Methyldopa
(British Approved Name, US Adopted Name, rINN)
Drug Nomenclature
International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):
USAN: Methyldopa
Pharmacopoeias. In China, Europe, International, Japan, and US.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Methyldopa). Colourless or almost colourless crystals or a white to yellowish-white crystalline powder. Slightly soluble in water; very slightly soluble in alcohol; freely soluble in dilute mineral acids. Protect from light.
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Methyldopa). A white to yellowish-white odourless fine powder which may contain friable lumps. Sparingly soluble in water; slightly soluble in alcohol; practically insoluble in ether; very soluble in 3N hydrochloric acid. Protect from light.
Methyldopate Hydrochloride
(British Approved Name Modified, US Adopted Name, rINNM)
Drug Nomenclature
Pharmacopoeias. In British and US.
British Pharmacopoeia, 2008 (Methyldopate Hydrochloride). A white or almost white, odourless or almost odourless, crystalline powder. Freely soluble in water, in alcohol, and in methyl alcohol; slightly soluble in chloroform; practically insoluble in ether. A 1 % solution in water has apH of 3.0 to 5.0. Protect from light.
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Methyldopate Hydrochloride). A white or almost white, odourless or almost odourless, crystalline powder. Freely soluble in water, in alcohol, and in methyl alcohol; slightly soluble in chloroform; practically insoluble in ether. A 1 % solution in water has a pH of between 3.0 and 5.0. Store at a temperature of 25°, excursions permitted between 15° and 30°.
Incompatibility. A haze developed over 3 hours when methyldopate hydrochloride 1 mg/mL was mixed with amphotericin B 200 micrograms/mL in glucose; crystals were produced with methohexital sodium 200 micrograms/mL in sodium chloride, and a haze developed when they were mixed in glucose. A crystalline precipitate occurred with tetracycline hydrochloride 1 mg/mL in glucose, and with sulfadiazine sodium 4 mg/mL in glucose or sodium chloride.
Adverse Effects
The adverse effects of methyldopa are mostly consequences of its pharmacological action. The incidence of adverse effects overall may be as high as 60% but most are transient or reversible. Drowsiness is common, especially initially and after an increase in dosage. Dizziness and lightheadedness may be associated with orthostatic hypotension; nausea, headache, weakness and fatigue, and decreased libido and impotence have also been reported quite often. The mental and neurological effects of methyldopa have included impaired concentration and memory, mild psychoses, depression, disturbed sleep and nightmares, paraesthesias, Bell’s palsy, involuntary choreoathetotic movements, and parkinsonism. As well as orthostatic hypotension, methyldopa is often associated with fluid retention and oedema, which responds to diuretics but may rarely progress to heart failure. Angina pectoris may be aggravated. Bradycar-dia, syncope, and prolonged carotid sinus hypersensitivity have been reported. Intravenous methyldopate has been associated with a paradoxical rise in blood pressure.
Methyldopa may produce gastrointestinal disturbances including nausea and vomiting, diarrhoea, constipation, and rarely pancreatitis and colitis. A black or sore tongue, and inflammation of the salivary glands, have occurred, and dry mouth is quite common. A positive Coombs’ test may occur in 10 to 20% of all patients on prolonged therapy but only a small proportion develop haemolytic anaemia. Thrombocytopenia and leucopenia, notably granulocytopenia, have occurred and warrant prompt withdrawal. Other hypersensitivity effects have included myocarditis, fever, eosinophilia, and disturbances of liver function. Hepatitis may develop, particularly in the first 2 or 3 months of therapy, and is generally reversible on stopping, but fatal hepatic necrosis has occurred. Antinuclear antibodies may develop and cases of a lupus-like syndrome have been reported.
Other adverse effects that have been reported in patients taking methyldopa include rashes, lichenoid and granulomatous eruptions, toxic epidermal necrolysis, a flu-like syndrome (of fever, myalgia, and mild arthralgia), nocturia, uraemia, nasal congestion, and retroperitoneal fibrosis. Hyperprolactinaemia may occur, with breast enlargement or gynaecomastia, galactorrhoea, and amenorrhoea.
Methyldopa may occasionally cause urine to darken on exposure to the air because of the breakdown of the drug or its metabolites.
