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Supplements Understanding the Diagnosis, Management, and Treatment Options for Neurogenic Orthostatic Hypoten

Managed Care Approach to the Treatment of Neurogenic Orthostatic Hypotension

Stuart H. Isaacson, MD

Neurogenic orthostatic hypotension (NOH) is an orphan disease that primarily affects patients with neurodegenerative disorders such as Parkinson’s disease and multiple system atrophy. The first step in the management of NOH is to discontinue or minimize the use of drugs that lower blood pressure. Nonpharmacologic therapy for NOH includes physical countermaneuvers, compression abdominal binders and lower extremity stockings, recognition and avoidance of orthostatic stressors, hydration, and salt supplementation. The manage-ment of NOH should also include interventions to prevent falls. Pharmacotherapy for NOH includes the mineralocorticoid drug fludrocortisone to expand plasma volume and the sympathomimetic drugs midodrine and droxidopa. Clinical efficacy, tolerability, and the role of each drug in the treat-ment paradigm are reviewed here.

                        Am J Manag Care. 2015;21:S258-S268

NOH is an uncommon disorder with multiple treat-ment considerations. Clinicians often must make use of nonpharmacologic treatments and pharmacotherapy to improve the daily activities and QOL of patients who suffer symptoms of NOH. Until recently, midodrine and fludrocortisone were the mainstays for drug therapy of NOH. The recent approval of droxidopa adds to the clinician’s armamentarium, providing patients with another alternative to treat symptoms of NOH.
http://isaac_image2.jpgOrthostatic hypotension (OH) caused by non-neurogenic mechanisms like volume depletion or cardiac failure is common, especially in elderly patients.1,2 In comparison, neurogenic orthostatic hypotension (NOH) is a rare disorder that occurs primarily in patients already given a diagnosis of a degenerative disease such as Parkinson’s disease (PD), diffuse Lewy body disease, pure autonomic failure, or multiple system atrophy (MSA).3 Patients with severe NOH suffer from debilitating symptoms that substantially impair their ability to complete activities of daily living and reduce their quality of life (QOL). Classic NOH symptoms, such as orthostatic dizziness and syn-cope, and less appreciated symptoms, such as coat-hanger pain and cognitive impairment, can force patients to cur-tail activities that involve standing or walking.4

As a rare disease, NOH has unique management challenges with few well-established treatments, and it requires a patient-oriented approach in which nonphar-macologic strategies may be augmented by pharmaco-therapy. In addition, patients with NOH might be treated with drugs for comorbid disorders that exacerbate NOH and, as a result, they are at risk for drug interactions and adverse effects.5-7

Treatment Goals and Plans

The goals of NOH treatment are to reduce symptoms, improve functional ability and QOL, and reduce the occurrence of falls and syncope.7 The associated risks of fractures, trauma, and functional decline make fall prevention an important priority in the management of patients with NOH.8 Considering that this disease reflects degenerative autonomic dysfunction, restoration of normal blood pressure responses is not a realistic treatment goal. Instead, maintaining standing and supine blood pressures within the range of cerebral autoregulation (approximately 90 mm Hg) will aid in reducing symptoms. Approximately half of patients with NOH also suffer from supine hypertension (SH).9 In these patients, an additional goal is to minimize increases in supine blood pressure.

The Figure7,10,11 depicts a treatment algorithm for managing NOH.7 Patients with NOH are often elderly with multiple comorbidities and a high rate of poly-pharmacy.5-7 Therefore, the first step in management is to assess the patient’s treatment regimen for drugs that cause OH.9 A strong emphasis on patient education is necessary to teach patients how to perform physi-cal countermaneuvers and implement other nondrug measures that improve QOL, including minimizing orthostatic stressors. The head of the bed should be maintained at 30 degrees or higher to minimize SH and reduce nocturnal diuresis. Pharmacotherapy is needed for patients who remain symptomatic despite nonpharmacologic interventions. Management options for NOH, through both nonpharmacologic treatment and pharmacotherapy, act by either volume expansion or vasoconstriction (see Table 17,10).7,10

Druginduced Orthostatic Hypotension

Receiving multiple drugs that can cause OH increases the risk of a patient suffering from symp-tomatic OH.5,12 Drug classes commonly linked to causing OH include diuretics, alpha1-antagonists, antidepressants, antipsychotics, levodopa and dopaminergic drugs for PD, and vasodilators (see Table 25,6,13-20).5,12-14 Within drug classes, specific agents may have an especially high risk of causing OH; some of these are listed on the American Geriatric Society Beers Criteria for Potentially Inappropriate Medication Use in Older Adults because they pose a risk for elderly patients in general. Drugs listed on the Beers Criteria because they increase the risk of OH in the elderly include amitriptyline, clomipramine, doxazosin, doxepin over 6 mg/day, imipramine, prazosin, terazosin, and trimipramine.15

In male patients, benign prostatic hypertrophy may be treated with an alpha1-antagonist, leading to exacerbation of OH. Prazosin, which has high affinity to alpha1-receptors and a rapid onset of action, is considered the alpha1-antagonist with the highest risk of causing OH.16 A recent analysis of medical claims data found that even “urospecific” alpha1-antagonists, such as silodosin and tamsulosin, were linked to a higher risk of hip fracture during early use, likely due to OH.21 An increased risk of hospitalization for hypotension has been reported in men soon after starting tamsulosin, with a 2-fold increase in risk during the first month of therapy.22 An analysis of the FDA Adverse Events Reporting System found a signal for most alphaantagonists, with a reporting odds ratio for OH of 2.66 for doxazosin, 3.31 for tamsulosin, 4.21 for alfuzosin, and 6.13 for terazosin.23

