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Jefferson Journal of Psychiatry

Volume 10 Issue 1 Article 5

January 1992

Domperidone for Drug-Induced -A Review

Daniel E. McDonald, M.D. University of British Columbia, Vancouver, BC,

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

This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Jefferson Journal of Psychiatry by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: [email protected]. Domperidone for Drug-Induced Orthostatic Hypotension-A Review

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

Abstract

Drug-inducedorthostatic hypotension (Olf) is a com monsidetifftct cfheterocyclic and AfAOI antidepressant medications. It usually does not respond to conservative treatment and drug treatments with mineralocorticoids or central antagonists such as have significant long-term side tifftcts that limit their use.Domperidone, a peripherally acting dopaminergic antagonist withjew sideeffects, has been used in a number qfsmall clinical trials to treat OH qfvarious etiologies. We reviewed 9 studies qfdomperidone in the treatment qf OH. A lthough limited by small sample sizes and poor design, these studiesgenerally showed successful treatment ofOH by domperidone. Further controlled studies qfdomperi done for antidepressant­ induced OH in relevant patient samplesare warranted.

INTRODUCTION

Drug-induced orthostatic hypot en sion (O H), a com mo n of heterocy­ clic and mon oamine oxidase inhibitor (MAO I) antide pressants, is often encounte red in clinica l practi ce (1,2). One study found th at seve re sympto matic O H (repeated fainting or fall ing) occurre d in 9% of patients on imi prami ne, I I% of patients on ph en elzin e, and 17% of patients on tranylcypromine (3). The adve rse consequences of drug-induced OH are evide nt, particul arly for th e elde rly whe re falls can result in broken hips. Newer antidepressants such as se ro to ne rg ic reuptak e inhibitors do not ca use significant blood pressure cha nges. H owever, some patients may need treat­ ment with het erocyclics and MAOIs because of refract ory or specificity of resp onse. For exam ple, patients may be preferentiall y responsive to MAO Is for ane rg ic bipolar depressions (4) or at ypical depression s (5) . Thus, for some patients it is important to treat side effects such as OH rather th an to switch to another antide pressant. Drug-induced OH, however, is ofte n difficult to manage (6). Conservative treatments su ch as patient education, vascular stoc kings, increased salt and in­ creased fluid intak e a re usu all y insufficient. Fludrocortison e, a mi ne ra locorticoid volume expa nde r, has been th e mo st com mo nly used ph armacologic agent for antide pressant-induce d OH. Fludrocortison e is effec tive in treating OH, but carries significant side effects such as resting hyperten sion , hypokalemia and congestive heart fai lure as well as other possibl e corticos teroid effects. Dopami nergic antago-

