Introduction
Pathophysiology of Blood Pressure Control Abnormalities Associated with Autonomic Nervous System Dysfunction
Clinical Features and Consequences of Blood Pressure Dysregulation in Patients with Autonomic Dysfunction
Neurogenic Orthostatic Hypotension
Neurogenic Supine Hypertension
Altered Diurnal Blood Pressure Patterns
Management of neurogenic orthostatic hypotension when neurogenic supine hypertension is also present
Drug | Droxidopa | Midodrine | Fludrocortisone | Pyridostigmine |
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MOA | ● NE prodrug ● Conversion to NE induces vasoconstriction and increases BP | ● α1-Adrenoreceptor agonist prodrug ● Raises BP by increasing vascular resistance | ● Raises BP by increasing intravascular volume via renal sodium reabsorption | ● AChE inhibitor ● Enhances ganglionic transmission |
Indication | ● Treatment of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” in adult patients with symptomatic nOH caused by primary autonomic failure (PD, MSA, and pure autonomic failure), DβHD, or NDAN | ● Treatment of symptomatic OH | ● Off-label usea | ● Off-label useb |
Dosage | ● 100–600 mg TID (per prescribing information) | ● 10 mg TID (per prescribing information) | ● 0.1–0.2 mg/day; off-label use | ● 30–60 mg; 1–3 times/day; off-label use |
PD/PK data | ● t1/2, 2.5 h ● tmax, 2 h ● Peak pressor effect 3.5 h after dosing (coincident with NE, tmax, 3–4 h) | ● t1/2, 3–4 h ● tmax, 1–2 h ● Peak effects: 1 h after dosing | ● Plasma t1/2: ≥ 3.5 h; biological half-life: 18–36 h ● tmax, 2 h ● Peak effects not reported for nOH/OH | ● t1/2, 1.8 h ● tmax, 1.7 h ● Peak effects not reported for nOH/OH |
Key BP-related clinical findings | ||||
Standing | ● Mean SBP increase in RCTs, 12 mmHg ● Significant increase in daytime SBP from baseline in 24-h BP study (mean increase, 8.4 mmHg; P = 0.01) | ● Mean SBP increase (2 meta-analyses), 17–21 mmHg | ● Mean SBP increase vs baseline (1 study), 7 mmHg (0.2 mg) | ● Mean SBP increase vs baseline (3 studies), 0–13 mmHg (60 mg) |
Sitting | ● Not available | ● Mean/median SBP increase (2 RCTs), ~ 20–40 mmHg (5–10 mg) | ● Mean SBP increase vs baseline (1 study), 16 mmHg (0.2 mg) | ● Mean SBP increase vs baseline (1 study), 4 mmHg (60 mg) |
Supine | ● Mean BP ≤ 140 mmHg for 6 h after dosing (mean dose, 1147 mg) ● No significant increase in night-time SBP in 24-h BP study (mean increase, 7.8 mmHgc P = 0.12) | ● Mean SBP > 160 mmHg for up to 5 h after dosing (10 or 20 mg) ● Mean SBP increase (3 RCTs), 3–19 mmHg (2.5–10 mg) | ● Mean SBP increase vs baseline (1 study), 15 mmHg (0.2 mg) ● Raises nocturnal (i.e., supine) BP to a greater magnitude than daytime (i.e., standing) BP (mean, 156 vs 134 mmHg) | Mean SBP increase vs baseline (4 studies), 2–11 mmHg (60 mg) |
SH rates | ● 1- to 2-wk RCTsd o SBP > 160 mmHg: 9.9% (PBO, 6.1%) o SBP > 180 mmHg: 3.1% (PBO, 1.5%) o SBP > 200 mmHg: 0% (both groups) • 8- to 10-wk RCTsd o SBP > 160 mmHg: 28.9% (PBO, 24.1%) o SBP > 180 mmHg: 7.9% (PBO, 4.6%) o SBP > 200 mmHg: 3.5% (PBO, 0.9%) ● Rate of night-time SBP elevation in 24-h BP study (vs off treatment) o SBP >160, 56% (off, 44%) o SBP >180, 17% (off, 28%) o SBP >200, 6% (off, 0%) | ● Rates of supine SBP > 200 mmHg (single-dose study) o 17% (10 mg) o 41% (20 mg) ● 4 wk of active treatment (10 mg), 6% experienced SH (≥ 180/110 mmHg) leading to study discontinuation ● 4 wk of active treatment (2.5–10 mg TID), 8% experienced SH (≥180/110 mmHg); led to study discontinuation in 4/6 cases | ● SH rates not available | ● SH rates not available |
