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Norepinephrine reuptake blockade to treat neurogenic orthostatic hypotension

G. Eisenhofer,D. Goldstein

Published 2021 in Clinical Autonomic Research

ABSTRACT

Neurogenic orthostatic hypotension (nOH) is a not infrequent consequence of neurodegenerative disorders and can result in impaired mobility, falls and associated fractures, decreased quality of life, hospitalizations, and increased mortality. The disorder often coexists with supine hypertension, which carries additional cardiovascular risks and complicates the treatment of nOH. While non-pharmacological measures such as elevation of the head of the bed at night, taking frequent, small, snack-like meals, hydration, compression stockings, and lifestyle modifications are important in the clinical management of nOH, there has been growing emphasis on pharmacological treatments. These include the orally active α-adrenergic receptor agonist midodrine, the norepinephrine pro-drug droxidopa, the sodium-retaining mineralocorticoid fludrocortisone, the acetylcholinesterase inhibitor pyridostigmine, and sympathomimetic amines such as amphetamines [9]. In this issue of Clinical Autonomic Research, Lo and colleagues describe the pharmacokinetic and pharmacodynamic properties of ampreloxetine (TD-9855), a novel inhibitor of the cell membrane norepinephrine transporter (NET), as a potential new treatment for nOH, currently under clinical development by the pharmaceutical company Theravance Biopharma [6]. If clinical trials underway confirm the efficacy and safety of the drug, the agent would expand the pharmacotherapeutic armamentarium against nOH. NET inhibitors for nOH is not a new concept, with other “oxetine” drugs, such as atomoxetine, being used [12, 13]. Of concern with these agents is the possibility of worsening supine hypertension. As Lo and colleagues report, ampreloxetine has a long plasma half-life of 30–40 h. This means that with daily dosing the levels of the drug would not plateau until after several days. Therefore, adverse effects might not appear immediately after initiating treatment. Blood pressure monitoring with attention to blood pressure at night will be key for patient safety. In addition to the issue of supine hypertension, the underlying pathophysiology can guide the choice of pharmacotherapy for nOH. Lo and colleagues focused on synucleinopathies, which are disorders characterized by the abnormal deposition of the misfolded protein, α-synuclein, in central or peripheral neurons or glial cells. Synucleinopathies include Parkinson disease (PD), dementia with Lewy bodies (DLB), pure autonomic failure (PAF), and multiple system atrophy (MSA). These disorders typically feature baroreflex failure [5]. Consequently, treatment with drugs that enhance the delivery of endogenous norepinephrine to the adrenergic vascular receptors, such as NET inhibitors, should result in a sustained pressor response. This potentially amplifies concern about worsening supine hypertension with ampreloxetine. Although there is some overlap in clinical presentations, the sites of the lesions in synucleinopathies vary, and in the study of Lo and colleagues the different disorders were lumped. Severe peripheral noradrenergic deficiency is a feature of PAF and PD with nOH but is rarely associated with MSA [3, 10]. Ampreloxetine therefore might be expected to produce larger, more sustained blood pressure increases in patients with preserved peripheral * Graeme Eisenhofer Graeme.Eisenhofer@uniklinikum-dresden.de

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