Diuretic therapy in syndromes associated with sodium and water retention∗

Report on Therapy Diuretic

Therapy

in Syndromes

with Sodium

and Water

Associated

Retention*

JOHN H. MOYER, M.D., F.A.C.C. uncf MORTON FUCHS, Philadelphia,

Pennsylvania

T

view that the primary effect is on chloride reabsorption while others favor the view that the primary effect is on sodium reabsorption. Definitive conclusions cannot be drawn since even though there is frequently a greater relative increase in the rate of chloride excretion, this could indicate an increased rate of excretion Increased rate of of cations other than sodium. water excretion usually follows increase in sodium and chloride excretion. During mercurial diuresis the glomerular filtration rate may rise, fall or show no change. Changes in renal plasma flow show a similar inOne must conclude from these consistency. observations that changes in alomcrular filtration rate or renal plasma flvw are not involved The effect in the diuretic effect of these agents. of mercurial diuresis on potassium excretion is Unless there is a massi\-e diuresis, povariatjle. tassium excretion is not increased significantly (Fig. l).g NV serious disturbances of potassium metabolism occur with the usual clinical use of mercurial diuretics. Many of the mercurial diuretics currently used are compounds formed I~)- the reaction of theophylline with an organic mercurial. The result of such a reaction is ta form a more stable, less toxic and more rapidly absorbed After intramuscular administracompound. tion of compounds of this type [for example, meralluride (Mercuhydrin@) ] absorption is The amount of theophylline virtually complete. present in a therapeutic dose of a mercuriai (98 mg.) is too small to exert any diuretic effect except by improving the rate of absorption of the mercurial.

HE DISCOVERY by Vogl that the organic mercurial merbaphen (Novasurol@) produced diuresis initiated extensive studies on the effects of such compounds that have continued up to the present time. Until recently, diuretic therapy centered largely around mercurial compounds. Numerous non-mercurial diuretics for oral administration have now appeared. The carbonic anh!-drase inhibitors and chlorothiazide, a compound with minimum carbonic anhydrase inhibitory effects, are outstanding examples. These agents appear to be indicated in the treatment of many diseases in which the kidneys fail to excrete adequate amounts of salt and water resulting in a wide variety of symptoms. The purpose of this paper is to review the pharmacodynamics and clinical use of these compounds. PH,~Rh~ACOLoGY

OF

MERCURL~L DIURETICS

Renal Function Studies: A substantial number of observations have been made on the effects of Except mercurial diuretics on renal functions. for a depression of renal tubular reabsorption of sodium chloride and water, no consistent change has been observed to occur.’ This is true of normal subjects or patients with edema and esperimental animals. It is generally assumed that specific transport systems are present in the cells of the renal tubule for the reabsorption and secretion of different ions and compounds present in the glomerular filtrate and the l)lood.“-5 The composition of the urine before and during mercurial diuresis indicates a highly selective inhibitory action on only a few of these transport mechanisms.6-9 There are proponents of the * From the Department vania.

of Internal

Medicine,

hf.D

Hahnemann

786

Medical

College and Hospital,

THE

AMERICAN

Philadelphia,

JOURNAL.

Pennsyl-

OF CARDIOLOGY

Diuretic

Therapy

in Sodium

anti

Water

ACETAZOLEhMlDE -

250

mpm

mm

(DIAMOX)

)

-F MERCVMATILIN i 80

787

Retention

(CUMERTILIN)

NQl

AMlNOPHYLLiN rJ=J ~MINOISOMETRADINE

wOLICToN1

1600 mpm _ -___ CnLDRMERODRlN 80

hla PLACEBO

K

Cl

C HL OROTHIAZIDE

lo

K

Cl

RALLURIDE !CC

Mercafdomerin: .i\ different type of compound was introduced more recently. The compound is known as mcrcaptomerin sodium (Thiomerin$ sodium). In this compound, the theophylline of mercurophyllinc* sodium has lIeen replaced 11) sodium thiogl@atc. This mercurial was studied after observations indicated that glutathione and cysteine reduce the cardiac toxicity~ of mercurials without influencing the diuretic effect. .\fter intramuscular or subcutaneous injection the rate of al)sorption of mercaptomerin is of the same order as the aforementioned compounds, but the potency is not as great (Fig. 3). This compound ii administered extensively I)!, the subcutaneous route because of the low incidence of local reactions and pain at the injcction site. Parentertll Administration: The rate of excretion of mercur); after subcutaneous, intramuscular and intravenous administration of meralluridr: is quite similar in patients with minima1 edema. This indicates that the rates of absorption from both sul)cutaneous and intramuscular sites arcs \rery rapid, i.e., up to 90 per cent within twentyfour hours. The increase in sodium excretion parallels the excretion of the mercurial. 111 patients \yith severe heart failure, the urinary excretion of mercurials may be delayed somewhat folIowinS intramuscuIar or subcutaneous injection due to the poor circulation (Fig. 3). Unless absorption is delayed, 30 per cent or more of a therapeutic dose of a mercurial given parent 95’)

rt

mgm

(NEOHYDRINI

Hq

WloMERlN

80

IM

FIG. 1, -4 compnrison of the rffect offilocebo. chlot-othlaride and nwailurtdc on urinnry tlcclrolytr excretion. When mera:luride was administered parenterally, the primary effect was an increase in sodium and chloride excretion with a When chlorominimal t-ffect on potassium excretion. thiazide was administered the primary effect was also on sodium and chloride excretion but therr was also a sig-nilicant increase in potassium excretion.

DE:CEMBk,K

5

mgm

WERCAPTOMERINI Hg (2Cc)

MERALLURIDE 80

mwn

I+3

(MERCUHYDR~NI (2CC)

I

L 20

40

60 INCREASE

100

80 IN

SODlUll

(YILL1EQUIVALENTS

120

140

160

EXCRETION 24

HOURS)

&nparaliue fotency of various orui and prr?‘entero/ d&r&c qents. Chlorothiazide administered orally was of the same order of potency as meralluride administered parenterally. Both of these agents were more potent than acrtazolamide and chlormerodrin given orally and mrrcaptomcrin given parrntcrally. FIG.

;!.

_

; z DL :

DEGRAOAllON

PRODUCTS

0 0

6

12

18

24

HOURS

FIG. 3. Comparison of excretion rate of meralluride (Mercuhydrin) followirrg the intravenous and intramuscular routes of ndmit&ration, in a patient with edema and heart failure. ;Ibout 70 per cent of the drug was excreted within twelve hours following administration by the intravenous route. The urinary excretion rate of meralluridc was delayed following the intramuscular route of administration due apparentlv to a decrease in the rate of absorption from the injection site. (From: Moyer, J. H., Seibcrt, R. A. and Handley, C. A. (3lrculation Res., 5 : 493, 1957.)

terally is usually excreted in less than six hours. Oral Mercurials: Oral therapy with mercurial diuretics was unsatisfactory until the recent introduction of chlormerodrin (Yeoh!-drin@). Since absorption of mercurial diuretics from the intestinal tract was so limited. the amount of

Moyer and Fuchs -4

1

500 LOG

DOSE_

m~llqroms

,

2000

,000 Dlomos

40 60 Nsohydrln-m,lllpromr

-

1

80 mercury

odnv”l*+srd-

FIG. 4. Dose w~~on~eCWUEto chlormrrodrin(nieohydrin) and acetnzokmide j.Oanmox) usiq weight fess /or ~oq4ariwn. When the dose of acetazolamide was increased from 250 mg. to 2,000 mg. there was no increase in the response. However, when the dose of chlormerodrin was increased progressively, there was an increase in the degree of The minimal effective dose appeared to be response. approximately four tablets (equivalent to 40 mg. Hg). When the dose was increased to six tablets the response was equivalent to 250 mg. of acetazolamide and when the dose of chlormerodrin was increase-d to eight tablets the response exceeded the response to acetazolamide by a significant degree. (From: Moyer, .J. H., McCann, R. G., Seibrrt, R. A., Dennis, E. rt’. and Hughes, W. J. Chronic Dis., 2: 670, 1955.)

