Jefferson Journal of Psychiatry Jefferson Journal of Psychiatry

Volume 10 Issue 1 Article 5

January 1992

Domperidone for Drug-Induced Orthostatic Hypotension-A Review 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 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 OrthostaticHypotension-A Review

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

Abstract

Drug-induced orthostatic hypotension (Olf) is a commonside tifftct cfheterocyclic and AfAOIantidepressant medications. It usually does not respond to conservative treatment and drugtreatments with mineralocorticoids or central dopaminergic antagonists such as metoclopramidehave significant long-term side tifftcts that limit their use. Domperidone, a peripherally actingdopaminergic antagonist withjew sideeffects, has been used in a number qfsmall clinical trials totreat 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 successfultreatment ofOH by domperidone. Further controlled studies qf domperidone for antidepressant­induced OH in relevant patient samplesare warranted.

INTRODUCTION

Drug-induced orthostatic hypot en sion (O H), a com mo n side effect of heterocy­clic a nd mon oamine oxidase inhibitor (MAO I) a n t ide pressan ts, is often encounte redin clinica l practi ce (1,2). One study found th at seve re sympto matic O H (repeatedfainting or fall ing) occurre d in 9% of pat ients on imi pra mi ne, I I% of patients onph en elzin e, and 17% of patients on tranylcypromine (3). The adve rse conseq uen ces ofdrug-induced OH are evide nt, particul arly for th e elde rly whe re fa lls can result inbroken hips . Newer ant idepressants suc h as se ro to ne rg ic reuptak e inhibitors do notca use significan t blood pressure cha nges. H owever, some patients may need treat­ment with het erocyclics a nd MAOIs because of refr act ory depression or specificity ofresp onse. For exa m ple, patients may be preferentiall y responsive to MAO Is fora ne rg ic bipolar depressions (4) or at ypical depression s (5) . Thus, for some patients itis important to treat side effec ts suc h as OH rather th an to switch to anothera nt ide pressa n t.

Drug-induced OH, however, is ofte n difficult to manage (6). Conservativetreatments su ch as patient educa t ion, vascular s toc kings, increased salt and in­creased fluid intak e a re usu all y insufficient. Fludrocortison e, a mi ne ra locorticoidvolume expa nde r, has been th e mo st com mo nly used ph armacologic agent fora n t ide pressan t-induce d OH. Fludrocortison e is effec tive in treating OH, but carriessignifican t side effects suc h as resting hyperten sion , hypokalemia and congestiveheart fai lure as well as other possibl e cor t icos teroid effec ts. Dopa mi nergic antago-

12

DOMPERIDONE FOR DRUG-IND UCED ORTHOSTATIC HYPOT ENSION 13

nist s suc h as met aclopramide have been exte ns ively used as a trea t me nt for OH inParkinson s disease a nd a uto no mic neurop athies, a nd have also been successful in th etreatment of MAOI-induced OH (7) . Lik e ot her ph en othiazine drugs, met aclopra­mide act s ce n trally a nd also has pot entiall y signifi cant side effects including ex tra py­ramidal sym ptoms, hyperprolactinemia a nd tardive dyskinesia .

Domperidone (trad en am e: Motilium) is a peripheral dop amine a ntagonist th atdoes not cross th e blood brain barrier, ha s no ce nt ra l dopaminergic ac t ivity, andth erefore is devoid of th ese risks (8) . Recently domperidone has been successfullyused in small clinical trials for OH secondary to Pa rk insons disease, diab eticau to no m ic neuropathy, ce n t ral neurological inju ry a nd d rug-induced OH. T hisa r t icle will review th e lit erature address ing domperidon e as a t reatm ent of OH. O urlit erature search revealed only nin e a r t icles focusin g on domperidone a nd ort hostatichypot en sion.

Domperidon e is mainly used as an upper gas t ro in tes t ina l mo ti lity agent (9).Lik e metoclopramide, it has antiem etic a nd gas t ropro kine tic pr operties. Dom peri­done is gen erally well tol erat ed and has a low incid en ce of side effects, pred omina ntlydry mouth (1.9 %), headach e (1.2 %), abdo minal cra m ps « 1%), and diarrhea « 1%)( 10). Althou gh it has no ce nt ral effects it ca n rai se prolacti n levels ( 10). It s usualdosage ran ge is 30 to 60 mg daily for upper gas troin tes t ina l mot ility d isorders.

Becau se of its a n t ie me tic properties, domp eridone was used to treat the nau seaa nd eme sis associa te d with dopaminergic agents in th e t reat men t of Pa rkinsonsd isease. The dopamine agoni st a pomo rphine a lso ca uses O H, likely med iat edthrou gh peripheral , rather th an ce ntra l, dopaminergic mech an ism s ( I I ) . A double­blind st udy (12) in 4 drug-free patients with Parkinson s disease found th e ac uteadministration of domperidone (100 ug/kg 1M), but not sa line, pr event ed th enausea , seda t ion, a nd art erial hypotension seen after apomo rphine injection (20ug/kg 1M). Poll ack e t al. (13) also st ud ied both th e acute a nd chro nic blood pr essureeffec ts of domperidon e in two se pa ra te stud ies of patients with Parkinsonism. In asing le-blind study involvin g 10 patients, domperidon e ( 12 mg 1M) or placebo wasad ministere d , followed by I mg of a pomo rphine. In th e placeb o condit ion, a pomor­phine significan t ly lowered supine a nd erect blood pr essures. The domperidonesignifica n t ly incr eased supine diastolic blood pr essure, erect systolic a nd diast olicblood pr essure, and blocked th e hypot en sive effects of a pomo rp hine. T he seconds tudy exa mined th e longer-t erm blood pr essure effects of domperidon e in 16 patientswith idiopathic Parkinson s dis ease chro nica lly treat ed with a variet y of dopa mi nergicdrugs. Five of th ese patients had occasional asymptoma tic OH. Patients were giveneithe r pla cebo or domperidone for on e week in a double blind cross-over design . Inth ese patients domperidon e slightly, but significan t ly, rai sed sup ine systo lic bloodpr essure a nd erect sys tolic a nd diastolic blood pr essure over th e one-week period.

