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At least 19 recordsLinked to original sources
PubMed1975

Plasma concentration of alpha-methyldopa and sulphate conjugate after oral administration of methyldopa and intravenous administration of methyldopa and methyldopa hydrochloride ethyl ester.

The plasma concentrations of free alpha-methyldopa and methyldopa sulphate conjugate were measured in 7 hypertensive patients with normal renal function following alpha-methyldopa (1 g) orally. Five of these patients subsequently received alpha-methyldopa ethyl ester (250 mg) (methyldopate) intravenously and two further patients received 250 mg of alpha-methyldopa intravenously. After oral administration a large amount of total plasma alpha-methyldopa was present as sulphate conjugate. There were wide interindividual differences in the ratio of free: conjugated alpha-methyldopa in plasma (ratio at 4 hours ranged from 3.73-0.83) suggesting that individual differences in the extent of sulphate conjugation may occur. There was no close correlation between the degree of conjugation and the fall in arterial pressure. At all time intervals examined, plasma concentrations were higher following intravenous alpha-methyldopa than alpha-methyldopate. The plasma concentration of alpha-methyldopa (free and esterified) 60 minutes after i.v. alpha-methyldopate was 1.7+/-0.3 mug/ml while at the same time after the same dose of methyldopa by the same route the mean concentration was 5.9 mug/ml. Although small amounts of sulphate conjugate were detected after i.v. alpha-methyldopate, insignificant quantities of conjugate were found after i.v. alpha-methyldopa. The average fall in mean arterial pressure was 27 mm/Hg following i.v. alpha-methyldopa but only 2.7 mm Hg following alpha-methyldopate. These results suggest that sulphate conjugation of alpha-methyldopa occurs in the gastrointestinal tract during absorption. Hydrolysis of alpha-methyldopa ethyl ester does not appear to be instantaneous and pharmacokinetic differences between the ester and free alpha-methyldopa have been demonstrated.

Administration, Oral↗
PubMed1978

The combined use of L-alpha-methyldopa hydrazine and methyldopa in the treatment of hypertension.

1. The combined use of alpha-methyldopa and L-alpha-methyldopa hydrazine (a peripheral decarboxylase inhibitor) has been studied, in a double-blind cross-over comparison, with alpha-methyldopa and L-alpha-methyldopa hydrazine placebo in the treatment of eight patients with essential hypertension. 2. L-alpha-methyldopa hydrazine did not enhance the antihypertensive effect of alpha-methyldopa. This suggests that because methyldopa can inhibit its own decarboxylation, peripheral decarboxylation is not an important metabolic pathway for methyldopa and elevated brain levels of methyldopa do not necessarily result in elevated brain levels of methyldopamine.

Adult↗
PubMed1978

Alpha-methyldopa and drug fever. A study of the metabolism of alpha-methyldopa in patients and normal subjects.

The metabolism of alpha-methyldopa was studied in 5 patients with febrile reactions to the drug, and compared with the metabolism in 5 patients without such reactions and in 4 normal subjects. A depression of the drug metabolism was found in drug fever patients, which may affect either the intestinal mucosal conjugation of the drug or the hepatic transformation. The decreased metabolism is assumed to be a possible causative mechanism of the adverse reaction.

Adult↗
PubMed1979

Electrophysiologic properties of methyldopa in man.

There is little information on the effects of methyldopa on the human conduction system. His bundle ECGs were obtained in 11 patients before and after the intravenous infusion of 100 mg of methyldopa. Antegrade refractory periods were obtained with the extrastimulus method. The significant results were as follows: the sinus rate was 71 +/- 4 beats per minute before, and 65 +/- 3 beats per minute after methyldopa (P less than 0.01). The mean A-H interval at a paced rate of 120 beats per minute was 113 +/- 14 msec before, and 135 +/- 18 msec after, methyldopa (P less than 0.05). The mean atrioventricular nodal functional refractory period was 430 +/- 23 msec before and 452 +/- 24 msec after methyldopa administration (P less than 0.001). The mean effective refractory period was 385 +/- 29 msec before, and 388 +/- 27 msec after methyldopa (P less than 0.01). The sinus node recovery time in the control state was 989 +/- 55 msec and 1102 +/- 66 msec after methyldopa infusion (P less than 0.05). Thus, methyldopa can impair conduction through the atrioventricular node and depress the sinus node.

Adult↗
PubMed1977

Atenolol, methyldopa, and chlorthalidone in moderate hypertension.