Effects on the blood. An analysis of drug-induced blood dyscrasias reported to the Swedish Adverse Drug Reaction Committee for the 10-year period 1966 to 1975 showed that haemolytic anaemia attributable to methyldopa had been reported on 69 occasions and had caused 3 deaths. This represented the vast majority of all the reports of drug-induced haemolytic anaemia. However, the actual incidence of haemolytic anaemia in patients receiving methyldopa is quite low; data from the Boston Collaborative Drug Surveillance Program indicated that only 2 of 1067 patients receiving methyldopa developed haemolytic anaemia, an incidence of about 0.2%. The proportion of patients with a positive Coombs’ test is much higher, being variously reported at 10 to 20%. It has been suggested that the high incidence of autoantibody formation may be due to inhibition of suppressor T-cells by methyldopa while the relatively low incidence of resultant haemolysis may be due to drug-associated impairment of the reticuloendothelial system which would normally clear the antibody-sensitised cells from the circulation.
Effects on the gastrointestinal tract. COLITIS. There has been a report of 6 cases of colitis associated with methyldopa. An auto-immune mechanism was proposed.
DIARRHOEA. Severe chronic diarrhoea was associated with methyldopa over periods of 2 and 7 years; it stopped in both cases on withdrawal of the drug.
PANCREATITIS. Increases in serum- and urinary-amylase activity accompanied by fever and suggestive of pancreatitis were associated with methyldopa in 2 patients, one of whom had symptoms of severe pancreatitis. Symptoms reappeared on rechallenge in both patients. A further report of acute pancreatitis in a patient who had recently begun methyldopa therapy (with a diuretic) also confirmed a recurrence of symptoms on rechallenge. In contrast to the acute form, chronic pancreatitis is not generally attributable to drug use. However, a case of florid chronic pancreatitis, with exocrine and endocrine insufficiency and heavy calcification over 30 months, associated with 2 periods of methyldopa treatment, has been reported. Symptoms in this patient, who was also receiving a thiazide, included severe diabetic ketoacidosis.
Effects on the heart. Sudden death in a number of patients receiving methyldopa has been associated with myocarditis (often with hepatitis and pneumonitis). The effect is thought to be due to hypersensitivity. Hypersensitivity myocarditis is generally marked by ECG changes, a slight rise in cardiac enzymes, cardiomegaly, and persistent sinus tachycardia, along with peripheral blood eosinophilia, and most patients will recover within days if the drug is withdrawn in time.
Effects on the liver. In a report of 6 cases of hepatitis in patients taking methyldopa, including a review of 77 cases from the literature, most patients presented with symptoms including malaise, fatigue, anorexia, weight loss, nausea, and vomiting, and histopathological changes resembling those of viral hepatitis. Fever occurred in 28 of the 83 patients; rashes and eosinophilia occurred rarely. Symptoms usually began 1 to 4 weeks after the first dose of methyldopa. Clinically apparent jaundice occurred as early as 1 week and as late as 3 years after the start of therapy, although only 6 or 7 patients presented with jaundice later than 3 months. Liver damage was not dose-related and had features suggestive of an immunologically-mediated hypersensitivity reaction. The histological changes included chronic active hepatitis, massive fatal necrosis, and cirrhosis. In a further analysis of 36 patients with liver damage due to methyldopa, hepatic injury tended to occur in 2 phases — acute and chronic. Acute damage developed within a few months of starting treatment, and was considered to be an allergic reaction to methyldopa metabolites. The chronic form usually occurred at least a year after starting methyldopa, and was characterised by an accumulation of fat in the liver. Recovery after withdrawal of methyldopa was directly related to duration of exposure and degree of liver damage. There was also a suggestion of genetic predisposition, as acute methyldopa-induced liver damage occurred in 4 members of a family. Idiosyncratic metabolism of methyldopa in susceptible patients may be responsible for expression of an antigen on the surface of liver cells with which circulating antibodies react. See also Fever, below.
Effects on mental function. Anecdotal reports have implicated methyldopa in disturbances of mental acuity including inability to concentrate, impaired calculating ability, and forgetfulness. These have been confirmed to some extent by psychometric studies. Impaired verbal but not visual memory has been reported in 10 patients receiving methyldopa with a diuretic. A crossover study in 16 patients also indicated impairment of cognitive function by methyldopa.
Effects on the nervous system. Involuntary choreoathetotic movements resembling those of Huntington’s chorea began in a 59-year-old man with cerebrovascular disease after an increase of his methyldopa dose from 1 to 1.5 g daily. He recovered when the drug was withdrawn. In another report methyldopa was associated with the development of bilateral choreiform movements in a patient without cerebrovascular disease but with chronic renal failure.
