March 2008 • Volume 18 • Supplement 1

Clinical Autonomic ResearchOfficial Journal of the American Autonomic Society,Clinical Autonomic Research Society andEuropean Federation of Autonomic Societies carUpdate on Neurogenic Orthostatic HypotensionPathophysiology, prevalence and treatment

Horacio Kaufmann(Editor)

123

Clinical Autonomic Research

March 2008

•Vol. 18

•Suppl. 1

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This supplement is based on a symposium that took place in New York Cityon April 20, 2007. Distinguished faculty met to discuss recent advances inorthostatic hypotension and what the future holds.

ClinicalAutonomicResearch

FACULTY

Horacio Kaufmann, MDF.B. Axelrod Professor of NeurologyProfessor of Medicine and PediatricsNew York University School of Medicine

David Robertson, MD, FACPElton Yates Professor of MedicineProfessor of Pharmacology and NeurologyVanderbilt University

Phillip A. Low, MDProfessor of NeurologyMayo Clinic College of Medicine

Roy Freeman, MB, ChBProfessor of NeurologyHarvard School of Medicine

Christopher J. Mathias, PhDProfessor Neurovascular MedicineImperial College School of MedicineUniversity College London

ClinicalAutonomicResearchOfficial Journal of the American AutonomicSociety, Clinical Autonomic Research Soci-ety, and European Federation of Autono-mic Societies

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Editors-in-Chief

Horacio KaufmannNew York University, New York, USA

Christopher J. MathiasImperial College London &University College London, UK

Associate Editors

Eduardo BenarrochMayo Clinic, USA

Jens JordanFranz Volhard Clinical Research Center,Germany

Vaughan MacefieldUniversity of Western Sydney, Australia

Managing Editor

Natalie BaileyClinical Autonomic Research530 First Avenue, Suite 9QNew York (NY) 10016-6497, USAFax: +1-646/224-8799E-Mail: clinicalautonomicresearch@gmail.com

Ronald SchondorfSMBD Jewish General Hospital, Canada

Wouter WielingUniversity of Amsterdam, The Netherlands

EDITORS/EDITORIAL BOARD

Manuscripts should be submitted online at:www.editorialmanager.com/autres. We stronglyencourage the use of our online system to trackall manuscripts throughout the peer reviewprocess. Any additional inquires should beemailed to the Managing Editor.

Editorial Board

Sir Roger Bannister,Pembroke College, UK(Editorial BoardChairman)

K Abe, Okayama UniversityMedical School, Japan

MJ Aminoff, University ofCalifornia, San Francisco

F Axelrod, New YorkUniversity MedicalCenter, USA

I Biaggioni, VanderbiltUniversity, USA

G Burnstock, Royal Free andUniversity CollegeMedical School, UK

M Chapleau, University ofIowa, USA

P Cortelli, Universita diBologna, Italy

NJ Christensen, University ofCopenhagen, Denmark

M Elam, University ofGoteborg, Sweden

J-L Elghozi, Hopital Necker,France

M Esler, Baker MedicalResearch Institute,Australia

O Foster, Atkinson Morley’sHospital, UK

R Freeman, Harvard MedicalSchool, USA

D Goldstein, NationalInstitute of NeurologicalDisorders and Stroke,USA

R Hainsworth, University ofLeeds, UK

MJ Hilz, University ofErlangen-Nurnberg,Germany

MJ Joyner, Mayo Clinic, USAP Low, Mayo Clinic, USAE McLachlan, Prince of Wales

Medical ResearchInstitute, Australia

C Morillo, FundacionCardiovascular, Colombia

UB Muthane, NationalInstitute of Mental Healthand Neurosciences, India

M Nogues, Raul CarreaInstitute of NeurologicalResearch, Argentina

D Robertson, VanderbiltUniversity, USA

I Schatz, University ofHawaii, USA

J-M Senard, INSERM U 317,Faculte de Medicine,France

KM Spyer, Royal Free andUniversity CollegeMedical School, UK

S Vernino, University ofTexas SW Medical Center,USA

G Wenning, InnsbruckMedical University,Austria

D Ziegler, Heinrich HeineUniversity, Germany

Volume 18 Æ Supplement 1 Æ March 2008

Update on neurogenic orthostatic hypotensionPathophysiology, prevalence and treatment

Horacio Kaufmann (Editor)

j INTRODUCTION

H. KaufmannNeurogenic orthostatic hypotension: New prospects in treatment. . . . . . . . . . 1

j ARTICLES

D. RobertsonThe pathophysiology and diagnosis of orthostatic hypotension . . . . . . . . . . . 2

P.A. LowPrevalence of orthostatic hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

R. FreemanCurrent pharmacologic treatment for orthostatic hypotension . . . . . . . . . . . 14

H. KaufmannL-dihydroxyphenylserine (Droxidopa): a new therapy for neurogenicorthostatic hypotensionThe US experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

C.J. MathiasL-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatichypotensionThe European experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

ClinicalAutonomicResearch

Cover design by Fabio Cutro

CONTENTS

This supplement is supported by an educational grant from Chelsea Therapeutics, Inc.,Charlotte, North Carolinawww.chelseatherapeutics.com

Neurogenic orthostatic hypotension is a disorder ofnoradrenergic neurotransmission. Upon standing,without norepinephrine release from postganglionicsympathetic terminals, vascular resistance does notincrease to compensate for the gravitational volumeshift and blood pressure falls. This compromisesblood supply to vital organs, particularly the brain.

In this supplement of Clinical Autonomic Research,five experts from different medical centers in theUnited States and the United Kingdom discuss recentadvances in our understanding and treatment ofneurogenic orthostatic hypotension. David Robertsondescribes the spectrum of blood pressure disorders,and why patients with orthostatic hypotension are soseverely impaired, sometimes unable to stand formore than a few seconds without losing conscious-ness. Phillip Low reviews the prevalence of neuro-genic orthostatic hypotension, which increases withage and in neurodegenerative diseases, particularlyParkinson’s disease and multiple system atrophy. Areview of the currently available pharmacologicaltherapies for the management of orthostatic hypo-tension by Roy Freeman makes it clear that moreeffective therapies are needed. In the next two articles,I review recent phase II studies of the norepinephrineprecursor droxidopa conducted in the United Statesand Christopher Mathias reviews clinical trials con-ducted across Europe.

Based on the success of the preliminary studieswith droxidopa, large multicenter phase III clinicaltrials have begun recently both in the United Statesand Europe. The hypothesis that led to the use of this

artificial aminoacid is elegant. Replenishing a missingneurotransmitter by a precursor aminoacid has asuccessful history in neuropharmacology with thetreatment of Parkinson’s disease. In the case ofdroxidopa, the precursor aminoacid is converted inthe body into norepinephrine, replenishing themissing neurotransmitter in autonomic failure. Thesimilarities between droxidopa and levodopa areimmediately apparent. Droxidopa has one added betahydroxyl group; otherwise, the molecules are identi-cal. Droxidopa is not a new agent. It is not available inthe United States or Europe, but it has been availablein Japan for over 25 years and has an excellent safetyrecord. Both the United States and the European trialsof droxidopa indicate that the agent is effective with aunique mechanism of action. These are good reasonsto be optimistic that the drug will soon be availablefor patients in the United States and Europe.

Treatment of neurogenic orthostatic hypotensionwith droxidopa, the precursor of the missing neuro-transmitter, is a promising therapeutic approach. Ifsuccessful, still needed, of course, are means to mod-ulate the autonomic response so that the increase innorepinephrine would occur at the appropriate times.Similar challenges were faced by levodopa in thetreatment of Parkinson’s disease. Fortunately, the en-zymes involved in catecholamine metabolism are nowwell known and they have already been the targets oftherapeutic strategies in combination with levodopa.

Horacio Kaufmann, MD

Neurogenic orthostatic hypotension:New prospects in treatment

INTRODUCTIONClin Auton Res (2008) 18[Suppl 1]:1DOI 10.1007/s10286-008-1006-6

CAR1006

Cardiovascular dysregulation

Disorders of cardiovascular dysregulation encompassa broad spectrum all the way from very low pressuresto very high pressures. Some of these disorders aredepicted in Fig. 1, where the broad middle group in-cludes the great majority of individuals, those withnormal blood pressures. On the right, hypertensionincludes approximately 10% of the population; thesepatients have blood pressures that are elevated whilethey are lying, while they are standing and while theyare upright. Separating the hypertensive patients fromnormal are the labile hypertensive patients, who oc-cupy the controversial and ill-defined borderland ofpressures ranging from 120/80 to 140/90. Conversely,

on the left extreme, are patients with low bloodpressure when standing, usually normal blood pres-sure while seated, and sometimes high blood pressurewhile lying down. These are individuals with ortho-static hypotension (OH). Between this group andnormal subjects are patients with the milder dysau-tonomias, postural tachycardia syndrome [13; 24](POTS) and neurally mediated syncope (NMS). POTSpatients have orthostatic tachycardia and symptomsof sympathetic activation on standing, while NMSpatients usually have normal pressures in all postures,but occasionally have ‘‘fainting’’ associated with abrief, usually less than 1 min, hypotension and/orbradycardia. POTS and NMS patients do not usuallyhave OH, and that is why their disorders are oftenclassified as ‘‘milder dysautonomias’’; patients with

David Robertson The pathophysiology and diagnosisof orthostatic hypotension

Received: 15 June 2007Accepted: 30 June 2007

j Abstract Orthostatic Hypoten-sion (OH) is a common manifes-tation of blood pressuredysregulation. OH takes a heavytoll on quality of life. It has manypotential etiologies, and manyeffects of aging can increase sus-ceptibility to OH. Neurologicaldisorders are especially likely tocause severe OH. In this briefreview, the pathogenesis of OH isconsidered, particularly in termsof autonomic neuropathy, multi-ple system atrophy (MSA), pureautonomic failure, baroreflex fail-ure, and dopamine beta hydroxy-lase deficiency. While OH isdifficult to treat, its control greatlyenhances the quality of life.

j Key words orthostatic hypo-tension Æ orthostatic hyperten-sion Æ autonomic Æ syncope Æfainting

ARTICLEClin Auton Res (2008) 18[Suppl 1]:2–7DOI 10.1007/s10286-007-1004-0

CAR1004

D. Robertson, MDAutonomic Dysfunction CenterDepts. of Medicine and PharmacologyVanderbilt UniversityAA 3228 Medical Center North1161 21st Avenue SouthNashville (TN) 37323-2195, USATel.: +1-615/343-8633Fax: +1-615/343-8649E-Mail: david.robertson@vanderbilt.edu

these disorders do not usually consider them mild in ageneral sense.

There is one very important difference betweenapproaches to treatment at the right and left ends ofthis spectrum. On the right, the blood pressure per-turbation usually has no associated symptoms. We donot treat these patients to make them feel better. Wetreat them to try to prevent complications of hyper-tension perhaps 20 or more years down the line. Onthe other hand, people on the left extreme havesymptoms that are often quite devastating. Suchpatients need help today. So, our strategy in thesepatients is to improve their functional capacity today,make them feel better, keep them active, and ourfocus is one of quality of life today. Many of the samemedicines used to treat OH are also used in an effortto treat POTS and NMS. Beta blockers have some-times been used in all categories of cardiovasculardysregulation depicted in Fig. 1, though the rationalefor their use in NMS and OH is questioned.

Orthostatic hypotension

Orthostatic hypotension is defined as a fall of systolicblood pressure of at least 20 mmHg or a fall of dia-stolic blood pressure of at least 10 mmHg within3 minutes of standing [20]. It is a physical finding andnot a diagnosis; so it may be symptomatic orasymptomatic. Most people who are symptomaticfrom OH have a much greater fall in pressure onstanding. Thus this is a very broad definition, andperhaps 50% of elderly patients might occasionallymeet these criteria [3]. Evaluation and therapy aretherefore primarily driven by symptoms.

Physiology of standing

Why do people get orthostatic hypotension? At onelevel the pathophysiology is quite straightforward.

When we stand, there is about 500–1,000 ml of bloodthat goes from the upper body to the lower body,primarily the lower abdomen, buttocks, and legs. Inresponse to this, there are compensatory effects fromactivation of the sympathetic nervous system, therenin-angiotensin system, and consequent aldoste-rone release. These come into play to help maintaincardiac output during the stress of upright posture.Because upright posture is a relatively late evolu-tionary development, our mechanisms for mainte-nance of upright posture may still be underconsiderable genetic pressure.

Orthostatic blood volume shift

While an individual is lying down, blood volume isdistributed throughout the body as depicted in Fig. 2.The second frame in the figure shows that same dis-tribution in a theoretical instantaneously uprighttransition. But in the third frame, it can be seen thatby 1 min of upright posture, the shift of perhaps500 ml of blood to the lower part of the body is welladvanced. The next phenomenon, depicted in thefourth frame, is perhaps even more important in thereal world of OH management. It illustrates that afterthe pooling of blood, there is a period of 20–30 minduring which substantial loss of plasma volume fromthe blood into the tissues occurs. This produces atleast as great a challenge to the cardiovascular systemas the more widely appreciated pooling of blood de-picted in frame 3. Indeed, in healthy subjects, there isa 14% fall in plasma volume within 20 min afterassumption of the upright posture, most of whichoccurs within the first 10 min. That 14% translatesinto about 430 ml of blood, close to the amount takenin a blood donation. Since the cellular component ofthe blood remains in the circulation, even thehematocrit, if you measure it carefully, changes, per-haps rising from 37 to 41 (Fig. 3). The lower hemat-ocrit of the supine posture occasionally puts

OH POTS Normotension LabileHBP

HBP

Orthostatic tachycardia

Orthostatic hypotension

NMS

Bradycardia/hypotension asymptomatic

symptomatic

Fig. 1 Cardiovascular dysregulation. OH: orthostatic hypotension; POTS:postural tachycardia syndrome; MNS: neurally mediated syncope; HBP: highblood pressure

SUPINE UPRIGHT

First blood pooling, then plasma loss

1 sec 1 min 30 min UPRIGHT UPRIGHT

Fig. 2 Postural hemodynamics

3

otherwise healthy persons into the usually accepted‘‘anemia’’ range of hematocrit, and has therefore beencalled ‘‘postural pseudoanemia [9]’’ for that reason.Thus, much of the ‘‘noise’’ in hematocrit measure-ment in clinical practice is actually not noise butreflective of changes in blood related to patient’sposture in the time leading up to the sampling.

