Document 9833

Angiotensin-Converting Enzyme Inhibitors (ACEI)
n. ~$oIjnisns:~us:uudsrsin~mOu~7u
riuidupia n.n. 1977 & i n i s ~ u n u u i n ~ u
~lmi%I a h ~ n (beta-sympathetic
i
activity)
Angiotensin Converting Enzyme Inhibitor (ACEI)
u. ~ ~ o i r r s ~ ~ u O n ~ m l u i i ~ n i u nUTQ
nPl"i
Zoui Captopril ~flui~~~snPnun~urin?iu~~u'iPnu
~ni~nnn~no~~uim~~nd~udld~~
n. ~udoini~nmnis~m4untjuu~.1On~iu
Ondelti 118: Cushman 7ud1.1~~1:203 ddlUul6
l h ' i u i l u i 1 7undu ACEI 6 0 n ~ u n u ~ u u i 7 u i o ~ i ~ d?uvo~riolmd?udniu(distal tubule) uni?i?oiid~du
~ ~ ~ u d ~ ~ ~ u o i u i ~ i ~ nu ~~ oo ~~a~~ ~i uu
riou i s niim ~drfludf<niur~wkr~iu$qOnnLLn::
i l i ~ u i r ~ ~ l X i n i s ~ 1 0 1 u i p 11
~ 1nidmkn5nui
u~~i
ilaai?:: ~fluh'u
2 -2
" i ,
Renin ~ f l u ~ o u ' l n ~ ~ ? u ~ ~ v i i u u i
u8duin~u6uinnunu.ruuiuvnu~nn~ori.r~~~n::u'iui
d
k n d i ~ u 1 7 ~ u n i ~ ~ ~ a d j u ~ u i n '1i d Onu
u u ~ ~ ~ u N-terminal decapeptide &iiludqunaq Angiotensin I
unp1?iu<~:l~ndi?iiqu'oddla', u6njiunisanwd
(Ang I) oonqln glycoprotein d ~ u n i iangiotens u ' u s y u ~ ~ ~ ~ n o n 7 u ~ o i i i m ~ u n i ~ ~ a ' u i ~ d n dsinogen
i ? ~ ~ ni :i n n i s a n w w u i i Ang I iiwnriouuinrio
n i s ~ ~ i u u ~ ~ ~ a ~ n i ~ a ~ ~LLR::
~ n Ang
u i n I~ ~
7~~u'u~ll'~~u"on?iu~~nnm
ACE1
i d v ~ dhuui l
"
d
u i m ¶ j i u 6 ~ ~ ~ u a . r i n o ~ ~ u n ~ u u i n u i u iu:~p n~ ~~d~~ u~ u~dm
o l d ~ n O n u ~ ~ u Angiotensin
l n u ~ ~ ~ Conw i ,
verting Enzyme (ACE) ~ d ~ c r i i u u i n u o u r o i d w
lrildnir
Carboxy terminal dipeptide oQn7ln Ang I r i l l 3 6
Angiotensin II (Ang ll) &flu Octopeptide (64fld 1)
5:uu Renin-Angiotensin-Aldosterone(RAA)
ACE Lflu protease Lou~aunddirnunirZinc
Renin flu enzyme d ~ k d ~ l i juxtagloln
x d .
unrii
merular cell ~ o d ~ n n i s u ~ ~ i : ~ ~ m v u ~ u ~ u n i ? : : ~group
d o i ~ UA:%~WU:~I~PULAQRL~~U
ld6o
dase
un:oii7::i4un~nioil
dipeptidyl pepti-
Kininase II
RENM, CONVERTING ENZYME AND VASCULAR TONE
Angiotensin II lunt:ua~ijond?u
uaaw~ijowdouvhiidniu (~du~n$u?l?nduaopILijon
1u$uci?$uodfi?:6uu~d
Renin ndi?;o
Ang II
dauuaddon) $il
Ang
$
11 aiui?naiiqlw'$trri~uod
a
1 d 2 1 "
7:r~uuinuuwou Renin ~ w u u u f i d n i d & i u & ~ n u i
r8u~ijarndou~dunirdd Ang ll u'rnnd&rijunuin
1
u ~ o ~ i n n i ~ i j w u i ~ a n1i wuenqini%:~u
lw
~ n gII
ii~iy~~uocjid~~~oni~u~~K~~
1
l u n t : ~ ~ m ~ ~ o w u j u u o d n i r ~ m ~ i n i ~ a a i u K ~ & ~ u ~ n~Ku~ijofihlfluaow
unir
~ijowiuK?uin
~ m u n t j u ~ n u l ¶ u i ~ s u aminopeptidase
nii
A 1wu7'.
~ n t i 0 ~ f i f i i f I L f Angiotensin
lu
Ill
~ r ~ n i ~ u % ' i n o ~Ang
u o ~II
Angiotensin Ill (Ang Ill) iiqndt4uu%ldai9
Ang II L f l u ~ ? ~ l 6 q l Renin
l l ~ : Angiotensin
~~
$ $ i l f l ~ i i n d j ~ u i i1
i ~ ~ulu~:uullils~fi:ufio~~
~ n u ? ~ R I i u ~ Z d C Ang
u II uin~miiiunuinlunis
A
A
1
A
II .sirh6~fu$uri~uod~¶fiadurn~nd:
r d f i u u ~ ~ d f i ~ n i ~ w u i ~ a i f i25%
n u i ruod
~ u ~Ang II
"
d
~ri?riu
i i r w i z uarns:&roulau'
guanylate cyclase ¶d
A
un: Ang II s r ~ i
uonqin Ang II n ~ u ~ ~ u u o d ~ u n s ' . u a ~ i j o ~ni?:itioqni~Lrfifiiuui~u~qu
~
1
1 .
l l i n v uinflux) Iwuiinis
uRI~i?rl~u~od~liuruo~uopii~
1 i i i j ~ ~ i ~ i i K q u i n r n u ~ ~ ~ ~ f i f i i u u l ~ i ~ a n(calcium
?
&
:
-
-4,
6uLdoqqin
ACE
ijoddui?u~uuinlu~¶fi~~o~L d i j ' ~ ~ L L d f i 4 ~ d 6 d i l ~ n ~ ~ V ' ~~ d? ~u~~du~~¶ If ?i ~ u
A
C i i u n . o ~ ~ n a ~ ~ u u ~muna~uudq:ldnt:{u
Ci~~¶a
wu~du~nuinlusiu~~~ulmrdouaniwlin~ui
l n ~ l a u 'protein kinase Ln: phospholipase $dq:'ld
~'rapl~iu~u~a~n~~d~
1 i l dm
uu
u inui si ua n ~ i
n s : { ~ ~ ~ ? ~ narachidonic
l9
acid lnuululouhu'
a c u a y u i i ACEI a i u i s n ~ a n u ~ n < u i ~ n i t ~ d o
cyclooxygenase viilriiinisah.rais prostaglandin
aniwuod glomeruli ua:fied~uu~nnnfiui[~ld~iu,
I
rbi'uuin$u~~~flunisd~ual~~iinnisrdduu~~da~nulu
nglplaswiidaisdir 1 d'luciiuqin glomeruli 16
4
4.
~:UU~~?I~LLA:URB~L~~A~~~BI~~
1
I.
