22 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS

0.5 mmol/l ATP

100 mol/l Diazoxide

Saponin

5 pA
20 s
Fig. 22.6 ATP-sensitive potassium channels. Patch clamp (see Ch. 3) record from insulin-secreting pancreatic B cell: saponin
permeabilised the cell, with loss of intracellular ATP, causing the channels to open (upward deection) until they were inhibited by ATP.
Addition of diazoxide, a vasodilator drug (which also inhibits insulin secretion; see text) reopens the channels. In smooth muscle, this
causes hyperpolarisation and relaxation. (Redrawn from Dunne et al. 1990 Br J Pharmacol 99, 169.)

JDVWURHQWHURORJLVWV SUHIHU WR XVH RFWUHRWLGH XQOLFHQVHG DIRECT ACTING VASODILATORS

LQGLFDWLRQVHH&KIRUWKLV,WPD\DOVRKDYHDSODFHLQ 7DUJHWV RQ ZKLFK GUXJV DFW WR UHOD[ YDVFXODU VPRRWK
WUHDWLQJK\SRWHQVLYHVKRFNVHHS PXVFOH LQFOXGH SODVPD PHPEUDQH YROWDJHGHSHQGHQW
FDOFLXP FKDQQHOV VDUFRSODVPLF UHWLFXOXP FKDQQHOV &D+
ENDOTHELIN UHOHDVHRUUHXSWDNHDQGHQ]\PHVWKDWGHWHUPLQH&D+VHQ
(QGRWKHOLQV DUH GLVFXVVHG DERYH LQ WKH FRQWH[W RI WKHLU
SK\VLRORJLFDOUROHVDVH[SODLQHGDERYHWKH\KDYHYDVRGLOD
WRU DQG YDVRFRQVWULFWRU DFWLRQV EXW YDVRFRQVWULFWLRQ SUH
GRPLQDWHV ,QWUDYHQRXV DGPLQLVWUDWLRQ FDXVHV WUDQVLHQW
YDVRGLODWDWLRQIROORZHGE\SURIRXQGDQGORQJOLYHGYDVR
FRQVWULFWLRQ 7KH HQGRWKHOLQV DUH HYHQ PRUH SRWHQW YDVR
FRQVWULFWRUVWKDQDQJLRWHQVLQ,,$V\HWWKH\KDYHQRFOLQLFDO
VLWLYLW\RIWKHFRQWUDFWLOHSURWHLQVVHH)LJ
Calcium antagonists
/W\SH FDOFLXP DQWDJRQLVWV DUH GLVFXVVHG LQ &KDSWHU 
$VZHOODVWKHLUDFWLRQVRQWKHKHDUWWKH\FDXVHJHQHUDO
LVHG DUWHULDO YDVRGLODWDWLRQ DOWKRXJK LQGLYLGXDO DJHQWV
H[KLELWGLVWLQFWSDWWHUQVRIUHJLRQDOSRWHQF\'LK\GURS\
XVHV DQG (7 DQWDJRQLVWV DUH OLFHQVHG RQO\ IRU WKH UDUH ULGLQHV HJ QLIHGLSLQH DFW SUHIHUHQWLDOO\ RQ YDVFXODU
GLVHDVHSULPDU\SXOPRQDU\K\SHUWHQVLRQVHHS VPRRWK PXVFOH ZKHUHDV YHUDSDPLO DFWV GLUHFWO\ RQ WKH
Vasoconstrictor substances
The main groups are sympathomimetic amines (direct
and indirect; Ch. 14), certain eicosanoids (especially
KHDUW QHJDWLYH FKURQRWURSLF DQG LQRWURSLF HIIHFWV LQ
DGGLWLRQWRFDXVLQJYDVRGLODWDWLRQGLOWLD]HPLVLQWHUPH
GLDWH LQ VSHFLFLW\ &RQVHTXHQWO\ UDSLGDFWLQJ GLK\GUR
