Midodrine

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Midodrine
Midodrine.svg
Clinical data
Trade names Amatine, Gutron, Orvaten, ProAmatine, others
Other namesST-1085; TS-701; 3,6-Dimethoxy-β-hydroxy-N-aminoethanonyl-2-phenylethylamine; 2-Amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide; 1-2',5'-Dimethoxyphenyl-1)-2 glycinamidoethanol
AHFS/Drugs.com Monograph
MedlinePlus a616030
License data
Pregnancy
category
  • AU:C
Routes of
administration 		By mouth [1]
Drug class α1-Adrenergic receptor agonist; Antihypotensive agent; Vasopressor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 93% (as desglymidodrine) [3] [4] [1]
Metabolism Deglycination [3] [1] [4]
Metabolites • Desglymidodrine [3] [1] [4]
Onset of action ≤1 hour [3]
Elimination half-life Midodrine: 0.5 hours [4]
Desglymidodrine: 2–4 hours [4] [1]
Duration of action 2–6 hours [3] [4]
Identifiers
  • (RS)-N-[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]glycinamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.151.349 100.050.842, 100.151.349 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C12H18N2O4
Molar mass 254.286 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • O=C(NCC(O)c1cc(OC)ccc1OC)CN
  • InChI=1S/C12H18N2O4/c1-17-8-3-4-11(18-2)9(5-8)10(15)7-14-12(16)6-13/h3-5,10,15H,6-7,13H2,1-2H3,(H,14,16) Yes check.svgY
  • Key:PTKSEFOSCHHMPD-UHFFFAOYSA-N Yes check.svgY
   (verify)

Midodrine, sold under the brand names ProAmatine and Orvaten among others, is a vasopressor or antihypotensive medication used to treat orthostatic hypotension (low blood pressure when standing) and urinary incontinence. [3] [5] [1] It is taken by mouth. [3] [1]

Contents

Side effects of midodrine include hypertension (high blood pressure), paresthesia, itching, goosebumps, chills, urinary urgency, urinary retention, and urinary frequency. [3] Midodrine is a prodrug of its active metabolite desglymidodrine. [3] [1] This metabolite acts as a selective agonist of the α1-adrenergic receptor. [3] [1] This in turn results in vasoconstriction and increased blood pressure. [3] [1]

Midodrine was discovered by 1971 [6] and was introduced for medical use in the United States in 1996.[ citation needed ]

Medical uses

Midodrine is indicated for the treatment of symptomatic orthostatic hypotension. It can reduce dizziness and faints by about a third, but can be limited by troublesome goose bumps, skin itch, gastrointestinal discomfort, chills, elevated blood pressure while lying down, and urinary retention. [7] A meta-analysis of clinical trials of midodrine or droxidopa in patients with low blood pressure when standing found that midodrine increased standing blood pressure more than droxidopa but that midodrine but not droxidopa increased the risk of high blood pressure when lying down. [8] Small studies have also shown that midodrine can be used to prevent excessive drops in blood pressure in people requiring dialysis. [9]

Midodrine has been used in the complications of cirrhosis. It is also used with octreotide for hepatorenal syndrome; the proposed mechanism is constriction of splanchnic vessels and dilation of renal vasculature. Studies have not been sufficiently well conducted to show a clear place for midodrine. [10]

Midodrine is used off-label to increase blood pressure in the treatment of postural orthostatic tachycardia syndrome (POTS) where increased transduction of venous alpha 1 adrenergic receptors increases venous return. [11] [12] [13]

Available forms

Midodrine is available in the form of 2.5, 5, and 10 mg oral tablets. [3] [1]

Contraindications

Midodrine is contraindicated in patients with severe organic heart disease, acute kidney disease, urinary retention, pheochromocytoma or thyrotoxicosis. Midodrine should not be used in patients with persistent and excessive supine hypertension. [14]

Side effects

Headache, feeling of pressure or fullness in the head, vasodilation or flushing face, scalp tingling, confusion or thinking abnormality, dry mouth, nervousness or anxiety, and rash, among others. [15]

Pharmacology

Mechanism of action

Midodrine is a prodrug which forms the active metabolite, desglymidodrine, which is an α1-adrenergic receptor agonist and exerts its actions via activation of α1-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Desglymidodrine does not stimulate cardiac β-adrenergic receptors.

Chemical structure of desglymidodrine. Desglymidodrine.svg
Chemical structure of desglymidodrine.

