Midodrine is an oral vasopressor agent that is receiving increasing interest as a therapy to reduce intensive care unit (ICU) admission and length of stay for patients who would otherwise require intravenous vasopressor infusions and invasive monitoring. Although usage trends increase, evidence for its effectiveness is conflicting. Adequacy and frequency of dosage, timing of initiation and patient selection are important factors to consider when prescribing midodrine for critically ill patients. This narrative review explores the historical context of midodrine usage, its pharmacological properties, current trends in use both within and outside the critical care environment, evidence to support its use, and finally, future research directions.
Historical context
Midodrine was patented in 1965 by Chemie Linz AG
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in Linz, Austria, and was first described in the medical literature in the 1970s as a novel peripherally acting α-agonist with good enteral absorption, efficacy and a long duration of action.
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Animal experiments revealed that α-(2,5-dimethoxyphenyl)-β-glycinamido-ethanol hydrochloride, or midodrine, and its active metabolite α-(2,5-dimethoxyphenyl)-β-aminoethanol (ST-1059 or desglymidodrine) effectively increase peripheral vascular tone and stimulate α-adrenergic receptors in intestine, bladder, bronchi and pupils
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without directly affecting cerebral blood flow.
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K. Wismayr. AT 241435; Eidem, US Patent 3,340,298 (1965, 1967 both to Chemie Linz Ag)
Pittner H, Stormann H, Enzenhofer R. Pharmacodynamic actions of midodrine, a new alpha-adrenergic stimulating agent, and its main metabolite, ST 1059. Arzneimittelforschung 1976; 26: 2145-54
Pittner H, Stormann H, Enzenhofer R. Pharmacodynamic actions of midodrine, a new alpha-adrenergic stimulating agent, and its main metabolite, ST 1059. Arzneimittelforschung 1976; 26: 2145-54
Tsuchida K, Yamazaki R, Kaneko K, Aihara H. Effects of midodrine on blood flow in dog vascular beds. Arzneimittelforschung 1986; 36: 1745-8
Plasma levels of the active metabolite, desglymidodrine, were significantly correlated with pressor activity,
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and midodrine’s reported venoconstrictive effect was 50–80% of noradrenaline-induced venoconstriction in vitro.
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Unlike other sympathomimetic agents with pressor effects, midodrine was equally efficacious in parenteral and enteral formulations.
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Kolassa N, Schützenberger WG, Wiener H, Krivanek P. Plasma level of the prodrug midodrine and its active metabolite in comparison with the alpha-mimetic action in dogs. Arch Int Pharmacodyn Ther 1979; 238: 96-104
Thulesius O, Gjöres JE, Berlin E. Vasoconstrictor effect of midodrine, ST 1059, noradrenaline, etilefrine and dihydroergotamine on isolated human veins. Eur J Clin Pharmacol 1979; 16: 423-4
Pittner H. Vasoconstrictor effects of midodrine, ST 1059, noradrenaline, etilefrine and norfenefrine on isolated dog femoral arteries and veins. Gen Pharmacol 1983; 14: 107-9
Pittner H, Stormann H, Enzenhofer R. Pharmacodynamic actions of midodrine, a new alpha-adrenergic stimulating agent, and its main metabolite, ST 1059. Arzneimittelforschung 1976; 26: 2145-54
Subsequent observational studies found clinical utility for midodrine’s α-sympathomimetic action and ease of oral administration for conditions such as urinary stress incontinence
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and ejaculation disorders,
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as well as orthostatic hypotension related to neurological conditions,
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neuroleptic medications
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and idiopathic postural hypotension in paediatric and adult populations.
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These pilot studies typically used oral doses of 2.5–5 mg two or three times daily. An early observational study also demonstrated midodrine’s safety and efficacy in increasing blood pressure in children with septic shock.
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Most of these early, small observational and double-blind studies reported minimal adverse events.