S\ULGLQHV XVXDOO\ SURGXFH UHH[ WDFK\FDUGLD ZKHUHDV
YHUDSDPLODQGGLOWLD]HPGRQRW
Drugs that activate potassium channels
thromboxane A2; Ch. 17), peptides (angiotensin II, 6RPHGUXJVHJPLQR[LGLOGLD]R[LGHUHOD[VPRRWKPXVFOH
antidiuretic hormone [ADH] and endothelin; Ch. 19)
and a group of miscellaneous drugs (e.g. ergot
alkaloids; Ch. 15).
Clinical uses include local applications (e.g. nasal
decongestion, co-administration with local
E\RSHQLQJ.$73FKDQQHOVVHH)LJ7KLVK\SHUSRODU
LVHV WKH FHOOV DQG VZLWFKHV RII YROWDJHGHSHQGHQW FDOFLXP
FKDQQHOV3RWDVVLXPFKDQQHODFWLYDWRUVZRUNE\DQWDJRQLV
LQJWKHDFWLRQRILQWUDFHOOXODU$73RQWKHVHFKDQQHOV
0LQR[LGLO DFWLQJ WKURXJK DQ DFWLYH VXOSKDWH PHWDER
anaesthetics). Sympathomimetic amines and ADH are OLWH LV DQ HVSHFLDOO\ SRWHQW DQG ORQJDFWLQJ YDVRGLODWRU
used in circulatory shock. Adrenaline is life-saving in XVHGDVDGUXJRIODVWUHVRUWLQWUHDWLQJVHYHUHK\SHUWHQ
anaphylactic shock and in cardiac arrest. ADH or VLRQXQUHVSRQVLYHWRRWKHUGUXJV,WFDXVHVKLUVXWLVPWKH
terlipressin (an analogue) has been infused DFWLYH PHWDEROLWH LV DFWXDOO\ XVHG DV D UXERQ FUHDP WR
WUHDWEDOGQHVVVHH&K,WFDXVHVPDUNHGVDOWDQGZDWHU
intravenously to stop bleeding from oesophageal
UHWHQWLRQVRLVXVXDOO\SUHVFULEHGZLWKDORRSGLXUHWLF,W
varices prior to surgery in patients with portal
FDXVHV UHH[ WDFK\FDUGLD DQG D DGUHQRFHSWRU DQWDJR
hypertension caused by liver disease.
QLVWLVXVHGWRSUHYHQWWKLV1LFRUDQGLO&KFRPELQHV
.$73 FKDQQHO DFWLYDWLRQ ZLWK 12 GRQRU DFWLYLW\ DQG LV
XVHGLQUHIUDFWRU\DQJLQD/HYRVLPHQGDQFRPELQHV.$73
FKDQQHO DFWLYDWLRQ ZLWK VHQVLWLVDWLRQ RI WKH FDUGLDF FRQ
VASODILATOR DRUGS WUDFWLOHPHFKDQLVPWR&D+E\ELQGLQJWURSRQLQ&&K
9DVRGLODWRU GUXJV SOD\ D PDMRU UROH LQ WKH WUHDWPHQW
RI FRPPRQ FRQGLWLRQV LQFOXGLQJ K\SHUWHQVLRQ FDUGLDF
IDLOXUHDQGDQJLQDSHFWRULVDVZHOODVVHYHUDOOHVVFRPPRQ
EXW VHYHUH GLVHDVHV LQFOXGLQJ SXOPRQDU\ K\SHUWHQVLRQ
272 DQG5D\QDXGVGLVHDVH
DQGLVXVHGLQGHFRPSHQVDWHGKHDUWIDLOXUHVHHS

$S\ULGLQHGUXJ<FDXVHVYDVRUHOD[DWLRQE\LQKLELWLQJD
5KRDVVRFLDWHGSURWHLQNLQDVHWKHUHE\VHOHFWLYHO\LQKLELWLQJVPRRWK
PXVFOHFRQWUDFWLRQE\LQKLELWLQJ&D+VHQVLWLVDWLRQ
vip.persianss.ir