This volume shift is reflected in BP during contin-uous blood pressure monitoring in a patient with OH.You can see in Fig. 4 that during monitoring after apatient with OH stands for about 20 min, the bloodpressure does not so much plummet immediately, butrather transitions downward over a few minutes as thepooling first and then the plasma volume shift becomesequentially engaged. It is noteworthy that many pa-tients with chronic OH tolerate degrees of hypotensionthat are quite low, at least for a few minutes.

Types of orthostatic hypotension

The interaction between the brain and the cardio-vascular system in blood pressure control is para-mount, and this has lead to an expansion of ourunderstanding of the different kinds of abnormalitieswhich occur on standing. First we now recognize thatin addition to the OH we commonly recognize be-tween 1 min and 3 min of standing, there is both anearlier form of OH (‘‘initial orthostatic hypotension’’,IOH [26] and a later form developing between 5 minand 45 min (‘‘delayed orthostatic hypotension’’ [5],DOH). IOH occurs immediately upon standing and isdetectable only by beat-to-beat blood pressure mon-itoring [12]. This occurs at a time when many normalsubjects, on arising from overnight sleep, may have atransient sense of impaired cerebral blood flow, butthis typically goes away in a few seconds. However,falls of 40/20 mmHg in the first 15 s of standing aresometimes seen, and this period is associated fairly

commonly with syncope in susceptible individuals. Itis due to a mismatch based on an initial increase invenous return, increase in right atrial pressure, andovercompensation, accompanied by the muscle-de-rived late dilatation in the legs due to the act ofstanding. Delayed orthostatic hypotension (DOH) hasrecently been systematically studied by Freeman andhis collaborators [6]. They found that among 230people who ultimately had OH; either on standing oron the tilt table, 46% had OH within 3 min, but an-other 15% had OH in the 3–10 min interval, and thenover the next half hour or so, an additional 39%manifested orthostatic pressures. The latter tended tobe younger patients, and many fell into the categoryof POTS.

Orthostatic hypertension

Perhaps surprisingly, some patients have orthostaticincreases rather than decreases in blood pressurewhen they stand. These individuals display orthostatichypertension [2; 23]. The more severely affected pa-tients have relatively rare disorders such as baroreflexfailure [11], mast cell activation disorder (mastocy-tosis) [22], hyperadrenergic POTS, or pheochromo-cytoma.

Signal amplification in dysautonomias

Patients with OH due to autonomic impairment havea range of remarkable clinical characteristics. Many ofthese derive from the loss of buffering reflexes. Thebaroreflex keeps blood pressures from having exces-sively large excursions; preventing pressure fromgetting too high when there is a pressor stimulus andpreventing pressure from getting too low when thereis a depressor stimulus. When the baroreflexes fail,

T iltto 75 degr

123/67 72/39 59/42

84 85 86H R

BP

Female52 years MSA

Fig. 4 Orthostatic hypotension in autonomic failure2100

2200

2300

2400

2500

2600

2700

2800

2900

supine

PV (ml) Male Black & White

37 41

hematocrit

upright

Fig. 3 Plasma volume shift and hematocrit

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stimuli that would not do very much in healthy per-sons may have a big impact on blood pressure in apatient with OH due to autonomic failure. There isthus huge signal amplification in going from normalindividuals to individuals with autonomic dysfunc-tion. There are a number of interesting consequencesof this. For example; food lowers blood pressure inhealthy individuals by only 1 mmHg, but in peoplewith autonomic dysfunction, food may lower bloodpressure by 40 mmHg [14; 19], and they may pass outwhen they try to stand after finishing a meal. Con-versely 16 ounces of water can raise blood pressureabout 40 mmHg in the hour or so after it is ingested[21]. This effect and that of food can sometimes beharnessed by patients to benefit blood pressure con-trol. Some drugs such as clonidine, which are used tolower blood pressure in hypertension, may display apressor effect in autonomic failure as there is bothhypersensitivity of vascular alpha adrenoreceptorsand loss of baroreflex buffering. Likewise, the tachy-cardic (beta-1) effect of isoproterenol (Isuprel) is 6-fold elevated in the OH of autonomic failure. Thedepressor (beta-2) effect of isoproterenol is 17-foldelevated in this disorder [18]. Just half of a 5 mg oralterbutaline tablet, such as is used in asthma withoutnotable depressor effect, is capable of reducing supineblood pressure by half in a patient with autonomicfailure.

Predisposing factors for orthostatic hypotension

There are a number of predisposing factors for OH,including dehydration, deconditioning, poor nutri-tion or the bodily changes that occur with aging(Table 1). The latter factors lead to more vulnera-bility to OH in the aging population. There are drugsadministered for other conditions that may con-comitantly cause OH. The tricyclic antidepressantsin chronic use have long been recognized as a causeof OH, and of course antihypertensive agents anddiuretics can do this as well. Vasodilators likenitroglycerin, hydralazine, and calcium channelblockers can also cause OH. A commonly unrecog-

nized cause of OH nowadays is tizanidine (Zanaflex).This problem arises simply because people are notexpecting this side effect. Tizanidine is used as amuscle relaxant in fibromyalgia. Patients generallysay it helps their condition, but it also is an alpha-2agonist and therefore has clonidine-like effects, andso may cause episodic OH at the time of the majoreffects of the drug.

Causes of orthostatic hypotension

Several neurological conditions (Table 2) give rise toOH. Autonomic neuropathy [25] may sometimes oc-cur in relatively pure form, and is recognized by itsspectrum of autonomic manifestations (Table 3). Itencompasses what used to be called acute pandysau-tonomia, but also includes many cases of what istermed pure autonomic failure, owing to early con-flation of the two pathophysiologies. Typically, it hasan onset over days to weeks. There is sympatheticfailure with OH and anhidrosis, which may be verysevere and then characteristically parasympatheticfailure is pronounced. Gastrointestinal, urological,and sicca changes are usually a hint that autonomicneuropathy may be the cause of the patient’s OH.Although there probably are many causes for this,some patients have an antibody to a component ofnicotinic receptor at the critical ganglion synapsewhere autonomic function is transduced. It may ac-count for up to 50% of these patients; so assessingthat antibody in the paraneoplastic panel identifiesthese individuals. Pure autonomic failure wasdescribed in the classical paper of Bradbury andEggleston in 1925. It is characterized by severe OH;insidious onset, slow progression, modest gastroin-testinal impairment, marked supine hypertension,

Table 1 Orthostatic hypotension: Causes I

• Predisposing factors– Dehydration– Deconditioning– Nutritional– Aging

• Medications– Tricyclic antidepressants (chronic)– Antihypertensives and diuretics– Vasodilators– Tizanidine (Zanaflex)

Table 2 Orthostatic hypotension: Causes II

• Autonomic neuropathy• Pure autonomic failure• Parkinson’s disease• Multiple system atrophy• Dementia with Lewy Bodies• Dopamine b hydroxylase deficiency• Brainstem lesions• Spinal cord injury

Table 3 Mainfestations of dysautonomia

• Impaired papillary function; dry eyes• Orthostatic hypotension and supine hypertension• Reduced gastrointestinal motility, gastroparesis, constipation or diarrhea• Bladder dysfunction• Male erectile dysfunction• Impaired sweating

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and often very low plasma norepinephrine levels [10].Other neurological systems are not involved. Thesepeople have a very good prognosis and often livedecades, and we have several patients who have livedinto their 90s with this. Parkinson’s disease withautonomic failure is associated with sympatheticneuropathy, and OH occurs in some, but not allParkinson’s disease patients [8]. The hypotension in afew of them can be quite severe and MIBG or PETstudies may help detect that, although we do not havegood benchmarking for these tests yet. Dementia withLewy Bodies is important to recognize in individualswith some Parkinsonian features, but progressivecognitive decline in these people may be more dra-matic, and include visual hallucinations. The auto-nomic failure and some of the cognitive aspects canimprove with cholinesterase inhibition. Multiple sys-tem atrophy (MSA) is very difficult problem becauseit involves not only the autonomic but also cerebellarand extrapyramidal systems [17]. MSA has theseverest outlook of any dysautonomia. Sleep apneaalso occurs commonly in MSA.

Dopamine beta-hydroxylase (DBH) deficiency isan extremely rare but instructive disorder, because itis a notable success story in terms of both diagnosisand therapy. The specific gene defect is in the DBHenzyme which produces norepinephrine from dopa-mine. Patients with this have severe OH, exerciseintolerance, and usually ptosis of the eyelids. Erectilefunction (primarily parasympathetic) is not pre-vented but retrograde ejaculation (due to sympa-thetic failure) occurs. These patients have nonorepinephrine in their neurons and instead theyhave stoichiometric replacement of norepinephrineby its precursor dopamine. DBH deficiency isinteresting to us because it is one example where weget almost a ‘‘Lazarus’’ effect in response to drox-idopa. Droxidopa is essentially a norepinephrinemolecule to which a carboxyl group is attached [7].This enables it to be absorbed orally, get past theliver and into the circulation where it is a substratefor the norepinephrine transporter and gets pumpedinto the sympathetic neuron. Within the neuron, andat other sites, droxidopa is decarboxylated toendogenous neurotransmitter norepinephrine,restoring sympathetic function. We reported a DBHdeficiency patient in 2005 who, in her early 20s, wasonly able to stand erect for about 2 min beforetherapy, but after she was placed on droxidopa sherapidly began to be able to do many more things,and took up running, first tentatively but ultimatelyin an increasingly athletic fashion. After about a yearof training she successfully completed the 26 mileNew Orleans Marathon [4]. Completion of thisbenchmark reflected both the drug and this patient’sdetermination.

The alien landscape of orthostatichypotension

j Orthostatic regulation of drug levels

Liver blood flow (LBF) in humans is posturedependent. In healthy subjects, LBF is 5% less in theseated posture than in the supine posture, but inpatients with OH that LBF decrement is a whopping30%. A consequence of this is that drugs like lido-caine which are removed from the blood by firstpass hepatic clearance will display dramaticallyposture-dependent plasma levels. When orthostatichypotensive patients are receiving intravenous lido-caine, levels of the drug are almost twice as highwhen they are seated as when they are supine. Sittingup can so elevate plasma lidocaine levels that sei-zures may occasionally be provoked when patientswith autonomic failure sit up [1].

j Garden hose ‘‘therapy’’ of orthostatichypotension

In OH due to autonomic failure, hyperventilationreduces blood carbon dioxide and this is attended byrapid fall in blood pressure in subjects with OH,sometimes 40 mHg within 60 s. Since hyperventila-tion may occur with physical exertion, this effectcontributes to the depressor effect of exercise. Con-versely, breathing through a dead space increasescarbon dioxide concentration in inspired air, and theeffect of this is to raise blood pressure 20 mHg ormore. Some patients are so sensitive to this effect thatthey can stand longer while breathing through a shortlength of garden hose [15].

j Afebrile hypotension as presentation of infection

Patients with severe autonomic failure have impairedcapacity to manifest a fever in response to infection.Instead they present with an acute fall in bloodpressure and a greatly reduced functional capacity.Such infections tend to be in the urinary tract or thelung. When patients note a substantial acute decre-ment in their functional capacity, they should haveurinalysis and a chest examination to rule out infec-tion [16].

j Wet shirt therapy in hot weather

When the hypohidrosis in autonomic failure is severe,the inability to perspire can lead to temperature ele-vation in patients exposed to hot weather (>90� F).This increase in temperature leads to a fall in blood

6

pressure and the patient feels greatly fatigued, andmay only be able to tolerate this temperature for a fewminutes. Providing ‘‘artificial perspiration’’ in theform of a wet shirt will help speed heat dissipationand allow more tolerance of hot weather with main-tenance of a higher blood pressure. Usually the wetshirt will provide benefit for about an hour before itmust be re-wetted [16].

j Acknowledgements The help of my colleagues in Vanderbilt’sAutonomic Dysfunction Center is acknowledged. I thank Ms EllaHenderson for help in the preparation of this manuscript. Sup-ported in part by the U.S. Public Health Service: P01-HL56693, R01HL71784, and RR 00095.

j Disclosure Dr. Robertson has served as a consultant for ChelseaTherapeutics.

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14. Mader SL (1988) Postprandial hypo-tension in the elderly. J Am Geriatr Soc36:84

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19. Robertson D, Wade D, Robertson RM(1981) Postprandial alterations in car-diovascular hemodynamics in auto-nomic dysfunctional states. Am JCardiol 48:1048–1052

20. Schatz IJ, Bannister R, Freeman RL,Goetz CG, Jankovic J, Kaufmann HC,Koller WC, Low PA, Mathias CJ, Po-linsky RJ, Quinn NP, Robertson D,Streeten DHP (1996) Consensus state-ment on the definition of orthostatichypotension, pure autonomic failure,and multiple system atrophy. Neurol-ogy 46:1470

21. Shannon JR, Jordan J, Diedrich A, Bia-ggioni I, Robertson RM, Robertson D(2000) Water drinking: an effectivetreatment for orthostatic and post-prandial hypotension in autonomicfailure. Circulation 102:700

22. Shibao C, Arzubiaga C, Roberts LJ, RajS, Black B, Harris P, Biaggioni I (2005)Hyperadrenergic postural tachycardiasyndrome in mast cell activation dis-orders. Hypertension 45:385–390

23. Streeten DH, Auchincloss JH Jr,Anderson GH Jr, Richardson RL, Tho-mas FD, Miller JW (1985) Orthostatichypertension. Pathogenetic studies.Hypertension 7:196–203

24. Thieben MJ, Sandroni P, Sletten DM,rud-Larson LM, Fealey RD, Vernino S,Lennon VA, Shen WK, Low PA (2007)Postural orthostatic tachycardia syn-drome: the Mayo clinic experience.Mayo Clin Proc 82:308–313

25. Vernino S, Low PA, Fealey RD, StewartJD, Farrugia G, Lennon VA (2000) Au-toantibodies to ganglionic acetylcholinereceptors in autoimmune autonomicneuropathies. N Engl J Med 343:847–855

26. Wieling W, Krediet CT, van DN, LinzerM, Tschakovsky ME (2007) Initialorthostatic hypotension: review of aforgotten condition. Clin Sci (Lond)112:157–165

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Orthostatic hypotension (OH) is a dynamic state andnot a disease in itself or necessarily a pathologic en-tity. Cross-sectional prevalences primarily reflect theinfluence of age (Fig. 1), but to some degree also re-flect the effects of medications, the degree of ortho-static stress, and the presence of abnormalities of theautonomic nervous system. This review considers theprevalence of OH in particular settings (such as long-term care facilities and outpatient clinics), and theprevalence of OH in patients with autonomic disor-ders associated with OH.