12 DOMPERIDONE FOR DRUG-IND UCED ORTHOSTATIC HYPOT ENSION 13 nist s such as met aclopramide have been exte nsively used as a treat ment for OH in Parkinson s disease and auto no mic neurop athies, a nd have also been successful in th e treatment of MAOI-induced OH (7) . Lik e ot her ph en othiazine drugs, met aclopra­ mide acts ce ntrally and also has pot entiall y signifi cant side effects including ex tra py­ ramidal sym ptoms, hyperprolactinemia and . Domperidone (trad en ame: Motilium) is a peripheral dop amine antagonist th at does not cross th e blood brain barrier, ha s no ce nt ra l dopaminergic activity, and th erefore is devoid of th ese risks (8) .Recently domperidone has been successfully used in small clinical trials for OH secondary to Park insons disease, diabetic au to no m ic neuropathy, ce ntral neurological injury and d rug-induced OH. T his article will review th e lit erature address ing domperidon e as a treatment of OH. O ur lit erature search revealed only nin e articles focusin g on domperidone and ort hostatic hypot en sion. Domperidon e is mainly used as an upper gastro intes tina l mo tility agent (9). Lik e metoclopramide, it has antiem etic and gast ropro kinetic properties. Dom peri­ done is gen erally well tol erated and has a low incid en ce of side effects, predominantly dry mouth (1.9 %), headache (1.2%), abdo minal cram ps « 1%), and « 1%) ( 10). Althou gh it has no cent ral effects it can raise prolacti n levels ( 10). Its usual dosage ran ge is 30 to 60 mg daily for upper gastrointestina l mot ility disorders. Becau se of its antieme tic properties, domp eridone was used to treat the nau sea and eme sis associate d with dopaminergic agents in th e treatmen t of Parkinsons disease. The agoni st apomo rphine also causes O H, likely med iat ed throu gh peripheral , rather th an ce ntra l, dopaminergic mechan ism s ( II ) . A double­ blind st udy (12) in 4 drug-free patients with Parkinson s disease found th e ac ute administration of domperidone (100 ug/kg 1M), but not sa line, pr evented th e , sedation, and arterial hypotension seen after apomo rphine injection (20 ug/kg 1M). Pollack et al. (13) also st ud ied both th e acute and chro nic blood pr essure effects of domperidon e in two se pa ra te studies of patients with . In a sing le-blind study involvin g 10 patients, domperidon e ( 12 mg 1M) or placebo was ad ministere d, followed by I mg of apomo rphine. In th e placebo condition, apomor­ phine significantly lowered supine and erect blood pr essures. The domperidone significantly incr eased supine diastolic blood pr essure, erect systolic and diastolic blood pr essure, and blocked th e hypot en sive effects of apomo rp hine. T he second study exa mined th e longer-term blood pr essure effects of domperidon e in 16 patients with idiopathic Parkinson s dis ease chro nically treated with a variet y of dopami nergic drugs. Five of th ese patients had occasional asymptomatic OH. Patients were given eithe r pla cebo or domperidone for on e week in a double blind cross-over design . In th ese patients domperidon e slightly, but significantly, raised sup ine systo lic blood pr essure and erect systolic and diastolic blood pr essure over th e one-week period. These encouraging results were not supporte d in other stud ies wit h domperi ­ don e a nd brom ocriptine. Agid et al. found th at domp eridone (60 mg/day) blocked -induced nau sea and vom iting and allowed for rapid attainme nt of high th erapeutic dos es of bromocriptine ( 14). There was, however, no protect ion agains t hypotension in thi s placebo-controlled study. All fou r patient s who had 14 J EFFERSON JOURNAL O F PSYCHIAT RY ort hos tatic hypoten sion (out ofa 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 (150 mg/day) had no effect on blood pr essure nor th e occurrence of ort hosta tic hypot en­ sion in 20 patients treated with high-dose brom ocriptine ( 15, 16), alt houg h th ese two reports se em to consist of th e sa me patient sa m ple. This discrepan cy in results with bromocriptine and apo mo rphine sugges ts th at brom ocriptine-induced postural hy­ pot en sion involves ce ntral mech anisms rather th an peripheral mechan isms. Althou gh th ese studies of domperidon e and dopamine ago nists have shown mixed results on blood pr essure effects, clinical studies of domperidone in treating OH have ge nerally been favorabl e. One report found th at domperidone (60 mg/day) was effective for treating th e OH of3 hyperten sive patients with concurre nt OH from severa l etiologies (17). Montastruc ct al. (I8) looked a t domp erid on c's effects in 8 patients with "severe symptoma tic orthosta tic hypoten sion " of va rious etiologies (3 patients had ce ntra l neurological injury, 2 cases had idiopathic OH, and 3 patien ts had drug-induced OH du e to or antimitotic medi cation ). Aft er 5 days of treatment with domperidone OH improved and sympto ms disappeared in all cases. Aft er 5.0 ± 1.4 months mean follow-up th e orthos ta tic drop was significantly reduced from 53.1 ± 4 mmHg before treatment to 25.0 ± 9.5 mmHg afte r domperidone. Domperidone ha s also been effective in treating symptomatic OH in diabetic autonomic neuropathy (19). Lopes de Faria et al. (20) studied 9 patients with diab etic auto no m ic neuropathy and showed th at ora l domperid one 30 mg/day for 3 days significantly decreased th e orthos ta tic drop in blood pr essure.Six of th ese patients maintained th eir im proveme nt after a 6-mo nth follow-up.

DISCUSSIO T

The mechanism of ac tion of domperidon e on blood pressure rem ains poorly underst ood . Peripherally ac ting dopamine may have vasodilating and naturieti c effects, and excessive dopamine release up on sta nding has been described in patients with OH (2 1). Met oclopramide is hypothesized to inhibit th ese effects and increase plasma levels of aldosterone and free epinephrine (22) .Domperidon e's peripheral dopaminergic blockad e may have simila r effects . Domperidon e is also a spec ific antagonist of D2 pr esynaptic dopamine receptors (23) . Since norepinephrine release is inhibited by dopaminergic activity on D2 receptors, domperidon e's effect on O H may be mediated through enha nce me nt of peripheral noradren ergic act ivity. Prelim­ inary stud ies, however, have not found significant incr eases in plasm a renin activity, ald ost erone, responsiven ess to ang iote nsin II, nor urinary ca techo lam ines th at might explain th e postural blood pr essure cha nges followin g domperidon e (20) . In sum mary, this review indi cates that domperidon e was effective in t he treat­ ment of sym ptomatic OH du e to varied causes including diab etic neu ropat hy, ce ntral neurological injury, Parkinsoni sm and some drug-induced OH. However, t hese studies are limited by small sample sizes, ope n clinica l design s, and th e inclusion of mult iple etiologies for OH. one compared domp eridon e to othe r effective 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 effective only for ce rtain etiologies of OH. Only on e patient in th ese studies had antide pressant-induce d OH. However, heterocyclic and MAOI antide press ants continue to be essentia l tools in our psychopharmacologic armame nta rium, despite th eir hypot en sive side effects. For some patients with antidepressant-induced OH, particul arly th ose who did not respond to antidepres­ sa nts th at do not have OH as a side effect, it will be clinica lly advantageous to treat th e OH rather than switching drugs. Becau se domperidon e is a well-tolerated medi cation with few side effects, it will be worthwhile to det ermine in controlled studies wh ether it is an effective treatment for antidepressant-induced O H in these patients. Since OH ca n be sympto matic or asy mpto matic, tra nsient or continuous, future clinical studies should ope ration aliz e th e defin iti on and measurement of OH in orde r to det ermine th e clinical versu s statis tica l sign ifica nce of trea tments.

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