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PubMed1976

A comparison of debrisoquine and methyldopa in hypertension.

Debrisoquine, an antihypertensive agent, was compared with methyldopa in a double-blind trial in the treatment of hypertension in 20 patients. The cross-over method was used to treat each patient with first one and then the other drug for two periods of six weeks each. Two placebo periods of two weeks each were also included, one before the trial, and the other between the two therapy periods. The maximum daily dose was 3 X 10 mg debrisoquine compared with 3 X 250 mg methyldopa. Hydrochlorothiazide, 50 mg daily, was added in all cases for the entire trial. Both preparations lowered blood pressure statistically significantly (p less than 0.005). Tablet for tablet, debrisoquine had a slightly more pronounced effect than methyldopa, but the difference was not statistically significant. Both drugs were well tolerated and in no case had treatment to be interrupted because of side effects. Debrisoquine produced less sedation and dizziness than methyldopa. The conclusion was that both drugs were equally effective in the doses studied and well tolerated and that debrisoquine is of value in the treatment of moderate hypertension.

Adult↗
PubMed1976

Pharmacokinetics of methyldopa in man.

Single doses of methyldopa were administered orally and intravenously as aqueous solutions to 12 healthy volunteers in a crossover study. Serial plasma and urine samples were analyzed specifically for methyldopa and its O-sulfate conjugate. Kinetic analyses of the results indicated that methyldopa disposition could be adequately represented by a two-compartment open model. Renal excretion accounted for about two-thirds of the plasma clearance of methylodopa. Absorption profiles were constructed with the aid of the pharmacokinetic model and contrasted with estimates of absorption which were model-independent. The mean fraction reaching the systemic circulation as methyldopa was estimated to be 0.25 (range 0.08-0.62 for n = 11). Although most of the absorption occurred within the first 5 hours oral administration, a minor component, suggestive of limited enterohepatic circulation, persisted from 9 to 36 hours. O-sulfate conjugation was route-dependent and appeared to be derived predominantly, if not exclusively, as a first-pass effect of absorption and/or enterophepatic circulation.

Administration, Oral↗
PubMed1993

Placebo substitution for methyldopa in geriatric hypertensive patients.

The aim of this study was to obtain an objective evaluation of the possibly inappropriate antihypertensive therapy of elderly patients; this was done by means of placebo substitution for methyldopa, one of the drugs taken by all the participating patients. Forty patients were recruited from a hospital outpatient clinic and randomly allocated to two groups. One group remained on treatment which included methyldopa, while a matching placebo tablet was substituted in the other group. The study was conducted over a period of 6 months in a single-blind manner. Methyldopa was reintroduced in the placebo group when one of the evaluation clauses was recorded. Only 2 patients in the placebo group required reintroduction of methyldopa tablets. In the rest of this group there was no significant difference between systolic and diastolic pressures before and after 6 months of placebo substitution. Withdrawal of unnecessary antihypertensive therapy in the elderly should be considered. Patients must be observed carefully and therapy reintroduced when blood pressures rise.

Aged↗
PubMedDate not supplied

Comparison of prazosin and methyldopa in essential hypertension: results of a randomized, double-blind, parallel trial.

The value of prazosin and methyldopa administration was compared in 16 patients with essential hypertension during a 6 month randomized, double-blind, parallel trial. Both drugs were administered in combination with hydrochlorothiazide, 50 mg twice daily, until recumbent diastolic blood pressure was decreased to less than 90 mm Hg or the patient was receiving prazosin, 5 mg q.i.d., or methylodpa, 500 mg q.i.d. Addition of either prazosin or methyldopa to hydrochlorothiazide lowered blood pressure significantly and to a similar degree without altering plasma renin activity. Heart rate and weight were significantly increased during prazosin, but not methyldopa, therapy. Symptomatic side effects occurred with equal frequency during treatment with both agents and did not result in alteration or discontinuation of therapy in any patient. A decrease in frequency of administration from q.i.d. to b.i.d. or t.i.d./b.i.d. to q.d. did not adversely affect blood pressure control. Substitution of propranolol for prazosin or methyldopa provided similar antihypertensive effectiveness with a significant decrease in heart rate.