OH in the normal aging population

The cross-sectional prevalence of OH in unselectedelders, aged 65 years or older, has been reported to be

between 5 and 30% [9, 13, 15, 22, 27]. The difference inthese estimates varies due to a number of factors, suchas the definition of OH, the segment of the populationstudied (age range, institutions), the composition ofthe population (healthy population versus selectgroups), the influence of medications and the level oforthostatic stress. The prevalence appears to be similarin North America [9], in Japanese in Hawaii [15] andin Finns in Finland [27]. In all of these studies theprevalence of OH increased with age.

Using the current standard of an orthostatic fall inblood pressure by 20 mmHg systolic or 10 mmHgdiastolic within 3 min of standing up or during head-up tilt, 5% of the normal healthy population inRochester, Minnesota has OH [10]. In the a multi-center, observational, longitudinal study by Rutanet al. (1992) in 5,201 men and women aged 65 years

Phillip A. Low Prevalence of orthostatic hypotension

Received: 14 June 2007Accepted: 30 June 2007

j Abstract Orthostatic hypoten-sion (OH) is defined as a fall inblood pressure of at least20 mmHg systolic or 10 mmHgdiastolic when standing or duringhead-up tilt testing. The preva-lence of OH increases with age,with disorders that affect auto-nomic nerve transmission, andwith increasingly severe ortho-static stress. In normal elderlysubjects, the prevalence of OH isreported to be between 5 and 30%.The actual prevalence depends onthe conditions during diagnostictesting, such as the frequency ofblood pressure recordings, thetime of day and the degree oforthostatic stress. Elderly subjectsare often taking medications, such

as antihypertensives and diureticsthat can cause or aggravate OH.Neurological diseases such as dia-betic neuropathy, Parkinson’sdisease, multiple system atrophyand the autonomic neuropathiesfurther increase the likelihood ofOH. The development of OH innormal subjects is associated withan increased mortality rate. OH indiabetes is also associated with asignificant increase in mortalityrate.

j Key words orthostatic hypo-tension Æ aging Æ neuropathy Æmortality Æ prevalence Æautonomic nervous system

ARTICLEClin Auton Res (2008) 18[Suppl 1]:8–13DOI 10.1007/s10286-007-1001-3

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P.A. Low, MDDepartment of NeurologyMayo Clinic200 First Street SWRochester (MN) 55905, USATel.: +1-507-2843375Fax: +1-507-2843133E-Mail: low@mayo.edu

or older at their initial examination, the prevalence ofasymptomatic OH (defined as a minimum fall insystolic BP by 20 mmHg or in diastolic BP by10 mmHg within 3 min of standing) was 16.2%.When the criteria for defining OH also included thosein whom the procedure was aborted due to dizzinessupon standing, this prevalence increased to 18.2%.The prevalence of symptomatic OH increased from14.8% in subjects aged 65–69 years to 26% in subjects85 years and older, clearly demonstrating the associ-ation between OH and aging [22].

OH and mortality rate

In a population-based study of 3,522 JapaneseAmericans in Hawaii aged between 71 and 92 years,

Masaki et al. [15] reported that the prevalence of OHwas 6.9%, and again that the prevalence increasedwith age (Fig. 1). They also found that the 4-year age-adjusted mortality rate was higher in those with OHthan in those without (56.6 versus 38.6 per 1,000person-years). With Cox proportional hazards mod-els, after adjusting for other risk factors, OH was asignificant independent predictor of 4-year all-causemortality, with a relative risk of 1.64 (95% CI 1.19 to2.26). Furthermore, there was a significant linearassociation between the change in systolic BP fall and4-year mortality rate (P < 0.001), suggesting a dose-response relationship [15].

Rose et al. [21] studied the association between OHand a 13-year mortality among middle-aged black andwhite men and women from the Atherosclerosis Riskin Communities Study (from the year 1987 to 1989). Atbaseline, 674 participants (5%) had OH. All-causemortality was higher among those with (13.7%) thanwithout (4.2%) OH (see Fig. 2). This association wasonly partly explained by ‘‘traditional’’ risk factors [21].

OH in defined groups

Although not true prevalences, the presence of OH insettings such as in nursing homes or outpatient clinicsis of interest. If the OH associated with aging is in-cluded, the ‘‘prevalence’’ is quite high in subjectsolder than 70 years of age. Table 1 lists seven preva-lences (as percentage of the affected group with OH)in particular settings, taken from studies carried outwith similar criteria in subjects who were otherwisegenerally healthy. These are perhaps the best esti-mates of the prevalence of OH based on current data.Therefore, a reasonable estimate of prevalence in

Fig. 1 The prevalence of OH increases with age. Prevalence rates of orthostatichypotension (OH) by 5-year age groups (71–74, 75–79, 80–84, and 85+) in theHonolulu Heart Program cohort (n = 3,522). Masaki et al. [15]

Fig. 2 Kaplan–Meier survival curves by OH status. Theseunadjusted Kaplan–Meier curves for all-cause mortalityby OH status show a gradual increase in mortality inthose free of OH at baseline, with an overall mortalityrate of 12% (n = 1,476) over the 13 years follow-upperiod. For the OH group, by contrast, the slope of thesurvival curve was considerably steeper, and at the end ofthe follow-up period, 32% (n = 217) of participants haddied. Rose et al. [22]

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ambulant older subjects, diagnosed during testingwith simple BP recordings, is between 10 and 30%.

OH and increasing orthostatic stress

When testing is done repeatedly and under conditionsof increased orthostatic stress, the percentage of sub-jects with OH increases. For instance, Ooi et al. [17]evaluated 991 long stay residents 60 years of age andolder who were able to stand and took four sets ofsupine and standing BP recordings before and afterbreakfast and before and after lunch. They found that13.3% of subjects had persistent OH, consistent withthe values reported in Table 1. However, they reportedthat 51.5% of subjects had OH at least once and thatOH was most common first thing in the morning [17].

OH and medications

Another variable that impacts upon the prevalence ofOH in elderly subjects is the effect of medications. In aVeteran Administration study of 342 veterans 75 yearsor older, 55% (189/342) had OH, of whom 33% andsymptoms of orthostatic intolerance, and 52 patientshad falls [19]. There was a significant relationshipbetween the presence OH and the number of medi-cations: with no drug 35% had OH; with one drug 58%had OH; with two drugs 60% had OH; with three drugs65% had OH. The antihypertensives Hydrochlorothi-azide (65% OH) and Lisinopril (60% OH), the durieticFurosemide (56% OH), the antidepressant Trazodone(58% OH), and the alpha-blocker Terazosin (54% OH)had the greatest propensity to cause OH.

OH and neurological disorders

Neurological disorders that affect the release of nor-adrenaline can cause OH. The prevalence of OH inautonomic disorders is summarized in Table 2.

j Diabetes and OH

In a cohort of adult diabetic patients (insulin-dependent diabetes mellitus and non-insulin-depen-dent diabetes mellitus) evaluated at the Mayo Clinic(Rochester, Minnesota) from 1987 to 1997 (mean ageover this decade 60 ± 12 years) 10% had OH. Toinvestigate the association between autonomic func-tion and symptoms of OH a population-based studyin 148 diabetic patients (83 with Type 1 diabetes)and 246 healthy controls was conducted. OH symp-toms (assessed using the ‘‘Autonomic SymptomProfile’’—a validated self-reporting instrument),standardized autonomic function tests (cardiovagal,adrenergic, sudomotor function), and a CompositeAutonomic Severity Score (CASS, which corrects forthe effects of age and gender [11]) were evaluated. ACASS score of 1–3 was used for either sudomotorand cardiovagal functional deficits and 0–4 foradrenergic deficits. Autonomic neuropathy (definedas a CASS score of 1 in at least 2 domains or ‡2 inone domain) was found in 54% of Type 1 diabetesand 73% of Type 2 diabetes. Despite the highprevalence of autonomic dysfunction, OH was foundin only 8.4% (Type 1) and 7.4% (Type 2) of diabeticpatients.

j Autonomic failure and OH

Allcock et al. [1] estimated the prevalence of OH inParkinson’s disease in a population of 237,564 in thecounty of Durham (UK). They identified 270 patientswith Parkinson’s disease of whom 104 (38.5%) agreedto participate. They reported that 47% had OH [1], aremarkably high incidence. Other reports in Parkin-son’s disease outpatient cohorts have estimated theprevalence of OH to be between 16 and 58% [25, 29].OH is an integral feature of the autonomic neuropa-thies, pure autonomic failure (PAF), and multiple

Table 1 Estimated ‘‘Prevalence’’ of OH in certain settings

Setting n Age(years)

‘‘Prevalence’’(%)

Study reference

Nursing home 250 61–91 11 Rodstein and Zeman [20]Medical outpatient 494 ‡65 24 Caird et al. [3]VA Geriatric unit 319 50–99 10.7 Myers et al. [16]Medical outpatients 186 ‡65 22 MacLennan et al. [12]Geriatric unit 272 83* 10 Lennox and Williams [8]Geriatric unit 247 ‡60 33 Palmer et al. [18]Medical outpatient 300 70* 6.4 Mader et al. [14]

Data taken from seven studies carried out with similar criteria in elderly sub-jects who were otherwise generally healthy. From this we can conclude that‘‘prevalence’’ is between 10 and 30%. * mean value; n, number of subjects.

Table 2 Estimated prevalence of OH in different autonomic disorders

Disorder Prevalence Reference

Aging 10–30% Table 2Diabetes 10%*Diabetics-Type 1 8.4% Low et al. [10]Diabetics-Type 2 7.4% Low et al. [10]Parkinson’s disease 47% Allcock et al. [1]Parkinson’s disease 48%; 37% Wood et al. [29]Parkinson’s disease 58% Senard et al. [25]Other autonomic neuropathies 10–50 per 100,000MSA 5–15 per 100,000PAF 10–30 per 100,000

*Prevalence for adult combined IDDM and NIDDM for the RochesterDiabetic Cohort for 1997 (PI: PJ Dyck)

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system atrophy (MSA, Shy-Drager syndrome). Theprevalence as cases per 100,000 is provided in Table 2.

The causes of OH

The causes of neurogenicOH are shown in Table 3. Thediseases with the highest prevalence of neurogenic OH,are MSA, PAF, diabetic autonomic neuropathy, auto-immune autonomic neuropathy and paraneoplasticautonomic neuropathies. In specialist spinal cord in-jury practices, tetraplegia is a common cause of OH.

In a prospective study of 90 consecutive patientsreferred with suspected OH, evaluated at the MayoAutonomic Laboratory, and confirmed to have OH,the diagnoses were:

PAF 33%MSA 26%Idiopathic (autoimmune autonomic neuropathy) 17%Diabetic Autonomic neuropathy 14%Miscellaneous 8%Olivo-ponto-cerebellar atrophy 2%

The cause of OH and prognosis

The prognosis depends on the specific disorder. Pa-tients with classic MSA have a median survival ofabout 7 years from the time of diagnosis [2]. Wenninget al. [28], however, reported a median survival of9.5 years, calculated by Kaplan–Meier analysis. Simi-lar results have been reported [23], and the sporadicOPCA variety has been suggested to have a longersurvival than the striatonigral variety [23]. The dif-ferences in survival time reported most likely relatesto the criteria used to define MSA.

The downhill course of patients with MSA ismarked by increasing rigidity, urinary incontinence,and inspiratory stridor, which may require trache-otomy. Death in MSA is commonly due to respira-tory obstruction or failure after worsening rigidity,akinesia, and bladder disorder. With the apprecia-tion of a spectrum of severities, an attempt has beenmade to relate the severity and distribution ofautonomic and non-autonomic involvement to theoutcome. We reviewed the clinical and autonomicfeatures of all patients with extrapyramidal andcerebellar disorders studied in the Mayo AutonomicReflex Laboratory from 1983 to 1989 [24]. OH, per-centage of anhidrosis on thermoregulatory sweattest, quantitative sudomotor axon reflex test, forearmresistance response and heart rate response to deepbreathing strongly regressed with severity of clinicalinvolvement. The severity and distribution of auto-nomic failure at the time of first evaluation waspredictive of a greater rate of progression 2 yearslater. Saito et al. [23] came to the same conclusion.The earlier and more severe the autonomic nervoussystem involvement (and to a lesser extent the stri-atonigral system involvement) the poorer the prog-nosis.

Information on the clinical features, progressionand outcome in PAF is somewhat limited. Some pa-tients with PAF have continued relatively symptomfree for many years, with standing blood pressures aslow as 80 mmHg. The natural history of PAF is that ofa slow progression taking place over some 10–15 years [2]. However, we should take into accountthe difficultly in diagnosing PAF. About 10% patientsoriginally thought to have PAF turn out to have MSA.Moreover, some patients are misdiagnosed as PAF,and later found to have autoimmune autonomicganglionopathy [6] with A3 acetylcholine receptorantibodies.

