What are the side effects of Midodrine (ProAmatine)?

Midodrine Side Effects

The most potentially serious adverse reaction associated with midodrine is supine hypertension, which occurs in up to 25% of patients, while the most common side effects include pilomotor reactions (piloerection, scalp pruritus/tingling), urinary symptoms (urgency, retention, frequency), and reflex bradycardia. 1

Most Serious Side Effect: Supine Hypertension

• Supine hypertension represents the primary safety concern requiring close monitoring and potential discontinuation of therapy. 1
• Marked elevation of supine systolic blood pressure occurred in approximately 13.4% of patients receiving 10 mg doses, with systolic pressures reaching approximately 200 mmHg in clinical trials. 1
• The risk is highest in patients with pre-existing elevated supine systolic pressures (mean 170 mmHg at baseline), and midodrine should not be used in patients with initial supine systolic pressure above 180 mmHg. 1
• To minimize supine hypertension risk, avoid doses within at least 4 hours of bedtime and consider elevating the head of the bed by 10 degrees during sleep. 2, 3
• The American Journal of Kidney Diseases recommends withholding midodrine if supine systolic hypertension develops. 4

Common Side Effects

Pilomotor Reactions (Alpha-Adrenergic Effects on Hair Follicles)

• Piloerection (goosebumps) occurred in 13.4% of patients in controlled trials. 1
• Paresthesia and pruritus, mainly of the scalp, occurred in 18.3% and 12.2% of patients respectively. 1
• These pilomotor reactions are associated with midodrine's action on alpha-adrenergic receptors of hair follicles and are generally mild. 1

Urinary Symptoms (Alpha-Receptor Effects on Bladder Neck)

• Urinary symptoms (dysuria, urgency, retention, frequency) occurred in 13.4% of patients in controlled trials. 1
• These effects result from midodrine's action on alpha-receptors of the bladder neck. 1
• In patients with spinal cord injury who void spontaneously, midodrine can insidiously cause progressive urinary retention and may aggravate detrusor-sphincter dyssynergia, potentially leading to hydroureteronephrosis. 5
• The American Journal of Kidney Diseases recommends monitoring for urinary retention and suggests that midodrine can antagonize alpha-adrenergic blockers, potentially causing urinary retention. 4

Cardiovascular Effects

• Bradycardia occurs through reflex parasympathetic (vagal) stimulation in response to midodrine's alpha-1 adrenergic-mediated increase in peripheral vascular resistance and blood pressure. 2
• The resulting blood pressure elevation activates arterial baroreceptors, leading to increased vagal tone and bradycardia. 2
• Particular caution is required when combining midodrine with other negative chronotropic agents (beta-blockers, digoxin, non-dihydropyridine calcium channel blockers), as this significantly increases bradycardia risk. 6, 4
• Chills occurred in 4.9% of patients. 1

Other Common Side Effects

• Headache and feeling of pressure/fullness in the head. 1
• Gastrointestinal symptoms including nausea, heartburn, pyrosis, and gastrointestinal distress. 1
• Vasodilation/flushing of the face. 1
• Nervousness/anxiety. 1
• Dry mouth. 1

Less Common but Clinically Significant Side Effects

• Nightmares have been reported as a novel adverse effect, particularly with evening dosing, potentially related to autonomic dysfunction. 7
• Visual field defects, dizziness, and confusion/thinking abnormality. 1
• Skin reactions including rash, erythema multiforme, dry skin, and skin hyperesthesia. 1
• Insomnia and somnolence. 1
• Asthenia, backache, and leg cramps. 1

Critical Drug Interactions and Contraindications

• Concomitant use with other alpha-adrenergic agents (ephedrine, pseudoephedrine, phenylpropanolamine) should be avoided as this may aggravate supine hypertension. 6, 4
• Midodrine may be poorly tolerated in heart failure patients and should be used with extreme caution, as the American College of Cardiology notes it can worsen cardiac function through increased afterload. 8
• The increased systemic vascular resistance can shift blood into pulmonary vasculature, potentially increasing left ventricular filling pressures and unmasking subclinical left ventricular dysfunction. 2

Monitoring Recommendations

• Essential to monitor both supine and sitting blood pressures in all patients maintained on midodrine. 1
• Monitor for bradycardia, particularly in hemodialysis patients and those on negative chronotropic agents. 4
• Assess for urinary retention, especially in patients with spinal cord injury or those on alpha-adrenergic blockers. 4
• In patients with spinal cord injury who develop urologic adverse effects, midodrine should be stopped and intermittent catheterization with antimuscarinic therapy should be considered. 5

Special Population Considerations

• In hemodialysis patients, midodrine is effectively cleared during dialysis with half-life reduced to 1.4 hours, and the combination of cool dialysate with predialysis midodrine may decrease intradialytic hypotension symptoms without significant side effects. 6, 4
• For patients with creatinine clearance less than 30 mL/minute or receiving hemodialysis, medication doses should generally be reduced. 4