23
\\hut are diuretics?
llo" do diuretics work?
What a r·c their
ptinciple sites of
action?
Why iknowing the
sites of ucUon
important?
Nttme the fh·e major
classes of di uretics.
CARBONIC ANHYDRASE INHIBITORS
Wlwt il> the function
of cur·booic
aub)'drase?
Huw docs a c:wbonic
a uhyd.-ase
inhibitor·produce dhu·csis?
Diuretics
Diurc>ti"' ;tn• dm' th.tt incrca.w the
Wllllllll' of llriJILI fluw.
In erwral, tlinrl'tit'affl•d ion tmn,port
in the: rwphron < hnKtlh u dul diuretics
prirnaril) mhibit n+ rl•ab,urplion.
\\'at('r i tlwn c·arrwd alonpas,iwlv io
ordt•r to lll<llntain an mmultc: t·quilibrium.
Proximal t·onvol ut<'<lluhulc (PCT)
Th ick ll'lt'l'nulng limb orloop of ll eul
e Distal C'Ouvol utt:d tulJII It• ( DCT)
Collc>C'I i nclut·t
Set• Figmt· 23 J .
This kum\hl t·lwlp' pn·tlkt·
Tlw ma nit udt• .mel pattl'm nf tliurc\is
Tlw \kit· t"ITt ·<:I\ oft lw nwdwation
TIIC pallt·m or t•lt•dmlytt·Jm,
1. C::nrhoult' .wh,dr.t,t• inhihitt>r.
1. l..nc>p cliun•tit'
3. Thrazitlt• cliun·tk'
1 0\IIIUtit• cJiuretit·\
.'>. Puta,\\illlll·\p.triudurrl'lic'
Carhom<: uuhHir.L\t' i\ .Ul t'OAIIlt:that
clt.tl ,t·tlw ii>llo\\illr<'adi;m:
T he II t ion prod tll't •d b) Ill!' ltt't'il
kdown of 112C0.1 i tt ua lly t•whllt tl-(Pd
for Na...
11ncl is nlso u t·d to t'tHnhhu· with II C0;1
in tlw lu n wn of til!' PCT \\'itltot t l LlttH
thcn> 1\ cl('t n ·.twd rPaho,orpt ton nf' 'IJa'
ant] 11('0 1 • th" n'"'lt' iu d111rt·'h
Sc<> Figure 2J-2.
167
168 Sectlon IV I Cardiovascular System

W.jor Locai>Ons of ion and Water Ea<Nnge In lhe Nephron

._., ,
. ......... o ...,._...,.
I..., -- i
-
- ....

- .-
, IO riclf.
O

· ...
........, ti!HI•M'd...
·-
•-...o-
..OCICift I'IIIJ'OIGf

u Perper - - -
..
Figure 23-1.Major locations of ion and water exchange in the nephron, showing sites of
action of the diuretic drugs. (Redrawn from Mycek MJ, Gertner SB, MM (Harvey
g n.,o ..n
RA Champe PC, eds]: Lippincott's Illustrated Reviews: Pilormacology, 2nd ed. Philadelphia.
Llpplncott·Raven Publishers, 1997,p 224.)

Ho\\ eflicient ith e It i' rd.lti\ t·h·\\ ··ak. l){'(·au'l' othl'l

diures:io; produ<.-cd by a sih· furtlwr along in lhl• rll'plmm t"an
carbonic anh)Clnl.\C l'(IIIIJX'Il'•'h' lor the incrt'iL\t:d '\a•
inhibitor? load.

Naml· lht." prototype

carhoni<- unh)draJ.e
inhibitor.

What i\ thl• route of

Onu or 1\'
admin·
i!.trution?