The development of OH worsens the prognosis ofpatients with diabetic neuropathy. Ewing et al. [4]reported a mortality rate of 50% at 2½ years in pa-tients with symptomatic diabetic autonomic neurop-athy. However, these patients had long-standing

Table 3 Causes of neurogenic orthostatic hypotension

1. AUTONOMIC DISORDERS WITHOUT CNS OR PNS INVOLVEMENTPure autonomic failure (PAF)

2. AUTONOMIC DISORDERS WITH BRAIN INVOLVEMENTi. Multiple system atrophy (MSA)ii. Wernicke Korsakoff syndromeiii. Posterior fossa tumorsiv. Baroreflex failurevi. Olivopontocerebellar atrophy

3. AUTONOMIC DISORDERS WITH SPINAL CORD INVOLVEMENTi. Traumatic tetraplegiaii. Syringomyeliaiii. Subacute combined degenerationiv. Multiple sclerosisv. Spinal cord tumors

4. AUTONOMIC NEUROPATHIESI. The acute autonomic neuropathiesi. Autoimmune autonomic ganglionopathy (AAG; acutepandysautonomia)

ii. Acute paraneoplastic autonomic neuropathyiii. Guillain-Barre syndromev. Botulismvi. Porphyriavii. Drug induced acute autonomic neuropathiesviii. Toxic acute autonomic neuropathies

II. The chronic peripheral autonomic neuropathiesA. Pure adrenergic neuropathyB. Combined sympathetic and parasympathetic failure

(Autonomic dysfunction clinically important)i. Amyloidii. Diabetic autonomic neuropathyiii. Paraneoplastic autonomic including panautonomic neuropathyiv. Sensory neuronopathy with autonomic failure (most commonly

associated with Sjogren’s syndrome)v. Familial dysautonomia (Riley-Day syndrome)vi. Autoimmune autonomic neuropathyvii. Dysautonomia of old age

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clinical autonomic neuropathy and died of renalfailure. Subsequent studies suggest that autonomicfailure worsens prognosis, but less dismally than wasoriginally thought [5]. The clinical and laboratoryfeatures of 229 patients with primary systemic amy-loidosis seen at the Mayo Clinic reported that mediansurvival from the time of diagnosis for patients withperipheral neuropathy, carpal tunnel syndrome, OHand cardiac failure was 60, 45, 9.5, and 6.5 months,respectively [7].

We have reviewed the Mayo Clinic experiencewith idiopathic autoimmune autonomic neuropathy.Patients seem to improve substantially over the firstyear followed by a slower rate of improvement overthe subsequent 4 years [26]. Overall, approximately 1in 3 patients makes a good functional recovery.However, the majority of patients are left with achronic debilitating illness with significant residualdeficits.

For patients with OH associated with aging, the co-existence of OH is associated with a worse prognosis[15].

Concluding thoughts

OH is a dynamic entity, it is frequent, and increaseswith age. Indeed, it is likely to be present in most ofthe elderly under circumstances of increased ortho-static stress. Its prevalence is further increased incertain neurologic disorders. The presence of OHworsens prognosis and increases mortality.

j Acknowledgement This work was supported in part by NationalInstitutes of Health (NS 32352, NS 44233, NS 43364), Mayo CTSA(U54RR 24150), and Mayo Funds.

j Disclosure Dr. Low has served as a cosultant for WR Medical,Viatris, Eli Lilly and Company, Chelsea Therapeutics, and QuigleyCorporation.

References

1. Allcock LM, Ullyart K, Kenny RA, BurnDJ (2004) Frequency of orthostatichypotension in a community basedcohort of patients with Parkinson’sdisease. J Neurol Neurosurg Psychiatry75:1470–1471

2. Bannister R, Low PA (1997) Multiplesystem atrophy and pure autonomicfailure. In: Low PA (ed) Clinical auto-nomic disorders: evaluation and man-agement. Lippincott-Ravel,Philadelphia, pp 555–576

3. Caird FI, Andrews GR, Kennedy RD(1973) Effect of posture on bloodpressure in the elderly. Br Heart J35:527–530

4. Ewing DJ, Campbell IW, Clarke BF(1980) The natural history of diabeticautonomic neuropathy. Q J Med 49:95–108

5. Hilsted J, Low PA (1997) Diabeticautonomic neuropathy. In: Low PA(ed) Clinical autonomic disorders:evaluation and management. Lippin-cott-Raven, Philadelphia, pp 487–507

6. Klein CM, Vernino S, Lennon VA,Sandroni P, Fealey RD, Benrud-LarsonLM, Sletten D, Low PA (2003) Thespectrum of autoimmune autonomicneuropathies. Ann Neurol 53:752–758

7. Kyle RA, Greipp PR (1983) Amyloido-sis: clinical and laboratory features in229 cases. Mayo Clin Proc 58:665–683

8. Lennox IM, Williams BO (1980) Pos-tural hypotension in the elderly. ClinExp Gerontol 2:313–329

9. Lipsitz LA (1989) Orthostatic hypo-tension in the elderly. N Engl J Med321:952–957

10. Low PA, Denq JC, Opfer-Gehrking TL,Dyck PJ, O’Brien PC, Slezak JM (1997)Effect of age and gender on sudomotorand cardiovagal function and bloodpressure response to tilt in normalsubjects. Muscle Nerve 20:1561–1568

11. Low PA, Benrud-Larson LM, SlettenDM, Opfer-Gehrking TL, Weigand SD,O’Brien PC, Suarez GA, Dyck PJ (2004)Autonomic symptoms and diabeticneuropathy: a population-based study.Diabetes Care 27:2942–2947

12. MacLennan WJ, Hall MR, Timothy JI(1980) Postural hypotension in old age:is it a disorder of the nervous system orof blood vessels? Age Ageing 9:25–32

13. Mader SL (1989) Orthostatic hypoten-sion. Med Clin North Am 73:1337–1349

14. Mader SL, Josephson KR, RubensteinLZ (1987) Low prevalence of posturalhypotension among community-dwell-ing elderly. JAMA 258:1511–1514

15. Masaki KH, Schatz IJ, Burchfiel CM,Sharp DS, Chiu D, Foley D, Curb JD(1998) Orthostatic hypotension pre-dicts mortality in elderly men: theHonolulu Heart Program. Circulation98:2290–2295

16. Myers MG, Kearns PM, Kennedy DS,Fisher RH (1978) Postural hypotensionand diuretic therapy in the elderly. CanMed Assoc J 119:581–585

17. Ooi WL, Barrett S, Hossain M, Kelley-Gagnon M, Lipsitz LA (1997) Patternsof orthostatic blood pressure changeand their clinical correlates in a frail,elderly population. JAMA 277:1299–1304

18. Palmer KT (1983) Studies into posturalhypotension in elderly patients. N ZMed J 96:43–45

19. Poon IO, Braun U (2005) High preva-lence of orthostatic hypotension and itscorrelation with potentially causativemedications among elderly veterans. JClin Pharm Ther 30:173–178

20. Rodstein M, Zeman FD (1957) Posturalblood pressure changes in the elderly. JChronic Dis 6:581–588

21. Rose KM, Eigenbrodt ML, Biga RL,Couper DJ, Light KC, Sharrett AR,Heiss G (2006) Orthostatic hypotensionpredicts mortality in middle-agedadults: the Atherosclerosis Risk InCommunities (ARIC) Study. Circula-tion 114:630–636

22. Rutan GH, Hermanson B, Bild DE,Kittner SJ, LaBaw F, Tell GS (1992)Orthostatic hypotension in olderadults. The Cardiovascular HealthStudy. CHS Collaborative ResearchGroup. Hypertension 19:508–519

23. Saito Y, Matsuoka Y, Takahashi A,Ohno Y (1994) Survival of patients withmultiple system atrophy. Intern Med33:321–325

24. Sandroni P, Ahlskog JE, Fealey RD,Low PA (1991) Autonomic involvementin extrapyramidal and cerebellar dis-orders. Clin Auton Res 1:147–155

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25. Senard JM, Rai S, Lapeyre-Mestre M,Brefel C, Rascol O, Rascol A, Monta-struc JL (1997) Prevalence of ortho-static hypotension in Parkinson’sdisease. J Neurol Neurosurg Psychiatr63:584–589

26. Suarez GA, Fealey RD, Camilleri M,Low PA (1994) Idiopathic autonomicneuropathy: clinical, neurophysiologic,and follow-up studies on 27 patients.Neurology 44:1675–1682

27. Tilvis RS, Hakala SM, Valvanne J, Er-kinjuntti T (1996) Postural hypoten-sion and dizziness in a general agedpopulation: a four-year follow-up of theHelsinki Aging Study. J Am Geriatr Soc44:809–814

28. Wenning GK, Ben Shlomo Y, Magalh-aes M, Daniel SE, Quinn NP (1994)Clinical features and natural history ofmultiple system atrophy. An analysis of100 cases. Brain 117:835–845

29. Wood BH, Bilclough JA, Bowron A,Walker RW (2002) Incidence and pre-diction of falls in Parkinson’s disease: aprospective multidisciplinary study. JNeurol Neurosurg Psychiatr 72:721–725

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Introduction

Orthostatic hypotension is the most incapacitatingsymptom of autonomic failure. Fortunately, with thehelp of non-pharmacological and pharmacologicalinterventions, most patients’ quality of life can beimproved substantially. The therapeutic interventionsto treat patients with orthostatic hypotension shouldbe implemented in stages and depend, in large part,on the severity of symptoms. Some patients may bemarkedly improved by education, counseling, re-moval of hypotensive medications and other non-pharmacological interventions, while more severelyafflicted patients require pharmacological interven-tions [9].

j Non-pharmacological measures

Patient education is the cornerstone of the manage-ment of orthostatic hypotension. Throughout the day,patients are subject to a number of orthostatic de-

mands for which there are simple but effectivecountermeasures. The time spent with patientsemphasizing these practical management principles isof inestimable value.

These include moving from a supine to standingposition in gradual stages; avoiding orthostatic stressin the morning when orthostatic tolerance is lowest[24]; minimizing straining and isometric exercise;should be discouraged; and avoiding deconditioning.Frequent small meals are preferable as food ingestionoften exacerbates orthostatic hypotension [19, 32].

Physical counter-maneuvers such as leg-crossingand squatting may be used to facilitate cerebralperfusion by increasing central blood volume andcardiac filling pressures [39]. The use of customfitted elastic stockings may also be used to provide agraded pressure to the lower extremity and abdo-men. Medications such as diuretics, anti-hyperten-sive agents, anti-anginal agents, anti-depressants andalpha adrenoreceptor antagonists should be taperedas these can cause or exacerbate orthostatic hypo-tension.

Roy Freeman Current pharmacologic treatmentfor orthostatic hypotension

Received: 18 June 2007Accepted: 5 July 2007

j Abstract Orthostatic hypoten-sion is treated effectively with thecombined use of non-pharmaco-logical and pharmacological inter-ventions. Patients should becounseled as to the nature of theunderlying disorder and reversiblecauses of orthostatic hypotensionshould be removed. Should symp-toms persist, pharmacologicaltreatment is implemented. Firstline pharmacotherapeutic inter-ventions include volume repletion

in combination with alpha-adre-noreceptor agonists. If unsuccess-ful there are several supplementaryagents with different mechanismsof action that may provide anadditive effect.

j Key words orthostatic hypo-tension Æ syncope Æautonomic failure Æsympathetic nervous system

ARTICLEClin Auton Res (2008) 18[Suppl 1]:14–18DOI 10.1007/s10286-007-1003-1

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R. Freeman, MD (&)Dept. of NeurologyHarvard Medical SchoolCenter for Autonomic and PeripheralNerve DisordersBeth Israel Deaconess Medical CenterOne Deaconess RoadBoston (MA) 02215, USATel.: +1-617/632-8454Fax: +1-617/632-0852E-Mail: rfreeman@bidmc.harvard.edu

j Volume expansion

Administration of fluid and sodium chloride

Plasma volume expansion is essential to improveorthostatic tolerance. The high nocturnal blood pres-sure causes a pressure natriuresis and results in noc-turnal volume and sodium chloride depletion. Severalmeasures are available for maintaining and repletingplasma volume (See Table 1). Patients should have adaily dietary intake of least 10 g (185 mmol) of so-dium per day accompanied by an increase in fluidintake of 2–2.5 l (in adults) per day. An early morningbody weight gain of about 1–2 kg usually impliesadequate extra-cellular fluid volume expansion [38].

Ingestion of approximately 500 cc of tap waterelicits a marked pressor response and improvementin symptoms in patients with autonomic failure. Thepressor response, a systolic blood pressure increase ofover 30 mmHg in some patients, is evident within5 minutes after the water ingestion [14].

9-a-Fluorohydrocortisone

9-a-Fluorohydrocortisone (fludrocortisone acetate), asynthetic mineralocorticoid, may be used if patientare unable to increase plasma volume effectively withfluid and salt [3, 11, 18]. This agent has a longduration of action and is well-tolerated by most pa-tients. Fludrocortisone increases the blood volumeand enhances the sensitivity of blood vessels to cir-culating catecholamines [7, 11]. Other potentialmodes of action include enhancing norepinephrinerelease from sympathetic neurons and increasingvascular fluid content [34].

Treatment is initiated with a 0.1 mg tablet and canbe increased to 0.3–0.5 mg daily [38]. Treatment mayunfortunately be limited by supine hypertension dueto an increase in the peripheral vascular resistance[4]. Other side effects include ankle edema, hypoka-lemia, headache and rarely congestive heart failure.Potassium supplementation is usually required, par-ticularly when higher doses are used.

