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PubMed1997

The effect of nifedipine and methyldopa on maternal cerebral circulation.

OBJECTIVE: To study how the treatment of severe gestational hypertension affects maternal middle cerebral artery velocimetry. DESIGN: Prospective, clinical, descriptive study. SETTING: John Radcliffe Maternity Hospital, Oxford, England. PARTICIPANTS: Pregnant and puerperal women who required acute or chronic antihypertensive treatment with nifedipine (n = 46) or methyldopa (n = 26), respectively. METHODS: Transcranial Doppler ultrasound examinations of maternal middle cerebral arteries were performed before and 45 min after nifedipine; and before and 48 hours after the onset of methyldopa therapy. Blood pressure and heart rate were also recorded. MAIN OUTCOME MEASURES: Clinical and transcranial Doppler changes induced by the antihypertensive medication. RESULTS: Blood pressure and middle cerebral artery velocities decreased significantly following both short- and long-acting antihypertensive therapy. Nifedipine-induced changes were more pronounced and uniform than those found after methyldopa (16.7% and 6.4% decrease in middle cerebral artery mean velocity, respectively). The middle cerebral artery mean velocity decrease was independent of changes in the blood pressure or heart rate. CONCLUSIONS: Maternal cerebral haemodynamics are influenced by antihypertensive treatment. The reduction of middle cerebral artery flow velocities following administration of nifedipine and methyldopa may suggest that cerebral vasodilatation is occurring, which is consistent with the concept that cerebral vasospasm is present in women with pre-eclampsia. The cerebral vasodilatation could result from a direct effect of the medication on the arteries in question.

Antihypertensive Agents↗
PubMed1988

Complete atrioventricular block induced by methyldopa.

We present two patients who developed complete heart block due to treatment with methyldopa. After discontinuing methyldopa, conduction disturbances completely disappeared and recurred upon rechallenge with the medication. It is assumed that methyldopa can impair the myocardial conduction system by its central sympatholytic effect. Conduction anomalies should be excluded prior to treatment with methyldopa, and during treatment with the medication, the patients should be routinely screened for the presence of conduction anomalies.

Aged↗
PubMed1986

Concentration and pH dependency of alpha-methyldopa absorption in rat intestine.

The intestinal absorption of alpha-methyldopa from perfused segments of rat intestine was determined. Jejunal and ileal segments were studied at pH 4.5, 6.0 and 7.4 at an alpha-methyldopa concentration of 0.01 mM, and at pH 6.0 at concentrations of 0.01, 0.10 and 10 mM. Intestinal absorption was found to depend on both concentration and pH but not on segment. A weak positive correlation (r = 0.5) was observed between net water absorption and alpha-methyldopa absorption, similar to that observed for amino acids. The low intestinal wall permeability of alpha-methyldopa under normal intestinal pH conditions (pH 7.4) is consistent with the incomplete oral bioavailability of this drug.

Animals↗
PubMed1976

Effects of methyldopa on prolactin and growth hormone.

The effects of administration of methyldopa on serum prolactin and growth hormone (GH) concentrations in hypertensive patients were studied. Single doses of methyldopa (750 or 1000 mg) significantly increased serum prolactin levels, peak concentrations occurring four to six hours after drug administrations. Long-term methyldopa treatment was associated with threefold to fourfold increases in basal prolactin levels compared with those in normal subjects. In patients treated with methyldopa for two to three weeks the GH response to insulin hypoglycaemia was significantly greater than in normal subjects and untreated hypertensive patients. In contrast, patients treated for prolonged periods (mean 13-4 months) had a GH reponse indistinguishable from normal.

Adult↗
PubMed1979

Randomised comparison of methyldopa and oxprenolol for treatment of hypertension in pregnancy.

Fifty-three pregnant women with moderately severe hypertension were randomly allocated to treatment with methyldopa or oxprenolol. There were no significant differences between the groups in age, height, weight, parity, or stage of gestation at the start of treatment. The outcome of pregnancy was better in the group treated with oxprenolol, with greater maternal plasma volume expansion and placental and fetal growth. No intrauterine deaths occurred in either group, and antepartum fetal distress, detected by oxytocin challenge testing, was evident in only one patient, who received methyldopa. This infant, and one other in the methyldopa group, died in the neonatal period. No neonatal deaths occurred in the oxprenolol-treated group. Even in this small number of patients these results were considerably better than those in untreated women with hypertension of similar severity. Apgar scores in both groups were equivalent at birth, while blood sugar concentrations were higher in the oxprenolol group. Oxprenolol appears to be safe and effective in controlling hypertension during pregnancy. There was no evidence of harmful effects on the fetus, and oxprenolol may offer a selective advantage over methyldopa for fetal growth and wellbeing in utero.