Drugs that act via cyclic nucleotides
Cyclase activation
0DQ\ GUXJV UHOD[ YDVFXODU VPRRWK PXVFOH E\ LQFUHDVLQJ
WKH FHOOXODU FRQFHQWUDWLRQ RI HLWKHU F*03 RU F$03 )RU
THE VASCULAR SYSTEM 22
LQFUHDVH F$03 LQ FDUGLDF PXVFOH 7KH\ KDYH D SRVLWLYH
LQRWURSLF HIIHFW EXW GHVSLWH VKRUWWHUP KDHPRG\QDPLF
LPSURYHPHQW LQFUHDVH PRUWDOLW\ LQ SDWLHQWV ZLWK KHDUW
IDLOXUHSRVVLEO\E\FDXVLQJG\VUK\WKPLDV'LS\ULGDPROH
H[DPSOH 12 QLWUDWHV DQG WKH QDWULXUHWLF SHSWLGHV DFW DVZHOODVHQKDQFLQJWKHDFWLRQVRIDGHQRVLQHVHH&K
WKURXJKF*03VHH&KVDQG%$<DS\UD DOVR FDXVHV YDVRGLODWDWLRQ E\ LQKLELWLQJ SKRVSKRGLHVWH
]RORS\ULGLQH DFWLYDWHV VROXEOH JXDQ\O\O F\FODVH YLD DQ UDVH,WLVXVHGWRSUHYHQWVWURNHEXWFDQSURYRNHDQJLQD
12LQGHSHQGHQWVLWHVHH&K7KHDJRQLVWVDGHQRVLQH 6HOHFWLYH3'(W\SH9LQKLELWRUVHJVLOGHQDOLQKLELWWKH
DQG3*,LQFUHDVHF\WRSODVPLFF$03VHH&K'RSDPLQH EUHDNGRZQRIF*033HQLOHHUHFWLRQLVFDXVHGE\QLWUHUJLF
KDVPL[HGYDVRGLODWRUDQGYDVRFRQVWULFWRUDFWLRQV,WVHOHF
WLYHO\ GLODWHV UHQDO YHVVHOV ZKHUH LW LQFUHDVHV F$03 E\
DFWLYDWLQJ DGHQ\O\O F\FODVH 'RSDPLQH ZKHQ DGPLQLV
WHUHG DV DQ LQWUDYHQRXV LQIXVLRQ SURGXFHV D PL[WXUH RI
FDUGLRYDVFXODUHIIHFWVUHVXOWLQJIURPDJRQLVWDFWLRQVRQ
QHUYHV LQ WKH SHOYLV 7KHVH UHOHDVH 12 &K  ZKLFK
DFWLYDWHVJXDQ\O\OF\FODVHLQVPRRWKPXVFOHLQWKHFRUSRUD
FDYHUQRVD7DNHQE\PRXWKDERXWDQKRXUEHIRUHVH[XDO
VWLPXODWLRQVLOGHQDOLQFUHDVHVSHQLOHHUHFWLRQE\SRWHQ
WLDWLQJ WKLV SDWKZD\ ,W KDV UHYROXWLRQLVHG WUHDWPHQW RI
DQG  DGUHQRFHSWRUV DV ZHOO DV RQ GRSDPLQH UHFHSWRUV HUHFWLOH G\VIXQFWLRQ VHH &K  DQG KDV WKHUDSHXWLF
%ORRGSUHVVXUHLQFUHDVHVVOLJKWO\EXWWKHPDLQHIIHFWVDUH SRWHQWLDOLQRWKHUVLWXDWLRQVLQFOXGLQJSXOPRQDU\K\SHU
YDVRGLODWDWLRQ LQ WKH UHQDO FLUFXODWLRQ DQG LQFUHDVHG WHQVLRQVHHFOLQLFDOER[SE\SRWHQWLDWLQJ12
FDUGLDF RXWSXW 'RSDPLQH ZDV ZLGHO\ XVHG LQ LQWHQVLYH
FDUHXQLWVLQSDWLHQWVLQZKRPUHQDOIDLOXUHDVVRFLDWHGZLWK
