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PubMed1988

The effects of long term methyldopa in patients with hypoxic cor pulmonale.

Methyldopa (alpha-methyldopa) was given to patients with cor pulmonale secondary to chronic obstructive airways disease (COAD) to determine its effect on pulmonary haemodynamics. Twenty-five patients were randomly allocated to methyldopa (750 mg daily) or placebo. Pulmonary haemodynamics were measured twice, 12 months apart. Conventional therapies were continued unchanged. The effects of the drug on pulmonary haemodynamics were inconclusive when considered overall, but total pulmonary vascular resistance (TPVR) fell in all patients on active therapy in whom measurements were obtained both at rest and upon exercise. Only one patient in the placebo group achieved this. Over the trial period there was one death in the active but five in the placebo group. Survival was unrelated to abnormalities in pulmonary haemodynamics at the commencement of the trial in this study although the numbers of patients was small. Postural hypotension developed in patients receiving methyldopa and limited the dose that could be administered. The problems involved in long term trials of vasodilators in hypoxic cor pulmonale are discussed.

Aged↗
PubMed1975

Central inhibitory effect of alpha-methyldopa on blood pressure, heart rate and body temperature of renal hypertensive rats.

The central inhibitory effect of alpha-methyldopa on blood pressure, heart rate and body temperature was studied in conscious renal hypertensive rats. Systemic administration of alpha-methyldopa decreased mean arterial blood pressure and body temperature and caused a short lasting increase in heart rate followed by a long lasting decrease. Inhibition of central decarboxylase activity prevented the decrease in blood pressure, heart rate and body temperature but not the initial increase in heart rate. Inhibition of peripheral decarboxylase activity blocked the increase in heart rate and partially reduced the decrease in heart rate and body temperature but did not affect the decrease in blood pressure. Alpha-Methyldopa also decreased blood pressure at an ambient temperature of 30 degrees C, but the decrease of body temperature was absent and the heart rate remained elevated for 7 hr. Similar results were obtained in normotensive rats. The decrease in heart rate was correlated with the decrease in body temperature in normotensive and renal hypertensive rats. These findings suggest that in the renal hypertensive rat the decrease in blood pressure and in body temperature depends on a central action of alpha-methyldopa metabolites.

Animals↗
PubMedDate not supplied

Effect of methyldopa treatment on peripheral sympathetic nerve function in the dog.

Administration of methyldopa (100 mg/kg, p.o. twice daily for 3 days) to mongrel dogs produced a significant decrease in the mean blood pressure (MBP) and heart rate (HR). Chronotropic responses to cardioaccelerator nerve stimulation and vasoconstrictor responses to lumbar sympathetic nerve stimulation were significantly attenuated in the treated dogs. Pressor and chronotropic responses to bilateral carotid occlusion (BCO) and tyramine were also markedly reduced following treatment with methyldopa, which is consistent with the clinical findings that chronic methyldopa treatment in hypertensive patients impairs cardiovascular reflexes. Methylnorepinephrine (MNE) was significantly less potent than norepinephrine (NE) in producing an increase in MBP or hindleg perfusion pressure, while the chronotropic and inotropic potency of MNE was about equal to NE. These results indicate that treatment with methyldopa in the dog does indeed produce an impairment of peripheral sympathetic neuronal function to certain organs and this peripheral effect of the drug may be of importance in accounting for its antihypertensive action in the dog.

Animals↗
PubMed1977

Evidence for an inhibitory action of methyldopa on spinal sympathetic reflexes.

The antihypertensive activity of methyldopa is mediated primarily by effects on the central nervous system. A number of centrally acting hypotensive substances has recently been shown to depress spinal pathways and reflexes as well as inhibiting supraspinal areas. The present series of experiments evaluated the potential influence of methyldopa on spinal mechanisms. Stimulation of an intercostal nerve evoked a two-component response (early and late) in the splanchnic nerve of anesthetized cats. The "late" phase involves supraspinal neurons, whereas, the "early" component involves only spinal pathways. The i.v. administration of 100 mg/kg of methyldopa reduced systemic blood pressure and both components of the evoked potential progressively. These experiments indicate that methyldopa exerts an effect of spinal sympathetic mechanisms which may contribute to the antihypertensive response to the compound.