Pharmacokinetics

After oral administration, midodrine is rapidly absorbed. The plasma levels of the prodrug peak after about half an hour, and decline with a half-life of approximately 25 minutes, while the metabolite reaches peak blood concentrations about 1 to 2 hours after a dose of midodrine and has a half-life of about 3 to 4 hours. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93%. [1]

Midodrine and desglymidodrine diffuse poorly across the blood–brain barrier and are therefore peripherally selective and are not associated with effects in the central nervous system. [16] [17] [18]

Neither midodrine nor desglymidodrine are substrates of monoamine oxidase. [3]

Chemistry

Midodrine, also known as 3,6-dimethoxy-β-hydroxy-N-aminoethanonyl-2-phenylethylamine, is a substituted phenethylamine derivative. [4]

Midodrine is an odorless, white, crystalline powder, soluble in water and sparingly soluble in methanol. [19]

Midodrine's experimental log P is -0.5 and its predicted log P ranges from -0.49 to -0.95. [20] [1] The predicted log P of its active metabolite desglymidodrine ranges from -0.01 to 0.15. [21] [22]

Stereochemistry

Midodrine contains a stereocenter and consists of two enantiomers, making it a racemate; i.e., a 1:1 mixture of (R)- and (S)-forms: [23]

Enantiomers of midodrine
(R)-Midodrin Structural Formula V1.svg
(R)-midodrine
CAS number: 133163-25-4		 (S)-Midodrin Structural Formula V1.svg
(S)-midodrine
CAS number: 133267-39-7

Synthesis

Acylation of 1,4-dimethoxybenzene with chloroacetyl chloride gives the chloroketone 2. The halogen is then converted to the amine 3 by any set of standard schemes, and the ketone reduced to an alcohol with borohydride (4). [24] Acylation of the amino group in this last intermediate with chloroacetyl chloride affords the amide 5. The halogen is then displaced with azide and the resulting product 6 reduced catalytically to the glycinamide, midodrine (7). [25]

Synthesis of midodrine See also: Midodrine synthesis.svg
Synthesis of midodrine See also:

History

Midodrine was discovered by 1971. [6] It was approved in the United States by the Food and Drug Administration (FDA) in 1996 for the treatment of dysautonomia and orthostatic hypotension.[ citation needed ]

In August 2010, the FDA proposed withdrawing this approval because the manufacturer, Shire plc, failed to complete required studies after the medicine reached the market. [29] [30] In September 2010, the FDA reversed its decision to remove midodrine from the market and allowed it to remain available to patients while Shire plc collected further data regarding the efficacy and safety of the drug. [31] Shire announced on September 22, 2011, that it was withdrawing completely from supplying midodrine. Midodrine remains available as a generic drug. [32]

Society and culture

Names

Midodrine is the generic name of the drug and its INN Tooltip International Nonproprietary Name, BAN Tooltip British Approved Name, and DCF Tooltip Dénomination Commune Française, while its DCIT Tooltip Denominazione Comune Italiana is midodrina. [6] [33] [34] In the case of the hydrochloride salt, its generic name is midodrine hydrochloride and this is its USAN Tooltip United States Adopted Name, BANM Tooltip British Approved Name, and JAN Tooltip Japanese Accepted Name. [6] [34] The drug is also known by its developmental code names ST-1085 and TS-701. [6] [34] [35] Midodrine has been sold under brand names including Amatine, Gutron, Midamine, Midon, and ProAmatine, among others. [6] [34]

Research

Midodrine was under development for the treatment of chronic fatigue syndrome, but no recent development for this indication has been reported. [5]

Related Research Articles

Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up (orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as neurogenic orthostatic hypotension. The drop in blood pressure may be sudden, within 3 minutes or gradual. It is defined as a fall in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg after 3 minutes of standing. It occurs predominantly by delayed constriction of the lower body blood vessels, which is normally required to maintain adequate blood pressure when changing the position to standing. As a result, blood pools in the blood vessels of the legs for a longer period, and less is returned to the heart, thereby leading to a reduced cardiac output and inadequate blood flow to the brain.

<span class="mw-page-title-main">Dysautonomia</span> Any disease or malfunction of the autonomic nervous system

Dysautonomia, autonomic failure, or autonomic dysfunction is a condition in which the autonomic nervous system (ANS) does not work properly. This may affect the functioning of the heart, bladder, intestines, sweat glands, pupils, and blood vessels. Dysautonomia has many causes, not all of which may be classified as neuropathic. A number of conditions can feature dysautonomia, such as Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, Ehlers–Danlos syndromes, autoimmune autonomic ganglionopathy and autonomic neuropathy, HIV/AIDS, mitochondrial cytopathy, pure autonomic failure, autism, and postural orthostatic tachycardia syndrome.