Combined treatment with low doses of different drugs is widely used for moderate hypertension. The effects of atenolol and methyldopa at two dose levels and in combination at the lower doses were studied in patients with moderate hypertension on continuous treatment with moderate hypertension on continuous treatment with chlorthalidone. The mean reduction in standing blood pressures obtained with atenolol 150 and 300 mg/day was about 27/17 mm Hg and with methyldopa 750 and 1500 mg/day about 28/14 mm Hg. Combined treatment with atenolol 150 mg/day and methyldopa 750 mg/day for four weeks resulted in a reduction of 38/25 mm Hg. No difference was observed between the two doses of methyldopa. The lower dose of atenolol was better than the lower dose of methyldopa in reducing lying and standing diastolic blood pressures. These findings show that in patients on continuous treatment with chlorthalidone the addition of atenolol alone or methyldopa alone or of atenolol and methyldopa in combination is effective in the treatment of moderate hypertension.

Adrenergic beta-Antagonists↗
PubMed1976

Methyldopa and propranolol or practolol in moderate hypertension.

The effect of a low dose of methyldopa combined with (a) a non-selective and (b) a selective beta-adrenoceptor antagonist was studied in a double-blind crossover trial in 24 carefully selected patients with moderate hypertension (mean initial lying blood pressure 189/117 mm Hg). Each patient received methyldopa 750 mg/day, propranolol 240 mg/day, practolol 600 mg/day, methyldopa 750 mg/day combined with propranolol 240 mg/day, methyldopa 750 mg/day combined with practolol 600 mg/day, and placebo for four weeks each according to a random sequence. After four weeks of therapy the most effective treatment, methyldopa combined with propranolol, reduced lying and standing blood pressures by 36-5/21-4 mm Hg and 44-7/25 mm Hg respectively. Thic combination had similar effects to those of the combination of methyldopa with the cardioselective agent practolol except that it reduced lying diastolic pressure further. The combination was more effective than either treatment alone. No significant differences were found between the effects of propranolol, practolol, or methyldopa at the doses used.

Adult↗
PubMed1977

Peripheral vascular actions of alpha-methyldopa in the dog.

The aim of these study was to investigate peripheral vascular actions of alpha-methyldopa. The following experimental procedures were used: hind-limb of the dog perfused with the animals own blood or with Krebs solution; nictitating membrane of the dog; isolated and perfused segments of the saphenous vein of the dog; superfused strips of the saphenous vein of the dog. In these preparations, effects of alpha-methyldopa on responses elicited by electrical stimulation and on release of 3H-noradrenaline were studied. In dogs pretreated with alpha-methyldopa (200 mg/kg, i.v., 36, 24 and 4 hr before the experiment) contractions of the nictitating membrane caused by cervical sympathetic electrical stimulation were markedly reduced: however, the frequency--response curve to stimulation in the hind-limb and responsiveness to noradrenaline were not significantly different of controls. Perfusion of the hind-limb with Krebs containing alpha-methyldopa (2.2 mM) resulted in a significant reduction of perfusion pressure responses to lumbar sympathetic electrical stimulation with augmented responsiveness to exogenous noradrenaline. Similar results were obtained in in vitro experiments. Effects of alpha-methyldopa were not prevented by cocaine nor by inhibition of decarboxylase by Ro 4-4602 (D,L-serine,2-(2,3,4-,trihydroxybenzyl) hydrazine hydrochloride). Alpha-methyldopa depresses the release of tritiated compounds evoked by electrical stimulation, in saphenous vein strips. This suggests that inhibition of transmitter release could be an important factor to understand peripheral actions of alpha-methyldopa.

Animals↗
PubMed1976

Antihypertensive efficacy of a single bedtime dose of methyldopa.

To compare the antihypertensive efficacy of methyldopa administered once at bedtime with the same total dose given three times daily, a double-blind crossover study was performed in 14 patients previously well controlled on methyldopa. Each patient received a total daily dose of 0.37 gm, 0.75 gm, or 1.5 gm of methyldopa, depending on the dose of drug that had previously been successful in that individual. The trial design included either 12 wk of methyldopa three times daily (TID) followed by 12 wk of single daily bedtime (HS) doses of methyldopa or administration of drug in the reverse order. Supine and erect blood pressures were recorded 4 times daily (8 a.m., 12 noon, 4 p.m., and 8 p.m.) every 4 wk throughout the study. Blood pressure control was excellent in all patients whether the drug was administered three times daily or at bedtime. Systolic pressures were slightly lower at 8 a.m., when methyldopa was given at bedtime than on doses three times daily, and systolic and diastolic pressures were slightly higher at 8 p.m. that at 8 a.m. on the bedtime regimen.

Aged↗
PubMed1978

[The combination of methyldopa with pindolol in the treatment of hypertension (author's transl)].

