Etiology
Healthy aging is associated with decreased autonomic buffering capacity, which can impair adaptation to orthostatic stress. This predisposes older people to orthostatic hypotension (OH), which may be triggered by medications (e.g., alpha-blockers [used for treating conditions such as benign prostatic hypertrophy], central sympatholytics, including tizanidine [used as a muscle relaxant] and methyldopa [used as an antihypertensive], tricyclic antidepressants, phosphodiesterase-5 inhibitors [used to treat erectile dysfunction], and antihypertensives, including beta-blockers) or other circumstances (e.g., volume depletion, physical deconditioning due to prolonged bed rest).[18]
Many diseases that cause peripheral neuropathy (most notably diabetes mellitus and amyloidosis) can produce autonomic neuropathy and neurogenic OH.[19][20]
Patients with Parkinson disease and dementia with Lewy bodies, two related conditions, frequently suffer neurogenic OH of varying severity. Other neurodegenerative disorders that affect the autonomic nervous system are less common but are associated with severe OH. These include pure autonomic failure (a Lewy body synucleinopathy in which mostly the peripheral autonomic nerves are involved, without a movement disorder phenotype) and multiple system atrophy (MSA, previously called Shy-Drager syndrome), which can have atypical parkinsonian features (MSA-P) or symptoms of cerebellar ataxia (MSA-C).[21]
An acute or subacute onset of progressive autonomic failure may be caused by an autoimmune autonomic ganglionopathy (often with antibodies against the ganglionic nicotinic acetylcholine receptor) or a paraneoplastic syndrome (most often small cell lung cancer, monoclonal gammopathies, or light-chain disease).[22]
Pathophysiology
When a healthy person stands, about 700 mL of blood pools in the leg veins and the lower abdominal veins. Venous return to the heart decreases, resulting in a transient decline in cardiac output. This leads to baroreflex-mediated sympathetic activation with an increase in cardiac stroke volume and peripheral vasoconstriction, as well as parasympathetic withdrawal with an increase in heart rate. These rapid hemodynamic changes prevent blood pressure from falling.
Failure of these mechanisms causes OH. Cerebral blood flow normally remains constant throughout a wide range of blood pressures by autoregulation, but the mechanism is overwhelmed when systolic blood pressure is around 50 mmHg at brain level (about 70 mmHg at cardiac level when a person is standing), leading to lightheadedness and syncope.
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