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

Prescott, Laurence F.; Buhs, Rudolf P.; Beattie, John; Speth, Otto C.; Trenner, Nelson R.; Lasagna, Louis

doi:10.1161/01.cir.34.2.308

Cited by 47 publications

(16 citation statements)

References 22 publications

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“…The mean features of the disposition and metabolism of a-methyldopa have been established in normal and hypertensive adults (Buhs, Beck, Speth, Smith, Trenner, Cannon & Laragh, 1964;Prescott, Buhs, Beattie, Speth, Trenner & Lasagna, 1966; Au, Dring, Grahame-Smith, Isaac & Williams, 1972;Kwan, Faltz, Breault, Baer & Totaro, 1976). The results of investigations conducted with radiolabelled a-methyldopa have shown that after intravenous dosage most of the administered radioactivity is excreted in the urine within 24 h and little excretion occurred beyond this time.…”

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confidence: 99%

A study of the disposition of alpha‐methyldopa in newborn infants following its administration to the mother for the treatment of hypertension during pregnancy.

Jones¹,

Cummings²,

Setchell³

et al. 1979

Brit J Clinical Pharma

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Harrow, Middlesex HAl 3UJ1 The nine infants participating in this study were born to mothers who received continuous therapy with a-methyldopa (0.75-2.0 g/day) for several weeks extending to the time of delivery. 2 The concentration of free and total (free plus conjugated) a-methyldopa was determined by gas chromatography-mass spectrometry in amniotic fluid, umbilical cord plasma and maternal plasma at delivery; also in urine collected over timed intervals from neonates during the first days after birth. 3 The results indicate that a-methyldopa administered to the mother is present in the infant at birth at a level comparable to the maternal level and persists for some days. The ratio of conjugated to free drug increases with time after birth. 4 The excretion of free and conjugated a-methyldopa in the urine indicated that the drug is slowly eliminated in the neonate by excretion in the urine and apparently by metabolism, mainly to the sulphate conjugate. 5 The concentration of free and conjugated a-methyldopa in amniotic fluid tended to be higher than in umbilical cord plasma but lower than in neonatal urine, conjugated drug predominated.

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confidence: 99%

A study of the disposition of alpha‐methyldopa in newborn infants following its administration to the mother for the treatment of hypertension during pregnancy.

Jones¹,

Cummings²,

Setchell³

et al. 1979

Brit J Clinical Pharma

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“…4), strongly suggest that these O-methylated metabolites are not physiologically inert. Prescott et al (1966) noted a 40% increase in the…”

Section: Discussionmentioning

confidence: 97%

“…Prescott et al (1966) observed that hypertensive patients taking AMD for 1 month have a 40% increase in the percentage excreted as 3-O-methyl-methyldopa (OMMD), compared with amounts excreted after a single dose. These authors also noted a direct linear correlation between the antihypertensive effect of AMD and the 24-hour urinary excretion of OMMD in chronically treated patients.…”

Section: Discussionmentioning

confidence: 99%

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Mechanism of action of methyldopa in the rat. Role of 3-O-methylated metabolites.

