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PubMed1980

Drug metabolism and liver function after methyldopa withdrawal.

1 The effects of methyldopa withdrawal on liver function and drug metabolism were investigated in ten elderly females suffering from the drug-induced orthostatic reaction and resistant hypertension. 2 There was a significant increase in serum albumin level, antipyrine metabolism and urinary excretion of D-glucaric acid 6 months after the methyldopa withdrawal. 3 The results suggest that patients treated with methyldopa might show a reduced metabolizing ability in spite of normal liver function tests.

Age Factors↗
PubMed1982

Oxprenolol, methyldopa and lipids in diabetes mellitus.

1 Twelve-week courses of oxprenolol and methyldopa were administered in a randomised, double-blind cross over study to ten insulin dependent hypertensive diabetics. 2 Prior to treatment, and at the end of each period of drug administration, fasting levels of high density lipoprotein, triglycerides, free fatty acids and cholesterol were measured. 3 Neither preparation altered levels of high density lipoprotein and cholesterol, but both drugs significantly reduced the free fatty acids. 4 Whereas oxprenolol did not alter triglyceride levels, methyldopa significantly elevated triglycerides above pre-treatment values. 5 Oxprenolol does not appear to influence lipoprotein fractions affecting the relative risks of coronary heart disease, but methyldopa seems to have potentially detrimental effects of triglyceride levels.

Adult↗
PubMed1983

The absorption and conjugation of methyldopa in patients with coeliac and Crohn's diseases during treatment.

The absorption and elimination of a single 500 mg dose of methyldopa has been studied after oral administration to 10 normal volunteers, 10 patients with coeliac disease, who were on a gluten-free diet, and to five patients with Crohn's disease. In patients with Crohn's disease the percentage of the dose recovered in urine (24%) was about one-half of normal (50%). This decreased absorption was associated with reduced plasma concentrations of both free and conjugated methyldopa and a decreased pharmacological response. In patients with coeliac disease the percentage of dose recovered in urine (43%) was similar to normals, indicating a normal absorption of the drug. However, the plasma concentrations of both free and conjugated methyldopa were significantly higher than normal, although there was no increase in drug-related effects. These findings confirm the importance of using indices other than drug plasma concentrations in the assessment of bioavailability in disease states.

Adult↗
PubMed1984

Chronic effects of metoprolol and methyldopa on calf blood flow in intermittent claudication.

In a placebo-controlled double-blind study 14 hypertensive patients with intermittent claudication were treated with metoprolol (100-200 mg daily) and methyldopa (500-1000 mg daily) for 3 weeks and their effects on heart rate, blood pressure as well as on resting and hyperaemic calf blood flow and vascular resistance were compared. In their antihypertensive effect metoprolol and methyldopa did not differ significantly. In 23 diseased limbs the calf blood flow and vascular resistance remained unchanged at rest during the trial. The active drugs reduced hyperaemic flow (P less than 0.05). The peak flow was reduced by 20% (P greater than 0.01) with metoprolol and by 15% with methyldopa below the initial level and by 17% and by 12% below the level recorded on placebo, respectively. Neither of the drugs influenced vascular resistance during reactive hyperaemia. Thus, in patients with intermittent claudication antihypertensives should be used with care.

Adult↗
PubMed1981

Adrenaline depletion in the hypothalamus of the rat after chronic alpha-methyldopa.

1. Individual anterior hypothalamic-preoptic nuclei were dissected from the brains of control and alpha-methyldopa treated (2 x 40 mg/kg, 5 days) rats, and the concentrations of adrenaline and other catecholamines were estimated. 2. By a combination of radioenzymatic assay and paper chromatography the concentrations of adrenaline, noradrenaline, dopamine, alpha-methylnoradrenaline and alpha-methyldopamine were determined concurrently in the same sample. 3. alpha-Methyldopa reduced the adrenaline levels of the hypothalamic nuclei by 47--68% of control concentrations. 4. A differential displacement of the parent catecholamines was observed and the depletions were ranked: adrenaline less than dopamine less than noradrenaline. 5. alpha-Methylnoradrenaline and alpha-methyldopamine were found in all hypothalamic nuclei. 6. The depletion of hypothalamic adrenaline by alpha-methyldopa could represent a pharmacological mechanism contributing to the antihypertensive action of the drug.

