Methyldopa metabolite

Yohimbe bark Centrally active antihypertensive agents Yohimbine (a major alkaloid in yohimbe bark) may antagonize guanabenz and the methyldopa metabolite through its oj-adrenoceptor antagonistic properties. 

Freed, C. R., and Asmus, P. A., 1979, Brain tissue and plasma assay of L-dopa and a-methyldopa metabolites by high-performance liquid chromatography with electrochemical detection,/. Neurochem. 32 163-168. 

In contrast to a-methyldopa-induced hemolytic anemia, most drug-induced hemolytic anemia, especially for penicillins [34] and cephalosporins [35], involves drug-dependent antibodies, presumably because the drug acts as a hapten to directly modify erythrocytes or form immune complexes [36], However, there are many examples where a drug, such as nomifensine, induces both drug- (or metabolite)-dependent and drug-... 

Another drug that is associated with a relatively high incidence of both drug-de-pendent and autoimmune antibodies is diclofenac [38], In some cases the specificity of the diclofenac-induced autoantibodies is very similar to that induced by a-methyldopa [39], Diclofenac is a secondary aromatic amine and is oxidized to reactive metabolites by both cytochromes P450 and myeloperoxidase [40], When patient sera were tested, it was addition of the 4-hydroxy metabolite that most commonly led to agglutination of red cells [41] this metabolite has the potential to be air oxidized to a reactive iminoquinone. 

Methyldopa is an false substrate for the dopamine-/ -hydroxylase resulting in a-methylnor-adrenaline. This metabolite is an a2-adrenoceptor agonist an induce, like clonidine, a centrally mediated reduction of sympathetic tonus. 

Approximately 50% of an orally administered dose of a-methyldopa is absorbed from the gastrointestinal tract. Both peak plasma drug levels and maximal blood pressure-lowering effects are observed 2 to 6 hours after oral administration. A considerable amount of unchanged a-methyldopa and several conjugated and de-carboxylated metabolites can be found in the urine. 

The presence of a-methyldopa and its metabolites in the urine reduces the diagnostic value of urinary catecholamine measurements as an indicator of pheochro-mocytoma, since these substances interfere with the fluorescence assay for catecholamines. 

Pharmacokinetic characteristics of methyldopa are listed in Table 11-2. Methyldopa enters the brain via an aromatic amino acid transporter. The usual oral dose of methyldopa produces its maximal antihypertensive effect in 4-6 hours, and the effect can persist for up to 24 hours. Because the effect depends on accumulation and storage of a metabolite (a-methylnorepinephrine) in the vesicles of nerve endings, the action persists after the parent drug has disappeared from the circulation. 

Table 6.2.2 Typical CSF profiles of HVA, 5HIAA and 3-methyldopa (3-MD) for the inborn errors of metabolism associated with a disruption of biogenic amine metabolism. A downward-pointing arrow indicates that a particular metabolite is below the established reference range. An upward pointing arrow is indicative that a metabolite is above the established reference range. WR indicates that the concentration of the metabolite is likely to be within the reference range. AADC Aromatic amino acid decarboxylase, PNPO pyridox(am)ine-5 -phosphate oxidase...

Disposition in the Body. Rapidly absorbed from the small bowel after oral administration and widely distributed in the tissues less than 1% of a dose reaches the brain bioavailability about 33%. Extensively metabolised mainly by decarboxylation to dopamine, which is further metabolised, and also by methylation to 3-0-methyldopa which accumulates in the central nervous system most of a dose is decarboxylated by the gastric mucosa before entering the systemic circulation the decarboxylase activity is inhibited by carbidopa and benserazide. Dopamine is further metabolised to noradrenaline, 3-methoxytyramine, and to the two major excretory metabolites, 3,4-dihydroxyphenyl-acetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid, HVA). During prolonged therapy, the rate of levodopa metabolism appears to increase, possibly due to enzyme induction. About 70 to 80% of a dose is excreted in the urine in 24 hours. Of the material excreted in the urine, about 50% is DOPAC and HVA, 10% is dopamine, up to 30% is... 

Type II reactions antibody-dependent cytotoxic type. The drug or metabolite combines with a protein in the body so that the body no longer recognises the protein as self, treats it as a foreign protein and forms antibodies (IgG, IgM) that combine with the antigen and activate complement which damages cells, e.g. penicillin- or methyldopa-induced haemolytic anaemia. 

Central mechanisms. Some agents may act within the CNS to modify autonomic control of sympathetic tone and blood pressure. Clonidine inhibits release of noradrenaline by an agonist action at the autoinhibitory a2-adrenoceptors on sympathetic nerve endings. Methyldopa is thought to work, at least in part, centrally, acting both as an inhibitory false substrate in the biosynthetic pathway, also producing an active metabolite with actions at aj-adrenoceptors. 

Methyldopa (Aldomet) is a centrally acting antihypertensive agent. It is a prodrug that exerts its antihypertensive action via an active metabolite. Although used frequently as an antihypertensive agent in the past, methyldopa s significant adverse effects limit its current use in the United States to treatment of hypertension in pregnancy, where it has a record for safety. 

In spite of its rapid absorption and short half-life, the peak effect of methyldopa is delayed for 6 to 8 hours even after intravenons administration, and the duration of action of a single dose is nsnally about 24 hours this permits once-or twice-daily dosing. The discrepancy between the effects of methyldopa and the measured concentrations of the drug in plasma is most likely related to the time required for transport into the CNS, conversion to the active metabolite storage of a-methyl norepinephrine, and its subsequent release in the vicinity of relevant 0.2 receptors in the CNS. This is a good example of the potential for a complex relationship between a drug s pharmacokinetics and its pharmacodynamics. Patients with renal failure are more sensitive to the antihypertensive effect of methyldopa, bnt it is not known if this is due to alteration in excretion of the drng or to an increase in transport into the CNS. 

ABSORPTION, METABOLISM, AND EXCRETION When administered oraUy, methyldopa is absorbed by an active amino acid transporter. Peak plasma concentrations occur after 2-3 hours. The drug is eliminated with a of 2 hours (prolonged to 4-6 hours in patients with renal failure). Methyldopa transport into the CNS apparently is an active process. Methyldopa is excreted in the urine primarily as the sulfate conjugate (50-70%) and as the parent drug (25%). The remainder is excreted as other metabolites, including methyldopamine, methylnorepinephrine, and O-methylated products of these catecholamines. 

Drug metabolism as a mechanism of drug activation Prodrugs (eg. levodopa. methyldopa, parathion) are inactive as administered and must be metabolized in the body to become active. Many drugs are active as administered and have active metabolites as well, eg, many benzodiazepines. 

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