SH-specific warning (in PI) | Monitor supine BP before and during treatment and more frequently when increasing doses. Elevate the head of the bed during rest or sleep; BP should be measured in this position. If SH persists, reduce or discontinue (boxed warning) | Can cause marked elevation of supine BP; should be used in patients whose lives are considerably impaired despite standard clinical care (boxed warning) | Dosage and salt intake should be carefully monitored to avoid the development of hypertension (warning) | None |
Common AEs | ● Headache ● Dizziness ● Nausea ● Hypertension | ● Supine and seated hypertension ● Paresthesia and pruritus (scalp) ● Piloerection ● Chills ● Urinary urgency, retention, frequency | ● Hypertension ● Edema ● Cardiac enlargement ● Congestive heart failure ● Potassium loss ● Hypokalemic alkalosis | ● Nausea ● Vomiting ● Diarrhea ● Abdominal cramps ● Increased salivation ● Excessive sweating ● Urinary incontinence |
Nonpharmacologic Management of Neurogenic Orthostatic Hypotension
Pharmacologic Management of Neurogenic Orthostatic Hypotension
Comparisons of Fludrocortisone, Pyridostigmine, Midodrine, and Droxidopa
Stepwise Treatment Approach for Managing Supine Hypertension in Patients with Neurogenic Orthostatic Hypotension
Step 1: Awareness and Recognition of Neurogenic Supine Hypertension in Patients With Neurogenic Orthostatic Hypotension
Step 2: Diagnosis of Neurogenic Supine Hypertension
Step 3: Nonpharmacologic Treatment of Neurogenic Supine Hypertension
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Elevating the head of the bed can reduce supine BP [14, 95]. During nighttime, patients should sleep with the head of the bed elevated at least 6 to 9 inches (approximately 30°) [59]. If nSH persists, the angle of recumbence can be increasingly elevated, and some patients may need to sleep in a near-seated position (eg, in a recliner) to reduce supine hypertension [59]. A head-up sleeping position will reduce BP and natriuresis while keeping the renin-angiotensin system activated so that there will be less of a BP drop in the morning [1••, 26, 59, 96].
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To reduce nocturnal hypertension, patients can be advised to eat a high-carbohydrate snack at bedtime, which not only lowers BP by directing blood flow to the splanchnic circulation, but also causes insulin release (which has direct vasodilator properties) [97] with resultant vasodilation [1••, 98].
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Nonpharmacologic treatments for nSH should be continued even when pharmacotherapy is implemented.
Step 4: Pharmacologic Treatment of Neurogenic Supine Hypertension and Treatment Monitoring
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After therapy is initiated and at regular intervals, nOH symptoms and the patient’s home BP log should be re-evaluated (Fig. 1).
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If symptoms of nOH emerge or are exacerbated in the morning, consider adjusting the timing of the antihypertensive agent to earlier in the evening after dinner.
Medication (mechanism/class) | Typical dose | Half-life |
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Captopril (angiotensin-converting enzyme inhibitor) [26] | 25 mg at bedtime | < 3 h [101] |
Eplerenone (mineralocorticoid receptor antagonist) [25] | 50 mg at bedtime | 4–6 h [106] |
Hydralazine (vasodilator; peripheral smooth-muscle relaxant) [44] | 10–25 mg at bedtime | 3–7 h [102] |
Losartan (angiotensin II receptor antagonist, acting on AT1 receptor subtype) [103] | 25–50 mg at bedtime | 2 h (metabolite 6–9 h)a [99] |
Nifedipine (calcium channel blocker)b [104] | 30 mg at bedtime | 2 hc [105] |
Nitroglycerin patch (vasodilator) [44] | 0.1 mg/h patch at bedtime (remove patch in morning) | 3 min [100] |