<span class="mw-page-title-main">Atenolol</span> Beta blocker medication

Atenolol is a beta blocker medication primarily used to treat high blood pressure and heart-associated chest pain. Although used to treat high blood pressure, it does not seem to improve mortality in those with the condition. Other uses include the prevention of migraines and treatment of certain irregular heart beats. It is taken orally or by intravenous injection. It can also be used with other blood pressure medications.

<span class="mw-page-title-main">Pyridostigmine</span> Medication used to treat myasthenia gravis

Pyridostigmine is a medication used to treat myasthenia gravis and underactive bladder. It is also used together with atropine to end the effects of neuromuscular blocking medication of the non-depolarizing type. It is also used off-label to treat some forms of Postural orthostatic tachycardia syndrome. It is typically given by mouth but can also be used by injection. The effects generally begin within 45 minutes and last up to 4 hours.

<span class="mw-page-title-main">Postural orthostatic tachycardia syndrome</span> Abnormally high heart rate after a postural change

Postural orthostatic tachycardia syndrome (POTS) is a condition characterized by an abnormally large increase in heart rate upon sitting up or standing. POTS is a disorder of the autonomic nervous system that can lead to a variety of symptoms, including lightheadedness, brain fog, blurred vision, weakness, fatigue, headaches, heart palpitations, exercise intolerance, nausea, diminished concentration, tremulousness (shaking), syncope (fainting), coldness or pain in the extremities, numbness or tingling in the extremities, chest pain, and shortness of breath. Other conditions associated with POTS include myalgic encephalomyelitis/chronic fatigue syndrome, migraine headaches, Ehlers–Danlos syndrome, asthma, autoimmune disease, vasovagal syncope, and mast cell activation syndrome. POTS symptoms may be treated with lifestyle changes such as increasing fluid, electrolyte, and salt intake, wearing compression stockings, gentle and slow postural changes, avoiding prolonged bedrest, medication, and physical therapy.

<span class="mw-page-title-main">Phenylephrine</span> Decongestant medication

Phenylephrine, sold under the brand names Neosynephrine and Sudafed PE among others, is a medication used as a decongestant for uncomplicated nasal congestion, to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids. It can be taken by mouth, as a nasal spray, given by injection into a vein or muscle, applied to the skin, or as a rectal suppository.

<span class="mw-page-title-main">Prazosin</span> Antihypertensive drug

Prazosin, sold under the brand name Minipress among others, is a medication used to treat high blood pressure, symptoms of an enlarged prostate, and nightmares related to post-traumatic stress disorder (PTSD). It is an α1 blocker. It is a less preferred treatment of high blood pressure. Other uses may include heart failure and Raynaud syndrome. It is taken by mouth.

<span class="mw-page-title-main">Dosulepin</span> Antidepressant

Dosulepin, also known as dothiepin and sold under the brand name Prothiaden among others, is a tricyclic antidepressant (TCA) which is used in the treatment of depression. Dosulepin was once the most frequently prescribed antidepressant in the United Kingdom, but it is no longer widely used due to its relatively high toxicity in overdose without therapeutic advantages over other TCAs. It acts as a serotonin–norepinephrine reuptake inhibitor (SNRI) and also has other activities including antihistamine, antiadrenergic, antiserotonergic, anticholinergic, and sodium channel-blocking effects.

Alpha-1 blockers constitute a variety of drugs that block the effect of catecholamines on alpha-1-adrenergic receptors. They are mainly used to treat benign prostatic hyperplasia (BPH), hypertension and post-traumatic stress disorder. Alpha-1-adrenergic receptors are present in vascular smooth muscle, the central nervous system, and other tissues. When alpha blockers bind to these receptors in vascular smooth muscle, they cause vasodilation.

<span class="mw-page-title-main">Phentolamine</span> An α-adrenergic antagonist medication

Phentolamine, sold under the brand name Regitine among others, is a reversible nonselective α-adrenergic antagonist.

<span class="mw-page-title-main">Tamsulosin</span> Medication

Tamsulosin, sold under the brand name Flomax among others, is a medication used to treat symptomatic benign prostatic hyperplasia (BPH) and chronic prostatitis and to help with the passage of kidney stones. The evidence for benefit with a kidney stone is better when the stone is larger. Tamsulosin is taken by mouth.

<span class="mw-page-title-main">Silodosin</span> Chemical compound

Silodosin, sold under the brand name Urief among others, is a medication for the symptomatic treatment of benign prostatic hyperplasia. It acts as an alpha-1 adrenergic receptor antagonist.

