Selective dopamine-1 agonist therapy in severe hypertension: Effects of intravenous fenoldopam

Selective Dopamine-1 Agonist Therapy in Severe Hypertension: of Intravenous Fenoldopam WILLIAM

B. WHITE,

FRANCISCO

ELLEN J. MCCABE. Fora,i”pro,l.

MD,* MARTHA

M. GONZALEZ,

.I. RADFORD,

MD,t SHERROLYN

RN.” ARNOLD

M. KATZ,

MD.

Effects

MD,* G. WEED, BA,t FACC*

Con,rrc,!c,,, and NCU or,eo,,.r. L”r,i.~i”“o

To determine the eNecu nl dopamkwl agonist therapy in .wvere bvoenen~ian. blood oressure. heat rate. rotecho,.

Plasma norepinepbrine increased during the fenonnldonam infusion: er4nenhrine and dosamine levels did not

sure >I20 mm Hg trange 124 to IMI) after intravenous fenoldopam therapy. Canstant inlesions of fenoldopam nerr titrated usward EYP~Y 10 to 20 min from an initial dose 010.1 &kg per min ioBmaximal dar do.9 &q per min. The therapeutic goat ol a supbir diastolic btwd pressure oi
the fenoldopam infusion, but mitrat Row veleeities during ~m~trtcular filling were wehanged. Side effeetl of inlnvenow lenotdopam were mild, transient and wwtatd wttb the marked vDsoditstq pmpertta of the drug. Thus, fenotdopam b safe and efNt”e as a psrenterat manetherapy in patients with severe essatiat and remww cutar hypertension. Preliminary data suggest that btmd pressure rrdtiteo with ~tleettw dopnmbr-I sgenbt tbw spy is wampsnied by improved ton wntrtcutar fundion. (.J 4m CON Curdial1988:11:1118-23)

Fenoldopam mesylate (Smith, Kline & French. 82526-l) is a potent renal and systemic vasodilator that stimulates patsynaphc dopamine receptors and is active both orally and parcnteratly (1). Unlike dopamme, fenoldopam lacks significant alpha- or beta-adrmergic agonist activity (1.2). Thus, higher doses of fcnoldopam dl: :~ot dwctly increase either heart rate or blood pressure. Renal effects of this drug include an increase in urinary flow rate. free water cltarance and fractional excretion of sodium (j,Y). Srudics in animals

(5,6) suggest lhat dopamine-I receptllr stimulation may induce a direct tubular effect to enhance sodium excretion in addition to the diuresir that occurs through increased renal bload flow. Hemodynamic effects of fenoldopam in mildly hypertensive patients have been evaluated after oral dosing of the drug (7). Acutely, fenoldopam results in a decrease in blood presrure mediated by a reduction in total peripheral resistance. The reduction in peripheral resistance is associated with an increase in cardiac index, heart rate, stroke volume and left ventricular ejection rate. In addition, renal blood Row increases by 40 to SOW in hypertensive patients, whereas renal vascular resistace decreases by a similar amount after acute and short-term therapy with oral fenoldopam (7.8). The findings of earlier studies with fenoldopam suggested that dopamine-I agonists would be an appropriate cla%s of drugs for hypertensive patients with renal insuffiictency or congestive heart failure. Recent pharmacokinetic study of intravenous adminisiration of fenoldapam 14) in hypertensive patients has shown that the drug n& an etimination half-time of
fenoldopam

makes it ideal for parentersl

we in rhe warnem

blond prewre

of acute hypertension. In this study. administration

we evaluated

of fenoldopam

patients

with

addition

to the evaluarino

the effects of the parenter~i

war titrxcd

upward hy 0.1 too.2 &kg

in a variety

miuwm

of hospmdirci:

in

hypertenwm.

f p:“sxcrcipon,c

of b!wx function

.od

WIS asFessed by Dop-

pler echocardiography.

bled

p:wwe

with

severe or accelerated

were strictly aged 14 to l? yeart

patientc.

hypertension

blood pressure >I20

nmm Hg) were \wdied

phase of the protocol

tscrecning

intensive

unit at the Louisiana

Center. The protocols institutional informed studies

review

during the acute

conventional

m the medical

of Connecticut State University

hoards of each mstmtti& into

and echocardiography

the protocol

;ncludcd

raptd-acting

hwory

and

m both

Medical

antthypertensive

center. therapies

before or at the dircontinuo-

81 the Universitv

of Connecticut.

and heart mtc were iooitored

min ior 30 to Yo mm after discontinuation diartolic

period.

