|ors. wrelrer
lr|s acl|v|ly or ca|c|ur crarre|s accourls lor |arolr|g|re's oroader c||r|ca| speclrur ol acl|v|ly |r corpar|sor W|lr
prerylo|r ard caroarazep|re rera|rs lo oe delerr|red.
va|ac|c|ov|r
Hechan|sm of act|on
va|ac|c|ov|r |s a prodrug, ar esler|l|ed vers|or ol ac|c|ov|r lral ras grealer ora| o|oava||ao|||ly (aooul 55) lrar
ac|c|ov|r (10-20). ll |s corverled oy eslerases lo lre acl|ve drug ac|c|ov|r, as We|| as lre ar|ro ac|d va||re,
v|a repal|c l|rsl-pass relaoo||sr. Acyc|ov|r |s se|ecl|ve|y corverled |rlo a roroprosprale lorr oy v|ra| lryr|d|re
||rase, Wr|cr |s lar rore ellecl|ve (3000 l|res) |r prosprory|al|or lrar ce||u|ar lryr|d|re ||rase. 3uosequerl|y, lre
roroprosprale lorr |s lurlrer prosprory|aled |rlo lre acl|ve lr|prosprale lorr, ac|c|o-0TP, oy ce||u|ar ||rases.
Ac|c|o-0TP |s a very polerl |rr|o|lor ol v|ra| 0NA po|yrerase; |l ras approx|rale|y 100 l|res r|grer all|r|ly lo v|ra|
lrar ce||u|ar po|yrerase. lls roroprosprale lorr a|so |rcorporales |rlo lre v|ra| 0NA, resu|l|rg |r cra|r lerr|ral|or.
ll ras a|so oeer sroWr lral lre v|ra| erzyres carrol rerove ac|c|o-0VP lror lre cra|r, Wr|cr resu|ls |r |rr|o|l|or
ol lurlrer acl|v|ly ol 0NA po|yrerase. Ac|c|o-0TP |s la|r|y rap|d|y relaoo||sed W|lr|r lre ce||, poss|o|y oy
ce||u|ar prospralases.

Ferlary|
Vecrar|sr ol acl|or
Ferlary| prov|des sore ol lre ellecls lyp|ca| ol olrer op|o|ds lrrougr |ls agor|sr ol lre op|o|d receplors. lls slrorg
polercy |r re|al|or lo lral ol rorpr|re |s |arge|y due lo |ls r|gr ||popr|||c|ly. 8ecause ol lr|s, |l car rore eas||y
perelrale lre CN3.
[18|

Ve|ox|car
Vecrar|sr ol acl|or
Ve|ox|car |rr|o|ls cyc|ooxygerase (C0X), lre erzyre respors|o|e lor corverl|rg aracr|dor|c ac|d |rlo proslag|ard|r
l2lre l|rsl slep |r lre syrlres|s ol proslag|ard|rs, Wr|cr are red|alors ol |rl|arral|or. Ve|ox|car ras oeer
sroWr, espec|a||y al |ls |oW lrerapeul|c dose, se|ecl|ve|y lo |rr|o|l C0X-2 over C0X-1.
[2|

Ve|ox|car corcerlral|ors |r syrov|a| l|u|d rarge lror 10 lo 50 ol lrose |r p|asra. Tre lree lracl|or |r syrov|a|
l|u|d |s 2.5 l|res r|grer lrar |r p|asra, due lo lre |oWer a|our|r corlerl |r syrov|a| l|u|d as corpared lo p|asra.
Tre s|gr|l|carce ol lr|s perelral|or |s ur|roWr,
[1|
oul |l ray accourl lor lre lacl lral |l perlorrs excepl|ora||y We|| |r
lrealrerl ol arlrr|l|s |r ar|ra| rode|s.

C|ar|lrroryc|r
Vecrar|sr ol acl|or
C|ar|lrroryc|r preverls oacler|a lror groW|rg oy |rlerler|rg W|lr lre|r prole|r syrlres|s. C|ar|lrroryc|r o|rds lo lre
suour|l 503 ol lre oacler|a| r|oosoreard lrus |rr|o|ls lre lrars|al|or ol pepl|des. C|ar|lrroryc|r ras s|r||ar
arl|r|croo|a| speclrur as erylrroryc|r oul |s rore ellecl|ve aga|rsl cerla|r grar-regal|ve oacler|a,
parl|cu|ar|y e|one||a pneumopn||a. 8es|des lr|s oacler|oslal|c ellecl, c|ar|lrroryc|r a|so ras oacler|c|da| ellecl or
cerla|r slra|rs sucr as laemopn||us |nl|uenzae, $rreprooooous pneumon|ae ard he|sser|a onorrnoeae.

