What is the mechanism of action of midodrine?

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, producing arteriolar vasoconstriction and venoconstriction of capacitance vessels, thereby increasing peripheral vascular resistance and elevating blood pressure without significant cardiac stimulation. 1

Pharmacological Mechanism

Prodrug Activation and Receptor Activity

• Midodrine undergoes enzymatic hydrolysis (deglycination) in many tissues to form desglymidodrine, the pharmacologically active metabolite 1, 2
• Desglymidodrine selectively activates alpha-1 adrenergic receptors on arteriolar and venous vasculature 3, 1
• The drug does not stimulate cardiac beta-adrenergic receptors, avoiding direct cardiac stimulation 1
• Desglymidodrine diffuses poorly across the blood-brain barrier, resulting in minimal central nervous system effects 1

Hemodynamic Effects

• Arteriolar constriction increases peripheral vascular resistance 4, 3
• Venoconstriction of capacitance vessels reduces venous pooling and improves central blood volume 3, 5
• Standing systolic blood pressure increases by approximately 15-30 mmHg at 1 hour after a 10 mg dose 1
• The pressor effect persists for 2-3 hours after administration 1
• Midodrine has no clinically significant effect on standing or supine pulse rates in patients with autonomic failure 1

Pharmacokinetics

Absorption and Metabolism

• Midodrine is rapidly absorbed after oral administration with peak plasma levels occurring at approximately 30 minutes 1
• The absolute bioavailability of desglymidodrine is 93%, and food does not affect bioavailability 1
• Desglymidodrine reaches peak blood concentrations 1-2 hours after dosing 1
• The prodrug (midodrine) has a half-life of approximately 25 minutes, while desglymidodrine has a half-life of 3-4 hours 1
• Neither midodrine nor desglymidodrine is significantly bound to plasma proteins 1

Elimination

• Renal clearance of desglymidodrine is approximately 385 mL/minute, with about 80% eliminated by active renal secretion 1
• Neither compound is a substrate for monoamine oxidase 1
• In hemodialysis patients, midodrine is effectively cleared during dialysis, reducing its half-life to 1.4 hours 3

Secondary Cardiovascular Effects

Reflex Bradycardia Mechanism

• The alpha-1 adrenergic-mediated increase in peripheral vascular resistance and blood pressure activates arterial baroreceptors 3
• Baroreceptor activation leads to increased vagal (parasympathetic) tone, resulting in reflex bradycardia 3
• This reflex mechanism requires monitoring, particularly when midodrine is co-administered with other negative chronotropic agents such as beta-blockers or non-dihydropyridine calcium channel blockers 3

Clinical Implications

• The European Society of Cardiology and American Diabetes Association recommend midodrine as a first-line pharmacological agent for symptomatic orthostatic hypotension 4, 3
• Midodrine is FDA-approved specifically for the treatment of symptomatic orthostatic hypotension 4, 1
• The drug is particularly useful in neurogenic orthostatic hypotension and intradialytic hypotension in hemodialysis patients 3
• Dosing should be individually tailored, typically 5-10 mg two to four times daily, with the last dose taken at least 4 hours before bedtime to minimize supine hypertension 4, 6