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March 2008 • Volume 18 • Supplement 1
Clinical Autonomic Research
Official Journal of the American Autonomic Society,
Clinical Autonomic Research Society and
European Federation of Autonomic Societies
Clinical Autonomic Research
Indexed in Current Contents, Medline, SCI and SCOPUS
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Pathophysiology, prevalence and treatment
Horacio Kaufmann
(Editor)
March 2008 • Vol. 18 • Suppl. 1
123
SUPPLEMENT
Update on Neurogenic Orthostatic Hypotension
www.car.springer.de
Clinical
Autonomic
Research
FACULTY
This supplement is based on a symposium that took place in New York City
on April 20, 2007. Distinguished faculty met to discuss recent advances in
orthostatic hypotension and what the future holds.
Horacio Kaufmann, MD
F.B. Axelrod Professor of Neurology
Professor of Medicine and Pediatrics
New York University School of Medicine
David Robertson, MD, FACP
Elton Yates Professor of Medicine
Professor of Pharmacology and Neurology
Vanderbilt University
Phillip A. Low, MD
Professor of Neurology
Mayo Clinic College of Medicine
Roy Freeman, MB, ChB
Professor of Neurology
Harvard School of Medicine
Christopher J. Mathias, PhD
Professor Neurovascular Medicine
Imperial College School of Medicine
University College London
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Clinical
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Research
CONTENTS
Volume 18 Æ Supplement 1 Æ March 2008
Update on neurogenic orthostatic hypotension
Pathophysiology, prevalence and treatment
Horacio Kaufmann (Editor)
j INTRODUCTION
H. Kaufmann
Neurogenic orthostatic hypotension: New prospects in treatment. . . . . . . . . . 1
j ARTICLES
D. Robertson
The pathophysiology and diagnosis of orthostatic hypotension . . . . . . . . . . . 2
P.A. Low
Prevalence of orthostatic hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
R. Freeman
Current pharmacologic treatment for orthostatic hypotension . . . . . . . . . . .
14
H. Kaufmann
L-dihydroxyphenylserine (Droxidopa): a new therapy for neurogenic
orthostatic hypotension
The US experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
C.J. Mathias
L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic
hypotension
The European experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
This supplement is supported by an educational grant from Chelsea Therapeutics, Inc.,
Charlotte, North Carolina
www.chelseatherapeutics.com
Cover design by Fabio Cutro
25
Clin Auton Res (2008) 18[Suppl 1]:1
DOI 10.1007/s10286-008-1006-6
INTRODUCTION
Neurogenic orthostatic hypotension:
New prospects in treatment
Neurogenic orthostatic hypotension is a disorder of
noradrenergic neurotransmission. Upon standing,
without norepinephrine release from postganglionic
sympathetic terminals, vascular resistance does not
increase to compensate for the gravitational volume
shift and blood pressure falls. This compromises
blood supply to vital organs, particularly the brain.
In this supplement of Clinical Autonomic Research,
five experts from different medical centers in the
United States and the United Kingdom discuss recent
advances in our understanding and treatment of
neurogenic orthostatic hypotension. David Robertson
describes the spectrum of blood pressure disorders,
and why patients with orthostatic hypotension are so
severely impaired, sometimes unable to stand for
more than a few seconds without losing consciousness. Phillip Low reviews the prevalence of neurogenic orthostatic hypotension, which increases with
age and in neurodegenerative diseases, particularly
Parkinson’s disease and multiple system atrophy. A
review of the currently available pharmacological
therapies for the management of orthostatic hypotension by Roy Freeman makes it clear that more
effective therapies are needed. In the next two articles,
I review recent phase II studies of the norepinephrine
precursor droxidopa conducted in the United States
and Christopher Mathias reviews clinical trials conducted across Europe.
Based on the success of the preliminary studies
with droxidopa, large multicenter phase III clinical
trials have begun recently both in the United States
and Europe. The hypothesis that led to the use of this
artificial aminoacid is elegant. Replenishing a missing
neurotransmitter by a precursor aminoacid has a
successful history in neuropharmacology with the
treatment of Parkinson’s disease. In the case of
droxidopa, the precursor aminoacid is converted in
the body into norepinephrine, replenishing the
missing neurotransmitter in autonomic failure. The
similarities between droxidopa and levodopa are
immediately apparent. Droxidopa has one added beta
hydroxyl group; otherwise, the molecules are identical. Droxidopa is not a new agent. It is not available in
the United States or Europe, but it has been available
in Japan for over 25 years and has an excellent safety
record. Both the United States and the European trials
of droxidopa indicate that the agent is effective with a
unique mechanism of action. These are good reasons
to be optimistic that the drug will soon be available
for patients in the United States and Europe.
Treatment of neurogenic orthostatic hypotension
with droxidopa, the precursor of the missing neurotransmitter, is a promising therapeutic approach. If
successful, still needed, of course, are means to modulate the autonomic response so that the increase in
norepinephrine would occur at the appropriate times.
Similar challenges were faced by levodopa in the
treatment of Parkinson’s disease. Fortunately, the enzymes involved in catecholamine metabolism are now
well known and they have already been the targets of
therapeutic strategies in combination with levodopa.
Horacio Kaufmann, MD
CAR 1006
Clin Auton Res (2008) 18[Suppl 1]:2–7
DOI 10.1007/s10286-007-1004-0
David Robertson
Received: 15 June 2007
Accepted: 30 June 2007
D. Robertson, MD
Autonomic Dysfunction Center
Depts. of Medicine and Pharmacology
Vanderbilt University
AA 3228 Medical Center North
1161 21st Avenue South
Nashville (TN) 37323-2195, USA
Tel.: +1-615/343-8633
Fax: +1-615/343-8649
E-Mail: [email protected]
ARTICLE
The pathophysiology and diagnosis
of orthostatic hypotension
j Abstract Orthostatic Hypoten-
sion (OH) is a common manifestation of blood pressure
dysregulation. OH takes a heavy
toll on quality of life. It has many
potential etiologies, and many
effects of aging can increase susceptibility to OH. Neurological
disorders are especially likely to
cause severe OH. In this brief
review, the pathogenesis of OH is
considered, particularly in terms
of autonomic neuropathy, multiple system atrophy (MSA), pure
autonomic failure, baroreflex failure, and dopamine beta hydroxylase deficiency. While OH is
difficult to treat, its control greatly
enhances the quality of life.
CAR 1004
Cardiovascular dysregulation
Disorders of cardiovascular dysregulation encompass
a broad spectrum all the way from very low pressures
to very high pressures. Some of these disorders are
depicted in Fig. 1, where the broad middle group includes the great majority of individuals, those with
normal blood pressures. On the right, hypertension
includes approximately 10% of the population; these
patients have blood pressures that are elevated while
they are lying, while they are standing and while they
are upright. Separating the hypertensive patients from
normal are the labile hypertensive patients, who occupy the controversial and ill-defined borderland of
pressures ranging from 120/80 to 140/90. Conversely,
j Key words orthostatic hypotension Æ orthostatic hypertension Æ autonomic Æ syncope Æ
fainting
on the left extreme, are patients with low blood
pressure when standing, usually normal blood pressure while seated, and sometimes high blood pressure
while lying down. These are individuals with orthostatic hypotension (OH). Between this group and
normal subjects are patients with the milder dysautonomias, postural tachycardia syndrome [13; 24]
(POTS) and neurally mediated syncope (NMS). POTS
patients have orthostatic tachycardia and symptoms
of sympathetic activation on standing, while NMS
patients usually have normal pressures in all postures,
but occasionally have ‘‘fainting’’ associated with a
brief, usually less than 1 min, hypotension and/or
bradycardia. POTS and NMS patients do not usually
have OH, and that is why their disorders are often
classified as ‘‘milder dysautonomias’’; patients with
3
OH
POTS
NMS
Normotension
Bradycardia/hypotension
Orthostatic tachycardia
Labile
HBP
HBP
asymptomatic
symptomatic
Orthostatic hypotension
1 sec
UPRIGHT
SUPINE
Fig. 1 Cardiovascular dysregulation. OH: orthostatic hypotension; POTS:
postural tachycardia syndrome; MNS: neurally mediated syncope; HBP: high
blood pressure
these disorders do not usually consider them mild in a
general sense.
There is one very important difference between
approaches to treatment at the right and left ends of
this spectrum. On the right, the blood pressure perturbation usually has no associated symptoms. We do
not treat these patients to make them feel better. We
treat them to try to prevent complications of hypertension perhaps 20 or more years down the line. On
the other hand, people on the left extreme have
symptoms that are often quite devastating. Such
patients need help today. So, our strategy in these
patients is to improve their functional capacity today,
make them feel better, keep them active, and our
focus is one of quality of life today. Many of the same
medicines used to treat OH are also used in an effort
to treat POTS and NMS. Beta blockers have sometimes been used in all categories of cardiovascular
dysregulation depicted in Fig. 1, though the rationale
for their use in NMS and OH is questioned.
Orthostatic hypotension
Orthostatic hypotension is defined as a fall of systolic
blood pressure of at least 20 mmHg or a fall of diastolic blood pressure of at least 10 mmHg within
3 minutes of standing [20]. It is a physical finding and
not a diagnosis; so it may be symptomatic or
asymptomatic. Most people who are symptomatic
from OH have a much greater fall in pressure on
standing. Thus this is a very broad definition, and
perhaps 50% of elderly patients might occasionally
meet these criteria [3]. Evaluation and therapy are
therefore primarily driven by symptoms.
Physiology of standing
Why do people get orthostatic hypotension? At one
level the pathophysiology is quite straightforward.
1 min
UPRIGHT
30 min
UPRIGHT
First blood pooling, then plasma loss
Fig. 2 Postural hemodynamics
When we stand, there is about 500–1,000 ml of blood
that goes from the upper body to the lower body,
primarily the lower abdomen, buttocks, and legs. In
response to this, there are compensatory effects from
activation of the sympathetic nervous system, the
renin-angiotensin system, and consequent aldosterone release. These come into play to help maintain
cardiac output during the stress of upright posture.
Because upright posture is a relatively late evolutionary development, our mechanisms for maintenance of upright posture may still be under
considerable genetic pressure.
Orthostatic blood volume shift
While an individual is lying down, blood volume is
distributed throughout the body as depicted in Fig. 2.