Jonas D. Treatment of female stress incontinence with midodrine: preliminary report. J Urol 1977; 118: 980-2
Riccabona M. [The conservative treatment of stress incontinence in women with midodrine] [German]. Wien Klin Wochenschr 1981; 93: 163-5
Jonas D, Linzbach P, Weber W. The use of midodrin in the treatment of ejaculation disorders following retroperitoneal lymphadenectomy. Eur Urol 1979; 5: 184-7
Riley AJ, Riley EJ. Partial ejaculatory incompetence: the therapeutic effect of midodrine, an orally active selective alpha-adrenoceptor agonist. Eur Urol 1982; 8: 155-60
Schirger A, Sheps SG, Thomas JE, Fealey RD. Midodrine. A new agent in the management of idiopathic orthostatic hypotension and Shy–Drager syndrome. Mayo Clin Proc 1981; 56: 429-33
Hebenstreit G. [Treatment of hypotension caused by psychopharmacological drugs] [German]. Wien Med Wochenschr 1981; 131: 109-12
Sazovsky H, Pittner H. [Diagnosis and therapy of hypotensive circulatory disorders in general practice. Experiences with Gutron using the Thulesius-diagram for diagnosis and supervision of therapy] [German]. Fortschr Med 1979; 97: 733-6
Hammerer I, Gassner I, Schwingshackl A. [The use of midodrin in the treatment of the orthostatic syndrome] [German]. Padiatr Padol 1981; 16: 59-68
Scholing WE. [Studies on the effect of the alpha-receptor stimulant, gutron, in the orthostatic syndrome] [German]. Wien Klin Wochenschr 1981; 93: 429-34
Weippl G. [Infectious toxic hypotension — effect and dosage of midodrine] [German]. Padiatr Padol 1979; 14: 211-6
Larger clinical trials in the 1990s established midodrine as a safe and effective agent for orthostatic hypotension.
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The first multicentre, double-blind, randomised controlled trial (RCT) evaluating the use of midodrine for moderate to severe orthostatic hypotension was conducted in the United States and published in 1993.
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This study assigned its 97 patients to either receive placebo, or midodrine at doses of 2.5 mg, 5 mg or 10 mg over a 4-week period. At 10 mg doses, midodrine increased standing systolic blood pressure by 28% and, at all doses, significantly improved symptoms of dizziness, weakness and syncope. A larger double-blind study of 171 patients, administering midodrine at 10 mg three times daily for a 4-week period found a similar increase in standing systolic blood pressure (24% mean increase) and reduction in mean symptom score for lightheadedness.
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These studies paved the way for midodrine to receive United States Food and Drug Administration (FDA) approval in 1996 for symptomatic orthostatic hypotension via its Accelerated Approval Program.
Jankovic J, Gilden JL, Hiner BC, et al. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med 1993; 95: 38-48
Fouad-Tarazi FM, Okabe M, Goren H. Alpha sympathomimetic treatment of autonomic insufficiency with orthostatic hypotension. Am J Med 1995; 99: 604-10
Low PA, Gilden JL, Freeman R, et al. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group. JAMA 1997; 277: 1046-51
Wright RA, Kaufmann HC, Perera R, et al. A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology 1998; 51: 120-4
Jankovic J, Gilden JL, Hiner BC, et al. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med 1993; 95: 38-48
Low PA, Gilden JL, Freeman R, et al. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group. JAMA 1997; 277: 1046-51
Other emerging uses for midodrine were also reported around this time. Midodrine as a pre-medication for chronic hypotension associated with haemodialysis was shown to be safe and provided extended haemodynamic and symptomatic benefit in doses ranging from 2.5 mg to 25 mg.
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Midodrine for reversal of hepatorenal syndrome was also described
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to improve renal plasma flow and glomerular filtration rate with improved one-month survival.
Fang JT, Huang CC. Midodrine hydrochloride in patients on hemodialysis with chronic hypotension. Ren Fail 1996; 18: 253-60
Flynn JJ, Mitchell MC, Caruso FS, McElligott MA. Midodrine treatment for patients with hemodialysis hypotension. Clin Nephrol 1996; 45: 261-7
Lim PS, Yang CC, Li HP, et al. Midodrine for the treatment of intradialytic hypotension. Nephron 1997; 77: 279-83
Cruz DN, Mahnensmith RL, Brickel HM, Perazella MA. Midodrine is effective and safe therapy for intradialytic hypotension over 8 months of follow-up. Clin Nephrol 1998; 50: 101-7
Angeli P, Volpin R, Piovan D, et al. Acute effects of the oral administration of midodrine, an alpha-adrenergic agonist, on renal hemodynamics and renal function in cirrhotic patients with ascites. Hepatology 1998; 28: 937-43
Angeli P, Volpin R, Gerunda G, et al. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 1999; 29: 1690-7
In 2010, however, the FDA decided to withdraw midodrine from the market due to the failure of its manufacturers to conduct any post-marketing studies to confirm clinical benefit for orthostatic hypotension.
