Midodrine - Drug Monograph

Introduction

Midodrine is a vasopressor agent primarily used for the treatment of orthostatic hypotension. It is a prodrug that is converted to its active metabolite, desglymidodrine, which acts as a selective alpha-1 adrenergic receptor agonist. First approved by the FDA in 1996, midodrine represents an important therapeutic option for patients with symptomatic orthostatic hypotension who have not responded adequately to conventional non-pharmacologic measures.

Mechanism of Action

Midodrine functions as a prodrug that undergoes enzymatic hydrolysis to form its active metabolite, desglymidodrine. This metabolite acts as a direct-acting sympathomimetic agent with selective affinity for peripheral alpha-1 adrenergic receptors. By stimulating these receptors in the arteriolar and venous vasculature, midodrine causes vasoconstriction, resulting in increased vascular tone and elevation of blood pressure. The drug has minimal effect on beta-adrenergic receptors and does not stimulate cardiac function or cause central nervous system effects due to its poor blood-brain barrier penetration.

Indications

FDA-approved indications:

• Treatment of symptomatic orthostatic hypotension

Off-label uses (based on clinical evidence):

• Prevention of vasovagal syncope
• Management of intradialytic hypotension in patients undergoing hemodialysis
• Postprandial hypotension

Dosage and Administration

• Initial dose: 2.5 mg orally three times daily
• Maintenance dose: 5-10 mg orally three times daily
• Maximum recommended dose: 30 mg daily (10 mg three times daily)

• Doses should be taken approximately 4 hours apart during waking hours
• Typically administered at approximately 4-hour intervals (e.g., upon awakening, midday, and late afternoon)
• Should not be administered within 4 hours of bedtime

• Renal impairment: Use with caution; consider reduced dosing
• Hepatic impairment: Use with caution
• Elderly: Start with lower doses; monitor closely
• Pediatric: Safety and effectiveness not established

Pharmacokinetics

Contraindications

• Severe organic heart disease
• Acute renal failure
• Urinary retention
• Pheochromocytoma
• Thyrotoxicosis
• Supine hypertension (systolic >180 mmHg)
• Known hypersensitivity to midodrine or any component of the formulation

Warnings and Precautions

• Cardiac disorders: Use with extreme caution in patients with cardiac conditions including angina, arrhythmias, and congestive heart failure
• Renal impairment: Monitor closely in patients with renal dysfunction
• Hepatic impairment: Use cautiously in patients with liver disease
• Visual disturbances: May cause pupillary dilation with potential for blurred vision
• Glycine analog: Contains glycine moiety; use caution in patients with hyperglycinemia

Drug Interactions

• Alpha-adrenergic blockers (e.g., doxazosin, terazosin): Antagonistic effect
• Beta-blockers: Potential for enhanced bradycardia and hypertension
• Corticosteroids: May potentiate pressor effects
• MAO inhibitors: Risk of hypertensive crisis
• Sympathomimetic agents: Additive pressor effects
• Digitalis glycosides: May enhance bradycardic effects

Adverse Effects

• Supine hypertension (40%)
• Paresthesia (13%)
• Pruritus (13%)
• Pilocrection (10%)
• Dysuria (6%)
• Urinary urgency/frequency (6%)

• Severe supine hypertension
• Cardiac arrhythmias
• Angina pectoris
• Visual disturbances
• Chills
• Skin rash

Monitoring Parameters

• Supine and standing blood pressure (before and after doses)
• Heart rate in both positions
• Signs and symptoms of supine hypertension
• Renal function (serum creatinine, BUN)
• Urinary symptoms (retention, frequency)
• Cardiac status in patients with pre-existing heart disease
• Therapeutic response (reduction in orthostatic symptoms)

• Baseline comprehensive assessment
• Weekly monitoring during dose titration
• Regular follow-up every 3-6 months during maintenance therapy

Patient Education

• Take medication during waking hours only, typically at 4-hour intervals
• Do not take within 4 hours of bedtime to minimize risk of supine hypertension
• Avoid lying flat during the day; elevate head of bed at night
• Rise slowly from sitting or lying positions
• Monitor for symptoms of high blood pressure while lying down (headache, pounding in ears)
• Report any urinary difficulties, cardiac symptoms, or visual changes
• Maintain adequate fluid intake unless contraindicated
• Avoid alcohol as it may worsen orthostatic hypotension
• Inform all healthcare providers about midodrine use
• Do not discontinue abruptly without medical supervision

References

1. FDA Prescribing Information: Midodrine Hydrochloride Tablets (2023) 2. Low PA, et al. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. JAMA. 1997;277(13):1046-1051 3. Izcovich A, et al. Midodrine for orthostatic hypotension and recurrent syncope: A systematic review. Neurology. 2014;83(13):1170-1177 4. Jhanji R, et al. Management of orthostatic hypotension. Continuing Education in Anaesthesia, Critical Care & Pain. 2010;10(1):8-13 5. Wright RA, et al. A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology. 1998;51(1):120-124 6. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. Midodrine monograph. Updated 2023 7. American Autonomic Society consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Neurology. 1996;46(5):1470