GHFUHDVHGUHQDOSHUIXVLRQDSSHDUHGLPPLQHQWGHVSLWHLWV Vasodilator drugs
EHQHFLDO HIIHFW RQ UHQDO KDHPRG\QDPLFV FOLQLFDO WULDOV
KDYH VKRZQ WKDW LW GRHV QRW LPSURYH VXUYLYDO LQ WKHVH Vasodilators act:
FLUFXPVWDQFHV DQG WKLV XVH LV REVROHWH 1HVLULWLGH D to increase local tissue blood ow
UHFRPELQDQW IRUP RI KXPDQ %W\SH QDWULXUHWLF SHSWLGH to reduce arterial pressure
%13 VHH &K  ZDV ZLGHO\ XVHG LQ WKH 86$ IRU WKH to reduce central venous pressure.
WUHDWPHQWRIDFXWHO\GHFRPSHQVDWHGKHDUWIDLOXUHEXWHI Net effect is to reduce cardiac preload (reduced lling
FDF\GDWDKDYHQRWEHHQLPSUHVVLYH2&RQQRUHWDO pressure) and afterload (reduced vascular resistance),
1LWURSUXVVLGHQLWURIHUULF\DQLGHLVDSRZHUIXOYDVRGL hence reduction of cardiac work.
ODWRUZLWKOLWWOHHIIHFWRXWVLGHWKHYDVFXODUV\VWHPZKLFK Main uses are:
DFWVE\UHOHDVLQJ12&K8QOLNHWKHRUJDQLFQLWUDWHV
ZKLFK SUHIHUHQWLDOO\ GLODWHFDSDFLWDQFH YHVVHOVDQG PXV
FXODUDUWHULHVLWDFWVHTXDOO\RQDUWHULDODQGYHQRXVVPRRWK
PXVFOH ,WV FOLQLFDO XVHIXOQHVV LV OLPLWHG EHFDXVH LW PXVW
EH JLYHQ LQWUDYHQRXVO\ ,Q VROXWLRQ SDUWLFXODUO\ ZKHQ
H[SRVHGWROLJKWQLWURSUXVVLGHK\GURO\VHVZLWKIRUPDWLRQ
RI F\DQLGH 7KH LQWUDYHQRXV VROXWLRQ PXVW WKHUHIRUH EH
PDGH XS IUHVKO\ IURP GU\ SRZGHU DQG SURWHFWHG IURP
OLJKW1LWURSUXVVLGHLVUDSLGO\FRQYHUWHGWRWKLRF\DQDWHLQ
WKHERG\LWVSODVPDKDOIOLIHEHLQJRQO\DIHZPLQXWHVVR
LW PXVW EH JLYHQ DV D FRQWLQXRXV LQIXVLRQ ZLWK FDUHIXO
PRQLWRULQJ WR DYRLG K\SRWHQVLRQ 3URORQJHG XVH FDXVHV
WKLRF\DQDWHDFFXPXODWLRQDQGWR[LFLW\ZHDNQHVVQDXVHD
antihypertensive therapy (e.g. AT1 antagonists,
calcium antagonists and 1-adrenoceptor antagonists)
treatment/prophylaxis of angina (e.g. calcium
antagonists, nitrates)
treatment of cardiac failure (e.g. angiotensin-
converting enzyme inhibitors, AT1 antagonists)
treatment of erectile dysfunction.
VASODILATORS WITH UNKNOWN