that could be removed from the urine after oral administration of previously available mercurials was less than 3 per cent of the dose administered. This necessitated the use of large doses that frequently caused gastrointestinal disNot only is chlormerodrin Iletter abtress. sorhed from the intestinal tract (up to 15 per cent), Ijut it is also several times more potent than other currently employed mercurials. It is essential that an adequate dose of this compound (four tablets or more per day which is equivalent to 40 mg. IJg) he administered if an cffccti1.e diuretic response is to he of>tained (Fig. 4). Increasing the dose at,o\re this amount increases the diuretic response progressively. An attriljutc of note with this compound, as with all organomercurials, is that daily administration results in persistent diuresi? and na triuresis. mercury

PHARIII~COLOGYOF CYTOYINE ANDXANTHINE DIURETICS Xanthine derivatives, such as aminophylline and various salts of theobromine, have long heen familiar ad,juncts in cardiac therap)-. These compounds are derivati\.es of purine which is found in nucleic acid. Despite much lower diuretic potent)- than other agents, the xanthines

are still extensively tried in edematous states. This is proba t)ly a reflection of the ahscnce of serious untoward reactions from thee compounds and the unavailal,ility of effective oral diuretics until comparatively- recentI>.. Aminometradine (Mictine”) and aminoisometradine (Rolicton*) are recently- introduced compounds proposed for use as oral diuretics. These compounds are derivatives of the p)-rimidint base c)-tosine which also occurs in nucleic acid. Aminophylline, aminoisometradine and aminometradine have similar effects on renal transport mechanisms for various electrolytes. All three cause an increase in excretion rate o! sodium and chloride, slight inhibition of atnmonia and phosphate without consistent changes in potassium and Kcarbonate excretion. The increase in water excretion is prohaN! secondark to the increase in sodium excretion. The maximum effects of intravenously administered aminophylline within occur two acutel) hours.“‘,” Aminoisometradine and aminometradine exhiljit their maximum effects within six to twel\:e hours after oral administration. PH.~RMACOLOGYOF CARBONIC:ANHYDR..ZSE INHIBITORS Early in the use of sulfanilamide, it lvas noted that the drug produced a consistent reduction of plasma hicarl,onate. Preceding this effect, the urine was &served to tIecome alkaline as a result of increased hicarhonate excretion.“,‘” The discovery that sulfanilamide is an inhii,itor of carbonic anhydras@ and the demonstration of a high concentration of this enzyme in the kidney’” provided a hasis for the mechanism of action of the drug. Carbonic anhydrase is a zinc-containin? enzyme that catal>-zcs the reversil)le rcaction:‘“~” HZ0 + (:O, ;=‘ H&O:: These reactions occur in the absence of the enzyme, hut the presence of carl,onic anhydrase greatly accelerates the rates. Compounds have lieen prepared with several hundred times the activity of sulfanilamide.‘” Among these, acetazolamide (Diamox’“‘) and ethoxzolamide (Cardrase’) arc the ones in current use as diuretics. Renal

Mrci~anisms

for

Maintainin,~

Acid-Base

The diuretic action of acetazolamide is intimately- related to the mechanisms for maintaining acid-),ase halance and particularI>- to the itnportant role of the kidney in this process.

IMnnce:

Diuretic

Sodium

in Sodium

l’hrrapy

Excretion Par

24

hrs.

1 I I I

Retention

anti Water

Potorsium

Excretion

Par 24

hrs.

; ,

Chloride

Excretion Per 24 hrr.

I

I I

rliamox

50 me. Day

1

Dlomor

250mg.

Day

I

Diomoa

250

mp. Day

5. The ektrolyte excretion response to ucrtnzolmmide mth cnnt~nuozrsdm/y ndnunistration. The grcatrst increase in sodium excretion occurred within the first twenty-four hours. This response droppc-d off rather rapidly with daily administration so that by the md of the third day, the patient no long-rl obtained a natriuretic responsr to the drug. I-rc.

Renal rnechanisnks contributing to acid-base balance are largely concerned \viLh conservation of base and carbonic anhydrase is of prime importancv in all thl:ssc mechanisms. The follo\ving renal processes are fundamental for understanding the effects of carbonic anhydrase inhibitors on the kidney. The CO, produced metabolically in tlie cells of the renal tubule i\ immediately con\ertcd to carl)onic acid I)!- thr enz\imr carlIonic anhydrase. Lfrine is acidified t)v the \ecrction of H+ deri\,ecl from carbonic acid furlned in the tubule cells in exchange for Na+ in the tut)ule lulnen.‘“,“’ The exchange of these ions nortnally conserves i~sc in several wa)s. First, there is virtually complete reabsorption of sodium hicarl)onatc presented to the tubules in the glomerular filtrate. Reabsorbed Na+ combines with bicarl)onate in the tubular cells and is returned to the I~lootl. The carbonic acid formed 1)~ the reaction of H+ with bicarbonate in the tubular fluid is con\-erred to Hz0 plus CO? and the latter is returned to the blood II)- diffusion. Second, even after all the I)icarl,onate is reahsorhed front the tul)utar fluid, the exchange of H+ for Nap’ continues to conserve base by other mechanisms. Secreted H+ converts NasHPO* frotn the glomerular filtrate to ?ITaH2P04. This furnishes additional Na + for the exchange process and the exchanged Nat is again returned to the blood as NaHCO.j. Third, in the absence of both NaHCOZj and YalHPO, in the tubular fluid H + and Nat cxchanqe would be self-limiting IXcause of an unfa\~oral)le H f gradient between the

tul)ular cell and the lumen fluid if it were not h formation of ammonia, an additional function of tul)ular cells. The exchanqc of H’ for Na+ from iYaC:l lvould result in the formation of a strong acid. As the tubular fluicl l>ecomes acid, the tubular cells respond IX s~nthcsizinq NH3. The atnmonia diffuses inti tile lut)ular fluid Mtlere iL immediately reacts M.ith H+ to form NH, +.?I Ammonia formation thuh permits H+ and NaS exchange to continur. The5c \everal processes are responsible for returnin? most of ttle Na+ from the glomerular filtrate to the extracellular fluid. Rmal &fftd of Carbonic :lni~ycim.rr Inirrhitors: The administration of sufl icient cthoxzolamide or acetazolamide to inhibit renal carbonic anhyclrasc exerts drastic effects on these tjasic. mechanisms. The decreased rate of carbonic acid formation in the cells of thy renal tubules greatl) reduces the rate of H+ and iYa +- exchange. Qualitati\.ely uniform results ha\,e t;ccn ohscr\cbd in all mammals studied. ‘l‘hc urine rapidlv hecomes alkaline and there is a marked increase in the rate of excretion of sodiu.m, potassium and bicarbonate, and a decrease of titratattle acid and ammonia.‘” \Vith the exccptivn of the increase in potassium excretion, all these changes arc explained I>)- the huppression of H+ and Na+ exchange. Potassium and H+ are believed to be secreted 1)~ the same meckanistn. Therefore, with decrrascd H+ formation, thr competition of the t\vo ions for the transport mechanism is removed and more potassium is cxcreted.z3 The stimulus for am-

Moyer

and Fuchs Clinical

are changes

Lrrnitntions:

\l:hen

administered, in

there

glomerular

therapeutic are

filtration

nv

doses significant

rate,

I~ut

a

blood flow is frequently seen after administration of these agents. The greatest limitations to the use of thrsc compounds are: (I) The limited potw~!~ (Figs. 2 and 4) ; (2) rlx development of acidosis, particularly in patients with renal damage: and (3) the de\-clopment of tolerance lvith continued daily administration (Fig. 5). The latter limits the use of these compounds to milder states of sodium retention wherein a daily and per&rent natriurctic response is not niandatory. slight

HOURS

FIG.