Animals↗
PubMed1978

Acute and chronic administration of alpha-methyldopa: regional levels of endogenous and alpha-methylated catecholamines in rat brain.

Acute administration of alpha-methyldopa (200 mg kg-1 s.c.) produced a short-lived decrease in dopamine levels in 5 regions of the rat brain. Maximal dopamine depletion was 55% in the corpus striatum and over 75% in other regions and occurred 4--6 h after alpha-methyldopa injection; dopamine levels recovered within 12 h. Maximal noradrenaline depletion of over 80% occurred in all regions 4--24 h after alpha-methyldopa and after 24 h noradrenaline levels were still significantly reduced from control values. In these acute studies alpha-methyldopamine accumulated rapidly in amounts equal to or greater than the depleted dopamine in all regions, reaching a peak at 4 h. By contrast, alpha-methylnoradrenaline accumulated more slowly reaching a peak at 6--24 h and was never present in amounts greater than the depleted noradrenaline. Following chronic administration of alpha-methyldopa (40 mg kg-1 s.c., twice daily 5 days) there was a similar depletion of noradrenaline and dopamine to that seen in the acute studies. The depletion was associated with a much smaller accumulation of alpha-methyldopamine. The striking feature of these results, however, was the large accumulation of alpha-methylnoradrenaline in all brain regions. This probably reflects the slow turnover and resistance to degradation by monoamine oxidase of alpha-methylnoradrenaline.

Animals↗
PubMed1987

Treatment of hypertension in pregnancy with methyldopa: a randomized double blind study.

Twenty-five patients whose pregnancies were complicated by chronic hypertension were entered in a double-blind study and randomly allocated to treatment with methyldopa (Aldomet) or placebo. Thirteen patients were in the treatment group and 12 in the placebo group. The two groups showed no significant difference in demographic and pretreatment laboratory profiles. Methyldopa-treated patients registering in the first trimester had a significant reduction in the mean arterial pressure (MAP) during the second and third trimesters (P less than 0.025). No significant differences in birth weight (BW), ponderal index (PI) were found when results were corrected for gestational age (GA), race, and sex. The mean GA was significantly prolonged in the methyldopa-treated group by 10.3 days (P less than 0.05). The frequency of superimposed pre-eclampsia was similar in both groups (33.3% vs. 38.4%). However, 75% of the superimposed pre-eclampsia occurred antepartum in the placebo group, while 80% of the methyldopa-treated group developed superimposed pre-eclampsia intrapartum. The results of this small study suggest that the treatment of hypertension in pregnancy may reduce MAP and possibly delay the occurrence of superimposed pre-eclampsia and thus afford a prolongation of the pregnancy.

Chronic Disease↗
PubMed1995

Labetalol vs. methyldopa in the treatment of pregnancy-induced hypertension.

OBJECTIVE: To assess the efficacy and safety of labetalol compared with methyldopa in the management of mild and moderate cases of pregnancy-induced hypertension (PIH). METHODS: One hundred four primigravidas with PIH were randomly allocated to receive either labetalol (group A) or methyldopa (group B). The dose of the drugs was doubled every 48 h to maintain a mean arterial blood pressure < or = 103.6 mmHg. Clinico-biochemical effects and frequency of side effects were studied. The statistical level of significance was taken at P < 0.05. RESULTS: Ten patients in group B (18.5%) developed significant proteinuria (> 30 mg/dl) whereas none developed proteinuria in group A. Labetalol was quicker and more efficient at controlling blood pressure, having a beneficial effect on renal functions and causing fewer side effects compared with methyldopa. The rate of induction of labor and rate of cesarean section for uncontrolled PIH was less in group A (48% and 1%, respectively) compared with group B (63.0% and 5.6%, respectively). Moreover a higher Bishop score at induction of labor was noticed in group A. CONCLUSIONS: Labetalol is better tolerated than methyldopa, gives more efficient control of blood pressure and may have a ripening effect on the uterine cervix.

