Midodrine, sold under the brand names ProAmatine and Orvaten among others, is an antihypotensive

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used to treat

orthostatic hypotension 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 ne ...

(low blood pressure when standing) and

urinary incontinence Urinary incontinence (UI), also known as involuntary urination, is any uncontrolled leakage of urine. It is a common and distressing problem, which may have a significant effect on quality of life. Urinary incontinence is common in older women ...

. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of midodrine include

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

(high blood pressure),

paresthesia Paresthesia is a sensation of the skin that may feel like numbness (''hypoesthesia''), tingling, pricking, chilling, or burning. It can be temporary or Chronic condition, chronic and has many possible underlying causes. Paresthesia is usually p ...

itching An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...

, goosebumps,

chills Chills is a feeling of coldness occurring during a high fever, but sometimes is also a common symptom which occurs alone in specific people. It occurs during fever due to the release of cytokines and prostaglandins as part of the inflammatory ...

, urinary urgency,

urinary retention Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include urinary incont ...

, and urinary frequency. Midodrine is a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

of its active metabolite desglymidodrine. This

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

acts as a selective

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the α₁-adrenergic receptor. This in turn results in

vasoconstriction Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vesse ...

and increased

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

. Midodrine was discovered by 1971 and was introduced for medical use in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

in 1996.

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 Goose bumps, goosebumps or goose pimples are the bumps on a person's skin at the base of body hairs which may involuntarily develop when a person is Tickling, tickled, cold or experiencing strong emotions such as fear, euphoria or sexual arousa ...

, skin itch, gastrointestinal discomfort, chills, elevated blood pressure while lying down, and

. 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. Small studies have also shown that midodrine can be used to prevent excessive drops in blood pressure in people requiring dialysis. Midodrine has been used in the complications of

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...

. It is also used with

octreotide 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 ...

for

hepatorenal syndrome Hepatorenal syndrome (HRS) is a life-threatening medical condition that consists of acute kidney failure, rapid deterioration in kidney function in individuals with cirrhosis or fulminant liver failure. HRS is usually fatal unless a liver transp ...

; 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. Midodrine is used

off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ca ...

to increase blood pressure in the treatment of

postural orthostatic tachycardia syndrome 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, ...

(POTS) where increased transduction of venous alpha 1 adrenergic receptors increases venous return.

Available forms

Midodrine is available in the

form Form is the shape, visual appearance, or configuration of an object. In a wider sense, the form is the way something happens. Form may also refer to: *Form (document), a document (printed or electronic) with spaces in which to write or enter dat ...

of 2.5, 5, and 10mg

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

tablets.

Contraindications

Midodrine is contraindicated in patients with severe organic heart disease, acute kidney disease,

pheochromocytoma Pheochromocytoma is a rare tumor of the adrenal medulla composed of chromaffin cells and is part of the paraganglioma (PGL) family of tumors, being defined as an intra-adrenal PGL. These neuroendocrine tumors can be sympathetic, where they relea ...

or thyrotoxicosis. Midodrine should not be used in patients with persistent and excessive supine hypertension.

Side effects

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

Pharmacology

Mechanism of action

Midodrine is a

which forms the active metabolite, desglymidodrine, which is an α₁-adrenergic receptor

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.

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 25minutes, 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 to4 hours. The absolute

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of midodrine (measured as desglymidodrine) is 93%. Midodrine and desglymidodrine diffuse poorly across the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

and are therefore peripherally selective and are not associated with effects in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

. Neither midodrine nor desglymidodrine are

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

s of

monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...

Chemistry

Midodrine, also known as 3,6-dimethoxy-β-hydroxy-''N''-aminoethanonyl-2-phenylethylamine, is a

substituted phenethylamine Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative (chemistry), derivative compounds of phenethylamine ...

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

. Midodrine is an odorless, white, crystalline powder, soluble in water and sparingly soluble in

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical compound and the simplest aliphatic Alcohol (chemistry), alcohol, with the chemical formula (a methyl group linked to a hydroxyl group, often ab ...

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

Stereochemistry

Midodrine contains a stereocenter and consists of two

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

s, making it a

racemate In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

; ''i.e.'', a 1:1 mixture of (''R'')- and (''S'')-forms:Rote Liste Service GmbH (Hrsg.): ''Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte)''. Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, , S. 196.

Synthesis

Acylation of 1,4-dimethoxybenzene with

chloroacetyl chloride Chloroacetyl chloride is a chlorinated acyl chloride. It is a bifunctional compound, making it a useful building block chemical. Production Industrially, it is produced by the carbonylation of methylene chloride, oxidation of vinylidene chlo ...

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). Acylation of the amino group in this last intermediate with

affords the amide 5. The halogen is then displaced with azide and the resulting product 6 reduced catalytically to the glycinamide, midodrine (7). Midodrine synthesis

History

Midodrine was discovered by 1971. It was approved in the United States by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) in 1996 for the treatment of

dysautonomia Dysautonomia, autonomic failure, or autonomic dysfunction is a condition in which the autonomic nervous system (ANS) does not work properly. This condition may affect the functioning of the heart, bladder, intestines, sweat glands, pupils, and ...

and

. In August 2010, the FDA proposed withdrawing this approval because the manufacturer,

Shire plc Shire plc was a UK-founded Jersey-registered specialty biopharmaceutical company. Originating in the United Kingdom with an operational base in the United States, its brands and products included Vyvanse, Lialda, and Adderall XR. Shire was acq ...

, failed to complete required studies after the medicine reached the market. 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. Shire announced on September 22, 2011, that it was withdrawing completely from supplying midodrine. Midodrine remains available as a

generic drug A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

Society and culture

Names

''Midodrine'' is the generic name of the drug and its , , and , while its is ''midodrina''. In the case of the hydrochloride

salt In common usage, salt is a mineral composed primarily of sodium chloride (NaCl). When used in food, especially in granulated form, it is more formally called table salt. In the form of a natural crystalline mineral, salt is also known as r ...

, its generic name is ''midodrine hydrochloride'' and this is its , , and . The drug is also known by its developmental code names ''ST-1085'' and ''TS-701''. Midodrine has been sold under brand names including ''Amatine'', ''Gutron'', ''Midamine'', ''Midon'', and ''ProAmatine'', among others.

Research

Midodrine was under development for the treatment of

chronic fatigue syndrome Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling Chronic condition, chronic illness. People with ME/CFS experience profound fatigue that does not go away with rest, as well as sleep issues and problems with memory ...

, but no recent development for this indication has been reported.

References

External links

{{Portal bar , Medicine Acetamides Alpha-1 adrenergic receptor agonists Antihypotensive agents Cardiac stimulants CYP2D6 inhibitors Methoxyphenethylamines Peripherally selective drugs Phenol ethers Phenylethanolamines Prodrugs Sympathomimetics Vasoconstrictors