Jefferson Journal of Psychiatry

Volume 10 | Issue 1 Article 5

January 1992

Domperidone for Drug-Induced

Orthostatic Hypotension-A Review
Daniel E. McDonald, M.D.
University of British Columbia, Vancouver, BC, Canada

Raymond W. Lam, M.D., F.R.C.P.(C)

University of British Columbia, Vancouver, BC, Canada

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Recommended Citation
McDonald, M.D., Daniel E. and Lam, M.D., F.R.C.P.(C), Raymond W. (1992) "Domperidone for Drug-
Induced Orthostatic Hypotension-A Review," Jefferson Journal of Psychiatry: Vol. 10 : Iss. 1 , Article 5.
DOI: https://doi.org/10.29046/JJP.010.1.002
Available at: https://jdc.jefferson.edu/jeffjpsychiatry/vol10/iss1/5

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 Domperidone for Drug-Induced Orthostatic
Hypotension-A Review
Daniel E. McDona ld , M.D.
Raymond W. Lam, M.D ., F.R.C.P.(C)

Abstract

Drug-induced orthostatic hypotension (Olf) is a commonside tifftct cfheterocyclic and AfAOI

antidepressant medications. It usually does not respond to conservative treatment and drug
treatments with mineralocorticoids or central dopaminergic antagonists such as metoclopramide
have significant long-term side tifftcts that limit their use. Domperidone, a peripherally acting
dopaminergic antagonist withjew side effects, has been used in a number qfsmall clinical trials to
treat OH qf various etiologies. We reviewed 9 studies qf domperidone in the treatment qf OH. A
lthough limited by small sample sizes and poor design, these studiesgenerally showed successful
treatment of OH by domperidone. Further controlled studies qf domperidone for antidepressant-
induced OH in relevant patient samples are warranted.

INTROD UCTION

Drug-induced orthostatic hypot en sion (O H), a co m mo n side effect of heterocy-clic a

nd mon oamine ox idase inhibitor (MA O I) a n t ide pressan ts, is often e nco u n te red in
clinica l practi ce (1,2). One st udy found th at seve re sym p to matic O H (repeated fainting or
fall in g) occ urre d in 9% of pat ients on imi p r a mi ne , I I % of patients on ph en elzin e , and
17% of pati ent s on tranylcypromin e (3). The adve rse co nseq uen ces of drug-induced OH are
evide n t, particul arly for th e elde rly whe re fa lls can res u lt in broken hips . Newer ant
idepressant s suc h as se ro to ne rg ic reupt ak e inhib it ors do not ca use sig n ifica n t blood
pressure cha nges. H owever, so me patient s may need treat-m ent with het erocycli cs a nd
MAOIs because of re fr act ory depression or specificity of resp on se. For ex a m ple, patients
m a y be preferentiall y resp on sive to MAO Is for a ne rg ic bipolar d epressions (4) or at ypi
cal d epression s (5) . Thu s, for some patients it is important to treat side effec ts suc h as OH
rath er th an to swi tc h to anoth er a n t ide pressa n t.

Drug-induced OH, however, is ofte n difficult to mana ge (6). Conservative treatm ents su
ch as pati ent ed uc a t io n , vascular s toc kings, inc re ased salt and in-creased fluid int ak e a
re usu all y insuffi cient. Fludrocortison e , a mi ne ra locorticoid volum e ex pa nde r, has been
th e mo st co m mo n ly used ph arm acolog ic agent for a n t ide pressa n t-ind uce d OH.
Fludrocortison e is effec t ive in treating OH , but carri es sign ifica n t side effec ts suc h as
resting hypert en sion , hypok al emia and congestive heart fai lure as well as ot her possibl e co
r t icos teroid effec ts. Dop a mi n e rg ic antago-

12
DOMPERIDO NE FOR DR UG-IND UCED ORTHOSTATIC HYPOT ENSIO N 13

nist s suc h as m et acl opramide ha ve been exte ns ively used as a trea t me n t for OH in
Parkinson s di seas e a nd a u to no m ic neurop athi es, a nd have also been successfu l in th e
treatm ent of MAOI-indu ced OH (7) . Lik e ot he r ph en othia zi ne dru gs, met acl opra-mide
act s ce n t rally a nd also has pot entiall y signifi cant side effects including ex t ra py-ramidal
sym p t o m s, hyp erprolactinemia a nd tardive dyskin esi a .
Domperidone (trad en am e: Motilium) is a periph eral dop amin e a ntago nist th at does
not cross th e blood brain barri er, ha s no ce n t ra l dop amin ergic ac t ivity, and th e refore is
devoid of th es e risk s (8) . Recently domperid on e has bee n successfully used in sm a ll
clinical trial s for OH secondary to Pa rk inson s diseas e , diab e ti c a u to no m ic neuropathy,
ce n t r a l neurological inju ry a nd d r ug-induced OH . T his a r t icle will revi ew th e lit
erature ad d ress ing domperidon e as a t reatm e nt of OH . O ur lit erature searc h reveal ed on
ly nin e a r t icles focu sin g on domperid one a nd ort hostatic hyp ot en sion.

