Clinical and Chemical Studies with α -Methyl-Dopa in Patients with Hypertension

Abstract

T HE -biochemical and pharmacologic properties of a-methyl-3,4-dihydroxy-DL-phenylalanine (DL-a-methyl-dopa) in man have been described in several reportsl-5 from this laboratory. These studies showed that, in addition to being a potent inhibitor of the decarboxylation of several aromatie L-amino acids, the compound has sedative and hypotensive properties. Thus, the agent has come to be looked upon as a potentially useful drug as well as an interesting bioehemical tool.The present report covers three phases of additional investigations: (1) further observations were made on the blood pressure lowering effects of the racemic (DL) form of the compound and preliminary data were obtained on its metabolism in man, (2) following resolution of the agent into its D and L isomers, these were tested comparatively and all activity was found to reside in the Lisomer, and (3) studies were initiated to evaluate the usefulness of L-a-methyl-dopa (Aldomet) as an antihypertensive agent. The conclusion is reached that Aldomet is a promising drug for the treatment of hypertension and has an interesting, albeit incompletely understood, mechanism of action.Materials and Methods ClinicalThe subjects were 52 patients with persistent primary hypertension; the age range was 32 to 67 years. Complications included: grade III retinopathy, nine cases; grade IV retinopathy, five cases; congestive heart failure, one case; and renal insuffieiency with azotemia, four cases. Twenty-eight of the patients were hospitalized and the others were studied as out-patients. All blood pressure measurements were by the arm cuffauscultatory technic. The protocols of individual studies are considered in the appropriate sections From the Experimental Therapeutics Branch,

Duration of effect of single daily dose methyldopa therapy.

“…The peak effect is delayed and occurs 6-9 h after the dose; the effect then declines with a half-life of approximately 10 h and only a small effect remains by 24-26 h. This time course is similar (0) to that found in earlier studies where the antihypertensive effect was measured after a single oral dose (Dollery & Harrington, 1962;Gillespie et al, 1962). The time course of antihypertensive effect does not correlate with the rapid serum half-life of methyldopa (1-2 h); however, it may correlate with a second phase serum half-life of methyldopa and/or metabolites (Stenbeak et al, 1977).…”

Methyldopa for Treatment of Hypertension

“…But since we know that methyldopa can be metabolized to L-alpha-methylnoradrenaline, which in turn undergoes 3-0-methylation (Gillespie et al, 1962;Carlsson and Lindqvist, 1962), we will have to separate the a-methyl from the physiological metanephrines before we can properly interpret our results. The disappearance of adrenaline in the urine of our patient following methyldopa is, however, suggestive of an inhibition of the decarboxylation.…”

Hypertension and Depression and Their Treatment

“…Methyldopa causes depletion of brain noradrenaline, serotonin and dopamine, a t least in the * Received 17 January 1973 experimental animal (Sourkes, 1965). Drowsiness is a common side effect initially unless the starting dose is small; tiredness may be a prominent feature and the patient may become tearful and depressed (Gillespie et al 1962;Smirk, 1963;Lauwers et al 1963;Johnson et al 1966; Horwitz elt al. 1967).…”