The second frame in the figure shows that same distribution in a theoretical instantaneously upright
transition. But in the third frame, it can be seen that
by 1 min of upright posture, the shift of perhaps
500 ml of blood to the lower part of the body is well
advanced. The next phenomenon, depicted in the
fourth frame, is perhaps even more important in the
real world of OH management. It illustrates that after
the pooling of blood, there is a period of 20–30 min
during which substantial loss of plasma volume from
the blood into the tissues occurs. This produces at
least as great a challenge to the cardiovascular system
as the more widely appreciated pooling of blood depicted in frame 3. Indeed, in healthy subjects, there is
a 14% fall in plasma volume within 20 min after
assumption of the upright posture, most of which
occurs within the first 10 min. That 14% translates
into about 430 ml of blood, close to the amount taken
in a blood donation. Since the cellular component of
the blood remains in the circulation, even the
hematocrit, if you measure it carefully, changes, perhaps rising from 37 to 41 (Fig. 3). The lower hematocrit of the supine posture occasionally puts
4
2900
PV (ml)
Male Black & White
2800
HR
84
Tilt
to 75 degr
123/67
2700
85
86
72/39
59/42
BP
2600
hematocrit
2500
Female
52 years
MSA
2400
2300
37
41
2200
2100
supine
upright
Fig. 4 Orthostatic hypotension in autonomic failure
Fig. 3 Plasma volume shift and hematocrit
otherwise healthy persons into the usually accepted
‘‘anemia’’ range of hematocrit, and has therefore been
called ‘‘postural pseudoanemia [9]’’ for that reason.
Thus, much of the ‘‘noise’’ in hematocrit measurement in clinical practice is actually not noise but
reflective of changes in blood related to patient’s
posture in the time leading up to the sampling.
This volume shift is reflected in BP during continuous blood pressure monitoring in a patient with OH.
You can see in Fig. 4 that during monitoring after a
patient with OH stands for about 20 min, the blood
pressure does not so much plummet immediately, but
rather transitions downward over a few minutes as the
pooling first and then the plasma volume shift become
sequentially engaged. It is noteworthy that many patients with chronic OH tolerate degrees of hypotension
that are quite low, at least for a few minutes.
commonly with syncope in susceptible individuals. It
is due to a mismatch based on an initial increase in
venous return, increase in right atrial pressure, and
overcompensation, accompanied by the muscle-derived late dilatation in the legs due to the act of
standing. Delayed orthostatic hypotension (DOH) has
recently been systematically studied by Freeman and
his collaborators [6]. They found that among 230
people who ultimately had OH; either on standing or
on the tilt table, 46% had OH within 3 min, but another 15% had OH in the 3–10 min interval, and then
over the next half hour or so, an additional 39%
manifested orthostatic pressures. The latter tended to
be younger patients, and many fell into the category
of POTS.
Orthostatic hypertension
Types of orthostatic hypotension
The interaction between the brain and the cardiovascular system in blood pressure control is paramount, and this has lead to an expansion of our
understanding of the different kinds of abnormalities
which occur on standing. First we now recognize that
in addition to the OH we commonly recognize between 1 min and 3 min of standing, there is both an
earlier form of OH (‘‘initial orthostatic hypotension’’,
IOH [26] and a later form developing between 5 min
and 45 min (‘‘delayed orthostatic hypotension’’ [5],
DOH). IOH occurs immediately upon standing and is
detectable only by beat-to-beat blood pressure monitoring [12]. This occurs at a time when many normal
subjects, on arising from overnight sleep, may have a
transient sense of impaired cerebral blood flow, but
this typically goes away in a few seconds. However,
falls of 40/20 mmHg in the first 15 s of standing are
sometimes seen, and this period is associated fairly
Perhaps surprisingly, some patients have orthostatic
increases rather than decreases in blood pressure
when they stand. These individuals display orthostatic
hypertension [2; 23]. The more severely affected patients have relatively rare disorders such as baroreflex
failure [11], mast cell activation disorder (mastocytosis) [22], hyperadrenergic POTS, or pheochromocytoma.
Signal amplification in dysautonomias
Patients with OH due to autonomic impairment have
a range of remarkable clinical characteristics. Many of
these derive from the loss of buffering reflexes. The
baroreflex keeps blood pressures from having excessively large excursions; preventing pressure from
getting too high when there is a pressor stimulus and
preventing pressure from getting too low when there
is a depressor stimulus. When the baroreflexes fail,
5
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
stimuli that would not do very much in healthy persons may have a big impact on blood pressure in a
patient with OH due to autonomic failure. There is
thus huge signal amplification in going from normal
individuals to individuals with autonomic dysfunction. There are a number of interesting consequences
of this. For example; food lowers blood pressure in
healthy individuals by only 1 mmHg, but in people
with autonomic dysfunction, food may lower blood
pressure by 40 mmHg [14; 19], and they may pass out
when they try to stand after finishing a meal. Conversely 16 ounces of water can raise blood pressure
about 40 mmHg in the hour or so after it is ingested
[21]. This effect and that of food can sometimes be
harnessed by patients to benefit blood pressure control. Some drugs such as clonidine, which are used to
lower blood pressure in hypertension, may display a
pressor effect in autonomic failure as there is both
hypersensitivity of vascular alpha adrenoreceptors
and loss of baroreflex buffering. Likewise, the tachycardic (beta-1) effect of isoproterenol (Isuprel) is 6fold elevated in the OH of autonomic failure. The
depressor (beta-2) effect of isoproterenol is 17-fold
elevated in this disorder [18]. Just half of a 5 mg oral
terbutaline tablet, such as is used in asthma without
notable depressor effect, is capable of reducing supine
blood pressure by half in a patient with autonomic
failure.
Predisposing factors for orthostatic hypotension
There are a number of predisposing factors for OH,
including dehydration, deconditioning, poor nutrition or the bodily changes that occur with aging
(Table 1). The latter factors lead to more vulnerability to OH in the aging population. There are drugs
administered for other conditions that may concomitantly cause OH. The tricyclic antidepressants
in chronic use have long been recognized as a cause
of OH, and of course antihypertensive agents and
diuretics can do this as well. Vasodilators like
nitroglycerin, hydralazine, and calcium channel
blockers can also cause OH. A commonly unrecog-
•
•
•
•
•
•
Impaired papillary function; dry eyes
Orthostatic hypotension and supine hypertension
Reduced gastrointestinal motility, gastroparesis, constipation or diarrhea
Bladder dysfunction
Male erectile dysfunction
Impaired sweating
nized cause of OH nowadays is tizanidine (Zanaflex).
This problem arises simply because people are not
expecting this side effect. Tizanidine is used as a
muscle relaxant in fibromyalgia. Patients generally
say it helps their condition, but it also is an alpha-2
agonist and therefore has clonidine-like effects, and
so may cause episodic OH at the time of the major
effects of the drug.
Causes of orthostatic hypotension
Several neurological conditions (Table 2) give rise to
OH. Autonomic neuropathy [25] may sometimes occur in relatively pure form, and is recognized by its
spectrum of autonomic manifestations (Table 3). It
encompasses what used to be called acute pandysautonomia, but also includes many cases of what is
termed pure autonomic failure, owing to early conflation of the two pathophysiologies. Typically, it has
an onset over days to weeks. There is sympathetic
failure with OH and anhidrosis, which may be very
severe and then characteristically parasympathetic
failure is pronounced. Gastrointestinal, urological,
and sicca changes are usually a hint that autonomic
neuropathy 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 of
nicotinic receptor at the critical ganglion synapse
where autonomic function is transduced. It may account for up to 50% of these patients; so assessing
that antibody in the paraneoplastic panel identifies
these individuals. Pure autonomic failure was
described in the classical paper of Bradbury and
Eggleston in 1925. It is characterized by severe OH;
insidious onset, slow progression, modest gastrointestinal impairment, marked supine hypertension,
6
and often very low plasma norepinephrine levels [10].
Other neurological systems are not involved. These
people have a very good prognosis and often live
decades, and we have several patients who have lived
into their 90s with this. Parkinson’s disease with
autonomic failure is associated with sympathetic
neuropathy, and OH occurs in some, but not all
Parkinson’s disease patients [8]. The hypotension in a
few of them can be quite severe and MIBG or PET
studies may help detect that, although we do not have
good benchmarking for these tests yet. Dementia with
Lewy Bodies is important to recognize in individuals
with some Parkinsonian features, but progressive
cognitive decline in these people may be more dramatic, and include visual hallucinations. The autonomic failure and some of the cognitive aspects can
improve with cholinesterase inhibition. Multiple system atrophy (MSA) is very difficult problem because
it involves not only the autonomic but also cerebellar
and extrapyramidal systems [17]. MSA has the
severest outlook of any dysautonomia. Sleep apnea
also occurs commonly in MSA.
Dopamine beta-hydroxylase (DBH) deficiency is
an extremely rare but instructive disorder, because it
is a notable success story in terms of both diagnosis
and therapy. The specific gene defect is in the DBH
enzyme which produces norepinephrine from dopamine. Patients with this have severe OH, exercise
intolerance, and usually ptosis of the eyelids. Erectile
function (primarily parasympathetic) is not prevented but retrograde ejaculation (due to sympathetic failure) occurs. These patients have no
norepinephrine in their neurons and instead they
have stoichiometric replacement of norepinephrine
by its precursor dopamine. DBH deficiency is
interesting to us because it is one example where we
get almost a ‘‘Lazarus’’ effect in response to droxidopa. Droxidopa is essentially a norepinephrine
molecule to which a carboxyl group is attached [7].
This enables it to be absorbed orally, get past the
liver and into the circulation where it is a substrate
for the norepinephrine transporter and gets pumped
into the sympathetic neuron. Within the neuron, and
at other sites, droxidopa is decarboxylated to
endogenous
neurotransmitter
norepinephrine,
restoring sympathetic function. We reported a DBH
deficiency patient in 2005 who, in her early 20s, was
only able to stand erect for about 2 min before
therapy, but after she was placed on droxidopa she
rapidly began to be able to do many more things,
and took up running, first tentatively but ultimately
in an increasingly athletic fashion. After about a year
of training she successfully completed the 26 mile
New Orleans Marathon [4]. Completion of this
benchmark reflected both the drug and this patient’s
determination.
The alien landscape of orthostatic
hypotension
j Orthostatic regulation of drug levels
Liver blood flow (LBF) in humans is posture
dependent. In healthy subjects, LBF is 5% less in the
seated posture than in the supine posture, but in
patients with OH that LBF decrement is a whopping
30%. A consequence of this is that drugs like lidocaine which are removed from the blood by first
pass hepatic clearance will display dramatically
posture-dependent plasma levels. When orthostatic
hypotensive patients are receiving intravenous lidocaine, levels of the drug are almost twice as high
when they are seated as when they are supine. Sitting
up can so elevate plasma lidocaine levels that seizures may occasionally be provoked when patients
with autonomic failure sit up [1].
j Garden hose ‘‘therapy’’ of orthostatic
hypotension
In OH due to autonomic failure, hyperventilation
reduces blood carbon dioxide and this is attended by
rapid fall in blood pressure in subjects with OH,
sometimes 40 mHg within 60 s. Since hyperventilation may occur with physical exertion, this effect
contributes to the depressor effect of exercise. Conversely, breathing through a dead space increases
carbon dioxide concentration in inspired air, and the
effect of this is to raise blood pressure 20 mHg or
more. Some patients are so sensitive to this effect that
they can stand longer while breathing through a short
length of garden hose [15].
j Afebrile hypotension as presentation of infection
Patients with severe autonomic failure have impaired
capacity to manifest a fever in response to infection.