6.

The effat

of chlorothiaride

on electrolyte excretion.

‘The maximum response was observed during the first six hours and the drug continued to bc rffcctive for twelve hours, rrturning to control lewle by about the eighteenth hour. The primary cffrct was to incrrase sodium and chloridr e.ucretion with a lessw cffrct on potassium and bicarbonate vscrction. munia

formation

output

of urine

cretion. not

Excretion

siqificantly

is an results

acid from

of chloride changed.

urine. a larger and

Increased solute phosphate

exis

increase

in renal

Diuretic @PC/: Recently, chlorothiazide (Diuril“) was introduced for oral use’l (Fiy. 13). Chlorothiazide is an effective inhil,itor of carbonic anhvdrase in r’itro. This does not appear to IX the primary mechanism for producing diuresis, however. 155th effective diuretic doses, the increased rate of sodium excretion is nearly I,alancerl l)y increased chloride excretion (Fig. 6). There ii a lesser chanye in the rate of hicarbonate and potassium excretion and urinar)- PH.“” The urinary electrol\-te pattern is somewhat similar to that seen during mercurial diuresis (Figs. 1 and 6). At hi+er dosage lelrels,

Each The effect o”f continuous admini.rtration of chlorothiazide on sodium excretion and weight loss. block represents a twenty-four--hour period during continuous administration of chlorothiazidc in the The patient continued to have a natriuretic response for approximately dose of 2,000 mg. a day. The weight three weeks and then the sodium excretion gradually approximated the sodium intake. loss was maintained due apparently to a reduction in extracellular fluid volume even when the sodium escrction approximated the intake. THE

AMERICAN

JOURSAL

OF

C.ARDIOLOOY

Ijiuretic

Therapy

in Sodium

the urine. t)ccomes alkaline front increased hicartwnatc excretion that is characteristic of cart)onic anllydrase inNAtion in the renal tubules. Acidosis and resistance to the diuretic action does not d?\ThJp on continued administration until there ij a reia ri\:e depletion of I)ody sodium (Fig, 7 ) .l’ii ~L’~ \t’hn this occurs, the excretion rate approxilnates the sodium intake and the patient rwnains at dry weight. During diuresis caused )J\ chlorothiazide, there is no significant change in ~l:-lomerular filtration rate (jr renal plasma fllJ\\- with ttieraprutic doses (Fig. 8). HUveVel-. \\i~n the doses exceed 10 ~ng. .‘kg., thcrc is wmt’ cIcpr~:ssion in glomerular filtration rate which is only a Lemporary response. In human IGoa
lTf,Jcf:

It

\VaS

recendy

ant1 Water

791

Retention

.50

05 I

I

60 RENAL

I

1

0 IO GLOMERULAR

I

I

120

100 BLOOD Mrnn

Rlood

I

I

20 30 FILTRATION

40 RATE

I

I

I

140 FLOW

I60 cc

I

50 cc I min

,

160 mln

60

I 200

Prerrur.

30 50 I I 70 MEAN808L009D0

I

I

I

110 PRE!%RE

I

mm.

120 lip.

I I30

Oh-

served tllat clllorothiazide will enhance the reSPOllSC IO antihypertensivc agcntsZg For example, \vhen chlorothiazide is gi\.en in con.junction \vitil an!. of the yanglionic Mocking agents. the dew requirenlcnt of the Mocking agent ib rcducctl 31 per cent or more in allout thrrcfourths of the patients (Fig. 10). The merhanism wlrrrrl)!- thi< is accomplished is not completcl!- understood. However, similar effects. althougll not as pronounced, are also observed with otller diuretic and natriurctic agents such as chlurmcrodrin when given continuously in adequate doses (Fig. 11) along with specific antihvp~rteiisi\-e :lgcnts which depress sympathctic nc’r\wus s);Wm activity. In tt1c cilsc 01 chlorotlliazirlr, the natriuretic effect is persistent and the hide effects with chlorothiazide are 1~5 marked than thaw observed with the use of oral mercurial diuretics. This makes it more feasitAc to ube this aynt on a long term tjasis in conjunction with antihypertensive agents. Chlorothiazide does not alter Mood pressure in the laboratory animal (Fig. 8). It likewise fails to product a significant reduction of I)lootl

FIG. ‘9. Dm re.rj~onse CWDCS IO chlorotht(bdt~ ord fwdrc cfdoro1hiarzda. The threshold dose of chlorothiazidc appeared to be approximately 125 my. whereas the threshold dose of hydrochlorothiazide was approximately 25 ms. l‘hc maximum rffcctive dose of chlorothiazidr appcarrd to br approximately 1,000 mg. given twice a day. At the maximum cffrctive dose of each dr~~g, thr ~IICI‘KSC in sodium cxcrction was about the sa1;‘c.

pressure consistently in patielltc Lvho arc allowed a re;;ular intake of salt and \vho are not rcceiving- collateral specific antihypertcnsi\.c agents. The drug iy much more effective as an antihyperterAYe agent bvhen given alone if the patient is placed on a highly restricted sodium intake. Freis”” RL is of the opinion that chlorotlliazide, throu+ its diuretic action. c~ecrcases total blood

Moyer

792

and Fuchs

NO

100 E s

m

---

SUPINE

-

UPRIGHT Chlorothlazlde

0 5Gm

15mgm _ _~~~

___-_;

b

/d

I

Mecamylamlne _ F-CONTROL

0

Reserpme

0.5

,~‘~,‘~‘,~“,~~‘,~~~,~~~,‘~‘1’~‘1’~~1’~~1 4 0 I 3 2

35mgm

o d

mgm

Dally

5 MONTHS

6

7

0 d

8

9

IO

FIG. 10. The Qect of chlorothiatide on thf blood ,~~PSSUIPrest)ome lo thr ,gnn~lmnic blocXiq mecnmylamine (Inuersine”) ~yiwn in combinatzon with wwrpinp. Even at half thr dosr of amylamine the reduction in blood pressure was much greater when rhlorothiazidr administcrcd concurrently. When the chlorothiazidr was discontinued, thv blood sure augmentation effect was lost. (From: Heidcr, C., Dennis, 1:. and May-cr, .l,vr. .\‘m 2’or.AAC/Z/I. SC., 71 : 456, 1958.)

volume thcrcl)y making ganglionic Mockade more effective. On the other hand, the increased excretion of sodium produced 1)); administration of chlorothiazidc and the suhsequent reduction in total body, sodium could explain the potentiation of the drug (Fig. 7). The continuous administration of chlorothiazide reduces the vasopressor response to norepinephrine (Fig. 12) and supposedly to sympathetic nervous system stimulation since norepinephrine is the chemical mediator of neuroeffector transmission The role which of vasoconstrictor impulses.“?

the sodium ion plays in hppertension is undoubtedly important although not clearly de. fined. \Vhatever the mechanism of its action, it appears that chlorothiazidc is an important ad,junct in the treatment of hypertension. It i:: still too early to e\:aluate the long term effect of this form of therapy on reduction of Mood pressure.

Controi N0rep,ncphrin.~~i rmn,

Alreialyio”

2mg

hd

I

1:~:. 11. 777~ rffrct of chlormcrodrin on the blood pr~~surc rqfmse to rauwnlfia. Chlormerodrin produces a siqnificant additional reduction in blood pressure which was lost when the chlormerodrin was discontinued. The blood pressure response was reproduced when the chlormerodrin was started again. (Upright blood pressures rccordcd.)

oqmt mecwas pres.I. H.

