What are the considerations for using atomoxetine (a norepinephrine reuptake inhibitor) in an older adult patient with orthostatic hypotension and potential autonomic dysfunction who has failed first-line therapies?

Atomoxetine Considerations in Older Adults with Orthostatic Hypotension

Critical Safety Concerns

Atomoxetine should be used with extreme caution in older adults with orthostatic hypotension and autonomic dysfunction, as the FDA label explicitly warns that it can worsen underlying cardiovascular conditions through increases in blood pressure and heart rate. 1

Cardiovascular Contraindications and Warnings

• Atomoxetine is contraindicated in patients with severe cardiovascular disorders that might deteriorate with clinically important increases in heart rate and blood pressure. 1
• The FDA warns that sudden deaths, stroke, and myocardial infarction have been reported in adults taking atomoxetine at usual doses, and consideration should be given to not using atomoxetine in adults with clinically significant cardiac abnormalities. 1
• Atomoxetine increases blood pressure and heart rate through its noradrenergic effects, which directly contradicts the pathophysiology of orthostatic hypotension where patients need blood pressure support in the upright position but risk supine hypertension. 1

Blood Pressure and Heart Rate Effects

• In adult clinical trials, atomoxetine caused mean heart rate increases of 7.5 beats/minute in extensive metabolizers and 11 beats/minute in poor metabolizers, with tachycardia reported as an adverse event in 1.5% of patients. 1
• The FDA label specifically states atomoxetine should be used with caution in patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease. 1
• Pulse and blood pressure must be measured at baseline, following dose increases, and periodically during therapy to detect clinically important increases. 1

When Atomoxetine Might Be Considered

Despite FDA warnings, atomoxetine may have a role as a second-line or third-line agent specifically in patients with neurogenic orthostatic hypotension who have failed first-line therapies (midodrine, fludrocortisone, droxidopa) and who do NOT have significant supine hypertension. 2, 3, 4

Mechanism and Rationale

• Atomoxetine blocks norepinephrine reuptake in sympathetic nerve terminals, increasing synaptic norepinephrine concentrations and raising blood pressure by harnessing residual sympathetic tone. 5, 4
• This mechanism is particularly relevant in patients with autonomic failure who retain some residual sympathetic activity. 5, 6
• Unlike midodrine and droxidopa, atomoxetine may cause less pronounced supine hypertension, though this advantage is not absolute. 4, 6

Evidence for Efficacy

• A case report demonstrated that low-dose atomoxetine (specific dose not detailed) was effective and safe for symptom improvement and blood pressure control over 10 weeks in an 84-year-old man with primary orthostatic hypotension who had failed fludrocortisone, midodrine, and pyridostigmine. 3
• A randomized crossover study showed that atomoxetine 18 mg alone did not significantly improve blood pressure or orthostatic tolerance in severely affected autonomic failure patients, but when combined with pyridostigmine 60 mg, produced a synergistic pressor effect with seated blood pressure increasing by 33±8/18±3 mm Hg and improved orthostatic tolerance. 5

Practical Management Algorithm

Step 1: Confirm First-Line Therapy Failure

• Document that the patient has failed or cannot tolerate midodrine (2.5-5 mg three times daily), fludrocortisone (0.05-0.3 mg daily), and/or droxidopa. 2
• Ensure non-pharmacological measures have been maximized: increased fluid intake (2-3 L daily), salt intake (6-9 g daily), compression garments, head-of-bed elevation, physical counter-maneuvers, and smaller frequent meals. 2

Step 2: Assess Cardiovascular Risk

• Obtain detailed cardiovascular history including assessment for family history of sudden death or ventricular arrhythmia. 1
• Perform physical examination and consider electrocardiogram and echocardiogram to assess for structural cardiac abnormalities, cardiomyopathy, or serious heart rhythm abnormalities. 1
• Do NOT use atomoxetine if the patient has severe cardiac or vascular disorders, clinically significant cardiac abnormalities, or a history of stroke or myocardial infarction. 1

Step 3: Measure Baseline Supine and Standing Blood Pressure

• Measure blood pressure after 5 minutes lying/sitting, then at 1 and 3 minutes after standing. 2
• Atomoxetine should be avoided or used with extreme caution if significant supine hypertension (>160/90 mm Hg supine) is present, as it will worsen this condition. 1, 4
• Document baseline heart rate, as atomoxetine will increase heart rate by approximately 7-11 beats/minute. 1