Instead they present with an acute fall in blood
pressure and a greatly reduced functional capacity.
Such infections tend to be in the urinary tract or the
lung. When patients note a substantial acute decrement in their functional capacity, they should have
urinalysis and a chest examination to rule out infection [16].
j Wet shirt therapy in hot weather
When the hypohidrosis in autonomic failure is severe,
the inability to perspire can lead to temperature elevation in patients exposed to hot weather (>90 F).
This increase in temperature leads to a fall in blood
7
pressure and the patient feels greatly fatigued, and
may only be able to tolerate this temperature for a few
minutes. Providing ‘‘artificial perspiration’’ in the
form of a wet shirt will help speed heat dissipation
and allow more tolerance of hot weather with maintenance of a higher blood pressure. Usually the wet
shirt will provide benefit for about an hour before it
must be re-wetted [16].
j Acknowledgements The help of my colleagues in Vanderbilt’s
Autonomic Dysfunction Center is acknowledged. I thank Ms Ella
Henderson for help in the preparation of this manuscript. Supported in part by the U.S. Public Health Service: P01-HL56693, R01
HL71784, and RR 00095.
j Disclosure Dr. Robertson has served as a consultant for Chelsea
Therapeutics.
References
1. Feely J, Wade D, Mcallister CB, Wilkinson GR, Robertson D (1982) Effect of
hypotension on liver blood-flow and
lidocaine disposition. New Eng J Med
307:866–869
2. Fessel J, Robertson D (2006) Orthostatic
hypertension: when pressor reflexes
overcompensate. Nat Clin Pract Nephrol 2:424–431
3. Forman DE, Lipsitz LA (1997) Syncope
in the elderly. Cardiol Clin 15:295–311
4. Garland EM, Raj SR, Demartinis N,
Robertson D (2005) Case report: Marathon runner with severe autonomic
failure. Lancet 366(Suppl 1):S13
5. Gibbons CH, Freeman R (2006) Delayed
orthostatic hypotension: a frequent
cause of orthostatic intolerance. Neurology 67:28–32
6. Gibbons CH, Freeman R (2006) Delayed
orthostatic hypotension: a frequent
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refractory orthostatic hypotension in
autoimmune autonomic neuropathy.
Neurology 65:1104–1106
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Pechnik S, Moak J, Saleem A, Sharabi Y
(2005) Neurocirculatory abnormalities
in Parkinson disease with orthostatic
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1339
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Biaggioni I, Ertl AC, Robertson D
(2005) Postural pseudoanemia: posturedependent change in hematocrit. Mayo
Clin Proc 80:611–614
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Accumulation of alpha-synuclein in
autonomic nerves in pure autonomic
failure. Neurology 56:980–981
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baroreflex failure - Hypertensive crisis,
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tachycardia, and malignant vagotonia.
Circulation 105:2518–2523
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Linzer M, van Lieshout JJ, Wieling W
(2007) Management of initial orthostatic hypotension: Lower body muscle
tensing attenuates the transient arterial
blood pressure decrease upon standing
from squatting. Clin Sci (Lond)
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Benarroch EE, Shen WK, Schondorf R,
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Neurology 45:S19–S25
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Cardiol 48:1048–1052
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(2000) Water drinking: an effective
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Clin Auton Res (2008) 18[Suppl 1]:8–13
DOI 10.1007/s10286-007-1001-3
Phillip A. Low
Received: 14 June 2007
Accepted: 30 June 2007
P.A. Low, MD
Department of Neurology
Mayo Clinic
200 First Street SW
Rochester (MN) 55905, USA
Tel.: +1-507-2843375
Fax: +1-507-2843133
E-Mail: [email protected]
ARTICLE
Prevalence of orthostatic hypotension
j Abstract Orthostatic hypoten-
sion (OH) is defined as a fall in
blood pressure of at least
20 mmHg systolic or 10 mmHg
diastolic when standing or during
head-up tilt testing. The prevalence of OH increases with age,
with disorders that affect autonomic nerve transmission, and
with increasingly severe orthostatic stress. In normal elderly
subjects, the prevalence of OH is
reported to be between 5 and 30%.
The actual prevalence depends on
the conditions during diagnostic
testing, such as the frequency of
blood pressure recordings, the
time of day and the degree of
orthostatic stress. Elderly subjects
are often taking medications, such
Orthostatic hypotension (OH) is a dynamic state and
not a disease in itself or necessarily a pathologic entity. Cross-sectional prevalences primarily reflect the
influence of age (Fig. 1), but to some degree also reflect the effects of medications, the degree of orthostatic stress, and the presence of abnormalities of the
autonomic nervous system. This review considers the
prevalence of OH in particular settings (such as longterm care facilities and outpatient clinics), and the
prevalence of OH in patients with autonomic disorders associated with OH.
CAR 1001
OH in the normal aging population
The cross-sectional prevalence of OH in unselected
elders, aged 65 years or older, has been reported to be
as antihypertensives and diuretics
that can cause or aggravate OH.
Neurological diseases such as diabetic neuropathy, Parkinson’s
disease, multiple system atrophy
and the autonomic neuropathies
further increase the likelihood of
OH. The development of OH in
normal subjects is associated with
an increased mortality rate. OH in
diabetes is also associated with a
significant increase in mortality
rate.
j Key words orthostatic hypotension Æ aging Æ neuropathy Æ
mortality Æ prevalence Æ
autonomic nervous system
between 5 and 30% [9, 13, 15, 22, 27]. The difference in
these estimates varies due to a number of factors, such
as the definition of OH, the segment of the population
studied (age range, institutions), the composition of
the population (healthy population versus select
groups), the influence of medications and the level of
orthostatic stress. The prevalence appears to be similar
in North America [9], in Japanese in Hawaii [15] and
in Finns in Finland [27]. In all of these studies the
prevalence of OH increased with age.
Using the current standard of an orthostatic fall in
blood pressure by 20 mmHg systolic or 10 mmHg
diastolic within 3 min of standing up or during headup tilt, 5% of the normal healthy population in
Rochester, Minnesota has OH [10]. In the a multicenter, observational, longitudinal study by Rutan
et al. (1992) in 5,201 men and women aged 65 years
9
Fig. 1 The prevalence of OH increases with age. Prevalence rates of orthostatic
hypotension (OH) by 5-year age groups (71–74, 75–79, 80–84, and 85+) in the
Honolulu Heart Program cohort (n = 3,522). Masaki et al. [15]
or older at their initial examination, the prevalence of
asymptomatic OH (defined as a minimum fall in
systolic BP by 20 mmHg or in diastolic BP by
10 mmHg within 3 min of standing) was 16.2%.
When the criteria for defining OH also included those
in whom the procedure was aborted due to dizziness
upon standing, this prevalence increased to 18.2%.
The prevalence of symptomatic OH increased from
14.8% in subjects aged 65–69 years to 26% in subjects
85 years and older, clearly demonstrating the association between OH and aging [22].
OH and mortality rate
In a population-based study of 3,522 Japanese
Americans in Hawaii aged between 71 and 92 years,
Fig. 2 Kaplan–Meier survival curves by OH status. These
unadjusted Kaplan–Meier curves for all-cause mortality
by OH status show a gradual increase in mortality in
those free of OH at baseline, with an overall mortality
rate of 12% (n = 1,476) over the 13 years follow-up
period. For the OH group, by contrast, the slope of the
survival curve was considerably steeper, and at the end of
the follow-up period, 32% (n = 217) of participants had
died. Rose et al. [22]
Masaki et al. [15] reported that the prevalence of OH
was 6.9%, and again that the prevalence increased
with age (Fig. 1). They also found that the 4-year ageadjusted mortality rate was higher in those with OH
than in those without (56.6 versus 38.6 per 1,000
person-years). With Cox proportional hazards models, after adjusting for other risk factors, OH was a
significant independent predictor of 4-year all-cause
mortality, with a relative risk of 1.64 (95% CI 1.19 to
2.26). Furthermore, there was a significant linear
association between the change in systolic BP fall and
4-year mortality rate (P < 0.001), suggesting a doseresponse relationship [15].
Rose et al. [21] studied the association between OH
and a 13-year mortality among middle-aged black and
white men and women from the Atherosclerosis Risk
in Communities Study (from the year 1987 to 1989). At
baseline, 674 participants (5%) had OH. All-cause
mortality was higher among those with (13.7%) than
without (4.2%) OH (see Fig. 2). This association was
only partly explained by ‘‘traditional’’ risk factors [21].
OH in defined groups
Although not true prevalences, the presence of OH in
settings such as in nursing homes or outpatient clinics
is of interest. If the OH associated with aging is included, the ‘‘prevalence’’ is quite high in subjects
older than 70 years of age. Table 1 lists seven prevalences (as percentage of the affected group with OH)
in particular settings, taken from studies carried out
with similar criteria in subjects who were otherwise
generally healthy. These are perhaps the best estimates of the prevalence of OH based on current data.
Therefore, a reasonable estimate of prevalence in
10
Table 1 Estimated ‘‘Prevalence’’ of OH in certain settings
Setting
n
Age
‘‘Prevalence’’ Study reference
(years) (%)
Nursing home
Medical outpatient
VA Geriatric unit
Medical outpatients
Geriatric unit
Geriatric unit
Medical outpatient
250
494
319
186
272
247
300
61–91 11
‡65
24
50–99 10.7
‡65
22
83*
10
‡60
33
70*
6.4
Rodstein and Zeman [20]
Caird et al. [3]
Myers et al. [16]
MacLennan et al. [12]
Lennox and Williams [8]
Palmer et al. [18]
Mader et al. [14]
Data taken from seven studies carried out with similar criteria in elderly subjects 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
Diabetes
Diabetics-Type 1
Diabetics-Type 2
Parkinson’s disease
Parkinson’s disease
Parkinson’s disease
Other autonomic neuropathies
MSA
PAF
10–30%
10%*
8.4%
7.4%
47%
48%; 37%
58%
10–50 per 100,000
5–15 per 100,000
10–30 per 100,000
Table 2
Low et al. [10]
Low et al. [10]
Allcock et al. [1]
Wood et al. [29]
Senard et al. [25]
*Prevalence for adult combined IDDM and NIDDM for the Rochester
Diabetic Cohort for 1997 (PI: PJ Dyck)
ambulant older subjects, diagnosed during testing
with simple BP recordings, is between 10 and 30%.
j Diabetes and OH
OH and increasing orthostatic stress
When testing is done repeatedly and under conditions
of increased orthostatic stress, the percentage of subjects with OH increases. For instance, Ooi et al. [17]
evaluated 991 long stay residents 60 years of age and
older who were able to stand and took four sets of
supine and standing BP recordings before and after
breakfast and before and after lunch. They found that
13.3% of subjects had persistent OH, consistent with
the values reported in Table 1. However, they reported
that 51.5% of subjects had OH at least once and that
OH was most common first thing in the morning [17].
