What are the dosing parameters, contraindications, and monitoring recommendations for midodrine in adults with symptomatic orthostatic hypotension after non‑pharmacologic measures have failed?

Midodrine Dosing Parameters, Contraindications, and Monitoring

Start midodrine at 2.5–5 mg 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 symptom response and standing blood pressure improvement. 1

Dosing Parameters

Initial and Maintenance Dosing:

• Begin with 2.5–5 mg orally three times daily at approximately 4-hour intervals during waking hours 1, 2
• Titrate upward by 2.5 mg increments at weekly intervals based on clinical response 3
• Target maintenance dose is typically 10 mg three times daily 4, 5
• Maximum dose is 10 mg three times daily (some sources cite up to 20 mg, but 10 mg is the standard effective dose) 1, 5
• The 10-mg dose increases standing systolic blood pressure by approximately 15–30 mmHg for 2–3 hours 1

Critical Timing Considerations:

• Administer the final daily dose at least 3–4 hours before bedtime (no later than 6 PM) to prevent supine hypertension during sleep 1, 2
• Doses should be spaced approximately 4 hours apart during waking hours 1
• For hemodialysis patients with intradialytic hypotension, give 5–10 mg orally 30 minutes before initiating dialysis 2

Mechanism of Action

Midodrine is a prodrug that undergoes enzymatic hydrolysis to desglymidodrine, a selective α₁-adrenergic agonist 2, 6. This active metabolite produces:

• Arteriolar constriction, increasing peripheral vascular resistance 2
• Venoconstriction of capacitance vessels, improving central blood volume 2
• Peak blood pressure effect at 1 hour post-dose 5
• Duration of action approximately 2–3 hours, with desglymidodrine half-life of ~4 hours 1, 5

Contraindications and Precautions

Absolute Contraindications:

• Active heart failure or significant cardiac dysfunction 1
• Severe renal disease where sodium retention would be harmful 1
• Pre-existing supine hypertension 1

Relative Contraindications and Cautions:

• Use caution when combining with negative chronotropic agents (beta-blockers, digoxin, non-dihydropyridine calcium channel blockers) due to risk of enhanced bradycardia 2
• Avoid concurrent use with other α-adrenergic agents (ephedrine, pseudoephedrine, phenylpropanolamine) due to additive supine hypertension risk 1
• Can antagonize α-adrenergic blockers (terazosin, prazosin, doxazosin), potentially causing urinary retention 1

Monitoring Requirements

At Each Clinical Visit:

• Measure blood pressure after 5 minutes supine/sitting, then at 1 minute and 3 minutes after standing 1
• Monitor both supine and standing blood pressures to detect treatment-induced supine hypertension 1
• Assess symptom improvement (dizziness, lightheadedness, syncope, weakness, fatigue) 3, 4
• Reassess within 1–2 weeks after any medication changes 1

Specific Monitoring Parameters:

• Supine hypertension is the most important limiting factor, occurring in up to 25% of patients 1, 6
• Monitor heart rate for reflex bradycardia, which occurs via baroreceptor-mediated vagal stimulation in response to increased blood pressure 2
• In hemodialysis patients, midodrine is effectively cleared during dialysis (half-life reduced to 1.4 hours) 2

Common Adverse Effects

The most frequently reported side effects include 1, 6, 3:

• Piloerection (scalp tingling/pruritus): 13.5% of patients 3
• Supine hypertension: 8–25% of patients 6, 3
• Urinary urgency/retention: 4% 3
• Gastrointestinal symptoms 2
• Paresthesias and chills 6
• Bradycardia (via reflex parasympathetic stimulation) 2

Evidence Base

Midodrine has the strongest evidence among pressor agents for orthostatic hypotension, supported by three randomized placebo-controlled trials demonstrating efficacy at doses of 5–20 mg three times daily. 1 The 10-mg dose significantly increased standing systolic blood pressure by 22 mm Hg (28%, p<0.001 versus placebo) and improved symptoms including dizziness, lightheadedness, syncope, weakness, fatigue, and low energy level 3, 4.

Combination Therapy

When midodrine monotherapy provides insufficient symptom control, add fludrocortisone 0.05–0.1 mg once daily (titrated to 0.1–0.3 mg daily) because the agents act via complementary mechanisms: midodrine provides direct α₁-adrenergic vasoconstriction while fludrocortisone causes mineralocorticoid-mediated volume expansion 1. Monitor for supine hypertension, hypokalemia, congestive heart failure, and peripheral edema when adding fludrocortisone 1.

Adjunctive Non-Pharmacologic Measures

These should be implemented concurrently with midodrine 1:

• Increase fluid intake to 2–3 L daily and dietary sodium to 6–9 g daily (unless contraindicated by heart failure) 1
• Elevate head of bed by ~10° during sleep to prevent nocturnal polyuria and mitigate supine hypertension 1, 2
• Teach physical counter-pressure maneuvers (leg crossing, squatting, muscle tensing) for symptomatic episodes 1
• Use waist-high compression garments (30–40 mmHg) and abdominal binders 1
• Encourage acute water ingestion ≥480 mL for temporary relief (peak effect at 30 minutes) 1

Treatment Goals

The therapeutic objective is minimizing postural symptoms and improving functional capacity, NOT restoring normotension. 1 Balance the benefits of increasing standing blood pressure against the risk of worsening supine hypertension 1, 2.

Special Populations

Hepatic Impairment: Initiate at the lower end of the dosing range (2.5 mg three times daily) and adjust based on clinical response, as specific hepatic dose adjustments are not provided in FDA labeling 1.

Hemodialysis Patients: Administer 5–10 mg orally 30 minutes before initiating hemodialysis; the drug is effectively cleared during dialysis 2.