Norepln $0. + m

FIG. 12. The @et of chlorothinzide on the blosd pressure re$xmse to nore~u~ephrinr. \Yhen norepinephrine was administered prior to the chlorothiazide a dose of 10 gamma per minute caused an increase in blood pressure of 40 mm. Hp systolic and 20 mm. Hg diastolic. After chlorothiazide was given for a period of five days the same dose of norepinephrinr had no effect on blood pressure. When the infusion rate of norepiwphrine was gradually increased to product the same drgrrc of blood pressure response, it was obsrrved that the infusion rate required was 20 gamma per minute. This indicates that chlorothiazide decreases the vascular response to norepinephrine. ‘,XE AMERICAN

JOURNAL

OF

C.ARDIOLOGY

Diuretic

Trifluoromethytnlorlde FIG.

13.

Structural

Therapy

Chlorothionde

formulas

in Sodium

793

and Water Retention

Hydrochlorothionde

for three

thiazide

deril--

atives.

PII -~RSI~COI.I.)GYOF NEWER DERIVAWJES

The advance in diuretic therapy observed with chlorothiazide has stimulated the evaluation of other lxnzothiadiazine derivatives in an attempt to impro1.e potency and decrease the incidence of side eff’ects. Figure 13 contains the structural formulas of two such derivatives which ha1.e been studied extensively. Trifluoromethyl thiazide (flumethiazide) * differs from chlorothiazidc in that the chloride atom on the benzene ring is H) replaced t,)- a trifluorinated methyl group. drochlorothiazidet has the same structure as chlorothiazide except that two hydrogcns ha1.e I)een added.

An e\.aluation of the effects of flumethiazide adminiytered intravenously reveals similar responses in renal hemodynamics as with chlorothia7idc.Z? .:(I Eight hundred mg. of this agent were administered orally to patients, and the escretion rates of water and electrolytes were dctermined. Glomerular filtration rate was dctermined concurrently 1)~ the inulin clearance method and renal plasma flow was estimated I,)the para-aminohippurate clearance technic. .-lcut~~ I?ffds: Following the administration of the drug: the ljlol,d pressure was checked ever) few millutr”s for any itnmecliate changes in tkod prcssut-e and then every thirty minutes for six hour\. Thrrnclof the second hour. actkit! cvtended beyond the sixth hour of the

* Available as adc rxol from E. R. Squibb & Sons, New York, NNJ York. t Availablr as hydrodiuril from hZcrck Sharp & I)ohmc. Inc.. Philaclrlphia, Pennsylvania. lJECEMH,~.R 10 5’1

CdNTROL I Hours After

THIAZIDE

2 cxua

4

3

5

6

14. 7‘he eject ofJumethzuridr on .wd~um mu&m, ing the oral administration of 800 my. in cisht

folloupatients.

FIG.

0

6

7

j

Control t Owq

’ Given

2

4

3 TIME-

IN

5

6

f

HOURS

L:tc. 15. ?%e !ffectof j?umettriorde on glonvrdar /i/tratm rote. There was no significant and consistent alteration in glomerular filtration rate following thv administration of 800 mg. of flumcthiazide by thr oral rouw to seven patirnts.

There was no significant change in either study. glomerular filtration rate (Fig. 151 or the renal plasma flow during the period of stud!.. Dose KPsfmtse Curvrs: Dose rctponsc curves were determined33,3’ in the outpatient clinic 1)) determining the acute weight response after forty-eight hours in a group of cardiac patients who rccei\.ed increasing doses of the dru,q and in hospitalized patients on a standard 50 mEq. sodium intake. The increase in sodium cscretion was used as the modality (natriuresis) for estiIn the stud!. at rtle outpatient mating response. clinx, the patients were free of diuretic therap!I)et\veen each dose of the dry for at least five days and lvere receiving maintenance doses of digitalis. X dose of 800 mg. yi\,ell twice a da\. Ilad the sa~ne effect on I\-eight response in this group of patients as did a dose of 500 my. of chlorothiazidc yivcn twice a da\ to tllc same group. L\‘h<%n 1,000 mg. \vas administered twice dail) the efrect was thcl same ai: 1,000 IP~. of chlorothiazide given twice clail\ l’lirrcfore, rhc maximum effective dose of I)ot ti clruqs is the

Moyer

and Fuchs

FIG. 16. Dosv ~PS~I~SPCWU~of j7umumc~hiatide~ using sodium

as a mrasurrment of potency. The threshold dose appeared to bc 125 mg. The maximum effective dose was approximately 2,000 mg. This response curve

excretion

is quite similar to thr response curve of chlorothiazide shown in Figure 9.

as

same. Increasing doses above 1,000 mg. twice a day produces no further increase in effectiveness, as was previously observed with chlorothiazide.2” M’hcn the increase in sodium excretion was used to determine the dose response, the observations summarized in Figure 16 were ohtained. This response is almost identical with a similar stud!- made on chlorothiazide (Fig. 9).

Studies of cxcretion3”,“6 indicated that hydrochlorothiazidc appeared in the urine within one hour after oral administration. At the end of six hours~appruximately 20 per cent of the total dose admi&ktered was excreted in the urine. The disposition of the remaining amount has not been determined. Maximum excretion was reached within three hours after administration and the plasma level reached maximum concentration within the first two hours and rarely exceeded 6 pg. ml. of plasma. Acute Diuretic Ejects: Hydrochlorothiazide was administered intravenously in a dose of 200 mg. Observations were made on glomerular filtration

rate t)y the inulin clearance technic and renal plasma flow was determined I)? the USCof paraaminohippuratc. After three successi\,e control periods were ol)tained the drug ~vas administered and successive thirty-minute collections were made for five hours. Immediately following intravenous administration of the drug there was a temporary reduction in the glomerular filtration rate. This returned to control values I\-ithin one hour. Despite the temporar), decrease in glomerular filtration rate there war an increase in salt and water excretion. It can IX concluded from these ol)scrvations that tile diuretic and natriuretic efi‘cct of the drug is a tulmlar response and is not due to an increase in qlornerular filtration rate. A measurement of the hourly urine response following the oral administration of a large oral dose of the drug showed a diuretic response heginning during the first hour with the maximum response during the third hour and a diuretic effect throughout the observation period of six hours or more. The same effect lvas demonstrated when the hourly increase in xodium and chloride cxcrction was compared with the control sodium and chloride excretion. lihtrolyte Exrrtion Studks: In order to dctermine the degree of response of clectrolvte excretion to various doses of hydrochlorothiazide, eighteen patients were studied. These patients ctrerc put on a 50 rnEq. sodium diet and control twenty-four hour urines were taken for several days until a fixed twenty-four--hour sodium excretion (40 to 48 mEq.) wab obtained. The patients wcrc then given the drug for two days and twenty-fourPhour urines were collected for determination of increased sodium, potassium and chloride excretion above control levels as in the studies on flumethiazide and chlorothiazide. The average of the first fort),-eight-hour excretion was compared to the control. The patient was then allowed to equilihratc and replenish sodium stores again without the drug. Increasing doses were administered after a period of equilibration was obtained for control sodium excretion. The doses used were 25, 50, 100, 200, 400 and 800 mg. per twenty-fourhour period. The dose response curve is graphed in Figure 17. It is noted that natriuretic activity starts at the 25 mg. dose level with a marked increase in electrolyte excretion at the 50 mg. dose level. There is an increasing electrolyte excretion up to 200 mg. above which the increased sodium excretion response levels off. In the effective dose THE AMERICAN

JOURNAL

OF CARDIOLOGY

Diuretic

Therap!,

in Sodium

and

Water

. ‘n\or~~.

SoduN'_t___m._-------__._* , *__----

: : : ;

. . . ..*

l

.*

..b

.* :*

..

. .. .