Adult↗
PubMed1997

Acute reactive hepatitis in pregnancy induced by alpha-methyldopa.

BACKGROUND: Alpha-methyldopa is an antihypertensive medication used commonly in pregnancy. Reactive hepatitis is a severe, uncommon reported side effect of this medication. To our knowledge, there has been only one other reported case of alpha-methyldopa-induced hepatitis associated with pregnancy in the United States. CASE: A patient at 17 weeks' estimated gestational age was evaluated for elevated maternal serum alpha-fetoprotein, which is used generally as a screening test for birth defects. A thorough history, physical examination, and laboratory evaluation were performed, and alpha-methyldopa-induced maternal hepatitis was diagnosed. CONCLUSION: The astute clinician should include maternal hepatic dysfunction in the differential diagnosis of an elevated maternal serum alpha-fetoprotein and should consider obtaining aminotransferase levels after initiation of alpha-methyldopa therapy during pregnancy.

Adult↗
PubMed1978

Synthesis and antihypertensive activity of some ester progenitors of methyldopa.

A variety of esters of methyldopa was synthesized with the objective of obtaining derivatives that would be more efficiently absorbed from the gastrointestinal tract than the free amino acid and would undergo conversion to methyldopa readily in the blood or target tissues. Two of the esters, alpha-pivaloyloxyethyl (4u) and alpha-succinimidoethyl (4w), were found to be more potent antihypertensive agents than methyldopa in animal models and were selected for further study in man. The amino esters were prepared by three different methods, including direct esterification of methyldopa without the use of N- or O-protecting groups.

Animals↗
PubMed1984

Serum lipids in normo- and hyperlipidemics after methyldopa and propranolol.

We report on serum lipoprotein changes after antihypertensive therapy in nine subjects with type II hyperlipoproteinemia and eight subjects with normolipidemia. They received placebo for 6 wk, followed by random order crossover between methyldopa and propranolol for 6 mo. Physical activity, diet, and other drugs were monitored for constancy. No other antihypertensive drugs were used. Doses required for normalization of blood pressure ranged between 40 to 360 mg/day for propranolol and 500 to 2500 mg/day for methyldopa. Mean blood pressure was equally lowered to normal by both drugs. Triglyceride levels increased after propranolol and after methyldopa. Subjects with normocholesterolemia developed higher serum triglyceride levels after each drug, whereas such a change did not occur in patients with hypercholesterolemia. Low-density lipoprotein cholesterol levels were reduced by methyldopa only in patients with baseline hypercholesterolemia. There was no correlation between lipoprotein level changes, dose required of either drug, or propranolol blood levels. The baseline lipoprotein metabolism disorder appears more likely to determine the type of changes in serum lipoprotein levels after these antihypertensive drugs.

Adult↗
PubMedDate not supplied

Interaction of alpha-methyldopa with autonomic reflex tachycardia in man.

Effects of alpha-methyldopa on cardiovascular reflexes were studied in normal healthy volunteers, and comparisons made with clonidine. Graded bicycle ergometer exercise and cumulative nitroprusside infusions were used as stimuli to autonomic reflexes. alpha-Methyldopa produced reduction in resting heart rate and a parallel shift in the stimulus-heart rate response relationship to nitroprusside and exercise 5 h after bolus intravenous dosing with 1,500 mg, but no effects at 0.5, 1.75, and 3 h during cumulative intravenous dosing with 1,875 mg. Clonidine produced a similar pattern of change in nitroprusside responses as early as 0.5 h after an intravenous dose of 300 micrograms. After atropine, alpha-methyldopa still produced a parallel shift in the nitroprusside stimulus-heart rate response relationship; however, clonidine reduced resting heart rate and abolished all increments in heart rate to nitroprusside infusion. Quantitative and qualitative differences in the effects of alpha-methyldopa and clonidine on autonomic reflexes in humans indicate differences in sites or mechanisms of action within the autonomic nervous system.

