What is the mechanism of action of Midodrine (Alpha-adrenergic agonist)?

From the Guidelines

Midodrine works primarily as an alpha-1 adrenergic receptor agonist that increases blood pressure by causing peripheral vasoconstriction, making it a valuable treatment for orthostatic hypotension. When taken orally, midodrine is a prodrug that gets converted in the body to its active metabolite, desglymidodrine, which then stimulates alpha-1 receptors on blood vessels 1. This stimulation causes the smooth muscle in the walls of blood vessels to contract, resulting in vasoconstriction and increased vascular resistance. The increased vascular resistance leads to elevated blood pressure, making midodrine particularly useful for treating orthostatic hypotension. Unlike many other vasopressors, midodrine has minimal effects on cardiac output or heart rate because it acts predominantly on peripheral blood vessels rather than directly on the heart.

The dosing of midodrine should be individually tailored, with a typical dose of up to two to four times 10 mg/day, with the first dose taken before arising and use avoided several hours before planned recumbency, particularly in patients with documented supine hypertension 1. Adverse events associated with midodrine include pilomotor reactions, pruritus, supine hypertension, bradycardia, gastrointestinal symptoms, and urinary retention. According to the 2017 ACC/AHA/HRS guideline, midodrine is reasonable in patients with recurrent vasovagal syncope with no history of hypertension, heart failure, or urinary retention 1.

Key points about midodrine's mechanism and use include:

• Midodrine is a prodrug that gets converted to its active metabolite, desglymidodrine, which stimulates alpha-1 receptors on blood vessels
• The medication increases blood pressure by causing peripheral vasoconstriction, making it useful for treating orthostatic hypotension
• Midodrine has minimal effects on cardiac output or heart rate because it acts predominantly on peripheral blood vessels rather than directly on the heart
• The dosing of midodrine should be individually tailored, with a typical dose of up to two to four times 10 mg/day
• Adverse events associated with midodrine include pilomotor reactions, pruritus, supine hypertension, bradycardia, gastrointestinal symptoms, and urinary retention.

From the FDA Drug Label

Midodrine forms an active metabolite, desglymidodrine, that is an alpha1-agonist, and exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Desglymidodrine does not stimulate cardiac beta-adrenergic receptors Desglymidodrine diffuses poorly across the blood-brain barrier, and is therefore not associated with effects on the central nervous system.

The mechanism of action of midodrine is through its active metabolite, desglymidodrine, which is an alpha1-agonist. It works by activating the alpha-adrenergic receptors of the arteriolar and venous vasculature, resulting in an increase in vascular tone and elevation of blood pressure. Key points about midodrine's mechanism include:

• No stimulation of cardiac beta-adrenergic receptors
• Poor diffusion across the blood-brain barrier, resulting in no effects on the central nervous system 2

From the Research

Mechanism of Midodrine

• Midodrine is a prodrug that undergoes enzymatic hydrolysis to form its pharmacologically active metabolite, desglymidodrine, after oral administration 3, 4.
• Desglymidodrine is a selective alpha 1-adrenoceptor agonist that increases standing systolic blood pressure and improves symptoms of orthostatic hypotension, such as dizziness, light-headedness, and syncope 3, 4.
• Midodrine is almost completely absorbed after oral administration and its active metabolite has a half-life of approximately 4 hours 4, 5.

Therapeutic Effects

• Midodrine significantly increases standing systolic blood pressure and improves standing time and energy level in patients with orthostatic hypotension 3, 5.
• The drug also improves clinical symptoms of orthostatic hypotension, including dizziness, light-headedness, and syncope 3, 4.
• Midodrine has been shown to be effective in the treatment of neurogenic orthostatic hypotension, with a significant linear relation between midodrine dosage and mean systolic blood pressure 5.

Comparison with Other Treatments

• Midodrine has similar efficacy to other sympathomimetic agents, such as norfenefrine, etilefrine, and dihydroergotamine, in the management of orthostatic hypotension 3, 4.
• Midodrine appears to cause less frequent and severe adverse effects associated with alpha-receptor agonism, such as piloerection and urinary hesitancy, compared to other treatments 4.
• Combination therapy with midodrine and pyridostigmine has been shown to be effective and safe in patients with neurogenic orthostatic hypotension, with midodrine being better than pyridostigmine at improving OH-related symptoms 6.