795

Retention

__--

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DOSE

Pdossium /_

IN

MIUIGRAMS

FIG. 17. Dose IPJ~OIIV cuwc to /~~‘drocl~lorothi/~:i~e measuring sodium, chloride and potassium fxcretion rates. The primary cffcct appeared to hc an incrcasc in chlorldc excretion with a Icsscr effect on sodium txcrc,tion. ‘l’hcrc was asigni lic;mt increase in potassium cxcrction as well.

potaGurn loss is approsimatcl~ one-half that of :odium and the most marked effect is on chlorurcsis \yhich is yreatcr than the natriuretic effect of‘ Ii)-drochlorothiazide.“’ This response is different from the response to chlorothiazidc and a mercurial dillrciic in Lvhich the sodium and chloride ~xcwtions arc more nearly equal or the chloride cxcrction is less titan sodium (Fig. range

1). The response to a single daily close of 400 me. comparrd to 200 nq. given &cc a dav is seen in Figure 1X. Tile initial natriuresis was somc\vhat qreatcr \vhtn the 400 mg. dose \vas given as compared to the 200 mg. dose. Ho\vevc~ , when tl~c 200 rnq. dose was rcpcatcc! twel\.e hours later. an additional natriuretic r-esponsc was ol)ccr\.ed. ‘The total twenty-four-hour esrretion rate of sodium was greater when the 400 mg. kvert‘ $-i\.cn in divided doses (200 my. l).i.cl.) instead of ;I sinqlv dose. (‘O.\IRIENT ou 'I‘HIAZIDE DERIV.~TIVES

Frown the data presented it appears quite olwious that all three thiazide derivatives are efA study of the dose reficient diuretic drqs. sponsc cur\w re\eals that the onset of activit\ of chlorothiazide and flumethiazidc starts at the 250 mg. close level and increases to the maximum effectiw dose of 2,000 mg. The onset of response with h)drochlorothiazide starts at 25 mg. and increases to a m:>ximum effective dose of 200 my. Tllerefore, in the effective dose range uf DECEMRhK

1')5')

2

4

6

B

10 TIME

12 IN

14

16

HOURS

FIG. 18. A conlpnrison of ihc PJPC~ O/ h.ydrtichlorothim=i~l~ on sodium ~xcr~tmn using a dosr of 400 ma. ei\-cn as a single

dose in a twenty-four-hour prriod as comparrtl to 200 mg. given every twelve hours. Following a sin+ dosr of 400 mg. therr was a greater initial increase in sodium excretion but due to the fact that the second 200 mg. dose of hydrochlorothiazide producvs a secondary rise in sodium cxcrction, the twenty-four--hour total sodium rscretion was greater when the drug was $1:cn in a disidrtl dose of 200 mg. twice a day.

796

Moyer and Fuchs

. ;

3(>-

a .E

2.5-

: 3 =

1 3-3

3.5 -

2-o-

2.8

Chlorothia~ zide IOOOmg.

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1

r-

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Hydrochlomthiozide Diomox

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1 hticnh 26

100

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B.I.D.

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13 Patients

t$pcoclon

20

Patient

5omg. OI: 20 Potienl

FIG. 17. -4 comfiarison of the weight 10s~ respon.re in a group of patirnts with congestive heart failure who were given the various drues for a Deriod of two davs in the doses indicated in the ‘iraph. O.D. = once daily: B.I.D. = twice daily; Q.I.D. = four times daily.

these drugs a dose of hydrochlorothiazide which will produce a specific response is one-tenth that of chlorothiazide or flumethiazide. However, at the maximum effective dose level of each compound for diuresis the natriuretic effect is the same for all three drugs. Hydrochlorothiazide also differs from the other two derivatives in that there is a greater chloruretic than natriuretic effect and potassium excretion is greater. This could result in a hypochloremic hypopotassemic alkalosis. Therefore, close observation for electrolyte imbalance must be maintained with the use of this agent as with the use of any potent drug of this kind. The clinical response to these agents is demonstrated I,)- the acute forty-eight-hour weight loss experienced in a group of patients with congestivc heart failure in our diuretic clinic (Fig. 19). These patients were on maintenance digitalis therapy and were free of diuretic therapy for at It is shown that the weight loss least five days. experienced by these patients is the same when the maximum effective dose of chlorothiazide and flumcthiazide was given. This response was greater than the response seen after an effective dose of chlormerodrin or acetazolamide was administered. 6Vhen the maximum effective dose of hydrochlorothiazide was given, the weight response was greater than that ohserved with the other two thiazide derivatives; this could infer a greater clinical effectiveness. LVe have also seen rather efficient diuresis with hydrochlorothiazide in patients who have appeared refractory to chlorothiazide. This may

not necessarily imply a greater diuretic activity for hydrochlorothiazide but may be a result of tolerance to chlorothiazide in those particular patients who are still responsive to hydrochlorothiazide. If so, then the factor of tolerance to one agent and not to the other may allow for more prolonged constant diuretic therapy by alternating these agents hefore or after tolerance starts to manifest itself. The advancement made in the diuretic field has been dramatic with the discovery- of these agents and future increased benefits will be anticipated with the investigation of other derivatives of the henzothiadiazine structure. THE

~k1~1c.41.

CSE

OP

DIURETICS

should be remembered that diuretic agents are only one aspect of therapy for the treatment of patients with abnormal sodium and water The diuretic is usually not a curative retention. measure, rather these agents improve only the symptoms associated with abnormal sodium and water retention. Consequently, when possible, it is preferable to correct the basic physiologic defect. It

DIURETICS IN THE TREATMENT

OF

HEAR.T FAILURE Mechanisms

oj Sodium

and

LITatrr Kvtention

and

Sodium and water retention is a common pathophysiologic manifestation of diseases The management of conof diverse etiology. gestive heart failure is only one arca that has been significantly improved by the judicious In the patient with heart failuse of diuretics. Edema:

THE

AMERICAN

JOURNAL

OF CARDIOLOGY

TXuretic

‘l‘herapy

in Sotlium

ure several \rcll known mechanisms operate to produce a~jnormal sodium and water retention: the final common pathway being direct and One mechanism indirect c.fYects on the kidney. associated \virlt the. reduction in cardiac output is the rcrluction in renal blood flo\v and glotnerular filtrCrriotj rate \2-hich is followed by decreased aodiuttt ;~ntl \cater excretion and the development of occult ccl~.ma.“h~“Y A srcr)ncl modus operandi in l’ormatiun of edema a;ttic inacti\;ation of adrenal cortical salt-retaining hormonex, particularl) aldostcrone. The relative increase of these hot-tnonc,\ itt the Ijlood going to the kidney!. stimulate\ the renal tul)ules to reabsorl) tnorr in sodium retention.il-‘,’ rexulting; sodium. Electrol~ tc retention can also cause stimulation of hypotltalamic o\moreceptors which is followed Iy the secrcticjn of additional antidiurctic hormone (.!DH). The result is further rctcntioti of water and incrl:ased Mood ~olumr which rcsult~ in a markedly increased \cnous pressttrc~ leading to rnanife>,t formation of edema. Other hormonal r~lationc arc as )-et not clearl>- under\tood. It ix the rcsultittg pathologic state of cdetna and its treatment that we are concerned xvith at tliis tinit.. It is quite obvious that the one common denuminatot is the reduction in Lyater and clectrol\.tc excretion tjv the kidncb-s. It is thcrcfore oh\‘-ious that the aim of therap!. in con%estivc heart failure is not only to improve tnyocardial function l)ut also to achieve a block in the al)ttortnal wtcntion of sodiutn and bvatcr. ‘t’REA7’MEX’l-

OF

HE

\R’I’