ua~anisqn~uai9~a~~uun~u~u
uamnndiu~uaisuuvndu~on~ilam~rnd (sodium reabsorption) : Ang ll qrns:{udauuu?nlm
(vascular tone) d a i i u n u i n h 6 ~ i y k n d i ~ 4 i ~ ~ i u n o ~T n u n s ~ v i i l r i ~ ~ m n i s u ~ aldosterone
~ais
viilri~bi'u
I
1
Ang II ~ r v i i ~ r i n 6 1 u ~ u o i S ~ u v o d ~ ~ d u ~ o ~ r i 3 8 nn~iisi nq n ~ u n K u u e ~ l a ~ ~ ~ u l u r i o l n u i?innis
nuu
un~?aiiduinfnuni~naln~de'ld%o
ns:{unisukris norepinephrine
qind~iurJuds:ainP~wi~nipl
1.2 ns:~ufn~nsddo~?u
Ang II i u c d
1.1
Anuiwuii ACEI aiqq:viilrir~ufiuirula~"huudgn
u'~aonuini~violnuin~ulc5
Tnuciiuni.raisldsiu
qinlflln;~~(atrial natriuretic peptide-ANP) Znnid
d
UUd
~ a d ~ ~ : u ~ d s : ~ ~ n C n:fwuii
u u i Ang
1.3 v i i ~ r i ~ ~ n a ~ ~ ~ u ~ i u ~ ~IIi ~i:ns:~ur~unisvii~iuua~s:uuds:aina'nTuui
a~uin~u
I
~ ~ ~ ~ n ~ ~ h ~ ~ n a ~ u p l ~ ~ i i u u n ' ~ e n 6 1 u r u n%uwi~ni~~'iauriiunaln
iSuuunni
4 dsznis Ao
uirlod
5.1 ns:{ulfiunlsu&uod119
norepine2. u ~ d a n i s u u ~ ~ ? n o d u ~ d ~ t W u ~ i 3 a m ~ r m
d
~lnl&u~udniuds:~in%uwi~nZi~
phrine
(vascular growth) qinnisanai wuji Ang 11 1::
5.2 ns:{u~:uuds:aind?un~idiauod
* I d
1
du~ns:{ulriinis~~i~K?,
~ ~ ' s ~ u u i n i n o ~ $ u ~ u o r u nuii~~iuns:urdsraind i ~ ~ s r ~ u P u ~ i ~ n ~ p l u
r i u ? ~ u u a d u ~ d r ~ u d o n v i i 1 r i ~ u i n ~ ~ a d u e o ~ 1 ~ 8 ~ ~ d 5.3 nsr.{ulriinis~bi'uK?~ins:ua
nuunu, ~A'n~dldZn
~ n u ~ ~ a u ~ i ~ i u i iI
nalnu'iliq~:
I
ds:ain3uwirnipls:uii~n~u~aads:ainul
,
,
riiuaisnsr~unis~~3ryuuimil~u&~inu'ra~~u~Co~
5.4 ariuayu, ~a?ulriinisun~nf.rmi
' 1 4
nirlnfnlijan (Platelet-Derived Growth Factor-PDGF)
nodu~on~8~~~~u~u~nuk~in'ln"~unisns
fli
?u alpha-l ~ 6 9
i n i ~ ~ n m a ~ u i u r y u i i n i t f n mACEI
X~u
unnqindrih Ang II oiqq:iiuaia
wisi%uwi~ni~~?u~riun
a i u i s n a ~ o u ~ o ~ ~ n i s u u i m i n n ~ u 4 ~ ~ u ~ ~ s:uudsrrinCmluG
o~d~plu
rwsi:~innisanwwuii ACE niqviilrinismou
u u i m i I r i n A i r 7 n R " ~ ~ u ~ duonqiniufidwuii
n~l~
5.
U R B A L ~ ~ ~
.
ACE1
I
a i u i s n ~ m n i s u u i ~ ? i ? u a d n ~ u ~ u o r i ? ~ ~ ~ aue~uuuns:{us:uuwisi%uwi~nZinlX
?un~
L ~ R I ~ ~ U I ~ L ~ U ? ~ D ~ ~ ' U ~ I ~ R ~ A ?1
IUKU~A~~IA
d A
unmnlm : Ang II i i u n u i n i i ~ l u n i s
%:UU
Renin-Angiotensin ~~%:~UIWBIUB(Tissue
v i i l ~ ~ i i n n i s u n A v ~ ~ ~ X u ~ 8 o n (efferent
u ~ ~ ~ i o o n Renin-Angiotensin)
d
arteriole) uo;l glomeruli adq:viil6usd&nlu2uuniulu
k'ln"ndi?ui~~6?~id~uiiu~nid
e
v
A - I
?nuinnd ACE n1nnuu~uiidniunjuuAliuuonqin
glomeruli dduln$U (intraglomerular hypertension)
f i a d m i u u l ~ o r ~ n n i s ~ d d u u ~ ~ d ~ d ~ ? i u ~ i u 1 9 n 19:~iluuaqin
uni~
ACE i i ' i l d ~ u n s : ~ ~ a ~ E j ooiqq:
~~~~j?
x d
nso.rdiurisuiid 1 ~u6ulnunisrdduurrds;luuu
i~utuunnodACE diiodhLunLundid 1 IXuridnn
iqk l n aund gn<nin:
fnu ACE diiad~ulde
~&auanlw(glomeruloscerotic change) 1 8 4 glomeruli
3
dnruiiuq:ns:{u~riiniqafi~ Ang II d i i u u ~ i d ~ a ~
ue:viilriais$ids:fuau'di~ 1 uadii;lniu ln'uri
& n i l ? (local Ang II) ~~rj?vii~u'~iinues:6u~¶a
fdsiu, ngfm gnnsaduiu glomeruli uhu'unannid
~ ~ H ~ ~ : L Laulocrine
UU
U% paracrine L~~10177:lft~
a
: &qliwurnuluni?:dni)
rlsingnisru$
3.
.r
u u ~ ~ ' i ~ u i n k u ' l i ~ u < u s : u uACE 7uns:~~a~ijon~au
2.
d
ui~niurinwm:na'lnnisoonqnnuo.~ui
nSm'iio&~~nm~innisAnnimi~
1 wu617unis?nwi
rflunisrru'ddiiuula'nluuin~~a: ids:b¶uIunis
m 9 l u ~ u ~ a i i m q d ~ ? u u i nACE1
ju
uAnis?nwiinou
dijuTnidmZjiin Tnuinisrrid~i3u3 n j u rduniaZo
auod (Zom?iuKuTaiindanad) q:im~iu&ufiuWnu
.r
d
msd6unisaniwuodqni ACE is:Ku~uoruouinnii
-I
ns:6uns:uaLijona<uayuii
Renin-Angiotensin
.r 4 2
i
2.1 n j u captopril-like 6 9 ~ 1 1 ~ d a l u l ~
oonqn$nidm&¶5nui'Lm'~au (active form) 'Iuum:
rZu9nir u1dd9u~:~nldiuu~~dadnidLumi-~u~m1
s:iuiuun~uo~uiq:iunuinii~~monisGi~iuno~ ~ X a i s ~ u m i T u ~ a n~'~ i ' l n ~ a ' l r l m " i ) d ~ ~ a : C ~ m
~~~:uaon~ijow~i3uoiiduin
s:uufi?lq
3U
:U
Kallikrein-Kinin I11I::
s:uu
2.2 n j u Pro-drug : ndi?'loK?oiq:
Bradykinin
Kallikrein - Kinin
6 ~A~IU&~<U~~U
41UU eni in-~ngiotensin uin ;dqdi
II q:ri3u$?riu?<u
aiuisnlunisonnqn~ni~~n&~?nui'lm'X~u
kniui
~o~~~a:aiswmiTu'lanT4:pn~uoon~inii~niuni~'lm
i
a i s Kininase
form)
1
K ~ U
ACEI q:iuaGiIfl
Bradykinin p n v i l a l u ~ n ~<ui~4:6iYn~d
d
Bradykinin
.r .iadnq:ddualflnisahd
Prostaglandin
a.r.i-4
r~uuuadnmoGilfluaon~onuuiui?L$uuin<u$uLod
i - .r
q:~<uqdnu
(inactive
uA~~in5uds:niuuir~a:uipnqmiiu~$i~
idq:inis~diuuudadnidLumiTuZjm
ACE ~ ~ u ~ i d u 6 n ~ o r u i u a i ~ns:rra$omu6'
,
9
~ l ~ l u a lBradykinin
s
7flrd~uurflu~isTdsiud'lii
qn$nida%5nu17n
odluqdd'liaiuisniqn$nidm&¶5nui
7flad7uqd'Lnno?wr~uriou im:iqngni~m&a?nui
(active diacid form) Tmuuu?unisrdiuuLLdad6d9u
.r
i"
uinq:finuunmu
i
r4u u i enalapril n n i u ~ $ i k l q :
pnrdiuuri3u enalaprilat ~~aiuisna:aiuldnfiu'lm'
~~a:iqn%nidm&a5nui aiswmiTu'lan'mjndi96d9u
7u~finq:pnu'uoon~inii~niuni~'lm
oiqiuidd9u
% 4 ""
n i ~ s : ~ u f i ~ l ~ ~ ~ ~ : u a o n ~ i j o n k u u n ~ ~ i i n ~ iuni rno oi sn n7i~~ u i n ' l n u i d LLa:r~oiiniqiuidd?uiuLii
v
.r .i
.r .i
uan~nnnuKdndi9ui6oiqq:ijunuinn'di~~n'oua
U1
.-
~uoruoGi7~~iimqn'IfiuC~
ACE ds:siuruoroom'?u
ACE1
2.3
T u ~ A1~
ni31lu'.raiisleii.r 7 uadaindu ACEI
njui'lipnLdiuuudadnidLumi
(non-metabolized) : RiulLodalulsnA:
~ G flipn
l~~
aiuisnu~~non'l~miu6nnm:ni~Tms~afi~ a i u G i ~ i ,' I i < ~ h ~ d ? ~ r d l ~ n ? : l Lu~s:q:'
*
" 4-
Ldiuua~dadnidrumiTuGn7n 1
~mi<u6nwm:n~lnnisoon~n%n~~ui
mdumo
1.
