What is the mechanism of action (MOA) of Midodrine (Midodrine hydrochloride)?

Mechanism of Action of Midodrine

Midodrine is a prodrug that is converted to its active metabolite desglymidodrine, which acts as a selective alpha-1 adrenergic receptor agonist in the arteriolar and venous vasculature, producing increased vascular tone and blood pressure elevation. 1

Pharmacological Properties

Active Metabolite Formation

• Midodrine undergoes enzymatic hydrolysis to form desglymidodrine, the pharmacologically active metabolite
• This conversion occurs in various tissues throughout the body 1
• Desglymidodrine is the compound responsible for the therapeutic effects 2

Receptor Specificity

• Desglymidodrine selectively activates alpha-1 adrenergic receptors 1
• It has minimal effect on cardiac beta-adrenergic receptors 1
• The drug diffuses poorly across the blood-brain barrier, limiting central nervous system effects 1

Vascular Effects

• Primary action is on the arteriolar and venous vasculature 1
• Increases vascular tone through alpha-1 receptor activation 1
• Produces elevation of blood pressure in standing, sitting, and supine positions 1
• Standing systolic blood pressure typically increases by 15-30 mmHg at 1 hour after a 10 mg dose 1
• Effects can persist for 2-3 hours after administration 1

Pharmacokinetics

Absorption and Distribution

• Midodrine is rapidly absorbed after oral administration 1
• Plasma levels of midodrine peak after approximately 30 minutes 1
• The absolute bioavailability of midodrine (measured as desglymidodrine) is 93% 1
• Food does not affect the bioavailability of desglymidodrine 1
• Neither midodrine nor desglymidodrine binds significantly to plasma proteins 1

Metabolism and Elimination

• Midodrine has a half-life of approximately 25 minutes 1
• Desglymidodrine reaches peak blood concentrations about 1-2 hours after dosing 1
• Desglymidodrine has a half-life of about 3-4 hours 1
• Renal elimination of midodrine is insignificant 1
• Desglymidodrine is primarily eliminated through active renal secretion (approximately 80%) 1
• Renal clearance of desglymidodrine is approximately 385 mL/minute 1
• Midodrine is removed by hemodialysis 1

Clinical Applications

The primary therapeutic application of midodrine is in the treatment of orthostatic hypotension, particularly:

• Neurogenic orthostatic hypotension 3, 4
• Intradialytic hypotension in hemodialysis patients 5
• Various forms of orthostatic hypotension resistant to non-pharmacological measures 2

Important Considerations

Dosing Timing

• The final daily dose should be taken at least 4 hours before bedtime to reduce the risk of supine hypertension 2
• For dialysis patients, a single dose of 5 mg administered 30 minutes before dialysis can improve intradialytic and postdialytic blood pressure 5

Potential Adverse Effects

• Piloerection (goosebumps)
• Pruritus (itching)
• Paresthesias
• Urinary retention (particularly in patients with spinal cord injury) 6
• Supine hypertension (in up to 25% of patients) 2
• Bradycardia due to reflex parasympathetic stimulation 5

Drug Interactions

• Should be used cautiously with other alpha-adrenergic agents (ephedrine, pseudoephedrine) 5
• May antagonize the actions of alpha-adrenergic blockers (terazosin, prazosin, doxazosin) 5
• Caution needed when used with negative chronotropic agents (beta-blockers, digoxin, non-dihydropyridine calcium channel blockers) 5

Midodrine represents an effective therapeutic option for orthostatic hypotension when used appropriately, with careful attention to dosing schedule and monitoring for potential adverse effects.