Adult↗
PubMed1983

Randomised controlled comparative study of methyldopa and oxprenolol in treatment of hypertension in pregnancy.

One hundred pregnant women with hypertension (defined as diastolic blood pressure at or above 95 mm Hg) were allocated at random to treatment with methyldopa or oxprenolol and were compared with nonhypertensive controls matched according to parity and gestation at delivery. The patients were also stratified into those entering the study early (before 32 weeks' gestation) and those entering late (after 32 weeks' gestation). Although there were no differences in diastolic blood pressure between the hypertensive groups before or during treatment, in the early entry group the systolic blood pressure at entry of those allocated to oxprenolol was significantly higher than that of those receiving methyldopa; this difference remained throughout the treatment period. Also in the early entry group further increments of drug treatment were required to control blood pressure of patients receiving oxprenolol than in those receiving methyldopa. The eventual fetal outcome for all patients treated with methyldopa was the same as that for those treated with oxprenolol; birth weight, placental weight, head circumference, and Apgar score were not significantly different and there were no stillbirths in either group.

Adult↗
PubMed1989

Cholestatic liver injury after prolonged exposure to methyldopa.

We describe a 75-year-old patient who presented with severe cholestatic liver disease. He had been receiving methyldopa, 250 mg daily, for 6 years. An extensive evaluation failed to reveal extrahepatic obstruction or serologic evidence of viral hepatitis. A liver biopsy disclosed marked cholestasis, without hepatitis, and was compatible with a rare form of methyldopa-induced liver injury. Cessation of drug treatment was followed by a slow but complete recovery. Cholestasis is a rare manifestation of methyldopa hepatotoxicity. Although methyldopa-associated liver injury usually appears after about 4 weeks of treatment, a history of a much longer exposure does not exclude this entity.

Aged↗
PubMedDate not supplied

Selective effects of alpha-methyldopa on myocardial cell components independent of cell size in normotensive and genetically hypertensive rats.

Alpha methyldopa has been shown to modify left ventricular mass and normalize mitochondria/myofibrils volume ratio in spontaneously hypertensive rats (SHR) when administered during the stage of developing cardiac hypertrophy (Tomanek et al., Cardiovas Res 23: 173, 1979). To evaluate the long-term effects of this antihypertensive agent, the drug was administered to SHR and normotensive (WKY) rats between the ages of 1 and 12 months. In another group of SHR and WKY, treatment was delayed until the age of 12 months and the animals were then treated for 3 months. Treatment with alpha-methyldopa had similar effects on systolic blood pressures in both SHR groups; group means (+/- SEM) were 151 +/- 1 in the long-term treatment group and 157 +/- 5 in the delayed treatment group compared to 178 +/- 4 and 176 +/- 3 for their respective controls. While left ventricular weight and cell size were significantly lower after early long-term treatment (compared to nontreated SHR), delayed treatment had no significant effect on these indices of left ventricular mass. Despite the effectiveness of early long-term treatment in modifying left ventricular mass, the relative volumes of mitochondria and myofibrils, as well as other cellular components (sarcoplasm), were not altered. In contrast, delayed treatment caused a significant increase (approximately twofold) in relative sarcoplasmic volume and a decrease in relative myofibrillar volume in both SHR and WKY. These findings indicate that shifts in the relative volumes of intracellular components after alpha-methyldopa are independent of cell size and blood pressure. Furthermore, the data suggest that the effects of alpha-methyldopa on the myocardial cell are dependent on or influenced by factors associated with the development or stabilization of hypertrophy and/or age.

Animals↗
PubMed1983

alpha-Methyldopa and depression: a clinical study and review of the literature.

A review of the literature showed that a high incidence or prevalence of depression in patients being treated with alpha-methyldopa has never been documented. In their study of hypertensive patients in a general medical clinic the authors found that symptoms of depression were no more common in 42 patients treated with alpha-methyldopa than in 38 patients treated with other antihypertensive agents. As with other centrally active agents, alpha-methyldopa appears able to produce many different behavioral symptoms, including mood changes, in predisposed individuals. Because alpha-methyldopa is a DOPA decarboxylase inhibitor but does not consistently affect mood or induce depression, its effects do not support a catecholamine hypothesis of depression.

Antihypertensive Agents↗
PubMed1976

The addition of Visken to methyldopa therapy in hypertension: a multicentre study.

