Combined Clinical and Metabolic Study of the Effects of Alpha-Methyldopa on Hypertensive Patients

Abstract

The urinary metabolites of orally admblistered 2-C -labeled a-methyldopa were measured in 20 hypertensive patients before and after treatment with [alpha]-methyldopa in a dose of 3.0 g daily for 3 months. There was consierable variation in the absorption, biotransf orma-tion and excretion of [alpha]-methyldopa after an oral dose, but differences in clinical response to [alpha]-methyldopa could not be attributed to this. Approximately 40% of the urinary excretion products of [alpha]-methyldopa was recovered as unchanged methyldopa, 31% as [alpha]-methyldopa-O-sulfate, 8% as 3-methoxy-[alpha]-methyldopa, 9% as neutral fraction, 3% as free base, and 3% as conjugated base. The percentage of 3-methoxy-[alpha]-methyldopa was increased following prolonged treatment with [alpha]-methyldopa, suggesting induction of catechol-O-methyl transferase. The percentage of 3-methoxy-[alpha]-methyldopa at the final study was correlated with reductions in standing blood pressure, but not with supine blood pressure. No other changes in the metabolism of [alpha]-methyldopa could be attributed to chronic administration of the drug, and no correlation was found between the excretion patterns of the other urinary metabolites of [alpha]-methyldopa and hypotensive effect. Tolerance to the hypotensive effect of [alpha]-methyldopa occurred in 4 patients, but in another 4 an increasing hypotensive effect was seen. The development of tolerance to the hypotensive action of [alpha]-methyldopa could not be explained on a metabolic basis. The inhibition of decarboxylation of tyrosine to tyramine and of tryptophan to tryptamine was studied at the initiation of therapy and again after chronic treatment with [alpha]-methyldopa. In the majority of patients, inhibition of decarboxylase was markedly increased after chronic treatment, especially when tryptophan was the substrate. In 4 patients, tolerance to the inhibition of decarboxylation of tyrosine, but not of tryptophan, occurred, and in 3 of these patients a good hypotensive effect was maintained. There was no correlation between the inhibition of decarboxylase and reduction of blood pressure.