OH and medications
Another variable that impacts upon the prevalence of
OH in elderly subjects is the effect of medications. In a
Veteran Administration study of 342 veterans 75 years
or older, 55% (189/342) had OH, of whom 33% and
symptoms of orthostatic intolerance, and 52 patients
had falls [19]. There was a significant relationship
between the presence OH and the number of medications: with no drug 35% had OH; with one drug 58%
had OH; with two drugs 60% had OH; with three drugs
65% had OH. The antihypertensives Hydrochlorothiazide (65% OH) and Lisinopril (60% OH), the durietic
Furosemide (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 noradrenaline can cause OH. The prevalence of OH in
autonomic disorders is summarized in Table 2.
In a cohort of adult diabetic patients (insulindependent diabetes mellitus and non-insulin-dependent diabetes mellitus) evaluated at the Mayo Clinic
(Rochester, Minnesota) from 1987 to 1997 (mean age
over this decade 60 ± 12 years) 10% had OH. To
investigate the association between autonomic function and symptoms of OH a population-based study
in 148 diabetic patients (83 with Type 1 diabetes)
and 246 healthy controls was conducted. OH symptoms (assessed using the ‘‘Autonomic Symptom
Profile’’—a validated self-reporting instrument),
standardized autonomic function tests (cardiovagal,
adrenergic, sudomotor function), and a Composite
Autonomic Severity Score (CASS, which corrects for
the effects of age and gender [11]) were evaluated. A
CASS score of 1–3 was used for either sudomotor
and cardiovagal functional deficits and 0–4 for
adrenergic deficits. Autonomic neuropathy (defined
as a CASS score of 1 in at least 2 domains or ‡2 in
one domain) was found in 54% of Type 1 diabetes
and 73% of Type 2 diabetes. Despite the high
prevalence of autonomic dysfunction, OH was found
in only 8.4% (Type 1) and 7.4% (Type 2) of diabetic
patients.
j Autonomic failure and OH
Allcock et al. [1] estimated the prevalence of OH in
Parkinson’s disease in a population of 237,564 in the
county of Durham (UK). They identified 270 patients
with Parkinson’s disease of whom 104 (38.5%) agreed
to participate. They reported that 47% had OH [1], a
remarkably high incidence. Other reports in Parkinson’s disease outpatient cohorts have estimated the
prevalence of OH to be between 16 and 58% [25, 29].
OH is an integral feature of the autonomic neuropathies, pure autonomic failure (PAF), and multiple
11
Table 3 Causes of neurogenic orthostatic hypotension
The cause of OH and prognosis
1. AUTONOMIC DISORDERS WITHOUT CNS OR PNS INVOLVEMENT
Pure autonomic failure (PAF)
2. AUTONOMIC DISORDERS WITH BRAIN INVOLVEMENT
i. Multiple system atrophy (MSA)
ii. Wernicke Korsakoff syndrome
iii. Posterior fossa tumors
iv. Baroreflex failure
vi. Olivopontocerebellar atrophy
3. AUTONOMIC DISORDERS WITH SPINAL CORD INVOLVEMENT
i. Traumatic tetraplegia
ii. Syringomyelia
iii. Subacute combined degeneration
iv. Multiple sclerosis
v. Spinal cord tumors
4. AUTONOMIC NEUROPATHIES
I. The acute autonomic neuropathies
i. Autoimmune autonomic ganglionopathy (AAG; acute
pandysautonomia)
ii. Acute paraneoplastic autonomic neuropathy
iii. Guillain-Barre syndrome
v. Botulism
vi. Porphyria
vii. Drug induced acute autonomic neuropathies
viii. Toxic acute autonomic neuropathies
II. The chronic peripheral autonomic neuropathies
A. Pure adrenergic neuropathy
B. Combined sympathetic and parasympathetic failure
(Autonomic dysfunction clinically important)
i. Amyloid
ii. Diabetic autonomic neuropathy
iii. Paraneoplastic autonomic including panautonomic neuropathy
iv. Sensory neuronopathy with autonomic failure (most commonly
associated with Sjogren’s syndrome)
v. Familial dysautonomia (Riley-Day syndrome)
vi. Autoimmune autonomic neuropathy
vii. Dysautonomia of old age
system atrophy (MSA, Shy-Drager syndrome). The
prevalence as cases per 100,000 is provided in Table 2.
The causes of OH
The causes of neurogenic OH are shown in Table 3. The
diseases with the highest prevalence of neurogenic OH,
are MSA, PAF, diabetic autonomic neuropathy, autoimmune autonomic neuropathy and paraneoplastic
autonomic neuropathies. In specialist spinal cord injury practices, tetraplegia is a common cause of OH.
In a prospective study of 90 consecutive patients
referred with suspected OH, evaluated at the Mayo
Autonomic Laboratory, and confirmed to have OH,
the diagnoses were:
PAF
MSA
Idiopathic (autoimmune autonomic neuropathy)
Diabetic Autonomic neuropathy
Miscellaneous
Olivo-ponto-cerebellar atrophy
33%
26%
17%
14%
8%
2%
The prognosis depends on the specific disorder. Patients with classic MSA have a median survival of
about 7 years from the time of diagnosis [2]. Wenning
et al. [28], however, reported a median survival of
9.5 years, calculated by Kaplan–Meier analysis. Similar results have been reported [23], and the sporadic
OPCA variety has been suggested to have a longer
survival than the striatonigral variety [23]. The differences in survival time reported most likely relates
to the criteria used to define MSA.
The downhill course of patients with MSA is
marked by increasing rigidity, urinary incontinence,
and inspiratory stridor, which may require tracheotomy. Death in MSA is commonly due to respiratory obstruction or failure after worsening rigidity,
akinesia, and bladder disorder. With the appreciation of a spectrum of severities, an attempt has been
made to relate the severity and distribution of
autonomic and non-autonomic involvement to the
outcome. We reviewed the clinical and autonomic
features of all patients with extrapyramidal and
cerebellar disorders studied in the Mayo Autonomic
Reflex Laboratory from 1983 to 1989 [24]. OH, percentage of anhidrosis on thermoregulatory sweat
test, quantitative sudomotor axon reflex test, forearm
resistance response and heart rate response to deep
breathing strongly regressed with severity of clinical
involvement. The severity and distribution of autonomic failure at the time of first evaluation was
predictive of a greater rate of progression 2 years
later. Saito et al. [23] came to the same conclusion.
The earlier and more severe the autonomic nervous
system involvement (and to a lesser extent the striatonigral system involvement) the poorer the prognosis.
Information on the clinical features, progression
and outcome in PAF is somewhat limited. Some patients with PAF have continued relatively symptom
free for many years, with standing blood pressures as
low as 80 mmHg. The natural history of PAF is that of
a slow progression taking place over some 10–
15 years [2]. However, we should take into account
the difficultly in diagnosing PAF. About 10% patients
originally thought to have PAF turn out to have MSA.
Moreover, some patients are misdiagnosed as PAF,
and later found to have autoimmune autonomic
ganglionopathy [6] with A3 acetylcholine receptor
antibodies.
The development of OH worsens the prognosis of
patients with diabetic neuropathy. Ewing et al. [4]
reported a mortality rate of 50% at 2½ years in patients with symptomatic diabetic autonomic neuropathy. However, these patients had long-standing
12
clinical autonomic neuropathy and died of renal
failure. Subsequent studies suggest that autonomic
failure worsens prognosis, but less dismally than was
originally thought [5]. The clinical and laboratory
features of 229 patients with primary systemic amyloidosis seen at the Mayo Clinic reported that median
survival from the time of diagnosis for patients with
peripheral neuropathy, carpal tunnel syndrome, OH
and cardiac failure was 60, 45, 9.5, and 6.5 months,
respectively [7].
We have reviewed the Mayo Clinic experience
with idiopathic autoimmune autonomic neuropathy.
Patients seem to improve substantially over the first
year followed by a slower rate of improvement over
the subsequent 4 years [26]. Overall, approximately 1
in 3 patients makes a good functional recovery.
However, the majority of patients are left with a
chronic debilitating illness with significant residual
deficits.
For patients with OH associated with aging, the coexistence of OH is associated with a worse prognosis
[15].
Concluding thoughts
OH is a dynamic entity, it is frequent, and increases
with age. Indeed, it is likely to be present in most of
the elderly under circumstances of increased orthostatic stress. Its prevalence is further increased in
certain neurologic disorders. The presence of OH
worsens prognosis and increases mortality.
j Acknowledgement This work was supported in part by National
Institutes 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 Quigley
Corporation.
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Clin Auton Res (2008) 18[Suppl 1]:14–18
DOI 10.1007/s10286-007-1003-1
Roy Freeman
Received: 18 June 2007
Accepted: 5 July 2007
R. Freeman, MD (&)
Dept. of Neurology
Harvard Medical School
Center for Autonomic and Peripheral
Nerve Disorders
Beth Israel Deaconess Medical Center
One Deaconess Road
Boston (MA) 02215, USA
Tel.: +1-617/632-8454
Fax: +1-617/632-0852
E-Mail: [email protected]
ARTICLE
Current pharmacologic treatment
for orthostatic hypotension
j Abstract Orthostatic hypoten-
sion is treated effectively with the
combined use of non-pharmacological and pharmacological interventions. Patients should be
counseled as to the nature of the
underlying disorder and reversible
causes of orthostatic hypotension
should be removed. Should symptoms persist, pharmacological
treatment is implemented. First
line pharmacotherapeutic interventions include volume repletion
Introduction
Orthostatic hypotension is the most incapacitating
symptom of autonomic failure. Fortunately, with the
help of non-pharmacological and pharmacological
interventions, most patients’ quality of life can be
improved substantially. The therapeutic interventions
to treat patients with orthostatic hypotension should
be implemented in stages and depend, in large part,
on the severity of symptoms. Some patients may be
markedly improved by education, counseling, removal of hypotensive medications and other nonpharmacological interventions, while more severely
afflicted patients require pharmacological interventions [9].
CAR 1003
j Non-pharmacological measures
Patient education is the cornerstone of the management of orthostatic hypotension. Throughout the day,
patients are subject to a number of orthostatic de-
in combination with alpha-adrenoreceptor agonists. If unsuccessful there are several supplementary
agents with different mechanisms
of action that may provide an
additive effect.
j Key words orthostatic hypotension Æ syncope Æ
autonomic failure Æ
sympathetic nervous system
mands for which there are simple but effective
countermeasures. The time spent with patients
emphasizing these practical management principles is
of inestimable value.
These include moving from a supine to standing
position in gradual stages; avoiding orthostatic stress
in 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 ingestion
often exacerbates orthostatic hypotension [19, 32].
Physical counter-maneuvers such as leg-crossing
and squatting may be used to facilitate cerebral
perfusion by increasing central blood volume and
cardiac filling pressures [39]. The use of custom
fitted elastic stockings may also be used to provide a
graded pressure to the lower extremity and abdomen. Medications such as diuretics, anti-hypertensive agents, anti-anginal agents, anti-depressants and
alpha adrenoreceptor antagonists should be tapered
as these can cause or exacerbate orthostatic hypotension.