Forty-one patients completed the study where Visken was added to the treatment regimen of patients whose blood pressures were poorly controlled on methyldopa or who were experiencing side-effects with methyldopa. Supine blood pressure was reduced from 177/108 mm Hg before Visken therapy to 159/96 mm Hg after twelve weeks of taking Visken. The dose of methyldopa was reduced from a mean 921 mg at the start to 445 mg at the end. Fourteen patients were able to stop methyldopa therapy. The number of side-effects reported was reduced as the study continued and fifteen patients commented that they felt better on Visken. Nine patients did not complete the trial, three of these because of side-effects, viz insomnia, lethargy and sleep disturbances.

Blood Pressure↗
PubMed1985

Alpha-methyladrenaline: a possible active metabolite of alpha-methyldopa in the rat brain.

To determine whether or not alpha-methyladrenaline (MA) is an active metabolite of alpha-methyldopa, a centrally-acting hypotensive compound, we measured MA in the rat brain using the high-performance liquid chromatographic electrochemical detection method. After five daily treatments of alpha-methyldopa given twice daily a dose of 40 mg/kg, we found trace amounts of MA in the hypothalamus and C1-C2 area (hypothalamus, 23.7 +/- 2.3 picomole/g, n = 7; C1-C2 area, 5.4 +/- 0.4 picomole/g, n = 4), as well as large amounts of alpha-methylnoradrenaline (MNA) (Hypothalamus, 16.6 +/- 0.4 nanomole/g, n = 7; C1-C2 area, 7.0 +/- 0.2 nanomole/g, n = 4). In these brain areas, the amount of endogenous adrenaline was reduced to 10.6% and 16.1% of the control values, respectively. The amounts of MA were only 9.0% and 6.2% of that of endogenous adrenaline in these respective areas whereas MNA was detected at approximately the same level as endogenous noradrenaline. These findings indicate that MA is synthesized from alpha-methyldopa to a very minute extent in the hypothalamus and C1-C2 area, and a large amount of MNA was synthesized in these areas. These are of interest considering the changes of endogenous adrenaline and noradrenaline. Our results raise doubts about the participation of MA on the main determinant of the central hypotensive effect of alpha-methyldopa.

Animals↗
PubMed1992

Methyldopa-induced colitis in a patient with membranoproliferative glomerulonephritis.

A 76-year-old man with membranoproliferative glomerulonephritis complicated by methyldopa-induced colitis is reported. Eight months after administration of methyldopa, mucous bloody stool was noted. A barium enema examination showed disappearance of haustra and a spastic rectosigmoid with pseudo-polyposis. Biopsy specimens obtained from the sigmoid mucosa revealed interstitial edema and small inflammatory cells. After cessation of methyldopa treatment, the sigmoid findings, blood pressure, and proteinuria were improved, suggesting that methyldopa not only induced the acute colitis but also worsened the nephrotic syndrome in this patient.

Acute Disease↗
PubMed1986

alpha-Methyldopa for climacteric hot flushes. A double-blind, randomized, cross-over study.

The effects of single evening doses of alpha-methyldopa and placebo have been compared in 40 women with climacteric hot flushes. The study was designed as a double-blind, randomized and cross-over investigation. Of the 24 patients who completed the study, 15 reported that they preferred the alpha-methyldopa treatment (p greater than 0.05). alpha-methyldopa seemed to affect both the severity (p less than 0.05) and the frequency of climacteric hot flushes (p greater than 0.05). It is concluded that alpha-methyldopa is efficacious against climacteric hot flushes when given as single evening doses, but further study is required to answer whether this dosage is as effective as a twice daily regimen.

Climacteric↗
PubMed1982

Evidence that alpha-methylepinephrine is an antihypertensive metabolite of alpha-methyldopa.

