Methyldopa

Structural formula
General
Non-proprietary name	Methyldopa
other names	( S ) -α-methyldopa; Methyldopum; ( S ) -3-Hydroxy-α-methyltyrosine; ( S ) -2-Amino-3- (3,4-dihydroxphenyl) -2-methylpropionic acid; L -3- (3,4-dihydroyphenyl) -2-methylalanine;
Molecular formula	C 10 H 13 NO 4
Brief description	colorless crystals
External identifiers / databases
EC number	209-089-2
ECHA InfoCard	100.008.264
PubChem	38853
ChemSpider	35562
DrugBank	DB00968
Wikidata	Q412621
Drug information
ATC code	C02 AB01
properties
Molar mass	211.22 g · mol -1
Melting point	approx. 306–307 ° C (decomposition) (methyldopa sesqui hydrate )
pK s value	2.25; 9.0; 10.35; 12.6
solubility	slightly soluble in water, insoluble in organic solvents, slightly soluble in dilute mineral acids
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances	no GHS pictograms
	no GHS pictograms
H and P phrases	H: no H-phrases
	P: no P-phrases
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Methyldopa is a synthetically produced amino acid that is used as a medicinal substance in high blood pressure therapy ( antihypertensive agent ).

Pharmacological properties

Mechanism of action

The pharmacological effect of methyldopa, of which only the L form [synonym: ( S ) -α-methyldopa] is pharmacologically active, results from the displacement of the physiological sympathetic neurotransmitters .

Point of attack of methyldopa in (nor-) adrenaline biosynthesis

As an amino acid, methyldopa is actively absorbed into the brain via the blood-brain barrier , where it is first decarboxylated to α-methyldopamine and then hydroxylated to α-methylnoradrenaline. The decarboxylation of methyldopa binds capacities of the decarboxylating enzyme, thereby inhibiting the decarboxylation of levodopa to dopamine , which in turn impairs the formation of norepinephrine , which is synthesized from dopamine. Norepinephrine normally causes blood pressure to rise by activating adrenoceptors by constricting blood vessels.
Methyldopa is a so-called false transmitter substance that can be stored, but has a higher affinity for α ₂ receptors than for α ₁ receptors relative to the actual, physiological transmitter substance . Centrally, the excitation of postsynaptic α ₂ -receptors increases the tolerance to lower blood pressure, or sets such a tolerance, since the vasomotor center in the elongated marrow is attenuated. The activation of presynaptic α ₂ receptors also ensures a peripheral reduction in noradrenaline release.

The effects set in two to six hours after administration and last for a period of about ten to 16 hours.

While the lowering of blood pressure at the start of treatment is primarily a result of the reduction in cardiac output , the primary blood pressure lowering factor in chronic therapy is the decrease in vascular resistance .

Pharmacokinetics

Methyldopa has an oral bioavailability of about 25% and a half-life of one and a half hours, a volume of distribution of 0.6 l / kg, and plasma protein binding is 10–15%.

Almost 50% of methyldopa is absorbed by the intestine, its metabolism , i.e. its enzymatic conversion to polar and thus more easily excretable substances, takes place in the intestines and the liver, it is excreted with the urine, the active metabolite is methyldopa- O- sulfate.

Indications

Since methyldopa belongs to the very small group of substances that have been used during pregnancy, it is the first choice for arterial hypertension during pregnancy (→ eclampsia ). The mechanism of action of methyldopa is mainly based on an inhibition of the central sympathetic action. Therefore, methyldopa is also called an antisympathotonic.

Side effects

Like most antisympathotonics, methyldopa is poorly tolerated by humans. Its administration can lead to minor side effects such as tiredness (occurs in over 10% of patients and usually settles by itself in the further course of therapy), dry nasal mucosa and slight gastrointestinal complaints (in 1–10% of patients) as well as harmless darkening of the Urine in contact with air (in less than one percent of patients) up to severe sedation that is reversible after a few days . Orthostatic dysregulations leading
to hypotension , extrapyramidal motor, Parkinson- like symptoms, skin reactions or immune hemolysis can also be observed. The Coombs test is positive in over 20% of patients who are permanently treated with methyldopa , but this is mostly not clinically relevant. Occasionally, however, haemolytic anemia can occur after chronic administration , but this is then mostly benign and has a mortality rate of less than 1%. Since more than one percent of those treated also suffer from liver damage, it is necessary to check the liver values once 14 days after the start of treatment and then every three months. In about 1–10% of patients, bradycardia , edema and depressive moods develop in the course of treatment with methyldopa . If this lasts longer than five days, a doctor must be consulted under all circumstances. In one to three percent of treated patients, there is also a fever and sometimes chills in the first week of treatment , which is usually a sign of general hypersensitivity to the substance. If an itchy rash, palpitations, shortness of breath, weakness and dizziness occur during treatment, a doctor should also be consulted immediately, as it may be a methyldopa allergy. Abrupt discontinuation of methyldopa can also lead to a so-called "rebound effect", which means that blood pressure and heart rate can rise sharply.

Because of these side effects, methyldopa, like other antisympathotonics, has lost much of its former importance. Elderly people should generally not take methyldopa.

Other Information

chemistry

Levodopa on the left, methyldopa on the right (as zwitterions , the residues are marked in red )

Methyldopa is an α, α-dialkylated α- amino acid , that is, at the α- C atom (blue) there is a further residue in addition to the C ₆ H ₃ (OH) ₂ CH ₂ residue, in this case a methyl residue . This distinguishes methyldopa from biogenic amino acids, which have an H atom on the α-C atom in addition to the acid group (-COOH), the amino group (-NH ₂ ) and the specific functional group (“remainder”) . Several syntheses for methyldopa are described in the literature. As a derivative of catechol, methyldopa is very sensitive to oxidation; Even in a weakly alkaline solution, decomposition by atmospheric oxygen takes place quickly.

Trade names

Monopreparations : Aldomet (CH), Aldometil (A), Dopegyt (D), Presinol (D), generics (D)

Web links

Commons : Methyldopa - Collection of pictures, videos and audio files

Individual evidence

↑ ^a ^b ^c ^d Entry on methyldopa. In: Römpp Online . Georg Thieme Verlag, accessed on July 15, 2019.
^ The Merck Index. An Encyclopaedia of Chemicals, Drugs and Biologicals . 14th edition, 2006, p. 1045, ISBN 978-0-911910-00-1 .
↑ Data sheet methyl-DOPA sesquihydrate from Sigma-Aldrich , accessed on November 4, 2016 ( PDF ).
↑ Technical information
^ Axel Kleemann , Jürgen Engel, Bernd Kutscher and Dietmar Reichert: Pharmaceutical Substances , 4th edition (2000), 2 volumes published by Thieme-Verlag Stuttgart, ISBN 978-1-58890-031-9 ; online since 2003 with biannual additions and updates.

[roempp-1] Entry on methyldopa. In: Römpp Online . Georg Thieme Verlag, accessed on July 15, 2019.

[MerckIndex-2] The Merck Index. An Encyclopaedia of Chemicals, Drugs and Biologicals . 14th edition, 2006, p. 1045, ISBN 978-0-911910-00-1 .

[Sigma-3] Data sheet methyl-DOPA sesquihydrate from Sigma-Aldrich , accessed on November 4, 2016 ( PDF ).

[4] Technical information

[A._Kleemann-5] Axel Kleemann , Jürgen Engel, Bernd Kutscher and Dietmar Reichert: Pharmaceutical Substances , 4th edition (2000), 2 volumes published by Thieme-Verlag Stuttgart, ISBN 978-1-58890-031-9 ; online since 2003 with biannual additions and updates.