15
Table 1 Volume expansion
Fluid and sodium chloride
9-a-Fluorohydrocortisone
Vasopressin analogs
Acute water ingestion
j Volume expansion
Administration of fluid and sodium chloride
Plasma volume expansion is essential to improve
orthostatic tolerance. The high nocturnal blood pressure causes a pressure natriuresis and results in nocturnal volume and sodium chloride depletion. Several
measures are available for maintaining and repleting
plasma volume (See Table 1). Patients should have a
daily dietary intake of least 10 g (185 mmol) of sodium per day accompanied by an increase in fluid
intake of 2–2.5 l (in adults) per day. An early morning
body weight gain of about 1–2 kg usually implies
adequate extra-cellular fluid volume expansion [38].
Ingestion of approximately 500 cc of tap water
elicits a marked pressor response and improvement
in symptoms in patients with autonomic failure. The
pressor response, a systolic blood pressure increase of
over 30 mmHg in some patients, is evident within
5 minutes after the water ingestion [14].
9-a-Fluorohydrocortisone
9-a-Fluorohydrocortisone (fludrocortisone acetate), a
synthetic mineralocorticoid, may be used if patient
are unable to increase plasma volume effectively with
fluid and salt [3, 11, 18]. This agent has a long
duration of action and is well-tolerated by most patients. Fludrocortisone increases the blood volume
and enhances the sensitivity of blood vessels to circulating catecholamines [7, 11]. Other potential
modes of action include enhancing norepinephrine
release from sympathetic neurons and increasing
vascular fluid content [34].
Treatment is initiated with a 0.1 mg tablet and can
be increased to 0.3–0.5 mg daily [38]. Treatment may
unfortunately be limited by supine hypertension due
to an increase in the peripheral vascular resistance
[4]. Other side effects include ankle edema, hypokalemia, headache and rarely congestive heart failure.
Potassium supplementation is usually required, particularly when higher doses are used.
Vasopressin analogs
The vasopressin analogs may be used to supplement
volume expansion. Arginine-vasopressin has a circadian rhythm that peaks during the night. Thus, the
increase in nocturnal urinary excretion in patients
Table 2 Sympathomimetic agonists
Midodrine
Ephedrine
Pseudoephedrine
Methylphenidate
Dextroamphetamine
with autonomic failure, which is in part due to the
increase in supine blood pressures, is also due to loss
of vasopressin neurons in the suprachiasmatic nucleus of the hypothalamus and the ensuing loss of the
normal AVP circadian rhythm [27].
The potent, synthetic vasopressin analog desmopressin acetate (DDAVP) acts on the V2 receptors in
the collecting ducts of the renal tubules and prevents
nocturia, weight loss and reduces the morning postural fall in blood pressure. DDAVP is usually
administered as a nasal spray (5–40 lg) or orally
(100–800 lg). Adverse events include water intoxication and hyponatremia [21]. Low doses of intranasal
desmopressin (5 lg) may be sufficient to attenuate
the nocturnal diuresis without placing the patient at
risk for hyponatremia [33].
j Sympathomimetic agents
The administration of sympathomimetic agents is
central to the management of patients with cardiovascular autonomic failure. Thus, if symptoms of
orthostatic intolerance persist once intravascular
volume is replenished the direct or indirect adrenergic agonists and antagonists should be administered
(See Table 2). The pressor response of these agents is
due to the reduction in venous capacity and the
constriction of the resistance vessels.
The available a1-adrenoreceptor agonists include
those with direct and indirect effects (ephedrine,
pseudoephedrine), those with direct effects (midodrine and phenylephrine) and those with only indirect
effects (methylphenidate and dextroamphetamine
sulphate).
The peripheral selective direct, a1-adrenoreceptor
agonist midodrine is the only agent approved by the
FDA for the treatment of orthostatic hypotension
[20]. Its efficacy has been demonstrated in doubleblind placebo controlled studies [15, 20, 42]. Midodrine, the prodrug is activated to desglymidodrine,
the active a-adrenoreceptor agonist. Midodrine has an
elimination half life of 0.5 hours and is undetectable
in plasma 2 hours after an oral dose. The agent
undergoes enzymatic hydrolysis (deglycination) in
the systemic circulation to form the active agent,
desglymidodrine. Desglymidodrine is 15 times more
potent than midodrine and is primarily responsible
for the therapeutic effect. The elimination half-life of
16
desglymidodrine is 2–4 hours. Desglymidodrine is
predominantly excreted by the kidneys.
Patient sensitivity to this agent varies and the dose
should be titrated from 2.5 mg to 10 mg three times a
day. The peak effect of this agent occurs 1 hour after
ingestion [42]. Potential side effects of midodrine
include pilomotor reactions, pruritus, supine hypertension, gastrointestinal complaints, and urinary
retention. Central nervous system side-effects occur
infrequently.
The mixed a-adrenoreceptor agonists—which act
directly on the a-adrenoreceptor and release norepinephrine from the post-ganglionic sympathetic neuron—include ephedrine, pseudoephedrine. There are
structural, pharmacological and therapeutic differences between these agents and midodrine. Ephedrine
is an agonist of a, b1 and b2 receptors. The b2
vasodilatory effects may attenuate the pressor effect
of this drug. Pseudoephedrine, a stereoisomer of
ephedrine has similar pharmacological and therapeutic properties [13]. Typical doses of the agents are
ephedrine: 25–50 mg three times a day; and pseudoephedrine: 30–60 mg three times a day. Because the
effectiveness of these agents is at least in part due to
the release of norepinephrine from the post-ganglionic neuron, these medications are in theory most
likely to benefit patients with partial or incomplete
lesions [1, 6, 10]. The indirect agonists, methylphenidate and dextroamphetamine, that release norepinephrine from post-ganglionic neurons are
infrequently used to treat orthostatic hypotension. In
a small head-to-head trial midodrine (mean dose
8.4 mg tid) improved standing blood pressure and
orthostatic tolerance more than ephedrine (22.3 mg
tid) [8]. In another trial, phenylpropanolamine
(12.5 mg) and yohimbine (5.4 mg) produced equivalent increases in standing systolic blood pressure
while methylphenidate failed to increase standing
systolic blood pressure significantly [13].
The use of the sympathomimetic agents (with the
possible exception of midodrine) may be complicated
by tachyphylaxis, although efficacy may be regained
after a short drug holiday. The central sympathomimetic side-effects such anxiety, tremulousness and
tachycardia that invariably accompany the use of
these agents are frequently intolerable to patients.
Midodrine, which does not cross the blood brain
barrier in significant amounts, does not have these
central sympathomimetic side-effects. There is evidence that phenylpropanolamine increases the risk of
hemorrhagic stroke in women [16] and the FDA has
suggested that phenylpropanolamine be removed
from all drug products.
Severe hypertension is an important adverse-effect
of all sympathomimetic agents. Patients should not
take these medications for 4 hours prior to recum-
Table 3 Supplementary therapy
Acetylcholinesterase inhibition
Caffeine
Erythropoietin
b-Blockers
Clonidine
Yohimbine
bency. Patients taking midodrine report piloerection,
pruritus and tingling. These are most likely peripheral
sympathomimetic effects of the drug.
j Supplementary therapy
There are rare patients who do not respond to first
line interventions and require additional agents to
treat their symptoms. These supplementary agents
may provide an additive therapeutic effect to the firstline therapies (see Table 3).
Acetylcholinesterase inhibition
The acetylcholinesterase inhibitor, pyridostigmine,
(60 mg) administered orally increased head-up tilt
blood pressure and reduced orthostatic hypotension
in patients with neurogenic orthostatic hypotension.
The associated increase in supine blood pressure may
not be as great as that seen with other pressors.
Twenty percent of patients report cholinergic sideeffects. The rationale for the use of this agent is that
inhibition of acetylcholinesterase enhance sympathetic ganglionic neurotransmission and that the effect is maximal while upright, when sympathetic
nerve traffic is greatest [35].
Caffeine
The methylxanthine caffeine has a well-established,
although modest, pressor effect that is in part due to
blockade of vasodilating adenosine receptors. The
pressor effect is subject to tachyphylaxis. Typical
caffeine doses are 100–250 mg three times a day, either as tablets or caffeinated beverages (one cup of
coffee contains approximately 85 mg of caffeine and
one cup tea contains 50 mg of caffeine) [25].
Erythropoietin
Erythropoietin increases standing blood pressure and
improves orthostatic tolerance in patients with
orthostatic hypotension [12, 28]. This agent corrects
the normochromic normocytic anemia that frequently
accompanies autonomic failure [2, 41] and diabetic
autonomic neuropathy [40].
17
Recombinant human erythropoietin, erythropoietin alpha, is administered subcutaneously or intravenously at doses between 25 and 75 U per kg three
times a week until a hematocrit that approaches
normal is attained. Lower maintenance doses
(approximately 25 U per kg three times a week) may
then be used. Iron supplementation is usually required, particularly during the period when the
hematocrit is increasing. Erythropoietin increases red
cell mass and central blood volume although the
precise mechanism of action of this agent is not resolved. There is evidence that the effect of erythropoietin is related to vascular tone regulation mediated
by the interaction between hemoglobin and the
vasodilator nitric oxide [29]. Supine hypertension
may accompany the use of erythropoietin [12, 28].
b-Blockers
Nonselective b-blockers, particularly those with
intrinsic sympathomimetic activity such as pindolol
and xamoterol, may have a limited place in the
treatment of orthostatic hypotension despite the wellacknowledged negative chronotropy and inotropy
associated with these medications [5, 22, 23, 37]. The
suggested mechanism of action of these medications
is the blockade of vasodilating b-2 receptors allowing
unopposed a-adrenoreceptor mediated vasoconstrictor effects to dominate. The pressor effect of these
agents has not been demonstrated consistently in
clinical trials [17].
Clonidine
Clonidine is an a2 agonist that usually produces a
central, sympatholytic effect and a consequent decrease in blood pressure. In patients with autonomic
failure, who have little central sympathetic efferent
activity, the effect of this agent on post synaptic a2
adrenoreceptors may predominate. The use of clonidine (0.1–0.6 mg per day) could therefore result in an
increase in venous return without a significant in-
crease in peripheral vascular resistance although
mechanism of action is still not clearly defined [36].
The use of this agent, at least theoretically, is limited
to patients with severe central autonomic dysfunction
in whom there is no ostensible effect of further
sympatholysis and the peripheral effect may dominate
[30, 31]. Clonidine should be used cautiously as
exacerbation of hypotension may occur. Side-effects
include somnolence, xerostomia and constipation.
Yohimbine
Yohimbine is a centrally and peripherally active
selective a2 adrenoreceptor antagonist that increases
sympathetic nervous system efferent output by
antagonizing central or presynaptic a2-adrenoreceptors or both. This agent, theoretically, should be more
effective in patients that have some residual sympathetic nervous system output, although this has not
always been borne out in clinical studies. Side effects
of yohimbine include anxiety, tremor, palpitations,
diarrhea and supine hypertension [13, 26].
