Pathophysiology and Treatment of Orthostatic Hypotension in Parkinsonian Disorders

Abstract

Orthostatic hypotension (OH) is defined as a sustained pathological reduction in blood pressure within 3 min after orthostatic stress such as tilt-table testing or active standing. Non-neurogenic OH is caused by either decreased cardiac output or impaired vasoconstriction without a primary autonomic disorder whereas neurogenic OH results from inadequate release of norepinephrine in the vasomotor sympathetic system. Once non-neurogenic causes of OH such as medications and cardiac problems are ruled out, neurogenic OH can be considered. Neurogenic OH can accompany parkinsonian diseases in different stages and is associated with increased risk of morbidity and mortality. The pathophysiology of neurogenic OH in parkinsonian diseases includes sympathetic neurocirculatory failure and impaired cardiovagal activity. The inadequate release of peripheral norepinephrine upon orthostatic stress is a final pathologic pathway for neurogenic OH and is important for many therapeutic interventions. With mild or early autonomic failure, OH that occurs beyond 3 min of standing (defined as delayed OH) can result in orthostatic intolerance. Supine hypertension and postprandial hypotension are frequent comorbidities and may exacerbate orthostatic hypotension. The non-pharmacologic therapies should be tried initially, followed by pharmacologic treatments. Common medications used in the treatment of OH include fludrocortisone, midodrine, pyridostigmine, and droxidopa. Only midodrine and droxidopa have received FDA approval for the treatment of orthostatic hypotension.

Parkinson disease-associated cognitive impairment

“…Moreover, a reduction in brain noradrenaline trans porter availability correlates with cognitive decline and orthostatic hypotension in PD 59 and neurogenic ortho static hypotension in PD owing to noradrenergic den ervation of the heart is independently associated with cognitive decline 60 . The underlying mechanism of this association is due to cerebral hypoperfusion caused by orthostatic hypotension, which impairs cognitive function, with noradrenalineenhancing drugs recom mended for the treatment of orthostatic hypotension 61,62 .…”

Parkinson disease-associated cognitive impairment

“…Moreover, a reduction in brain noradrenaline transporter availability correlates with cognitive decline and orthostatic hypotension in PD 59 , and neurogenic orthostatic hypotension in PD owing to noradrenergic denervation of the heart is independently associated with cognitive decline 60 . The underlying mechanism of this association is due to cerebral hypoperfusion caused by orthostatic hypotension, which impairs cognitive function, with noradrenaline-enhancing drugs recommended for the treatment of orthostatic hypotension 61,62 . Of note, the properties of noradrenergic neurons make them more susceptible to oxidative DNA damage compared with other neurons 63 , an increasing problem in patients with reduced blood flow during orthostasis.…”

Neurogenic Orthostatic Hypotension: State of the Art and Therapeutic Strategies

“…The pathophysiology of SH is more complex and stems from an impaired baroreflex mechanism and a chronically activated renin-angiotensin system. 52 Impaired baroreflex buffering of the BP, inappropriate natriuresis, higher blood volume, and residual sympathetic tone acting on hypersensitive postsynaptic adrenoreceptors in nOH, all play an important role. 53 During the day, while patients spend most of their time in a seated or upright position and blood pressure is low, sodium excretion is decreased, and blood volume is increased.…”

“…nOH patients with an impaired baroreflex do not appropriately compensate for this shift and thus develop SH. 52 These patients also have chronically activated renin-angiotensin system that exacerbates this problem. In this feedback loop, SH causes nocturnal pressure-diuresis and hypovolemia leading to worsening of early morning orthostatic symptoms.…”