Summary
Synopsis
Midodrine, a peripheral α-adrenergic agonist, finds use in the clinical management of patients with orthostatic hypotension or hypotension secondary to other clinical conditions or drug therapies. Midodrine is almost completely absorbed after oral administration and undergoes enzymatic hydrolysis to form its pharmacologically active metabolite, de-glymidodrine. In patients with refractory orthostatic hypotension oral midodrine increases standing blood pressure and improves symptoms of orthostatism, such as weakness, syncope, blurred vision and fatigue, without any associated cardiac stimulation. Comparative studies have shown midodrine to be clinically at least as effective as other sympathomimetic agents (norfenefrine, etilefrine, dimetofrine and ephedrine) and dihydroergotamine in this regard. Additionally, midodrine appears to cause less frequent and severe adverse effects associated with α-receptor agonism such as piloerection and urinary hesitancy. The most commonly experienced adverse effects — piloerector reactions, gastrointestinal disorders, and cardiovascular complaints — are generally mild and can be controlled by reducing the dosage of midodrine. Thus, midodrine is at least as useful as other currently available options in the management of orthostatic or secondary hypotension, and represents a stepping stone towards optimal therapy.
Pharmacological Properties
Midodrine is a potent and selective, peripherally acting α-receptor agonist which, to date, has not been shown to act preferentially on either α1- or α2-receptors. After oral or intravenous administration it causes modest increases in supine and standing blood pressures in healthy volunteers. In patients with orthostatic hypotension it substantially increases blood pressure, decreases venous capacity (i.e. increases venous tone) and lowers supine and standing heart rates. A simultaneous and substantial increase in peripheral vascular resistance observed in hypotensive patients has been suggested as the cause of increased blood pressure. Midodrine also causes a significant reduction in plasma and blood volume.
The metabolic effects of midodrine in patients have not been fully investigated but data to date suggest that midodrine does not affect blood sugar or urea levels or have any effect on glucose tolerance, serum lipids, insulin or uric acid. Midodrine appears to have no central nervous system activity and does not affect pulmonary or renal function, bone marrow, blood coagulation or fibrinolysis.
Pharmacokinetic studies show that midodrine is rapidly and almost completely absorbed in healthy volunteers, achieving a maximum plasma concentration of about 10 to 50 µg/L within 40 minutes of a 2.5 to 5mg dose. After oral or intravenous administration, midodrine undergoes enzymatic hydrolysis in the systemic circulation to release its pharmacologically active metabolite, de-glymidodrine. Peak plasma concentrations of de-glymidodrine are reached about 1 hour after a single oral midodrine dose in volunteers and in hypotensive patients. However, in patients mean peak plasma concentrations of the metabolite appear higher than those seen in volunteers (27 vs 4.7 µg/L)- This wide variability may be due to inter-individual differences in midodrine absorption and metabolism, or may reflect differences in dosages administered or assay procedures used. Absolute bioavailability of midodrine (as de-glymidodrine) is 93% for oral tablets and 90% for oral solution. Midodrine is cleared from plasma after 2 hours (elimination half-life of 30 minutes) while de-glymidodrine can be detected in plasma after 10 hours and has an elimination half-life of about 3 hours.
Midodrine undergoes extensive metabolism, with only 2 to 4% of a single dose excreted unchanged. Apart from de-glymidodrine, other metabolites have yet to be identified. Excretion of midodrine and de-glymidodrine is primarily urinary. Over a 24-hour period, 81 and 75% of a single 5mg intravenous and oral dose, respectively, is recovered in urine in healthy volunteers.
Therapeutic Trials
Most clinical experience with midodrine has been obtained in patients with severe refractory orthostatic hypotension. However, a few studies have been reported in patients with hypotension secondary to infection, haemodialysis, anaesthesia, psychotropic drug therapy, and spinal cord lesions.
Data from 2 multicentre studies which investigated over 1800 patients with orthostatic hypotension have shown that oral midodrine 2.5 to 10 mg/day consistently increased mean supine and standing blood pressures (by a maximum of 15/7 and 19/8mm Hg, respectively), reduced heart rates (by a maximum of 14 beats/min in sympathicotonic patients) and markedly improved subjective orthostatic symptoms in at least 69% of patients. Similar results have been reported in long term studies in which patients received oral midodrine treatment for up to 5 years.