FAII.URE

Rrst: III patients with heart failure, digitalis and clecreased pil)xical activity are of pritnarv importance. OnI\, when these more simple measure< prol’e to Ije inadequate are diuretics indicated. \Vhett cardiac failure is severe, cxercise rcducrs the qlomerular filtration still farther, resulting: in socium and water retcntion.“l Since qlumcrular filtration rate is highest when the pat&it i4 in rhr supine position at rest and drcreast~x a> the upright position is nssumeci, initialI> it ib Ijest to have these patients at rect in Iled. In using Iced rest for the treattnent of heart failure. this should lje \Gewed as a tetnporar) measure: only- since many secondaryphysiologic altcrationx follow eucessiAy prolonged rrst in

and

Water

lictelltiun

797

Ix~_t. Rut, rcstrictcd activity should lx acl\ised Once heart failure as a pernianetit measure. has developed. it is rare that cardiac function returns cnlircl! to normal irtrspccti\.r of tlte etiolvyy of the disease or the [hc*rapeutic lltxjgram applied. Moreo\.er, thy tnc)fc’ i‘rNlrrctttl> and more se\ crely a patient clcconlpcniatcs tlte ntore difficrtlt it is to improve tit(’ cardiac status C:!Jtlscquclltl\ , LVC to anything near normal. t)cliebrc that it is prcferaI)le to II\<’ tn;iZitnum thrrap) rather than take a cltatlcc of undertrcatmettt. Sr\.cre and progreA\-c heart lrtilurc develops in man\ more patients frottt inadcquatc tilerap)- than the numijer \vlticli Ita\7 diflicult) frotn the side effects associatctl \vit!t oxrtrcatnicnt. &.rtrjc~tvf So/t ZntukP: Sodiunt chloride intake should also )j(‘ %gi\.cn primarv consideration in L’~all!. I\-atet many patient5 \vith cclema.‘” intake is of little itnportance ho lonq its xodiutn In fact, ;I large intake is rigidly restricted. urinary \~olun-ie will often protn~~tv ;ttl increast in sodium excretion. Generall!~. the tnorc se\.erc the heart f’ailurc the less salt can Ix excreted t>) the kidney. Thus. in a patient with mild heart failure, restriction of salt intake to 3 gm. daili- \vill ))c adc\vith tnodcratcl\severe quatc. In patients heart failure. the daily salt int;tke &~~‘ld I)c rcIn patients with stricrrd to Its\ than 1.5 yn. sc‘\Terc heart failure, the salt intake should IJ~ \t:hett restricted to less than SO0 tng. per da\-. effective diuretics are given continuwsl~-, the salt intake usually can Ix lilxralizcd. For rffectivc low salt diets the family and the patient should IJC instructed in the methods and virtue5 of a low salt diet I))- someone adequatel!; trained in this field. This cannot I)c crltphastzcd too It is not cnougti fur tlic physician to IllUC t1. merely instruct the patient to “go on a 10~~ salt All too often, patients bill qo I’or b-ears diet.” without proper dietary instruction.

(1 ) Cri1.e a parenteral mercurial diuretic initiallv wlten heart failure is severe, e.~., meralluride, 2 cc. intramuscularly daily or ntercaptotnerin 3 to 3 cc. dail\- for three to Ii\-c day\ until yross cdrma has disappeared. (2) Cltlorothiazide (Diurill or flumetltiazidc (adrmcJ1) can be used in place of the mercurial in a dose of 1,000 mg. ever) eight to twelve hours or 100 nq. of h~ctrochlorothiazitlr (h).drodiuril) can I)e given e\-er) t\vcl\.c hours. .\ftet the emcrgencv iq con&o&d, the dew sl~ould tjcx

Moyer decreased IO the minimally effective dose but no less than 250 mg. of chlorothiazide or 25 mg. of h!droclllorothiazide should be given every other da).. (3) I;or mnintenance tlrrra&, chlorothiazide or flumethiazide (250 mg. daily to 1,000 mg. twice a day) or hvdrochlorothiazide (25 mg. dail) to 100 nlg. twice a da)-) may be given by the oral route. Oral mercurial diuretics such as chlormerodrin (n’eohydrin), five to eight tablets daily, can I)c used also. TYl~rn lIeart jailure is mild, compensation may also be maintained with acetazolamide (250 mg.) or cthoxzolamide (250 mg.) or aminoisometradine (600 to 1,200 111g. per da).) given every other day or daily for three consecutive days of each week. In moderate to were heart failure, these compounds will rarely l)e adequate for maintenance therapy. Then chlorothiazidr (250 to 1,000 my. I1.i.d.) or flumethiazide (250 to 1,000 mg. t1.i.d.) or hydrochlorothiazide (50 to 100 mg. 1l.i.d.) or chlormerodrin (one to two tablets after each meal and at bedtime) must IX used if the oral route of administration is to IX employed. Otherwise, parenterally administered mercurial agents must IK given in adequate doses (1 to 4 cc.) and as frequently as necessary to maintain the edemafree state. Diuretics used in this manner increase sodium and water excretion and thus decrease Mood volume and venous return of I,lood to the heart. Right auricular filling pressure is thus reduced and cardiac output increases. DILRETICS IN PREMENSTRUAL EDEMA EDEhlA OF PREGNANCY

AND

The problem of premenstrual edema has been recognized as a syndrome resulting from hormonal imbalance. It is present in perhaps 40 per cent of women, and is associated with gain in weight, subcutaneous edema, emotional tension, breast turgidity and a state of anxiety and tension. It seems logical that the hormonal e\.ents of the last few days of the menstrual cycle result in either a direct or indirect effect on the renal tubules I)y an increase in tubular ahsorption of sodium and water.“fi.-aX Edema of pregnancy may he seen as an exaggeration of a pre-existing disease such as congesti1.e heart failure, nephritis, etc., or it may be the manifestation of an impending toxemia of pregnancy. It is to he remembered, however, that e\.en during normal pregnancy the blood volume increases from 30 to 50 per cent and that there is a positive salt balance (retention of salt

and Fuchs and water) that reaches a maximum t)y the thirty-sixth week of gestation. \\‘hatevcr the interrelated factors in edema of preg-nanc). may IK, the common denominator is, once more, increased tuhular real)sorption of sodium and water which can t)e 1)locked IJ~ appropriate diuretic therapy. Treatment of Premenstrual Edema: The desired cffcct is to increase sodium and water cxcrction. Edema is not marked in this disease entity. An outline of therapy is as follo\vs: 1. During the last five to seven davs of the menstrual cycle: (a) low sodium diet; (1,) chlorothiazide or flumethiazide in a dose of 500 mg. twice a day or hydrochlorothiazide, 50 to 100 mg. daily, or acctazolamide, 230 mg. (one tahlet) or cthoxzolamide, 125 my. (one tablet) daily. Treatment q/ Edema of Prqgnanry: The desired effect is to decrease sodium and water retention. Since pre-existing disease may 1Je responsible for edema in this entity, a close medical survey must he completed. When no ot)\-ious causes of edema are found, then therap\. may 1~ summarized as follows : (1) At first sign of edema : low sodium diet. (2) If not controlled l)y diet; chlorothiazide,* 500 to 1,000 mg. twice a da), or acetazolamide, 2.50 mg. or ethoxzolamicle, 125 mg. may be given r\‘ery other clay if edema is not marked. EDEMA ASSOCIATED IVITH KEKAL

DISEME

Factors Causing Salt and Water Retention: In the nephrotic syndrome not onI!- does the factor of decreased glomerular filtration and renal I)lood flow result in a decreased sodium excretion, hut also an excessi\:e loss of protein in the urine occurs. This results in decreased colloid osmotic pressure of the l)lood, an additional cause for fluid loss to the tissues.lg Thus, not only is there a need for a natriuretic agent but also tlettcr results ma)’ 1~ ol)tainccl frequently by an agent which increases the plasma osmotic effect, such as salt-poor human albumin Albumin someadministered intravenously. times appears to have a natriuretic and diuretic effect on the kidney which is unrelated to its osmotic activity. Heightened mineral corticoid activity, increased pituitary secretion of antidiuretic substances, and osmotic shifts of fluid and electrolytes have all been cited individually * Flumethiazide ably be used here authors.

and hydrochlorothiazide can probbut this has not hem studied by the

TIl,S AMERICAN

JCXJRNAI.