8oserlar
Vecrar|sr ol acl|or
8oserlar |s a corpel|l|ve arlagor|sl ol erdolre||r-1 al lre erdolre||r-A (ET-A) ard erdolre||r-8 (ET-8) receplors.
urder rorra| cord|l|ors, erdolre||r-1 o|rd|rg ol ET-A or ET-8 receplors causes pu|rorary vasocorslr|cl|or. 8y
o|oc||rg lr|s |rleracl|or, ooserlar decreases pu|rorary vascu|ar res|slarce. 8oserlar ras a s||grl|y r|grer all|r|ly
lor ET-A lrar ET-8.
0|c|olerac
Vecrar|sr ol acl|or
Tre exacl recrar|sr ol acl|or |s rol erl|re|y |roWr, oul |l |s lrougrl lral lre pr|rary recrar|sr respors|o|e lor
|ls arl|-|rl|arralory, arl|pyrel|c, ard ara|ges|c acl|or |s |rr|o|l|or ol proslag|ard|rsyrlres|s oy |rr|o|l|or
ol cyc|ooxygerase (C0X). ll a|so appears lo exr|o|l oacler|oslal|c acl|v|ly oy |rr|o|l|rg oacler|a| 0NA syrlres|s.
[1|

lrr|o|l|or ol C0X a|so decreases proslag|ard|rs |r lre ep|lre||ur ol lre sloracr, ra||rg |l rore sers|l|ve lo
corros|or oy gaslr|c ac|d.
[o|rar|on neeoeo|
Tr|s |s a|so lre ra|r s|de-ellecl ol d|c|olerac. 0|c|olerac ras a |oW lo roderale
prelererce lo o|oc| lre C0X2-|soerzyre (approx|rale|y 10-lo|d) ard |s sa|d lo rave, lrerelore, a soreWral |oWer
|rc|derce ol gaslro|rlesl|ra| corp|a|rls lrar roled W|lr |rdorelrac|r ard asp|r|r.
[o|rar|on neeoeo|

Tre acl|or ol ore s|rg|e dose |s rucr |orger ( lo 8 rours) lrar lre very srorl ra|l-||le lral lre drug |rd|cales.
[o|rar|on
neeoeo|
Tr|s cou|d oe parl|y oecause |l pers|sls lor over 11 rours |r syrov|a| l|u|ds.
[1Z|

0|c|olerac ray a|so oe a ur|que reroer ol lre N3Al0s. Trere |s sore ev|derce lral d|c|olerac |rr|o|ls
lre ||poxygerase palrWays,
[o|rar|on neeoeo|
lrus reduc|rg lorral|or ol lre |eu|olr|eres (a|so pro-|rl|arralory aulaco|ds).
Trere |s a|so specu|al|or
[oy unom?|
lral d|c|olerac ray |rr|o|l prospro||pase A2 as parl ol |ls recrar|sr ol acl|or.
Trese add|l|ora| acl|ors ray exp|a|r lre r|gr polercy ol d|c|olerac - |l |s lre rosl polerl N3Al0 or a oroad
oas|s.{3cro|er. Prarraco|ogy ol 0|c|olerac 3od|ur. Ar J ol Ved|c|re vo|ure 80 Apr|| 28, 198
Trere are rar|ed d|llererces arorg N3Al0s |r lre|r se|ecl|ve |rr|o|l|or ol lre lWo suolypes ol cyc|o-
oxygerase, C0X-1 ard C0X-2.
[o|rar|on neeoeo|
Vucr prarraceul|ca| drug des|gr ras allerpled lo locus or se|ecl|ve
C0X-2 |rr|o|l|or as a Way lo r|r|r|ze lre gaslro|rlesl|ra| s|de-ellecls ol N3Al0s |||e asp|r|r. lr pracl|ce, use ol
sore C0X-2 |rr|o|lors W|lr lre|r adverse ellecls ras |ed lo rass|ve ruroers ol pal|erl lar||y |aWsu|ls a||eg|rg
Wrorglu| dealr oy rearl allac|, yel olrer s|gr|l|carl|y C0X-se|ecl|ve N3Al0s sucr as d|c|olerac rave oeer We||-
lo|eraled oy rosl ol lre popu|al|or.
[o|rar|on neeoeo|

8es|des lre We||-|roWr ard oller-c|led C0X-|rr|o|l|or, a ruroer ol olrer ro|ecu|ar largels ol d|c|olerac lral cou|d
corlr|oule lo |ls pa|r-re||ev|rg acl|ors rave recerl|y oeer |derl|l|ed. Trese |rc|ude:
8|oc|age ol vo|lage-deperderl sod|ur crarre|s (aller acl|val|or ol lre crarre|, d|c|olerac |rr|o|ls |ls
reacl|val|or a|so |roWr as prase |rr|o|l|or)
[o|rar|on neeoeo|