Adult↗
PubMed1991

In vivo pharmacokinetics of levodopa and 3-O-methyldopa in muscle. A microdialysis study.

In the present study in vivo microdialysis sampling coupled to high-performance liquid chromatography with electrochemical detection, was used to study the pharmacokinetics of levodopa and 3-O-methyldopa in skeletal muscle in dog, after intravenous administration of levodopa. For comparison, the pharmacokinetic parameters of both compounds were simultaneously determined in plasma using blood collection. Muscle microdialysis samples and blood were continuously collected for 4 h after the administration of levodopa (25 mg/kg). Pharmacokinetic profiles of levodopa in plasma and muscle were different. The mean Tmax value of levodopa in plasma and muscle was 0.16 h and 1.0 h, respectively. The AUC0----inf for levodopa in plasma was nearly 18-fold higher in plasma than in muscle. The 3-O-methyldopa concentration increased very rapidly after the administration of levodopa, to reach a plateau after 2.5 h and 3 h in plasma and muscle, respectively. The AUC0----4 for 3-O-methyldopa was 3.6-fold higher in plasma than in muscle. The ratio levodopa/3-O-methyldopa, reflecting the metabolic rate of levodopa, was 3.5 times higher in plasma than in muscle, at the peak value of levodopa, and then rapidly declined to values lower than 1, one hour after administration of the drug. We compared our results with literature data from postmortem studies done in rat experiments. We concluded that levodopa is not accumulating in muscle as such, but is converted to 3-O-methyldopa probably before leaving the plasma compartment.

Animals↗
PubMed2006

[Simultaneous determination of levodopa and methyldopa in human serum by capillary electrophoresis].

A simple capillary electrophoresis method was developed for the determination of levodopa and methyldopa in human serum. The effects of pH and concentration of buffer, voltage and injection time on separation were investigated. As a result, an optimized separation was obtained with a fused-silica capillary of 60.2 cm (50 cm effective length) x 75 microm i. d. in a running buffer of 40 mmol/L sodium tetraborate (pH 9.5) with an applied voltage of 22 kV at 25 degrees C. Sample introduction was performed at 3.45 kPa (0.5 psi) for 7 s and on-column detection was made with a diode array detector at 200 nm. The linear responses covered the ranges from 1.0 to 64.0 mg/L (r = 0.999 8) for methyldopa and from 1.0 to 71.0 mg/L (r = 0.999 4) for levodopa. The detection limits (S/N = 3) of methyldopa and levodopa were shown to be 0.6 mg/L and 0.8 mg/L, respectively. The recoveries for levodopa and methyldopa in human serum were between 82.8% and 88.8% with relative standard deviations between 2.10% and 2.63%.

English Abstract↗
PubMed1984

Exaggeration of defective platelet function by methyldopa in hypothyroidism.

Platelet function was analyzed in two hypothyroid patients who were taking methyldopa. Results from these two patients are compared to those obtained in seven others with hypothyroidism on no medications. Bleeding times in the two drug patients were 33 and 26 minutes compared to normal values (4.0 to 8.0 minutes) in the other hypothyroid individuals. In addition, platelet aggregation responses to epinephrine, collagen, and ristocetin were abnormal in these two patients; these were normal in the others with hypothyroidism. Repeat studies were done in the first drug patient when she was euthyroid and still receiving methyldopa. Her bleeding time decreased to 11 minutes, platelet retention increased from 31% to 75%, and abnormal aggregation responses corrected to normal. Factor VIII coagulant activity, VIII antigenic activity, VIII ristocetin cofactor activity, and two-dimensional immunoelectrophoresis of VIII antigen were normal. These findings suggest that methyldopa can potentiate the mild platelet function defect seen in patients with hypothyroidism.

Adult↗
PubMed1989

Methyldopa-induced systemic lupus erythematosus.