Domperidon e is m ainly used as a n upper gas t ro in tes t ina l mo ti lity age n t (9). Lik e
m etoclopramid e , it has anti em etic a nd gas t ro p ro kine t ic pr op erti es. Dom pe ri-done is
gen erally well tol erat ed and has a low incid en ce of sid e effec ts, pred o m ina n tly dry
mouth (1.9 %) , headach e (1.2 %), a bdo m inal cra m ps « 1%), a nd diarrhea « 1%) ( 10).
Althou gh it ha s no ce n t ra l effects it ca n rai se p rol acti n level s ( 10) . It s usual dosa ge
ran g e is 30 to 60 mg daily for upper gas troin tes t ina l mot ility d isord ers.
Becau se of it s a n t ie me t ic prop erties, do mp eridone was used to treat t he nau sea a
nd e me sis associa te d with dopamin ergic age n ts in th e t reat m en t of Pa r kinso ns d iseas
e . The dop amine agoni st a po mo r p hine a lso ca use s O H , likel y m ed iat ed throu gh
peripheral , rather th an ce n t ra l, dop aminergic mech an ism s ( I I ) . A double-blind st udy
(12) in 4 dru g-free pati ents with Parkinson s di sease found th e ac ute administration of
domperidone (100 ug/kg 1M), but not sa line , pr event ed th e nausea , sed a t io n , a nd art
erial hypot ension seen aft er a pomo r p h ine inj ecti o n (20 ug /kg 1M). Poll a ck e t al. (13)
also st ud ied both th e acu te a nd chro n ic blood pr essu re effec ts of domperidon e in two se
pa ra te st ud ies of patients with Parkinson is m . In a sing le-b lind st udy involvin g 10 pati
ents, domperidon e ( 12 mg 1M) or placeb o was ad m in iste re d , foll owed by I m g of a po
mo r p h ine . In th e placeb o co nd it io n, a po mor-phine sig n ifica n t ly lowered su p ine a
nd e rect blood pr essures. Th e domperidone sig n ifica n t ly incr e ased su p ine diastolic
blood pr essure , erec t systolic a nd d ia st olic blood pr essure, and block ed th e hypot en sive
effec ts of a po mo rp h ine . T he second s t udy exa m ine d th e lon g er-t erm blood pr essure
effec ts of domperidon e in 16 pati ent s with idiopathic Parkinson s dis eas e ch ro n ica lly
treat ed with a variet y of dop a mi ne rgic drugs. Five of th es e patients had occa sional asym
p t om a t ic OH . Pati ent s we re give n eit he r pla cebo or domperidone for on e we ek in a
double blind cro ss-ove r design . In th ese pati ents domperidon e slightly, but sig n ifica n t ly,
rai sed sup ine systo lic blood pr essure a nd e rect sys t olic a nd di astolic blood pr essure ove
r th e on e-week period.
These e nco uraging results were not su p po r te d in ot her s t ud ies wit h domperi - don
e a nd brom ocriptine . Agid e t a l. found th at do mp e ridone (60 mg/day) block ed brom
ocriptine-induced nau sea a nd vom it ing a nd allowed for ra pid a ttain me n t of high th
erapeutic dos es of bromocriptine ( 14). There wa s, however, no prot ect ion agains t hypot
ension in thi s pla ceb o-controll ed st udy . All fou r pa ti e nt s wh o had
14 J EFFERSO N JOURNAL O F PSYCHIA T RY