32 patients with moderate or severe hypertension (16 men and 16 women, aged 32--75 years) were treated with alpha-methyldopa (daily dose: 750 mg) + placebo for 2 weeks, then with alpha-methyldopa + pindolol (15--45 mg daily) for 12 weeks. These patients had been under alpha-methyldopa monotherapy before the trial with unsatisfactory results. The simultaneous administration of alpha-methyldopa and pindolol considerably decreased the systolic and diastolic blood pressure, both sitting and standing, and the heart rate. The combination of methyldopa and pindolol was significantly more effective than methyldopa alone.

Adult↗
PubMed1975

Effect of alpha-methyldopa on dopamine synthesis and release in rat striatum in vitro.

The effect of alpha-methyldopa and alpha-methyldopamine (alpha-MDA) on the rate of hydroxylation of radioactive tyrosine was studied in striatal slices from rat brain. This was done by measuring the formation of 3-H-H2O as well as the accumulation of 3-H-dopamine (3-H-DA) from L-3, 5-3-H-tyrosine. alpha-Methyldopa, at tissue concentrations similar to those found in vivo after systemic administration, produced a decrease in both 3-H-H2O and 3-H-DA. The marked decrease (91thyldopa injection, also inhibited 3-H-H2O formation. The inhibitory effect of alpha-methyldopa on 3-H-H2O formation was not reduced by the addition of brocresine, which prevents the formation of alpha-MDA. The effects of alpha-methyldopa and alpha-MDA on the release of 3-H-DA that had been taken up into brain slices, was also studied. Although alpha-methyldopa, 1000 muM, did not increase the release of 3H-DA from tissue, alpha-MDA did. However, the latter was more potent in inhibiting 3-H-H2O formation from 3-H-tyrosine than in releasing 3-H-DA. These results, as well as the close similarity between the percent reduction of 3-H-H2O formation and tissue 3-H-DA levels, suggest that alpha-methyldopa decreases tissue levels of dopamine by inhibiting tyrosine hydroxylase activity in DA neurons.

Animals↗
PubMed1977

Role of central and peripheral mechanisms in the action of alpha-methyldopa on blood pressure and renin secretion.

The mechanism by which alpha-methyldopa lowers arterial pressure and suppresses renin secretion was investigated in pentobarbital-anesthetized dogs in which changes in renal perfusion pressure were prevented by adjusting a suprarenal aortic clamp. After intravenous alpha-methyldopa (100 mg/kg) mean arterial pressure (MAP) decreased form 127+/-3 to a mean minimum of 107+/-4 mm Hg (P less than .01) and plasma renin activity (PRA) decreased from 20.6+/-4.8 to 10.9+/-1.7 ng/ml/3 hr (P less than .05). Blockade of peripheral dopa decarboxylase with intravenous carbidopa (20 mg/kg) significantly attenuated the hypotensive action of intravenous alpha-methyldopa but MAP still decreased from 145+/-6 to 130+/-5 mm Hg(P less than .001). Intravenous carbidopa completely abolished the fall in PRA produced by intravenous alpha-methyldopa (16.8+/-2.8 to 16.9+/-2.1 ng/ml/3 hr.) Intraventricular carbidopa (3 microng/kg/min) did not block the hypotensive (135+/-8 to 113+/-7 mm Hg, P less than .01) or renin-lowering effect (24.3+/-5 to 13.4+/-3.2 ng/ml/3 hr, P less than .01) of intravenous alpha-methyldopa (0.5 mg/kg decreased MAP from 118 +/- 5 to 104 +/- 5 mm Hg (P less than 0.001) but had no effect on PRA (23.4+/-6 TO 19.4+/-7 NG/ML/3 hr.) Intraventricular alpha-methylnorepinephrine (2 microng/kg) also decreased MAP from 127+/-5 to 112+/-3mm Hg (P less than .006) but again failed to significantly alter PRA (36.1+/-11.8 to 37.2+/-15 ng/ml/3 hr). These results indicate that there is both a central and peripheral component to the antihypertensive effect of alpha-methyldopa in the dog and that the suppression of renin secretion results from a peripheral action of the drug.

Animals↗
PubMed1979

Central hypotensive action of alpha-methyldopa: an iontophoretic study in the cat.

The central site and mechanism of alpha-methyldopa-induced hypotension were examined with the microiontophoretic technique which permits the topical application of drugs to single neurons of the bulbar vasomotor center in decerebrate cats. Cardiovascular neurons were identified by their response to an increase in arterial blood pressure following a small intravenous pressor dose of norepinephrine. Microiontophoretic application of alpha-methyldopa was found to have an inhibitory effect on the spontaneous firing rate of cardiovascular neurons. Furthermore, alpha-methyldopa was found to completely block the excitatory response of cardiovascular neurons to iontophoretically applied norepinephrine. Non-cardiovascular neurons, recorded from the same brain area, were unaffected by iontophoretic application of alpha-methyldopa at the same or greater doses that produced responses in cardiovascular neurons. While peripheral factors cannot be entirely ruled out, the present findings are contrary to the postulate that alpha-methyldopa lowers arterial blood pressure by stimulating central alpha-adrenoceptors, causing a reduction of sympathetic outflow to the periphery. Rather, the data indicate that alpha-methyldopa or its metabolites act directly on central alpha-adrenoceptors in a manner which results in reduced activity.