8|oc|age ol ac|d-sers|rg |or crarre|s (A3lCs)
[o|rar|on neeoeo|

Pos|l|ve a||osler|c rodu|al|or ol KCN0- ard 8K-polass|ur crarre|s (d|c|olerac opers lrese crarre|s, |ead|rg
lo ryperpo|ar|zal|or ol lre ce|| rerorare)
lr|qu|rod
Vecrar|sr ol acl|or
Tre exacl recrar|sr ol acl|or |r Wr|cr |r|qu|rod ard |ls ara|ogs acl|vale lre |rrure sysler |s rol yel |roWr.
Neverlre|ess, |l |s |roWr lral |r|qu|rod acl|vales |rrure ce||s lrrougr lre lo||-|||e receplor Z (TLRZ), corror|y
|rvo|ved |r palroger recogr|l|or.
[5|
Ce||s acl|valed oy |r|qu|rod v|a TLR-Z secrelecylo||res (pr|rar||y |rlerleror-
d (lFN-d), |rler|eu||r- (lL-) ard luror recros|s laclor-d (TNF-d)).
[|
Trere |s ev|derce lral |r|qu|rod, Wrer app||ed
lo s||r, car |ead lo lre acl|val|or ol Largerrars ce||s, Wr|cr suosequerl|y r|grale lo |oca| |yrpr rodes lo acl|vale
lre adapl|ve |rrure sysler.
[Z|
0lrer ce|| lypes acl|valed oy |r|qu|rod |rc|ude ralura| ||||er
ce||s, racroprages ard 8-|yrprocyles.
[Z|

NeW researcr ras sroWr lral |r|qu|rod ras arl|-pro||leral|ve ellecls |r v|lro lral are |rdeperderl ol |rrure sysler
acl|val|or or lurcl|or. lr|qu|rod exerls |ls ellecl oy |rcreas|rg |eve|s ol lre op|o|d groWlr laclor receplor (00Fr).
8|oc||rg 00Fr lurcl|or W|lr s|RNA lecrro|ogy resu|led |r |oss ol ary arl|pro||leral|ve ellecl ol |r|qu|rod.
[8|

a|c|lao|re
Vecrar|sr ol acl|or
a|c|lao|re |s ar ara|og ol pyr|r|d|re. ll |s a der|val|ve ol lre ralura||y ex|sl|rg deoxycyl|d|re, rade oy rep|ac|rg
lre rydroxy| group |r pos|l|or 3' W|lr arydroger.
ll |s prosprory|aled |r T ce||s ard olrer llv largel ce||s |rlo |ls acl|ve lr|prosprale lorr, ddCTP. Tr|s acl|ve
relaoo||le Wor|s as a suoslrale lor llv reverse lrarscr|plase, ard a|so oy |rcorporal|or |rlo lre v|ra| 0NA, rerce
lerr|ral|rg lre cra|r e|orgal|or due lo lre r|ss|rg rydroxy| group. 3|rce za|c|lao|re |s areverse
lrarscr|plase |rr|o|lor |l possess acl|v|ly or|y aga|rsl relrov|ruses.
8ulorpraro|
Vecrar|sr ol acl|or
8ulorpraro| exr|o|ls parl|a| agor|sl ard arlagor|sl acl|v|ly al lre op|o|d receplor ard agor|sl acl|v|ly al lre r op|o|d
receplor.
[2|
3l|ru|al|or ol lrese receplors or cerlra| rervous sysler reurors causes ar
|rlrace||u|ar |rr|o|l|or ol adery|ale cyc|ase, c|os|rg ol |rl|ux rerorare ca|c|ur crarre|s, ard oper|rg ol
rerorare polass|ur crarre|s. Tr|s |eads lo ryperpo|ar|zal|or ol lre ce|| rerorare polerl|a| ard suppress|or ol
acl|or polerl|a| lrarsr|ss|or ol ascerd|rg pa|r palrWays. 8ecause ol |ls r-agor|sl acl|v|ly, al ara|ges|c doses
oulorpraro| |rcreases pu|rorary arler|a| pressure ard card|ac Wor|. Add|l|ora||y, r-agor|sr car cause dyspror|a al
lrerapeul|c or superlrerapeul|c doses; lr|s g|ves oulorpraro| a |oWer polerl|a| lor aouse lrar olrer op|o|d drugs.







10 RIGHTS OF DRUG ADMINISTRATION




1. Right Drug

2. Right Patient

3. Right Dose

4. Right Route

5. Right Time & Frequency

6. Right Documentation

7. Right History and Assessment
(Complete patient drug/relevant history)

8. Drug approach and Right to Refuse

9. Right Drug-Drug Interaction and Evaluation
(drug-food incompatibilities/interaction)

10. Right Education and Information
(Teach pt about the drug he is taking)