<span class="mw-page-title-main">Dimetofrine</span> Chemical compound

Dimetofrine, also known as dimethophrine or dimetophrine and sold under the brand names Dovida, Pressamina, and Superten, is a medication described as a sympathomimetic, vasoconstrictor, and cardiac stimulant. It is said to be similarly or less effective than midodrine in the treatment of orthostatic hypotension and shows substantially lower potency.

<span class="mw-page-title-main">Norfenefrine</span> Sympathomimetic drug

Norfenefrine, also known as meta-octopamine or norphenylephrine and sold under the brand name Novadral among others, is a sympathomimetic medication which is used in the treatment of hypotension. Along with its structural isomer p-octopamine and the tyramines, norfenefrine is a naturally occurring endogenous trace amine and plays a role as a minor neurotransmitter in the brain.

<span class="mw-page-title-main">Etilefrine</span> Chemical compound

Etilefrine, sold under the brand name Effortil among others, is a sympathomimetic medication used as an antihypotensive agent to treat orthostatic hypotension. It is usually used by mouth, but is also available as an injectable.

<span class="mw-page-title-main">Droxidopa</span> Synthetic amino acid/norepinephrine prodrug

Droxidopa, also known as L-threo-dihydroxyphenylserine (L-DOPS) and sold under the brand names Northera and Dops among others, is sympathomimetic medication which is used in the treatment of hypotension and for other indications. It is taken by mouth.

<span class="mw-page-title-main">Alpha blocker</span> Class of pharmacological agents

Alpha blockers, also known as α-blockers or α-adrenoreceptor antagonists, are a class of pharmacological agents that act as antagonists on α-adrenergic receptors (α-adrenoceptors).

<span class="mw-page-title-main">Orthostatic headache</span> Medical condition

Orthostatic headache is a medical condition in which a person develops a headache while vertical and the headache is relieved when horizontal. Previously it was often misdiagnosed as different primary headache disorders such as migraine or tension headaches. Increasing awareness of the symptom and its causes has prevented delayed or missed diagnosis.

<span class="mw-page-title-main">Dopamine beta hydroxylase deficiency</span> Medical condition

Dopamine beta (β)-hydroxylase deficiency is a human medical condition involving inadequate dopamine beta-hydroxylase. It is characterized by increased amounts of serum dopamine and the absence of norepinephrine (NE) and epinephrine.

<span class="mw-page-title-main">Desglymidodrine</span> Antihypotensive agent active metabolite

Desglymidodrine is the active metabolite of the prodrug antihypotensive agent midodrine. It acts as a selective α1-adrenergic receptor agonist. Desglymidodrine is formed from midodrine via deglycination.