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Health care professional appeals and consumer complaints led to this action being delayed
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pending phase 4 trials. A phase 4, double-blind, placebo-controlled, randomised tilt-table study was finally published in 2016 which showed that patients receiving stable doses of midodrine for more than 3 months had a statistically significant increase in time to tilt-table-induced syncopal symptoms.
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Nevertheless, this scrutiny stimulated interest to demonstrate midodrine’s efficacy across many patient groups and clinical settings, with more than half of all published literature on midodrine appearing since this time.
Fairman KA, Curtiss FR. Regulatory actions on the off-label use of prescription drugs: ongoing controversy and contradiction in 2009 and 2010. J Manag Care Pharm 2010; 16: 629-39
Somberg JC. The midodrine withdrawal. Am J Ther 2010; 17: 445
Dhruva SS, Redberg RF. Accelerated approval and possible withdrawal of midodrine. JAMA 2010; 304: 2172-3
Smith W, Wan H, Much D, et al. Clinical benefit of midodrine hydrochloride in symptomatic orthostatic hypotension: a phase 4, double-blind, placebo-controlled, randomized, tilt-table study. Clin Auton Res 2016; 26: 269-77
Pharmacology of midodrine
Midodrine is a peripherally acting α-receptor agonist available as 2.5 mg and 5 mg tablets. It does not act preferentially on either α1- or α2-receptors,
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but its active metabolite, desglymidodrine, selectively stimulates α1-receptors.
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It causes modest increases in supine and standing blood pressure in a dose-dependent manner.
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Its other pharmacodynamic effects are to increase peripheral vascular resistance, increase venous tone and release of atrial natriuretic peptide,
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and reduce circulating plasma and blood volume
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(Figure 1).
McTavish D, Goa KL. Midodrine. A review of its pharmacological properties and therapeutic use in orthostatic hypotension and secondary hypotensive disorders. Drugs 1989; 38: 757-77
Yamazaki R, Tsuchida K, Aihara H. Effects of alpha-adrenoceptor agonists on cardiac output and blood pressure in spinally anesthetized ganglion-blocked dogs. Arch Int Pharmacodyn Ther 1988; 295: 80-93
Pittner H, Stormann H, Enzenhofer R. Pharmacodynamic actions of midodrine, a new alpha-adrenergic stimulating agent, and its main metabolite, ST 1059. Arzneimittelforschung 1976; 26: 2145-54
Wright RA, Kaufmann HC, Perera R, et al. A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology 1998; 51: 120-4
Lamarre-Cliche M, Souich PD, Champlain JD, Larochelle P. Pharmacokinetic and pharmacodynamic effects of midodrine on blood pressure, the autonomic nervous system, and plasma natriuretic peptides: a prospective, randomized, single-blind, two-period, crossover, placebo-controlled study. Clin Ther 2008; 30: 1629-38
McTavish D, Goa KL. Midodrine. A review of its pharmacological properties and therapeutic use in orthostatic hypotension and secondary hypotensive disorders. Drugs 1989; 38: 757-77
Midodrine has poor blood-brain barrier penetration
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and, therefore, no direct central nervous system activity. It has no myocardial β-adrenoreceptor activity but indirectly increases end-diastolic volume and stroke volume, decreases heart rate and circulating noradrenaline levels via baroreceptor stimulation,
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and causes QT prolongation.
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It has no significant metabolic or endocrine effects. It has no effect on serum lipids, insulin, or uric acid levels.
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It also does not have any established effect on pulmonary, renal,
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coagulation
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or immune function.