Thirteen months after starting methyldopa therapy, a 55-year-old white male patient presented with a syndrome of hemolytic anemia, arthritis, photosensitivity, and a positive antinuclear antibody test result. Methyldopa-induced antinuclear antibodies were mainly IgG, directed against class H1 histones. Antibodies to native DNA and nonhistone proteins were not detected. Upon withdrawal of methyldopa therapy, and with a short course of prednisone and danazol therapy, the patient's symptoms and hemolytic anemia resolved. His clinical symptoms and serologic abnormalities returned to normal and remained negative after 2 years of followup.

Antibodies, Antinuclear↗
PubMed1977

Clinical and cardiovascular effects of alpha methyldopa in combination with decarboxylase inhibitors.

The peripheral decarboxylase inhibitor carbidopa, given (100 mg/day) for 6 wk in a double-blind trial, lowered supine diastolic pressure of 10 patients with essential hypertension treated with alpha methyldopa by a small (6 mm Hg) but significant (p less than 0.05) amount. Large doses of benserazide (1.5 gm) did not modify the hypotensive effect of 1.0 gm of alpha methyldopa in untreated hypertension but significantly reduced the central nervous side effects of sedation and dry mouth. These studies indicate that extensive peripheral decarboxylation is not necessary for alpha methyldopa to lower blood pressure and would be compatible with the central nervous site of hypotensive action of this drug.

Adult↗
PubMed1977

Guanabenz and methyldopa on hypertension and cardiac performance.

In previous placebo-controlled studies, guanabenz was shown to be a safe and effective antihypertensive drug without acute effects on cardiac function. In view of its therapeutic advantages, a double-blind comparison of guanabenz with methyldopa was performed in a group of 36 patients over 6 mo. Both drugs produced statistically and clinically significant decreases in blood pressure with similar side effects. No laboratory or electrocardiographic abnormalities were found other than positive Coombs' tests which developed in 3 patients during methyldopa therapy. Cardiac performance in 26 of the patients, as measured by noninvasive techniques, showed no significant changes from either drug except for a progressive and statistically significant increase in systolic time interval (QS2) and the ratio of the pre-ejection period to left ventricular ejection time (PEP/LVET) during methyldopa therapy. For an additional 6 mo, continued efficacy and safety were shown under open conditions in those patients who had received guanabenz. The study suggests that guanabenz may be an important new antihypertensive drug because of effectiveness, absence of adverse cardiac effects, and paucity of side effects.

Adult↗
PubMedDate not supplied

Some paradoxical aspects of the cardiovascular pharmacology of alpha-methyldopa.

In an effort to help explain why it is often difficult to demonstrate hypotension with alpha-methyldopa on an acute basis in normotensive anesthetized animals, the drug was administered intravenously in single doses of either 50, 100, or 200 mg/kg to chloralose-anesthetized cats while monitoring mean arterial pressure; the systolic pressor response in arterial pressure to bilateral occlusion of the common carotid arteries; hind limb vascular resistance in a vascularly isolated, extracorporeally perfused but neurally intact hind limb; and the response of hind limb vascular resistance to CCO. Alpha-methyldopa failed to cause any significant hypotension and also failed to affect vasomotor tone to the hind limb vasculature, but the drug augmented the pressor response to CCO on MAP and hind limb vascular resistance. Alpha-methyldopa also had no effect on hind limb vascular resistance when added directly to the extracorporeally perfused hind limb vascular resistance when added directly to the extracorporeally perfused hind limb circuit, indicating a lack of direct vascular smooth muscle dilating properties in these preparations. It is postulated that the augmented baroreceptor demonstrated may help th explain why it is difficult to record hypotension on an acute experimental basis with this drug. Such actions of alphamethyldopa might also provide a basis for understanding the development of tolerance to the antihypertensive effects of the drug and instances of paradoxical hypertension with it when these occur in the hypertensive human.

Animals↗
PubMedDate not supplied

Guanadrel sulfate compared with methyldopa for mild and moderate hypertension.