MECHANISM OF ACTION
DQG LQKLELWLRQ RI WK\URLG IXQFWLRQ FRQVHTXHQWO\ QLWUR Hydralazine
SUXVVLGHLVXVHIXORQO\IRUVKRUWWHUPWUHDWPHQWXVXDOO\ +\GUDOD]LQHDFWVPDLQO\RQDUWHULHVDQGDUWHULROHVFDXVLQJ
XSWRKPD[LPXP,WLVXVHGLQLQWHQVLYHFDUHXQLWVIRU
K\SHUWHQVLYH HPHUJHQFLHV WR SURGXFH FRQWUROOHG K\SR
WHQVLRQ GXULQJ VXUJHU\ DQG WR UHGXFH FDUGLDF ZRUN
GXULQJWKHUHYHUVLEOHFDUGLDFG\VIXQFWLRQWKDWRFFXUVDIWHU
FDUGLRSXOPRQDU\E\SDVVVXUJHU\
Phosphodiesterase inhibition
DIDOOLQEORRGSUHVVXUHDFFRPSDQLHGE\UHH[WDFK\FDUGLD
DQGLQFUHDVHGFDUGLDFRXWSXW,WLQWHUIHUHVZLWKWKHDFWLRQ
RI LQRVLWRO WULVSKRVSKDWH RQ &D+ UHOHDVH IURP WKH VDUFR
SODVPLFUHWLFXOXP,WVRULJLQDOFOLQLFDOXVHZDVLQK\SHU
WHQVLRQDQGLVVWLOOXVHGIRUVKRUWWHUPWUHDWPHQWRIVHYHUH
K\SHUWHQVLRQ LQ SUHJQDQF\ EXW LW FDQ FDXVH DQ LPPXQH
GLVRUGHU UHVHPEOLQJ V\VWHPLF OXSXV HU\WKHPDWRVXV VR
3KRVSKRGLHVWHUDVHV 3'(V VHH &K  LQFOXGH DW OHDVW  DOWHUQDWLYHDJHQWVDUHQRZXVXDOO\SUHIHUUHGIRUORQJWHUP
GLVWLQFWLVRHQ]\PHV0HWK\O[DQWKLQHVHJWKHRSK\OOLQH WUHDWPHQWRIK\SHUWHQVLRQ,WKDVDSODFHLQWUHDWLQJKHDUW
DQG SDSDYHULQH DUH QRQVHOHFWLYH 3'( LQKLELWRUV DQG IDLOXUHLQSDWLHQWVRI$IULFDQRULJLQLQFRPELQDWLRQZLWKD
KDYH DGGLWLRQDO DFWLRQV 0HWK\O[DQWKLQHV H[HUW WKHLU ORQJDFWLQJRUJDQLFQLWUDWHVHHFOLQLFDOER[S
PDLQHIIHFWVRQEURQFKLDOVPRRWKPXVFOHDQGRQWKH&16
DQG DUH GLVFXVVHG LQ &KDSWHUV  DQG  ,Q DGGLWLRQ WR Ethanol
LQKLELWLQJ 3'( VRPH PHWK\O[DQWKLQHV DUH DOVR SXULQH (WKDQROVHH&KGLODWHVFXWDQHRXVYHVVHOVFDXVLQJWKH
UHFHSWRUDQWDJRQLVWV&K3DSDYHULQHLVSURGXFHGE\ IDPLOLDU GUXQNDUGV XVK 6HYHUDO JHQHUDO DQDHVWKHWLFV
RSLXP SRSSLHV VHH &K  DQG LV FKHPLFDOO\ UHODWHG WR HJSURSRIROFDXVHYDVRGLODWDWLRQDVDQXQZDQWHGHIIHFW
PRUSKLQH+RZHYHUSKDUPDFRORJLFDOO\LWLVTXLWHXQOLNH
PRUSKLQHLWVPDLQDFWLRQEHLQJWRUHOD[VPRRWKPXVFOH
,WVPHFKDQLVPLVSRRUO\XQGHUVWRRGEXWVHHPVWRLQYROYH
D FRPELQDWLRQ RI 3'( LQKLELWLRQ DQG EORFN RI FDOFLXP
&K