Vasopressin analogs

The vasopressin analogs may be used to supplementvolume expansion. Arginine-vasopressin has a circa-dian rhythm that peaks during the night. Thus, theincrease in nocturnal urinary excretion in patients

with autonomic failure, which is in part due to theincrease in supine blood pressures, is also due to lossof vasopressin neurons in the suprachiasmatic nu-cleus of the hypothalamus and the ensuing loss of thenormal AVP circadian rhythm [27].

The potent, synthetic vasopressin analog desmo-pressin acetate (DDAVP) acts on the V2 receptors inthe collecting ducts of the renal tubules and preventsnocturia, weight loss and reduces the morning pos-tural fall in blood pressure. DDAVP is usuallyadministered as a nasal spray (5–40 lg) or orally(100–800 lg). Adverse events include water intoxica-tion and hyponatremia [21]. Low doses of intranasaldesmopressin (5 lg) may be sufficient to attenuatethe nocturnal diuresis without placing the patient atrisk for hyponatremia [33].

j Sympathomimetic agents

The administration of sympathomimetic agents iscentral to the management of patients with cardio-vascular autonomic failure. Thus, if symptoms oforthostatic intolerance persist once intravascularvolume is replenished the direct or indirect adrener-gic agonists and antagonists should be administered(See Table 2). The pressor response of these agents isdue to the reduction in venous capacity and theconstriction of the resistance vessels.

The available a1-adrenoreceptor agonists includethose with direct and indirect effects (ephedrine,pseudoephedrine), those with direct effects (mido-drine and phenylephrine) and those with only indirecteffects (methylphenidate and dextroamphetaminesulphate).

The peripheral selective direct, a1-adrenoreceptoragonist midodrine is the only agent approved by theFDA for the treatment of orthostatic hypotension[20]. Its efficacy has been demonstrated in double-blind placebo controlled studies [15, 20, 42]. Mido-drine, the prodrug is activated to desglymidodrine,the active a-adrenoreceptor agonist. Midodrine has anelimination half life of 0.5 hours and is undetectablein plasma 2 hours after an oral dose. The agentundergoes enzymatic hydrolysis (deglycination) inthe systemic circulation to form the active agent,desglymidodrine. Desglymidodrine is 15 times morepotent than midodrine and is primarily responsiblefor the therapeutic effect. The elimination half-life of

Table 1 Volume expansion

Fluid and sodium chloride9-a-FluorohydrocortisoneVasopressin analogsAcute water ingestion

Table 2 Sympathomimetic agonists

MidodrineEphedrinePseudoephedrineMethylphenidateDextroamphetamine

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desglymidodrine is 2–4 hours. Desglymidodrine ispredominantly excreted by the kidneys.

Patient sensitivity to this agent varies and the doseshould be titrated from 2.5 mg to 10 mg three times aday. The peak effect of this agent occurs 1 hour afteringestion [42]. Potential side effects of midodrineinclude pilomotor reactions, pruritus, supine hyper-tension, gastrointestinal complaints, and urinaryretention. Central nervous system side-effects occurinfrequently.

The mixed a-adrenoreceptor agonists—which actdirectly on the a-adrenoreceptor and release norepi-nephrine from the post-ganglionic sympathetic neu-ron—include ephedrine, pseudoephedrine. There arestructural, pharmacological and therapeutic differ-ences between these agents and midodrine. Ephedrineis an agonist of a, b1 and b2 receptors. The b2

vasodilatory effects may attenuate the pressor effectof this drug. Pseudoephedrine, a stereoisomer ofephedrine has similar pharmacological and thera-peutic properties [13]. Typical doses of the agents areephedrine: 25–50 mg three times a day; and pseudo-ephedrine: 30–60 mg three times a day. Because theeffectiveness of these agents is at least in part due tothe release of norepinephrine from the post-gangli-onic neuron, these medications are in theory mostlikely to benefit patients with partial or incompletelesions [1, 6, 10]. The indirect agonists, methylphe-nidate and dextroamphetamine, that release norepi-nephrine from post-ganglionic neurons areinfrequently used to treat orthostatic hypotension. Ina small head-to-head trial midodrine (mean dose8.4 mg tid) improved standing blood pressure andorthostatic tolerance more than ephedrine (22.3 mgtid) [8]. In another trial, phenylpropanolamine(12.5 mg) and yohimbine (5.4 mg) produced equiva-lent increases in standing systolic blood pressurewhile methylphenidate failed to increase standingsystolic blood pressure significantly [13].

The use of the sympathomimetic agents (with thepossible exception of midodrine) may be complicatedby tachyphylaxis, although efficacy may be regainedafter a short drug holiday. The central sympathomi-metic side-effects such anxiety, tremulousness andtachycardia that invariably accompany the use ofthese agents are frequently intolerable to patients.Midodrine, which does not cross the blood brainbarrier in significant amounts, does not have thesecentral sympathomimetic side-effects. There is evi-dence that phenylpropanolamine increases the risk ofhemorrhagic stroke in women [16] and the FDA hassuggested that phenylpropanolamine be removedfrom all drug products.

Severe hypertension is an important adverse-effectof all sympathomimetic agents. Patients should nottake these medications for 4 hours prior to recum-

bency. Patients taking midodrine report piloerection,pruritus and tingling. These are most likely peripheralsympathomimetic effects of the drug.

j Supplementary therapy

There are rare patients who do not respond to firstline interventions and require additional agents totreat their symptoms. These supplementary agentsmay provide an additive therapeutic effect to the first-line therapies (see Table 3).

Acetylcholinesterase inhibition

The acetylcholinesterase inhibitor, pyridostigmine,(60 mg) administered orally increased head-up tiltblood pressure and reduced orthostatic hypotensionin patients with neurogenic orthostatic hypotension.The associated increase in supine blood pressure maynot be as great as that seen with other pressors.Twenty percent of patients report cholinergic side-effects. The rationale for the use of this agent is thatinhibition of acetylcholinesterase enhance sympa-thetic ganglionic neurotransmission and that the ef-fect is maximal while upright, when sympatheticnerve traffic is greatest [35].

Caffeine

The methylxanthine caffeine has a well-established,although modest, pressor effect that is in part due toblockade of vasodilating adenosine receptors. Thepressor effect is subject to tachyphylaxis. Typicalcaffeine doses are 100–250 mg three times a day, ei-ther as tablets or caffeinated beverages (one cup ofcoffee contains approximately 85 mg of caffeine andone cup tea contains 50 mg of caffeine) [25].

Erythropoietin

Erythropoietin increases standing blood pressure andimproves orthostatic tolerance in patients withorthostatic hypotension [12, 28]. This agent correctsthe normochromic normocytic anemia that frequentlyaccompanies autonomic failure [2, 41] and diabeticautonomic neuropathy [40].

Table 3 Supplementary therapy

Acetylcholinesterase inhibitionCaffeineErythropoietinb-BlockersClonidineYohimbine

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Recombinant human erythropoietin, erythropoie-tin alpha, is administered subcutaneously or intrave-nously at doses between 25 and 75 U per kg threetimes a week until a hematocrit that approachesnormal is attained. Lower maintenance doses(approximately 25 U per kg three times a week) maythen be used. Iron supplementation is usually re-quired, particularly during the period when thehematocrit is increasing. Erythropoietin increases redcell mass and central blood volume although theprecise mechanism of action of this agent is not re-solved. There is evidence that the effect of erythro-poietin is related to vascular tone regulation mediatedby the interaction between hemoglobin and thevasodilator nitric oxide [29]. Supine hypertensionmay accompany the use of erythropoietin [12, 28].

b-Blockers

Nonselective b-blockers, particularly those withintrinsic sympathomimetic activity such as pindololand xamoterol, may have a limited place in thetreatment of orthostatic hypotension despite the well-acknowledged negative chronotropy and inotropyassociated with these medications [5, 22, 23, 37]. Thesuggested mechanism of action of these medicationsis the blockade of vasodilating b-2 receptors allowingunopposed a-adrenoreceptor mediated vasoconstric-tor effects to dominate. The pressor effect of theseagents has not been demonstrated consistently inclinical trials [17].

Clonidine

Clonidine is an a2 agonist that usually produces acentral, sympatholytic effect and a consequent de-crease in blood pressure. In patients with autonomicfailure, who have little central sympathetic efferentactivity, the effect of this agent on post synaptic a2

adrenoreceptors may predominate. The use of cloni-dine (0.1–0.6 mg per day) could therefore result in anincrease in venous return without a significant in-

crease in peripheral vascular resistance althoughmechanism of action is still not clearly defined [36].The use of this agent, at least theoretically, is limitedto patients with severe central autonomic dysfunctionin whom there is no ostensible effect of furthersympatholysis and the peripheral effect may dominate[30, 31]. Clonidine should be used cautiously asexacerbation of hypotension may occur. Side-effectsinclude somnolence, xerostomia and constipation.

Yohimbine

Yohimbine is a centrally and peripherally activeselective a2 adrenoreceptor antagonist that increasessympathetic nervous system efferent output byantagonizing central or presynaptic a2-adrenorecep-tors or both. This agent, theoretically, should be moreeffective in patients that have some residual sympa-thetic nervous system output, although this has notalways been borne out in clinical studies. Side effectsof yohimbine include anxiety, tremor, palpitations,diarrhea and supine hypertension [13, 26].

Conclusion

With the help of non-pharmacological and pharma-cological interventions, most patients’ quality of lifecan be improved substantially. Treatment should beinitiated in stages. First, patients should be counseledas to the nature of the underlying disorder andreversible causes of orthostatic hypotension should beremoved. If symptoms persist, pharmacologicaltreatment is implemented. Many patients will beadequately treated by education, counseling, removalof hypotensive medications and other non-pharma-cological interventions while more severely afflictedpatients require pharmacological interventions.

j Disclosure Dr. Freeman has served as a consultant for ChelseaTherapeutics.

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7. Davies IB, Bannister RG, Sever PS,Wilcox CS (1978) Fludrocortisone inthe treatment of postural hypotension:altered sensitivity to pressor agents[proceedings]. Br J Clin Pharmacol6:444P–445P

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26. Onrot J, Goldberg MR, Biaggioni I,Wiley RG, Hollister AS, Robertson D(1987) Oral yohimbine in human auto-nomic failure. Neurology 37:215–220

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29. Rao SV, Stamler JS (2002) Erythropoi-etin, anemia, and orthostatic hypoten-sion: the evidence mounts. Clin AutonRes 12:141–143

30. Robertson D, Goldberg MR, HollisterAS, Wade D, Robertson RM (1983)Clonidine raises blood pressure in idi-opathic orthostatic hypotension. Am JMed 74:193–199

31. Robertson D, Goldberg MR, Tung CS,Hollister AS, Robertson RM. (1986)Use of alpha 2 adrenoreceptor agonistsand antagonists in the functionalassessment of the sympathetic nervoussystem. J Clin Invest 78:576–581

32. Robertson D, Wade D, Robertson RM(1981) Postprandial alterations in car-diovascular hemodynamics in auto-nomic dysfunction states. Am J Cardiol48:1048–1052

33. Sakakibara R, Matsuda S, Uchiyama T,Yoshiyama M, Yamanishi T, Hattori T(2003) The effect of intranasal desmo-pressin on nocturnal waking in urina-tion in multiple system atrophypatients with nocturnal polyuria. ClinAuton Res 13:106–108

34. Schatz IJ, Miller MJ, Frame B (1976)Corticosteroids in the management oforthostatic hypotension. Cardiology61(suppl 1):280–289

35. Singer W, Opfer-Gehrking TL, McPheeBR, Hilz MJ, Bharucha AE, Low PA(2003) Acetylcholinesterase inhibition:a novel approach in the treatment ofneurogenic orthostatic hypotension. JNeurol Neurosurg Psychiatry 74:1294–1298

36. Victor RG, Talman WT (2002) Com-parative effects of clonidine and dihy-droergotamine on venomotor tone andorthostatic tolerance in patients withsevere hypoadrenergic orthostatichypotension. Am J Med 112:361–368

37. West JN, Stallard TJ, Dimmitt SB,Smith SA, Williams A, Littler WA(1990) Xamoterol in the treatment oforthostatic hypotension associatedwith multiple system atrophy (Shy-Drager syndrome). Q J Med 74:209–213

38. Wieling W, van Lieshout JJ, Hains-worth R (2002) Extracellular fluid vol-ume expansion in patients withposturally related syncope. Clin AutonRes 12:242–249

39. Wieling W, van Lieshout JJ, van Leeu-wen AM (1993) Physical manoeuvresthat reduce postural hypotension inautonomic failure. Clin Auton Res3:57–65

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Autonomic failure, like Parkinson’s disease, is aneurotransmitter disorder. While Parkinson’s diseaseis a disorder of dopamine neurotransmission, auto-nomic failure is a disorder of norepinephrine neuro-transmission. The idea that deficient dopamineneurotransmission in Parkinson’s disease could beovercome by treatment with oral levodopa, the aminoacid precursor of dopamine, led to the most suc-cessful therapeutic intervention in 20th century neu-rology.

Although levodopa is the amino acid precursor ofboth dopamine and norepinephrine, treatment withlevodopa leads to an increase in dopamine but not toa significant increase in norepinephrine levels. Nor-epinephrine is synthesized from levodopa in two steps(Fig. 1). The first step is the decarboxylation oflevodopa to dopamine by the enzyme L-aromaticamino acid decarboxylase. The second step, catalyzedby the enzyme dopamine beta hydroxylase, is thehydroxylation of dopamine to norepinephrine.

