Methyldopa

Last updated
Methyldopa
Methyldopa.svg
Methyldopa molecule ball.png
Clinical data
Trade names Aldomet, Aldoril, Dopamet, others
Other namesL-α-Methyl-3,4-dihydroxyphenylalanine
AHFS/Drugs.com Monograph
MedlinePlus a682242
License data
Pregnancy
category
  • AU:A
Routes of
administration
By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability approximately 50%
Metabolism Liver
Onset of action 4 to 6 hrs [1]
Elimination half-life 105 minutes
Duration of action 10 to 48 hrs [1]
Excretion Kidney for metabolites
Identifiers
  • (S)-2-amino-3-(3,4-dihydroxyphenyl)-2-methyl-propanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.008.264 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H13NO4
Molar mass 211.217 g·mol−1
3D model (JSmol)
  • C[C@](N)(Cc1ccc(O)c(O)c1)C(=O)O
  • InChI=1S/C10H13NO4/c1-10(11,9(14)15)5-6-2-3-7(12)8(13)4-6/h2-4,12-13H,5,11H2,1H3,(H,14,15)/t10-/m0/s1 X mark.svgN
  • Key:CJCSPKMFHVPWAR-JTQLQIEISA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure. [1] It is one of the preferred treatments for high blood pressure in pregnancy. [1] For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred. [1] It can be given by mouth or injection into a vein. [1] Onset of effects is around 5 hours and they last about a day. [1]

Contents

Common side effects include sleepiness. [1] More severe side effects include red blood cell breakdown, liver problems, and allergic reactions. [1] Methyldopa is in the alpha-2 adrenergic receptor agonist family of medication. It works by stimulating the brain to decrease the activity of the sympathetic nervous system. [1]

Methyldopa was discovered in 1960. [2] It is on the World Health Organization's List of Essential Medicines. [3]

Medical uses

Methyldopa is used in the clinical treatment of the following disorders:

Side effects

Methyldopa is capable of inducing a number of adverse side effects, which range from mild to severe. Nevertheless, they are generally mild when the dose is less than 1 gram per day. [5] Side effects may include:

Rebound/withdrawal

Rebound hypertension via withdrawal on account of tolerance upon the abrupt discontinuation of methyldopa has been reported. [6]

Mechanism of action

The mechanism of action of methyldopa is not fully clear. Although it is a centrally acting sympathomimetic, it does not block reuptake or transporters. It may reduce the dopaminergic and serotonergic transmission in the peripheral nervous system and it indirectly affects norepinephrine (noradrenaline) synthesis. Methyldopa acts on alpha-2 adrenergic receptors, which are found on the pre synaptic nerve terminal. [1] This inhibits the synthesis of norepinephrine by inhibiting tyrosine hydroxylase.

The S-enantiomer of methyldopa is a competitive inhibitor of the enzyme aromatic L-amino acid decarboxylase (LAAD), which converts L-DOPA into dopamine. L-DOPA can cross the blood brain barrier and thus methyldopa may have similar effects. LAAD converts it into alpha-methyldopamine, a false prescursor to norepinephrine, which in turn reduces synthesis of norepinephrine in the vesicles. Dopamine beta hydroxylase (DBH) converts alpha-methyldopamine into alpha-methylnorepinephrine, which is an agonist of the presynaptic α2-adrenergic receptor causing inhibition of neurotransmitter release.

Pharmacokinetics

Maximum decrease in blood pressure occurs 4-6 hours after oral dosage. The half-life of methyldopa is 105 minutes. [7] Methyldopa exhibits variable absorption from the gastrointestinal tract. It is metabolized in the liver and intestines and is excreted in urine.

History

When methyldopa was first introduced, it was the mainstay of antihypertensive treatment, but its use has declined on account of relatively severe adverse side effects, with increased use of other safer and more tolerable agents such as alpha blockers, beta blockers, and calcium channel blockers. Additionally, it has yet to be associated with reducing adverse cardiovascular events including myocardial infarction and stroke, or overall all-cause mortality reduction in clinical trials. [8] Nonetheless, one of methyldopa's still current indications is in the management of pregnancy-induced hypertension (PIH), as it is relatively safe in pregnancy compared to many other antihypertensives which may affect the fetus.

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 mins 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">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

<span class="mw-page-title-main">Clonidine</span> Medication for high blood pressure

Clonidine, sold under the brand name Catapres among others, is an α2-adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal, menopausal flushing, diarrhea, spasticity, and certain pain conditions. It is used orally, by injection, or as a transdermal skin patch. Onset of action is typically within an hour with the effects on blood pressure lasting for up to eight hours.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (ARBs), and beta blockers.

<small>L</small>-DOPA Chemical compound

l-DOPA, also known as levodopa and l-3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize l-DOPA, make it via biosynthesis from the amino acid l-tyrosine. l-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, l-DOPA itself mediates neurotrophic factor release by the brain and CNS. l-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Pharmacopa, Atamet, and Stalevo. As a drug, it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

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

Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth.

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

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.

