What are the parameters for midodrine (Midodrine) in treating orthostatic hypotension?

Midodrine Parameters for Orthostatic Hypotension

Midodrine should be initiated at 10 mg three times daily, taken at approximately 4-hour intervals during daytime hours when upright activity is needed, with the last dose no later than 6 PM to prevent supine hypertension. 1

FDA-Approved Indication and Patient Selection

• Midodrine is the only FDA-approved medication specifically indicated for symptomatic orthostatic hypotension 1, 2
• Use midodrine only in patients whose lives are considerably impaired despite standard clinical care, including non-pharmacologic treatment (support stockings, fluid expansion, lifestyle alterations) 2
• Continue midodrine only in patients who report significant symptomatic improvement after initiation 2
• The FDA approval is based on midodrine's effect on 1-minute standing systolic blood pressure, a surrogate marker considered likely to correspond to clinical benefit 2

Dosing Protocol

Standard Dosing

• Start with 10 mg three times daily (morning, midday, late afternoon) at approximately 4-hour intervals 1
• Administer doses during daytime hours when the patient needs to be upright and active 1
• The last dose must be taken no later than 6 PM (at least 3-4 hours before bedtime) to minimize supine hypertension 1, 3, 4

Alternative Dosing Considerations

• Some guidelines suggest initiating at 2.5-5 mg three times daily and titrating upward based on response 4
• Maximum dose can be titrated up to 10 mg two to four times daily based on individual response 4
• For hemodialysis patients: administer 5-10 mg orally 30 minutes before initiating hemodialysis 3

Expected Hemodynamic Effects

• Standing systolic blood pressure increases by approximately 15-30 mmHg at 1 hour after a 10 mg dose 2, 5
• The pressor effect persists for 2-3 hours after dosing 2
• Supine and sitting blood pressure rise by 16/8 mmHg and 20/10 mmHg respectively on average 2
• Midodrine has no clinically significant effect on standing or supine pulse rates in patients with autonomic failure 2

Pharmacokinetic Parameters

• Midodrine is a prodrug that is rapidly absorbed with peak plasma levels at approximately 30 minutes 2
• The active metabolite desglymidodrine reaches peak blood concentrations 1-2 hours after dosing 2
• Desglymidodrine has a half-life of approximately 3-4 hours 2
• Absolute bioavailability is 93% and is not affected by food 2
• In hemodialysis patients, the half-life is reduced to 1.4 hours as midodrine is effectively cleared by dialysis 1, 3

Mechanism of Action

• Midodrine is converted to desglymidodrine, a selective alpha-1 adrenergic agonist 2
• Produces arteriolar constriction (increasing peripheral vascular resistance) and venoconstriction of capacitance vessels (improving central blood volume) 3
• Does not stimulate cardiac beta-adrenergic receptors, resulting in minimal cardiac effects 1, 2
• Poorly penetrates the blood-brain barrier, avoiding central nervous system effects 1, 2

Monitoring Parameters

Blood Pressure Monitoring

• Measure blood pressure after 5 minutes of lying/sitting, then at 1 and 3 minutes after standing to document orthostatic changes 4
• Monitor supine blood pressure regularly to detect treatment-induced supine hypertension 4
• Consider ambulatory blood pressure monitoring to identify abnormal diurnal patterns 3

Clinical Response Assessment

• The therapeutic goal is to minimize postural symptoms, not to restore normotension 1, 4
• Assess improvement in symptoms including dizziness/lightheadedness, weakness/fatigue, syncope, low energy level, and impaired ability to stand 5, 6
• Reassess patients within 1-2 weeks after medication changes 4
• Monitor orthostatic vital signs at each follow-up visit 4

Safety Monitoring

• Monitor for urinary retention or urgency (occurs in 4% of patients) 1
• Monitor for bradycardia, particularly when used with other negative chronotropic agents 1
• Monitor for gastrointestinal symptoms 1
• If using fludrocortisone concurrently, check electrolytes, BUN, and creatinine periodically 4

Common Side Effects

• Piloerection (goosebumps) is the most common side effect, reported in approximately 13.5% of patients 1, 6
• Supine hypertension occurs in up to 25% of patients but can be minimized by avoiding doses within several hours of bedtime 3
• Scalp pruritus/tingling (13.5%) 6
• Urinary retention or urgency (4-8%) 1, 6
• Bradycardia (due to reflex parasympathetic stimulation from increased blood pressure) 3
• Gastrointestinal symptoms 1

Critical Drug Interactions and Precautions

Contraindications and Cautions

• Use cautiously in patients with congestive heart failure 1
• Use cautiously with other negative chronotropic agents (beta-blockers, digoxin, non-dihydropyridine calcium channel blockers) 1
• Avoid concomitant use with other alpha-adrenergic agents as this may aggravate supine hypertension 1
• Midodrine can antagonize alpha-adrenergic blockers (terazosin, prazosin, doxazosin) and could result in urinary retention 1
• Patients with pre-existing sustained supine hypertension above 180/110 mmHg were routinely excluded from clinical trials 2

Non-Pharmacological Adjuncts (Must Be Implemented Concurrently)

• Increase fluid intake to 2-2.5 liters daily (unless contraindicated by heart failure) 1, 4
• Increase salt intake to 6-9 grams daily (unless contraindicated) 1, 4
• Use compression garments (waist-high stockings 30-40 mmHg and abdominal binders) 1, 4
• Teach physical counter-pressure maneuvers (leg-crossing, squatting, muscle tensing) 1, 4
• Elevate head of bed by 10 degrees during sleep to prevent nocturnal polyuria and ameliorate nocturnal hypertension 3, 4
• Eat smaller, more frequent meals to reduce postprandial hypotension 4

Combination Therapy Considerations

• For non-responders to midodrine monotherapy, consider adding fludrocortisone 0.05-0.1 mg daily 4
• Fludrocortisone acts through a different mechanism (sodium retention and vessel wall effects), making it complementary to midodrine's alpha-1 adrenergic stimulation 4
• When adding fludrocortisone, monitor for supine hypertension, hypokalemia, congestive heart failure, and peripheral edema 4
• For refractory cases, pyridostigmine may be considered as it has a favorable side effect profile 4

Critical Pitfalls to Avoid

• Do not administer midodrine after 6 PM 4
• Do not use in patients with active heart failure or severe supine hypertension 4
• Do not simply reduce the dose of offending antihypertensive medications; switch to alternative therapy instead 4
• Do not combine multiple vasodilating agents without careful monitoring 4
• Do not overlook volume depletion as a contributing factor 4
• Do not continue midodrine in patients who do not demonstrate symptomatic improvement during initial treatment 1, 2