Animals↗
PubMed1977

Plasma O-methyldopa in levodopa-induced dyskinesias. A bioclinical investigation.

The peripheral metabolism of Dopa has been studied in correlation with the clinical occurrence of Leyodopa-induced dyskinesias in Parkinson patients. Within the group of patients treated with a peripheral decarboxylase inhibitor (PDI), the combination of all the plasma levels of O-Methyldopa from patients with dyskinesias shows significantly higher values than those from patients without dyskinesias. For Dopa itself, no significant differnece can be detected. Such high O-Methyldopa levels seem to be due to a progressive accumulation of this compound and not to a higher degree of formation. In contrast, no significantly different Dopa or O-Methyldopa levels are found within the group of patients treated with L-Dopa alone. These results are discussed in relation to some of the suspected mechanisms involved in Levodopa-induced dyskinesias.

Aged↗
PubMed1996

Intestinal absorption studies on peptide mimetic alpha-methyldopa prodrugs.

Two dipeptide mimetic prodrugs, 1 and 2, and two tripeptide mimetic prodrugs, 3 and 4, of L-alpha-methyldopa were evaluated for intestinal absorption by in-situ single pass rat jejunal perfusion studies and by in-vitro uptake experiments in brush-border membrane vesicles (BBMVs) prepared from rat intestine. In the perfusion studies, compound 1 demonstrated a 3.5-fold increase in permeability (Pm* = 2.27) as compared with that of alpha-methyldopa (Pm* = 0.65), indicating that this prodrug was better absorbed in the intestine than its parent drug. Other prodrugs showed no significant improvement in intestinal permeability. The results correlated with the results of BBMV uptake studies. In the presence of an inward proton gradient, compound 1 showed Michaelis-Menton saturable kinetics of BBMV uptake with a low value of K(m) (0.06 +/- 0.13 mM) and a high value of Vmax/K(m)(36.38 nmol (mg protein)-1/30s mM-1) at a low concentration range and a linear uptake at high concentrations with Kd = 0.14 +/- 0.02 mM. Compounds 2 and 3 were mainly taken up in BBMVs via passive diffusion. Compound 4 was taken up in BBMVs basically via the carrier-mediated transport system, while the rate of uptake was much lower than that of compound 1. The uptake of compounds 1 and 4 was significantly inhibited by dipeptides L-Gly-L-Pro and L-Gly-L-Phe, and cephradine, a beta-lactam known to be transported via the dipeptide carrier system, indicating that both compounds were taken up in BBMVs via the H(+)-coupled dipeptide-mediated transport system. In contrast to the complicated uptake profile of alpha-methyldopa, the higher rate of BBMV uptake with less variation demonstrated on compound 1 suggested that the attached nonessential amino acid moiety, D-phenylglycine, is a feasible delivery tool in carrying the parent drug through the intestine.

Animals↗
PubMed1971

A within-patient comparison of debrisoquine and methyldopa in hypertension.

In a titrated dose cross-over trial of debrisoquine and methyldopa in 38 hypertensive patients neither drug was superior in lowering supine or standing diastolic pressure with a minimum of side effects. Methyldopa caused significantly greater reduction of supine (P<0.001) and standing (P<0.02) systolic pressure but caused intolerable side effects in two patients. Tiredness was the most characteristic and troublesome side effect with methyldopa and postural hypotension was prominent in patients while on debrisoquine.

Adolescent↗
PubMed1974

Methyldopa liver damage.

Twenty patients are described in whom liver damage appeared to be directly related to the administration of methyldopa. Sixteen had hepatitic syndromes from which they recovered on stopping methyldopa; four of these patients had recurrences of jaundice after a second course of the drug. Features suggestive of active chronic hepatitis were found in two patients. There were two deaths attributed to methyldopa, one of these being in a patient with pre-existing undiagnosed macronodular cirrhosis.