Horacio Kaufmann L-dihydroxyphenylserine (Droxidopa):a new therapy for neurogenic orthostatichypotension

The US experience

Received: 18 June 2007Accepted: 30 June 2007

j Abstract Neurogenic ortho-static hypotension results fromfailure to release norepinephrine,the neurotransmitter of sympa-thetic postganglionic neurons,appropriately upon standing. Indouble blind, cross over, placebocontrolled trials, administration ofdroxidopa, a synthetic amino acidthat is decarboxylated to norepi-nephrine by the enzyme L-aro-matic amino acid decarboxylaseincreases standing blood pressure,ameliorates symptoms of ortho-static hypotension and improvesstanding ability in patients withneurogenic orthostatic hypoten-sion due to degenerative auto-nomic disorders. The pressoreffect results from conversion ofdroxidopa to norepinephrine out-side the central nervous systemboth in neural and non-neuraltissue. This mechanism of actionmakes droxidopa effective in

patients with central and periph-eral autonomic disorders.

j Key words autonomic failure Æorthostatic hypotension ÆDOPS Æ droxidopa Æmultiple system atrophy Æpure autonomic failure ÆParkinson’s disease Ænorepinephrine Æ bloodpressure Æ autonomic nervoussystem

ARTICLEClin Auton Res (2008) 18[Suppl 1]:19–24DOI 10.1007/s10286-007-1002-2

CA

R1002

H. Kaufmann, MD (&)Dysautonomia Research LaboratoryNew York University School of Medicine530 First AvenueNew York (NY)10016, USATel.: +1-212/263-7225Fax: +1-646/349-3476E-Mail: horacio.kaufmann@med.nyu.edu

Dopamine beta hydroxylase is the rate-limiting en-zyme and it creates a ‘‘bottle neck’’ like effect, so thattaking levodopa orally results in an increase indopamine levels but not to a significant increase innorepinephrine levels.

Fortunately, the possibility of overcoming thislimitation and realizing another therapeutic break-through using a precursor amino acid to replace adeficient catecholamine neurotransmitter, in this casenorepinephrine, was made possible by the discovery,in the 1950’, that an artificial amino acid, 3,4-threo-dihydroxyphenylserine, identical to levodopa but withan added beta hydroxyl group (Fig. 2) was convertedto norepinephrine in a single step by the enzyme L-aromatic amino acid decarboxylase, thus bypassingthe need for dopamine beta hydroxylase and its bottleneck effect [3, 15].

Droxidopa was first used successfully to treat oneparticular form of autonomic failure: congenitaldeficiency of the enzyme dopamine beta hydroxylase.Robertson and Biaggioni and Man in’t Veld et al.showed that after oral administration, droxidopa was

taken up by post-ganglionic sympathetic neurons,decarboxylated to NE, stored and released appropri-ately when standing up [2, 12]. Droxidopa has nowbeen used to treat orthostatic hypotension in severalautonomic disorders, including familial amyloidpolyneuropathy [16], autoimmune autonomic neu-ropathy [5], pure autonomic failure (PAF), Parkin-son’s disease and multiple system atrophy [MSA; 4,10, 11, 13].

3,4-Threo-dihydroxyphenylserine has four steroi-somers [1]. Early studies used a racemic mixture thatcontained both the D and L isoforms of 3,4-threo-di-hydroxyphenylserine but only the L-isoform is con-verted to biologically active L-norepinephrine.Furthermore, the D-stereoisomer of 3,4-threo-di-hydroxyphenylserine might competitively inhibit thedecarboxylation of the L stereoisomer to L-norepi-nephrine [8]. Thus, the pure L isoform of 3,4-threo-dihydroxyphenylserine (droxidopa) is the preferredformulation for treatment.

Here I will review the most recent studies con-ducted in the United States using droxidopa in thetreatment of orthostatic hypotension in patients withdegenerative autonomic disorders, including PAF andMSA.

Studies of droxidopa in the United States

We conducted a comprehensive study of droxidopa inpatients with severe symptomatic orthostatic hypo-tension due to MSA or PAF [11]. We examined theeffect of droxidopa on standing blood pressure andorthostatic tolerance, as well as its pharmacokineticsand its mechanism of action.

Fig. 1 Catecholamine pathway: Norepinephrine is synthesized from levodopain two steps. The first step is the decarboxylation of levodopa to dopamine byL-aromatic amino acid decarboxylase. The second step is the hydroxylation ofdopamine to norepinephrine by the rate-limiting enzyme dopamine betahydroxylase. Droxipoda bypasses this rate-limiting enzyme and is converted tonorepinephrine in a single step by L-aromatic amino acid decarboxylase

Fig. 2 Levodopa and droxipoda: The similar chemical structure of droxipoda(3,4-threo-dihydroxyphenylserine) and levodopa (3,4-dihydroxy-L-phenylala-nine). Note that droxidopa has an added beta hydroxyl group

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j Dose titration study

Because patients with autonomic failure have differ-ent degrees of adrenergic denervation supersensitiv-ity, we individualized the dose of droxidopa for eachpatient in a single blind dose-ranging study.

Patients received progressively higher dosages ofdroxidopa, beginning with 200 mg followed by 400,1,000, 1,600, and 2,000 mg on successive days. Thedose ranging study was terminated when the ortho-static fall in systolic blood pressure after 3 min ofstanding was consistently < 20 mm Hg, or the patienthad a sustained supine systolic blood pressure of> 200 mm Hg or diastolic blood pressure of> 110 mm Hg; or when a maximum dose of 2,000 mgof droxidopa was reached. The optimal dose ofdroxidopa varied between 200 mg and 2,000 mg(mean dose ± SE was 1,137 ± 131 mg).

j Double blind, crossover, placebo controlled study

Once the individual dose of droxidopa was deter-mined, patients were enrolled in a double blindcrossover study lasting 3 days. On days 1 and 3 eitherdroxidopa (at the dose previously determined in thedose ranging study) or placebo was given at 7:00 am.Day 2 was a washout day. As shown in Fig. 3administration of droxidopa significantly increasedblood pressure in all patients (P < 0.001 versus pla-cebo), both while supine and after standing for 1 minand for 3 min.

The pressor effect began 1 h after droxidopaadministration and lasted for 6 h while standing andfor 8 h while supine. The highest standing blood

pressure occurred 3.5 h after droxidopa administra-tion (P < 0.00001 versus placebo, see Fig. 3). Therewere no significant changes in heart rate followingadministration of droxidopa or placebo.

There was a clear symptomatic improvement in allpatients after taking droxidopa. Patients were lesslightheaded and reported feeling better. This wasnoticeable in the patient’s ability to stay standing.Patients were able to stand for the 1-min bloodpressure determination 96% of the time after receiv-ing either droxidopa or placebo. However, for the 3-min blood pressure measurement, patients were ableto stand 94% of the time after receiving droxidopa butonly 84% of the time after receiving placebo(P < 0.001).

Adverse events

Droxidopa was well tolerated by all patients and therewere no significant side effects. The frequency of su-pine hypertension (systolic pressure > 180, dia-stolic > 110 mmHg or both) was higher on droxidopathan on placebo (45% vs. 23% of blood pressuremeasurements, P < 0.00001). After receiving droxid-opa, the frequency of supine systolic and diastolichypertension was similar in MSA and PAF patients.However, on placebo, diastolic, but not systolic, su-pine hypertension was more common in MSA pa-tients than in PAF (25% vs. 3%, P < 0.05). One patienthad hyponatremia, which reversed after saline infu-sion. Another patient had transitory chest pain withelectrocardiographic ST segment depression, butcardiac enzymes were normal.

Mechanism and site of action of droxidopa

Droxidopa could exert its pressor effect in three dif-ferent ways [9] (Fig. 4):

1. As a central stimulator of sympathetic activity.Because droxidopa crosses the blood brain barrier,it could, at least theoretically, act as a centralstimulator of sympathetic outflow. It could beconverted to epinephrine and activate sympatheticpreganglionic neurons in the spinal cord.

2. As a peripheral sympathetic neurotransmitter. As ithad been shown in patients with dopamine betahydroxylase (DBH) deficiency [2, 12] droxidopacould be taken up by post ganglionic peripheralsympathetic neurons, transformed to norepineph-rine intraneuronally, and released when sympa-thetic neurons are activated, i.e., act as aphysiologic sympathetic neurotransmitter inperipheral sympathetic neurons.

Fig. 3 Standing blood pressure after droxipoda and placebo administration.The effect of droxipoda and placebo on mean arterial pressure (MAP) after3 min standing. Time 0 (arrow) represents the time of drug administration(7 am). Meals were served at -1 (6 am) and 6 h (1 pm). *P < 0.05 (L-DOPS vs.placebo). All data are mean ± SEM, (n = 19). Data from Kaufmann et al. [11]

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3. As a circulating hormone. Norepinephrine syn-thesized from droxidopa could also act as a cir-culating hormone. The enzyme aromaticaminoacid decarboxylase is widely expressedthroughout the body, in the stomach, kidney andliver. Thus, droxidopa could be converted to nor-epinephrine outside neurons, and then releasedinto the blood stream were it would exert a pressoreffect as a circulating hormone.

j Decarboxylase inhibitior study

To determine whether the pressor action of droxidopawas due to its metabolism to norepinephrine inside oroutside the central nervous system we used carbidopaas a pharmacological probe [11]. Carbidopa is aninhibitor of L-aromatic-amino-acid decarboxylasethat does not cross the blood-brain barrier. Therefore,carbidopa’s inhibition of L-aromatic-amino-aciddecarboxylase and its blockade of norepinephrinesynthesis from droxidopa is confined to tissues out-side the brain and it does not affect the decarboxyl-ation of droxidopa to norepinephrine within thecentral nervous system.

If the mechanism of action of droxidopa is in thecentral nervous system, a large dose of carbidopataken before droxidopa should not prevent its pressoreffect. Indeed, it may even increase its pressor effect,similarly to the enhanced anti parkinsonian effect oflevodopa when it is administered with carbidopa.Conversely, if the mechanism of action of droxidopais through its conversion to norepinephrine outsidethe central nervous system, either in neural or non-

neural tissue, then concomitant administration ofcarbidopa will block the pressor effect of droxidopa.

In a double-blind placebo controlled study, sixpatients [11] sequentially received droxidopa alone onday 1, 200 mg of carbidopa alone on day 2, and 200mg of carbidopa combined with droxidopa on day 3.

As expected, droxidopa taken alone increasedstanding blood pressure in all patients. Carbidopataken alone had no effect on blood pressure. However,when carbidopa was administered together withdroxidopa the increase in blood pressure previouslyseen with droxidopa alone was completely abolished(Fig. 5). From this study we concluded that thepressor effect of droxidopa was due to it conversioninto norepinephrine outside the brain, either in neu-ronal or non-neuronal tissues.

After carbidopa administration plasma levels ofdroxidopa were higher than when droxidopa wasadministered without carbidopa (4,556 ± 1,011 ng/ml,P < 0.01, versus droxidopa alone). In addition, car-bidopa markedly attenuated the increase in plasmanorepinephrine levels. Six hours after concomitantcarbidopa and droxidopa administration, the venousplasma norepinephrine level had only increased from216 ± 125 to 407 ± 271 pg/ml (P < 0.05, versus drox-idopa alone).

j Droxidopa in patients with PD taking levodopaand a decarboxylase inhibitor

Levodopa/carbidopa therapy is a mainstay in thetreatment of Parkinson disease. Because carbidopainhibits the conversion of droxidopa to norepineph-rine, droxidopa may be ineffective in the treatment of

Fig. 4 Possible mechanisms of action ofdroxidopa—Droxidopa could exert its pressor effect inthree ways: 1. Because droxidopa crosses the blood brainbarrier, it could be converted to epinephrine and activatesympathetic preganglionic neurons in the spinal cord. 2.Droxidopa could be taken up by post ganglionicsympathetic neurons, converted to norepinephrineintraneuronally, and released when sympathetic neuronsare activated. 3. Droxidopa could be converted tonorepinephrine outside neurons (in the stomach, kidneyand liver), released into the blood stream and exert apressor effect as a circulating hormone

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orthostatic hypotension in patients with Parkinsondisease treated with levodopa/carbidopa. However, toblock the pressor effect of droxidopa it is necessary tocompletely inhibit the enzyme aromatic aminoaciddecarboxylase. To achieve complete inhibition ofaromatic aminoacid decarboxylase a high dose ofcarbidopa (200 mg) is required. Lower dosages ofcarbidopa, such as those commonly used to treatParkinson disease, should not abolish the pressoreffect of droxidopa. Indeed, studies of droxidopa inEurope included patients with PD who were alsotaking benzeraside, an aromatic aminoacid decar-boxylase inhibitor, at a low dose, together with levo-dopa (i.e., Madopar, see Mathias, this supplement).Because benzerazide at a low dose does not com-pletely inhibit the enzyme aromatic aminoaciddecarboxylase, patients with PD still experienced thedesired pressor effect of droxidopa.

j Therapeutic implications

A peripheral mechanism of action makes droxidopaan exciting new treatment option in both central andperipheral autonomic disorders. In patients withdestruction of peripheral autonomic neurons (i.e., inthe Lewy body disorders), droxidopa can be con-verted to norepinephrine in non-neuronal tissues,released to the blood stream and act as a circulatingvasoconstrictor hormone. In patients with centralautonomic disorders and preserved peripheral auto-nomic neurons (i.e., MSA), droxidopa is converted tonorepinephrine outside the central nervous system,both in neuronal and non-neuronal tissue. In thesepatients, droxidopa-derived norepinephrine acts as aneurotransmitter and a circulating hormone.

j Pharmacokinetic study

We investigated the pharmacokinetics of droxidopaand the generated norepinephrine and determined therelationship between the pressor response and venousplasma norepinephrine levels [6, 11]. The peak drox-idopa level of 1,942 ± 224 ng/ml was attained 3 h afterits ingestion (P < 0.001). Plasma norepinephrine in-creased from the baseline level of 294 ± 80 pg/ml to806 ± 235 pg/ml (P < 0.05) 2 h after droxidopa administration. Norepinephrine peaked at 1,250 ± 208 pg/ml 6 h after droxidopa ingestion (P < 0.005, see Fig. 6).Plasma levels of norepinephrine remained significantlyelevated for at least 46 h. The levels of norepinephrineassociated with an increase in blood pressure wereabove 700 pg/ml (see Fig. 7), similar to the norepi-nephrine levels necessary to increase blood pressurewhen norepinephrine is infused.

