Midodrine

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Midodrine
Midodrine.svg
Clinical data
Trade names Amatine, Proamatine, Gutron, others
Other names2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxy-ethyl]-acetamide
AHFS/Drugs.com Monograph
MedlinePlus a602023
License data
Pregnancy
category
  • AU:C
Routes of
administration
By mouth
ATC code
Legal status
Legal status
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
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Midodrine is a vasopressor/antihypotensive agent (it raises the blood pressure). Midodrine was approved in the United States by the Food and Drug Administration (FDA) in 1996 for the treatment of dysautonomia and orthostatic hypotension. 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. [2] [3] 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. [4] Shire announced on September 22, 2011, that it was withdrawing completely from supplying midodrine and leaving it to several generics to supply the drug. [5]

Contents

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. [6] 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. [7] Small studies have also shown that midodrine can be used to prevent excessive drops in blood pressure in people requiring dialysis. [8]

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. [9]

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. [10]

Side effects

Headache, feeling of pressure/fullness in the head, vasodilation/flushing face, scalp tingling, confusion/thinking abnormality, dry mouth, nervousness/anxiety and rash. [11]

Pharmacology

Mechanism of action

Midodrine is a prodrug which forms an active metabolite, desglymidodrine, which is an α1-receptor agonist and exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Desglymidodrine does not stimulate cardiac beta-adrenergic receptors. Desglymidodrine diffuses poorly across the blood–brain barrier, and is therefore not associated with effects on the central nervous system.

Desglymidodrine--a major metabolite Desglymidodrine.svg
Desglymidodrine—a major metabolite

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%. [12]

Chemistry

Midodrine is an odorless, white, crystalline powder, soluble in water and sparingly soluble in methanol. [13]

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: [14]

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). [15] 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). [16]

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

Related Research Articles

Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when standing up 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">Hypotension</span> Abnormally low blood pressure

Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is indicated by two numbers, the systolic blood pressure and the diastolic blood pressure, which are the maximum and minimum blood pressures within the cardiac cycle, respectively. A systolic blood pressure of less than 90 millimeters of mercury (mmHg) or diastolic of less than 60 mmHg is generally considered to be hypotension. Different numbers apply to children. However, in practice, blood pressure is considered too low only if noticeable symptoms are present.

Atenolol is a beta blocker medication primarily used to treat high blood pressure and heart-associated chest pain. Atenolol, however, does not seem to improve mortality in those with high blood pressure. 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 and chronic Orthostatic Hypotension

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 typically given by mouth but can also be used by injection. The effects generally begin within 45 minutes and last up to 6 hours.

<span class="mw-page-title-main">Methyldopa</span> Medication used to treat high blood pressure

Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure. It is one of the preferred treatments for high blood pressure in pregnancy. For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred. It can be given by mouth or injection into a vein. Onset of effects is around 5 hours and they last about a day.

<span class="mw-page-title-main">Nimodipine</span> Antihypertensive drug of the calcium channel blocker class

Nimodipine, sold under the brand name Nimotop among others, is calcium channel blocker used in preventing vasospasm secondary to subarachnoid hemorrhage. It was originally developed within the calcium channel blocker class as it was used for the treatment of high blood pressure, but is not used for this indication.

<span class="mw-page-title-main">Octreotide</span> Octapeptide that mimics natural somatostatin pharmacologically

Octreotide, sold under the brand name Sandostatin among others, is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. It was first synthesized in 1979 by the chemist Wilfried Bauer, and binds predominantly to the somatostatin receptors SSTR2 and SSTR5.

<span class="mw-page-title-main">Tilt table test</span> Medical procedure often used to diagnose dysautonomia or syncope

A tilt table test (TTT), occasionally called upright tilt testing (UTT), is a medical procedure often used to diagnose dysautonomia or syncope. Patients with symptoms of dizziness or lightheadedness, with or without a loss of consciousness (fainting), suspected to be associated with a drop in blood pressure or positional tachycardia are good candidates for this test.

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">Pure autonomic failure</span> Medical condition

Pure autonomic failure (PAF) is an uncommon, sporadic neurodegenerative condition marked by a steadily declining autonomic regulation. Bradbury and Eggleston originally described pure autonomic failure in 1925.

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

Levosalbutamol, also known as levalbuterol, is a short-acting β2 adrenergic receptor agonist used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). Evidence is inconclusive regarding the efficacy of levosalbutamol versus salbutamol or salbutamol-levosalbutamol combinations, though levosalbutamol is believed to have a better safety profile due to its more selective binding to β2 receptors versus β1.

<span class="mw-page-title-main">Isradipine</span> Antihypertensive drug of the calcium channel blocker class

Isradipine is a calcium channel blocker of the dihydropyridine class. It is usually prescribed for the treatment of high blood pressure in order to reduce the risk of stroke and heart attack.

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

Levobunolol is a non-selective beta blocker. It is used topically in the form of eye drops to manage ocular hypertension and open-angle glaucoma.

<span class="mw-page-title-main">Nitrendipine</span> Antihypertensive drug of the calcium channel blocker class

Nitrendipine is a dihydropyridine calcium channel blocker. It is used in the treatment of primary (essential) hypertension to decrease blood pressure and can reduce the cardiotoxicity of cocaine.

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

Tolvaptan, sold under the brand name Samsca among others, is an aquaretic drug that functions as a selective, competitive vasopressin receptor 2 (V2) antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca. Tolvaptan, as Jynarque, was granted approval for medical use in the United States in April 2018.

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

Droxidopa is a synthetic amino acid precursor which acts as a prodrug to the neurotransmitter norepinephrine (noradrenaline). Unlike norepinephrine, droxidopa is capable of crossing the protective blood–brain barrier (BBB).

<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.

Orthostatic syncope refers to syncope resulting from a postural decrease in blood pressure, termed orthostatic hypotension.

Supine hypertension is a paradoxical elevation in blood pressure upon assuming a supine position from a standing or sitting position. It is assumed to be a manifestation of disorders of the autonomic nervous system or due to side effects of medications such as midodrine and droxidopa.

References

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  2. U.S. proposes withdrawal of Shire hypotension drug, 16 August 2010.
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  4. Midodrine (ProAmatine, generic) Proposed Market Withdrawal – Update 10 September 2010.
  5. Shire plc. "Shire Provides Update on ProAmatine® (midodrine HCl)". www.prnewswire.com.
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  7. 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.
  8. 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.
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  12. "Midodrine".
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