Is midodrine (alpha-adrenergic agonist) suitable for treating orthostatic hypotension due to autonomic neuropathy in patients with end-stage renal disease (ESRD) and severe coronary artery disease (CAD), with or without mild heart failure (HF)?

Use of Midodrine for Orthostatic Hypotension in ESRD Patients with Severe CAD

Midodrine should be used with caution in ESRD patients with severe CAD and orthostatic hypotension due to autonomic neuropathy, with careful monitoring for cardiac side effects, especially in those with heart failure. 1

Efficacy of Midodrine in ESRD Patients

• Midodrine is effective for treating symptomatic orthostatic hypotension in dialysis patients by maintaining central blood volume and cardiac output while causing a marginal increase in peripheral vascular resistance 1
• A single 5mg dose administered 30 minutes before dialysis significantly improves intradialytic and postdialytic systolic and diastolic blood pressures compared to sessions without midodrine 1
• Long-term efficacy has been demonstrated for more than 8 months without development of adverse events in dialysis patients 1
• Midodrine is effectively cleared by hemodialysis with a reduced half-life of 1.4 hours during dialysis, which may actually help reduce the risk of sustained hypertension 1

Special Considerations for CAD and Heart Failure Patients

• Midodrine should be used cautiously in patients with congestive heart failure and in those using other negative chronotropic agents such as beta-blockers, digoxin, and non-dihydropyridine calcium channel blockers 1
• Patients should be monitored for bradycardia, as midodrine is associated with reflex parasympathetic stimulation 1
• The peripheral selective α1-adrenergic agonist properties of midodrine exert a pressor effect through both arteriolar constriction and venoconstriction of capacitance vessels, which may affect cardiac workload 1
• In patients with heart failure, drug selection should prioritize medications shown to improve outcomes in heart failure with reduced ejection fraction, including ACE inhibitors, ARBs, beta-blockers, and aldosterone receptor antagonists 1

Dosing Recommendations

• Dosing should be individually tailored, starting with 5mg before dialysis sessions 1
• For general orthostatic hypotension management, dosing can be up to 10mg three times daily, with the first dose taken before arising 1
• The final daily dose should be taken at least 4 hours before bedtime to reduce the risk of supine hypertension 2
• In ESRD patients, since midodrine is administered on dialysis days, both the prodrug and active metabolite are effectively removed by hemodialysis, reducing the risk of developing sustained hypertension 1

Monitoring and Precautions

• Monitor for supine hypertension, which occurs in less than 10% of patients on long-term therapy 1
• Watch for bradycardia, especially in patients already on negative chronotropic agents 1
• Avoid concomitant use with other α-adrenergic agents such as ephedrine, pseudoephedrine, and phenylpropanolamine, as this may aggravate supine hypertension 1
• Be aware that midodrine can antagonize the actions of α-adrenergic blockers (such as terazosin, prazosin, and doxazosin) and could result in urinary retention 1
• Common side effects include piloerection, scalp itching or tingling, nausea, heartburn, urinary urgency, headache, nervousness, and sleep disturbance 1, 2

Alternative or Adjunctive Approaches

• Non-pharmacological measures should be tried first, including gradual staged movements with postural change, mild isotonic exercise, physical counter-maneuvers, and increased fluid intake if not contraindicated 1
• For resistant orthostatic hypotension, consider combination therapy such as cool dialysate with midodrine, which may decrease frequency and intensity of symptoms without additional side effects 1
• In patients with refractory symptoms, sertraline has shown benefit for idiopathic orthostatic hypotension and intradialytic hypotension 1
• Fludrocortisone (9-α-fluorohydrocortisone) is another first-choice drug that acts through sodium retention, but may cause supine hypertension, hypokalemia, and congestive heart failure 1

Conclusion for Clinical Practice

• Midodrine is the only medication approved by the FDA for treatment of symptomatic orthostatic hypotension 1
• For ESRD patients with severe CAD, especially those with heart failure, start with a low dose (2.5-5mg) before dialysis and titrate carefully while monitoring cardiac parameters 1
• The benefits of improved orthostatic tolerance and reduced symptoms must be balanced against the potential risks of supine hypertension and cardiac effects in this vulnerable population 1