~Adqinniuru'ild
~ ~ u ~ n i ~ ~ n w m : ~ m ~ d a i i d :a i s ~ m 6i ~ u 1 ~ : o o n ~ n $ n i ~ m & a ? n u i ' l ~ n ~ n s ~ ~ ~ a :
r ~ u n i s u i ~ n i u q m s ~ m i nACEI
o ~ upis:¶iin
44
a i u i s n r r i d l X 3 n?uluG Zo
oonqiniidniunidln$duun
lisinopril
A
T n 7 4 ~ f l 4 (sulfhydryl-containing ACEI)
'lm'llriul
Captopril, Zofenoprilat
1.2 n j u ACEI ~ i a i s m i f u o n ? a o d 7 u
ACEI)
" a
rlq?Guui ACEI n l m n i n i s A n w i , 5uirsnd
1.1 n j u ACEI d i a i s a ' ~ l r l ~ a o d 7 u
T P I M ~ ~ J (carboxyl-containing
uilunju6niusn'lo
ds:3n'miw
ua:didiuilfluds:~n~~'lnu i o d ~ i 3 u
i u i n ~ra:~~mnGI'i~niluXiu~n&¶?nui
idq:
uandr~uu~~uu~fl~iium9iu~~mndid
m i u m i ~ i d1i
~XU~~UI
nisdiui ACEI uila'nidmGiin i n i ? a a i o
iunuinlunis?nniu~:~innisAnni
Enalapril, Cilazapril, Lisinopril, Perindopril, Quinapril,
o i l 4 4 ACEI
Ramipril, Benazepril
uK~wuii'lm'uamouauo~piouii~Z
'lX~rri
1.3 n j u ACEI diaisvloavloiaodlu
1.
7dsnm?iuKuT~Gmq~
T n s ~ a h d (phosphoryl-containing ACEI) linriui
2.
7uni9zii?7q9iu
3.
.r
7uni?,w&nKiu~uofi~7qninrijon
(post
Fosinopril
~4nisrlidmiurjnnm:Tns.~afidLmi6 ids:Tua66ou
uin7unisdauFinid~lGiin
failure)
myocardial infarction protection)
(Congestive heart
luls~1mui~aiialnu~~wizoci1~~~1~
4.
L ~ ~ u ~ ~ I ~ I ~ I(diabetic
~ ~ u nephropathy)
~u?~u
uonqin$u'uu6? ujwuii ACEI iusniq6au
uw:n'il6~ii~us~noi1~niuu~iudt:nis
1X~lri
Quinapril
Captopril
Accupril
Carboxyl
Prodrug
aidiiqnd
U1
&nl?h'l
d
[email protected]~<U{U Zinc
Enalapril
Lisinopril
Perindopril
Ramipril
Capoten
Renitec
Zestril
Coversyl
Tritace
lnhibace
Sulfhydry
Carboxyl
Carboxyl
Carboxyl
Carboxyl
CarboxylZinc
Id
llild
Id
IuId
Id
Id
Id
Quinaprilat
-
Enalaprilat
-
Perindoprilat
Ramiprilat
Cilazaprilat
75
60
30
75
50-60
60
RAnio
I~ii
Iuii
Liii
lliii
oonqnf3iId
2.3
3-8
2-4
mdhinuini~gmiuni~ 60
Cilazapril
(%)
L~UD
H
I?
I
U R ~ Y ~ ~ U
Iuii
g d u 35%
91flBIHlP
d
30
uld
2-4
1-2
4-8
3-4
3.1
2
11
12.6
31
17
9
24
10
30
30
('LUU%~)
60
48
10-40
25-50
5-20
10-40
2-8
2.5-10
1.25-5
<iu?un?uiu
1-2
2-4
1-2
1
1
1
i
nniuvuin
735
9
7:14
7;lo
8;13
730
11;16
YLUEL'2RIn
-
oonqn%q.rqn (4'29~4)
A
?ru~n?~a?rn
(au.1
YLUXl??
oonqnd(nu)
~UI~UI
"
(un.)/nk
(liouolul?)
~~ussun?udos:~u~nu'u~u~~om
snqn~no~szuuds:ain6mTuu"naiin-
3uwi~nim nw:snuwLidui~iinqin'uu?unitdiu~?
~oqiiqniu ~ ~ n s z ~ u r j i u o ~ u u ~ u n i ~ n i ~ m w o n ~ u
n. ACEI 1uT~nmiunYuruGmq~
ao&ud14 1 (Neurohormonal Activation - NHA)
1
1
'luni?zdnEiirj? n?iu6'ulsGnq:u$u 3
wnni?:mo~y~u (insulin resistance)
ilqiu ~afiuimslijoniiiuoonqinrr'?'LqLLdw:miq
i~wuLnuolu{d.iuruiuqiu
(aiin~<u<u~u¶iju
:
(stroke volume). ~ ~ f l n l f l 6 ~ V ~ 4 (heart
r r ' ~ ' Lrate)
~
non - insulin dependent) i ~ f l ~ u 1,
l ~ @?Wi?lu
lu
KulwGmqq, {hulsm6?u
u : u 1 1
l L ~ : ~ ~ 4 n * i ~ V ~ ~ L & (peripheral
~ ~ ~ ~ ~ vascun d ? ~ d
ACEI r f l u u i n ~ ~ l u l j i ~ n
u ' i u i l h n i ~ m ~ i i n u i n ~ u k1o un~szqinnioAnui
u
aGuayuiiu16'qnrjiq riiq:iunuinAiK~~.~Iuni~
i n w i l s m r i 7 l ~ u ~ z u w o n ~ i j o n ~ ~ ~uaz/u?o
uo$~~6~
lar resistance)
~nuulniinlsLd~uuLLds~~unidiul
1
~u l i i i ~ r ~ i l u i l q i u ' l n~:n'i'L6~iin~l?iu6'uirLGnp~
3
~ u l n u ~ ~ ~ i ~ ~ ~ ~ ~ ~ ~ i l ~ i u n ( i
-4
~~ond?udwiu~ d n i n ~ z ~ u u d i K ~ ~ i u w n '
catecholamine ~ l n ¶ : ~ u d ¶ : ~ l n
~~us:wir'luuidludon ~$us:6"nsm~?'.p, r6us:~u
%MI~M~~LLA:Y:UU
Renin-Angiotensin Aldosterone
~ i ~ i ~ u ? o n ' i l f i ~ i I m n i ~ : ~ d ~ a r $ u u k&wu
i1~~ijo
.