University

immediately

blood pwsure

Scieemng

State

oral or parenteral

were admimstered

tion of the mfusion:

hy the

center

tConnecticut

Fluid inlake and urinary output

infusions were abruptly discmttinued

Loutsiana

and the

and w&n

from all patients.

At

Medical

for this study were approved

consent was obtained for entry

centers.

the iniw

sod u.innry radium

levels tConnecticut

measured during the infusion

Fcnoldopam

(supme dwtohc

and mfwionl

care unit at the University

hemodialysir

measured

oiienoldopam

Reiwe diwontinuing

values. urinalydr

center onlyl uas performed.

Methods

per min ma maximal

for 2 to 4 h after the goal diastolic

and plasma catecholamine wcrc

dose level. f*wkloni~rn

per min. Infusions

was achtevd

won. hiood chemistry lercl\.

Eighteen

rate of I.5 @kg

were then kept consxmr

onlvl

Study patients.

above 90 to 95 mm Hg. Rfter

oi 10 mm on a particular

very severe or accelerated

side effect% leit ventricular

WE maintained

a mimmum

oral agents were administered

blood pressure we% >I20

the

every 2 to 5

of rhe infusion znd when the wpinc

mm Hg. Alter

the infu-

sion. patients remained in the hospital for 3 days while blood

nhysical examination. comolete blood couot. serum chemirtry deterrrinations. urinalysis and urinary sodium analysis.

oress”re

and heart rate were evaluated

chest X nv film, and I2 lead elecrrocardioaram IECGI. A minimumofthree supme blood pressure me&emems were taken within an hour of starting the ienoldopam mfuxon IO

inations. mrawrement of blood chemistry values. complete blood coum and ECGsl. Finally. 7 to 10 days after hospital discharge. patients were reevaluated in the clinics to assess the history

sity of Connecticut).

values and hematologic

performed.

if clinically

subtraction

appropriate,

arteriography

was

to exclude renovascular

under

control and safety data were obtained (daily physical exam-

establish the baseline blond pressure. In one center Wniverdigital

and broueht

and physical

examinations.

blood

chemistry

data. These snfcty d&a.

including

discontinued at the time of entry into the study and were withheld until the ienoldopam infusion was discontinued.

follow-up. were obtained in all 18 patients. Echocardiawaphy. Sector-guided Wmade echocardiog. raphy war performed by standard techniques using a Hewlett-Packard system. A11 patients were imaged in the lcit

Criteriafor exchoio~$vmz rhb sredy inalrrdcd: pregnancy or lactation, diastolic blood pressure > 170 mm Hg. acute

Left

myocardial

Rexhek

disease after the study. Antihypertensive

infarction

chmmocytoma.

or crescendo

need for hcmodialyris

clinically apparent hypothyroidism pamine antagonists (for example, pramide). lnlusion

titration

pine collection

protocol.

medications

angina pectorts. or peritoneal

and treatment phenothiarines.

Alter

scrsemng

of plasma catecholamines

ter only) and urinary

sodium

were

gheo-

ICritikon column.

Dinemapp

unit)

and confirmed

Heart ra;e~was continuously

obtained at 2. 5 and IO min after dosing and evw 10 min during goal oi therspy war reduction prebare to it IO mm He or by supine diastolic

blood prerure

with

and Devereux

studmr,

socen-

a mercury wth

star-

and heart rate vere

any change in fenoldopam maintenance iniuion. The of supine diastolic blood 40 mm Hg II the barclinc

was > I50 mm Hg. Diartolic

laovolumic

IIOI

window.

by the method

of

using the Penn mearurement

trxtion of the time from the R wave to aortic valve clowrc from the time from the R wave to mitml valve opening (I I). was recorded at a paper speed of 10x3cm/s. and values fcr

measuring devtce

monitored

from the left pancternal

mass was calculated

convention\.

(both centers) and combined

dard ECG leads. The blood ore,ure

position

dialysis.

(Connecticut

by means of an aotomated

decuhitus ventricular

with dometoclo-

Doppler and M-mode cchocardiography IConnecticut center only), a diluted solution of fenoldopam was administered at a constant infusion rate of 0. I &kg per min. Blood prerwre was monitored

lxeral

three to five consecutive ventricular

relaxation

time. calculated

by rub

cardiac cycles were averaged. Left

and left atrial internal dimensions

usmg the leading edge methods

according

were measored to the standards

suggested by the American Society of Echocardiography Left ventricular(LV) fractional shortening was derived from the following formula: iLV internal dimension in dirstote - LV mternal dimension m systolellLV internal dimen-

tI?).

