Neurogenic orthostatic hypotension in Parkinson's disease: evaluation, management, and emerging role of droxidopa

Abstract

Neurogenic orthostatic hypotension (nOH) is due to failure of the autonomic nervous system to regulate blood pressure in response to postural changes due to an inadequate release of norepinephrine, leading to orthostatic hypotension and supine hypertension. nOH is common in Parkinson's disease (PD). Prevalence varies throughout the course of PD, ranging from 40% to 60%, and resulting in symptomatic nOH in approximately half. Symptomatic nOH, including lightheadedness, can limit daily activities and lead to falls. Symptomatic nOH can also limit therapeutic options for treating PD motor symptoms. Clinical evaluation should routinely include symptom assessment and blood pressure measurement of supine, sitting, and 3-minute standing; 24-hour ambulatory blood pressure monitoring can also be helpful. Non-pharmacological management of symptomatic nOH involves education, physical maneuvers, and adequate hydration. Current pharmacological treatment of symptomatic nOH includes salt supplement, fludrocortisone, midodrine, pyridostigmine, and other empiric medications. Despite these options, treatment of symptomatic nOH remains suboptimal, often limited by severe increases in supine blood pressure. Droxidopa, an oral prodrug converted by decarboxylation to norepinephrine, is a promising therapeutic option for symptomatic nOH in PD, improving symptoms of nOH, daily activities, falls, and standing systolic blood pressure in several recent trials. These trials demonstrated short-term efficacy and tolerability, with comparable increases in standing and supine blood pressures. Longer-term studies are ongoing to confirm durability of treatment effect.

Keywords: (pre)syncope; autonomic; falls; lightheadedness; norepinephrine; treatment.

Figure 1

Overlapping causes of symptomatic nOH (Venn diagram): 1) autonomic failure of NE pathways upon standing; 2) dopaminergic and other medications causing lower SBP; and 3) suboptimal hydration leading to reduced circulating blood volume. Note: *Medications include dopaminergic, diuretics, central adrenergic inhibitors, alpha-1 antagonists, nitrates. Abbreviations: nOH, neurogenic orthostatic hypotension; SBP, systolic blood pressure; s-SBP, standing SBP.

Figure 2

Treatment goals for patients with symptomatic nOH. Abbreviations: nOH, neurogenic orthostatic hypotension; s-SBP, standing systolic blood pressure.

Figure 3

Management of symptomatic nOH. Abbreviations: nOH, neurogenic orthostatic hypotension; s-SBP, standing systolic blood pressure.