Effects on sexual function. Methyldopa has been associated with numerous cases of sexual dysfunction. In males failure to maintain erection, decreased libido, impaired ejaculation, and gynaecomastia have occurred, while in females decreased libido, painful breast enlargement, and delayed or absent orgasm have been reported. The reported incidence varies and there is some evidence that sexual dysfunction may be underreported: while only 2 of 30 men receiving methyldopa spontaneously reported erection failure the actual incidence on questioning was 16 of 30.
Fever. In a report of 78 cases of methyldopa-induced fever, fever occurred 5 to 35 days after the first exposure to methyldopa in 77 patients and one day after recommencing methyldopa in the remaining patient. Rigors, headache, and myalgia were common accompanying symptoms, but eosinophilia and skin rashes were not seen. The majority of patients did not appear seriously ill, but 4 patients presented with symptoms of septic shock. Biochemical evidence of liver damage was found in 61% of patients but jaundice was uncommon. In the majority of patients, symptoms were relieved within 48 hours of stopping the drug.
Lupus erythematosus. The incidence of antinuclear antibodies was 13% in 269 hypertensive patients taking methyldopa (irrespective of other medication), compared with 3.8% in 448 hypertensive patients not taking methyldopa. However, methyldopa-induced lupus has been reported only rarely.
Overdosage. Ingestion of methyldopa 2.5 g produced coma, hypothermia, hypotension, bradycardia, and dry mouth in a 19-year-old man. His serum-methyldopa concentration 10 hours after ingestion was 19.2 micrograms/mL compared with serum concentrations of about 2 micrograms/mL in patients receiving therapeutic doses of methyldopa. He recovered after treatment with intravenous fluids.
Retro peritonea I fibrosis. A 60-year-old patient developed retroperitoneal fibrosis and a positive direct Coombs’ test associated with methyldopa given in a daily dose of 750 mg with ben-droflumethiazide 2.5 mg for about 5 years.
Treatment of Adverse Effects
Withdrawal of methyldopa or reduction in dosage causes the reversal of many adverse effects. If overdosage occurs, the benefit of gastric decontamination is uncertain, but patients who present within 1 hour may be given activated charcoal. Treatment is largely symptomatic, but if necessary, intravenous fluid infusions may be given to promote urinary excretion, and vasopressors given cautiously. Atropine may be given for bradycardia. Severe hypotension may respond to placing the patient in the supine position with the feet raised. Methyldopa is dialysable.
Precautions
Methyldopa should be used with caution in the elderly, and in patients with hepatic or renal impairment or with a history of haemolytic anaemia, liver disease, or depression. Care is also advisable in patients with parkin-sonism. It should not be given to patients with active liver disease or depression and it is not recommended for phaeochromocytoma.
It is advisable to make periodic blood counts and to perform liver function tests at intervals during the first 6 to 12 weeks of treatment or if the patient develops an unexplained fever. Patients taking methyldopa may produce a positive response to a direct Coombs’ test; if blood transfusion is required, prior knowledge of a positive direct Coombs’ test reaction will aid cross-matching.
Methyldopa may cause sedation; if affected, patients should not drive or operate machinery.
Breast feeding. Methyldopa is distributed into breast milk in small amounts. In a study of 3 breast-feeding women, concentrations of free methyldopa in the breast milk were found to be between 19 and 30% of those in the plasma after a 500-mg dose. Detectable levels were found in the plasma of only 1 infant and adverse effects were seen in none. It was estimated that the amount of methyldopa a breast-fed infant would receive would be about 0.02% of the maternal dose. In another study over a 3-month period no adverse effects were found in a breast-feeding infant whose mother was taking methyldopa, although the drug was detectable in the infant’s urine. The American Academy of Pediatrics considers that methyldopa is therefore usually compatible with breast feeding.
Porphyria. Methyldopa has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.
Pregnancy. Methyldopa is commonly used in the management of hypertension during pregnancy. There is little evidence of adverse effects on fetal development. However, it crosses the placenta and reduced blood pressure has been reported in infants born to mothers receiving the drug. There has also been a report of tremor in 7 infants associated with maternal methyldopa use in pregnancy. Depressed noradrenaline concentrations in the CSF were noted in the 3 infants examined leading to successful treatment of the other 4 infants with atropine: tremor was abolished in 2 and substantially reduced in the other 2.