""
(RAA)
lmu catecholamine qrriiu~joinsinis
rauolun$u{d~u~lnsuu~n'luiuio~i~uflaaia:
*
r6uuod~?i?'L~rrwznisun~n~dniuedtiudomd~udwi~
qduguuudiroi ACEI u1l4rfluuiu'u~rsnuio~fl~ui
1
[email protected] RAA vii'lfiinn
uulu1Zu.r (monotherapy) ~ ~ ~ ? n ~ i f l ? i U ~ U ~ i
nisumniuo~riuGem~inqn~uo~
Ang II wFou6ui
a c i i ~ ' l s i i n i u 4 o 4 i ~ m ~ d i ~ ~ u o ~ n i s l 4ACEI
uin$u
n"lunluqd$u
-
m
4
..I-
f l a s l f l l ~ i ~ u ~ l d ~ d ~ ~ ~ ~ ~ ~ ~ ~ f
4
nisk~ua~~irLwr~nEjolarZuuluii~niu~in~n%uo~
aldosterone nj$u ACE1 ~ d i q n ~ ~ f i m ~ u n l Y ~ f l udi & i u ~ u n i ~~~uluns~~{d~ukiflryuiludo
Ang II i~di~:[email protected]'indni, t n r n i c r u i u ? i u u?isodudionisriin
niwuinoi.ludd ~nurowi:oriidi.~~uni?z~~?iu$u ni?:ldrlumaiiiuukilu~Ejon~~&~
~iu'uflaaia:rrwz~i
~wirn~diu'nlsnsz{uszuu RAA u?oiis:Ku Renin
61uruni!ujriiq:rfluui$u~~sniqzl+nnp1aiu6u
' 1
t%uuwinniidn'i u?oniq:$iniminGomldrf;u.r
lwiinlXz
lm4i~lnu"i~ud~bu'Lnanu'i~dn'i
(unilateral renal
lmu&qldu6'? f l q i u ~ ~ a s ~ : ~ ~ i s ~ i l u
ischemia)
lijonuiwnn?iunidlwiinq.~Cndsrnouhu
2
q i n n i s A n w w u i i ACEI inw'lnlunisam
r w ~,l raoai'i tdu auC?&i Cnqzmou
n ? i u ~ u ~ w i r m ~ & u w i u o ~ i d ~ o n ~ i n i ~ nRM
~ i a s z u u auo~~ouiu'ufla~i~zuiiuihuunwriiuuuinnii
luns:ttarEjontt&? u j o i w z i q n i i a RAA i u ~ d ~ i u m'iuruniriso ACEI
1 A A
~Ejondouuw:luruoruoou 1n " ~ i,i q n i a m n i m k ~ a i s
oil! rdu oiq6ou diqznouauodZdo
norepinephrine ~lndwluds:~ln~uw1Ln'ifl,Amnis
uin'iuruni uruz$fluqdoiq oiqWuiu'uflaai?::
%
Kdazauuodul ~~wzlnEjola~zuulmu~~nlsa51d u u i n i i 1 1 ~ i u q w o
~a1uquusduods:6un~iu~ulwir~:dou,
aldosterone L L A : L ~ U ~ ~ U I O ~ L ~ D ~ I U W ~ U U I ~ L ~ ; U ~ ~ W
2
u i n u u rra:uon?in<
ACE1 ujiqn%6iurou'l-nu'
diunnid u?'ilpllsd
A,
kininase II aduqnsnlalu bradykinin i d n ' l l f i i i
ai~uyodnaiu6u i i ~ f l u a i i m d j u ~ i
'
1
bradykinin f i u u i n u u un:iiqn&uiuuaondomr~u
( l i n s i u a i ~ u q )u7oy'iuqii
2
f l s i r r ~ ~ u d k i h u h ' w1Auri ruiu?iu,
uut¶uKu
IuCulu~Ejomqd,ni?rldrrmar$uun"1, l s ~ l n i ndu6u
'
~ u ~ : ~ : ~ L ~ f l ~ < ACE1
lul
Lu'lullfl~fll~
J
o
~ n w i ~ ~ i u ~ u l n ~ n ~ ~ ~ u r j n ~ r ~ u l f l u u u i n u i ~ q ~ u i nl s f l i i i i ? u ~ ? u r r w : n ? i u ~ n d n i v o d
n i u q z i i d 1 ~~iIm~in~~iuKuliilwirm~~~flu
1
L¶U captopril ?uuuin 150 un.i8?u~u1dn'11filiim
&'
(End organ involvement) rdulnbu~uaa, n h u l u o
oinisu'id~!u~uin uwzu'nqzl4rfluui~u 3 l u p
v
~~l~uuiunzu?'soii?l7?lu
u u u n i s ~ n w i r 0 u & i ~ u u ' (Stepped
u
care therapy)
A
~IAIUI
&~PI?IU~IK~UI~L~UKU
lmu
ad~un'uXquuiu'uflaaiqzn'ouLauorflu$uwn, LLR:
l + u i 6 i u r u m i r f l u i u 2 u ~ ~ ~ ~ n ~ ~ ~ ~ ~ ~ ~i o~w i~z l u ~l d a~ ui ~ri i rn0 u
l 6i o ~ l K 5 u u i u w i u . a ~ n l
lZrr?fi~
ln"uanr6Gm:l+uihi
3 dold d i o i w z r i l u ACEI
d
n a i u a ~ m a n u ~ ~ n i ~ u 3 u ui ~i nu i
u~oui&iu~rnwliiuu
(naonquuiou 1 i a d l u n $ u u i
aiuisnu~uisuil~niu~6iuw:n~du?oa~dn~~
57:
uuiuuwonrEjonrrn~rflud~ulu~)odidlsn'niu
r -2
f l ~ ? f l u ~ u iACEI
i
L ~ U ~ B B I ~ L Z U ~ ~ ~ V U I ~ ~ n'llfi{d?ulfifl?lUhU~~81~~
~IW~A
~ ~ n i w u a d i i ? mu i n n ~ a i u 6 ' u u i ~ a i i n
aiuisnwnn?iu5u~nirmaGmdouu?oprrsddiunwid
~idiu
' l n " u ~ ~ u w : u f i ~ z ~ a " ~ u i ~ ~ ~ ~ ~ u ~ ' l i l ~ n a~i~~ ~i ui uw ~~ ui dl ri i~luwd ~x nr n ? u d ~ n inisnonriiCdniu
u?on?iuqunidrwn'l
~Kuiniuniic~urindsznou~u
ACEI l i i i u w ~ i u l u r r i
u i n G q i s m i ~ q ~ u1
d i Cidiuiun6q n i x
~Zondluaijuuluii~niuana~uaz~iill;lrnr~u.~n'
f
~nld~riluni~z~oi~q::~unisinwifi~iun'ulaG[ilq~
uinrZonld~iu~uinuuoi~qz~iilfiLiimni~:lnq
6quuintju ACE1 'L~LU~I:~U l6LLfi
r;uuwrjuli
niq:iijnisnszius:uu
?&
:
RAA
rrazii
Renin l u ~ i j o n p didlin~::L~umuoiq60uuqu
l m i ~ : i & f i ~ l ~ r o o ' i l ~ n n ' u& i n i s q n
~ U ~ I ~ L ? U Y ~ Y ~ (fixed
~ L ~ cardiac
~ Q P Ioutput)
Q~LL
rm:~ ~
a i ~ r r r : : u + ~ ~ m ~ i u ~ m i u m i ~(ui nXi ~s u
~?uais
' L ~ ~ ~ ~ ~ T ~ . ~ " U I Y U I U U A B B I L ~ B1B I ¶(??~%~dil ~ ~ ~
catecholamine),
rwsie~:~~viilfiGuim~ijom~u~n'~on~in
r ' d
ACEI)
f
ii.~u%G~u
(unriu~d~u<iiln~~u~u"i~r~u~u+oijnis
~ ~ a z ~ u o r u o1
d is?uii~~nuinrijnmldL~u~uinuu
d
; ~ ~ o d ~ A ~ d o m < W ~ ik~adal qr hn d ) u?ojdqu<an
fiuimm~oluoiui~r~6~~dfi~iu6ulaGnujp~o~
ni?zfi~iun'ulaGnqdhunirm~iu2ndnZj
n i ~ ~ u n i l u ~ f i u i ~ ~ u i ~ ~Zo
. ~LUlIUi~n
IU, i i ~ u i ~ d ~
mi<
ACE[
'luuilu~ijonpdiho.~lhkni~inwi
niq:rudi<
--
~nqz~ijuans::nu~unidiLa~aq
Aan4utri
"
--L.
i i u u f i a r i u u nuaonur0uiiu)
jd~uruiu~iu~~uijliai'~duoonni~
I
(microalbuminuria) ~ ~ f l : i j n l f ~ n ~ f i < ~ l l I p
41 ACEI aiuisnilo~~uuionlaoni~riinnis~d~uu-
--
u d a d ~ a o u a n i w a o d ~ (g~omeru~osc~erosis)
~~n'
lnuan
a
L.
u s . ~~u~ glomeruli r i ~ u o n ~ ~ l j w u ~ u u ~ a n p i ~ ~ u p i u
latwlun$u&
1
y"rl~um~iu~ulaGnp~~ijni~::fi~l~
& J L U A ~ ~ ~ U{ d
~ ~~ uU~ u d i ~ ~ i ' l ~ e l i ~ u u i ~ ' u f l a a i ~ ~
L
nisla' ACE1 ~ ~ ? ~ ~ ~ I ~ ~ : : ~ ~ u R ~ P I ~ I u ~ u
l ~ i i n l m ' ~ u ~ z ~ m f l ~ ~ i l d ,~. ~ n n ~ ~ u 7 ~ ~ i j ~ m ~ i ~ 6 i a u ~ ~ ~
uuimuod ACEI ila'pi~mzkulfluuuim~n'1~~u'il~~6~
' f
d m 1d ~ a u i m ~ i d u u ~
l u n i ~ n s ~ i i u i i uijuaiunia:Gui
0 1 q q : l f l ~ ~ u n 7 l ~ l 6~
ACEI
A U ~ I ~ ~ I ~ I ~ ~ W ~ ~ ~ U U A ? U I ~
3
u u q i n n i s o i r ~ d n ~ ~ n n i s~d7i u ~ ~ i i d n l u i w u i u i u
~?uu+ons::{us:uu
RAA l6uri
ni~::m~iun'~laGnp~n~m~Zju~G~in
r ~ u ~ i j o n u m ~ i ~ r i u d ~ n ~ ~(Bilateral
a o ~ i i drenal
iu
artery stenosis) u+or~u~ij'iln1d~iud1n+i41miidu~d
i u ~ u s i u i ~ l n o d r ~ j u d l n ~ (Unilateral
zuq
renal artery
stenosis in a single kidney )
1uy"di17uidmss~ui ACE1 y n n i i u a d o
nisn1unssn'rra:iio~fluiofi~ulunisla'ui
1~y"d~u~ijlril~~'u~ua~~u~~s~rr~zl6iu
uiuirflaai~ruin~iiuuuimod~~6~
lmuq::Yiill;fiui~
~flu<nsiunis~iii~o~iiwni~:G~lqA'uLu
d
~:u'n~¶~dauuuda~vo~ii~niufnuni~
r:uud~:~ln6Glfuu~ (Neurohormonal adaptation i
~~no~fiuo~pioni~n~iu~ufaGmn
NHA)
n i ~ a m f i ~ i m d o n < q u i n o o n q i n f (low
i ~ l ~ cardiac
output) ~~n:~fluualfi~iiniginsua~idu
(vicious cycle)
2
4
ndi~~o~:inirnr:{u~:u~rl~:ain~uwi-
L M ~ Au&
catecholamine ijualfikfiur~nmunai?kiin
ua~idun~uui~aduus~kiuniu~#u~ijnm~
(rfiu afterload) v m : ~ ~ u ? ~ u ~ z i n i s n ~ : { u n i s u
Renin qin1nvii1fi~iu?:6u Ang II &q:!ua"l&fiu
,
' x
l & ~ l ~ n K ? l f i u ~ wk~ufilfiu
~on
aldosterone kiin61
4
.
