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

Mechanism of Action of Midodrine

Midodrine is a prodrug that forms the active metabolite desglymidodrine, which acts as an alpha-1 adrenergic receptor agonist to increase vascular tone and elevate blood pressure through arteriolar and venous vasoconstriction. 1

Pharmacodynamics

• Desglymidodrine (the active metabolite) selectively activates alpha-1 adrenergic receptors in the arteriolar and venous vasculature, producing both arteriolar constriction (increasing peripheral vascular resistance) and venoconstriction of capacitance vessels (improving central blood volume) 2, 1
• Unlike other sympathomimetic agents, desglymidodrine does not stimulate cardiac beta-adrenergic receptors, resulting in blood pressure elevation without significant cardiac stimulation 1
• The active metabolite diffuses poorly across the blood-brain barrier, thus avoiding central nervous system effects 1

Pharmacokinetics

• After oral administration, midodrine is rapidly absorbed with plasma levels peaking after approximately 30 minutes 1
• The prodrug midodrine has a relatively short half-life of about 25 minutes 1
• Desglymidodrine (active metabolite) reaches peak blood concentrations 1-2 hours after administration and has a half-life of 3-4 hours 1, 3
• The absolute bioavailability of midodrine (measured as desglymidodrine) is 93%, and food does not affect the bioavailability 1
• Deglycination of midodrine to desglymidodrine occurs in many tissues throughout the body 1
• Renal elimination of midodrine itself is insignificant, while desglymidodrine has a renal clearance of approximately 385 mL/minute, with about 80% eliminated through active renal secretion 1

Clinical Effects

• Administration of midodrine results in a significant increase in standing, sitting, and supine systolic and diastolic blood pressure in patients with orthostatic hypotension 1
• Standing systolic blood pressure is typically elevated by approximately 15-30 mmHg at 1 hour after a 10 mg dose, with effects persisting for 2-3 hours 1, 4
• The blood pressure response shows a linear relationship with the dose of midodrine 3
• Midodrine has no clinically significant effect on standing or supine pulse rates in patients with autonomic failure 1

Primary Clinical Application

• Midodrine is FDA-approved for the treatment of symptomatic orthostatic hypotension, particularly effective in neurogenic orthostatic hypotension 2, 1
• It is considered a first-line drug for symptomatic orthostatic hypotension according to cardiovascular autonomic neuropathy guidelines 5
• The drug is particularly useful in patients with diabetic autonomic neuropathy and other forms of neurogenic orthostatic hypotension 5, 6
• Midodrine is also effective for intradialytic hypotension in hemodialysis patients, where it is effectively cleared during dialysis 5, 2

Common Side Effects

• The most common adverse effects include piloerection (goosebumps), pruritus (itching), paresthesias, urinary retention, and chills 7
• Supine hypertension can occur in up to 25% of patients but can be minimized by avoiding doses within several hours of bedtime 5, 7
• Other potential side effects include bradycardia (due to reflex parasympathetic stimulation), gastrointestinal symptoms, and headache 5, 8

Midodrine represents an important therapeutic option for orthostatic hypotension, offering significant clinical benefits with a manageable side effect profile when properly administered and monitored.