Midodrine: A Peripheral Selective α1-Adrenergic Agonist for Orthostatic Hypotension
Midodrine hydrochloride is a first-line medication for symptomatic orthostatic hypotension that works as a peripheral selective α1-adrenergic agonist to increase blood pressure through arteriolar constriction and venoconstriction of capacitance vessels. 1
Mechanism of Action
Midodrine is a prodrug that undergoes enzymatic hydrolysis after oral administration to form its active metabolite, desglymidodrine. This metabolite:
- Acts as a selective α1-adrenoceptor agonist
- Exerts a pressor effect through arteriolar constriction
- Causes venoconstriction of capacitance vessels
- Maintains central blood volume and cardiac output
- Increases peripheral vascular resistance
FDA-Approved Indication
Midodrine is specifically indicated for the treatment of symptomatic orthostatic hypotension in patients whose lives are considerably impaired despite standard clinical care, including:
- Non-pharmacologic treatment (support stockings)
- Fluid expansion
- Lifestyle alterations 2
Clinical Use and Dosing
Dosing Regimen:
- Initial dose: 2.5-5 mg three times daily
- Can be titrated up to 10 mg three times daily
- First dose should be taken before arising in the morning
- Last dose should be taken at least 4 hours before bedtime to avoid supine hypertension
- Doses should be taken approximately 3-4 hours apart during daytime hours 1
Administration Timing:
- First dose: Before getting out of bed in the morning
- Second dose: Midday
- Final dose: Late afternoon (no later than 4 hours before bedtime) 1
Efficacy
Midodrine has been shown to:
- Increase standing systolic blood pressure by 22 mmHg (28%) compared to placebo 3
- Improve symptoms of orthostatic hypotension including dizziness, lightheadedness, weakness, fatigue, and syncope 4, 3
- Enhance standing time and energy levels 5
- Be as effective as or more effective than other agents (dihydroergotamine, norfenefrine, fludrocortisone, etilefrine) 5, 6
Adverse Effects
Common side effects include:
- Piloerection (goosebumps)
- Scalp itching or tingling
- Paresthesias
- Urinary retention or urgency
- Supine hypertension (in up to 25% of patients)
- Bradycardia (due to reflex parasympathetic stimulation)
- Gastrointestinal symptoms
- Chills 1, 5
Special Considerations
Supine Hypertension Management:
- Avoid taking the last dose within 4 hours of bedtime
- Monitor for supine hypertension, especially in patients with documented history
- Discontinue if severe supine hypertension develops 1
Contraindications and Cautions:
- Use cautiously in patients with congestive heart failure
- Use with caution in patients taking negative chronotropic agents (beta-blockers, digoxin, non-dihydropyridine calcium channel blockers)
- Avoid concomitant use with other α-adrenergic agents (ephedrine, pseudoephedrine, phenylpropanolamine)
- May antagonize α-adrenergic blockers (terazosin, prazosin, doxazosin)
- May cause urinary retention, particularly in patients with spinal cord injury 1, 7
Pharmacokinetics:
- Midodrine is effectively cleared by hemodialysis
- Half-life is reduced to 1.4 hours during hemodialysis 1
Clinical Pearls
Midodrine is the only medication approved by the FDA specifically for symptomatic orthostatic hypotension 1
Treatment should focus on minimizing postural symptoms rather than restoring normotension 1
Non-pharmacological measures should be tried first before initiating midodrine therapy:
- Identifying and correcting reversible causes (volume depletion)
- Avoiding exacerbating medications (psychotropics, diuretics, α-blockers)
- Behavioral strategies (gradual position changes, physical counter-maneuvers)
- Increased fluid and salt intake if not contraindicated
- Use of elastic garments 1
In patients with vasovagal syncope who are ≥40 years old with recurrent episodes and no history of hypertension, heart failure, or urinary retention, midodrine is a reasonable treatment option 1
Midodrine should be continued only for patients who report significant symptomatic improvement 2