Methyldopa

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Methyldopa
Skeletal formula of methyldopa
Ball-and-stick model of the methyldopa molecule
Names
Trade namesAldomet, Aldoril, Dopamet, others
Other namesL-α-Methyl-3,4-dihydroxyphenylalanine
Clinical data
Main usesHigh blood pressure in pregnancy[1]
Pregnancy
category
  • AU: A
  • US: B (No risk in non-human studies)
Routes of
use
by mouth, IV
Onset of action4 to 6 hrs[2]
Duration of action10 to 48 hrs[2]
Defined daily dose1 to 2 gram[3]
External links
AHFS/Drugs.comMonograph
MedlinePlusa682242
Legal
License data
Legal status
Pharmacokinetics
Bioavailabilityapproximately 50%
MetabolismLiver
Elimination half-life105 minutes
ExcretionKidney for metabolites
Chemical and physical data
FormulaC10H13NO4
Molar mass211.217 g·mol−1
3D model (JSmol)
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Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure.[2] It is one of the preferred treatments for high blood pressure in pregnancy.[2] For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred.[2] It can be given by mouth or injection into a vein.[2] Onset of effects is around 5 hours and they last about a day.[2]

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

Methyldopa was discovered in 1960.[4] It is on the World Health Organization's List of Essential Medicines.[5] The wholesale cost in the developing world is about US$4.31–9.48 per month.[6] In the United States it costs less than $25 per month.[7]

Medical uses

Methyldopa is used for high blood pressure including pregnancy-induced hypertension such as pre-eclampsia.

Dosage

The defined daily dose is 1 gram for the levorotatory version and 2 grams for the racemic version.[3] This is generally started at 250 mg two to three times a day for the first two days and than increased every few days by 250 mg until the typical long term dose of 1.5 grams is reached.[1] The maximum dose is 3 grams.[1]

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.[8] Side effects may include:

Rebound/withdrawal

Rebound hypertension via withdrawal on account of tolerance upon the abrupt discontinuation of methyldopa has been reported.[9]

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.

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

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.[10] 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

References

  1. 1.0 1.1 1.2 "METHYLDOPA oral - Essential drugs". medicalguidelines.msf.org. Retrieved 31 August 2020.
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 "Methyldopa". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  3. 3.0 3.1 "WHOCC - ATC/DDD Index". www.whocc.no. Retrieved 31 August 2020.
  4. 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.
  5. 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.
  6. "Methyldopa". International Drug Price Indicator Guide. Retrieved 8 December 2016.
  7. Hamilton R (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 140. ISBN 9781284057560.
  8. British National Formulary 56. September 2008. pp. 95–96. ISBN 978-0-85369-778-7.
  9. Methyldopa (PIM 342) Archived 2008-03-13 at the Wayback Machine
  10. Mah GT, Tejani AM, Musini VM (October 2009). "Methyldopa for primary hypertension". The Cochrane Database of Systematic Reviews (4): CD003893. doi:10.1002/14651858.CD003893.pub3. PMC 7154320. PMID 19821316.

External links

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