Conclusion
With the help of non-pharmacological and pharmacological interventions, most patients’ quality of life
can be improved substantially. Treatment should be
initiated in stages. First, patients should be counseled
as to the nature of the underlying disorder and
reversible causes of orthostatic hypotension should be
removed. If symptoms persist, pharmacological
treatment is implemented. Many patients will be
adequately treated by education, counseling, removal
of hypotensive medications and other non-pharmacological interventions while more severely afflicted
patients require pharmacological interventions.
j Disclosure Dr. Freeman has served as a consultant for Chelsea
Therapeutics.
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Clin Auton Res (2008) 18[Suppl 1]:19–24
DOI 10.1007/s10286-007-1002-2
Horacio Kaufmann
ARTICLE
L-dihydroxyphenylserine (Droxidopa):
a new therapy for neurogenic orthostatic
hypotension
The US experience
Received: 18 June 2007
Accepted: 30 June 2007
H. Kaufmann, MD (&)
Dysautonomia Research Laboratory
New York University School of Medicine
530 First Avenue
New York (NY)10016, USA
Tel.: +1-212/263-7225
Fax: +1-646/349-3476
E-Mail: [email protected]
j Abstract Neurogenic ortho-
static hypotension results from
failure to release norepinephrine,
the neurotransmitter of sympathetic postganglionic neurons,
appropriately upon standing. In
double blind, cross over, placebo
controlled trials, administration of
droxidopa, a synthetic amino acid
that is decarboxylated to norepinephrine by the enzyme L-aromatic amino acid decarboxylase
increases standing blood pressure,
ameliorates symptoms of orthostatic hypotension and improves
standing ability in patients with
neurogenic orthostatic hypotension due to degenerative autonomic disorders. The pressor
effect results from conversion of
droxidopa to norepinephrine outside the central nervous system
both in neural and non-neural
tissue. This mechanism of action
makes droxidopa effective in
j Key words autonomic failure Æ
orthostatic hypotension Æ
DOPS Æ droxidopa Æ
multiple system atrophy Æ
pure autonomic failure Æ
Parkinson’s disease Æ
norepinephrine Æ blood
pressure Æ autonomic nervous
system
Although levodopa is the amino acid precursor of
both dopamine and norepinephrine, treatment with
levodopa leads to an increase in dopamine but not to
a significant increase in norepinephrine levels. Norepinephrine is synthesized from levodopa in two steps
(Fig. 1). The first step is the decarboxylation of
levodopa to dopamine by the enzyme L-aromatic
amino acid decarboxylase. The second step, catalyzed
by the enzyme dopamine beta hydroxylase, is the
hydroxylation of dopamine to norepinephrine.
CAR 1002
Autonomic failure, like Parkinson’s disease, is a
neurotransmitter disorder. While Parkinson’s disease
is a disorder of dopamine neurotransmission, autonomic failure is a disorder of norepinephrine neurotransmission. The idea that deficient dopamine
neurotransmission in Parkinson’s disease could be
overcome by treatment with oral levodopa, the amino
acid precursor of dopamine, led to the most successful therapeutic intervention in 20th century neurology.
patients with central and peripheral autonomic disorders.
20
Fig. 2 Levodopa and droxipoda: The similar chemical structure of droxipoda
(3,4-threo-dihydroxyphenylserine) and levodopa (3,4-dihydroxy-L-phenylalanine). Note that droxidopa has an added beta hydroxyl group
Fig. 1 Catecholamine pathway: Norepinephrine is synthesized from levodopa
in two steps. The first step is the decarboxylation of levodopa to dopamine by
L-aromatic amino acid decarboxylase. The second step is the hydroxylation of
dopamine to norepinephrine by the rate-limiting enzyme dopamine beta
hydroxylase. Droxipoda bypasses this rate-limiting enzyme and is converted to
norepinephrine in a single step by L-aromatic amino acid decarboxylase
Dopamine beta hydroxylase is the rate-limiting enzyme and it creates a ‘‘bottle neck’’ like effect, so that
taking levodopa orally results in an increase in
dopamine levels but not to a significant increase in
norepinephrine levels.
Fortunately, the possibility of overcoming this
limitation and realizing another therapeutic breakthrough using a precursor amino acid to replace a
deficient catecholamine neurotransmitter, in this case
norepinephrine, was made possible by the discovery,
in the 1950’, that an artificial amino acid, 3,4-threodihydroxyphenylserine, identical to levodopa but with
an added beta hydroxyl group (Fig. 2) was converted
to norepinephrine in a single step by the enzyme Laromatic amino acid decarboxylase, thus bypassing
the need for dopamine beta hydroxylase and its bottle
neck effect [3, 15].
Droxidopa was first used successfully to treat one
particular form of autonomic failure: congenital
deficiency 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 appropriately when standing up [2, 12]. Droxidopa has now
been used to treat orthostatic hypotension in several
autonomic disorders, including familial amyloid
polyneuropathy [16], autoimmune autonomic neuropathy [5], pure autonomic failure (PAF), Parkinson’s disease and multiple system atrophy [MSA; 4,
10, 11, 13].
3,4-Threo-dihydroxyphenylserine has four steroisomers [1]. Early studies used a racemic mixture that
contained both the D and L isoforms of 3,4-threo-dihydroxyphenylserine but only the L-isoform is converted to biologically active L-norepinephrine.
Furthermore, the D-stereoisomer of 3,4-threo-dihydroxyphenylserine might competitively inhibit the
decarboxylation of the L stereoisomer to L-norepinephrine [8]. Thus, the pure L isoform of 3,4-threodihydroxyphenylserine (droxidopa) is the preferred
formulation for treatment.
Here I will review the most recent studies conducted in the United States using droxidopa in the
treatment of orthostatic hypotension in patients with
degenerative autonomic disorders, including PAF and
MSA.
Studies of droxidopa in the United States
We conducted a comprehensive study of droxidopa in
patients with severe symptomatic orthostatic hypotension due to MSA or PAF [11]. We examined the
effect of droxidopa on standing blood pressure and
orthostatic tolerance, as well as its pharmacokinetics
and its mechanism of action.
21
pressure occurred 3.5 h after droxidopa administration (P < 0.00001 versus placebo, see Fig. 3). There
were no significant changes in heart rate following
administration of droxidopa or placebo.
There was a clear symptomatic improvement in all
patients after taking droxidopa. Patients were less
lightheaded and reported feeling better. This was
noticeable in the patient’s ability to stay standing.
Patients were able to stand for the 1-min blood
pressure determination 96% of the time after receiving either droxidopa or placebo. However, for the 3min blood pressure measurement, patients were able
to stand 94% of the time after receiving droxidopa but
only 84% of the time after receiving placebo
(P < 0.001).
Fig. 3 Standing blood pressure after droxipoda and placebo administration.
The effect of droxipoda and placebo on mean arterial pressure (MAP) after
3 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]
j Dose titration study
Because patients with autonomic failure have different degrees of adrenergic denervation supersensitivity, we individualized the dose of droxidopa for each
patient in a single blind dose-ranging study.
Patients received progressively higher dosages of
droxidopa, beginning with 200 mg followed by 400,
1,000, 1,600, and 2,000 mg on successive days. The
dose ranging study was terminated when the orthostatic fall in systolic blood pressure after 3 min of
standing was consistently < 20 mm Hg, or the patient
had 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 mg
of droxidopa was reached. The optimal dose of
droxidopa 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 determined, patients were enrolled in a double blind
crossover study lasting 3 days. On days 1 and 3 either
droxidopa (at the dose previously determined in the
dose ranging study) or placebo was given at 7:00 am.
Day 2 was a washout day. As shown in Fig. 3
administration of droxidopa significantly increased
blood pressure in all patients (P < 0.001 versus placebo), both while supine and after standing for 1 min
and for 3 min.
The pressor effect began 1 h after droxidopa
administration and lasted for 6 h while standing and
for 8 h while supine. The highest standing blood
Adverse events
Droxidopa was well tolerated by all patients and there
were no significant side effects. The frequency of supine hypertension (systolic pressure > 180, diastolic > 110 mmHg or both) was higher on droxidopa
than on placebo (45% vs. 23% of blood pressure
measurements, P < 0.00001). After receiving droxidopa, the frequency of supine systolic and diastolic
hypertension was similar in MSA and PAF patients.
However, on placebo, diastolic, but not systolic, supine hypertension was more common in MSA patients than in PAF (25% vs. 3%, P < 0.05). One patient
had hyponatremia, which reversed after saline infusion. Another patient had transitory chest pain with
electrocardiographic ST segment depression, but
cardiac enzymes were normal.
Mechanism and site of action of droxidopa
Droxidopa could exert its pressor effect in three different 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 central
stimulator of sympathetic outflow. It could be
converted to epinephrine and activate sympathetic
preganglionic neurons in the spinal cord.
2. As a peripheral sympathetic neurotransmitter. As it
had been shown in patients with dopamine beta
hydroxylase (DBH) deficiency [2, 12] droxidopa
could be taken up by post ganglionic peripheral
sympathetic neurons, transformed to norepinephrine intraneuronally, and released when sympathetic neurons are activated, i.e., act as a
physiologic sympathetic neurotransmitter in
peripheral sympathetic neurons.
22
Fig. 4 Possible mechanisms of action of
droxidopa—Droxidopa could exert its pressor effect in
three ways: 1. Because droxidopa crosses the blood brain
barrier, it could be converted to epinephrine and activate
sympathetic preganglionic neurons in the spinal cord. 2.
Droxidopa could be taken up by post ganglionic
sympathetic neurons, converted to norepinephrine
intraneuronally, and released when sympathetic neurons
are activated. 3. Droxidopa could be converted to
norepinephrine outside neurons (in the stomach, kidney
and liver), released into the blood stream and exert a
pressor effect as a circulating hormone
3. As a circulating hormone. Norepinephrine synthesized from droxidopa could also act as a circulating hormone. The enzyme aromatic
aminoacid decarboxylase is widely expressed
throughout the body, in the stomach, kidney and
liver. Thus, droxidopa could be converted to norepinephrine outside neurons, and then released
into the blood stream were it would exert a pressor
effect as a circulating hormone.
j Decarboxylase inhibitior study
To determine whether the pressor action of droxidopa
was due to its metabolism to norepinephrine inside or
outside the central nervous system we used carbidopa
as a pharmacological probe [11]. Carbidopa is an
inhibitor of L-aromatic-amino-acid decarboxylase
that does not cross the blood-brain barrier. Therefore,
carbidopa’s inhibition of L-aromatic-amino-acid
decarboxylase and its blockade of norepinephrine
synthesis from droxidopa is confined to tissues outside the brain and it does not affect the decarboxylation of droxidopa to norepinephrine within the
central nervous system.
If the mechanism of action of droxidopa is in the
central nervous system, a large dose of carbidopa
taken before droxidopa should not prevent its pressor
effect. Indeed, it may even increase its pressor effect,
similarly to the enhanced anti parkinsonian effect of
levodopa when it is administered with carbidopa.