or t hos tat ic hypot en sion (out of a tot al of 17 su bjects) were in th e do m pe ridone group.
Two furth er report s by th e sa m e gro u p found th at larger doses of domperidon e (150 m
g /day) had no effec t on blood pr essure nor th e occ u r re nce of or t hos t a t ic hypot e n-sion
in 20 patients treat ed with high-dose brom ocriptin e ( 15, 16), a lt ho ug h th ese two rep orts
se e m to co ns is t of th e sa me patient sa m p le. This discre pan cy in result s wit h
bromocriptine a nd a po mo r p hine sugges ts th at br om ocriptine-in d uced postural hy-pot en
sion involves ce n t ral m ech anisms rather th an periph e ral m ech an isms.
Althou gh th ese st ud ies of domperidon e a nd dop amine ago nist s ha ve sho wn mixed
results on blood pr essure effects, clinical st ud ies of domperidone in treat in g OH hav e ge
nera lly been favorabl e . One rep ort found th at d ompe r id one (60 mg/day) wa s effec t ive
for treating th e OH of3 hypert en sive pati ent s with conc u r re n t OH from seve ra l e t iolog
ies (17). Mont astruc c t a l. (I8) look ed a t do mp e rid on c 's effec ts in 8 patients with "severe
sym p t om a t ic or t h os ta t ic hypot en sion " of va rio us e t iolog ies (3 patients had ce n t ra
l neurological injury, 2 cases had idiopathic OH , a nd 3 pa ti en ts had drug-induced OH du e to
clomipramine or antimitotic m edi cation ). Aft er 5 da ys of treatm ent with domperidone OH
improved a nd sym p to ms disappea red in all cases . Aft er 5 .0 ± 1.4 months mean follow-up
th e or t hos ta t ic d rop was sig nifica n t ly reduced from 53.1 ± 4 mmHg before treatm ent to
25 .0 ± 9.5 m mHg afte r domperidone. Domperidone ha s a lso been effec t ive in treating sym
p tomat ic OH in diabetic a u t o nom ic neuropathy (19). Lopes de Fari a e t a l. (20) st ud ied 9
pati ent s with di ab etic a u to no m ic neurop athy a nd sho we d th at ora l domperid one 30 m
g/da y for 3 days sig n ifica n t ly decreas ed th e or t hos ta t ic drop in blood pr essure . Six of
th ese patients maintained th eir im p ro ve me n t a fte r a 6-mo n t h foll ow-u p.

DISC USSIO T

Th e m ech anism of ac t io n of domperidon e on blood pressu re rem ains poorl y underst

ood . Peripherall y ac t ing d op amine may have vasod ilat ing and naturi eti c effects, and
excessive dop amin e rel ea se up on sta nd ing ha s been d es cr ibed in pat ient s with OH (2
1). M et oclopramide is hypothesized to inhibit th es e effec ts and incr ea se pla sma levels of
aldost erone and fr e e e p inep h r ine (22) . Domperidon e 's peripheral dopamin ergic block ad
e may have sim ila r effec ts . Domperidon e is a lso a spec ific a n tago n ist of D2 pr esynapti c
dopamin e recept ors (23) . Si nce norepineph r in e relea se is inhibit ed by dopaminergic
activity on D2 receptors, domperidon e 's effec t on O H may be m ediat ed through e n ha nce
me n t of peripheral noradren e rgic act ivity. Prel im - inary st ud ies, how ever, hav e not found
sig n ifica n t incr ea ses in pla sm a re n in act ivit y, ald ost erone , responsiven ess to a ng io te
ns in II , nor urinary ca techo lam ines th at might ex p la in th e postural blood pr essure cha
nges followin g domperidon e (20) .
In su m m ary, this review indi cat es that domperidon e wa s effec t ive in t he treat-
m ent of sym p t o m a t ic OH du e to varied ca uses including di ab etic neu ro pat hy, ce
ntral neurological inju ry, Parkinsoni sm a nd so m e dru g-induced OH. Howeve r, t hese st
ud ies a re limit ed by s mall sam p le sizes, ope n clin ica l d esign s, a nd th e inclu sion of
m u lt iple e t iologies for OH . one com pared do mp eridon e to ot he r effec t ive treat -
m ent s for OH. The mechan is m for domperidon e ' s act ion on blood pr essu re is
DOMPERIDO E FOR DRUG-INDUC ED O RT HOSTATIC HYPOT ENSIO N 15

unknown , so domperidone may be effec t ive on ly for ce r tain e t iolog ies of OH . Only on e
pati ent in th es e st ud ies had a n t ide pressan t-ind uce d OH . H oweve r , he t e rocycl ic and
MAOI a n t ide p ress a n ts co n t in ue to be essen t ia l tools in ou r psyc hopharmacologi c a r
ma me n ta r iu m, d espit e th eir hyp ot en sive side effec ts . Fo r some patients with antid
epressant-induced OH, particul arly th ose who did not respond to antidepres - sa n ts th at do
not hav e OH as a side effec t, it will be clin ica lly advantageous to treat th e OH rather than
switc h ing drugs. Becau s e domperidon e is a we ll-tolerat ed m edi cation with few side effec
ts, it will be worthwhil e to det ermine in controlled s t ud ies wh eth er it is a n effec t ive
treatm ent for antid epressant -induced O H in t hese pati ents. Sin ce OH ca n be sym p to mat
ic or asy m p to ma t ic, tra nsient or continuous , future clinical st ud ies sho u ld o pe ration
aliz e th e defin iti o n and measurement of OH in orde r to d et ermine th e clinical versu s
statis t ica l sign ifica nce of t rea t m e n ts.

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