February 08, 2017
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Drug therapy for managing primary orthostatic hypotension

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Primary orthostatic hypotension is a condition that is overlooked and undertreated.

It is clinically defined as a decrease of 20 mm Hg in systolic or 10 mm Hg in diastolic BP within 3 minutes of standing. Primary orthostatic hypotension (OH) symptoms are a result of cerebral hypoperfusion due to autonomic nervous system dysfunction leading to an overcompensation of CV mechanisms in response to reduced venous return.

Symptoms are nonspecific, including light-headedness, visual changes, weakness, cognitive impairment and syncope. As a result, primary OH can be a significant cause of morbidity, disability or death if left untreated. There are several possible causes of primary OH, such as Parkinson’s disease, multiple system atrophy, pure autonomic failure, Lewy body dementia, autoimmune autonomic ganglionopathy, rare hereditary disorders or idiopathic causes. The management of this disease is a fine balance between nonpharmacological and pharmacological interventions.

Nonpharmacological strategies are first-line therapy in primary OH. When recommending any of the below strategies it is important to assess the patient’s disease severity, comorbidities and willingness/ability to perform these tasks. Discontinuing offending medications or switching medication administration to bedtime should be considered initially. Avoiding large carbohydrate-rich meals, limiting alcohol, maintaining adequate hydration and adding salt daily can also increase BP. The use of abdominal binders or compression stockings, or engaging in physical maneuvers such as standing with legs crossed, squatting, isometric exercises, toe raises or thigh, buttock and calf muscle contractions, and bending over at the waist can be performed to alleviate symptoms and raise BP.

All patients with primary OH should be instructed to rise slowly from supine or sitting to upright positions. Additionally, patients should sleep with the head of the bed elevated using pillows or a wedge, and rise slowly by sitting on the edge of the bed for several minutes while performing thigh, buttock or calf contractions. Canes or other walking assist devices should be utilized in the elderly and if moderate or severe symptoms are present.

Pharmacotherapeutic options

Genevieve Hale, PharmD, BCPS
Genevieve Hale

If nonpharmacological strategies fail, pharmacological therapy is indicated. However, evidence surrounding pharmacotherapeutic options for primary OH is limited. The most commonly used agents are midodrine, droxidopa (Northera, Lundbeck), fludrocortisone and pyridostigmine (see Table below).

Midodrine, an alpha-1 agonist, was the first medication approved by the FDA for the treatment of OH. Midodrine has substantial effects in primary OH as the peak onset occurs within 1 hour and lasts up to 4 hours. Midodrine is typically used first-line; however, patients with acute kidney injury, pheochromocytoma, thyrotoxicosis, pre-existing persistent excessive supine hypertension or urinary retention should avoid midodrine use. Also, it should not be administered within 4 hours of bedtime due to the risk for supine hypertension. Midodrine’s active metabolite, desglymidodrine, is renally eliminated and patients with chronic kidney disease should initiate therapy with doses no greater than 2.5 mg three times daily, with the dose increased slowly.

Droxidopa is a synthetic norepinephrine prodrug and is also FDA-approved for OH treatment. Droxidopa is particularly effective in patients with primary OH complicated by Parkinson’s disease, multiple system atrophy, dopamine beta-hydroxylase deficiency, pure autonomic failure or nondiabetic autonomic neuropathy. Given droxidopa’s mechanism of action, clinicians should be cautious if a patient is concomitantly on medications that increase norepinephrine such as sympathomimetic agents, alpha-1 agonists or alpha-2 agonists, as negative synergistic effects may occur.

Fludrocortisone, a mineralocorticoid, works by expanding volume intravascularly through increasing sodium reabsorption from the distal tubules and enhancing the sensitivity of alpha-adrenoreceptors. Fludrocortisone has been shown to improve both standing and supine BP, especially in patients with diabetes or Parkinson’s disease. As this agent has an extensive side effect profile consisting of, but not limited to, electrolyte abnormalities, weight gain and other metabolic effects, supine hypertension and edema, patients on long-term treatment must be monitored closely. It is also not recommended in patients with hypertension, HF and chronic kidney disease.

Pyridostigmine, an acetylcholinesterase inhibitor, is a good alternative for those at risk for supine hypertension as it has modest effects on supine or sitting BP. However, it is less effective for patients with severe autonomic failure. Pyridostigmine has a plethora of cholinergic effects, which may limit tolerance to this agent. In addition, patients with bradycardia or cardiac arrhythmias should be monitored carefully when receiving this agent as atrioventricular block and cardiac arrest have been reported with use. In patients with chronic kidney disease, glaucoma or respiratory diseases, such as asthma or chronic obstructive pulmonary disease, pyridostigmine may worsen these conditions.

Other therapies

Alternative pharmacological therapies in patients with primary OH include atomoxetine, sympathomimetic agents and octreotide (see Table).

Atomoxetine, a selective norepinephrine reuptake inhibitor, has recently demonstrated promising benefits in raising BP by increasing norepinephrine concentration in peripheral sympathetic neurons. However, in patients with serious structural cardiac abnormalities, cardiomyopathy, liver failure or severe mental illness, this agent should be avoided due to possible side effects, including sudden death, stroke, MI, hepatotoxicity, suicidal ideation, depression and aggressive behavior.

Salvage therapies for primary OH are octreotide and sympathomimetic agents. Octreotide is an injectable somatostatin analogue that causes vasoconstriction and has been shown to provide mild increases in BP. However, this agent promotes nocturnal BP lowering; therefore, symptoms may worsen as many patients typically have diminished BP upon waking. Patients with gastrointestinal issues, diabetes and thyroid disease must be monitored while on octreotide closely as gallstones, biliary sludging, gastrointestinal discomfort, dysglycemia and hypothyroidism may occur.

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Sympathomimetic agents, such as phenylpropanolamine and pseudoephedrine, cause modest BP increases. As noted above, use with droxidopa is not advised, and concomitant use with monoamine oxidase inhibitors is contraindicated. Sympathomimetic agents should be used with caution in patients with open-angle glaucoma, CAD, HF, prostatic hypertrophy, hyperthyroidism and urinary retention as these agents may exacerbate these conditions.

The goals of primary OH therapy are to reduce symptoms and to negate contributing insults, such as offending agents. Nonpharmacological strategies should be utilized in patients with mild symptoms. In patients with moderate to severe symptoms, pharmacological therapy should be considered. Selection of medications should be based on adverse effects, monitoring parameters, and concomitant disease and drug interactions. Initial treatment with midodrine, droxidopa, fludrocortisone and/or pyridostigmine is suggested. If symptoms progress, alternative agents such as atomoxetine, octreotide or sympathomimetic agents can be trialed.

Disclosure: Hale reports no relevant financial disclosures.