These encouraging results were not supporte d in other s tud ies wit h domperi ­don e a nd brom ocriptine. Agid e t a l. found th at domp eridone (60 mg/day) blockedbromocriptine-induced nau sea a nd vom iting and allowed for ra pid a ttainme nt ofhigh th erapeutic dos es of bromocriptine ( 14). There was, however, no protect ionagains t hypotension in thi s placebo-controlled study. All fou r pa tient s who had

14 J EFFERSON JOURNAL O F PSYCHIAT RY

ort hos tat ic hypoten sion (out of a tot al of 17 subjects) were in th e domperidone group.Two further reports by th e sa me gro up found th at larger doses of domperidon e (150mg/day) had no effec t on blood pr essure nor th e occurre nce of ort hos ta t ic hypot en­sion in 20 patients treat ed with high-dose brom ocriptine ( 15, 16), a lt houg h th ese tworeports se em to consist of th e sa me patient sa m ple. This discrepan cy in results withbromocriptine a nd a po mo rphine sugges ts th at br om ocriptine-induced postural hy­pot en sion involves ce n tral mech anisms rather th an peripheral mechan isms.

Althou gh th ese stud ies of domperidon e and dopamine ago nist s have shownmixed results on blood pr essure effects, clinical stud ies of domperidone in treat ingOH have ge nera lly been favorabl e. One rep ort found th at domperidone (60 mg/day)was effec t ive for treating th e OH of3 hypert en sive patients with concurre n t OH fromsevera l e t iolog ies (17). Mont astruc c t a l. (I8) looked a t domp erid on c's effec ts in 8patients with "severe symptoma tic or thosta t ic hypot en sion " of va rious et iolog ies (3patients had ce ntra l neurological injury, 2 cases had idiopathic OH, a nd 3 pa tien tshad drug-induced OH du e to clomipramine or antimitotic medi cation ). Aft er 5 daysof treatment with domperidone OH improved a nd sympto ms disappea red in allcases. Aft er 5.0 ± 1.4 months mean follow-up th e orthos ta tic d rop was significan t lyreduced from 53.1 ± 4 mmHg before treatment to 25.0 ± 9.5 mmHg afte rdomperidone. Domperidone ha s a lso been effect ive in treating symptomatic OH indiabetic a utonomic neuropathy (19). Lopes de Faria et a l. (20) stud ied 9 patients withdiab etic a uto no m ic neuropathy a nd showed th at ora l domperid one 30 mg/day for 3days significa n t ly decreased th e orthos ta tic drop in blood pr essure. Six of th esepatients maintained th eir im proveme nt a fte r a 6-mo nth follow-up.

DISCUSSIO T

The mech anism of ac t ion of domperidon e on blood pressure rem ains poorlyunderst ood . Peripherally ac t ing dopamine may have vasod ilat ing and naturieti ceffects, and excessive dopamine release up on sta nd ing has been described in pat ient swith OH (2 1). Met oclopramide is hypothesized to inhibit th ese effec ts and increaseplasma levels of aldosterone and free epinephrine (22) . Domperidon e's peripheraldopaminergic blockad e may have simila r effec ts . Domperidon e is a lso a spec ifica n tagonist of D2 pr esynaptic dopamine receptors (23) . Since norepinephrine releaseis inhibited by dopaminergic activity on D2 receptors, domperidon e 's effec t on O Hmay be mediated through enha nce me nt of peripheral noradren ergic act ivity. Prel im­inary stud ies, however, have not found significa n t incr eases in plasm a renin act ivity,ald ost erone, responsiven ess to a ng iote ns in II , nor urinary ca techo lam ines th at mightexplain th e postural blood pr essure cha nges followin g domperidon e (20) .

In sum mary, this review indi cates that domperidon e was effect ive in t he treat­ment of sym ptoma tic OH du e to varied ca uses including diab etic neu ropat hy, ce ntralneurological inju ry, Parkinsoni sm a nd some drug-induced OH. However, t hesestud ies a re limited by small sample sizes, ope n clinica l design s, a nd th e inclu sion ofmult iple et iologies for OH. one compared domp eridon e to othe r effec t ive treat ­ments for OH. The mechanism for domperidon e's act ion on blood pressu re is

DOMPERIDO E FOR DRUG-INDUCED ORTHOSTATIC HYPOTENSION 15

unknown, so domperidone may be effec t ive only for ce rtain et iolog ies of OH. Onlyon e patient in th ese stud ies had a nt ide pressan t-induce d OH. However, he terocyclicand MAOI a ntide press a n ts cont inue to be essen t ia l tools in our psychopharmacologica rmame nta r ium, despit e th eir hypot en sive side effec ts . For some patients withantidepressant-induced OH, particul arly th ose who did not respond to antidepres­sa n ts th at do not have OH as a side effect, it will be clinica lly advantageous to treatth e OH rather than switching drugs. Becau se domperidon e is a we ll-toleratedmedi cation with few side effec ts, it will be worthwhile to det ermine in controlleds tud ies wh ether it is a n effec t ive treatment for antidepressant -induced O H in thesepatients. Sin ce OH ca n be sympto matic or asy mpto matic, tra nsient or continuous,future clinical stud ies should ope ration aliz e th e defin iti on and measurement of OHin orde r to det ermine th e clinical versu s statis t ica l sign ifica nce of t rea tments.

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