Midodrine has been compared with placebo in several double-blind studies. Although the drug only had a modest and statistically non-significant effect on blood pressure and heart rate compared with placebo, it consistently improved subjective symptoms of orthostatism compared with placebo, despite a pronounced placebo effect on subjective symptom improvement seen in some studies. Comparative studies with other sympathomimetic agents have shown that midodrine 3 to 30 mg/day is at least as effective as dimetofrine 200 to 500 mg/day, ephedrine 18 to 72 mg/day, etilefrine 15 or 50 mg/day and norfenefrine 7.5 to 15 mg/day with regard to increasing standing blood pressure and improving subjective orthostatic symptoms. Furthermore, in contrast to these other agents which may have cardiac stimulating properties, midodrine consistently reduced supine and standing heart rates.
Oral midodrine (mean daily dose 20.1mg) and dihydroergotamine (mean daily dose 39.9mg) had similar, but slight, effects on standing systolic blood pressure (mean increase ⩽ 3mm Hg) but both treatments markedly improved the ability of patients to stand while maintaining a systolic blood pressure above 80mm Hg. Initial results suggest that combined midodrine/fludrocortisone treatment enhances the effect of midodrine monotherapy (mean daily dose 25.4mg) in patients with refractory orthostatic hypotension. Fludrocortisone 0.1 mg/day monotherapy had no significant effect on blood pressure in this study.
Clinical data on the use of midodrine in patients with hypotension secondary to psychotropic drug therapy, anaesthesia, infection, spinal cord lesions, and haemodialysis are limited to a small number of studies. Nonetheless, it is evident that midodrine also has some benefit in these special patient groups. Supine blood pressure was elevated in all patient groups after oral midodrine therapy except in patients with spinal cord lesions. Although supine blood pressure was not significantly altered in this latter group, these patients showed complete resolution of symptoms related to low blood pressure (collapse and dizziness) after midodrine treatment. Further clinical experience would help to establish a more definitive role for midodrine in secondary hypotension.
Adverse Effects
Midodrine is well tolerated in short and long term studies. The incidence of patients reporting adverse effects was 7.9% in 3030 patients treated with midodrine for hypotensive disorders for periods of less than 1 day up to 15 months, with 1.4% of patients withdrawing from therapy because of adverse effects.
Pilomotor reactions (55% of adverse effects reported), gastrointestinal complaints (12.6%), cardiovascular effects (9.4%) and central nervous system effects (8.4%) are the most frequently reported adverse effects in midodrine-treated patients. These reactions are generally mild and disappear on reducing the dosage of midodrine. As might be expected from the pharmacological profile of midodrine, supine hypertension affects a substantial proportion of patients (25% in 1 study) receiving midodrine therapy and may be controlled by reducing the dosage.
Dosage and Administration
Patients with orthostatic hypotension should initially receive midodrine 2.5mg 2 to 3 times daily. Gradual weekly titration to a maximum recommended daily dose of 40 mg/day may be necessary in patients with severe refractory orthostatic hypotension although in most patients a maintenance dose of 30 mg/day in 3 or 4 daily doses is adequate. During long term therapy, regular blood pressure monitoring is recommended.
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Various sections of the manuscript reviewed by: H. Grobecker, Lehrstuhl für Pharmakologie, Universität Regensburg, Regensburg, Federal Republic of Germany; H. Kaufmann, Mount Sinai Medical Center, New York, New York, USA; K. Lossnitzer, Medizinische Klinik der Klinik Sulzbach/Saar der Bundesknappschaft-Akademisches Lehrkrankenhaus der Universitat des Saarlands, Sulzbach, Federal Republic of Germany; H. Sato, First Department of Medicine, Osaka University School of Medicine, Osaka, Japan; A. Schirger, Mayo Clinic, Rochester, Minnesota, USA; H. Shionoiri, Second Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Japan; G. Sloman, Cardiovascular Unit, Epworth Hospital, Richmond, Victoria, Australia; P.K. Zachariah; Division of Hypertension and Internal Medicine; Mayo Clinic, Rochester, Minnesota, USA.
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McTavish, D., Goa, K.L. Midodrine. Drugs 38, 757–777 (1989). https://doi.org/10.2165/00003495-198938050-00004
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DOI: https://doi.org/10.2165/00003495-198938050-00004