Midodrine

Summary

Synopsis

Midodrine is a prodrug which undergoes enzymatic hydrolysis to the selective α₁-adrenoceptor agonist desglymidodrine after oral administration.

Oral midodrine significantly increases 1- minute standing systolic blood pressure compared with placebo. The drug also improves standing time and energy level and clinical symptoms of orthostatic hypotension including dizziness, light- headedness and syncope.

Comparative studies have shown midodrine to have similar efficacy to dihydroergotamine mesylate, norfenefrine, fludrocortisone and etilefrine, and to be more effective than dimetofrine and ephedrine in patients with orthostatic hypotension.

Midodrine is well tolerated, with the most commonly reported adverse events being piloerection, pruritus, paraesthesias, urinary retention and chills. The risk of supine hypertension, which is associated with midodrine therapy in up to 25% of patients, can be reduced by taking the final daily dose at least 4 hours before bedtime.

Thus, oral midodrine is an effective therapeutic option for the management of various forms of orthostatic hypotension. This well- tolerated agent is likely to be useful in conjunction with standard nonpharmacological care.

Pharmacological Overview

The sympathomimetic agent midodrine is a prodrug which is converted to its pharmacologically active metabolite desglymidodrine after oral administration. Desglymidodrine, a selective α₁-adrenoceptor agonist, increases blood pressure via arterial and venous vasoconstriction.

Single oral doses of midodrine (2.5, 10 and 20mg) dose-dependently increased standing systolic blood pressure 1 hour postdose in patients with orthostatic hypotension; the duration of action of midodrine 10mg was approximately 4 hours. Midodrine also increased the time patients were able to stand motionless compared with placebo (4 vs 2 minutes). In diabetic patients with severe orthostatic hypotension, midodrine 10mg significantly improved standing blood pressure, cerebral blood flow and cognitive function.

Desglymidodrine reached peak plasma concentrations (0.027 mg/L) about 1 hour after a 5 to 10mg oral dose of midodrine in fasted patients with orthostatic hypotension. The absolute bioavailability of midodrine (as desglymidodrine) is 93% after oral administration. The elimination half-life of desglymidodrine is about 2 to 3 hours (0.49 hours for midodrine). Although the distribution of midodrine in humans has not been established, it does not appear to cross the blood-brain barrier after oral administration. Desglymidodrine is excreted primarily in the urine; faecal elimination of midodrine or desglymidodrine is insignificant.

Therapeutic Use

Recently published results of 2 placebo-controlled studies (involving a total of 268 patients) which used 1-minute standing blood pressure 1 hour postdose as a surrogate end-point for clinical efficacy showed that midodrine (10mg 3 times daily for 3 or 4 weeks) significantly increased standing systolic blood pressure by up to 22mm Hg in patients with orthostatic hypotension. In addition, a higher proportion of patients receiving midodrine versus placebo had a ≥10mm Hg increase in 1-minute standing systolic blood pressure (47 vs 28%). Midodrine significantly improved clinical symptoms of orthostatic hypotension, including dizziness, lightheadedness, syncope and depression. The drug also significantly improved the global evaluation score (incorporating lightheadedness, standing time and orthostatic energy level) compared with placebo when assessed by patient or investigator.

Small, predominantly crossover and short term comparative studies have shown midodrine to have an efficacy at least similar to that of dihydroergotamine mesylate, norfenefrine, fludrocortisone and etilefrine, and to be more effective than dimetofrine and ephedrine in patients with orthostatic hypotension.

Tolerability

Midodrine is well tolerated in most patients with orthostatic hypotension. The most common adverse events associated with the use of midodrine 10mg 3 times daily in a 3-week placebo-controlled trial in 171 patients included piloerection (13%), scalp or general pruritus (10 and 2%), scalp or general paraesthesia (9% each), urinary retention (6%) and chills (5%). 18% of 82 midodrine recipients withdrew because of adverse events. The use of midodrine 10mg 3 times daily has been associated with supine hypertension in up to 25% of patients enrolled in clinical trials.

Although the metabolic effects of midodrine have not been fully investigated, the drug does not appear to affect blood glucose or insulin levels, glucose tolerance, serum lipid profiles, or uric acid or urea levels. In addition, it does not appear to affect pulmonary or renal function, bone marrow, blood coagulation or fibrinolysis.

Dosage and Administration

The recommended initial dosage of midodrine in patients with orthostatic hypotension is 2.5mg administered orally 2 to 3 times daily. This dosage is gradually increased to the recommended maintenance dosage of 10mg 3 times daily if needed. The dose interval is 3 to 4 hours, with the final dose given at least 4 hours before bedtime to reduce the risk of supine hypertension. To maximise the therapeutic efficacy of midodrine, the dosage should be individualised for each patient.

Blood pressure should be monitored regularly during treatment and the use of midodrine should be stopped if supine blood pressure increases excessively. Treatment should be continued only in patients with symptomatic improvement during initial treatment. Midodrine should be used with caution in patients with renal or hepatic dysfunction, and is contraindicated in patients with severe heart disease, acute renal disease, urinary retention, phaeochromocytoma or thyrotoxicosis.