\\1ral arc the dinicaJ uses Clam'(lllla-kct<volamide dt'C'rt>iL\l''

of acel;uolnmidl'? prndudiun uf aqut>ou' humor .
l <>taholal alf..alusi., and acute mounlmn
si<.'k-nt·s-kl•tawlanmlt> mhih1ts
carhonic nuhnlrase at·ido b. r!.'sulting
111 slin1ul.ttiun uf respiration.
Epik•psy

What Ul'l' this llypert:h l oremi(' nwtaholic acidosis

drugs' cuuH·d bv loss of b1 carhonall'
adverse cO'cct s? Potassium cic>piPtion t•auscd by lht>
'odnun load and incr<>:twd fin,, ratt•
pa\1 Llw I
X'T
Rt>nalt..tbrlus
Pan ''he,ia
Chapter 23 I Diuretics 169

ProximalTubule
Interstitial
space

Na•

K+

H+ Na•

H2C03 I ! Hco3•
t---

\ H2C03
 HC03"

CD
C02 + H20
CA
t
C02 +H20

Figure 23-2. NaHC03 reabsorption In the proximal tubule and mechanism of

diuretic action of carbonic anhydrase (CA) inhibitors. A antiporter: S symporter:
CH = ion channel.(The actual reaction catalynd by carbonic anhydrase Is OH 1 C02
¢HC03 ;
however.H20 ¢OH- + H.and HC0 3 + H ¢ H1C01, so that the net
react1on is
H20 + C02 FH2C03 .) Numbers in parentheses lndic.1te stoichiOmetry (Redrawn
from
Goodman and Gilman [eds]: The Phormocologe 8as1s of TheropeuiJCS, 7th ed. New
York.
Macmillan. 198S. p 693.Used with permission of The McGraw-Hill
Companies.)

Dro'' \illt'\'
lnl<•rstiti,tl rll'phriti' \td;vul;. midl' i.a
\ulfondnudt> dt• ri\ .11i\ l

LOOP DIURETICS

l\ amc the loop diuretics. Furowmid< ( l.ml'o:l t'lhat'r\lllt'

,tc..·td
( Etl<•(·nu ), <lnd hmm t.umlt• l Mil lilt'\)

What are the mechanism Loop dmrdl<'' \ ork h\ hl<x·k111the

of ncUon nn d site of action Na+fK+/2CJ- c.•.o-t ntnsport system
of these drugs? in the thick a...ccndiug llmh of the
loop of Henle.

Why are the loop diu1e· Bc>c·ausc> tlwy haw till' ltigh <•st t•ffkacy of
tics nlso called "high lll dlnrt• tie
ceiling diuretics"'?

Why are they the most 2.'59f to :l!)q of N.tCIis uonnalh

efficacious diuretics? rl'absorht>d at the• ii\Cl'lldinloop of
r lf'nlc Sill'' dcm 11\lr<'=.mt along the
170 Settion IV I Cardiovascular System

nephron (di,tal t •muluh·d tuhult• and

c-ofb:ting dut-1) c·anuut full\ l'flmlwnsatE>
if 'a '" reah\orpticm 111 tln•loup of lll•nlc
is bloch·tl.

llo\\ do loop djurcti<:!> affect Loop diurl'lit·,int·n•aw till' C.,:z • t'lmlt'nl

Cat+ metabolism? of tltt.• urint•.

\\hut arc the clinical uses of Pulmonan l'tk•m,t

loop dim·eli<:!>? :\cute h}l ·rmlt't'lni.t .md h\ pt•rlwkmia,
and : t·ult• n·nall:tilun

What i\ the route of [\'or or.1l

administration?