u a : ~ n ~ o ~ ~ l u i i ~ n i u r r a : u ~ u n i uU u iA
v
x
A
~
L
aiohlquln~u &~ufi?lqiqpnn?:{ulfiu
afterload LIU:L~~N preload naon~?aiviilGo~jlu
x i
Tginsuuriuuinaur~nu1 ua:ii'Ld~ni?:fi?ls
d u t ~ a ? ~ u ~ ~ srra:qinnisinwi
~lu~~n
acuayu
auyi3iuiii ACEI a i u i ~ o ~ u i ~ ~ n iAng
i v o II~
s?uiiq aldoslerone 1R~~a:rii~:ninigin~uu~iu
&ndi?lAldu5u
preload
anfiuimr~omquinoonqinfi~lq
+
n~z{usruuds:ain7uwi~ni~
T'
J
rio4fi~lsauiufn
rfiu afterload dofi?i?19
x
J
nA'l~L~ofi?i?'L9~141~'1~~~~4
/
f i u i m ~ ~ o n i ~ ~ i q ~ u f i o q fxi ~ ~ q u i n v u
J
I
rfiu preload uinvu
n i ~ l $ u i ACEI [email protected]:H'al~gur~aa
I. niol4ui
aldosterone m j 6 u l ~ o ~ACE1
~ u l7:Gllr;i
aldosterone
"
-4
~fluuiuuiu~vnriud
nmnd nisiduod;'iLLa:rnLlAorrinmnd
mj6uuomnodi
aiimrZu? (First - line therapy) i l ~ ~ f i u ~ i n u n n l s ~:viill1'nmfiuinaua~ui~uilaai~::n~ln'71nnis
i i
anuiwuii ACEI riudmjrZu? o~qq:laiua~awi:
~nwiwuiids:uina~s~uu~vo~~d~u~iini?:ri?l~A
{d?uui~niju~iiainislrjuinuilrjruui:lunis?nwi
1~R'Ibiuin (NYHA class II-Ill) q:RlulTflAnuUln
~d~uii.Il~A'u~un~~u~rsa
ui~uflaai?::i1+odr~l11~rrdkaiuisnnmln"uinod
2. n i ~ l a ' u ACEI
i
rfluuiuuiuiaoai?urk
lUhpL17d
(NYHA class IV) *adnls~nwii?uui3
~ i q h f l a ~ i ' ~(Second
:
- line therapy) ~flU&?iU
uuiui?ufu6 d i ~ ~ l f i d s ~ b a ~ u i n m i u nrwsi::
qwj
fu~iiuiuirilaai~:rin~::~nrSonl4ri]uuinuiurrsn
oiiaoonqnb~un::iir~ua~ui~a~uds:idn?iniwaa6u
:A '
lunis?n'nwni?:G~l~A'u~un~
~ ~ o u i ~ u n ~ u u i n t w l u un:h
~nu~awi:~di~~~~inunnis~n~i~i
;
i?uniruiir~unisGuninodfi~kqrZniinisl4
Y i ~ n i u o ~ r a o t u i i r ~ u i l ~ u ~ i ~ u l u n i ~ : r iACEI
~l~~
iu
u i r i u ~ n i l n n i u 6 a l u n 1 s ? n w i ~ d ~ u ~ ~ l ~aA
; 'u~u
ouialsn'niulunsGG?Iqr?umi~AniiiuA'urun?
i l ~ u i r d u n ~ i r ~ ~ n ' mw? i u i i m d n ~ ~ u n i ~ ~ n i u ~luszu:l'sufiuu~orrri~risru:qu~rs~
?noa~?~~
4. ~ n l s ~ ~ 4u ?Ilalui?uf~
l
(Quadruple
(diastolic dysfunction) ~ ~ ~ o i 9 9 : : 1 8 G i ~ ~ ~ 8 ~ ~ l n
; ' i o o n u i n r i i u l d ~ u ~ m ~ ~ s ~ ~ u ~ ~ l ~ o m ~ ~ : l utherapy
~ r ~ i $: fuiuirflaal?:
io~
- ACE1 - Z7on~u-uiuuiu
r i : ? 1 ~ v i i 1 l 1 ' f i u i n a ~ ~ o n i ~ n @ u ~ n 1 d r ~ u d h d n i u n m n d unomdoaniju& 1) Tmutawi:uinuiuu~om~aom
"
nijulurmsn wuiiuon~oaiuisnnm~~saWiuniu~~o
ldX?u
Kromer L L A : A ~ ~ : ~ ~ G I ~ I ? ~ ~ W ~ L ~ ~ U U L ~ U U 'Ludon (pulmonary arteriolar resistance) LLA::LLSd
unnisinuiluniju{~~u~iini~rG~l~~u~u~~sruz~u
Kulu~orm~uuu?ilm'~nii
ACEI ttui~ruui::n'qrlaY
h d (NYHA class II) ~ L A : ~ ~ " ? u ~ I ~ u ~ s ~ I ? : ~ ~ ~'L~TIAI~U
'D~
(hydralazine) ~w'udhriu?16od41nlflu
~ ~ u u i u ~ ~ ~ m ~ S ~ m r ~ m a Trw~i:q:ian~:[uIfi
mu~ani::
Tnu~&miniju ACEI un::nPsoZqon%u lud?a:u::
Zu 1 go 6 fdmiliwuiilunijuilm' ACEI aiuisn
u i d norepinephrine u l n i d i u o d l d l s ~ n l u nisi*
~ ~ u d s : 3 n ~ n i w n i s G i ~ i u n n ~ u i ' l ~ u i n n i i n i j u ~u1i ~k 4 nuiuiwtui! ~iodsounniTilnuluinnii$
?ui+wn:u
~ n u u a m d ~ f i r i i u i i { i l ? u i ~ i ACEI
iu
%
ACEI 1u{ilau
aiuisnr~u~~iununiu7unisoonn'i~'~niuliuinau Cm$iuttn:Cmfla.r.r:Taluni~1a'~i
*
%
H'alobirt~na
~rn::uiunu rr?ounjnmnuimri?l~ AAY:KUVB~
1. n i s r d ~ u u r ~ d n ~ n i n i i ~Kandi?
iuuo~~~
catecholamine L
aldosterone ~ U L ~11~::61ll1'
A
liuA'?i?Cidfiuluni?::ri~l~A'urun?q::iinismouauad
ACE1 i?u{u&on?u unn'9::~A'lu~li;dn'uni~~r;i
ACE1
RAA r~o5nuirrs~Kulu
glomeruli M
~ w ' u ~ n i r Z u ~ ~ : ~ ~ m n ~ i ~ n i r r a w i z ~ ~ i u ~ i u i sPmuns:
n l u[uns:i:usu
~muijnisumt~nod~~ur~om~rmdni'ilfln
(efferent renal
Gu&uoari?k (fractional shortening) L~il<uilfiu
~uo~i~ii~uii=1~7unijun'lm~um~on%ui~um'~unis
1
arteriole) ~d1!urdol4ul
ACE1 ~ d ~ u i d q n % ~ a n i i
ACEI
4
_
"
a
8
.I_
~nwi!uamd~rt"riiu-fn~quii
nislr;i ACE1 ~a?uL;iW
~ I ~ ~ : ~ ~ u A L ~ u ~ ~ R ~ ~ ~ s glomeruli
I ~ I ~ ~ ~( A~A ~ u
filtration rate) u%nn creatinine clearance
n i r u i u ' y i l a a i ~ : ~ i ~ ~ r u u i z a u u i n n i i n i s l 4 ~ ~ ~ nglomerular
~u
bld'ur~d b
{ ~ ~ ~ u I ~ s I u ~ I ~ ~
l u n ~ u { d ~ u ~ i i n i ~ z r i ~ l ~ A ' u ~ u n~nk;jujdqu
~lrjuin
1
Tnurawi::lusiun'16fiuiruuiqd
~ n t m s i ~ $ u ~ i o n i s r ~ m n i ~ : f i w ~ i n ~ ~ o n % ua:Graiiugdnu
un"~u
~ u r i i m ~ ? i u K u P n mq:&ijunr$uionis
i
o d i a ~ s n ' m i u u n n i ~ ? n w i ~ u ~ : u : u i ? ~ ~ d m " ~ d i i y " oriiuld
~~
%
Gi~iunodlmuinuu 6dtu~qs7:kum"un"?uni~lfi
auirayurrn:~mniuunniyinw7uinnild
f i u l n a u l i i l rioLhnlsnnaou (initial testing dose)
3. nisl4 ACEI rfluuiuuiu~aiui?unii
IiouLiW0 rdu 6.25 un.Yod captopril u+o 2.5 un.Yad
uiuirilaal?::rrn:~~~n~u
(Third-component therapy)
4
4 ,
enalapril ~mu~awi~otiidid
~ufiun'~m?uui~~~ijflm
qin+oVninnunum?i Ang II rflunin~z4unisuia
-
.