OF

CARDIOI.OGY

Diuretic as mechanisms

producing

Therapy

salt and water

in Sodium reten-

Possibly all of these factors tion in ncphrosis. are invol\.ed. Trratmuzt: The treatment may be summarized as follow : (1 I Rrd rest. (2) I. ow sodium diet. (3,1 C:lilorothiazide or flumethiazidc, 500 to 1,000 mg. t1.i.d. or hydrochlorothiazide, 50 to 100 ma. t1.i.d. (4) 11’ the first three therapeutic procedures do not C(JIltrd edema in one week, a se\.en-day trial of .\C:TH administered intravenously as 25 units in 1,000 CC. of 5 per cent dextrose in water cnc’r an eight-hour period daily or as 40 units given intramuscularly ever); “gel,“ Ten mg. of predtwel1.e hours? ma) ~JC tried. nisonc nlay I)e gi\.en every six hours for four doses, tht%n 5 mg. every six hours for eight doses, then 5 mq. e\‘er)’ twelve hours for eight doses as Diuresis usually occurs as the an altcrnati\.e. The steroid (or ACTH) therapy is withdrawn. mechanihrn is poorly understood. WC have noted that maximum diuresis can IX olttained when administration of chlorothiazide or hvdrochlorothiazide is .\tarted just as the steriid is For this purpose 500 to 1,000 mg. withc1rab.n. of chlorothiazide should be given every eight to twelve hours. The drug should be started on the last clay of steroid administration and continued thereafter as long as the diuretic and natriurcric eflcct i> desired. (ii II’ there is no response to the aforementioned rrqimens. administer 100 gm. of salt-poor human all~min intravenously e\rer!. other day. This is an cspensil-e procedure. (6) Finall), parentera mercurials (meralluriclc? 1 to 2 cc. daily) may be tried when edema is se\.ere and unrexponsive to the measures outlined pry\-iously. DIURETICS

IN HEPATIC DISEASE

Hcpatic disease presents the problem of disorderrd protein fi,rmation which results in a decreased colloid osmotic pressure of blood. Thiy reqlrircq the use of an osmotic diuretic such as salt-poor human albumin intravenously. There may I)e a decreased inactivation of saltretainin,c steroids which results in sodium and water rctcntion. At the present stage of our knowledge this can be controlled only 1,~ a natriuretic agent. ‘liec~trrwnt: Since the edema usually is associated with inadequate protein formation with reduction in blood osmotic pressure, the under-

and

Water

Retention

lying liver d&case should I)e treated actively. However, other factors such as decreased hepatic inactivation of salt-retaining steroids ma)- be treated I))- a%cnts acting to IAock the renal tut)ular reabsorption of sodium. Thus, treatmcnt for cdem;r or ascitcs ma\ IX outlined as follows : Low sodium diet and decreased ph) sical (1) activiry. (3) In presence of significant h!-I1oal tjuminemia (serum albumin less than 3 ym. per cent) give a high protein diet and ma)- use salt-poor human albumin, giving 100 gm. intravenously every other day to achieve diuresis. The expcnse may IX a contraindication here. Increase sodium and water cscrction by (3j giving meralluride: 2 cc. intramuscularly daily as needed to control massive edema. If response to meralluride is not adequate (4) gi1.e chlorothiazide or flumethiazide, 500 to 1,000 mg. every eight hours or h)~drochlorothiazide, 100 to 200 mg. ever)- twc1L.e hours. ;\fter massive edema is controlled. main(5) tcnance therapy may Ix continued with chlorothiazide or flumethiazide, 500 to 1,JOO mq. daily t)) mouth or h! drochlorothiazidc, 50 to 300 mg. Use the smallest effective dose. daily. TRE;ZTMIINT 01; IATROCENIC EDEN.\ The increasingly common syndrome, “iatrogenie steroid edema” results from the therapeutic use of steroids huch as cortisone, hvdrocortiyone, prednisolone and prednisone. ‘Tilt,- affect the kidney to induce edema indircctl! I)!. the enhancement of renal tubular rcal)sorption of sodium. Diuretic agents, particularl>. chlorothiazide and the organomcrcurials. ha\~l hcen particularly helpful in the management of this complication. Trc,utment: Lt’hcn sodium retention and edema I)ccotne a problem it is preferalAc to discontinue the steroid but this is not al\va)-s possit,le. In the latter case, the edema can usuall!- be treated 1,). daily and continuous administration of chiorothiazide,* 500 to 1,000 mg. evcrv eight hours, or chlormerodrin, two tablets foul- times a day. 1Vhen these agents are not adequate when given alone, they should then t)r x:-i\-enin combination. Parentcral meralluride is also effective Ijut when used for this purpose it must be g-iven every twelve hours since the maximum increaTe * Flumethiazide ably also effcctiw authors.

and hydrochlorothiazide arc probbut have not bwn studied by the

800

Moyer

in sodium excretion occurs during this period. During the subsequent twelve-hour period (when the drug is not given again) there is actually retention of sodium. SUMM.4RI’

In discussing some of the more common clinical syndromes of edema, we note that renal retention of sodiutn and water is a common denominator hut that other factors such as decreased colloid osmotic pressure of the blood, decreased blood flow to the liver and decreased or abnormal hormonal activity may he the primary event and must he given primary therapeutic consideration. It is also seen that in varying dc;=rees of importance, natriuretic (or diuretic) agents are a therapeutic common denominator for the treatment of symptoms associated with cscessi\rc sodium and water retention. REFERENCES

Phnrmncol.. 9: 210, 1954. 4. BERLINER: R. W., KENNEDY, T. .J., .JR. and HILTON, and renal tubular secretion of in the do,q and man. Am. J.

Physiol., 154: 537, 1948. 5. FAWAZ. G. and F.~w.Az, E. N.

6.

7.

administration (Prontylin). 58, 1937. 13.

Mechanism ofaction of mercurial diuretics. II. Proc. Sm. EX~PT. Biol. @ .Med., 87: 30) 1954. CAPRUNY, E. 3. and FARAH, A. Effects of the mercurial diuretic, mersalyl on the concentration of protein-bound sulfhydryl in the cytoplasm of dog kidney cells. J. Pharma~ol G? &ber. Therap., 117: 101, 1956. The influence of sulfFARAH. ,I.and MARESII, G. hydryl compounds on diuresis and renal and cardiac circulatory changes caused by mersalyl. J.

Yvk 9.

and

xanthine

diuretics.

Ann.

h’ew

Acnd. SC., 74: 344, 1958.

10.

Muocl;., G. H.. AMES. A. III, FOULKS, J. and GILMAN, r\. Effect of drugs on renal secrrtion of potassium in the dog. Am. J. Ph.ysiol., 161 : 151, 1950. HAN~LEY, CI. A., TELFORD, J. and LAFORGE, M. Xanthine and mercurial diuretics and renal tubular transport of glucose and p-aminohippurate in the dog-. Proc. SK. Expu. Biol. @ Med., 71 :

11,

DAVIS,J.
12.

The effect of theophylline ethylene diamin? on rrnal function in control subjects and in patients with congestivr heart failure. J. Clin. Invest., 28 : 1459, 1949. SOUTHWORT~I, H. Acidosis associated with the SHOCK,

B.

and

Sou~I~wowrrt,

H.

LTrinary

'1'.and KEILEN. D. Sulfanilamide as a inhibitor of carbonic a&J-draw. h’cilwe, Imdnn, 146: 164: 1940. 15. DAVENPOK.I. H. W. and LVKHCLMI. X. 1:. Renal carbonic anhydrasr. Proroc.SW. Exprr. Biol. e specific

Mfd., 16.

48: 53. 1941.

KEILEN,

D.

and

MANN,

7’.

Carbonic

anhydrasc.

Nnturr, London. 144: 442, 1939. 17. PE.I.ERMANN, M. I,. and HAKALA. N. V.

18.

Molecular

kinetics and elcctrophoretic studies on carbonic anhydraw. .J. Bial. Chem., 145: 701. 1942. MILLER, \V. H., DESSERT, A. M. and KOHLIN. R. O., JR. Hctrrocyclic sulfonamides as carbonic anhydrasr inhibitors. J. Am. Chm. Xx.. 72: 4893,

1950. 19. PITTS, R. F. and .~LEXANDER, R. S.

