CAR Supplement on Neurogenic Orthostatic Hypotension

Intro

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.

Dr. Robertson
Abstract  Orthostatic Hypotension (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.
Dr. Low
Abstract  Orthostatic hypotension (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 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.
Dr. Freeman
Abstract  Orthostatic hypotension 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 in combination with alpha-adrenoreceptor agonists. If unsuccessful there are several supplementary agents with different mechanisms of action that may provide an additive effect.
Dr. Kaufmann
Abstract  Neurogenic orthostatic 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 patients with central and peripheral autonomic disorders.
Dr. Mathias
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.
 
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