Zavisca¹,

Breau²,

Wurtman³

1979

Circulation Research

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SUMMARYWe studied the effect of 3-O-methyl-methyldopa (OMMD), the 3-O-methylated metabolite of the antihypertensive drug methyldopa (a-methyldopa, AMD), on blood pressure in the spontaneously hypertensive rat. OMMD lowered blood pressure in a dose-related manner when given orally or intraperitoneally. Its action lasted longer than that of AMD, and daily oral administration produced a cumulative fall in blood pressure. Oral and intraperitoneal OMMD produced similar reductions of blood pressure and similar tissue OMMD levels. After intraperitoneal injection of different doses, levels of OMMD measured in brain, spinal cord, and plasma correlated with the magnitude of the antihypertensive effect. No AMD was detected in tissues after either route of administration, which suggests that the antihypertensive effect was not based on demethylation of OMMD to AMD. Peripheral inhibition of the enzyme, aromatic amino acid decarboxylase (AAAD), failed to suppress OMMD's effect on blood pressure; in contrast, central inhibition of AAAD did decrease OMMD's antihypertensive effect. These observations suggest that 3-O-methylated metabolites may participate in the antihypertensive effect of AMD. Ore Res 45: 684-690, 1979 AN AMINE metabolite acting in the central nervous system (CNS) mediates the antihypertensive effect of methyldopa (a-methyldopa, "Aldomet," AMD), a widely used antihypertensive drug (Dollery and Bulpitt, 1975;Henning, 1975;Van Zwieten, 1973). Considerable evidence supports the view that the active agent is o-methyl-norepinephrine (AMNE), the decarboxylated and /?-hydroxylated product of AMD. However, the exact nature of the active agent and the mechanism by which it affects blood pressure remain obscure.Previous experiments in our laboratory (Lo et al., 1976) demonstrated a dose-related accumulation of O-methylated metabolites in the brains and spinal cords of mice given isotopically labeled AMD. These O-methylated metabolites seem to be produced or stored in catecholaminergic (CA) neurons, since their accumulation is prevented by destruction of CA nerve terminals with 6-hydroxy-dopamine (Lo et al., 1976). Repeated administration of isotopically labeled AMD to mice was associated with a considerable increase in levels of some of these 3-O-methylated metabolites in brains and spinal cords. This evidence raises the possibility that O-methylated metabolites might participate in AMD's antihypertensive effects, especially when multiple doses are given.Other evidence also supports the possibility that O-methylated metabolites might be involved. Prescott et al. (1966) observed that hypertensive patients taking AMD for 1 month have a 40% increase in the percentage excreted as 3-O-methyl-methyldopa (OMMD), compared with amounts excreted after a single dose. These authors also noted a direct linear correlation between the antihypertensive effect of AMD and the 24-hour urinary excretion of OMMD in chronically treated patients. These results suggest that the O-methylation of AMD can be induced and might assume therapeutic ...

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“…By competitively inhibiting the sympathetic effects of norepinephrine, it decreases systemic arterial pressures and also decreases plasma renin activity. 3 Both methyldopa and a-methyl norepinephrine are renally excreted. 4 In adults with normal renal function (glomerular filtration rate: 90-120 mL/min), elimination is completed in 24 to 48 hours and rebound effects from chronic therapy have been reported within 48 hours, most prominently manifested by tachycardia and hypertension.…”

Section: Discussionmentioning

confidence: 99%

Prenatal Exposure to Methyldopa Leading to Hypertensive Crisis and Cardiac Failure in a Neonate

Tang²,

Rivero

et al. 2014

Pediatrics

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A 2-week-old infant with normal intracardiac anatomy presented to the emergency department in a hypertensive crisis with acute cardiac failure. Despite extensive evaluation, no underlying disease was found. The patient’s hypertension and cardiac dysfunction resolved after 1 week of supportive care in the PICU, and she was discharged within 2 weeks of presentation. The patient’s history revealed transplacental exposure to the α-adrenergic agonist methyldopa for 10 weeks before delivery. Her age at presentation and the self-limited nature of cardiac sequelae with complete resolution of cardiac dysfunction suggest withdrawal effects from this exposure. Whereas the rebound hypertensive effects of α-adrenergic agonists are well established in the adult population, this report shows an unusual adverse outcome of in utero exposure to methyldopa.

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

Abstract: ALPHA-METHYLDOPA (a-methyl-3,4-di-IA hydroxy-L-phenylalanine [Aldomet]

Cited by 47 publications

References 22 publications

A study of the disposition of alpha‐methyldopa in newborn infants following its administration to the mother for the treatment of hypertension during pregnancy.

A study of the disposition of alpha‐methyldopa in newborn infants following its administration to the mother for the treatment of hypertension during pregnancy.

Mechanism of action of methyldopa in the rat. Role of 3-O-methylated metabolites.

Prenatal Exposure to Methyldopa Leading to Hypertensive Crisis and Cardiac Failure in a Neonate

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