Conversely, if the mechanism of action of droxidopa
is through its conversion to norepinephrine outside
the central nervous system, either in neural or non-
neural tissue, then concomitant administration of
carbidopa will block the pressor effect of droxidopa.
In a double-blind placebo controlled study, six
patients [11] sequentially received droxidopa alone on
day 1, 200 mg of carbidopa alone on day 2, and 200
mg of carbidopa combined with droxidopa on day 3.
As expected, droxidopa taken alone increased
standing blood pressure in all patients. Carbidopa
taken alone had no effect on blood pressure. However,
when carbidopa was administered together with
droxidopa the increase in blood pressure previously
seen with droxidopa alone was completely abolished
(Fig. 5). From this study we concluded that the
pressor effect of droxidopa was due to it conversion
into norepinephrine outside the brain, either in neuronal or non-neuronal tissues.
After carbidopa administration plasma levels of
droxidopa were higher than when droxidopa was
administered without carbidopa (4,556 ± 1,011 ng/ml,
P < 0.01, versus droxidopa alone). In addition, carbidopa markedly attenuated the increase in plasma
norepinephrine levels. Six hours after concomitant
carbidopa and droxidopa administration, the venous
plasma norepinephrine level had only increased from
216 ± 125 to 407 ± 271 pg/ml (P < 0.05, versus droxidopa alone).
j Droxidopa in patients with PD taking levodopa
and a decarboxylase inhibitor
Levodopa/carbidopa therapy is a mainstay in the
treatment of Parkinson disease. Because carbidopa
inhibits the conversion of droxidopa to norepinephrine, droxidopa may be ineffective in the treatment of
23
Fig. 5 Droxidopa plus decarboxylase inhibitior study. The effect of droxipoda,
decarboxylase inhibitior (DCI), droxidopa and DCI, and placebo on mean arterial
pressure (MAP) after 3 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 (versus placebo). All data are mean ± SEM, (n = 6). Data from
Kaufmann et al. [11]
orthostatic hypotension in patients with Parkinson
disease treated with levodopa/carbidopa. However, to
block the pressor effect of droxidopa it is necessary to
completely inhibit the enzyme aromatic aminoacid
decarboxylase. To achieve complete inhibition of
aromatic aminoacid decarboxylase a high dose of
carbidopa (200 mg) is required. Lower dosages of
carbidopa, such as those commonly used to treat
Parkinson disease, should not abolish the pressor
effect of droxidopa. Indeed, studies of droxidopa in
Europe included patients with PD who were also
taking benzeraside, an aromatic aminoacid decarboxylase inhibitor, at a low dose, together with levodopa (i.e., Madopar, see Mathias, this supplement).
Because benzerazide at a low dose does not completely inhibit the enzyme aromatic aminoacid
decarboxylase, patients with PD still experienced the
desired pressor effect of droxidopa.
Fig. 6 Plasma levels of droxipoda and norepinephrine. Venous plasma levels of
droxipoda 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]
j Pharmacokinetic study
We investigated the pharmacokinetics of droxidopa
and the generated norepinephrine and determined the
relationship between the pressor response and venous
plasma norepinephrine levels [6, 11]. The peak droxidopa level of 1,942 ± 224 ng/ml was attained 3 h after
its ingestion (P < 0.001). Plasma norepinephrine increased from the baseline level of 294 ± 80 pg/ml to
806 ± 235 pg/ml (P < 0.05) 2 h after droxidopa admi
nistration. Norepinephrine peaked at 1,250 ± 208 pg/
ml 6 h after droxidopa ingestion (P < 0.005, see Fig. 6).
Plasma levels of norepinephrine remained significantly
elevated for at least 46 h. The levels of norepinephrine
associated with an increase in blood pressure were
above 700 pg/ml (see Fig. 7), similar to the norepinephrine levels necessary to increase blood pressure
when norepinephrine is infused.
j Therapeutic implications
A peripheral mechanism of action makes droxidopa
an exciting new treatment option in both central and
peripheral autonomic disorders. In patients with
destruction of peripheral autonomic neurons (i.e., in
the Lewy body disorders), droxidopa can be converted to norepinephrine in non-neuronal tissues,
released to the blood stream and act as a circulating
vasoconstrictor hormone. In patients with central
autonomic disorders and preserved peripheral autonomic neurons (i.e., MSA), droxidopa is converted to
norepinephrine outside the central nervous system,
both in neuronal and non-neuronal tissue. In these
patients, droxidopa-derived norepinephrine acts as a
neurotransmitter and a circulating hormone.
Fig. 7 Relationship between blood pressure and norepinephrine levels after
droxidopa administration. Changes in systolic blood pressure (SBP) versus
plasma concentration of norepinephrine after droxidopa administration. Solid
curve represents the line of best fit. All data are mean ± SEM, (n = 8). Data
from Kaufmann et al. [11]
24
j Responses in patients with MSA and patients
with PAF
Prior to droxidopa ingestion, MSA and PAF patients
had similar blood pressures and similar heart rates,
both while supine and while standing. The mean dose
of 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. Following
droxidopa administration, systolic blood pressure in
the supine position increased more in patients with
PAF than in patients with MSA (P < 0.05). There was
a trend towards higher systolic blood pressure in
patients with PAF after 1 min in the standing position
but this did not reach statistical significance. The
finding that the pressor response to droxidopa in
supine patients with PAF was more pronounced than
in patients with MSA indicate a peripheral mechanism
of action. Indeed, because of their widespread loss of
sympathetic terminals, patients with PAF have
markedly exaggerated pressor responses to circulating norepinephrine [7, 14].
In summary, Droxidopa effectively raises standing
blood pressure and ameliorates symptoms of orthostatic hypotension in patients with central and
peripheral autonomic disorders. The pressor effect of
droxidopa is due to its conversion to norepinephrine
outside the brain, both in neuronal and non neuronal
tissues. In patients with peripheral autonomic disorders and degeneration of sympathetic neurons (e.g.
PAF), droxidopa is converted to norepinephrine in non
neuronal tissue. In patients with central autonomic
degeneration and preserved peripheral sympathetic
neurons (e.g. MSA), droxidopa is converted to norepinephrine in neuronal and non neuronal tissue.
j Acknowledgment I am grateful to Dr. Lucy Norcliffe-Kaufmann
for her help designing the figures.
j Disclosure Dr. Kaufmann has served as a consultant for Chelsea
Therapeutics.
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Taylor MD (2001) L-threo-dihydroxyphenylserine (L-threo-DOPS; droxidopa) in the management of neurogenic
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V (1981) Pharmacologic distinction of
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Clin Auton Res (2008) 18[Suppl 1]:25–29
DOI 10.1007/s10286-007-1005-z
Christopher J. Mathias
ARTICLE
L-dihydroxyphenylserine (Droxidopa)
in the treatment of orthostatic
hypotension
The European experience
Received: 25 October 2007
Accepted: 26 November 2007
Prof. C.J. Mathias, DPhil, DSc, FRCP,
FMedSci
Neurovascular Medicine Unit
Faculty of Medicine
Imperial College London at St Mary’s
Hospital
Praed Street
London W2 1NY, UK
Tel.: +44-0207/8861-468
Fax: +44-0208/8861-540
E-Mail: [email protected]
C.J. Mathias, DPhil, DSc, FRCP,
FMedSci (&)
Autonomic Unit
National Hospital for Neurology and
Neurosurgery
Institute of Neurology
University College London
London, WCIN 3 BG, UK
j Abstract Neurogenic orthostatic
hypotension is a cardinal feature of
generalised autonomic failure and
commonly is the presenting sign in
patients with primary autonomic
failure. Orthostatic hypotension
can result in considerable morbidity and even mortality and is a
major management problem in
disorders such as pure autonomic
failure, multiple system atrophy
and also in Parkinson’s disease.
Treatment is ideally two pronged,
using non-pharmacological and
pharmacological measures.
Drug treatment ideally is aimed at
restoring adequate amounts of the
neurotransmitter noradrenaline.
This often is not achievable because
of damage to sympathetic nerve
terminals, to autonomic ganglia or to
central autonomic networks. An
alternative is the use of sympathomimetics (that mimic the effects
of noradrenaline, but are not identical to noradrenaline), in addition to
other agents that target physiological
mechanisms that contribute to blood
pressure control.
L-threo-dihydroxyphenyslerine
(Droxidopa) is a pro-drug which
has a structure similar to noradrenaline, but with a carboxyl
group. It has no pressor effects in
this form. It can be administered
orally, unlike noradrenaline, and
after absorption is converted by the
enzyme dopa decarboxylase into
noradrenaline thus increasing levels of the neurotransmitter which is
identical to endogenous noradrenaline. Experience in Caucasians and
in Europe is limited mainly to
patients with dopamine beta
hydroxylase deficiency. This review
focuses on two studies performed
in Europe, and provides information on its efficacy, tolerability and
safety in patients with pure autonomic failure, multiple system
atrophy and Parkinson’s disease. It
also addresses the issue of whether
addition of dopa decarboxylase
inhibitors, when combined with
l-dopa in the treatment of the motor
deficit in Parkinson’s disease, impairs the pressor efficacy of Droxidopa.
j Key words l-dihydroxyphenylserine Æ orthostatic hypotension Æ
autonomic failure Æ
noradrenaline Æ multiple system
atrophy Æ Parkinson’s disease
CAR 1005
26
Introduction
Orthostatic (or postural) hypotension (OH) is a cardinal manifestation of generalised autonomic failure
and often is the presenting feature in patients with
primary autonomic failure due to pure autonomic
failure (PAF) and multiple system atrophy (MSA) [9].
It is increasingly recognised also in Parkinson’s disease [11]. It results in a number of symptoms, mainly
as a result of hypoperfusion of organs, including the
skeletal musculature. Organs above the level of the
heart, such as the brain, are particularly susceptible
to hypoperfusion; this can result in dizziness, visual
disturbances, cognitive deficits and loss of consciousness [1, 6]. Orthostatic hypotension can reduce
mobility, result in falls, and may cause trauma and
injuries, at times with devastating effects including
death. The symptomatic consequences of OH, taken
together can substantially reduce a patients quality of
life.
There are many causes of OH that can be considered under the mechanisms responsible - neurogenic,
non-neurogenic and drug induced [12]. Non-neurogenic OH is rectified more readily than neurogenic
OH, which often is difficult to treat, with management
dependent on a combination of non-pharmacological
measures and drugs [3, 10]. A key factor in neurogenic OH is reduction in sympathetic nerve activity,
and thus a reduction of the neurotransmitter, noradrenaline at the synaptic cleft. To replace this deficiency a variety of drugs that mimic noradrenaline
have been used, that include ephedrine and midodrine, which are of partial benefit and have limitations
to their use because of adverse effects. The ideal approach would be replacement of noradrenaline itself.