Adult↗
PubMed1970

Hypotensive action and side effects of clonidine-chlorthalidone and methyldopa-chlorthalidone in treatment of hypertension.

In an open, randomized, cross-over study the hypotensive action and side effects of clonidine-chlorthalidone and methyldopa-chlorthalidone combinations were compared. The diastolic morning blood pressure could be reduced to 95 mm. Hg or below in significantly more patients with clonidine than with methyldopa. Side effects, however, were more commonly encountered during the clonidine than during the methyldopa phase.

Adult↗
PubMed1981

Plasma sex hormone concentrations in men with hypertension treated with methyldopa and/or propranolol.

Serum concentrations of LH, FSH, testosterone and prolactin were measured in patients with hypertension treated with propranolol (34 cases), methyldopa (13 cases), and methyldopa + propranolol (11 cases). The results were compared with those obtained in 18 controls (hospital out-patients). There were no differences in these hormone concentrations in the various groups, and no difference between those complaining of impotence (13 cases) and those with normal sexual function. Impotence in hypertensive men on treatment with methyldopa cannot be explained by abnormalities in secretion of the reproductive hormones.

Adult↗
PubMed1985

A novel therapeutic approach for reversal of left ventricular hypertrophy and blood pressure control in hypertensive patients treated with alpha-methyldopa or propranolol.

A recently added goal in the control of primary hypertension is the reversal of left ventricular hypertrophy which may occur early in the disease and which can have serious consequences. We have attempted to define the hemodynamic parameters which distinguish most sensitively between the long-term effects of two antihypertensive drugs, alpha-methyldopa and propranolol, with a view to determining the optimal conditions under which each of the drugs may be used therapeutically. Twenty matched hypertensive patients, all with established left ventricular hypertrophy, were divided at random into two groups who received either alpha-methyldopa or propranolol as monotherapy. Dosage was titrated until blood pressures were normalized (diastolic blood pressure (DBP) less than or equal to 95 mmHg) (1 mmHg = 133.322 Pa); then therapy was maintained for 48-52 weeks. Supine and erect blood pressures, heart rates, and eight echocardiographic indices were recorded before commencement of therapy and at the 48- to 52-week period. Stepwise discriminant analysis identified erect DBP, erect heart rate, and posterior wall thickness of the left ventricle as being the parameters which distinguished most clearly the therapeutic effects of the chosen drugs. Using these three parameters, all 20 patients were correctly classified into their respective drug groups. We propose that these results may form the basis of a more rational choice of antihypertensive therapy with alpha-methyldopa or propranolol for hypertensive patients based on the initial determination of these three parameters.

Adult↗
PubMedDate not supplied

The hypotensive activity and side effects of methyldopa, clonidine, and guanfacine.

Clonidine (Catapres, Catapresan), guanfacine (Estulic), and methyldopa (Aldomet) are the prototypes of centrally acting antihypertensive drugs. Clonidine and guanfacine are lipophilic drugs that readily penetrate into the brain, where they stimulate alpha-adrenergic receptors in the pontomedullary region. The stimulation of these central alpha-adrenergic receptors has been shown to activate an inhibiting neuron, which causes a reduction of peripheral sympathetic tone and a subsequent fall in arterial blood pressure and heart rate. Both a centrally initiated reduction of vagus reflex activity and the activation of presynaptic alpha 2-adrenergic blocking agents in the heart may contribute to the bradycardia. Studies indicate that methyldopa also penetrates into the brain, where it is converted into alpha-methylnorepinephrine. This amine may stimulate the same central alpha-adrenergic receptors as those activated by clonidine, which will result in a hypotensive effect. Possibly, alpha-methyldopamine might also play a role. Accordingly, the modes of action of clonidine and alpha-methyldopa probably are very similar at a basic level. The central adrenergic receptors probably are located postsynaptically. Their receptor demand corresponds more closely to that of the alpha 2-subtype. Central alpha 1-adrenergic receptors might possibly play a part in the modulation of vagally induced baroreflex bradycardia. A discussion on the pharmacological basis of the side effects of the centrally acting antihypertensives has been limited to those adverse reactions that are somehow related to alpha-adrenergic receptors. Sedation, a common side effect, appears to be mediated by central alpha 2-adrenergic receptors, at least in animal models.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Effects of methyldopa metabolites on amine transmitters and adrenergic receptors in rat brain.