In a two-year study of 547 hypertensive patients receiving diuretics, the addition of guanadrel sulfate or methyldopa reduced elevated blood pressure to a similar degree and provided good control in 70% of the patients. Guanadrel-treated patients experienced less frequent and less severe drowsiness than methyldopa-treated patients. The frequency of morning orthostatic faintness was low and similar in both treatment groups. Guanadrel produced no tissue toxicity. Guanadrel sulfate, a postganglionic sympathetic inhibitor, is nearly free of central nervous system side effects and is recommended over methyldopa for step 2 therapy when diuretics alone fail to control mild or moderate hypertension.

Antihypertensive Agents↗
PubMed1987

Short-term hemodynamic effects of intravenous methyldopa in patients with congestive heart failure.

The acute hemodynamic effects of intravenous methyldopa were studied in six patients with chronic congestive heart failure (New York Heart Association class IV) at 4-6 hours after a 750-mg bolus (period A) and 6-12 hours after a maintenance infusion of 1-2 mg/minute (period B). For period A, the most consistent and striking finding was a significant (48%) fall in pulmonary wedge pressure (33 +/- 6 to 17 +/- 2 mm Hg; p less than 0.05). Stroke volume increased 39% (23 +/- 3 to 32 +/- 4 ml/m2; p less than 0.05), while peripheral vascular resistance decreased 15% (3331 +/- 363 to 2841 +/- 241 dynes.s.cm-5; p less than 0.05). Heart rate fell from 97 +/- 7 to 76 +/- 3 beats/minute (p less than 0.05) with a nonsignificant decline in mean right atrial pressure (18 +/- 4 to 9 +/- 1 mm Hg). These hemodynamic changes were either sustained or enhanced during period B. Concomitant clinical improvement was also noted. As an agent with potent vasodilatory and antiadrenergic properties, methyldopa permitted a rise in stroke volume by virtue of unloading and possible inhibition of sympathetic activity that led to increased density of beta-adrenergic receptors of the heart (up-regulation). Significant reduction of ventricular filling pressure was attributed to venodilation and probable improved diastolic function. In selected patients with severe congestive heart failure, particularly underscored by excessive sympathetic tone, methyldopa may be considered as an alternative agent to improve cardiac performance and clinical symptomatology.

Aged↗
PubMed2001

Pharmacokinetic study of methyldopa in aorta-coarctated rats using a microdialysis technique.

The pharmacokinetics of methyldopa (12.5, 25 and 50 mg kg(-1), i.p.) was studied in anesthetized sham-operated (SO) and abdominal aorta-coarctated (ACo) rats using a microdialysis technique. A non-linear relationship between the area under the curve (AUC) and dose was observed in SO rats. However, in ACo rats the AUC showed a proportional increase with dose. Abdominal aortic coarctation produced significant differences in the estimates of clearance (Cl) and the elimination rate constant from the dialysate (K(ed)) after the administration of 50 mg kg(-1)of methyldopa (K(ed)SO, 0.31 +/- 0.09; ACo, 0.66 +/- 0.09(*)h(-1): Cl SO, 30.8 +/- 10.1; ACo, 78.6 +/- 13.3(*)mlkg(-1)min(-1);n= 6,(*)P< 0.05 vs SO). In conclusion, this study, by using a microdialysis technique, suggests that abdominal aortic coarctation seems to produce changes in the pharmacokinetics of methyldopa in rats.

Animals↗
PubMed1991

Risk of serious morbidity associated with hydralazine versus methyldopa treatment in hypertensive patients.

The medical records of patients presenting to the Hammersmith Hospital hypertension clinic between 1971 and 1981 were examined to determine presenting clinical data, treatment regimes, and both cardiovascular and non cardiovascular mortality and morbidity. When compared with 1004 patients receiving treatment other than hydralazine 310 patients on hydralazine had a significantly higher risk of developing renal disease (RR = 2.71) in men, and severe weight loss in women (RR = 3.06). Renal disease risk also tended to be high in women on hydralazine (RR = 1.95) compared with all other treatments, but this was not statistically significant and could be explained by poorer renal function and significantly higher untreated blood pressure in the hydralazine treated group at presentation. The 422 patients who were treated with methyldopa but not hydralazine had similar risk factors for cardiovascular disease compared with a group of 167 who received hydralazine but not methyldopa. Comparisons of event rates failed to find significant differences in morbidity or mortality between these two groups. The age adjusted male mortality was 14/1000 patient years on hydralazine and 12/1000 on methyldopa and 13/1000 and 6/1000 years for women respectively. There was no evidence of an increased risk of either renal disease (RR = 0.3 in men, RR = 0.3 in women) on hydralazine or weight loss (RR = 0.7 in men, RR = 1.6 in women), with similar presenting data. Systemic lupus erythematosus was a rare complication (2 of 314) of treatment with hydralazine.