α-Methyl-<i>p</i>-tyrosine Chemical compound

α-Methyl-p-tyrosine (AMPT), or simply α-methyltyrosine, also known as racemetirosine, is a tyrosine hydroxylase enzyme inhibitor and is therefore a drug involved in inhibiting the catecholamine biosynthetic pathway. AMPT inhibits tyrosine hydroxylase whose enzymatic activity is normally regulated through the phosphorylation of different serine residues in regulatory domain sites. Catecholamine biosynthesis starts with dietary tyrosine, which is hydroxylated by tyrosine hydroxylase and it is hypothesized that AMPT competes with tyrosine at the tyrosine-binding site, causing inhibition of tyrosine hydroxylase.

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">Entacapone</span> Chemical compound

Entacapone, sold under the brand name Comtan among others, is a medication commonly used in combination with other medications for the treatment of Parkinson's disease. Entacapone together with levodopa and carbidopa allows levodopa to have a longer effect in the brain and reduces Parkinson's disease signs and symptoms for a greater length of time than levodopa and carbidopa therapy alone.

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

Labetalol is a medication used to treat high blood pressure and in long term management of angina. This includes essential hypertension, hypertensive emergencies, and hypertension of pregnancy. In essential hypertension it is generally less preferred than a number of other blood pressure medications. It can be given by mouth or by injection into a vein.

<span class="mw-page-title-main">Carvedilol</span> Oral blood-pressure medication

Carvedilol, sold under the brand name Coreg among others, is a medication used to treat high blood pressure, congestive heart failure (CHF), and left ventricular dysfunction in people who are otherwise stable. For high blood pressure, it is generally a second-line treatment. It is taken by mouth.

The alpha-2 (α2) adrenergic receptor is a G protein-coupled receptor (GPCR) associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α2-adrenergic receptor in the central and peripheral nervous systems.

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

Rilmenidine is a prescription medication for the treatment of hypertension. It is marketed under the brand names Albarel, Hyperium, Iterium and Tenaxum.

<span class="mw-page-title-main">Norepinephrine</span> Catecholamine hormone and neurotransmitter

Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" is more commonly used in the United Kingdom, whereas "norepinephrine" is usually preferred in the United States. "Norepinephrine" is also the international nonproprietary name given to the drug. Regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic.

<span class="mw-page-title-main">Atipamezole</span> Veterinary drug

Atipamezole, is a synthetic α2 adrenergic receptor antagonist indicated for the reversal of the sedative and analgesic effects of dexmedetomidine and medetomidine in dogs. Its reversal effect works by competing with the sedative for α2-adrenergic receptors and displacing them. It is mainly used in veterinary medicine, and while it is only licensed for dogs and for intramuscular use, it has been used intravenously, as well as in cats and other animals(intravenous use in cats and dogs is not recommended due to the potential for cardiovascular collapse. This occurs due to profound hypotension caused by reversal of the alpha 1 effects while the reflex bradycardia is still in effect.). There is a low rate of side effects, largely due to atipamezole's high specificity for the α2-adrenergic receptor. Atipamezole has a very quick onset, usually waking an animal up within 5 to 10 minutes.

<span class="mw-page-title-main">Droxidopa</span> Synthetic amino acid which metabolizes into the neurotransmitter norepinephrine

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">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">Dopamine beta hydroxylase deficiency</span> Medical condition

Dopamine beta (β)-hydroxylase deficiency is a condition involving inadequate dopamine beta-hydroxylase. It is characterized by increased amounts of serum dopamine and the absence of norepinephrine (NE) and epinephrine. Dopamine is released, as a false neurotransmitter, in place of norepinephrine. Other names for norepinephrine include noradrenaline (NA) and noradrenalin. This condition is also sometimes referred to as "norepinephrine deficiency". Researchers of disorders such as schizophrenia are interested in studying this disorder, as patients with these specific diseases can have an increase in the amount of dopamine in their system and yet do not show other symptoms of DβH deficiency.

<span class="mw-page-title-main">Dopamine (medication)</span> Hormone used as a medication

Dopamine, sold under the brandname Intropin among others, is a medication most commonly used in the treatment of very low blood pressure, a slow heart rate that is causing symptoms, and, if epinephrine is not available, cardiac arrest. In newborn babies it continues to be the preferred treatment for very low blood pressure. In children epinephrine or norepinephrine is generally preferred while in adults norepinephrine is generally preferred for very low blood pressure. It is given intravenously or intraosseously as a continuous infusion. Effects typically begin within five minutes. Doses are then increased to effect.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 "Methyldopa". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  2. Walker RS (2012). Trends and Changes in Drug Research and Development. Springer Science & Business Media. p. 109. ISBN   9789400926592. Archived from the original on 2016-09-14.
  3. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  4. Malha L, Podymow T, August P (2018). "39 - Hypertension in Pregnancy". Hypertension: A Companion to Braunwald's Heart Disease (3rd ed.). Elsevier. pp. 361–373. doi:10.1016/B978-0-323-42973-3.00039-1. ISBN   978-0-323-42973-3.
  5. British National Formulary 56 . September 2008. pp.  95–96. ISBN   978-0-85369-778-7.
  6. Methyldopa (PIM 342) Archived 2008-03-13 at the Wayback Machine
  7. "DailyMed - METHYLDOPA tablet, film coated". dailymed.nlm.nih.gov. Retrieved 2022-07-25.
  8. Mah GT, Tejani AM, Musini VM (October 2009). "Methyldopa for primary hypertension". The Cochrane Database of Systematic Reviews. 2009 (4): CD003893. doi:10.1002/14651858.CD003893.pub3. PMC   7154320 . PMID   19821316.