What is the recommended dosing for midodrine (prodrug that acts as an alpha-1 adrenergic receptor agonist) in the treatment of orthostatic hypotension?

Midodrine Dosing for Orthostatic Hypotension

The recommended starting dose of midodrine for orthostatic hypotension is 10 mg three times daily, administered at approximately 4-hour intervals during daytime hours when the patient needs to be upright, with the last dose no later than 6 PM and never within 4 hours of bedtime. 1

Standard Dosing Regimen

• Start with 10 mg three times daily at approximately 4-hour intervals during waking hours when upright activity is needed 2, 1
• A typical schedule includes: shortly before or 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 and not after the evening meal to reduce the risk of supine hypertension during sleep 1

Dose Adjustments

• Single doses as high as 20 mg have been used, but severe and persistent supine hypertension occurs at a high rate (approximately 45%) at this dose 1
• Total daily doses greater than 30 mg have been tolerated by some patients, though safety and usefulness have not been systematically established 1
• For patients with renal impairment, initiate treatment at 2.5 mg doses and titrate cautiously, as the active metabolite desglymidodrine is renally excreted 1

Evidence Supporting This Dosing

The 10 mg three times daily regimen is supported by high-quality randomized controlled trials demonstrating significant improvements in standing systolic blood pressure (22 mmHg increase, 28% improvement, p<0.001) and orthostatic symptoms including syncope, dizziness, weakness, and energy level 3, 4. The half-life of the active metabolite desglymidodrine is approximately 4 hours, supporting the three-times-daily dosing schedule 5. Peak blood pressure effects occur at 1 hour post-dose with a dose-dependent linear relationship between midodrine dosage and systolic blood pressure response 5.

Critical Safety Considerations

• Monitor supine and standing blood pressure regularly and discontinue if supine blood pressure increases excessively 1
• Continue midodrine only in patients who demonstrate symptomatic improvement during initial treatment 1
• Use cautiously in patients with congestive heart failure and those taking negative chronotropic agents (beta-blockers, digoxin, non-dihydropyridine calcium channel blockers) 2
• Avoid concomitant use with other alpha-adrenergic agents as this may aggravate supine hypertension 2
• Midodrine can antagonize alpha-adrenergic blockers (terazosin, prazosin, doxazosin) and may result in urinary retention 2

Common Side Effects

• Piloerection (goosebumps) is the most common side effect, reported in approximately 13.5% of patients 2, 4
• Supine hypertension occurs in approximately 8% of patients at standard doses 4
• Urinary urgency or retention occurs in approximately 4% of patients 4
• Scalp pruritus/tingling may occur 4

Special Population: Hemodialysis Patients

• For dialysis patients, a single 5 mg dose administered 30 minutes before dialysis improves intradialytic and postdialytic blood pressure 2
• Midodrine is effectively cleared by hemodialysis with its half-life reduced to 1.4 hours 2

Treatment Context

Midodrine is FDA-approved and represents the only medication with this specific indication for symptomatic orthostatic hypotension 6, 2. However, non-pharmacological measures should be implemented first or concurrently, including increased fluid intake (2-2.5 liters daily), increased salt intake (unless contraindicated), compression garments, and physical counter-pressure maneuvers 2. The therapeutic goal is to minimize postural symptoms rather than restore normotension 6, 2.