What is midodrine used for in the treatment of orthostatic hypotension?

Midodrine: Clinical Indications and Use

Primary FDA-Approved Indication

Midodrine is FDA-approved specifically for the treatment of symptomatic orthostatic hypotension in patients whose lives are considerably impaired despite standard non-pharmacologic care. 1

The FDA emphasizes that midodrine should be reserved for patients who remain significantly disabled after attempting non-pharmacologic interventions including support stockings, fluid expansion, and lifestyle modifications. 1 Treatment should only be continued in patients who report significant symptomatic improvement. 1

Mechanism of Action

Midodrine is a prodrug that undergoes enzymatic hydrolysis to form desglymidodrine, a selective alpha-1 adrenergic receptor agonist. 2 This active metabolite produces:

• Arteriolar constriction, increasing peripheral vascular resistance 2
• Venoconstriction of capacitance vessels, improving central blood volume 2
• No significant cardiac stimulation, due to specificity for peripheral alpha-receptors and poor blood-brain barrier penetration 3

Specific Clinical Applications

Neurogenic Orthostatic Hypotension

The American Diabetes Association recommends midodrine as a first-line drug for symptomatic orthostatic hypotension in cardiovascular autonomic neuropathy. 2 This represents a Class I recommendation with Level A evidence. 2

Midodrine is particularly effective for neurogenic orthostatic hypotension due to: 2, 4

• Shy-Drager syndrome (multiple system atrophy)
• Bradbury-Eggleston syndrome (pure autonomic failure)
• Diabetic autonomic neuropathy
• Parkinson's disease

The ACC/AHA/HRS guidelines support midodrine use for patients with syncope due to neurogenic orthostatic hypotension. 2

Intradialytic Hypotension

Midodrine is highly effective for intradialytic hypotension in hemodialysis patients. 2 The American Journal of Kidney Diseases recommends administering 5-10 mg orally 30 minutes before initiating hemodialysis to prevent intradialytic hypotension and improve hemodynamic stability. 2

A key pharmacokinetic consideration: midodrine is effectively cleared during dialysis, with its half-life reduced to 1.4 hours during hemodialysis. 2, 3

Clinical Efficacy

Midodrine produces clinically meaningful improvements: 5, 6

• Increases standing systolic blood pressure by 22-27 mmHg (approximately 28% increase) at the 10 mg dose 6
• Improves symptoms including dizziness, lightheadedness, syncope, weakness, fatigue, and low energy level 5, 6
• Increases standing time and ability to perform daily activities 7

The European Society of Cardiology supports midodrine as adjunctive therapy for orthostatic hypotension, with dosing of 5-20 mg three times daily. 2

Dosing Recommendations

Standard dosing: Start with 10 mg three times daily (morning, midday, late afternoon), taken at approximately 4-hour intervals during daytime hours when the patient needs to be upright. 3

Critical timing consideration: The last dose must be taken no later than 6 PM (at least 3-4 hours before bedtime) to minimize supine hypertension during sleep. 2, 3

For hemodialysis patients: 5-10 mg administered 30 minutes before dialysis initiation. 2

Important Safety Considerations

Supine Hypertension

Supine hypertension occurs in up to 25% of patients but can be minimized by avoiding doses within several hours of bedtime. 2 The FDA warns that midodrine can cause marked elevation of supine blood pressure (>200 mmHg systolic). 1

To mitigate supine hypertension: 2

• Sleep with head of bed elevated at 10 degrees
• Avoid doses after 6 PM
• Consider ambulatory blood pressure monitoring

Bradycardia

Midodrine causes bradycardia through reflex parasympathetic (vagal) stimulation in response to increased peripheral vascular resistance and blood pressure. 2 Patients require monitoring for bradycardia, particularly when used with: 2

• Beta-blockers
• Non-dihydropyridine calcium channel blockers
• Digoxin
• Other negative chronotropic agents

Other Common Side Effects

• Piloerection (goosebumps) - most common side effect 3, 7
• Scalp pruritus/tingling (13.5% of patients) 6
• Urinary retention or urgency (4%) 3, 6
• Gastrointestinal symptoms 2
• Headache 2

Contraindications and Cautions

Use cautiously in: 3

• Congestive heart failure
• Severe renal disease
• Pre-existing supine hypertension

Avoid concomitant use with: 3

• Other alpha-adrenergic agents (may aggravate supine hypertension)
• Alpha-adrenergic blockers like terazosin, prazosin, doxazosin (midodrine antagonizes their effects and could cause urinary retention)

Treatment Philosophy

The therapeutic goal is to minimize postural symptoms, NOT to restore normotension. 2, 3 The American Diabetes Association emphasizes that treatment should be "thoroughly balanced between the goal of increasing standing blood pressure and the avoidance of a marked increase in supine blood pressure." 2

Non-pharmacological measures should be implemented first or concurrently, including: 3, 8

• Increased fluid intake (2-2.5 liters daily)
• Increased salt intake (6-9g daily, unless contraindicated)
• Compression garments
• Physical counter-pressure maneuvers (leg-crossing, squatting, muscle tensing)