What is the mechanism of action of Midodrine (prodrug converted to desglymidodrine)?

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, causing vasoconstriction of arteriolar and venous vasculature, thereby increasing vascular tone and elevating blood pressure. 1

Pharmacological Properties

• Midodrine is rapidly absorbed after oral administration with plasma levels peaking after approximately 30 minutes 1
• The active metabolite desglymidodrine is formed through enzymatic hydrolysis (deglycination) of midodrine in various tissues 1, 2
• Desglymidodrine reaches peak blood concentrations about 1-2 hours after midodrine administration 1
• The half-life of midodrine is approximately 25 minutes, while desglymidodrine has a half-life of about 3-4 hours 1
• The absolute bioavailability of midodrine (measured as desglymidodrine) is 93%, and food does not affect the bioavailability 1

Mechanism of Action Details

• Desglymidodrine exerts its actions via activation of alpha-1 adrenergic receptors specifically in the arteriolar and venous vasculature 1
• This activation produces:
  • Arteriolar constriction (increasing peripheral vascular resistance) 3
  • Venoconstriction of capacitance vessels (improving central blood volume) 3
• Desglymidodrine diffuses poorly across the blood-brain barrier, resulting in minimal central nervous system effects 1, 3
• Unlike some other sympathomimetics, desglymidodrine does not stimulate cardiac beta-adrenergic receptors, avoiding cardiac stimulation 1, 4

Pharmacodynamic Effects

• Administration of midodrine results in elevation of standing, sitting, and supine systolic and diastolic blood pressure 1
• Standing systolic blood pressure typically increases by approximately 15-30 mmHg at 1 hour after a 10 mg dose, with effects persisting for 2-3 hours 1
• Midodrine has no clinically significant effect on standing or supine pulse rates in patients with autonomic failure 1
• Beyond its direct vasoconstrictive effects, midodrine has been shown to:
  • Decrease norepinephrine levels 5
  • Increase plasma atrial natriuretic peptide (ANP) levels, suggesting enhanced venous return 5
  • Demonstrate sympatholytic influences that are independent of blood pressure effects 5

Clinical Applications

• Midodrine is FDA-approved for the treatment of symptomatic orthostatic hypotension 3
• It is particularly useful in:
  • Neurogenic orthostatic hypotension 3
  • Intradialytic hypotension in hemodialysis patients 3

Potential Adverse Effects

• Common side effects include piloerection, pruritus, paresthesias, urinary retention, and chills 2
• Midodrine can cause supine hypertension in up to 25% of patients, which can be minimized by avoiding doses close to bedtime 2
• In patients with spinal cord injury, midodrine may increase vesical sphincter tone, potentially leading to urinary retention 6
• Rare adverse effects include nightmares, particularly with evening dosing 7

Pharmacokinetic Considerations

• Renal elimination of midodrine itself is insignificant 1
• Desglymidodrine has a renal clearance of approximately 385 mL/minute, with about 80% eliminated by active renal secretion 1
• In hemodialysis patients, midodrine is effectively cleared during dialysis, reducing its half-life to 1.4 hours 3

Midodrine's selective alpha-1 adrenergic agonist properties make it valuable in treating orthostatic hypotension with fewer side effects compared to less selective sympathomimetic agents 4.