Atypical antipsychotic drugs with high alpha1-antagonist activity increase the risk of OH, especially clozapine, iloperidone, and quetiapine. Increased rates of OH have been reported with the low-potency drugs chlorpromazine and thioridazine.14 Volume depletion and autonomic dysfunction are risk factors for developing symptomatic OH with alpha1-antagonists and antipsychotic drugs.14,16 Tricyclic antidepressants can cause OH and increase the risk of falling, with the highest risks identified for amitriptyline, imipramine, and doxepin. Monoamine oxidase inhibitors and trazodone can also cause OH.17

A new class of diabetes drugs, the sodium glucose co-transporter 2 inhibitors (canagliflozin, dapagliflozin, empagliflozin), causes an osmotic diuresis via increased renal excretion of glucose.24 They can cause symp-tomatic hypotension in certain groups of susceptible patients, including patients with impaired renal func-tion, the elderly, patients undergoing coadministration of diuretics, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers, and those with low systolic blood pressure.25 However, a meta-analysis of clinical trial data did not find a significant risk of OH.24 Considering how important it is for patients with NOH to maintain optimal intravascular volume, it may be pru-dent for them to avoid this class of drugs.

Dopaminergic drugs used to treat motor symptoms of PD can lower blood pressure and may exacerbate NOH. Levodopa can cause reductions in blood pressure in patients who have PD, and higher doses were linked to an increased risk of falls in one study.18,26 Dopamine agonists also commonly cause OH, which can be symp-tomatic.19 Symptomatic OH has also been noted with selegiline and amantadine.6,19

Antihypertensive drugs, particularly diuretics, can cause OH. In epidemiologic studies of patients with PD, diuretics increased the odds of OH by more than 5-fold and the odds of falling by more than 3-fold.6,26 Probably because negative effects on cardiac conduction and contractility prevent a compensatory increase in heart rate when standing, the nondihydropyridine calcium channel blockers diltiazem and verapamil can cause OH.20 Despite the risk of OH with some antihypertensive drugs, maintaining blood pressure control is an important goal because uncontrolled hypertension exacerbates OH and increases the risk of falling.7,27

Physical Countermaneuvers and Patient Education

Physical countermaneuvers that reduce venous pooling are an important strategy patients can use to increase orthostatic tolerance and prevent syncope. These measures include crossing one’s legs while standing, squatting, and tensing muscles in the legs, thighs, and buttocks.28,29 Routine use of leg-crossing in patients with autonomic failure can increase blood pressure by approximately 20/10 mm Hg. Bending forward can also increase orthostatic tolerance; this maneuver lowers the head to heart level and increases cardiac output through abdominal compression.30 Video instructions and tutorials that demonstrate these techniques can be viewed at www.syncopedia.org31 and An important limitation for physical countermaneuvers is that patients who are elderly or debilitated may have difficulty performing them.

In addition to physical countermaneuvers, patients can employ external devices to increase their functionalability. Patients with adequate balance can use folding chairs when they feel lightheaded or have been walking for extended distances.33 In addition, elastic and pull-string abdominal binders can be used to increase standing blood pressure.34,35 Abdominal binders reduce pooling of blood in the splanchnic circulation, a greater contributor to venous pooling than the lower extremities. Thigh-high or waist-high compression stockings that provide at least 15 to 20 mm Hg of compression can also help reduce venous pooling on standing.7 However, abdominal binders and compression stockings can be difficult for patients to put on without assistance.36

Patients with NOH need to learn how to manage activities and conditions that cause orthostatic stress or exacerbate the disease. When they change positions, they should do so slowly to allow time for autonomic adaption. For instance, in going from a supine position to walking, patients should sit before standing and stand for several minutes before walking.37 Large meals, especially those high in carbohydrates and consumed with alcohol, can cause postprandial OH by causing vasodilation in the splanchnic circulation.38 Compared with 3 standard meals, eating 6 small meals has been shown to improve orthostatic symptoms and standing tolerance.35 Exercise, especially with activities that are recumbent or done in water, are encouraged in order to prevent deconditioning, which can exacerbate NOH.7 However, patients should avoid exercising in the morning, when orthostatic symptoms are typically worse.

Patients with NOH must be diligent to maintain intravascular volume because volume depletion can exacer-bate symptoms. The American Society of Hypertension recommends that NOH patients drink 1.5 to 2 L of water daily.7 In addition, they should consume 6 to 10 g of salt daily, taking 1 g of salt (as tablets) with each meal if needed. Drinking 300 to 500 mL of water over 3 to 4 minutes can induce a pressor effect that has an onset within 10 to 15 minutes, peaks at 40 minutes, and can last over an hour.3,10,39 Rapid water drinking induces hypo-osmolality in the portal vein, which triggers a sympathetic reflex. Drinking water is an important option for managing morning symptoms of NOH, as well as postprandial OH. As one expert notes, “Being free, readily available, and highly effective in many patients, water is the first-line ‘drug’ for NOH.”10

Additionally, patients should be advised to elevate the head of the bed at least 30 degrees to lower SH and reduce nocturnal diuresis. This may also improve baroreflex failure. Patients should be encouraged to document blood pressure measurements and orthostatic symptoms in a diary.3 This may be helpful in identifying orthostatic stressors and nondrug strategies to minimize orthostatic symptoms.

Fall Prevention

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