, Volume 38, Issue 5, pp 757–777 | Cite as


A Review of its Pharmacological Properties and Therapeutic Use in Orthostatic Hypotension and Secondary Hypotensive Disorders
  • Donna McTavish
  • Karen L. Goa
Drug Evaluation



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.


Orthostatic Hypotension Spinal Cord Lesion Midodrine Dihydroergotamine Supine Blood Pressure 
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  1. Aiazzi L, Caprioli G, Castelli C, Poma A, Baldrighi V. A new approach to the diagnosis and treatment in out-patients of orthostatic hypotension. Archivio di Medicina Interna 32: 2–12, 1980Google Scholar
  2. Brändle J, Lageder H, Irsigler K. Investigations of the effect of midodrine on carbohydrate and fat metabolism with particular reference to the diabetic metabolic state. Wiener Klinische Wochenschrift 89: 164–167, 1977PubMedGoogle Scholar
  3. Carpinella G, Gabba F. Midodrine in the treatment of orthostatic hypotension. Rivista di Patologia e Clinica 34: 476–484, 1979Google Scholar
  4. Coniglio S. The use of a new alpha-adrenergic drug in the treatment of essential hypotension: results of a controlled clinical trial. Archivio di Medicina Interna 32: 14–28, 1980Google Scholar
  5. Ehringer H. Studies on the peripheral hemodynamics in man after intravenous infusion of a small dose of dl-l-(2′,5′-dimethoxyphenyl)-2-glycinamidoethanol-(1)-hydrochloride (= ST 1085). International Journal of Clinical Pharmacology, Therapy and Toxicology 4: 415–420, 1971Google Scholar
  6. Engel K, Havelec L, Klausgraber F, Pramer I. Comparative studies and evaluation of the therapeutic usability of midodrin (Gutron.®) in the hypotension syndrome. Wiener Medizinische Wochenschrift 124: 501–507, 1974PubMedGoogle Scholar
  7. Geddo G, Rossi L, Gerboni D, Porcile M, Gabbarini L. Midodrine in the prophylaxis of arterial hypotension during peridural anesthesia. XXXVth National Congress of the Italian Society for Anesthesia, analgesia reanimation and intensive therapy, Venice, September 22–25, 1983Google Scholar
  8. Grobecker H, Kees F, Linden M, Schrader E, Weite S. Studies on the bioavailability of midodrine and α-2,5-dimethoxyphenyl-β-aminoethanol hydrochloride. Arzneimittel-Forschung 37: 447–450, 1987PubMedGoogle Scholar
  9. Hammerer I, Gassner I, Schwingshackl A. The use of midodrine in the treatment of the orthostatic syndrome. Pädiatrie und Pädologie 16: 59–68, 1981PubMedGoogle Scholar
  10. Hebenstreit G. Treatment of hypotension caused by psychopharmacological drugs. A double-blind study. Wiener Medizinische Wochenschrift 131: 109–112, 1981PubMedGoogle Scholar
  11. Hitzenberger G, Mösslacher H, Slany J. Hemodynamic effects of a new substance (2′-5′-dimethoxyphenyl-2-glycinamidoethanol-1-hydrochloride) after intravenous administration. International Journal of Clinical Pharmacology 4: 323–327, 1973Google Scholar
  12. Hofmann G, Dafalias Ch. The modification of neuroleptic-induced hypotension by a new alpha-sympathomimetic drug. Praktische Arzt 33: 1127–1132, 1979Google Scholar
  13. Kahle D. What can a circulatory agent do for patients paralysed by a transverse lesion of the cord? Arztliche Praxis 32: 2793–2794, 1980Google Scholar
  14. Kaufmann H, Brannan T, Krakoff L, Yahr MD, Mandeli J. Treatment of orthostatic hypotension due to autonomic failure with a peripheral alpha-adrenergic agonist (midodrine). Neurology 38: 951–956, 1988PubMedCrossRefGoogle Scholar
  15. Kiesewetter E, Deimer E, Fischer M, Höcker P, Mermon R, et al. Tolerance studies of the alpha-sympathomimetic Gutron®. Wiener Medizinische Wochenschrift (Suppl. 37), 1976Google Scholar
  16. Kratz H. Treatment of hypotensive circulatory dysregulation in practice with GUTRON. Wiener Medizinische Wochenschrift 125: 189–192, 1975PubMedGoogle Scholar
  17. Kratz H. Comparative clinical study on an antihypotensive therapy with Gutron® and a depot preparation. Dr. Med 7: 36–38, 1978Google Scholar