Studies of catecholamine concentrations in defined nuclei from the anterior hypothalamic-preoptic regions and the medulla oblongata, known to contribute to cardiovascular control, were measured following acute or chronic methyldopa administration. These studies indicated that methyldopa was enzymatically converted to methyldopamine and methylnorepinephrine, and in some areas to methylepinephrine which replaced endogenous epinephrine. The predominant metabolite was methylnorepinephrine, which accumulated in concentrations higher than endogenous norepinephrine levels. (-)Methylnorepinephrine was found to be 6 times more potent and 75 times more selective for alpha 2-adrenergic receptors than (-) norepinephrine, and it is suggested that this alpha 2-adrenergic receptor action, particularly in the nucleus tractus solitarius, contributes to a major part of the antihypertensive effect of methyldopa.

Animals↗
PubMed1979

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

We studied the effect of 3-O-methyl-methyldopa (OMMD), the 3-O-methylated metabolite of the antihypertensive drug methyldopa (alpha-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.

Animals↗
PubMed1982

Minoxidil in severe and moderately severe hypertension, in association with methyldopa and chlortalidone.

Minoxidil is a potent antihypertensive drug widely used in severe arterial hypertension and in that refractory to treatment. Its effectiveness in less severe forms of hypertension was evaluated in 15 patients who had either a severe to moderate arterial hypertension not previously treated, or who did not tolerate the side effects of other antihypertensive drugs. The usefulness of methyldopa and chlortalidone to prevent a potential minoxidil-induced tachycardia and fluid retention, respectively, was also tested. The patients were initially treated with chlortalidone 100 mg/day, and methyldopa 500 mg/day. Minoxidil was then given in increasing doses until the diastolic blood pressure was equal to or inferior to 90 mmHg. This occurred consistently at doses which ranged from 5 to 50 mg/day (average, 29 mg). Treatment with minoxidil was continued for four months; tolerance to the drugs was not observed. Low doses of methyldopa and chlortalidone were effective in controlling the tachycardia and the retention of sodium and water induced by minoxidil. The three associated drugs were well tolerated and the life quality improved in most patients. Hypertrichosis was the most consistent side effect. Two patients were withdrawn from the study after the blood pressure was controlled by minoxidil, because of the appearance of angor in one, and edema and heart failure in the other.

Adult↗
PubMed1977

Comparison of sotalol hydrochloride and methyldopa in essential hypertension.

In a non-blind randomized comparison of sotalol hydrochloride and methyldopa in essential hypertension, the two drugs were equivocal in effect in reaching a preset hypotensive aim, in the maximum decreases from the baseline and in the mean reductions per week from the baseline. Milligram for milligram, sotalol was about twice as potent as methyldopa. No volunteered side-effects were noted for methyldopa; 3/19 for sotalol.

Humans↗
PubMed1982

Hepatitis and hemolytic anemia associated with methyldopa therapy.

The reported incidences of methyldopa-induced hepatitis and hemolytic anemia is notably small; however, practitioners should be aware of its association with these disorders. The mechanisms responsible for these adverse reactions have not been fully explained, but possible multisystem involvement is being recognized. Although the number of reported cases of hepatitis and AIHA seen concurrently in patients on methyldopa is few, one should recognize that the potential for such association does exist. The presence of a single system disorder should alert the practitioner to monitor for other disorders that may result from methyldopa therapy.

Anemia, Hemolytic↗