What is the recommended dosing, contraindications, adverse effects, monitoring, and alternative therapies for midodrine in a patient with symptomatic orthostatic hypotension refractory to non‑pharmacologic measures?

Midodrine for Symptomatic Orthostatic Hypotension

Recommended Dosing

Midodrine should be initiated at 2.5–5 mg three times daily during waking hours, with doses spaced approximately 4 hours apart (morning, midday, and late afternoon), and the final dose must be taken at least 4 hours before bedtime—never after 6 PM—to prevent supine hypertension during sleep. 1, 2

• The standard target dose is 10 mg three times daily, which increases standing systolic blood pressure by approximately 15–30 mmHg for 2–3 hours and has been validated in three randomized placebo-controlled trials. 2, 3

• Titrate upward by 2.5 mg increments at weekly intervals based on symptom response and standing blood pressure, up to a maximum of 10 mg three times daily (30 mg total daily dose). 1, 3

• In patients with renal impairment, start at 2.5 mg three times daily because the active metabolite desglymidodrine is renally excreted. 1, 4

• Single doses up to 20 mg have been used, but supine hypertension occurs in approximately 45% of patients at this dose, making it unsafe for routine use. 1

Contraindications and Precautions

Midodrine is contraindicated in patients with severe supine hypertension (supine systolic BP >200 mmHg), acute renal disease, urinary retention, pheochromocytoma, and thyrotoxicosis. 1

• Avoid midodrine in patients with active heart failure or significant cardiac dysfunction, as peripheral vasoconstriction can worsen cardiac afterload. 2

• Use cautiously in patients taking negative chronotropic agents (beta-blockers, digoxin, non-dihydropyridine calcium channel blockers) because midodrine causes reflex bradycardia via parasympathetic stimulation. 4

• Do not combine midodrine with other α-adrenergic agonists (ephedrine, pseudoephedrine, phenylpropanolamine), as this markedly increases the risk of supine hypertension. 4

• Midodrine can antagonize α-adrenergic blockers (terazosin, prazosin, doxazosin, tamsulosin), potentially causing urinary retention; these combinations should be avoided. 4, 5

Adverse Effects

The most common adverse effects are piloerection (goosebumps), scalp pruritus or tingling, urinary urgency, and supine hypertension, which occurs in 8–25% of patients. 3, 6

• Piloerection and scalp tingling occur in approximately 13.5% of patients and are usually mild and dose-related. 3

• Supine hypertension is the most important limiting adverse effect and warrants discontinuation if it becomes severe or symptomatic. 4, 1

• Other reported side effects include nausea, heartburn, headache, nervousness, and sleep disturbance, though these are generally mild. 4

• Midodrine has minimal cardiac and central nervous system effects because it does not cross the blood-brain barrier and is specific for peripheral α₁-adrenergic receptors. 4

Monitoring Requirements

Measure supine (or seated) blood pressure after 5 minutes of rest, then standing blood pressure at 1 minute and 3 minutes after standing at baseline and at each follow-up visit to detect both orthostatic improvement and supine hypertension. 2

• Monitor for reflex bradycardia, particularly in patients on other negative chronotropic agents. 4

• Reassess the patient within 1–2 weeks after initiating therapy or changing doses to evaluate symptom response and blood pressure effects. 2

• The therapeutic goal is to minimize postural symptoms and improve functional capacity, NOT to normalize standing blood pressure. 2

• Discontinue midodrine if the patient does not report significant symptomatic improvement during initial treatment, as the drug should only be continued in responders. 1

• In hemodialysis patients, midodrine is effectively cleared by dialysis (half-life reduced to 1.4 hours), so the risk of supine hypertension is lower, but monitoring remains essential. 4

Combination Therapy for Inadequate Response

When midodrine monotherapy provides insufficient symptom control, add fludrocortisone 0.05–0.1 mg once daily, as the two agents act via complementary mechanisms—α₁-adrenergic vasoconstriction (midodrine) plus mineralocorticoid-mediated sodium retention and volume expansion (fludrocortisone). 2

• Fludrocortisone should be titrated to 0.1–0.3 mg daily based on response, with monitoring for supine hypertension, hypokalemia, congestive heart failure, and peripheral edema. 2

• Avoid fludrocortisone in patients with active heart failure, severe renal disease, or pre-existing supine hypertension. 2

• Check electrolytes, BUN, and creatinine periodically when using fludrocortisone due to its mineralocorticoid effects. 2

Alternative Therapies for Refractory Cases

For patients who remain symptomatic despite optimal midodrine and fludrocortisone therapy, consider adding pyridostigmine 60 mg three times daily, particularly when supine hypertension limits further pressor use, as pyridostigmine does not worsen supine blood pressure. 2

• Pyridostigmine enhances ganglionic sympathetic transmission by inhibiting acetylcholinesterase and preferentially raises blood pressure in the upright position. 2

• Common side effects of pyridostigmine include nausea, vomiting, abdominal cramping, sweating, salivation, and urinary incontinence, which are generally manageable. 2

• Droxidopa is FDA-approved and particularly effective for neurogenic orthostatic hypotension in Parkinson's disease, pure autonomic failure, and multiple system atrophy, though it is not available in Canada except through Health Canada's Special Access Programme. 2

• Sertraline (a selective serotonin reuptake inhibitor) has shown benefit in small studies for intradialytic hypotension and neurocardiogenic syncope by improving central sympathetic outflow. 4

• L-carnitine (20 mg/kg intravenously with each dialysis session) reduced the frequency of intradialytic hypotension from 44% to 18% in hemodialysis patients, likely through improved vascular and cardiac muscle function. 4

Essential Non-Pharmacologic Adjuncts

Before and during midodrine therapy, implement non-pharmacologic measures: increase fluid intake to 2–3 L daily and dietary sodium to 6–9 g daily (unless contraindicated by heart failure), teach physical counter-pressure maneuvers (leg crossing, squatting, muscle tensing), use waist-high compression garments (30–40 mmHg), and elevate the head of the bed by 10 degrees. 2

• Acute water ingestion of ≥480 mL provides temporary relief with peak effect at 30 minutes. 2

• Smaller, more frequent meals reduce postprandial hypotension. 2

• Gradual positional changes—sitting on the bedside for 2–3 minutes before standing—help prevent symptomatic drops. 2

Critical Pitfalls to Avoid

• Never administer the final midodrine dose after 6 PM or within 4 hours of bedtime, as this dramatically increases the risk of nocturnal supine hypertension. 2, 1

• Do not simply reduce the dose of offending antihypertensive medications; switch to alternatives with minimal orthostatic impact (long-acting dihydropyridine calcium channel blockers or RAS inhibitors). 2, 5

• Do not combine multiple vasodilating agents (ACE inhibitors + calcium channel blockers + diuretics) without careful monitoring in patients with orthostatic hypotension. 2

• Do not overlook volume depletion as a contributing factor—assess fluid status, recent diuretic use, vomiting, diarrhea, or heat exposure. 2

• Discontinue alpha-1 blockers (doxazosin, prazosin, terazosin, tamsulosin) completely rather than dose-reducing, as these are the most frequent drug cause of orthostatic hypotension. 5