Interactions
The hypotensive effects of methyldopa are potentiated by diuretics, other antihypertensives, and drugs with hypotensive effects. However, there have been reports of paradoxical antagonism of the hypotensive effects by tricyclic antidepressants, antipsychotics, and beta blockers. Sympathomimetics may also antagonise the hypotensive effects.
There may be an interaction between methyldopa and MAOIs and care is required if they are given together. Caution is also needed with catechol-O-methyltransferase inhibitors, such as entacapone, since they might reduce the metabolism of methyldopa. Patients receiving methyldopa may require lower doses of general anaesthetics.
Alpha blockers. Urinary incontinence occurred when methyldopa was given wilhphenoxybenzamine in a patient who had undergone bilateral lumbar sympathectomy.
Antipsychotics. Antipsychotics may enhance the hypotensive effects of methyldopa but a paradoxical increase in blood pressure has also been reported. A woman with SLE taking trifluoperazine up to 15 mg daily and prednisone up to 120 mg daily was given methyldopa up to 2 g and triamterene for high blood pressure. Her blood pressure rose further to 200/140 mmHg. After stopping trifluoperazine blood pressure returned to 160/100 mmHg.
In another report, 2 patients with essential hypertension who had been taking methyldopa for 3 years and 18 months respectively developed symptoms of dementia within days of taking haloperidol for anxiety. In both patients the symptoms resolved rapidly on stopping haloperidol.
Cephalosporins. A pustular pruritic eruption occurred after use of cefazolin by a patient taking methyldopa. A previous similar case involved use of cefradine with methyldopa.
Digoxin. Syncope associated with carotid sinus hypersensitivity has been reported to be possibly enhanced by methyldopa in a patient taking digoxin and chlortalidone. In another report, sinus bradycardia developed in 2 patients taking methyldopa and digoxin.
Iron. After results in healthy subjects indicated that the absorption of methyldopa was reduced by 73% and 61% respectively when taken with a dose of ferrous sulfate or ferrous gluconate, 5 hypertensive patients taking methyldopa were also given ferrous sulfate 325 mg three times daily for 2 weeks. All patients experienced a rise in systolic pressure, and 4 had a rise in diastolic pressure, amounting to more than 15/10 mmHg in some patients after 2 weeks. Blood pressure fell again when the ferrous sulfate was stopped.
Levodopa. For reference to a mutual interaction between methyldopa and levodopa, see Antihypertensives, under Levodopa, Interactions.
Lithium. For reference to the development of lithium toxicity when given with methyldopa.
Sympathomimetics. A 31-year-old man whose hypertension was well controlled with methyldopa and oxprenolol suffered a severe hypertensive episode when he took a preparation containing phenylpropanolamine for a cold.
Pharmacokinetics
After oral use methyldopa is variably and incompletely absorbed, apparently by an amino-acid active transport system. The mean bioavailability has been reported to be about 50%. It is extensively metabolised and is excreted in urine mainly as unchanged drug and the O-sulfate conjugate. It crosses the blood-brain barrier and is decarboxylated in the CNS to active alpha-methylnoradrenaline.
The elimination is biphasic with a half-life of about 1.7 hours in the initial phase; the second phase is more prolonged. Clearance is decreased and half-life prolonged in renal impairment. Plasma protein binding is reported to be minimal. Methyldopa crosses the placenta; small amounts are distributed into breast milk.
Uses and Administration
Methyldopa is an antihypertensive that is thought to have a mainly central action. It is decarboxylated in the CNS to alpha-methylnoradrenaline, which is thought to stimulate alpha2 adrenoceptors resulting in a reduction in sympathetic tone and a fall in blood pressure. It may also act as a false neurotransmitter, and have some inhibitory actions on plasma renin activity. Methyldopa reduces the tissue concentrations of dopamine, noradrenaline, adrenaline, and serotonin.
Methyldopa is used in the management of hypertension, although other drugs with fewer adverse effects are generally preferred. Methyldopa may, however, be the treatment of choice for hypertension in pregnancy. Oedema and tolerance sometimes associated with methyldopa therapy may be reduced when it is given with a thiazide diuretic.
Methyldopa is given orally as the sesquihydrate, but doses are usually expressed in terms of anhydrous methyldopa. Methyldopa sesquihydrate 1.13 g is equivalent to about 1 g of anhydrous methyldopa. For hypertensive crises, methyldopa has been given intravenously as methyldopate hydrochloride.
