In an adult with symptomatic orthostatic (neurogenic) hypotension refractory to non‑pharmacologic measures, how should midodrine be initiated, titrated, monitored, and what are its contraindications and second‑line alternatives?

Midodrine for Symptomatic Orthostatic Hypotension

Initiation and Dosing

Start midodrine at 2.5–5 mg orally three times daily (morning, midday, late afternoon), with the last dose no later than 6 PM, and titrate up to 10 mg three times daily based on standing blood pressure response and symptom relief. 1

• The standard effective dose is 10 mg three times daily, which increases standing systolic blood pressure by 15–30 mmHg for 2–3 hours and significantly improves symptoms of lightheadedness, dizziness, and syncope. 1, 2
• A dose-response study demonstrated a significant linear relationship between midodrine dosage (2.5,10, or 20 mg) and mean systolic blood pressure increase, with peak effect at 1 hour post-dose. 3
• Midodrine has the strongest evidence base among pressor agents for orthostatic hypotension, supported by three randomized placebo-controlled trials demonstrating efficacy at doses ranging from 5–20 mg three times daily. 1
• The active metabolite desglymidodrine has a half-life of approximately 4 hours, supporting a two-to-three-times-daily dosing schedule. 3

Mechanism of Action

• Midodrine is a prodrug that undergoes enzymatic hydrolysis to desglymidodrine, a selective alpha-1 adrenergic receptor agonist. 4, 5
• Desglymidodrine produces arteriolar constriction (increasing peripheral vascular resistance) and venoconstriction of capacitance vessels (improving central blood volume) without significant cardiac stimulation. 4, 6

Critical Timing to Prevent Supine Hypertension

The last dose of midodrine must be taken at least 3–4 hours before bedtime (not later than 6 PM) to reduce the risk of supine hypertension during sleep. 1

• Supine hypertension occurs in up to 25% of patients but can be minimized by avoiding evening doses. 4, 5
• Elevate the head of the bed by 10 degrees during sleep to prevent nocturnal polyuria, maintain favorable fluid distribution, and ameliorate nocturnal hypertension. 1
• Monitor both supine and standing blood pressure at each visit to detect treatment-induced supine hypertension. 1

Monitoring Parameters

Measure blood pressure after 5 minutes lying/sitting, then at 1 and 3 minutes after standing to document orthostatic changes and assess treatment response. 1

• The therapeutic goal is minimizing postural symptoms and improving functional capacity, NOT restoring normotension. 1
• Reassess the patient within 1–2 weeks after initiating or adjusting midodrine. 1
• Monitor for adverse effects including piloerection, pruritus, paresthesias, urinary retention, chills, and bradycardia. 5, 6
• Bradycardia occurs through reflex parasympathetic (vagal) stimulation in response to midodrine's alpha-1 adrenergic-mediated increase in peripheral vascular resistance and blood pressure. 4

Contraindications and Precautions

Avoid midodrine in patients with:

• Severe supine hypertension (systolic BP >180 mmHg supine). 1
• Acute kidney disease or urinary retention. 5, 6
• Thyrotoxicosis or pheochromocytoma. 6

Use with caution when co-administering:

• Beta-blockers, non-dihydropyridine calcium channel blockers, or other negative chronotropic agents, as these may enhance bradycardia. 4
• The combination of midodrine and beta-blockers can lead to more pronounced bradycardia and potentially reduced ejection fraction. 4

Adjunctive Non-Pharmacological Measures

Implement these measures alongside midodrine therapy:

• Increase fluid intake to 2–3 liters daily and salt consumption to 6–9 grams daily, unless contraindicated by heart failure. 1
• Use waist-high compression stockings (30–40 mmHg) and abdominal binders to reduce venous pooling. 1
• Teach physical counter-maneuvers (leg crossing, squatting, stooping, muscle tensing) during symptomatic episodes, particularly effective in patients under 60 years with prodromal symptoms. 1
• Eat smaller, more frequent meals to reduce postprandial hypotension. 1

Combination Therapy for Inadequate Response

If midodrine alone provides insufficient symptom control, add fludrocortisone 0.05–0.1 mg once daily, titrating to 0.1–0.3 mg daily. 1

• The two agents act via complementary mechanisms: midodrine provides alpha-1 adrenergic vasoconstriction while fludrocortisone increases plasma volume through sodium retention and vessel wall effects. 1
• When adding fludrocortisone, monitor for supine hypertension, hypokalemia, congestive heart failure, and peripheral edema. 1
• Avoid fludrocortisone in patients with active heart failure, significant cardiac dysfunction, or pre-existing supine hypertension. 1

Second-Line Alternatives

For patients refractory to midodrine or with contraindications:

• Droxidopa is FDA-approved and particularly effective for neurogenic orthostatic hypotension in Parkinson's disease, pure autonomic failure, and multiple system atrophy. 1
• Pyridostigmine 60 mg orally three times daily is recommended for elderly patients with refractory orthostatic hypotension, especially those with concurrent supine hypertension, as it does not worsen supine blood pressure and does not cause fluid retention. 1
• Pyridostigmine works by inhibiting acetylcholinesterase, enhancing ganglionic sympathetic transmission and increasing peripheral vascular resistance preferentially in the upright position. 1

Special Populations

In hemodialysis patients with intradialytic hypotension:

• Administer midodrine 5–10 mg orally 30 minutes before initiating hemodialysis to effectively prevent intradialytic hypotension and improve hemodynamic stability. 4
• Midodrine is effectively cleared during dialysis, reducing its half-life to 1.4 hours. 4

In patients with hepatic impairment:

• Initiate midodrine at the lower end of the dosing range (2.5 mg three times daily) and adjust based on clinical response, as the FDA label does not provide specific hepatic dose adjustments. 1

Common Pitfalls to Avoid

• Do not administer midodrine after 6 PM, as this significantly increases the risk of nocturnal supine hypertension. 1
• Do not simply reduce the dose of offending antihypertensive medications; switch to alternative agents (long-acting dihydropyridine calcium channel blockers or RAS inhibitors) that are less likely to worsen orthostatic hypotension. 1
• Do not combine multiple vasodilating agents (ACE inhibitors + calcium channel blockers + diuretics) without careful monitoring. 1
• Do not overlook volume depletion as a contributing factor before initiating pharmacotherapy. 1
• Do not use fludrocortisone in patients with heart failure or supine hypertension. 1