I
"
isutuifiuir~~iluii~niuljlouodtfluq:dfonia
2. V-HeFT-II (The Second Veterans AdI
~ l u i l g i l s i o n i a ~ l m a i u ~ ~ u ~ ~ C ussuiid{ilill?u
uinu~
ministration Vasodilator Heart Failure Trial) WU~I
ruiuaiu dq1'ilniar~u~donia:lmsiuqdniiy'ilsuka
enalapril ~ i u i ~ n a m < n ~ i n i ~ n i u ~ o ~ { i l s u n i s z
ldodu6a
~uruna1~5niinisla"lu~msmisu6uhydralazine
2. nia:fd~~naiuuq<% ~ t ~ u u a ~ACEI
inui
(<~YI~IU
18% L~UUKU
25%, P = 0.016)
~ U i d ~ n & oaldosterone
d
flilnl~~zamni~ut~~~ma3. CONSENSUS-II (The Cooperative New
iiiuuoonniililaaia: 4
nssu~nrduilnislfiui
Scandinavian Enalapril Survival Study ll) WU~I
iaunirnisl3rJumaiuumm~imus?u'l~uifuflaaia:
enalapril f a u ~ u u i ~ ~ ~ n % u u ~ z u i f u i l ~ a i ? : a i u
n~u~q:viil~drrmaduuk~luii~niu~?u
Pnurslwi:
nmoiilsiniwlX 27% l~{dauniazfial~R'u~uea~u~~
eriwi~1u{dauddlm?iu~~~6a
(NYHA class IV)
I"4
uintju NSAIDS dol%i?unir ACEI 7:
uenqinuuilunisi4nw ACEI lu{dawMilq
I
I
~~uToniaiduqsionia1dunrduu~~uinuu
IWYIZ
6u~uaauknhu~uofial~sim~~om
lir~ri
NSAIDS ~ : ~ u r ? ~ n i s a h ~prostaglandin
ais
(ddrgu
4. SAVE (Survival and Ventricular En3
r i s ~ a u s u i u u a o m ~ i j a m ~ ~ m ~ l d ~Yiil~tiilniu
a~.~ln)
largement) I* captopril (&?in 6.25 un. quii.1 150
fuTdumaiuuni~lmaoln9rra: NSAIDS roilaiuisn
un.) lu{dauukn6iuii:ofla1qmiuddn?iu~ndnfl
ns:~ulu'i~mnia:rnijok~luh~niuneon~unia:~n.~lu
lunisiiuniuodhhisuIsu (LVEF < 40%) ~ h u i u
i?iuuw Culn"
Ifiniulu 3-16 i u wuii captopril niuisnam<msi
4. y ' d ~ u d d ~ i n i s i 7 ' u u l j l i o n ~ i n f i a 2 ~ ~ imiusauaa:<msiniu~inP~~1fia2~lX
~
(19% 37%
m u w u ( o i n i s u j W p l ~ d u ~ o u j I ~ ; ~ i u i s n miur3iKu)
n a u q u ~ i n i ~ ~i~utunia:fia2~RIu~u~?
~~lX)
Iljnas
5. AlRE (The Acute Infarction Ramipril
I d ACEI ~muiowizoriiriil~usiuddplaiu~~dnZ~u Efficacy) wu6l ramipril a l u l ~ n a m i m ~ i n i u ~ u ~ d
1
n13iiumisod~o~ii?~~~aum~~~na'iuod~~A"a
rwn:oi7
ui2~~u~uaaniuuk~innA"iu~uohksi~
&
viilGnaiuKuTnlnamw ~~a:YiiWnRIiu~uofiaI~uim
27%
~omuin$ulh
[email protected]"auri;ji~rdu6njiuaC~a~u
5. {dsu~uuil~lun?au'1orfioofin1~
ndua5 Iunisl% ACEI 7nrnniszuilqRIuruasdu
& ""
uin$uiou 1 ds:~au~lnsu~:i~ulXa'mL~wi:nsG
16ndiaJiiliuu6a iio~9uCofiiu~imsim
2unisl$ui
*la'uiduuuiud 3 u & ~ i n ~ 2 n n ~ o n 3nazuiu'u
u
uuiuueomdomynn% sauii.~ ACEI <.ruininla:
ui2~Xu~unafauXaun'.9'1~9uqzXo.r7n'nwXaun1suik
flaaist.rdslrilhua un:~udnis2nwaCuayuni~%
ACE1 ~fluuiuuiud2 ukqinl~uiiiuilari?: Tmu
3.
4
-
ni~a*n~i~m~u'ua~uni1la'ui
ACEI sYnrn~dauw'7'lo
L ~ ~ ~ I u ~ ~ I Y L ~ ~ u U ~ ~ ~ ~
niinis2+~qon~uafi~:~~ilunis~nm~uszu~ku
1
odialsiiniu nisLijenlduintju$rguuluuiuLL~n uj
1. SOLVD (Studies of Left Ventricular
IridurjnjiurCuryuSwo unr.l"unsGiflquirsuDysfunction) ~ ~ 6 l n i f lenalapril
u'
10 un. La'l-r&d
A
diastolic
i ~ u ~ ~ i ~ d ~ i n f l ~ o n % ~ ~ ~ ~ : ~ i f u fn~r~nQius~'urn~iuKa
l a ~ i ? : m ~ h ~ ~(left~ ~ventricular
~~~
Bjlt~aa(BIISIP~
2)
."
l u n ~ u ~ d a u d i f l q u i n i s i i u 6 a s o ~ ~ s u ~ r f t e l i udysfunction)
~ouniiu?n~$inir
35%) ds~nn7zi
eqnisluniju NYHA class 11-III aiuisn~n<msinis
nwlX 16%
(ejection-fraction
I
~d~lum~wjrrA"auin~uurjl~r
Rqon%uunzuiiiuflaaiaz
40% mortality reduction
36% reduction in sudden
enalapril
failure
SAVE
Late
captopril
postinfarct
death vs. nitrate- hydralazine
1,115
42 months
37% reduction
in risk of CHF
LV dysfunction
AlRE
Early postinfarct
ramipril
clinical heart failure
1,986
15 months
27% mortality
reduction
CONSENSUS
=
Cooperative North Scandinavian Enalapril Survival Study
SOLVD
=
Studies of Left Ventricular Dysfunction
V-HeFT-II
=
VA Cooperative Vasodilator Heart Failure Trial
SAVE
=
Survival and Ventricular Enlargement
AlRE
=
Acute Infarction Ramipril Efficacy
LV dysfunction
=
Low ventricular ejection fraction
(qin Opie. Drugs for the Heart: 1995:115)
i
n. ACEI 1 w r n ~ r ~ & n a ' l U 1 w o ~ l ~ u i n ~ i i ~ m
nlsuulufiulmouo~fio~fiql7(ventricu-
3
3
A,
d
n i ~ : n d i u ~ u o , i k u i n ~ i j o n o i i ~ ~ u ~ r s ~ ~laru dilatation) ~ f l u u ~ ~ u n i s d n ~ i ~ ~ u ~ f i
3
3
riimnA'iu~uofi~l~niurfluni~::dw~1~~ouuinu~~r~::
%i?nadinisd%i?~ioLflunis¶nr¶uX?uniouuiuni
r f l u a i r u ~ n i s n i u d d i 6~~i r u ~ d ~ u l u ~ r i i n ~ ~ o . r 4 riufiuim~un.rfiq~q
in
rioriufiuins~ijomd9:qu~m
w
I s n ~ n ~ m r i j ~ n f i ~ l ~ d i j w u i ~ n i w ~ u ~ ~ n u aonqin(li79
~ i n u u u (stroke volume) n'innlnnisdsirniiilljuK?i1i
i
nlsrdnuuridn4rruu atherosclerosis Inuu'n7:i
ilq<u~du.liid 1 1Xrrrirwm¶iu, oiquin, nqiui'u
InGnqq, ruiu?iu, quuu<i4, luuiilurijomqq, d7-G
Y
aiui~n~~ufiuins~ijom~~r1~~iiuu
1X~Fjuqwo uuqunisiiiqr~iriruquiiuuiolddou1
~fluuaviil~ni~~u~~uo~~~umi~
LJU~
3
A U ~ ~ ~ ~ ~ ~ A ~ L ~ ~ U ~ S A U A B P I L ~ ~ P ~:~iinni?:nA'iu~~ofi?~~du~u~?miuui
~ ~ ~ ~ ~ ? ~ ~ L ¶ U ~ U
A'
~iieriimni~:ndiu~uofi~l~miuqrinis
uon9inuuqunis&LA'? h ~ n i u K ~ i n n 1 n n i s
d
r d n u u o d n . r ~ d i 6 ~ u o ~ n d i u r ~ o f i ? ~ ~ ~ ~ d ? u dd?u,iLioLiufiuimsrijom1uniiuu1dr<uqiiqniu
miu
*
d
A
~8:~4u¶?nfJd I ~ ~ ~ : ~ ~ I ¶ L ~ < ~ U L L ~ A ~ Y U I R L L A : ~ ~
&?unlsns:~u NHA L~UL'~~~?&~I?:G~'L~A"U
ns4uo4fio4r?um?r?n (ventricular remodeling) lnu
i q ~ d( d 3) vii~fiir8ulijand?udniuumm'?( r i u
3
ds:neu~?uuu?unis~iouKq~io~d~
aflerload), ~ n l ~ 6 ~ ~ ~ 4 ~ l k (lfiu
f u ~
3
n i s ~ n u u i u o o n a a . r n n " ~ u o f i ~ l ~ d ~ u d preload) d4unT?u~4uum~:ijnisLiuLLs4~uniu1u
n l u (Infarct expansion) ~flu~u?ufllTd~iiplnlfl~& fif14ii?h~?umTr?n(ventricular wall tension) orilquln
w
A'
qiniiniouinrSon rrn:ndiuruollil~uTr?nariuniu
~.r~fluairu~di~iryao~nis~iim
infarct expansion uoq
3
A'
I m u ~ ~ ~ i : ' i l i i ~ ~ ~ ~ i ~ d n i s m i u u a . r n ~ i u ~ u o ndiuLuoii?l9dqu~niu
~iinrflu
rrn:wfouriuinnlnanr¶u
A'
A"
uinnan?"iqun:odXiuu61
rir\una:no~ndiuruo~:
r~uuuin~~a:n?iuuuiuo~n~iu~~ofi~l~
%mod kcrriin:uiaLdaqmaonr?ni quviilfiriinfiqlq
ui~n.rrra:inisinuuiuaon
~'urunqlu&y
.