Cardiovascular Diseases↗
PubMed1981

Reduction of menopausal hot flushes by methyldopa. A double blind crossover trial.

In a double-blind study, methyldopa was shown to be significantly more effective than placebo in reducing menopausal hot flushes. The median reduction in the number of hot flushes was 38% with placebo and 65% with methyldopa. The active metabolite of methyldopa, alpha-methylnoradrenaline, is an alpha 2-adrenoceptor agonist. Since the alpha 2-adrenoceptor agonist clonidine also reduces hot flushes, while the alpha 2-adrenoceptor antagonist yohimbine produces flushes, it is speculated that menopausal hot flushes might result from a reduced stimulation of alpha 2-adrenoceptors, probably in the CNS.

Climacteric↗
PubMed1985

The pharmacokinetics of alpha-methyldopa in dogs.

alpha-Methyldopa was intraarterially and orally administered to dogs at two dose levels in a randomized complete crossover design. The appearance of secondary peaks in the plasma concentration-time profiles indicated the presence of enterohepatically recycled methyldopa. This was established by the absence of a secondary peak following readministration of a dose after biliary cannulation and the detection of methyldopa in the bile of a cannulated dog. Enterohepatic recirculation was estimated to account for a mean of 16.2% of the area under the plasma concentration-time profile after intraarterial administration. Total systemic clearance, defined as the sum of elimination by all routes from the general circulation of the administered dose, and corrected for enterohepatic recirculation, averaged (+/- SD) 99.4 +/- 24.6 ml/min in the dog. An extended average apparent terminal half-life of 6.0 +/- 5.2 hr was exhibited after oral administration compared to an average half-life of 3.1 +/- 1.8 hr following intraarterial administration. Elimination kinetics were linear in the dose range studied. Oral plasma concentration data suggest that the apparent bioavailable fraction may be dose dependent.

Administration, Oral↗
PubMed1990

A comparison of no medication versus methyldopa or labetalol in chronic hypertension during pregnancy.

Three hundred women with mild chronic hypertension at 6 to 13 weeks' gestation were randomly allocated to receive either methyldopa or labetalol or be in the control group. Thirty-seven women (12%) were excluded for various reasons. Of the remaining 263 patients, 90 received no drug, 87 received methyldopa, and 86 received labetalol. All 263 were followed throughout pregnancy with serial renal function tests and serial assessment of fetal status. There were no differences among the three groups in mean systolic or diastolic blood pressures, mean gestational age, or initial laboratory findings at time of entry. Patients treated with medications had significantly lower (p less than 0.0001) systolic and diastolic blood pressures throughout gestation compared with the no-medication group. Among the control group there was a spontaneously significant lowering (p less than 0.0001) of both systolic and diastolic blood pressures at 14 to 26 weeks' gestation. However, there were no differences among the three groups regarding the incidences of either superimposed preeclampsia (15.6%, 18.4%, and 16.3%, respectively), abruptio placentae (2.2%, 1.1%, and 2.3%, respectively), or preterm delivery (10%, 12.5%, and 11.6%, respectively). In addition, there were no differences among the groups regarding gestational age at delivery, birth weight, incidence of fetal growth retardation, or neonatal head circumference. There was one midtrimester loss in the methyldopa group and one stillbirth in each of the other groups. We conclude that treatment of maternal blood pressure in mild chronic hypertension during pregnancy did not improve perinatal outcome.

Adult↗