$QDXWRLPPXQHGLVHDVHDIIHFWLQJRQHRUPRUHWLVVXHVLQFOXGLQJMRLQWV
EORRGSODWHOHWVVNLQDQGSOHXUDOPHPEUDQHV,WLVFKDUDFWHULVHGE\
FKDQQHOV6HOHFWLYH3'(W\SH,,,LQKLELWRUVHJPLOULQRQH DXWRDQWLERGLHVLQFOXGLQJDQWLERGLHVGLUHFWHGDJDLQVW'1$ 273

vip.persianss.ir
22 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS

INDIRECTLY ACTING VASODILATOR DRUGS WKHUHE\FDXVLQJIXQFWLRQDODQWDJRQLVPRIWKHFRQVWULFWRU

7KHWZRPDLQJURXSVRILQGLUHFWO\DFWLQJYDVRGLODWRUGUXJV WRQHFDXVHGE\V\PSDWKHWLFQHUYHVDQGDQJLRWHQVLQ,,
DUHLQKLELWRUVRIWKHPDLQYDVRFRQVWULFWRUV\VWHPVQDPHO\ 0DQ\ XVHIXO GUXJV DFW E\ EORFNLQJ WKH UHQLQ
WKHV\PSDWKHWLFQHUYRXVV\VWHPVHH&KIRUDGLVFXVVLRQ DQJLRWHQVLQDOGRVWHURQHV\VWHP5$$6VHH7DEOHIRU
RI GUXJV WKDW LQWHUIHUH ZLWK V\PSDWKHWLF QHXURWUDQVPLV DVXPPDU\RIVHOHFWLYHDQWDJRQLVWVZKLFKFDQEHLQKLE
VLRQDQGWKHUHQLQDQJLRWHQVLQDOGRVWHURQHV\VWHP LWHGDWVHYHUDOSRLQWV
7KH FHQWUDO FRQWURO RI V\PSDWKHWLFDOO\ PHGLDWHG YDVR  UHQLQUHOHDVHDGUHQRFHSWRUDQWDJRQLVWVLQKLELW
FRQVWULFWLRQ LV EHOLHYHG WR LQYROYH  DGUHQRFHSWRUV DQG UHQLQUHOHDVHDOWKRXJKWKHLURWKHUDFWLRQVFDQ
DOVR DQRWKHU FODVV RI UHFHSWRU WHUPHG WKH LPLGD]ROLQH , UHVXOWLQDVPDOOLQFUHDVHLQSHULSKHUDOYDVFXODU
UHFHSWRUSUHVHQWLQWKHEUDLQVWHPLQWKHURVWUDOYHQWUROD UHVLVWDQFH
WHUDO PHGXOOD &ORQLGLQH DQ DGUHQRFHSWRU DJRQLVW  UHQLQDFWLYLW\UHQLQLQKLELWRUVLQKLELWFRQYHUVLRQRI
QRZ ODUJHO\ REVROHWH DV DQ DQWLK\SHUWHQVLYH GUXJ DQG DQJLRWHQVLQRJHQWRDQJLRWHQVLQ,
PR[RQRGLQHDQ,UHFHSWRUDJRQLVWORZHUEORRGSUHVVXUH  $&($&(LQKLELWRUV$&(,VVHHEHORZEORFN
E\ UHGXFLQJ V\PSDWKHWLF DFWLYLW\ FHQWUDOO\ ,Q DGGLWLRQ FRQYHUVLRQRIDQJLRWHQVLQ,WRDQJLRWHQVLQ,,
PDQ\ YDVRGLODWRUV HJ DFHW\OFKROLQH EUDG\NLQLQ VXE  DQJLRWHQVLQ,,UHFHSWRUV$7UHFHSWRUDQWDJRQLVWV
VWDQFH3H[HUWVRPHRUDOORIWKHLUHIIHFWVE\VWLPXODWLQJ $5%VVHHEHORZ
ELRV\QWKHVLVRIYDVRGLODWRUSURVWDJODQGLQVRURI12RURI  DOGRVWHURQHUHFHSWRUVDOGRVWHURQHUHFHSWRU
ERWK E\ YDVFXODU HQGRWKHOLXP VHH DERYH DQG &K  DQWDJRQLVWVVHHEHORZ