When methyldopa is given orally its effects reach a maximum in 4 to 6 hours after a single dose, although the maximum hypotensive effect may not occur until the second or third day of continuous treatment; some effect is usually apparent for 48 hours after withdrawal of methyldopa. When given intravenously the hypo-tensive effect may be obtained within 4 to 6 hours and last for 10 to 16 hours. It lowers the standing, and to a lesser extent the supine, blood pressure.
In hypertension, the usual initial adult oral dose is 250 mg of methyldopa two or three times daily for 2 days; this is then adjusted, not more frequently than every 2 days according to response, up to a usual maximum dose of 3 g daily. The usual maintenance dosage is 0.5 to 2 g of methyldopa daily. In the elderly an initial dose of 125 mg twice daily has been used; this dose may be increased gradually if necessary, but should not exceed 2 g daily.
An initial dose for children is 10 mg/kg daily in 2 to 4 divided doses, increased as necessary to a maximum of 65 mg/kg or 3 g daily, whichever is less.
Preparations
British Pharmacopoeia, 2008: Methyldopa Tablets; Methyldopate Injection;
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Methyldopa and Chlorothiazide Tablets; Methyldopa and Hydro-chlorothiazide Tablets; Methyldopa Oral Suspension; Methyldopa Tablets; Methyldopate Hydrochloride Injection.
Single-ingredient Preparations
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.
Argentina: Aldomet; Dopagrand; Dopatral; Australia: Aldomet; Aldopren¤; Hydopa; Nudopa¤; Austria: Aldometil; Presinol¤; Belgium: Aldomet; Presinol¤; Brazil: Aldomet; Aldotensin; Angimet; Cardin¤; Cardiodopa; Dimipress; Dopametil; Ductomet; Etildopanan; Kindomet; Metilbio; Metilcord; Metilprod; Pressodopa; Tensioval; Tildomet; Canada: Aldomet¤; Dopamet¤; Novo-Medopa¤; Nu-Medopa; Chile: Aloset; Czech Republic: Dopegyt; Denmark: Aldomet; Dopamet¤; France: Aldomet; Equibar¤; Germany: Aldometil¤; Dopegyt; Presinol¤; Presinol; Sembrina¤; Greece: Aldomet; Hong Kong: Aldomet; Dopamet; Dopegyt; Hungary: Dopegyt; India: Alphadopa; Dopagyt; Ireland: Aldomet; Dopagen¤; Dopamet¤; Elanpres¤; Meldopa; Israel: Aldomin; Italy: Aldomet; Elanpress¤; Medopren; Presinol¤; Malaysia: Aldomet¤; Dopamet¤; Dopegyt; Mexico: Aldomet; Amender; Biotenzol¤; Ehlindopa¤; Hipten¤; Medopal¤; Prodop; Pulsoton¤; Selm; Tenzone¤; Toparal; Yuremetil D¤; Netherlands: Aldomet; Sembrina¤; Norway: Aldomet; Dopamet¤; Medopal¤; New Zealand: Aldomet¤; Prodopa; Portugal: Aldomet; Russia: Dopegyt (Допегит); South Africa: Aldomet; Alphamex¤; Arcanadopa¤; Hy-Po-Tone; Normopress; Pharmet¤; Sinepress¤; Singapore: Dopegyt; Spain: Aldomet; Sweden: Aldomet; Dopamet¤; Switzerland: Aldomet; Dopamet¤; Thailand: Aldomet; Dopamed; Dopasian; Dopegyt; Isomet; Medopa; Medopate¤; Mefpa; Metpata; Servidopa¤; Siamdopa; United Kingdom: Aldomet; Dopamet¤; Medomet¤; Metalpha¤; United States: Aldomet¤; Venezuela: Aldomet; Alfadopan; Almepan
Multi-ingredient Preparations
Argentina: Normatensil; Austria: Aldoretic; Brazil: Hydromet; Canada: Aldoril¤; Apo-Methazide; Novo-Doparil¤; PMS-Dopazide¤; Supres¤; Germany: Caprinol¤; Sali-Presinol¤; Sembrina-Saltucin¤; Greece: Hydromet¤; Ireland: Hydromet¤; Italy: Aldotride¤; Medozide; Saludopin; Netherlands: Hydromet¤; Portugal: Aldoretic; South Africa: Aldoretic¤; Hydromet¤; Spain: Hydromet¤; Picten¤; Sweden: Hydromet¤; Switzerland: Aldoretic¤; United Kingdom: Hydromet¤; United States: Aldoclor; Aldoril
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