What is the mechanism of action of Midodrine (Midodrine) in treating orthostatic hypotension?

Mechanism of Action of Midodrine

Midodrine works as a prodrug that is converted to its active metabolite desglymidodrine, which selectively activates alpha-1 adrenergic receptors in blood vessels, causing arteriolar constriction and venoconstriction, thereby increasing peripheral vascular resistance and improving central blood volume to raise blood pressure. 1

Pharmacodynamics and Metabolism

• Midodrine is rapidly absorbed after oral administration with peak plasma levels occurring after approximately 30 minutes 1
• The prodrug midodrine is converted to desglymidodrine through enzymatic hydrolysis, which is the pharmacologically active metabolite 1, 2
• Desglymidodrine reaches peak blood concentrations about 1-2 hours after administration and has a half-life of approximately 3-4 hours 1
• The active metabolite desglymidodrine diffuses poorly across the blood-brain barrier, thus avoiding central nervous system effects 1
• Neither midodrine nor desglymidodrine binds significantly to plasma proteins 1

Mechanism of Vascular Effects

• Desglymidodrine acts as a selective alpha-1 adrenergic receptor agonist, primarily affecting the vasculature 3, 1
• The activation of alpha-1 receptors produces two key effects:
  • Arteriolar constriction, which increases peripheral vascular resistance 3, 4
  • Venoconstriction of capacitance vessels, which improves central blood volume 3, 4
• These combined effects lead to an increase in standing blood pressure of approximately 15-30 mmHg at 1 hour after a 10 mg dose, with effects persisting for 2-3 hours 1
• Unlike other sympathomimetic agents, midodrine does not stimulate cardiac beta-adrenergic receptors, resulting in no clinically significant effect on heart rate 1, 2

Clinical Effects in Orthostatic Hypotension

• Midodrine significantly increases standing systolic blood pressure compared to placebo, with peak effects occurring at approximately 1 hour post-dose 5
• The drug demonstrates a linear dose-response relationship between dosage and mean systolic blood pressure 5
• In clinical trials, midodrine improved symptoms of orthostatic hypotension including dizziness, lightheadedness, syncope, weakness, and fatigue 6
• The FDA has approved midodrine specifically for the treatment of symptomatic orthostatic hypotension 7, 3

Elimination and Excretion

• Renal elimination of the parent compound midodrine is insignificant 1
• Desglymidodrine is primarily eliminated through active renal secretion with a clearance of approximately 385 mL/minute 1
• In hemodialysis patients, both midodrine and its active metabolite are effectively cleared during dialysis, reducing its half-life to 1.4 hours 3

Comparative Efficacy and Safety

• Clinical studies have shown midodrine to be at least as effective as other sympathomimetic agents (norfenefrine, etilefrine, dimetofrine, and ephedrine) and dihydroergotamine in treating orthostatic hypotension 2, 8
• Midodrine appears to cause fewer and less severe adverse effects associated with alpha-receptor agonism compared to other sympathomimetics 2
• Common side effects include piloerection (goosebumps), pruritus, paresthesias, urinary retention, and supine hypertension 8, 6

Midodrine represents an important therapeutic option for orthostatic hypotension, particularly in neurogenic forms, with a well-established mechanism of action and favorable safety profile compared to other available treatments 7, 3.