d
riuqn%uoq Ang II
rfiu norepinephrine
'
/"uqn"pressin
d
L
~ % ~ n i s r raldosterone
&
7di
3
r8uurijamrrn~~n~niqiq Liuniskquo~Gi~uiiqniu
~~uns~sunuinuasni~n~::~w~::uud~::uino'~bwG
(Neurohormonal
1
na'sni~:niiu~weG~l~uim~i~m
activation-NHA)
6 ' 4 6 ~ % i i n i ~ ~ iACEI
i
u?'lflnudoil&o
ACEI fiiuitnrryni.r NHA l&iiqdo.rniLlGilnit
rfiu preload LA:: alterload L ~ u u A ~ l l ventricular
~Pl
wall tension
UAZAP~~IYL~~W
ventricular
remodeling
~.rlX ~u~ofi~ui~o~o.rnirni~~?~nni
16 (fli
4)
~~n~iufiiui~n'luni~iiu~~no.rri?lq
-L
\
nr;b::uu%unnnin
(NHA)
~Gufiuinsu~~ru.rKuilufio.rri~lq
vnr:¶q.rlnuefik%
-L
rfiu~wi~~~ewguineonqinri~lq
x
~fiuu~.rsiu'ufio.rriq'Lquinuu
(wall tension)
a d i 4 unuinuewi
ACEI
'~uni~n~a~~~~auni~u'auuiu~aue~n'e~n'al~~a
(ventricular remodeling)
CONSENSUS-II
1515-4
GISSI-3
Total number treated
3,044
27,442
9,435
Drug and daily dose
Enalaprilat IV
Captopril
Lisinopril
1 mg over 2 h,
6.25 mg initially,
2.5-5 mg initially,
then up to 20 mg 2X
increased to50 mg 2X
increased to10 mg 1X
daily
daily
daily
Duration (days)
41 to 180
28 days
42 days
Patient population
AM1 within 24 h of onset
AM1 within 24h of onset
AM1 within 24 h of onset
Mean delay time
15 h
60%>6h
65'%>6h
Age, years
66 mean
72% below 70
63 mean
Gender male (%)
73
74
78
BP exclusion levels
100160
100 systolic
100 systolic
Hypotension as side-
25 (cuntroll0)
21 (control 10)
9 (control 4)
0.8 increase
0.46 decrease*
0.8 decreas
lo0/.
956 decrease'
11% decrease
(p = 0.04)
(p = 0.03); 17%
effect (56)
Mortality change,
absolute %
Mortality change as
increase
risk reduction
decrease with nitroglycerin
(p = 0.003)
'35days.
+ persistent
hypotension, systolic blood presure below 90 mmHg for more than 1 hour.
( q l n Opie. Drugs for the Heart
: 1995:120)
"
2
diluii.rniuu'ouo$uR'? oiqqr~iinuu%n~quum:
4. luniazlml~surniwoinluimaiu~~~~z/mi~)naiuul~uu~rdad+i(orthostatic hypotension) &?uiod
n'uTII%mg.r
kuiu6?uuuinuiii 1 riautauo lmu~owi:luQ~l?u
f l ~ ? ~ u i n i s i n w i l K u a ~ 3 u d u r i % n ~ ~ R l ~qi i~ o i qP I ? T ~ ~ L ~ A B I ~ I T L ~ U ~uinniiqP;iK?r~n
I
ACEI a i u i s n a : ~ ~ n i ~ ~ i i m ' ~ n ~ ~ o u a n i w r r a : a i u i ~ nn?iuKul~Gnliudo(iidriu? rnu uinlrjijainiso:ls
an6mnnisriinln?lu lu{d~u~uiu?iu~~aiiw~~u?o rw'~?iuKu~aiin~almGno$~uSi?d
80-90 uu.dson ?I
~ d . r ~ u ~ ~ u ~ K ~ n u n i sLewis
i n wua:nmr
i a o ~ (1993)
aiuisnlfiuido'LX
d
r r ~ : r ~ o i i r ~ u n ~ l n d i r w ~ n u o n ~ u i r o ' L d ~ i n n i ~ ~ m 1.3 nisviidiunodln~fim.r : a~rinq:
n ? l ~ ~ ~ l ~ G ~ L ~ ~~ ~d f ~l Li Ql d~ ll :i ~~ ~?l d ~ d ~8u~u66un?iuKulnir~M"~n
l d ~
~ i u i n ~ i i u ~ d i u u%
~od
f i 1i ~ ~d1u1iynoy'il?un?~uKulir*~~Gm~~~~nr~u~
r ~ ~ u d ~ u i j l n ~ d o u a n ~ w i n r u ~ u ~ i u r ~ ~ : i l if n
oonui6uiiaai?: ( u i n n i i 30 un.15'~)iioiir3uCo
lnaodiidiu u ? o i l m r i u . r C i ~ ~oiqq:viilGIn?iu
iu~
i d i % m L ~ ~ & : ~ o dACE1
~ ~ L~~fl~d6ldlLR~¶YR~nlT~$uuw,iilX 'd.riin~3u4oriiu%mLqulunisl~ui
ACEI
r i i n l n ~ ~ o u a n i w u ' ~ a u r i i i ~ r r i i n l m ~ d o u a n ~ w ~ r r R l ~ 1.4 d $ u i ~ ~ G ~ ~ K ~ u u(angioedema)
sd
wu
lKFiou$idu'ou (0.1%) LLiiioii6umTiuuindqn
('Lini?dunnnuinirflaai~:uinnii 500 un.15~)
ACEI n"ujaiuisna:~ou?o~moinsini~w"iriiul~nlri$i ~w~i:oiq13uai~u?l~~~u%m~X
rrn:'Lljaiuisnnim
~d'L6
~m~'LM~Gd?usiulmq:ida%u~Xdni~?