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It has been safely administered in pregnancy
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Zachariah PK, Bloedow DC, Moyer TP, et al. Pharmacodynamics of midodrine, an antihypotensive agent. Clin Pharmacol Ther 1986; 39: 586-91
Dominiak P, Kees F, Welzel D, Grobecker H. Cardiovascular parameters and catecholamines in volunteers during passive orthostasis. Influence of antihypotensive drugs. Arzneimittelforschung 1992; 42: 637-42
Iwase S, Mano T, Saito M, Ishida G. Long-acting alpha 1-adrenoceptive sympathomimetic agent suppresses sympathetic outflow to muscles in humans. J Auton Nerv Syst 1991; 36: 193-9
Iribarren C, Round AD, Peng JA, et al. Validation of a population-based method to assess drug-induced alterations in the QT interval: a self-controlled crossover study. Pharmacoepidemiol Drug Saf 2013; 22: 1222-32
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] [German]. Wien Klin Wochenschr 1977; 89: 164-7
Zachariah PK, Bloedow DC, Moyer TP, et al. Pharmacodynamics of midodrine, an antihypotensive agent. Clin Pharmacol Ther 1986; 39: 586-91
Puchmayer V, Herdovà J, Krejcová H, Masopust J. Midodrine, a new therapeutic agent: recent experience. Int Angiol 1993; 12: 113-8
Felsner P, Hofer D, Rinner I, et al. Continuous in vivo treatment with catecholamines suppresses in vitro reactivity of rat peripheral blood T-lymphocytes via α-mediated mechanisms. J Neuroimmunol 1992; 37: 47-57
Glatter KA, Tuteja D, Chiamvimonvat N, et al. Pregnancy in postural orthostatic tachycardia syndrome. Pacing Clin Electrophysiol 2005; 28: 591-3
Al-Ghamdi B. Midodrine in pregnancy: a case report and literature review. Cardiol Pharmacol 2015; 4: 144
Desglymidodrine, the active metabolite, is generated from midodrine by the enzymatic cleavage of the amino acid glycine. The oral bioavailability of desglymidodrine is 93%. The mean maximum concentration in plasma for midodrine is 20–30 minutes after oral administration and 60 minutes for desglymidodrine.
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Binding to plasma proteins is less than 30%. Midodrine is cleared from plasma after 2 hours,
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with an elimination half-life of 30 minutes.
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The elimination half-life of desglymidodrine is 3 hours.
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Grobecker H, Kees F, Linden M, et al. [The bioavailability of midodrin and alpha-2,5-dimethoxyphenyl-beta-aminoethanol hydrochloride] [German]. Arzneimittelforschung 1987; 37: 447-50
McTavish D, Goa KL. Midodrine. A review of its pharmacological properties and therapeutic use in orthostatic hypotension and secondary hypotensive disorders. Drugs 1989; 38: 757-77
Grobecker H, Kees F, Linden M, et al. [The bioavailability of midodrin and alpha-2,5-dimethoxyphenyl-beta-aminoethanol hydrochloride] [German]. Arzneimittelforschung 1987; 37: 447-50
Grobecker H, Kees F, Linden M, et al. [The bioavailability of midodrin and alpha-2,5-dimethoxyphenyl-beta-aminoethanol hydrochloride] [German]. Arzneimittelforschung 1987; 37: 447-50
Midodrine undergoes extensive metabolism in various tissues including the liver (predominantly by cytochrome P450 isoforms CYP2D6 and CYP1A2
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), with only 4% of a single dose excreted unchanged.
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Excretion of midodrine and desglymidodrine is primarily urinary. Haemodialysis can reduce the elimination half-life of desglymidodrine to 90 minutes. In end-stage chronic kidney disease, the elimination half-life can be as long as 10 hours.
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Akimoto M, Iida I, Itoga H, et al. The in vitro metabolism of desglymidodrine, an active metabolite of prodrug midodrine by human liver microsomes. Eur J Drug Metab Pharmacokinet 2004; 29: 179-86
McTavish D, Goa KL. Midodrine. A review of its pharmacological properties and therapeutic use in orthostatic hypotension and secondary hypotensive disorders. Drugs 1989; 38: 757-77
Blowey DL, Balfe JW, Gupta I, et al. Midodrine efficacy and pharmacokinetics in a patient with recurrent intradialytic hypotension. Am J Kidney Dis 1996; 28: 132-6
Common adverse effects are related to midodrine’s α-agonist properties. Pilomotor reactions (piloerection, scalp pruritus) are the most frequently reported adverse effects followed by gastrointestinal and genitourinary complaints (nausea, abdominal pain, urinary retention, dysuria), cardiovascular effects (supine hypertension, bradycardia) and central nervous system effects (paraesthesia, taste and smell disturbance). Although up to 80% of patients may experience one or more of these adverse effects,
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they are dose-dependent and generally mild. Singular case reports describe midodrine use associated with takotsubo cardiomyopathy,
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intracerebral haemorrhage,
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reversible cerebral vasoconstriction syndrome,
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myoclonic seizures,
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vascular ischaemia,
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and ileus.