Jion in dtastole. Doppler eehorardiography.

Mitral

Row velocity

was in-

terroEilted usine a 1.25 MHz continuous wave transducer placed at the czzrdiac apex 1131. Mitral peak Row velouties were mcawred in early diabtok (E wave) and late diasrole (A WLIYC:: three to five consecutiw bats were avenged. All Doppler ilnd M-mode echocardiograms were coded and read by an expcnienccd

echocardiognpher

(M.J.R.).

who was

Time.

m,ruter

Figure 2. Blood prerrure and bean rate immediatelyafterdaconle”oldopam in to padents. No down titralion was performed. Ord agents were administered when diaslolic blood pressure exceeded I20 mm Hg after stopping the mforion. t*p c 0.05. *‘p < 0.02. **‘p < O.wt.

timationof inlrmenaur Figur. 1. Effec!s of inwavenou~ fcnoldopam on blood prewre (BP) dunnp tilmtton and maintenance phases for up to 3 h. Average dare IU rchwe goal dias!olx blood presswe was 0.34 * 0.22 &kg per min.

(Fig. I). Blood dimensnons. movoluroic iog, peak Row velocities statistically

relaxation

time. fractional

and the A/E ratio were compared

at baseline and after 3 h of fenoldopam

therapy

blwd

samples for catc-

dctcrminations were collected at haseline from an heparin lock after the patient had been at wt and

supine for 45 min. Subsequent samples were drawn after 2 b of mau~ienance fenoldopam infusion

time).

therapy

Plasma dopamine.

nephrmc levels were determined chromatography

(or about 3 h of total

epinephrinc

sod norepi-

by high performance

and electrochemical

detection

liquid

(14).

goal of thempy. pam required

the goal diastolic

to 1701%

fenoldo-

blood preswre

until the diastolic

blood pressure was >I20

pressure began to increase within

had renal afiery stenosis (4

was as expected; effects

patiemn) or nephrosclemsis (10 palientr) or both; baseline serum creatmine was bl.5 mcldl in seven of these oatients. Four patients were admitted to the study with ‘rebound

centrations

hypenension

nephrine,

with abrupt withdrawal

from aloha-

in individual

not observed.

patients

classes of drugs (for example, residual shown).

renal

the

blood oressure

levels 2120 mm Hg &thin 30 min (Fig. 2). H&t rate became progressively lower during the first 30 min after cessation of administration of the drug. Rebound hyperten-

ptil)

who underwent

mm Hg. Blood

5 min of discontinuing

infusion and 8 of the 10 patients had diastolic

age from 34 to 72 years. Ten p.xnds

asaoiiated

The average dose of intravenous

to thieve

sure reduction

Eighteen patients were studied at

arwriography

reduced from X4/132

At one center (University of Connecticutl, fenoldopam was discontinued abrumlv and the blood ore~~ure and heart wtf responses were observed without additional therapy

the two centers. There were I4 men and 4 women ranging in digital subtraction

was

sion above baseline values wal

Resufts Palient characteristia.

pressure

mm Hg after Ki min of therapy. There were no instances of “overshoot” hypotension and all 18 patients achieved the

was 0.34 ? 0.22 /rglkg per min.

using a two-tailed paired I test. Plasma catecbolamiw. Venous choLlmine indwelling

shanen-

potentiation

of fenold-pam

wilh

labetalol.

Blood prer

various

standard

hydralazine,

of there

was not

capto-

agents from

seen (data

not

Plasma entecholamines. Catecholamines were assessed in IO of the patients. Plasma epinephrine and dopamine condid not change after fenoldopam 36 t 32 &ml

theraw

teoi-

at baseline to 39.2 34 pglmibu&

2 agonist therapy.

fenoldopam;

Blood pressure and heart rate data. The blood orc~surc was reduced by It/t4 mm Hg at the initial dose of d.1 &kg per min tp < 0.01 for systolic: p < O.Wt for diastolic) and

during fenoldopam). Plasma norepinephrine levels increased significantly from 362 * 222 pgiml at baseline to 550 r 381 pglml after fenoldopam therapy (Fig. 3). Parients with reflex tachycardia had the largest increases in plasma norepinrphrine: however. because of the small number of subjects, a

most patients reached the goal supine diastolic blood pres sure a! a dose of 0.3 to 0.4 &kg per min (Fig. I!. Heart rate increased significantly from 77 to 89 beatslmin (p < 0.01) at 0.3 wkg

per min.