Table 22.4 Summary of drugs that inhibit the reninangiotensinaldosterone system

Class Druga Pharmacokinetics Adverse effectsb Uses Notes

ACE Captopril Short acting Cough Hypertension ACEIs are cleared

inhibitors t1/2 2 h Hypotension Heart failure mainly by renal
Dose 23 times Proteinuria After MI excretion
daily Taste disturbance
Enalapril Pro-drug active Cough As captopril Lisinopril, perindopril,
metabolite Hypotension ramipril, trandalopril
enalaprilat Reversible renal are similar
t1/2 11 h impairment (in patients Some are licensed
Dose 12 times with renal artery stenosis) for distinct uses (e.g.
daily stroke, left ventricular
hypertrophy)
Angiotensin Valsartan t1/2 6 h Hypotension Hypertension ARBs are cleared by
receptor Reversible renal Heart failure hepatic metabolism
blockers impairment (in patients
(ARBs) with renal artery stenosis)
Losartan Long-acting As valsartan As valsartan Irbesartan is similar,
metabolite Diabetic with t1/2 1015 h
t1/2 8 h nephropathy
Candesartan t1/2 510 h As valsartan As valsartan Given as prodrug
Long acting ester (candesartan
because receptor cilexetil)
complex is stable
Renin Aliskiren Low oral As valsartan, also Essential Contraindicated in
inhibitor bioavailability diarrhoea hypertension patients with renal
t1/2 24 h disease, diabetes
Aldosterone Eplerenone t1/2 35 h As valsartan, especially Heart failure after
antagonists hyperkalemia MI
Nausea, diarrhoea
Spironolactone Prodrug converted As eplerenone Primary
to canrenone, which Also oestrogenic effects hyperaldosteronism
has t1/2 24 h (gynaecomastia, Heart failure
menstrual irregularity, Oedema and
erectile dysfunction) ascites (e.g. in
hepatic cirrhosis)

a
All drugs listed are orally active.
b
Adverse effects common to all drugs listed include hyperkalemia (especially in patients with impaired renal function) and
teratogenesis.
ACEI, angiotensin-converting enzyme inhibitor; MI, myocardial infarction.
274

vip.persianss.ir
 THE VASCULAR SYSTEM 22
Binding
sites
Active site

ACE

C-terminal of Captopril
angiotensin I

NH2 B
A
Zn2+ Zn2+
N N
PLASMA MEMBRANE
CH3 H 2C CH2
O CH2 CH3 CH3
H HS CH2
C N
COOH C C N CH2 C C
N H C CH CH
H O
O C O C O
Cleavage
point O O

HN NH2 HN NH2
H C H C
X NH X NH

Fig. 22.7 The active site of angiotensin-converting enzyme. [A] Binding of angiotensin I. [B] Binding of the inhibitor captopril, which
is an analogue of the terminal dipeptide of angiotensin I.