References

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  2. ↑ "Proamatine- midodrine hydrochloride tablet". DailyMed. Retrieved 14 August 2021.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 "ProAmatine® (midodrine hydrochloride) Tablets" (PDF). fda.gov. Food and Drug Administration. Retrieved 28 August 2024.
  4. 1 2 3 4 5 6 7 Gilden JL (2004). "Midodrine and Other Sympathomimetics". Primer on the Autonomic Nervous System. Elsevier. pp. 413–415. doi:10.1016/b978-012589762-4/50113-4. ISBN   978-0-12-589762-4.
  5. 1 2 "GE Healthcare". AdisInsight. 21 October 2021. Retrieved 28 August 2024.
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  7. ↑ Izcovich A, González Malla C, Manzotti M, Catalano HN, Guyatt G (September 2014). "Midodrine for orthostatic hypotension and recurrent reflex syncope: A systematic review". Neurology. 83 (13): 1170–1177. doi:10.1212/WNL.0000000000000815. PMID   25150287. S2CID   5439767.
  8. ↑ Chen JJ, Han Y, Tang J, Portillo I, Hauser RA, Dashtipour K (December 2018). "Standing and Supine Blood Pressure Outcomes Associated With Droxidopa and Midodrine in Patients With Neurogenic Orthostatic Hypotension: A Bayesian Meta-analysis and Mixed Treatment Comparison of Randomized Trials". The Annals of Pharmacotherapy. 52 (12): 1182–1194. doi:10.1177/1060028018786954. PMID   29972032. S2CID   49674644.
  9. ↑ Prakash S, Garg AX, Heidenheim AP, House AA (October 2004). "Midodrine appears to be safe and effective for dialysis-induced hypotension: a systematic review". Nephrology, Dialysis, Transplantation. 19 (10): 2553–2558. doi:10.1093/ndt/gfh420. PMID   15280522.
  10. ↑ Karwa R, Woodis CB (April 2009). "Midodrine and octreotide in treatment of cirrhosis-related hemodynamic complications". The Annals of Pharmacotherapy. 43 (4): 692–699. doi:10.1345/aph.1L373. PMID   19299324. S2CID   207263346.
  11. ↑ Narasimhan B, Aggarwal D, Satish P, Kantharia B, Aronow WS (October 2022). "Postural orthostatic tachycardia syndrome: pathophysiology, management, and experimental therapies". Expert Opin Investig Drugs. 31 (10): 1017–1025. doi:10.1080/13543784.2022.2121697. PMID   36094001.
  12. ↑ Vasavada AM, Verma D, Sheggari V, Ghetiya S, Chirumamilla PC, Kotak RA, et al. (May 2023). "Choices and Challenges With Drug Therapy in Postural Orthostatic Tachycardia Syndrome: A Systematic Review". Cureus. 15 (5): e38887. doi: 10.7759/cureus.38887 . PMC   10259876 . PMID   37313107.
  13. ↑ Benarroch EE (December 2012). "Postural tachycardia syndrome: a heterogeneous and multifactorial disorder". Mayo Clin Proc. 87 (12): 1214–1225. doi:10.1016/j.mayocp.2012.08.013. PMC   3547546 . PMID   23122672.
  14. ↑ "Midodrine - FDA prescribing information, side effects and uses". Drugs.com. Retrieved 30 June 2022.
  15. ↑ "Midodrine (Oral Route) Side Effects - Mayo Clinic". www.mayoclinic.org.
  16. ↑ Costa-Pinto R, Jones DA, Udy AA, Warrillow SJ, Bellomo R (December 2022). "Midodrine use in critically ill patients: a narrative review". Crit Care Resusc. 24 (4): 298–308. doi:10.51893/2022.4.R. PMC   10692611 . PMID   38047013.
  17. ↑ Cruz DN (May 2000). "Midodrine: a selective alpha-adrenergic agonist for orthostatic hypotension and dialysis hypotension". Expert Opin Pharmacother. 1 (4): 835–840. doi:10.1517/14656566.1.4.835. PMID   11249519.
  18. ↑ McClellan KJ, Wiseman LR, Wilde MI (January 1998). "Midodrine. A review of its therapeutic use in the management of orthostatic hypotension". Drugs Aging. 12 (1): 76–86. doi:10.2165/00002512-199812010-00007. PMID   9467688.
  19. ↑ "DailyMed - MIDODRINE HCL- midodrine hydrochloride tablet". DailyMed . Retrieved 5 January 2023.
  20. ↑ "Midodrine". PubChem. Retrieved 1 August 2024.
  21. ↑ "Desglymidodrine". PubChem. Retrieved 1 August 2024.
  22. ↑ "Metabolite desglymidodrine". DrugBank Online. Retrieved 1 August 2024.
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  24. ↑ Moreau P, Finiels A, Meric P (20 March 2000). "Acetylation of dimethoxybenzenes with acetic anhydride in the presence of acidic zeolites". Journal of Molecular Catalysis A: Chemical. 154 (1): 185–192. doi:10.1016/S1381-1169(99)00373-8. ISSN   1381-1169.
  25. ↑ Cao T, Martini ML, Park K, Kaniskan HÜ, Jin J (1 January 2022). "8.02 - Pyrimidines and Their Benzo Derivatives". In Black DS, Cossy J, Stevens CV (eds.). Comprehensive Heterocyclic Chemistry IV. Oxford: Elsevier. pp. 86–228. doi:10.1016/B978-0-12-818655-8.00041-X. ISBN   978-0-12-818656-5.
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  28. ↑ Zoelss & W. Karl-Anton Ing DE 2523735 (1974 to Lentia GmbH).
  29. ↑ U.S. proposes withdrawal of Shire hypotension drug, 16 August 2010.
  30. ↑ O'Riordan M. "FDA recommends withdrawal of midodrine". Food and Drug Administration. FDA proposes withdrawal of low blood pressure drug [press release]. August 16, 2010. TheHeart.org. Retrieved 1 April 2011.
  31. ↑ Midodrine (ProAmatine, generic) Proposed Market Withdrawal – Update Archived 28 March 2012 at the Wayback Machine 10 September 2010.
  32. ↑ Shire plc. "Shire Provides Update on ProAmatine® (midodrine HCl)". www.prnewswire.com (Press release).
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  35. ↑ Schlesser JL (1990). Drugs Available Abroad: A Guide to Therapeutic Drugs Available and Approved for Use Outside the U. S. Gale Research. pp. 139, 356. ISBN   978-0-8103-7177-4 . Retrieved 30 August 2024.

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