A progressive. smooth reduction in blood pressure was observed over the first 60 min of the fenoldopam infwon

significant

dopamine,

relation

norepinephrine


between change in heact rati and plasma

levels could no1 be established.

Urinary volume and sodium levels. Dota on urinary sodium excretion were avnilable for 15 patients. An avenge

from 35 ? 7 mm at baseline to 28 2 6 mm during maintenance fcnoldopsm infusion; isovolumic relaxation time @ordiurcsis infusion

of 195 r (range

320 ml occurred I20 to 880 mll.

during

the fenoldopam

Fractional

excretion

of

sodium increased from 0.86 c 0.64?4 at baseline to 1.77 e 0.80% by the end of infusion (p < O.OI). Spcciiic gravity of theurine decreased from LOl6at baseline to I.UO9ar the end of infusion (P z 0.05). Fxbocardiegrapldc

tindin@

paired echocardiograms the effects of fcnoldopam

(Tat&

1). Nine

were of sufficient therapy.

of the

quality

IO

to assess

Five paired echocardio-

grams were of sufficient quality to a5scss isovolumic rclaxation time. Tbe left ventricular mass was 235 f 159g (normal range 110 to 180). Left atrial dimension. left ventncular dimension at diastole, fractional sbortenine and peak Row velocity

during early and late diastolic

after fenoldopam

therapy.

rected for heart rate) decreased from U.36 msibeztslmin

(fOUr p2!ient$. Sy”IptorW,tK patients). unifocal ventricular

I” One,. PalpitallOnS ,tWo cctopic acrivity (one patient),

ache (one patientl.

Side effects were resolved after 30 to 60

min of dircontinualion

of the infusion.

No abnormalities

wsrc detected in the hernatologic or chemistry uated at I, 2 or 7 days after fcnoldopam.

studies cval-

filling did no* change

End-systolic

dimension

Dkcussion

decreased

Bldre I”f”V””

The results of this study show that

I

After ,“f”Y,“”

vI I0.I 47 65

findings.

intravenous administration of fenoldopam. a new dopammereceptor agonist, decreased blood pressure in a variety of

Tsbk 1. Variables of Lcfl Ventricular Function During Fenoldopam Infusion in Nine Patients Wth Pawed Ecbocardiogams

11.8 i 42.7 r il.1 t 1s 0 >

t 0.63 to 0.56 -i

minor T-wave changes on the ECG (one patient) and head-

Principal

LA size @ml, kanctmilalIhoncnlng (pa) EnddiarlDUr dlmmrio” ,mro> End-ryrtOliLdilllellio” klla, PIaL “cloclly MS, *,“a, syllole Early dlawhc 6umg AIE ratio I”R1‘ ,mr,

I.Ol

(Fig. 41.

Adverse side effects. There were no serious side etkcts in the entire patient group. Hence, no infusions were discontinued prematurely. The side effects observed were flushing

II.3 T I!.? 47.7 f I, 5 48.0 ? 1’) b z b P.

paucnts wth very severe or wxelerated hypertension. Furthermore, fenoldopam was well tolerated and did not cause cxccssivc hypotcnsion when admimstercd by conctant infusion.

After

discontinuation

of the drug.

blood

pressure

rapidly increased toward baseline level but did not rebound

toexceed

“Xl?,,?, 1fi7f011

I,*,:“?, I,,~:“.?2

baseline blood pressure values. The most consistcm side effects offcnaldopam were those associated with the agent’s vascdilbtory properties (for example. flushing and increased heart rate). Previous with fenddopam. The ef-

67 1

34.4 * xl+

tcnsive

i 14i ” :” 2

‘p< rJ.ol.+p rebxalrn dim: LA = M iltnum

I 6

(9

I ,I T057

,,,l,ng.lYRT = I,O”“IU.IC

phamrdogic rtudiks IIS) fcnoldooam

fectc of oral (7.8) and intravenous pat~erds~ include

stimulation

receptors in the renal vasculature In normoten~~ve patients.

of specific

ib! bvoerdapkdne

that result in vasodilation.

blood pressure and heart rate are

nor appreciably severely

s&ted

by fenoldopom

hypcrtcmive

duccd

marked

raw

Thw

patxnt\.

reduction rcwlts

(7.R.161

that reduced

vascular

dnpamine-I

pathogcncn esxnlial

add

tX!. In our wdy

intnwcnow

in blood suppon

rcccptor

ac;ivoy

cxpreracd

may contribute of elevated

at the

in part 10 the

blood

in bar!

produced

in our partems

norepmepbnnc

strated

unaccompanied

with

prcswrc

of Ventura

increase

in

increase

findings

dam of Murphy

who

m mdd hvoenension.

inephrine

arsc&ed

Ihc

IS not unlike

hydralarine

(17) or nitrcnd!pine

stimulntion

utilized

(IS).

associated

with

fenol-

in olasma

vasodilatory

that of other

after with the

intravenous

The increase

with

fenoldopam

output

norepinephrine

but are m concordance

et al. (IX

demon-

rate and cardiac

in plasma

in

are in partial

an oral dose offcnoldopam. dooam

lime

ua\

tone i< incrcacd

t.111~ well

wilh

the reduced energebcs

mcarurablc.