  18. Lachner O, Lillie Ch, Rot A. The pharmacological properties of midodrin and its clinical application in patients with hypotensive circulatory disturbance. Wiener Klinische Wochenschrift 86: 344–348, 1974PubMedGoogle Scholar
  19. Lassmann H, Stockinger L. Autoradiographic studies of the uptake and accumulation of Gutron®. Wiener Medizinische Wochenschrift (Suppl. 37): 9–11, 1976Google Scholar
  20. Lossnitzer K, Letzel H. Therapeutic effect of midodrine in hypotensive orthostatic circulatory dysregulation. Therapiewoche 32: 6071–6076, 1982Google Scholar
  21. Lossnitzer K, Letzel H. The activity of midodrine in orthostatic circulatory dysregulation. Medizinische Welt 34: 1190–1193, 1983PubMedGoogle Scholar
  22. Lukasik S, Markiewicz M, Petelenz T, Slopecka G, Axentii I, et al. Clinical drug evaluation. Use of Gutron® (midodrine) in the treatment of arterial hypotension syndrome. Polish Medical Weekly 39: 329–332, 1984Google Scholar
  23. Mancusi L, Cerciello A, Tripepi C, Torelli L. Subarachnoid anesthesia and midodrine. Minerva Anestesiologica 53: 19–26, 1987PubMedGoogle Scholar
  24. Marini U, Cecchi A, Venturini M. Controlled clinical investigation of dimetophrine versus midodrine in the management of moderately decreased arterial blood pressure. Current Medical Research and Opinion 9: 265–274, 1984PubMedCrossRefGoogle Scholar
  25. Paumgartner G, Pokorny D, Grabner G. Experimental and clinical experience with a new sympathicomimetic (2′,5′-dimethoxyphenyl -2-glycinarnido-ethanol-1-hydrochloride). Wiener Klinische Wochenschrift 82: 490–494, 1970PubMedGoogle Scholar
  26. Pittner H, Stormann H, Enzenhofer R. Pharmacodynamic actions of midodrine, a new α-adrenergic stimulating agent, and its main metabolite, ST 1059. Arzneimittel-Forschung 26: 2145–2154, 1976PubMedGoogle Scholar
  27. Sazovsky H, Pittner H. Diagnosis and therapy of hypotensive disturbances in the circulatory regulation in general practice. Fortschritte Med 97: 733–736, 1979Google Scholar
  28. Schirger A, Sheps SG, Thomas JE, Fealey RD. Midodrine. A new agent in the management of idiopathic orthostatic hypotension and Shy-Drager syndrome. Mayo Clinic Proceedings 56: 429–433, 1981PubMedGoogle Scholar
  29. Scholing WE. Studies on the effect of the alpha-receptor stimulant, GutronR, in the orthostatic syndrome. Wiener Klinische Wochenschrift 93: 429–431, 1981PubMedGoogle Scholar
  30. Schramek G, Wolkerstorfer H. Therapy of constitutional hypotension.Google Scholar
  31. Experiences with midodrine. Wiener Medizinische Wochenschrift 123: 571–573, 1973Google Scholar
  32. Steinbach K, Weidinger P. The effect of midodrine on orthostatic hypotension. Wiener Klinische Wochenschrift 85: 621–624, 1973PubMedGoogle Scholar
  33. Thulesius O. Pathophysiological classification and diagnosis of orthostatic hypotension. Cardiology 61(Suppl. 1): 180, 1976PubMedCrossRefGoogle Scholar
  34. Thulesius O, Gjores JE, Berlin E. Vasoconstrictor effect of midodrine, ST 1059, noradrenaline, etilefrine and dihydroergotamine on isolated human veins. European Journal of Clinical Pharmacology 16: 423–424, 1979PubMedCrossRefGoogle Scholar
  35. Vukovich RA, Caruso FS, Cohen J, Colquhoun J. Correction of severe orthostatic hypotension by midodrine: a new alpha adrenoceptor agonist. Abstract. Clinical Pharmacology and Therapeutics 45: 123, 1989Google Scholar
  36. Weippl G. Infectious-toxic hypotension — effect and dosage of midodrine. Pädiatrie und Pädologie 14: 211–216, 1976Google Scholar
  37. Zachariah PK, Bloedow DC, Moyer TP, Sheps SC, Schirger A, et al. Pharmacodynamics of midodrine, an antihypotensive agent. Clinical Pharmacology and Therapeutics 39: 586–591, 1986PubMedCrossRefGoogle Scholar

Copyright information

© ADIS Press Limited 1989

Authors and Affiliations

  • Donna McTavish
    • 1
  • Karen L. Goa
    • 1
  1. 1.ADIS Drug Information ServicesAucklandNew Zealand

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