Step 4: Consider Combination Therapy with Pyridostigmine

• If atomoxetine is to be used, strongly consider combining it with pyridostigmine 60 mg rather than using atomoxetine alone, as the combination produces synergistic blood pressure increases and improved orthostatic tolerance. 5
• Pyridostigmine facilitates cholinergic neurotransmission in autonomic ganglia to increase sympathetic outflow, complementing atomoxetine's peripheral norepinephrine reuptake blockade. 5, 4
• The combination is particularly valuable in severely affected patients where monotherapy with either agent fails. 5

Step 5: Initiate Low-Dose Atomoxetine with Close Monitoring

• Start with atomoxetine 18 mg once daily (lower than the FDA-recommended 40 mg starting dose for ADHD), as this dose has been studied in orthostatic hypotension. 3, 5
• Measure blood pressure (supine and standing) and heart rate at baseline, after 1-2 weeks, and periodically thereafter. 1
• Monitor for symptoms of cardiac disease including exertional chest pain, unexplained syncope, palpitations, or worsening orthostatic symptoms. 1
• Discontinue immediately if supine hypertension worsens significantly, tachycardia develops, or any cardiovascular symptoms emerge. 1

Step 6: Assess Response and Adjust

• Evaluate symptom improvement (reduction in dizziness, lightheadedness, falls, syncope) and standing blood pressure after 2-4 weeks. 3
• The therapeutic goal is minimizing postural symptoms and improving functional capacity, NOT achieving specific blood pressure targets. 2
• If inadequate response after 4 weeks, consider adding pyridostigmine 60 mg if not already prescribed, rather than increasing atomoxetine dose. 5

Critical Monitoring Parameters

• Supine and standing blood pressure at every visit - atomoxetine can cause clinically important increases in supine blood pressure that may lead to end-organ damage. 1, 4
• Heart rate monitoring - watch for tachycardia (≥20 bpm increase from baseline or resting heart rate >100 bpm). 1
• Cardiovascular symptoms - chest pain, palpitations, syncope, or worsening orthostatic intolerance require immediate cardiac evaluation and likely atomoxetine discontinuation. 1
• Liver function - although rare, atomoxetine can cause severe liver injury; discontinue if jaundice or laboratory evidence of liver injury develops. 1

Common Pitfalls to Avoid

• Do not use atomoxetine as a first-line agent - midodrine, fludrocortisone, and droxidopa have stronger evidence and FDA approval specifically for orthostatic hypotension. 2
• Do not ignore supine hypertension - atomoxetine will worsen supine hypertension, which can cause stroke, myocardial infarction, and end-organ damage. 1, 4
• Do not use standard ADHD dosing - the FDA-recommended starting dose of 40 mg daily for ADHD is too high for orthostatic hypotension; use 18 mg daily instead. 1, 5
• Do not overlook medication-induced orthostatic hypotension - the European Society of Cardiology emphasizes that drug-induced autonomic failure is the most frequent cause of orthostatic hypotension; discontinue or switch culprit medications (diuretics, alpha-blockers, vasodilators) before adding atomoxetine. 2
• Do not use atomoxetine in patients taking MAOIs - atomoxetine is contraindicated within 2 weeks of MAOI discontinuation. 1
• Do not use atomoxetine in patients with narrow-angle glaucoma or pheochromocytoma - these are absolute contraindications. 1

Special Considerations in Older Adults

• Older adults (≥85 years) with orthostatic hypotension, moderate-to-severe frailty, or limited life expectancy should have blood pressure-lowering treatment deferred until blood pressure is >140/90 mm Hg, making the management of concurrent hypertension and orthostatic hypotension particularly complex. 7
• The European Society of Cardiology recommends that asymptomatic orthostatic hypotension during hypertension treatment should not trigger automatic down-titration of therapy, as intensive blood pressure lowering may actually reduce the risk of orthostatic hypotension by improving baroreflex function. 7
• However, this principle does NOT apply to adding pressor agents like atomoxetine, which increase blood pressure through different mechanisms and carry cardiovascular risks. 1

Alternative Approaches if Atomoxetine is Contraindicated

• Pyridostigmine alone (60 mg three times daily) may be beneficial in refractory neurogenic orthostatic hypotension with a favorable side effect profile and no worsening of supine hypertension. 2
• Combination midodrine plus fludrocortisone for non-responders to monotherapy, with careful monitoring for supine hypertension. 2
• Non-pharmacological intensification including acute water bolus (≥480 mL) for temporary relief with peak effect at 30 minutes, and stricter adherence to compression garments and physical counter-maneuvers. 2, 4