The

in hvoertcnsive

rapid

left

relaxation

end-systolic associated

relax-

and corrc-

measured

(IO).

by

Improvement

may also be due in pan 10

volume

with

f;llinp curves

time

isovolumic oatients

&lriculx

Lime-activity

in the wwolumic

Invo+ve

increhw

et al. (71. who

in hean

hy a change

a modest

a significant

(Fng. 3). Thee

to the r~pnrl a slgniticant

ofion

or improved

reduced

wall

myocardial

tension

from

after-

load reduction.

administrauon

rate

plasma cootrail~t

mic rela.wtion

radionuclide-derived

coocIu\iun5

hypertension.

Fcnoldopam

thetic

in-

at low infusion

to prewoub

dopammergic

or maintenance

of

fenoldopom

prcrwre

noreobr

‘propenies

vasodiiators The increased

fenoldopam

patients goned. tance

studies

in severely

after fcnoldopam therapy In patients with congestive

fcnoldopam

signdicantly

and increases

effect on puln~onary dopamine

agonist

increases

myocardial

have oat ye! been rcheart failure (21). oral

decreases

cardiac vascular therapy

hyperlcnsive

systemic

index

vascular

but apparently

resistance

or p&ad.

has positive

inotropic

fcnoldopam

sympa-

pressure reduction

induces without

a prompt,

serious

smooth

side effects.

in blood pressure

resis-

ha,

little

Whether effccls

or

in patients with hyperten-

contractility

sive heart disease remains to be determined. Clinicat significance of the findings. Coos&ml

such as

is also prob-

hemodynamic

reduction

Rapid.

is indicated

infusion

of

in blood

but not abrupt,

in most patients

with

ably rcsponsable for the minor T-wave changes and incrcascd ventricular ectopic activity noted in two of our

severe or xc&rated hypertension. prescore by intravenous fenoldopam

o&nts because these abnormalitica *ere absent on ECGs laken within h of discontinuing the drug infusion.

a clinically imporwt diuresis. obviating the need for a loop diuretic. Thus, the future of therapy with selective dononinr

I

Renal function qploximately in’usion.

studies.

A clinicidly

siEnificant

400 ml in 3 to 4 h occurred Because

no patient

m this study

diwcsir

during received

of

fenoldopam

therapy.

The

observed

diuretics

renal

increase

in so-

dium excretion during the infusion of fenoldooam severely hypenenswe~study group is consistent’with ously

reponed

hyp&ensive subjects induced

in renal were

paformed sodium

waler

of fenoldopam (3.15.19).

loaded.

h dose-related

increase studies

effects patients

were

oafurcsis

plasma

Row.

o&ditTerent

in individuals and volume

The

who we!c before

in our previ-

and mildlv

studies,

in which

fenoldopam

in association

from

intake

in normal

in those

oral or mwwenou

with

n 50%

conditions

of

these

because

they

were

ourc

carcful!v

monitored

the Rnoldopam

for

dosing.

0~ hypertensive study group was admitted dlrcctly ta the hospital. with no prior resw~clioos io sodium intake and no wner lo;idmg. and many had abnormid renill funclion. Sim&x duesir after iotrnveoouc administration offenoldnpam hna been reported

in B revercly

hypertensive

by wwigators in Spain 1201. Fxbocardiagraphic data. Of particular elects

of mlrweoou~

fcnoldopam

population

interest

on left ventricular

were

the

petfor-

mancc. The echocardiographic data demonwatc modest improvement in left ventricular function arrociated with a rcdwion in left ventricular end-ay\tolic dimension poaaibly accondary

to ventricular

was improved

unloading.

Uiastolic

in three of the five patients

performance

in whom

may

wit? excessive

immcdlatcly bcforc or during the infusion. it i: assumed that this “diuwis” was a result of increased renal perfusion during

agonists

the drug

~sovoIu-

failure.

be in the treatment

blood volume.

The reduction in blood is often associated with

of hypertensive

including

patients

those with heart and