L-threo-dihydroxyphenylserine (Droxidopa) has a
structure which is similar to noradrenaline but with a
carboxyl group. It can be administered orally, and is
acted upon by the ubiquitous enzyme L-aromatic
amino acid decarboxylase (dopa decarboxylase),
which is found all over the body. It is converted directly to noradrenaline. It is likely to have both neuronal and extra neuronal effects, with a direct effect
through noradrenaline on target organs. Droxidopa
has been highly successful in replacing deficient or
absent noradrenaline in patients with dopamine beta
hydroxylase deficiency [4, 5, 15]. In Japan, it has been
approved since 1989 use for in the treatment of
neurogenic OH due to various disorders, that include
familial amyloid polyneuropathy, haemodialysis induced hypotension, and MSA and PD [8, 14, 16, 17,
18]. Experience with Droxidopa, especially in primary
autonomic failure and PD in Caucasians is limited.
Because of its potential value in the management of
symptomatic orthostatic hypotension, two Phase II
studies were performed in Europe. These were multicentre, multinational studies. An escalating dose of
Droxidopa was used in the first study in patients with
PAF and MSA. In the second a randomised double
blind placebo controlled study was performed using
three doses of Droxidopa in patients with MSA or PD.
This review will describe key components from
each of these studies, and will focus on whether
inhibition of the enzyme dopa decarboxylase, which
converts Droxidopa to noradrenaline, can influence
its ability to reduce orthostatic hypotension.
Droxidopa in pure autonomic failure and multiple
system atrophy
This study was performed in 6 PAF and 26 MSA
patients with symptomatic orthostatic hypotension
[7]. It was an open dose ranging study with a one
week run in period, following which three doses of
Droxidopa, 100, 200 and 300 mg were administered
twice daily. The incremental dose adjustment was
dependent on the blood pressure response and an
improvement in symptoms. When optimum dosage
was reached the dosage was maintained for a 6 week
period. The study therefore determined both the
efficacy and the tolerability of increasing doses of
Droxidopa in treating symptomatic orthostatic
hypotension in PAF and MSA. This dose escalating
trial was performed in ten centres within three
countries in Europe. A key primary variable was to
determine the extent of decrease in orthostatic fall in
systolic blood pressure.
Table 1 provides details of the response to Droxidopa. The effects of Droxidopa persisted even at the
last individual visit, with orthostatic systolic blood
pressure reductions of 20, 29 and 23 mmHg respectively. In 25 patients (78%) OH had improved, and in
14 (44%) OH was not measurable. Importantly the
mean supine systolic BP levels were not elevated
(Table 1). Thus Droxidopa, particularly in the highest
doses, was efficacious in reducing OH (Fig. 1).
In this study, symptoms associated with orthostatic
hypotension, that included light headedness, dizziness and blurred vision were assessed while on and
when off Droxidopa drug. These were evaluated using
bi-polar scales with ten point numeric objectivity.
They showed an improvement in both objective and
subjective evaluations of benefit (Fig. 2).
Droxidopa was well tolerated. There were two
serious adverse events; laryngeal dyspnoea and syncope. The first was on 100mg twice daily and the
second on 300 mg twice daily. Both could be attributed to the disease itself rather than to the drug. Supine hypertension was not reported.
27
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*
Baseline orthostatic SBP decrease
Final visit supine SBP
Reduction in orthostatic SBP decrease
Reduction in orthostatic DBP decrease
Noradrenaline while supine
Noradrenaline at end of standing period
n = 32*
54.3 ± 27.7
120.9 ± 31.6
)23.2 ± 28.0
)9.4 ± 17.0
562.5 ± 1,024.2 (n = 30)
1,096.8 ± 1,228.8
n = 25*
55.8 ± 24.6
118.9 ± 30.3
)28.4 ± 54.4
)10.9 ± 31.0
779.5 ± 1,214.1 (n = 23)
1,350.1 ± 1,612.4
n = 17*
60.6 ± 24.9
117.2 ± 31.9
)22.7 ± 36.4
)11.5 ± 22.6
966.1 ± 969.3 (n = 14)
1,361.9 ± 864.3 (n = 16)
Last individual visit*
Baseline orthostatic SBP decrease
Final visit supine SBP
Reduction in orthostatic SBP decrease
Reduction in orthostatic DBP decrease
Noradrenaline while supine
Noradrenaline at end of standing period
n = 7*
48.7 ± 38.8
129.3 ± 28.4
)19.7 ± 13.9
)9.2 ± 8.8
472.1 ± 341.7
1,304.6 ± 1,077.5
n = 8*
45.6 ± 22.0
114.1 ± 24.6
)28.5 ± 22.2
)5.1 ± 8.6
379.6 ± 394.9 (n = 7)
1,303.5 ± 1,659.8
n = 17*
60.6 ± 24.9
117.1 ± 31.9
)22.7 ± 36.4
)11.5 ± 22.6
966.1 ± 969.3 (n = 14)
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 decrease
data 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 baseline
SBP = systolic blood pressure; DBP = diastolic blood pressure
From: 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 of
neurogenic 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.
In summary, Droxidopa was an effective drug
which reduced the orthostatic fall in blood pressure in
patients with PAF and MSA. It improved symptoms of
Droxidopa in multiple system atrophy and
in Parkinson’s disease
120
Deterioration
Orthostatic BP fall at last visit (mmHg)
OH and was well tolerated. It did not result in supine
hypertension. The most effective of the three tested
doses was 300 mg twice daily.
100
Improvement
80
60
40
MSA
20
PAF
0
-20
-40
0
20
40
60
80
100
Orthostatic BP fall at baseline (mmHg)
120
140
Fig. 1 Orthostatic systolic blood pressure decrease at baseline and at individual
last visit. Individual orthostatic blood pressure decrease (mm Hg) after 5-minuties’
standing at last visit is plotted against decrease at baseline (all 32 ‘‘efficacyevaluable’’ patients). Each point below the line represents a patient whose
condition improved between baseline and last visit, and every point above this
line a patient whose condition deteriorated. From: Mathias CJ, Senard J-M, Braune
S, Watson L, Aragishi A, Keeling J, Taylor M. L-threo-dihydroxphenylserine (Lthreo-DOPS; droxidopa) in the management of neurogenic 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.
This study was designed to determine the minimum
effective dose of Droxidopa that safely reduced the
orthostatic fall in systolic blood pressure in comparison with placebo. After screening and evaluation a
total of 121 patients with either MSA or PD were
randomized and received doses of 100, 200, 300 mg of
Droxidopa or matching placebo. The drug was
administered three times daily, as was placebo. It was
conducted in 30 centres within 4 European countries.
The screening period was between two seven days and
the treatment continued for 28 days. Data was obtained in 55 patients with MSA and in 66 with Parkinson’s disease. A preliminary report recently has
been presented [13].
Droxidopa treatment resulted in a reduction in the
orthostatic fall in blood pressure with each of the
Droxidopa doses, unlike with placebo. It was noted
that in the previous study the same patient had
escalating doses with individual comparisons, unlike
this second study with different individuals on different doses of drugs. There was no clear dose response improvement but the 300 mg dose was the
28
Baseline Score
0
1
2
3
4
5
6
7
8
9
10
Improvement
0
Score after Treatment
Fig. 2 Transition table for the symptom ‘‘Lightheadedness. 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-threodihydroxphenylserine (L-threo-DOPS; droxidopa) in
the management of neurogenic orthostatic
hypotension: a multi-national, multi-centre, doseranging study in multiple system atrophy and pure
autonomic failure. Clin Aut Res 2001, 11; 235–242.
All
6
1
4
2
1
3
8
4
3
5
5
6
0
7
1
8
2
9
0
Deterioration
10
All
4
most effective in reducing OH. Even with this dose
mean levels of supine blood pressure were not elevated after acute or chronic dosage. The drug remained efficacious 28 days of treatment.
In this study up to 900mg of Droxidopa was used
each day, and adverse effects on heart rate were
analysed. There was neither bradycardia nor tachycardia with any of the doses, at day 0 or after 28 days
of treatment.
The majority of patients in this study had mild to
moderate symptoms of dizziness, tiredness and visual
disturbance. There was no loss of consciousness before or after drug or placebo treatment. There was an
overall trend towards improvement in symptoms but
this did not reach statistical significance. The reasons
for the apparent dissociation between objective
improvement in OH and subjective reduction in
symptoms remains unclear. It may reflect the different individual characteristics of each group, or
insensitivity of the symptom scales used.
Droxidopa was well tolerated, with similar adverse
effects in each of the treatment groups when compared with placebo. Most of the symptoms were mild.
One patient had supine hypertension.
In summary, therefore, 300 mg tid of Droxidopa
was more effective than either 100 or 200 mg in the
majority of patients with MSA or PD. It was well
tolerated and with few side effects.
Droxidopa in patients on dopa decarboxylase
inhibitors
Dopa decarboxylase is essential for the conversion of
Droxidopa into noradrenaline and would be expected
noradrenaline to reduce the formation of a dopa
decarboxylase inhibitor and thus the prodrugs pres-
1
5
1
1
8
2
4
2
2
1
3
32
sor effect. In each of the studies described there were
patients treated with a combination of L-dopa and
dopa decarboxylase inhibitors. In the first study these
included MSA patients, and in the second both MSA
and PD patients.
There were no obvious differences in the beneficial
response of Droxidopa in the first study with patients
on a dopa decarboxylase inhibitor. Similar observations were made in the second study, where over 80%
of the PD patients were on a dopa decarboxylase
inhibitor. In a previous study in 4 PAF and 2 MSA
patients, pre-treatment with 200mg of the dopa
decarboxylase inhibitor Carbidopa, prior to Droxidopa, blunted the pressor effects of Droxidopa [2].
Plasma noradrenaline levels rose from 294 ± 80 to
806 ± 235 pg/mL in Droxidopa treated patients
compared to 216 ± 125 to 407 ± 271 after Droxidopa
treated patients had been pretreated with Carbidopa,
which thus attenuated, but did not abolish, the rise in
levels of plasma noradrenaline. It is important to note
that the dose of carbidopa used in this study [2] was
substantially higher than the dose used in clinical
preparations when combined with l-dopa, these usually being 25mg for 100mg of l-dopa. In each of the
European studies reported there was a beneficial
pressor effect of Droxidopa despite the presence of a
dopa decarboxylase inhibitor; this may reflect
incomplete inhibition of dopa decarboxylase with the
clinical preparations used to treat the motor deficits.
The pressor effect may even have been higher without
an inhibitor.
Conclusions
Treatment with Droxidopa, which results in the
formation of noradrenaline, has been demonstrated
29
in two pan European studies to be effective, well
tolerated and safe when used to treat orthostatic
hypotension in patients with pure autonomic failure, multiple system atrophy, and Parkinson’s disease.
j Acknowledgements Major investigators have included Professor
P Cortelli, Professor J M Senard, and many colleagues in participating centres.
Disclosure Prof. C.J. Mathias was the Principal Investigator of both
studies reviewed, which were supported by Sumitomo Pharmaceuticals, Japan. He is a Consultant for Chelsea Therapeutics, USA.
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Clinical
Autonomic
Research
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