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Pathak A, Raoul V, Montastruc JL, Senard JM. Adverse drug reactions related to drugs used in orthostatic hypotension: a prospective and systematic pharmacovigilance study in France. Eur J Clin Pharmacol 2005; 61: 471-4
Ramanath VS, Andrus BW, Szot CR, et al. Takotsubo cardiomyopathy after midodrine therapy. Tex Heart Inst J 2012; 39: 158-9
Sandroni P, Benarroch EE, Wijdicks EF. Caudate hemorrhage as a possible complication of midodrine-induced supine hypertension. Mayo Clin Proc 2001; 76: 1275
Shankar Kikkeri N, Nagarajan E, Premkumar K, Nattanamai P. Reversible cerebral vasoconstriction syndrome due to midodrine in a patient with autonomic dysreflexia. Cureus 2019; 11: e4285
Ye X, Ling B, Wu J, et al. Case report: severe myoclonus associated with oral midodrine treatment for hypotension. Medicine (Baltimore) 2020; 99: e21533
Rubinstein S, Haimov M, Ross MJ. Midodrine-induced vascular ischemia in a hemodialysis patient: a case report and literature review. Ren Fail 2008; 30: 808-12
Pathak A, Debats P, Galinier M, et al. Intestinal obstruction associated with oral midodrine. Clin Auton Res 2004; 14: 202-3
In critical care settings, when administered as an intravenous vasopressor weaning agent, the most common adverse effect is reflex bradycardia
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which is proportional to midodrine dose.
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Drug interactions may occur with concomitant prescription of antiarrhythmics, β-blockers, antipsychotics, monoamine oxidase inhibitors and tricyclic antidepressants metabolised by cytochrome CYP2D6
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as well as ranitidine, metformin and procainamide, which compete with desglymidodrine at acute tubular secretion sites in the kidney.
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Rizvi MS, Trivedi V, Nasim F, et al. Trends in use of midodrine in the ICU: a single-center retrospective case series. Crit Care Med 2018; 46: e628-33
Costa-Pinto R, Yong ZT, Yanase F, et al. A pilot, feasibility, randomised controlled trial of midodrine as adjunctive vasopressor for low-dose vasopressor-dependent hypotension in intensive care patients: the MAVERIC study. J Crit Care 2022; 67: 166-71
Castrioto A, Tambasco N, Rossi A, Calabresi P. Acute dystonia induced by the combination of midodrine and perphenazine. J Neurol 2008; 255: 767-8
Ali A, Farid S, Amin M, et al. Comparative clinical pharmacokinetics of midodrine and its active metabolite desglymidodrine in cirrhotic patients with tense ascites versus healthy volunteers. Clin Drug Investig 2016; 36: 147-55
Midodrine daily doses of up to 120 mg (in divided doses) have been reported in the literature with no adverse effects, even in patients with end-stage chronic kidney disease.
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Overdosage may present as severe hypertension, bradycardia, urinary retention and piloerection.
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Hypertension can be managed with nitrovasodilator or α-sympatholytic infusions (glyceryl trinitrate, sodium nitroprusside, phentolamine). Bradycardia can be managed with atropine.
Rizvi MS, Trivedi V, Nasim F, et al. Trends in use of midodrine in the ICU: a single-center retrospective case series. Crit Care Med 2018; 46: e628-33
Drambarean B, Bielnicka P, Alobaidi A. Midodrine treatment in a patient with treprostinil-induced hypotension receiving hemodialysis. Am J Health Syst Pharm 2019; 76: 13-6
Whitson MR, Mo E, Nabi T, et al. Feasibility, utility, and safety of midodrine during recovery phase from septic shock. Chest 2016; 149: 1380-3
Wong LY, Wong A, Robertson T, et al. Severe hypertension and bradycardia secondary to midodrine overdose. J Med Toxicol 2017; 13: 88-90