What is the recommended dosage of midodrine (prodrug) for treating orthostatic hypotension?

Midodrine for Orthostatic Hypotension: Indications and Dosage

Primary Indication

Midodrine is the only FDA-approved medication specifically indicated for symptomatic orthostatic hypotension, and should be initiated at 10 mg three times daily during daytime hours when the patient needs to be upright. 1

Dosing Regimen

Standard Dosing

• Start with 10 mg three times daily at approximately 4-hour intervals during daytime hours 2, 1
• Recommended schedule: upon arising in the morning, midday, and late afternoon (not later than 6 PM) 1
• Doses may be given at 3-hour intervals if required to control symptoms, but not more frequently 1
• The last dose must be taken at least 4 hours before bedtime to prevent supine hypertension during sleep 3, 1

Dose Titration

• Single doses as high as 20 mg have been used, but severe supine hypertension occurs in approximately 45% of patients at this dose 1
• Total daily doses greater than 30 mg have been tolerated but safety has not been systematically established 1
• Standing systolic blood pressure typically increases by 15-30 mmHg at 1 hour post-dose, with effects persisting for 2-3 hours 1, 4

Special Populations

• Renal impairment: Initiate at 2.5 mg doses, as desglymidodrine is renally excreted 1
• Hemodialysis patients: Single 5 mg dose administered 30 minutes before dialysis improves intradialytic and postdialytic blood pressure 2
• No dose adjustment needed for elderly patients or based on sex 1

Clinical Efficacy Evidence

The evidence base for midodrine is robust, with three randomized placebo-controlled trials demonstrating efficacy 3:

• 10 mg doses significantly improved standing systolic BP by approximately 22-30 mmHg 4, 5
• Symptom improvement (dizziness, lightheadedness, syncope) was significant compared to placebo 6, 5
• Time to syncopal symptoms increased by 521 seconds (approximately 8.7 minutes) on tilt-table testing 7

Treatment Algorithm

Step 1: Non-Pharmacological Measures First

Before or concurrent with midodrine initiation 2, 3:

• Increase fluid intake to 2-3 liters daily (unless contraindicated by heart failure) 3
• Increase salt intake to 6-9 grams daily (unless contraindicated) 3
• Use waist-high compression stockings (30-40 mmHg) and abdominal binders 3
• Teach physical counter-maneuvers: leg crossing, squatting, muscle tensing 3
• Elevate head of bed by 10 degrees during sleep 3

Step 2: Initiate Midodrine

• Start 10 mg three times daily (morning, midday, late afternoon before 6 PM) 1
• Monitor standing and supine blood pressure regularly 1
• Therapeutic goal is minimizing postural symptoms, not restoring normotension 2, 3

Step 3: Assess Response and Adjust

• Continue only if symptomatic improvement occurs during initial treatment 1
• If insufficient response, consider adding fludrocortisone 0.05-0.1 mg daily 2, 3
• Combination therapy with midodrine and fludrocortisone is appropriate for non-responders to monotherapy 2

Critical Safety Considerations

Supine Hypertension

• Most important limiting factor with midodrine therapy 3
• Monitor supine blood pressure regularly; discontinue if excessive elevation occurs 1
• Never administer after evening meal or within 4 hours of bedtime 1
• Supine systolic BP ≥200 mmHg occurred in 22% at 10 mg and 45% at 20 mg doses 1

Common Side Effects

• Piloerection (goosebumps) is common 2
• Urinary retention or urgency (4% of patients) 2, 6
• Scalp pruritus/tingling (13.5% of patients) 5
• Bradycardia and gastrointestinal symptoms 2

Drug Interactions and Contraindications

• Use cautiously with beta-blockers, digoxin, and non-dihydropyridine calcium channel blockers 2
• Avoid concomitant use with other alpha-adrenergic agents (may aggravate supine hypertension) 2
• Can antagonize alpha-blockers (terazosin, prazosin, doxazosin) and cause urinary retention 2
• Avoid in patients with active heart failure or severe cardiac dysfunction 3

Mechanism of Action

Midodrine is a prodrug converted to desglymidodrine, a selective peripheral alpha-1 adrenergic agonist 1:

• Increases vascular tone through arteriolar and venous constriction 1
• Does not stimulate cardiac beta-receptors 1
• Poor blood-brain barrier penetration (minimal CNS effects) 2, 1
• Peak effect at 1-2 hours post-dose with half-life of 3-4 hours 1
• Bioavailability 93%, not affected by food 1

Monitoring Parameters

• Measure BP after 5 minutes lying/sitting, then at 1 and 3 minutes after standing 3
• Monitor both standing and supine blood pressure at each visit 3
• Check electrolytes if using combination therapy with fludrocortisone 3
• Reassess within 1-2 weeks after medication changes 3
• Discontinue if no symptomatic improvement or if supine hypertension develops 1