Adolescent↗
PubMed1990

Methyldopa-induced hemolytic anemia in a 15 year old presenting as near-syncope.

Methyldopa is an antihypertensive medication which is available generically and under the trade name Aldomet that is widely prescribed in the adult population and infrequently used in children. Methyldopa causes an autoimmune hemolytic anemia in a small percentage of patients who take the drug. We report a case of methyldopa-induced hemolytic anemia in a 15-year-old boy who presented to the emergency department with near-syncope. The boy had been treated with intravenous methyldopa during a trauma admission seven weeks prior to presentation. Evaluation revealed a hemoglobin of three grams, 3+ Coombs' test with polyspecific anti-human globulin and monospecific IgG reagents, and a warm reacting autoantibody. Transfusion and corticosteroid therapy resulted in a complete recovery of the patient. Emergency physicians treating children must be aware of this syndrome in order to diagnose and treat it correctly. A brief review of autoimmune and drug-induced hemolytic anemias is provided.

Adolescent↗
PubMed1981

Antihypertensive effect of atenolol (100 mg once a day) and methyldopa (250 mg thrice a day). A double-blind cross-over multicentre study.

In a double-blind cross-over multicentre study lasting for 16 weeks, the antihypertensive effect of atenolol (100 mg once a day) was compared with that of methyldopa (250 mg thrice a day) in 48 patients with mild to moderately severe hypertension. At the end of the trial, atenolol was superior to methyldopa in achieving clinically relevant BP levels, less than 150/95 mmHg (p less than 0.001), and in respect to patients' drug preference (p less than 0.04). The BP levels after the first 2 weeks of treatment with either drug were identical but, in contrast to methyldopa, atenolol caused further significant reduction in BP during the following 4 weeks. This finding implies that one should hesitate to start additional therapy until after at least six weeks of atenolol treatment, whereas no further reduction in BP can be expected after the first 2 weeks of treatment with methyldopa. Two patients had to be withdrawn from the study during treatment with atenolol, as they developed severe bradycardia and dyspnoea, respectively. Other side-effects were few and of minor clinical importance.

Adult↗
PubMed1980

Comparative studies of guanfacine and methyldopa.

1. The antihypertensive effects of the new phenylacetylguanidine compound, guanfacine, a sympathetic inhibitor with a central site of action, were compared with methyldopa in 20 out-patients with essential or renal hypertension (WHO grade I-II). 2. During a 6-week period in randomized cross-over conditions, guanfacine 3.5 mg daily caused a mean decrease of 24% in mean arterial blood pressure (MAP). A normalization of blood pressure (BP < 145/95 mm Hg) was achieved in 50% of the patients and a 'good control' (BP < 160/100 mm Hg; > 145/95 mm Hg) in 90%. 3. Methyldopa 1.2 g daily led to a mean decrease in MAP of 12%. Normalization of blood pressure occurred in 15% and a 'good control' was achieved with 45% of the patients. Failure due to intolerance or ineffectiveness was observed in 40% of patients. 4. During therapy with guanfacine the following side-effects were noted: dryness of the mouth (n = 5), marked sedation (n = 2), constipation (n = 2), orthostasis (n = 1), collapse (n = 1) and atrioventricular block grade I on ECG (n = 1). Methyldopa caused headaches (n = 4), gastrointestinal disturbances (n = 4) and dryness of the mouth (n = 1). 5. The experience so far available seems to indicate that guanfacine is an effective antihypertensive drug which is more active than methyldopa in the doses used in this study.

Adult↗
PubMed1983

Reticuloendothelial cell function in alpha-methyldopa-induced hemolytic anemia.