\Vlmt arc the adverse effect'>? Volume clc>pl<'limt

Ototoxidty- C\IWl'l 'tlly "ltt'll 11 cd iu
conj11nt'liou wi th 1111
Hlltiuolycllsidc
ll yp(·nuicemi:•
ll ypokalr>Jnia
H YJ1omaglt(·st•mi:l
ll}1ll'lC<tk{'tttla
11;.-lwrrhlon·nHc' 1111 l.tholl(' alkalmis
l ntcrslilialuepltrilis Loop cluu('(ic·'an'
sulfon,unitll' clt>ri\ .tliws

THIAZIDE DIURETICS

What arc the)'? Sulfonamidl' dc-ri\ .tliH·s n•latt-d

stntchJr.LII} 111 IIH' c·.uhunw anh)tlr.Lw
inltihitol"\

Chlorolhi.vitlt•-prtlllll l"'
I h drcx:hlumthi:vult• ( ll)dru DI U IUL)
\letohvotw aml l nd.tp.unitk··thiat.ith•
analOgi It'

Wlwrt.• do the} work? All thi;vides \\urk 111 tlw c•arh st•gnwnt of
the distnlt·omolutt•tl tuhuk·: .

llow do they work? They blcwk '1/a f /CI to tnm porton the
luminul itlt• of' tlw di talconvolut<'d
tubule.

I low effective are lhiazides? They an· oul) lllndt•rutd)• dlc•ttivt·

hecaus<> mot ()f tlw liltt•n•d I"a 1s
nbsorbt•d hefon· it n•adw I lw
I)C1·.
\\1mt are the mes of
thi:uidc ? Tht'\ are uwd to lrt•al:
J-IllCrtl'nsion

Which thiazides are most
cffeclhf.•?
llo" do truazides affect
Cu2• Je,el<>?
Whnt u•·c the !> ide effects
of thia:l'ido diuretics?
OSMOTIC DIURETICS
\\hat are the most common!)
u'ed osmotic diuretics?
\\'hat i' their mechani'IUl
of ucHon?
\\ hat are Lhe clinical uses
of these ch·ugs?
What is the route of
adrninish·ation?
What are the toxicities
\ociatcd with osmotic
diuretics?
Chapter 23 I Diuretics 171
Conw·stin• heart failure
'\t·phrmis
lhp<'n·.tlt·•uria
:-.q>hm c·nic- clialwte" ""'P•dus
TiuazJcl!'s ha'e thE' abilil) to pnxluce a
11\TK'rnsmolar uriJW and thus di111inish
polyuria.
t\llthiaL.idt•s an• equalh clft•divc; tl•c)
difTl•r onh tn potc>nt'\
Thta7idcs, unlil.l·loop diurctic:s im:-
rease Ca1• l<'wls in tlw blood, so \\,ttch
lor h)1>ert·.tk·c••nitl.
II}1>okaiL•ntia
ll vpochlnn•m i c nwtahnlk·
ulkalui., llypcruric:Clltia
IJypNglyt·t•n• ht
llypc•rl lpidc•min
1ryponatrt•mia
I hV<'rt·ake111ia
\l;um•tol and urt•a
o..molic diurdic-s arE> frc·d) flltc•rahlt'
suhstanc·t•s; Olll'l' tht.•\ bc<:onw a
compout·nt of the lumin;tllluicl tlu•\
cn•alt' ;Ill o'motie t'fft·<.·t along tlw t•ntirc>
nt'phmn but l'spcciall} at the P< T and
t>t>llt'f.·tin,g duct
Osmoli< cluarcticarc mainl) ll t·d in t1
ho,pital setting to trf'at mt·rea,c.·d
intmeranml and intraocular pr!•ssure .llld
acute.· renal fitilure.
TlwsP drugs must be given JV; other
r11odc ·s of ltd ministration will t·austl
call lllrl i c clinnh ca.
I 1)1lO\'C>IC'mia
I hvc.•matrc•mia
Can cause pulmonary edema bt'<.·.wse
tht·) rapidh cntt'r the C\tr.lct>llular
comp.lrtnwnt .mel pull ",tter out of cdls
I72 Section IV I Cardiovascular System

POTASSIUM-SPARING DIURETICS

Che examples of this class Spanmoladurw (Alda<:toaw)

of drugs. t\miloaiclt• ( \1idam or)
TnamkrPill' (O)Tl'Oium )

What is thei r mechanism Tlw\ work primarily hy inhihililllht• pa

of action? agt• of odium in tht> luminal fluid into
llw print'ipal wllof the latl' distal
ronvolutpd tubuk• and <:orti<.-.11 ('OIIl'cting
tubult• uh t·quentl}. this prc\cnt\ thl•
mowmt·nt of K fmm thl'\C tl'Us into the
luminal lhml S :t• Fip;lU'l' 2.'3 '3.