inisk
~ ~ ~ ~ g l ~ ~ i bradykinin
n ~ ' L n ~ l
-4
~~Ciii.rl~cl.r~mzu'oH'iuIuni~Ia'cli
ACEI luniallaGi
?snis?n:nwiyO~u& adrenaline L U I I ~ ~ I ~
ii?uGdfiui
n14naiin
1. NIIu'1.al;cl.r
1.5 ni?:Wrrna~iuulurijom@.~Tnurawi:
~ ~ I ~ ~ ~ I u ~ ' ~ I ? ~U%
IUI~
wYI~~~I~?U
I ~ D ~ L
1.1 'Lo :wu'L6uouuinwoeun?s qu'lnisni
2
unniiqG?dui 2-15% (nunirnrJ:u~d'iud~nw)
miu
ld~rnaduunmunuu~o~6uiuirflaai~:nfjudvii'lri
~dlfUtl?YMq~Ulfi
quus~n"rmnmi~6u
~ ~ ~ ~ d w o ~ i n i ~ q u i o i n i ~ u i nI ~~L LaR: A A U U & ~ I U ) I ~ ~ I U ~ ? U ~ ? U
ACEI
d1~3uhoia.ruqmuilu~~n
d o i i ~ ~ m ~ i n n i s ~ ~ u n ~nii?rioudq:l4
iul~
1.6 duij?u<d o i s w u ~ ~ f i i n. r~ i ~ l j u i n r i n
ao.rhns:fiuni~'Lo (cough reflex) R~)uN:~:L~~u
~ruulorrri~
1, T:~ILIRO,
llji~auu: 10uin~~naid5u,
ACEI &lKndiamltbiCi4BI'u
n ~ i ~ ~i . ur ~ : u n n d i ~ ~ i n l o ~ i n u ~ o m a u ~ ~ u % n2.i ~ :~8H'iuIunl~l#ui
w
lKllri
fi?lq?iu ( ~ ~ i ~ i ~ s i u n " ~ i q q : ~ ~ n ' lijnisnj
n'uin)
2.1~ n i ?~: n ? i ~u K u l~~ G n @
~
~
Y
~
~
l bradykinin
~
~ U% ~
~
l
? ~ ~ i~n ~ ~ u~ ~ & m
3
~au~lmaa~Ci~iuu%ilm~iu~Ci~~~u?
prostaglandin rla:'L~iinl~naao4l4NSAlDs lioam
~~~iod~Z
misKdndi?d?uamoini~'Lo~ ( i l d ' L ~ ~ ~ 1 ~ ~ 1 ~ ~ 2.2
~ l nni ?' :~n ?~ i u
~ ~ u l ~ ~ ~ * ~ ~?:idviilri
' L ~ l l l ~ l L & n ~ L i ;LLA~'LW?IU~~
'~d
L$ulurLinis&.anodGi, WunaSuu u?oridu.riolm?iu
2
2.3 n i ? : n i ~ q m ~ u n i ~ ~ u ~ ~ u u~~ut jroim
uinnuqin NSAIDS 16
v
2
~ufi?lqLooo%miu,nRliuruofi~lquui~~~:qnKuni
u'nisnw~o~K~i?unisl$
ACE1 uuiniihunir
oonnoqJ o n
u l 6 i u ~ m n r ~ u nifedipine
u
olTq:d?uaa0lnlT~8~6
2.4 IIi?:G?dtITTd uilunqu ACEI ynzqi
m ~ u n l n u%ui.r~1u6i"h'LIjuin
n
niq
u~~oni~nluns~d~ilri~~nGni~l~~
q:so8.ammoininls:uim
4 L ~ oinisq:uiuld
U
lud?~'Lnsuiad2 ua: 3
LodlX lmullj6oduqwul
1.2 A~IUD~~~RGPI~Il ~ ~ u ~ ~ ~ i : l u Q i l ? u f i ?
I ~ ~ U L U R ? ~ ~ ~ B ; ~ U ~ I ~ U ~ ~ ~ ~ ~ ? : ~ ~ ~ L ~ : ~ U ~ ~ ~ ~ U I ~
1.
Side-effects, Class
Cough -common
Hypotension-variable (renal artery stenosis ; severe heart failure)
Deterioration of renal function (related to hypotension)
Angioedema (rare but potentially fatal)
Renal failure (rare, bilateral renal artery stenosis)
Hyperkalemia (in renal failure, or with K-retaining diuretics)
Skin reactions
2.
Contraindications
Renal-bilateral renal artery stenosis or equivalent lesions
Pre-existing hypotension
Severe aortic stenosis or obstructive cardiomyopalhy
Pregnancy (NB : recent FDA warning)
3.
Side-effects first described for high-dose captopril
Neutropenia especially with collagen vascular renal disease
Proteinuria
Loss of taste
Oral lesions; scalded-mouth syndrome (rare)
3.
~raJi~~ffa~P'nvcuz~n'uii~nizue~cn
captopril
3.1 i n ~ E j e n u i ~ a i i n i i ~ ~ n ~ a p l : i u ~ ~ i i ~ a u
~~fi.rlljr~u%nCn4i~uKu~~uais~al~n~aluK~ui
u%llj uml?n~:&uKu~n'ufiui~uiu~i~~q.r
1 1uYy
11qulnqiu
~~~:Tnu~awi:~di~~~lusi~diiTs~~~~~u
X.4-l
&u?4o.rnirnqiuijnrln~no.r~uo~uo~nuqKu
3.2 l n n i ~ r l ~ o o n u i 5 u f l a a iwurls:ui~
~:
4
""
1% Tnurawidutiu~lnsucaptoplil 9uinq.r r~:ii
wuitaniwuo.rlnod~ouu6?
3.3 i;u~ljFujtaoiuis &u<u~n'unuinuid
flqq~uwu60uuin~wsi:nis14uuinuid~ia.r
3.4 k ~ A l ~ r ] l 6hktn.4:
n
scalded-mouth
syndrome ( h u u i n )
I u ~ d ~ u G ? I ~ & ~i iunn~a~ a n r n a i i u a ~ u
%m~quiiACEI aiui~onmo'olnnismiu nm.o'nsinis
~ii~llj?lqAIu~un?
~ ~ n : 6 o ~ u o u l s ~ ~ u i~~ i nf i ~ki
ilo~n'unisPii~~ulsnluigin~ufi~;Au1X
(ii~flud~uriou
6Iil~sirdsr1ua~qinuiioni=juikim~?iu~u1nfi~1
n'iqinuiuinld)
f l q ~ U ' U ~ l ~ : < l l f ACE1
l ~ ~ l L f l ~ ~ l . ~ l l 2l l l d
2.
3.
CAPPP group. The
Captopril Prevention
Project: A prospective intervention trial of
angiotensin converting enzyme inhibition in
the treatment of hypertension. J Hypertens
1990; 8:985-990.
4. Cohn JN, Johnson G. Ziesche S, et al.
Comparison of enalapril with hydralazine
-
~jnirui~uflaai~:lu~1u6~~l~AIu~una~iimdouuSo
isosorbide dinitrate in the treatment of chronic
diunfiw afi:r~uui'l~en~uX?uo'iuinrfluquusq
u;ei atrial fibrillation ~iimhuiau
3. luQd~ou~jnujiu~~eGalqmiu
qinnis
anwl$Jl~?u2 nqulud wuii ACEI aiuisnfimo'nsi
n ~ s n i u l ~ e ; o r i i ~ ~ G u d i K r y(6%
n i ~ih
~ i11%)
i ~ 61
6ulll'Kdum's:u:~~sn
qln GISSI-Ill nisl3 lisinopril hun'u nitro-
congestive heart failure. N Engl J Med 1991;
325:303- 310.
5.
J. Rasmussen K, et al. On behalf of the
..
m
glycerin
miul&
CONSENSUS Il-Swedberg K, Held P, Kjekshus
CONSENSUS II Study Group. Effects of the
early administration of enalapril on mortality in
patients with acute myocardial infarction.
n l ~ ~ ~ u ~ ~ e m ~ f i : ~ ? ~ i i ~ ~ 1 u 1 ~ n f i B l t m ~Results
l n l s of the Cooperative New Scandinavian
17%
d
a~ijds:lu~&in k u ~ o w i z e r i i ~ b ~ ~ u
Enalapril Survival Study II (CONSENSUS 11).
siu6ijeini~~lquju~un~i~uX~u
N Engl J Med 1992; 327:678-684.
n i ~ : l m ~ ~ e u ~ n i ~ ~ ~: niinis
~ u i u ~ i u 6. Daly P, Rouleau J-L, Cousineau D, et al.
anwauira~u4'mlquiiACEI ~?unirnim?uqurui
Effects of captopril and a combination of
4.
u?iu (&u5u.g'3u), nauqunaiuKuIfii?n (oiqhu
niruin~~aiuKuirmi~u
1) aiuisofimo'nsinismiu,
ln?iu, 5msinisuji~lmuS~rjim'm~d~uu1~1~
&1~wu
severe congestive heart failure. Br Heart J
~uuini=jut!u1
1986; 56:152-157.
hydralazine
and
isosorbide
dinitrate on
myocardial sympathetic tone in patients with
7.
Dworkin LD, Benstein JA, Parker M, et al.
Calcium antagonists and converting enzyme
inhibitors reduce renal injury by different
mechanisms. Kidney lnt 1993; 43:808-814.
8.
Dzau VJ, Hollenberg NK. Renal response to
captopril in severe heart failure : Role of
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`