Several medullary cardiovascular relay nuclei contain high concentrations of epinephrine and phenylethanolamine-N-methyl transferase (PNMT), the enzyme which catalyzes the conversion of norepinephrine to epinephrine. Since alpha-methylnorepinephrine, a metabolite of alpha-methyldopa, has been shown to be a substrate for adrenal PNMT, we postulated that alpha-methylnorepinephrine would also be a substrate for central PNMT, resulting in the synthesis of alpha-methylepinephrine. Therefore, alpha-methylepinephrine could be an active metabolite of alpha-methyldopa. We have investigated this hypothesis. 1) The centrally-active PNMT inhibitor SKF-64139 attenuated the hypotensive response to alpha-methyldopa in spontaneously hypertensive rats at doses that had little effect on the hypotensive response to clonidine. 2) In radioligand binding studies, alpha-methylepinephrine was as potent as norepinephrine in competing for alpha 2-receptors, more potent than epinephrine, norepinephrine, or alpha-methylnorepinephrine in competing for beta-receptors, and less potent than epinephrine, norepinephrine, or alpha-methylnorepinephrine in competing for alpha 1-receptors. 3) Intracerebroventricular administration of methylepinephrine (1-40 micrograms) to Sprague-Dawley rats elicited profound hypotension and bradycardia. alpha-Methylepinephrine was more potent than epinephrine in lowering blood pressure. We conclude that alpha-methylepinephrine is a centrally active depressor agent and could therefore be an active metabolite of alpha-methyldopa.

Animals↗
PubMed1982

Potassium disposition and neuroendocrine effects of propranolol, methyldopa and clonidine during dynamic exercise.

In order to determine the changes in potassium disposition with antirenin, antihypertensives during dynamic physical activity, a double-blind placebo controlled study was undertaken using normal volunteers receiving placebo or single and multiple dose clonidine, methyldopa and propranolol 0.2 mg. followed by 0.1 mg. bid x 7 days, 500 mg. followed by 250 mg. bid x 7 days or 80 mg. followed by 40 mg. bid x 7 days, respectively. Prior to study, 2 hours post dosing and coincident with immediate pre-exercise on treadmill, at graded increases of exercise and 2 hours post exercise (approximately 4 hours post dosing), blood was sampled for potassium, renin concentration, aldosterone and catecholamines. Blood pressure (BP) and heart rate (HR) were measured. The results demonstrate no greater increase in potassium over placebo with single or multiple dose clonidine or methyldopa. Following the initial dose of propranolol, 80 mg., there was a statistically greater rise in potassium over that seen with placebo but not observed with multiple dose. This may be related to the low multiple dose regimen. There were minor but significant changes in norepinephrine, renin and systolic pressure with multiple dose clonidine and methyldopa and in renin, heart rate and systolic and diastolic pressure with propranolol. Overall, the adrenergic responses, to exercise with methyldopa and propranolol are more biochemically altered than functionally impaired, yet the latter is related to dose and the underlying age and state of health of the group being studied.

Aldosterone↗
PubMed1983

Influence of alpha-methyldopa treatment on adrenergic receptor binding in rat forebrain.

We studied the influence of 6 days treatment with alpha-methyldopa (50 mg/kg s.c.) twice daily on radioligand binding to alpha 1 [3H)prazosin), alpha 2 [3H)clonidine) and beta[3H)dihydroalprenolol (DHA] receptors in rat forebrain. A 27% rise (p less than 0.05) in the Bmax for (3H)prazosin without change in Kd was found. Following alpha-methyldopa, the Kd for (3H)clonidine was increased from 1.78 +/- 19 to 3.03 +/- nM and Bmax fell from 197 +/- 20 to 167 +/- 19 fmoles/mg protein (p less than 0.05). These findings suggest that chronic alpha-methyldopa therapy induces changes in alpha 1 and alpha 2 receptors which may modify the antihypertensive effect of alpha-methyldopa.

Animals↗
PubMed1982

Methyldopa poisoning.

A case of methyldopa overdose, confirmed by quantitative blood analysis, is presented. The clinical manifestations were coma, hypothermia, hypotension, bradycardia, and dry mouth. This combination of clinical findings, previously considered characteristic of phenothiazines or tricyclic antidepressants poisoning, should also raise the suspicion of methyldopa overdose. Methyldopa is a commonly used antihypertensive agent. Surprisingly, reports on overdose are exceedingly rare [1, 2]. We have recently treated a case of methyldopa overdose in which the presenting signs resembled those of psychotropic drug poisoning.

Adult↗
PubMed1976

Effect of methyldopa treatment on cardiac function and myocardial blood flow in mongrel dogs.

Administration of methyldopa (100 mg/kg, orally twice daily for a period of 3 days) to mongrel dogs produced significant reductions in blood pressure and heart rate. The hypotensive effect of the drug was due to a reduction in peripheral resistance. Methyldopa treatment also produced a significant decrease in coronary vascular resistance. Studies on the left ventricular function indicated that treatment with methyldopa does not compromise the ability of the myocardium to respond to an increased work load. Thus, the beneficial effect of this agent on the myocardial circulation, together with its lack of any detrimental effect on the cardiac function suggest that methyldopa may be an effective agent for the control of hypertension.

Animals↗