2 patients having alpha-methyldopa-induced hemolytic anemia were followed sequentially using an in vitro assay of autologous monocyte-macrophage activity to determine if their reticuloendothelial system (RES) function was abnormal and thus could be related to the mechanism of lysis. RES function was evaluated while the patients were actively hemolyzing and during remission, following discontinuance of the drug. The results indicated that RES activity is normal in patients having hemolytic anemia due to alpha-methyldopa administration. Also, following cessation of drug therapy, the patients' IgG-coated red cells interacted significantly for a prolonged period (4-5 months) with autologous or normal allogeneic monocyte-macrophages. This was associated with a concurrent reticulocytosis and indicates a persistent low-level hemolytic phase throughout this period, even though hemoglobin and hematocrit values remained within the normal ranges. Although levels of IgG sensitizing the patients' red cells were essentially constant during the hemolytic phase and when the patients were in complete remission, significant monocyte-macrophage activity was only evident during the hemolytic period. In an attempt to explain this phenomenon, it is postulated that hemolysis in patients receiving alpha-methyldopa is related to the interaction of drug with red cell membrane proteins which results in a variably expressed 'altered' antigen which is recognized by 'autoantibody'. The proper expression of the Fc portion of the immunoglobin molecule to result in specific recognition by receptors on monocyte-macrophages depends upon the extent of the antigen alteration by alpha-methyldopa. If the drug does not result in appropriate antigen alteration, then, although 'autoantibody' may still bind to the red blood cell, its Fc region is not readily recognized by monocyte-macrophages and little or no erythrophagocytosis occurs.

Aged↗
PubMedDate not supplied

Pharmacokinetics of methyldopa. Plasma levels following single intravenous, oral and multiple oral dosage in normotensive and hypertensive subjects.

1. The pharmacokinetics of methyldopa after oral and intravenous administration was studied in hypertensive and normotensive patients. After intravenous administration methyldopa plasma concentrations decayed according to a two-compartment open model. 2. For intravenous administration the overall elimination constant Ke1 was 0.56 +/- 0.03 h-1, the volume of distribution of the central compartment 0.29 +/- 0.80 1 kg-1 and the plasma clearance rate 11.2 +/- 0.6 1 h-1. 3. Plasma half-times during the beta-phase of the methyldopa plasma decay curve following intravenous and oral administration were 2.8 +/- 1.3 and 2.1 +/- 0.7 h, respectively. 4. Maximal plasma levels in hypertensive out-patients show great variation and range from 0 to 1.9 microgram ml-1. 5. No relationships were found between maximal methyldopa plasma levels in patients under treatment and control of hypertension.

Administration, Oral↗
PubMed1977

Treatment of hypertension in pregnancy with methyldopa: blood pressure control and side effects.

A total of 242 women with moderate hypertension in pregnancy completed a controlled trial of methyldopa (Aldomet). The hypotensive effect of methyldopa was similar to its action in non-pregnant individuals and greatly reduced the frequency of severe hypertension occurring antenatally and in labour. As pregnancy advanced, an increasing daily dose of methyldopa was needed and there was a greater use of additional hypotensive therapy. Seventeen (14-5 per cent) women assigned to methyldopa had to be transferred to another drug or had to stop treatment completely because of minor side effects, of which the commonest were lack of energy and dizziness. No serious side effects were encountered. Nine per cent of the untreated women developed severe hypertension which required treatment later in their pregnancies. Six weeks after delivery, nearly all the patients were able to stop treatment.

Blood Pressure↗
PubMed1988

Comparison of antihypertensive efficacy and perinatal safety of labetalol and methyldopa in the treatment of hypertension in pregnancy: a randomized controlled trial.

Labetalol was compared with methyldopa in a randomized controlled trial involving 176 pregnant women with mild to moderate hypertension. Diastolic blood pressure below 86 mmHg was obtained in a similar proportion of women given labetalol or methyldopa. Intrauterine death occurred in four women treated with methyldopa, and the one neonatal death on day 1 occurred in the labetalol group. The average birthweight and the proportion of preterm or small-for-gestational-age babies were similar in both groups. Heart rate, blood pressure, blood glucose, respiratory rate, and Silverman score of the babies did not differ between the two treatment groups, whether the comparison was made for all the infants, or only for those that were preterm or small-for-gestational-age. These data indicate that maternal beta-blockade with labetalol is as safe as methyldopa for the fetus and the newborn.

Adult↗