Midodrine: Mechanism, Uses, and Clinical Application
Midodrine is an alpha-1 adrenergic agonist prodrug primarily used to treat orthostatic hypotension by increasing vascular tone and elevating blood pressure through its active metabolite desglymidodrine. 1
Mechanism of Action
Midodrine works through a specific mechanism:
- After oral administration, midodrine is rapidly absorbed and converted to its active metabolite, desglymidodrine
- Desglymidodrine is a selective alpha-1 adrenergic receptor agonist that activates receptors in arteriolar and venous vasculature
- This activation increases vascular tone and elevates blood pressure 1
- Unlike other sympathomimetics, desglymidodrine:
- Does not stimulate cardiac beta-adrenergic receptors
- Diffuses poorly across the blood-brain barrier, minimizing central nervous system effects 1
Pharmacokinetics
- Midodrine is a prodrug with nearly complete oral absorption (93% bioavailability) 1
- Plasma levels peak after approximately 30 minutes with a half-life of about 25 minutes
- The active metabolite desglymidodrine reaches peak concentration in 1-2 hours with a half-life of 3-4 hours
- Food does not affect the bioavailability of desglymidodrine
- Neither midodrine nor desglymidodrine binds significantly to plasma proteins
- Renal clearance of desglymidodrine is approximately 385 mL/minute, with about 80% by active renal secretion 1
- Midodrine is effectively cleared by hemodialysis 1
Clinical Uses
Midodrine is primarily indicated for:
Orthostatic Hypotension: FDA-approved for symptomatic orthostatic hypotension in patients whose lives are considerably impaired despite standard clinical care 1
Intradialytic Hypotension: Used to prevent hypotension during hemodialysis sessions 2
- A single 5 mg dose administered 30 minutes before dialysis improves intradialytic and postdialytic blood pressures 2
Dosing
- Standard dosing: 10 mg three times daily 2, 1, 3
- Initial dosing may start at 2.5-5 mg three times daily and titrate up 4
- Last daily dose should be taken at least 4 hours before bedtime to avoid supine hypertension 4, 1
- For dialysis patients: 5 mg administered 30 minutes before the dialysis session 2
Clinical Efficacy
Midodrine has demonstrated efficacy in:
- Increasing standing systolic blood pressure by 15-30 mmHg at 1 hour after dosing, with effects persisting for 2-3 hours 1, 5
- Improving symptoms of orthostatic hypotension including dizziness, lightheadedness, and syncope 3, 6
- Increasing standing time and energy levels in patients with neurogenic orthostatic hypotension 7, 3
- Comparative studies show midodrine to be at least as effective as other sympathomimetics (norfenefrine, etilefrine) and dihydroergotamine, and more effective than dimetofrine and ephedrine 7, 8
Adverse Effects
Common side effects include:
- Piloerection (goosebumps)
- Scalp itching or tingling
- Urinary retention or urgency
- Supine hypertension (in up to 25% of patients) 7
- Other reported effects: nausea, heartburn, headache, nervousness, and sleep disturbance 2
Precautions and Contraindications
Midodrine should be used with caution in:
- Patients with congestive heart failure 2
- Patients using other negative chronotropic agents (beta-blockers, digoxin, non-dihydropyridine calcium channel blockers) 2
- Patients with pre-existing sustained supine hypertension above 180/110 mmHg 1
Concomitant use with other alpha-adrenergic agents should be avoided as it may aggravate supine hypertension 2
Monitoring
- Regular monitoring of supine and standing blood pressure is essential 4
- The goal of treatment is to minimize orthostatic symptoms and improve standing time for activities of daily living, not to normalize blood pressure 4
- Supine hypertension should be monitored, especially when taking doses close to bedtime 4, 1
Midodrine represents an important therapeutic option for managing orthostatic hypotension, particularly in patients who have failed standard non-pharmacological interventions.