Methyldopa

(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,

• 555-30-6
• 41372-08-1 (Methyl -dopa sesquihydrate )

C02AB01

Colorless crystals

About 306-307 ° C ( decomposition) ( Methyldopa sesquihydrate · )

Low in water, insoluble in organic solvents, slightly soluble in dilute mineral acids

Template: Infobox chemical / molecular formula search available

Methyldopa is an amino acid synthesis, which is used as a drug in hypertension therapy ( antihypertensive ).

• 2.1 Chemistry

Pharmacological properties

Mechanism of Action

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

As amino acid methyldopa is actively absorbed across the blood- brain barrier into the brain, where it is first decarboxylated to α -methyl dopamine and then hydroxylated to α -methyl noradrenaline. Decarboxylation of methyldopa binding capacity of decarboxylating enzyme, thereby inhibiting the decarboxylation of L-dopa to dopamine, which in turn affects the production of noradrenaline, which is synthesized from dopamine. Norepinephrine normally makes using Adrenozeptorenaktivierung on blood vessel constriction for an increase in blood pressure. Methyldopa is a so-called false carrier substance which can be stored, however, relative to the actual physiological carrier material has a higher affinity for α2 - receptors than to α1 - receptors. Central increases the excitation of postsynaptic α2 - receptors tolerance to lower blood pressure, or represents such a because the vasomotor center is attenuated in the medulla oblongata. The activation of presynaptic α2 - receptors also ensures peripherally for a reduction of noradrenaline release.

The effect is a two to six hours after administration and maintains for a period of approximately ten to 16 hours.

During the beginning of treatment is the reduction of blood pressure mainly a consequence of the reduction in cardiac output, the primary hypotensive factor is the decrease in vascular resistance in chronic therapy.

Pharmacokinetics

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

Approximately 50 % of methyldopa is absorbed from the intestine, and metabolism, so its enzymatic conversion to polar and thus better excretable substances takes place in the intestines and the liver, it is excreted in the urine, the active metabolite is methyldopa -O- sulfate.

Indications

Since methyldopa belongs to the very small group of substances for which there are experiences in the use during pregnancy, it is next to hydralazine in arterial hypertension in pregnancy ( eclampsia → ) is the drug of first choice. The mechanism of action of methyldopa is mainly due to an inhibition of central Sympathikuswirkung. Methyldopa therefore also referred to as Antisympathotonikum.

Side effects

Like most antisympathotonics is also methyldopa for humans poorly tolerated. Minor side effects such as fatigue can from his administration (occurring in about 10 % of patients and lies mostly in the further course of therapy by itself), dry nasal mucosa and mild gastrointestinal discomfort ( 1-10 % of patients ) and harmless darkening of the urine resulting in contact with air (less than one percent of the patients ) to severe, reversible after a few days sedation. Likewise, leading to hypotension, orthostatic dysregulation, extrapyramidal, Parkinson-like symptoms, skin reactions or immunohemolysis can be observed. With over 20% of patients who are permanently treated with methyldopa, the Coombs test is positive, but this is not usually clinically relevant. Occasionally it may cause a certain hemolytic anemia after chronic administration, however, this is then usually benign and has a fatality rate of less than 1%. As it comes to liver damage in about one percent of those treated, is a liver monitoring only 14 days after the start of treatment and quarterly thereafter necessary. In about 1-10 % of patients develop in the course of therapy with methyldopa, bradycardia, edema and depressive moods. Take this for longer than five days, under all circumstances, consult a doctor. In one to three percent of treated patients, it also comes in the first week of treatment to fever and sometimes chills, which is usually a sign of a general hypersensitivity to the substance. If, during the treatment itchy rash, palpitations, shortness of breath, weakness, and dizziness upon is also a doctor immediately as it can be a Methyldopaallergie. Abrupt discontinuation of methyldopa may also lead to a so-called "rebound effect", that is, blood pressure and heart rate can increase dramatically.

Due to these side effects methyldopa, as well as other antisympathotonics, lost much of its former importance. Old people should generally not take methyldopa.

Other Information

Chemistry

Methyldopa is a α, α -dialkylated amino acid α, that is, at the α - carbon atom (blue) is adjacent to the C6H3 (OH) 2CH2 residue at yet another radical, in this case, a methyl radical. Methyldopa This is different from biogenic amino acids, wearing a H atom on the α - carbon atom next to the acid group (-COOH), the amino group (-NH2) and the specific functional group ( "rest" ). In the literature, several syntheses of methyldopa are described.