Droxidopa in neurogenic orthostatic hypotension

Abstract

Neurogenic orthostatic hypotension (nOH) is a fall in blood pressure (BP) on standing due to reduced norepinephrine release from sympathetic nerve terminals. nOH is a feature of several neurological disorders that affect the autonomic nervous system, most notably Parkinson disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), and other autonomic neuropathies. Droxidopa, an orally active synthetic amino acid that is converted to norepinephrine by the enzyme aromatic L-amino acid decarboxylase (dopa-decarboxylase), was recently approved by the FDA for the short-term treatment of nOH. It is presumed to raise BP by acting at the neurovascular junction to increase vascular tone. This article summarizes the pharmacological properties of droxidopa, its mechanism of action, and the efficacy and safety results of clinical trials.

Keywords:

• autonomic failure
• autonomic neuropathy
• blood pressure
• catecholamines
• dopamine-beta hydroxylase deficiency
• L-DOPS
• multiple system atrophy
• Parkinson disease
• pure autonomic failure
• syncope

Financial & competing interests disclosure

The authors were supported by funding from the National Institutes of Health (U54NS065736 and 1U01NS078025-01) and the Dysautonomia Foundation, Inc. H. Kaufmann receives research support from the National Institutes of Health (U54NS065736 and 1U01NS078025-01) and the Dysautonomia Foundation, Inc. H Kaufmann has also served as Editor in Chief for Clinical Autonomic Research and has received compensation as a consultant/advisory board member for Lundbeck, Eli Lilly, Pfizer, and Astra Zeneca. L Norcliffe-Kaufmann receives research support from the National Institutes for Health (U54NS065736), the Dysautonomia Foundation, Inc and the MSA Coalition. JA Palma receives research support from the Dysautonomia Foundation, Inc. and has received compensation as a consultant/advisory board member for Lundbeck.

Key issues

• Neurogenic orthostatic hypotension (nOH) is a severely disabling disorder suffered by patients with autonomic failure due to defective norepinephrine release from sympathetic postganglionic terminals upon standing.

• The Food and Drug Administration (FDA) approved droxidopa in 2014 for the treatment of orthostatic dizziness, lightheadedness, or “feeling about to faint” in adult patients with symptomatic neurogenic OH associated with Parkinson disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), dopamine β-hydroxylase deficiency, and nondiabetic autonomic neuropathy.

• Droxidopa is an orally active synthetic amino acid that is converted to norepinephrine by the aromatic L-amino acid decarboxylase (dopa-decarboxylase), the same enzyme that converts L-DOPA into dopamine in the treatment of PD.

• Phase III clinical trials showed that droxidopa treatment led to significant improvement in symptoms of neurogenic OH (dizziness, lightheadedness, or feeling about to faint) with an associated increase in standing systolic BP; the effectiveness of droxidopa beyond 2 weeks has not been proven.

• The most significant concern when using droxidopa is supine hypertension. To avoid it, droxidopa should be carefully titrated and patients should sleep in a semi-sitting position (30-degree elevation of the head and torso).

Notes