Late DistalTubule and Collecting Duct

Lumen (-) (+) lnter-

Pnncipal cell Stllial
space

---,."""=:"'- HC03'

--1'""'--- cr

Principal cell

Figure 23-3. Na' reabsorption in the late discal tubule and collecting duct and mecha·
nlsm of diuretic action of Na'" channel inhi bitors. Cl reabsorption (not shown) occurs
both paraccllularly and rranscellularly.and the precise mechanism of Cl transport appears
to be species-spec•fic. A = antiporter:CH ion channel: CA carboniC anhydrase.
Num bers In parentheses tndteate stoichiometry Destgnated voltages are the potenttal
dtffer ences across the tndtcated membrane or cell. (Redrawn from Goodman and Gilman
(eds): The PhormocoloftC 8osJs a(Theropeutx;s. 7th ed, p 703 New York. Macmtllan. 1985.
Used Wlth permission of The McGraw-Hill Companies.)

Whot b the efficacy of
thce drug ?
What h 'Pironolactone?
\\hut urc the clinical indi
cutiom for th E.- me of spiro
nolacton e?
Are tht•·c prc,bloms asso
ciated with administration
of \pimnolactone?
Ho'' doc'spironolactone
differ from lriamterenc and
amiloridt.>?
What are the ad'erse
effects of potu....ium-sparing
drugs?
Chapter 23 I D1uret1cs 173
\\ t'•l.Tht·\ ilrt' used tcKf.t) primarily in
t'<>njun<'llon \\ ith anotlu: r diurdit• \Uc::h
a thi<V.Idl' in ordt·r<LS to limit 1\ \\,t.stin .
Tim dn1g is a \'\lltlwtic sh>roid th<ll "a
<.'<liiiJlt't itiw antagoni't fiJr tlw
lllllll'r<tiO<.'<)rlK'<IItl aldostt'rww It hiuds to
aldust<·mnt· n.·c::<:ptor 'ill's und JWC'\ t•nh
tlw formation of mt·diJLor protdns that
st unulalt t lw \;a /K 1 pump
Primal) h l raldoskrmtl\lll (f'..oun\
S\mlrnnw)
Edt· natm".. talC\ c::amc::d hy 't't'tlll<bn·
aldmtt•mnism. t•spc::dalh c::1rrhosis
•wphrotk· S}ndrolllt', and t•anklt
fai ln rt•
Cyn ct'OII I<I.'• ti n and i mpol t'ntt', nwi n).(
to spi ronoladont'\ stnwt n ral si n1il arity
to progf•\tc•m•w
t\ miloridt' and lriJmlert•m• wor
imlC'pt'ndC'nlh of aldo tt.·ronc t,,dirt•t:tly
hloc:kmtlw 'sa- chamwl; therefort·,
tl t-\C' .l t·nh t';lll IX' 11\t'(l c::H·n in c-.t.s('s nf
II\ poaldo t<·ronism such ;ts \cldl\on\ di
C';tw I n ('()lllr..t\l. spuunohu.:tmw
WCJIIin·s C'lt-vatC'clleq J,of .Jldostt•rone to
haw an t•ffc::ct.
11\'pt rlalt•mia-most important dl(•ct to
\\<Itch for
letabolit. a<:idosis-bc<.<tlll\t' of tn
tntnlC'dlultlr shift or,,..
ion...
lbrd}, lriamtt•rt•nt! fonnr('n;ll slclnC' .