What is the mechanism of action of midodrine (alpha-adrenergic agonist) in treating hypotension (low blood pressure)?

From the Guidelines

Midodrine works in hypotension-related syncope (HRS) by activating alpha-1 adrenergic receptors in blood vessels, causing vasoconstriction that increases peripheral vascular resistance and raises blood pressure. As a prodrug, midodrine is converted in the body to its active metabolite, desglymidodrine, which directly stimulates these receptors 1. This mechanism is particularly helpful for patients with orthostatic hypotension or neurally mediated syncope by maintaining adequate blood pressure when changing positions. The typical dosing regimen is 2.5-10 mg taken three times daily, with the last dose at least 4 hours before bedtime to avoid supine hypertension, as recommended by the 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope 1. Patients should start at a low dose (2.5 mg) and gradually increase based on response and tolerability. Midodrine should not be taken when lying down, and patients should monitor for potential side effects including piloerection (goosebumps), scalp tingling, urinary retention, and supine hypertension. Some key points to consider when using midodrine include:

• The medication has a relatively short duration of action (2-3 hours), which necessitates multiple daily doses but also helps minimize nighttime hypertension.
• Midodrine is the only medication approved by the Food and Drug Administration for the treatment of symptomatic orthostatic hypotension, as noted in a study on cardiovascular autonomic neuropathy in diabetes 1.
• The use of midodrine may be limited by supine hypertension, and other common side effects include scalp tingling, piloerection, and urinary retention, as reported in the 2017 ACC/AHA/HRS guideline 1. Overall, midodrine is a useful treatment option for patients with hypotension-related syncope, particularly those with orthostatic hypotension or neurally mediated syncope, as supported by the guidelines and studies 1.

From the FDA Drug Label

Mechanism of Action: 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. The mechanism of action of midodrine in patients with orthostatic hypotension 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 2.

• The active metabolite desglymidodrine does not stimulate cardiac beta-adrenergic receptors.
• Desglymidodrine has a limited effect on the central nervous system due to its poor diffusion across the blood-brain barrier.

From the Research

Mechanism of Action of Midodrine in Orthostatic Hypotension

• Midodrine is a peripheral alpha-adrenergic agonist that undergoes enzymatic hydrolysis to form its pharmacologically active metabolite, desglymidodrine 3, 4.
• Desglymidodrine is a selective alpha 1-adrenoceptor agonist that increases standing blood pressure and improves symptoms of orthostatic hypotension, such as weakness, syncope, blurred vision, and fatigue 3, 4.
• The mechanism of action of midodrine involves the activation of alpha 1-adrenergic receptors, which causes vasoconstriction and increases blood pressure 3, 4.

Efficacy of Midodrine in Orthostatic Hypotension

• Midodrine has been shown to be effective in increasing standing systolic blood pressure and improving standing time and energy level in patients with orthostatic hypotension 3, 4.
• Comparative studies have shown midodrine to be clinically at least as effective as other sympathomimetic agents and dihydroergotamine in the management of orthostatic hypotension 3, 4.
• Midodrine has also been shown to improve health-related quality of life and reduce the frequency of syncope in patients with recurrent reflex syncope 5, 6.

Safety and Tolerability of Midodrine

• Midodrine is generally well-tolerated, with the most commonly reported adverse events being piloerection, pruritus, paraesthesias, urinary retention, and chills 3, 4.
• The risk of supine hypertension, which is associated with midodrine therapy, can be reduced by taking the final daily dose at least 4 hours before bedtime 4.
• Midodrine has been shown to be safe and effective in patients with orthostatic hypotension, with a low risk of serious adverse events 5, 6.