Fig. 5 Droxidopa plus decarboxylase inhibitior study. The effect of droxipoda,decarboxylase inhibitior (DCI), droxidopa and DCI, and placebo on mean arterialpressure (MAP) after 3 min standing. Time 0 (arrow) represents the time ofdrug administration (7 am). Meals were served at )1 (6 am) and 6 h (1 pm).*P < 0.05 (versus placebo). All data are mean ± SEM, (n = 6). Data fromKaufmann et al. [11]

Fig. 6 Plasma levels of droxipoda and norepinephrine. Venous plasma levels ofdroxipoda and norepinephrine after droxidopa administration (Time 0, 7 am).Meals were served at )1 (6 am) and 6 h (1 pm). All data are mean ± SEM,(n = 8). Data from Kaufmann et al. [11]

Fig. 7 Relationship between blood pressure and norepinephrine levels afterdroxidopa administration. Changes in systolic blood pressure (SBP) versusplasma concentration of norepinephrine after droxidopa administration. Solidcurve represents the line of best fit. All data are mean ± SEM, (n = 8). Datafrom Kaufmann et al. [11]

23

j Responses in patients with MSA and patientswith PAF

Prior to droxidopa ingestion, MSA and PAF patientshad similar blood pressures and similar heart rates,both while supine and while standing. The mean doseof droxidopa in the MSA group was 1,327 ± 441 mg(mean ± SD) for a mean weight of 78 ± 12 kg(mean ± SD) and in the PAF group 875 ± 650 mg(P = 0.09) for a mean weight of 77 ± 21 kg. Followingdroxidopa administration, systolic blood pressure inthe supine position increased more in patients withPAF than in patients with MSA (P < 0.05). There wasa trend towards higher systolic blood pressure inpatients with PAF after 1 min in the standing positionbut this did not reach statistical significance. Thefinding that the pressor response to droxidopa insupine patients with PAF was more pronounced thanin patients with MSA indicate a peripheral mechanismof action. Indeed, because of their widespread loss ofsympathetic terminals, patients with PAF have

markedly exaggerated pressor responses to circulat-ing norepinephrine [7, 14].

In summary, Droxidopa effectively raises standingblood pressure and ameliorates symptoms of ortho-static hypotension in patients with central andperipheral autonomic disorders. The pressor effect ofdroxidopa is due to its conversion to norepinephrineoutside the brain, both in neuronal and non neuronaltissues. In patients with peripheral autonomic disor-ders and degeneration of sympathetic neurons (e.g.PAF), droxidopa is converted to norepinephrine in nonneuronal tissue. In patients with central autonomicdegeneration and preserved peripheral sympatheticneurons (e.g. MSA), droxidopa is converted to nor-epinephrine in neuronal and non neuronal tissue.

j Acknowledgment I am grateful to Dr. Lucy Norcliffe-Kaufmannfor her help designing the figures.

j Disclosure Dr. Kaufmann has served as a consultant for ChelseaTherapeutics.

References

1. Bartholini J, Constantinidis J, Puig M,Tissot R, Pletscher A (1975) The ste-reoisomers of 3,4-dihydroxyphenylser-ine as precursors of norepinephrine. JPharmacol Exp Ther 193:523–532

2. Biaggioni I, Robertson D (1987)Endogenous restoration of noradrena-line by precursor therapy in dopamine-beta-hydroxylase deficiency. Lancet2:1170–1172

3. Blaschko H, Burn JH, Langemann H(1950) The formation of noradrenalinefrom dihydroxyphenylserine. Br JPharmacol 5:431–437

4. Freeman R, Landsberg L, Young J(1999) The treatment of neurogenicorthostatic hypotension with 3,4-DL-threo-dihydroxyphenylserine: a ran-domized, placebo-controlled, crossovertrial. Neurology 53:2151–2157

5. Gibbons CH, Vernino SA, KaufmannH, Freeman R (2005) L-DOPS therapyfor refractory orthostatic hypotensionin autoimmune autonomic neuropathy.Neurology 65:1104–1106

6. Goldstein DS, Holmes C, Kaufmann H,Freeman R (2004) Clinical pharmaco-kinetics of the norepinephrine precur-sor L-threo-DOPS in primary chronicautonomic failure. Clin Auton Res14:363–368

7. Hague K, Lento P, Morgello S, Caro S,Kaufmann H (1997) The distribution ofLewy bodies in pure autonomic failure:autopsy findings and review of the lit-erature. Acta Neuropathol (Berl)94:192–196

8. Inagaki C, Fujiwara H, Tanaka C (1976)Inhibitory effect of (+)threo-3,4-di-hydroxy-phenylserine (DOPS) ondecarboxylation of ())threo-dops. JpnJ Pharmacol 26:380–382 Issn: 0021-5198

9. Kaufmann H (1996) Could treatmentwith DOPS do for autonomic failurewhat DOPA did for Parkinson’s dis-ease? Neurology 47:1370–1371

10. Kaufmann H, Oribe E, Yahr MD (1991)Differential effect of L-threo-3,4-di-hydroxyphenylserine in pure auto-nomic failure and multiple systematrophy with autonomic failure. JNeural Transm Park Dis Dement Sect3:143–148

11. Kaufmann H, Saadia D, VoustianioukA, Goldstein DS, Holmes C, Yahr MD,Nardin R, Freeman R (2003) Norepi-nephrine precursor therapy in neuro-genic orthostatic hypotension.Circulation 108:724–728

12. Man in’t Veld AJ, Boomsma F, van denMeiracker AH, Schalekamp MA (1987)Effect of unnatural noradrenaline pre-curser on sympathetic control andorthostatic hypotension in dopamine-beta-hydroxylase defficiency. Lancet2:1172–1175

13. Mathias CJ, Senard JM, Braune S,Watson L, Aragishi A, Keeling JE,Taylor MD (2001) L-threo-dihydroxy-phenylserine (L-threo-DOPS; droxid-opa) in the management of neurogenicorthostatic hypotension: a multi-na-tional, multi-center, dose-rangingstudy in multiple system atrophy andpure autonomic failure. Clin Auton Res11:235–242

14. Polinsky RJ, Kopin IJ, Ebert MH, WeiseV (1981) Pharmacologic distinction ofdifferent orthostatic hypotension syn-dromes. Neurology 31:1–7

15. Schmiterlow CG (1951) The formationin vivo of noradrenaline from 3:4-di-hydroxyphenylserine (noradrenalinecarboxylic acid). Br J Pharmacol 6:127–134

16. Suzuki T, Higa S, Tsuge I, Sakoda S,Hayashi A, Yamamura Y, Takaba Y,Nakajima A (1980) Effect of infusedL-threo-3,4-dihydroxyphenylserine onadrenergic activity in patients withfamilial amyloid polyneuropathy. Eur JClin Pharmacol 17:429–435

24

Christopher J. Mathias L-dihydroxyphenylserine (Droxidopa)in the treatment of orthostatichypotension

The European experience

Received: 25 October 2007Accepted: 26 November 2007

j Abstract Neurogenic orthostatichypotension is a cardinal feature ofgeneralised autonomic failure andcommonly is the presenting sign inpatients with primary autonomicfailure. Orthostatic hypotensioncan result in considerable morbid-ity and even mortality and is amajor management problem indisorders such as pure autonomicfailure, multiple system atrophyand also in Parkinson’s disease.Treatment is ideally two pronged,using non-pharmacological andpharmacological measures.

Drug treatment ideally is aimed atrestoring adequate amounts of theneurotransmitter noradrenaline.This often is not achievable becauseof damage to sympathetic nerveterminals, to autonomic ganglia or tocentral autonomic networks. Analternative is the use of sympat-homimetics (that mimic the effectsof noradrenaline, but are not identi-cal to noradrenaline), in addition toother agents that target physiologicalmechanisms that contribute to bloodpressure control.

L-threo-dihydroxyphenyslerine(Droxidopa) is a pro-drug whichhas a structure similar to nor-adrenaline, but with a carboxyl

group. It has no pressor effects inthis form. It can be administeredorally, unlike noradrenaline, andafter absorption is converted by theenzyme dopa decarboxylase intonoradrenaline thus increasing lev-els of the neurotransmitter which isidentical to endogenous noradren-aline. Experience in Caucasians andin Europe is limited mainly topatients with dopamine betahydroxylase deficiency. This reviewfocuses on two studies performedin Europe, and provides informa-tion on its efficacy, tolerability andsafety in patients with pure auto-nomic failure, multiple systematrophy and Parkinson’s disease. Italso addresses the issue of whetheraddition of dopa decarboxylaseinhibitors, when combined withl-dopa in the treatment of the motordeficit in Parkinson’s disease, im-pairs the pressor efficacy of Drox-idopa.

j Key words l-dihydroxyphenyl-serine Æ orthostatic hypotension Æautonomic failure Ænoradrenaline Æ multiple systematrophy Æ Parkinson’s disease

ARTICLEClin Auton Res (2008) 18[Suppl 1]:25–29DOI 10.1007/s10286-007-1005-z

CA

R1005

Prof. C.J. Mathias, DPhil, DSc, FRCP,FMedSciNeurovascular Medicine UnitFaculty of MedicineImperial College London at St Mary’sHospitalPraed StreetLondon W2 1NY, UKTel.: +44-0207/8861-468Fax: +44-0208/8861-540E-Mail: c.mathias@imperial.ac.uk

C.J. Mathias, DPhil, DSc, FRCP,FMedSci (&)Autonomic UnitNational Hospital for Neurology andNeurosurgeryInstitute of NeurologyUniversity College LondonLondon, WCIN 3 BG, UK

Introduction

Orthostatic (or postural) hypotension (OH) is a car-dinal manifestation of generalised autonomic failureand often is the presenting feature in patients withprimary autonomic failure due to pure autonomicfailure (PAF) and multiple system atrophy (MSA) [9].It is increasingly recognised also in Parkinson’s dis-ease [11]. It results in a number of symptoms, mainlyas a result of hypoperfusion of organs, including theskeletal musculature. Organs above the level of theheart, such as the brain, are particularly susceptibleto hypoperfusion; this can result in dizziness, visualdisturbances, cognitive deficits and loss of con-sciousness [1, 6]. Orthostatic hypotension can reducemobility, result in falls, and may cause trauma andinjuries, at times with devastating effects includingdeath. The symptomatic consequences of OH, takentogether can substantially reduce a patients quality oflife.

There are many causes of OH that can be consid-ered under the mechanisms responsible - neurogenic,non-neurogenic and drug induced [12]. Non-neuro-genic OH is rectified more readily than neurogenicOH, which often is difficult to treat, with managementdependent on a combination of non-pharmacologicalmeasures and drugs [3, 10]. A key factor in neuro-genic OH is reduction in sympathetic nerve activity,and thus a reduction of the neurotransmitter, nor-adrenaline at the synaptic cleft. To replace this defi-ciency a variety of drugs that mimic noradrenalinehave been used, that include ephedrine and mido-drine, which are of partial benefit and have limitationsto their use because of adverse effects. The ideal ap-proach would be replacement of noradrenaline itself.

L-threo-dihydroxyphenylserine (Droxidopa) has astructure which is similar to noradrenaline but with acarboxyl group. It can be administered orally, and isacted upon by the ubiquitous enzyme L-aromaticamino acid decarboxylase (dopa decarboxylase),which is found all over the body. It is converted di-rectly to noradrenaline. It is likely to have both neu-ronal and extra neuronal effects, with a direct effectthrough noradrenaline on target organs. Droxidopahas been highly successful in replacing deficient orabsent noradrenaline in patients with dopamine betahydroxylase deficiency [4, 5, 15]. In Japan, it has beenapproved since 1989 use for in the treatment ofneurogenic OH due to various disorders, that includefamilial amyloid polyneuropathy, haemodialysis in-duced hypotension, and MSA and PD [8, 14, 16, 17,18]. Experience with Droxidopa, especially in primaryautonomic failure and PD in Caucasians is limited.Because of its potential value in the management ofsymptomatic orthostatic hypotension, two Phase II

studies were performed in Europe. These were multi-centre, multinational studies. An escalating dose ofDroxidopa was used in the first study in patients withPAF and MSA. In the second a randomised doubleblind placebo controlled study was performed usingthree doses of Droxidopa in patients with MSA or PD.

This review will describe key components fromeach of these studies, and will focus on whetherinhibition of the enzyme dopa decarboxylase, whichconverts Droxidopa to noradrenaline, can influenceits ability to reduce orthostatic hypotension.

Droxidopa in pure autonomic failure and multiplesystem atrophy

This study was performed in 6 PAF and 26 MSApatients with symptomatic orthostatic hypotension[7]. It was an open dose ranging study with a oneweek run in period, following which three doses ofDroxidopa, 100, 200 and 300 mg were administeredtwice daily. The incremental dose adjustment wasdependent on the blood pressure response and animprovement in symptoms. When optimum dosagewas reached the dosage was maintained for a 6 weekperiod. The study therefore determined both theefficacy and the tolerability of increasing doses ofDroxidopa in treating symptomatic orthostatichypotension in PAF and MSA. This dose escalatingtrial was performed in ten centres within threecountries in Europe. A key primary variable was todetermine the extent of decrease in orthostatic fall insystolic blood pressure.

Table 1 provides details of the response to Drox-idopa. The effects of Droxidopa persisted even at thelast individual visit, with orthostatic systolic bloodpressure reductions of 20, 29 and 23 mmHg respec-tively. In 25 patients (78%) OH had improved, and in14 (44%) OH was not measurable. Importantly themean supine systolic BP levels were not elevated(Table 1). Thus Droxidopa, particularly in the highestdoses, was efficacious in reducing OH (Fig. 1).

In this study, symptoms associated with orthostatichypotension, that included light headedness, dizzi-ness and blurred vision were assessed while on andwhen off Droxidopa drug. These were evaluated usingbi-polar scales with ten point numeric objectivity.They showed an improvement in both objective andsubjective evaluations of benefit (Fig. 2).