Action Potentials↗
PubMed1979

Selective stimulation of central alpha-autoreceptors following treatment with alpha-methyldopa and FLA 136.

1. The accumulation of normetanephrine in the rat brain induced by the monoamine oxidase inhibitor nialamide was inhibited following alpha-methyldopa and 4-amino-3-(2,6-dichlorobenzylidenehydrazino)-1,2,4-triazole (FLA 136). It was not changed following alpha-methylmetatyrosine despite a greater disappearance of noradrenaline than after alpha-methyldopa. The alpha-adrenoreceptor blocking agent yohimbine increased the nialamide-induced accumulation of normetanephrine and completely antagonized the actions of alpha-methyldopa and FLA 136, indicating that the effects of the two drugs are due to stimulation of alpha-adrenoreceptors. 2. The flexor reflex activity of spinalized rats was not influenced by alpha-methyldopa and alpha-methylmetatyrosine at the doses used in the biochemical experiments, as previously found for FLA 136, indicating no stimulation of classical, postsynaptic, central alpha-adrenoreceptors. 3. The biochemical effects of alpha-methyldopa and FLA 136 might be caused by stimulation of alpha-autoreceptors on the cell bodies and the nerve terminals of noradrenaline neurons. A similar mechanism might be involved in the hypotension reported by other investigators following these drugs.

Adrenergic alpha-Agonists↗
PubMed1976

Comparative study of metoprolol and alpha-methyldopa in untreated essential hypertension.

The hypotensive actions of metoprolol and alpha-methyldopa have been compared in 37 men with previously untreated essential hypertension; 36 belonged to stage 1 and 1 to stage 2 of the WHO classification. After four weeks of placebo treatment the patients were randomly allocated to treatment with either of the two drugs. Treatment was started with metoprolol 75 mg daily or alpha-methyldopa 375 mg and was doubled after eight weeks. Satisfactory blood pressure control was defined as systolic blood pressure below 160 mm Hg and diastolic below 95 mm Hg. The patients were examined every four weeks and in those with unsatisfactory control the dose was gradually increased up to a maximum daily dose of metoprolol 450 mg or alpha-methyldopa 2250 mg. The trial lasted for 24 weeks after randomization. Five patients dropped out of the study. After six months, satisfactory blood pressure control was recorded in 16 out of 17 patients and 14 out of 15 patients treated with metoprolol and alpha-methyldopa, respectively. The average reduction in blood pressure produced by the two drugs was comparable. One patient in the alpha-methyldopa group developed drug exanthema and two patients a positive Coombs' test. Other side effects were few and did not differ between the two compounds.

Blood Pressure↗
PubMed1979

The effects of desmethylimipramine on the pharmacological actions of alpha methyldopa in man.

The effect of pretreatment with the tricyclic antidepressant desmethylimipramine (DMI) 75 mg daily for 3 days on the action of oral methyldopa 750 mg was investigated in a double blind crossover design in volunteers. DMI pretreatment caused a small but not significant increase in supine systolic and diastolic blood pressure and heart rate. However, the effects of methyldopa on lying and standing blood pressure and heart rate were not markedly altered by pretreatment. In particular, the fall in standing blood pressure after methyldopa was present with and without DMI and the sedative action of methyldopa was similar. DMI alone reduced saliva production. No evidence was found that tricyclic antidepressant drugs significantly modify the hypotensive effect of methyldopa in man.

Adult↗
PubMed1978

Methyldopa-induced pancreatitis.

An acute febrile illness associated with gastrointestinal upset developed in a patient within one week after starting treatment with methyldopa. The illness was characterized by prompt subsidence of symptoms when the patient withdrew therapy secondary to gastrointestinal upset, and recrudescence of symptoms when methyldopa therapy was reinitiated. This was associated with hyperamylasemia, hyperlipasemia, hyperpyrexia, and epigastric pain, both on admission to the hospital and upon rechallenge with methyldopa. Although gastrointestinal upset has been reported as an untoward side effect of methyldopa, this is the first report to our knowledge of documented methyldopa-induced hyperamylasemia and hyperlipasemia secondary to pancreatitis.

Amylases↗