‘The natuw

of

the renal tubular mechanism for acidifying the urine. ;Im. .J. Physiol., 144: 239, 1945. PITTS, R. I:. and LOTSPEICH, \\‘. D. Bicarbonate ,4m. and thch renal wyulation of acid base halancr.

J. Phvriol., 147: 138. 1948. 21. FERC&N, E:. B.. JR. A study of the rcqrlation

of ammonia cscrction‘in the rat. .J. Phyciol.: 112: 420, 1951. MAREN. ‘I‘. H.. MAYER, E. and \~'ADSJVORTII,H. C:. Carbonic anhydrasc inhibition. I. The pharmacology of diamox (2-acetyl-amino-1,3,4-this. Bull. .Johns H7pkin.r Hosp.. diazole-5 sulfonamide). the raw

22.

of urinary

95: 199, 1954. 23. BERLINER, R. \‘I:.. KENNEDY, T. J.. JR. and ORLOFF, Relationship between acidification of the urine J. and potassium metabolism. ;Im. J. .MP~., 11 : 274, 1951. Benzothia24. NOVELLO, E. C. and SPRAGUE, .i. C. M. diazinc dioxides as novel diuretics. ./. .lm. Chm

sot., 79: 2028, 1957. 25. FORD, R. V., MOYER, Clinical thiazidc

J. H., and SPURR, C:. L. and laboratory observations on chloro(Diuril). .Irch. Int. .I.fed., 100: 582,

1957. 26. BEYER, K. H. 27.

‘Thr mechanism of action of chlorothiazidc. .4nn. iV~~~~York Acad. SC., 71 : 363, 1958. BEYER, K. H., RAER. J. E., Russo, H. F. and HAIM(6-chlor-7.sulfamylBACII. .'r. s. Chlorothiazidc Thr rn1 ,I -dioxide). 1,2.4-bcnzothiadiazine hancemrnt of sodium chloride excretion. Fed.

Pm., 16 : 282, 1957. 28. Russo, H. F., BAER, J. E., NOLL., R. M. and B~YF,R,

29.

30.

187, 1949.

M.

36:

14. MANN,

Pharmacol. 2 Exper. Thmp., 92: 73, 1948. ‘The mechanism 8. MUDGE, G. H. and WEINER, I. M. of mercurial

Sr~Auss.

of paraaminobcnzcne-sulfonamide Pr:~c. S’oc. !?:yfi~r. &al. e :\frd.,

changrs due to sulfanilarnidc administration. N1111.J~~hn.>H:;pXms Hosp., 63: 41, 1938.

20.

Mechanism of 1. PI-r-rs, R. F. and SARTORIUS, 0. \V. action and therapeutic use of diuretics. PhUm/zcol. Rm, 2: 161, 1950. 2. WESTON? R. E. The mode and mechanism of mercurial diurrsis in normal subjects and edematous cardiac patients. ilnn. ,VPZ York Acad. SC., 65: 576, 1958. 3. DALE, R. A. and SANDERSOR., P. H. Observations on the character of mercurial diuresis. Brit. J.

J. C:. Salyrgan p-aminohippuratr

and Fuchs

N. W.

31.

K. H. Evaluation of chlorothiazide, a saluretic diuretic au,rnt, in the dog. /‘pd. Proc., 16: 333, 1957. ChloroHEIDER, C.. DENNIS, I-). and MOYER, .J. H. thiazide potentiation of ganglionic blockage in .4nn. Xew York patients with hypertension. Amd. SC., 71 : 456, 1958. FREIS, E. D., WANKO, A., WILSOS, I. and PARRISH: A. E. Chlorothiazidc in hypertensive and normotensivc patients. Ann. ;Verel York Acnd. SC., 71 : 450, 1958. E. 1). C:hlorothiazidc in hypertension. FREIS,

Heart Bull.,

7: 105, 1958.

‘THE AMERICAN JOCRNAL

OF CARDIOI.OGY

Diuretic 32. BE,AVERS. R. \\:. and

Therapy \,\‘.P.

BLACKMORE.

chlorothiazide on vascular reactivity. Kx,k,. Riof. CC .1I~d.. 98: 133, 1958.

in Sodium Effect of Pr0c. sot.

FUCHS, hf., Born,, 7‘. and MOYER, J. H. Evaluation of flrlmrthiazide (trifluoromethyl thiazide J in the out-patient clinic. Am. ./. &r&u/., 3: 676. 1959. 34. Bonr. ‘I’., FUCHS, M., IRIE, S. and hfoxs. J. H. Furtiwr observations on flumrthiazide. X new oral diuretic. Ax. .1. Cardiol., 4: 464, 1959. 35. Fr:ws. hi.. Born,, ‘r.. IRIE, S. and h,foYER, J. H. Preliminary ev.k~ation of hydrochlorothiazidr (hvdrodiuril). M. RK. e Ann.. 51: 782, 1958. :36. h,lcn’erc. d. H., Fr~c~rs, M., IRIE, S. and Boon, T.

41.

33.

42.

43.

44.

Somt, observations on the pharmacology of hydrochlorothiazidc. :ln/. J. Cardto/., 3: 113. 1959. 37.

Fr:crrs,

38.

and .\~OYER,J. II. A review of the pharmacology and clinical ohwrvations of hydrochlorothiazide. :frch. Int. .Ved. (In press.) h’feRRrl.1.. ;I. .J. ICdrma and decreased renal blood flow in patients with chronic congestive heart failure; evidence of “forward failure” as the primarv course of edema. .J. Cfzn. Inwst., 25: 389,

hl.,

MALLIN,

S.,

IRIE,

S..

HERNANDOS,

S.

1946. 39.

40.

DECEMBER

45.

46.

h~oKoI.oFF, ,I., Ross, G. and LEITER, L. Renal plasma flow and sodium reabsorption and excretion in congestive heart failure. J. Clin. Incest. 2-‘: 1, 1948. BLAKE: W., WEGRIA, B., KEATING, R. P. and WARD, H. P. The effect of increased renal venous pressure on renal function. Am. J. Physiol., 157: 1. 1949.

I')jl)

801

and Water Retention

G. and EMERSON, G. W., JR. The role of qonadal and adrenal cortical hormones in the production of edema. Ann. Itzf. .lled., 14: 757, 1940. LEUTSCHER, .J. A.. JR. and JOHNSON.B. B. Observations on the sodium retaininS corticoid (aldostrronc) in the urine of children and adults in wlation to sodium balance and rderna. .I. Clir,. Inwsf., 33: 1441, 1954. BARTLER! F. (:. The role of aldostcronc in normal homeostasis and in certain dircasc states. ‘Wetabolism, 5 : -369, 1956. SIP\CLAIR-SWTII, B., KATTUS, A. .\., GESFST, J. and NEL~MAN. E. V. The renal mechanism of rlectrolyte rxcrction and the metabolic balances of t,lectrolytes and nitrogen in congcstivc cardiac failure; thy effects of exercise, rest and aminophyllin. lilrll. Johns Hopkins Hosp., 84: 369, 1949. SCI~ROE~ER, H. .\. Studies on congestive heart failure. I. The importance of restriction of salt as compared to water. .4m. Heart J., 22: 141,

TRORN,

!941. ISEEAL, S. I.. pre-menstrual

469, 1953. 47. MORTON, J. tension.

The clinical tension.

H. Am. J.

Clinical

pattern

and etiology

of

I~~ternat. Rec. .\Ied.. 166: study

of pre-menstrual

Obst. @ Gym., 65: 1182, 1953. 48. GREENBI.ATT, R. B. Pre-menstrual tension syndromes. GP, 11: 66, 1955. 49. LARAGH, J. H. Mechanisms of edema formation. Am .I Afpd. 21 : 423 1956