Droxidopa was well tolerated. There were twoserious adverse events; laryngeal dyspnoea and syn-cope. The first was on 100mg twice daily and thesecond on 300 mg twice daily. Both could be attrib-uted to the disease itself rather than to the drug. Su-pine hypertension was not reported.

26

In summary, Droxidopa was an effective drugwhich reduced the orthostatic fall in blood pressure inpatients with PAF and MSA. It improved symptoms of

OH and was well tolerated. It did not result in supinehypertension. The most effective of the three testeddoses was 300 mg twice daily.

Droxidopa in multiple system atrophy andin Parkinson’s disease

This study was designed to determine the minimumeffective dose of Droxidopa that safely reduced theorthostatic fall in systolic blood pressure in compar-ison with placebo. After screening and evaluation atotal of 121 patients with either MSA or PD wererandomized and received doses of 100, 200, 300 mg ofDroxidopa or matching placebo. The drug wasadministered three times daily, as was placebo. It wasconducted in 30 centres within 4 European countries.The screening period was between two seven days andthe treatment continued for 28 days. Data was ob-tained in 55 patients with MSA and in 66 with Par-kinson’s disease. A preliminary report recently hasbeen presented [13].

Droxidopa treatment resulted in a reduction in theorthostatic fall in blood pressure with each of theDroxidopa doses, unlike with placebo. It was notedthat in the previous study the same patient hadescalating doses with individual comparisons, unlikethis second study with different individuals on dif-ferent doses of drugs. There was no clear dose re-sponse improvement but the 300 mg dose was the

Table 1 Dose effects of L-threo-DOPS (Droxidopa) expressed as change from baseline, in multiple system and pure antonomic failure patients.

L-threo-DOPS dose

100 mg twice daily 200 mg twice daily 300 mg twice daily

Last individual visit per dose* n = 32* n = 25* n = 17*Baseline orthostatic SBP decrease 54.3 ± 27.7 55.8 ± 24.6 60.6 ± 24.9Final visit supine SBP 120.9 ± 31.6 118.9 ± 30.3 117.2 ± 31.9Reduction in orthostatic SBP decrease )23.2 ± 28.0 )28.4 ± 54.4 )22.7 ± 36.4Reduction in orthostatic DBP decrease )9.4 ± 17.0 )10.9 ± 31.0 )11.5 ± 22.6Noradrenaline while supine 562.5 ± 1,024.2 (n = 30) 779.5 ± 1,214.1 (n = 23) 966.1 ± 969.3 (n = 14)Noradrenaline at end of standing period� 1,096.8 ± 1,228.8 1,350.1 ± 1,612.4 1,361.9 ± 864.3 (n = 16)

Last individual visit* n = 7* n = 8* n = 17*Baseline orthostatic SBP decrease 48.7 ± 38.8 45.6 ± 22.0 60.6 ± 24.9Final visit supine SBP 129.3 ± 28.4 114.1 ± 24.6 117.1 ± 31.9Reduction in orthostatic SBP decrease )19.7 ± 13.9 )28.5 ± 22.2 )22.7 ± 36.4Reduction in orthostatic DBP decrease )9.2 ± 8.8 )5.1 ± 8.6 )11.5 ± 22.6Noradrenaline while supine 472.1 ± 341.7 379.6 ± 394.9 (n = 7) 966.1 ± 969.3 (n = 14)Noradrenaline at end of standing period� 1,304.6 ± 1,077.5 1,303.5 ± 1,659.8 1,361.9 ± 864.3 (n = 16)

Analysis used all available data, with n values as shown in asterisked (*) rows unless otherwise specified against mean values. Orthostatic blood pressure decreasedata were obtained after 5 min standing and are measured in mm Hg. Noradrenaline plasma concentration are pg/ml� Data for noradrenaline at end of standing time represent actual values and are not presented as change from baselineSBP = systolic blood pressure; DBP = diastolic blood pressureFrom: Mathias CJ, Senard J-M, Braune S, Watson L, Aragishi A, Keeling J, Taylor M. L-threo-dihydroxphenylserine (L-threo-DOPS; droxidopa) in the management ofneurogenic orthostatic hypotension: a multi-national, multi-centre, dose-ranging study in multiple system atrophy and pure autonomic failure. Clin Aut Res 2001, 11;235–242.

0 20 40 60 80 100 120 140

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Fig. 1 Orthostatic systolic blood pressure decrease at baseline and at individuallast visit. Individual orthostatic blood pressure decrease (mm Hg) after 5-minuties’standing at last visit is plotted against decrease at baseline (all 32 ‘‘efficacy-evaluable’’ patients). Each point below the line represents a patient whosecondition improved between baseline and last visit, and every point above thisline a patient whose condition deteriorated. From: Mathias CJ, Senard J-M, BrauneS, Watson L, Aragishi A, Keeling J, Taylor M. L-threo-dihydroxphenylserine (L-threo-DOPS; droxidopa) in the management of neurogenic orthostatichypotension: a multi-national, multi-centre, dose-ranging study in multiplesystem atrophy and pure autonomic failure. Clin Aut Res 2001, 11; 235–242.

27

most effective in reducing OH. Even with this dosemean levels of supine blood pressure were not ele-vated after acute or chronic dosage. The drug re-mained efficacious 28 days of treatment.

In this study up to 900mg of Droxidopa was usedeach day, and adverse effects on heart rate wereanalysed. There was neither bradycardia nor tachy-cardia with any of the doses, at day 0 or after 28 daysof treatment.

The majority of patients in this study had mild tomoderate symptoms of dizziness, tiredness and visualdisturbance. There was no loss of consciousness be-fore or after drug or placebo treatment. There was anoverall trend towards improvement in symptoms butthis did not reach statistical significance. The reasonsfor the apparent dissociation between objectiveimprovement in OH and subjective reduction insymptoms remains unclear. It may reflect the differ-ent individual characteristics of each group, orinsensitivity of the symptom scales used.

Droxidopa was well tolerated, with similar adverseeffects in each of the treatment groups when com-pared with placebo. Most of the symptoms were mild.One patient had supine hypertension.

In summary, therefore, 300 mg tid of Droxidopawas more effective than either 100 or 200 mg in themajority of patients with MSA or PD. It was welltolerated and with few side effects.

Droxidopa in patients on dopa decarboxylaseinhibitors

Dopa decarboxylase is essential for the conversion ofDroxidopa into noradrenaline and would be expectednoradrenaline to reduce the formation of a dopadecarboxylase inhibitor and thus the prodrugs pres-

sor effect. In each of the studies described there werepatients treated with a combination of L-dopa anddopa decarboxylase inhibitors. In the first study theseincluded MSA patients, and in the second both MSAand PD patients.

There were no obvious differences in the beneficialresponse of Droxidopa in the first study with patientson a dopa decarboxylase inhibitor. Similar observa-tions were made in the second study, where over 80%of the PD patients were on a dopa decarboxylaseinhibitor. In a previous study in 4 PAF and 2 MSApatients, pre-treatment with 200mg of the dopadecarboxylase inhibitor Carbidopa, prior to Droxid-opa, blunted the pressor effects of Droxidopa [2].Plasma noradrenaline levels rose from 294 ± 80 to806 ± 235 pg/mL in Droxidopa treated patientscompared to 216 ± 125 to 407 ± 271 after Droxidopatreated patients had been pretreated with Carbidopa,which thus attenuated, but did not abolish, the rise inlevels of plasma noradrenaline. It is important to notethat the dose of carbidopa used in this study [2] wassubstantially higher than the dose used in clinicalpreparations when combined with l-dopa, these usu-ally being 25mg for 100mg of l-dopa. In each of theEuropean studies reported there was a beneficialpressor effect of Droxidopa despite the presence of adopa decarboxylase inhibitor; this may reflectincomplete inhibition of dopa decarboxylase with theclinical preparations used to treat the motor deficits.The pressor effect may even have been higher withoutan inhibitor.

Conclusions

Treatment with Droxidopa, which results in theformation of noradrenaline, has been demonstrated

0

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Fig. 2 Transition table for the symptom ‘‘Light-headedness. Dizziness’’ Analysis group: Overall,N = 32. (0 = not at all, 10 = very severe). Each *represents one patient (p = 0.0125). From:Mathias CJ, Senard J-M, Braune S, Watson L,Aragishi A, Keeling J, Taylor M. L-threo-dihydroxphenylserine (L-threo-DOPS; droxidopa) inthe management of neurogenic orthostatichypotension: a multi-national, multi-centre, dose-ranging study in multiple system atrophy and pureautonomic failure. Clin Aut Res 2001, 11; 235–242.

28

in two pan European studies to be effective, welltolerated and safe when used to treat orthostatichypotension in patients with pure autonomic fail-ure, multiple system atrophy, and Parkinson’s dis-ease.

j Acknowledgements Major investigators have included ProfessorP Cortelli, Professor J M Senard, and many colleagues in partici-pating centres.

Disclosure Prof. C.J. Mathias was the Principal Investigator of bothstudies reviewed, which were supported by Sumitomo Pharma-ceuticals, Japan. He is a Consultant for Chelsea Therapeutics, USA.

References

1. Heims HC, Martin NH, Critchley HD,Jager HR, Mathias CJ, Cipolotti L.(2006). Cognitive functioning in or-thostatic hypotension due to pure au-tonomic failure. Clin Aut Res 16:113–120

2. Kaufmann H, Saadia D, VoustianioukA, Goldstein DS, Holmes C, Yahr MD,Nardin R, Freeman R. (2003) Norepi-nephrine precursor therapy in neuro-genic orthostatic hypotension.Circulation. 108:724–728

3. Lahrmann H, Cortelli, Hilz M, MathiasCJ, Struhal W, Tassinari M. (2006)European Federation of NeurologicalSociety guidelines on the diagnosis andmanagement of orthostatic hypoten-sion. Europ J Neurol 13:930–6

4. Man in’t Veld AJ, Van den MeirackerAH, Boomsma F, Schalekamp MADH.(1987) Effect of unnatural noradrena-line precursor on sympathetic controland orthostatic hypotension in dopa-mine beta-hydroxylase deficiency.Lancet ii:1172–5

5. Mathias CJ, Bannister R, Cortelli P,Heslop K. Polak J, Raimbach SJ,Springall DB, Watson L. (1990) Clinicalautonomic and therapeutic observa-tions in two siblings with posturalhypotension and sympathetic failuredue to an inability to synthesize nor-adrenaline from dopamine because of adeficiency of dopamine beta-hydroxy-lase. QJM, New Series 75(278):617–633

6. Mathias CJ, Mallipeddi R, Bleasdale-Barr K. (1999) Symptoms associatedwith orthostatic hypotension in pureautonomic failure and multiple systematrophy. J Neurol 246(10):893–898

7. Mathias CJ, Senard J-M, Braune S,Watson L, Aragishi A, Keeling J, TaylorM. (2001) L-threo-dihydroxphenylser-ine (L-threo-DOPS; droxidopa) in themanagement of neurogenic orthostatichypotension: a multi-national, multi-centre, dose-ranging study in multiplesystem atrophy and pure autonomicfailure. Clin Aut Res 11:235–242

8. Mathias CJ, Bannister R. (2002) Dopa-mine beta-hydroxylase deficiency. In:Mathias CJ, Bannister R, (eds.) Auto-nomic failure. A textbook of clinicaldisorders of the autonomic nervoussystem. 4th ed. Oxford and New York:Oxford University Press pp. 387–401

9. Mathias CJ. (2003) Autonomic diseases– clinical features and laboratory eval-uation. JNNP 74:31–41

10. Mathias CJ. (2003) Autonomic diseases– Management. JNNP 74:42–47

11. Mathias CJ. (2005) CardiovascularAutonomic Dysfunction in Parkinson’sDisease and Parkinsonian Syndromes.In: Ebadi M, Pfeiffer RF. (Eds.) Par-kinson’s Disease. CRC Press LLC, NewYork 295–317

12. Mathias CJ. (2006) Orthostatic hypo-tension and orthostatic intolerance. In:DeGroot LJ, Jameson JL, de Kretser D,Grossman AB, Marshall JC, Melmed S,Potts JT, Weir GC. (Eds.) Endocrinol-ogy. 5th edition. Elsevier Saunders,Philadelphia PA, USA 2613–2632

13. Mathias CJ, Senard JM, Cortelli P.(2007) A double-blind, randomized,placebo-controlled study to determinethe efficacy and safety of droxidopa inthe treatment of orthostatic hypoten-sion associated with multiple systematrophy or Parkinson’s disease. ClinAut Res 17:272. abstract

14. Narabayashi H, Nakanishi T. (1987)Therapeutic effects of L-DOPS in Par-kinson’s disease, double-blind com-parative study against placebo ascontrol in patients with long-termlevodopa therapy. Clin Eva1 15:423–457

15. Robertson D, Goldberg MR, Onrot J,Hollister AS, Wiley R, Thompson JG,Robertson RM. (1987) Isolated failureof autonomic noradrenergic neuro-transmission. Evidence for impairedbeta-hydroxylation of dopamine NewEngl. J. Med 314:1494–7

16. Sobue I, Senda Y, Hirayama K, et al.(1987) Clinical pharmacological evalu-ation of L-threo-3-4-dihydroxyphenyl-serine (L-DOPS) in Shy-Drager’ssyndrome and its related diseases. Anationwide double-blind comparativestudy. Jpn J Clin Exp Med 141:353–378

17. Suzuki T, Higa S, Sakoda S, et al. (1982)Pharmacokinetic studies of oral L-threo-3,4-dihydroxyphenylserine innormal subjects and patients withfamilial amyloid polyneuropathy. Eur JClin Pharmacol 23:463–468

18. Yanagisawa N, Ikeda S, Hashimoto T,Hanyu N, Nakagawa S, Fujimori N,Ushiyama M. (1998) Effects of L-threo-Dops on orthostatic hypotension inParkinson’s disease. No To Shinkei50:157–63

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