Pharmacology Update

Midodrine: A New Drug for Orthostatic Hypotension

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Midodrine hcl (proamatine, roberts pharmaceuticals) recently received an accelerated approval by the FDA for the treatment of symptomatic orthostatic hypotension. Midodrine is the prodrug of desglymidodrine, an alpha 1-agonist. The drug is indicated for the treatment of patients whose lives are severely impaired by orthostasis since there are some risks from the medication, and its benefits have not been clearly established.

Potential Advantages

Desglymidodrine acts only on the alpha adrenergic receptors of the arteriolar and venous vasculature. It does not stimulate beta-adrenergic receptors in cardiac tissue and does not penetrate well across the blood-brain barrier.1 In a small study (n = 8), midodrine was found to be more effective than ephedrine in increasing systolic and diastolic standing blood pressure.2

Midodrine increased standing systolic blood pressure by about 20 mmHg and standing diastolic blood pressure by about 15 mmHg assessed one hour after administration. Significant improvement in symptoms (syncope, increase in energy level, and depression) were reported with midodrine.3

Potential Disadvantages

The overall response rate for midodrine was reported to be less than 50% (47%). Adverse effects include paresthesia (18%), piloerection (13%), dysuria (13%), and pruritus (12%). Supine hypertension (about 200 mmHg) was reported in 13.4% of patients treated with midodrine, 10 mg tid.1 Midodrine should be avoided in patients with supine hypertension (> 170 mmHg). It should be used with caution in patients with urinary retention, bradycardia (or with drugs that may cause bradycardia), diabetes, renal, or hepatic dysfunction, and those on fludrocortisone with a history of visual problems.1

Prescribing Information

Midodrine is supplied in 2.5 mg and 5 mg tablets. The recommended dose is 10 mg tid at four-hour intervals upon rising, midday, and late afternoon (not later than 8:00 pm). Doses may be given at three-hour intervals if required to control symptoms.

Comments

Orthostatic hypotension is defined as a fall of more than 20 mmHg systolic blood pressure on standing.4 Orthostatic symptoms include lightheadedness, weakness, dizziness, syncope, visual disturbances, and lack of energy. A major cause of orthostatic hypotension is the lack of neurally mediated vasoconstriction (i.e., autonomic failure) to compensate for gravitational effects of pooling.4 Diagnoses that may result in autonomic failure include Shy-Drager syndrome and Bradbury-Eggleston syndrome, diabetes, Parkinson’s disease, multiple sclerosis, and neuropathy.

The goal of treatment is to improve the patient’s functional capacity and quality of life. Pharmacologic therapies have included fludrocortisone and ephedrine, but these drugs have only resulted in limited success.5,6 Fludrocortisone often causes marked fluid retention and hypokalemia, while ephedrine has a short duration of action and potential for tachyphylaxis.6

Midodrine is the only FDA-approved agent for this condition. Its approval was based on surrogate markers (i.e., increase in systolic blood pressure ³ 10 mmHg 1 hour after a dose) in studies in neurogenic orthostatic hypotension with less than 50% of the patients responding. The drug does not reverse nor stabilize the disease process.6 The clinical benefit of midodrine in improving the ability to carry out activities of daily living have not been verified.1

Clinical Implications

The drug may be useful in a small number of patients with disabling orthostatic hypotension who are unresponsive to other maneuvers.

References

1. ProAmatine TM Product Information. Roberts Pharmaceuticals. September 1996.

2. Fouad-Tarazi FM, et al. Am J Med 1995;99:604-610.

3. Jankovic J, et al. Am J Med 1993;95:38-48.

4. Mathias CJ. Neurology 1995;45 (Suppl 5):S6-S11.

5. Gilden J. Int Angiol 1993;12:125-131.

6. Robertson D, et al. Neurology 1995; 45 (Suppl 5): S26-S32.