Renin inhibitors UHFHLYLQJ GLXUHWLFV $&(,V DIIHFW FDSDFLWDQFH DQG UHVLVW

$OLVNLUHQ DQ RUDOO\ DFWLYH QRQSHSWLGH UHQLQ LQKLELWRU DQFH YHVVHOV DQG UHGXFH FDUGLDF ORDG DV ZHOO DV DUWHULDO
ZDV GHYHORSHG DQG UHJLVWHUHG DV DQ DQWLK\SHUWHQVLYH SUHVVXUH7KH\DFWSUHIHUHQWLDOO\RQDQJLRWHQVLQVHQVLWLYH
GUXJ ,W LV D WULXPSK RI GUXJ GHVLJQ DQG ORZHUV EORRG YDVFXODU EHGV ZKLFK LQFOXGH WKRVH RI WKH NLGQH\ KHDUW
SUHVVXUH EXW KDV EHHQ FOLQLFDOO\ VRPHZKDW XQVXFFHVVIXO DQGEUDLQ7KLVVHOHFWLYLW\PD\EHLPSRUWDQWLQVXVWDLQLQJ
ZLWK DGYHUVH HIIHFWV WKDW LQFOXGH GLDUUKRHD FRPPRQ DGHTXDWH SHUIXVLRQ RI WKHVH YLWDO RUJDQV LQ WKH IDFH RI
DFXWH UHQDO IDLOXUH DQG UDUHO\ DQJLRHGHPD DQG VHYHUH UHGXFHGSHUIXVLRQSUHVVXUH&ULWLFDOUHQDODUWHU\VWHQRVLV
DOOHUJLFUHDFWLRQV UHSUHVHQWV DQ H[FHSWLRQ WR WKLV ZKHUH $&( LQKLELWLRQ
UHVXOWVLQDIDOOLQJORPHUXODUOWUDWLRQUDWHVHHEHORZ
Angiotensin-converting enzyme inhibitors &OLQLFDOXVHVRI$&(LQKLELWRUVDUHVXPPDULVHGLQWKH
7KH UVW $&(, WR EH PDUNHWHG ZDV FDSWRSULO )LJ  FOLQLFDOER[
DQ HDUO\ H[DPSOH RI VXFFHVVIXO GUXJ GHVLJQ EDVHG RQ D
FKHPLFDONQRZOHGJHRIWKHWDUJHWPROHFXOH9DULRXVVPDOO
SHSWLGHV KDG EHHQ IRXQG WR EH ZHDN LQKLELWRUV RI WKH Clinical uses of angiotensin-
HQ]\PH &DSWRSULO ZDV GHVLJQHG WR FRPELQH WKH VWHULF converting enzyme inhibitors
SURSHUWLHV RI VXFK SHSWLGH DQWDJRQLVWV LQ D QRQSHSWLGH
PROHFXOHWKDWZDVDFWLYHZKHQJLYHQE\PRXWK&DSWRSULO Hypertension.
KDVDVKRUWSODVPDKDOIOLIHDERXWKDQGPXVWEHJLYHQ Cardiac failure.
RUWLPHVGDLO\0DQ\RIWKH$&(LQKLELWRUVGHYHORSHG Following myocardial infarction (especially when there
VXEVHTXHQWO\ 7DEOH  ZKLFK DUH ZLGHO\ XVHG LQ WKH is ventricular dysfunction).
FOLQLFKDYHDORQJHUGXUDWLRQRIDFWLRQDQGDUHDGPLQLV In people at high risk of ischaemic heart disease.
WHUHGRQFHGDLO\ Diabetic nephropathy.
Pharmacological effects Chronic renal insufciency to prevent progression.
$&(LQKLELWRUVFDXVHRQO\DVPDOOIDOOLQDUWHULDOSUHVVXUH
LQKHDOWK\KXPDQVXEMHFWVZKRDUHFRQVXPLQJWKHDPRXQW
RI VDOW FRQWDLQHG LQ D XVXDO :HVWHUQ GLHW EXW D PXFK
ODUJHU IDOO LQ K\SHUWHQVLYH SDWLHQWV SDUWLFXODUO\ WKRVH Unwanted effects
LQ ZKRP UHQLQ VHFUHWLRQ LV HQKDQFHG HJ LQ SDWLHQWV $GYHUVHHIIHFWV7DEOHGLUHFWO\UHODWHGWR$&(LQKLEL
WLRQDUHFRPPRQWRDOOGUXJVRIWKLVFODVV7KHVHLQFOXGH

7KHOHDGFRPSRXQGZDVDQRQDSHSWLGHGHULYHGIURPWKHYHQRPRI
%RWKURSVMDFDUDFDD6RXWK$PHULFDQVQDNH,WZDVRULJLQDOO\

FKDUDFWHULVHGDVDEUDG\NLQLQSRWHQWLDWLQJSHSWLGH$&(LQDFWLYDWHV 6HYHUHQDUURZLQJRIWKHUHQDODUWHU\FDXVHGIRUH[DPSOHE\DWKHURPD
EUDG\NLQLQ&K &K 275

vip.persianss.ir