Methyldopa is a centrally acting hypotensive agent.
Methyldopa is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. However, because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes), current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics).502,1200 Centrally acting agents such as methyldopa may be considered as add-on therapy if goal blood pressure cannot be achieved with the recommended drugs.501,502,503,504,1200 (See Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.) Some experts state that centrally acting agents such as methyldopa generally are reserved as a last-line treatment option because of the drug's ability to cause substantial adverse CNS effects, especially in geriatric patients.1200
IV methyldopate hydrochloride may be used for the management of hypertension when parenteral hypotensive therapy is necessary.
Methyldopa generally is most effective when used with a diuretic. The use of a diuretic may prevent tolerance to methyldopa and permit reduction of methyldopa dosage.122,126,127 Diuretics may also prevent sodium retention and increased plasma volume that may occur after prolonged methyldopa therapy. (See Cautions: Cardiovascular Effects.) Methyldopa also has been used with other antihypertensive agents, permitting a reduction in the dosage of each drug and, in some patients, minimizing adverse effects while maintaining blood pressure control. (See Drug Interactions: Diuretics and Hypotensive Agents.) The possibility that geriatric patients may not tolerate the adverse cognitive effects of centrally acting hypotensive agents such as methyldopa should be considered.126 Methyldopa is generally considered to be safe for use in patients with renal failure.
For additional information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults and also see Uses: Hypertension in Pediatric Patients in the Thiazides General Statement 40:28.20.
Methyldopa has been used effectively for the management of hypertension in pregnant women without apparent substantial adverse effects on the fetus.104,105,106,107,108,126,130,143
The goal of antihypertensive treatment in pregnant women with hypertension is to minimize the acute complications of maternal hypertension while avoiding therapy that would compromise fetal well-being.130 Antihypertensive therapy is recommended in pregnant women with chronic hypertension who have persistent, severely elevated levels of blood pressure (e.g., systolic blood pressure of 160 mm Hg or higher or diastolic blood pressure of 105 mm Hg or higher); it is less clear whether antihypertensive therapy should be initiated in women with mild to moderate chronic hypertension.130,540 The American College of Obstetricians and Gynecologists (ACOG) and other experts currently recommend use of one of several agents (labetalol, nifedipine, or methyldopa) when initiation of antihypertensive therapy is necessary in a pregnant woman.130,502,540 In women who are already receiving antihypertensive therapy prior to pregnancy, ACOG states there are insufficient data to make recommendations regarding the continuance or discontinuance of such therapy; treatment decisions should be individualized in these situations.130 Alternatively, other experts state that women with hypertension who become pregnant should be transitioned to methyldopa, nifedipine, and/or labetalol during pregnancy.1200 Antihypertensive therapy can reduce the risk of severe hypertension but has not been shown to prevent the development of preeclampsia.540 Use of methyldopa in association with careful prenatal management during pregnancy appears to be safe for mother and fetus.106,107,108,109,110,111,126,130,143 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)
IV methyldopate hydrochloride has been used for the management of hypertensive emergencies; however, because of the slow onset of action of this drug, other agents (e.g., labetalol, esmolol, fenoldopam, nicardipine, sodium nitroprusside)502,542,1200 are preferred.
Methyldopa and methyldopate hydrochloride are not recommended for use in patients with pheochromocytoma.
Methyldopa is administered orally; methyldopate hydrochloride is administered by IV infusion. IM or subcutaneous administration of methyldopate hydrochloride is not recommended because of unpredictable absorption.
Methyldopate hydrochloride IV infusions are prepared by adding the required dose of the drug to 100 mL of 5% dextrose injection. Alternatively, the required dose may be administered in 5% dextrose injection in a concentration of 100 mg/10 mL. The IV infusion should be administered slowly over a period of 30-60 minutes. ADD-Vantage® vials labeled as containing 50 mg/mL of methyldopate hydrochloride should be diluted and administered according to the manufacturer's directions. Vials containing solutions of methyldopate hydrochloride for injection and reconstituted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Dosage of methyldopa must be adjusted according to the patient's blood pressure response and tolerance. Adverse effects such as drowsiness may be minimized by starting dosage increases in the evening or by giving a larger dose at bedtime than in the morning. Geriatric patients may respond to smaller doses of methyldopa.
The usual initial oral dosage of methyldopa in adults is 250 mg 2 or 3 times daily for 2 days.600 Dosage may then be increased or decreased at intervals of at least 2 days until an adequate response is achieved.600 The usual maintenance dosage of methyldopa recommended by the manufacturers is 0.5-2 g daily given in 2-4 divided doses; dosages exceeding 3 g daily are not recommended by the manufacturers, although occasionally some patients have responded to such dosages.600 Some experts state that the usual dosage range is 0.25-1 g daily in 2 divided doses;1200 it usually is preferable to add another antihypertensive agent to the regimen than to increase maximum methyldopa dosage beyond 1 g daily because of poor patient tolerance of increasing dosages of the drug.149 In some patients, administration of methyldopa as a single daily dose at bedtime may provide adequate blood pressure control during maintenance therapy.
In children, the usual initial oral dosage of methyldopa is 10 mg/kg daily, given in 2-4 divided doses.600 Dosage is adjusted until an adequate response is achieved.600 The maximum oral dosage in children is 65 mg/kg daily or 3 g daily, whichever is less.600
When methyldopa is administered with other hypotensive drugs, the initial oral dosage in adults should not exceed 500 mg daily in divided doses. Tolerance to methyldopa may occur between the second and third month of therapy and an increase in dosage or concomitant use of a thiazide diuretic may be required to restore effective blood pressure control.
When combination therapy is required, commercially available products containing methyldopa in fixed combination with a thiazide diuretic should not be used initially. Dosage should first be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio in a commercially available fixed-combination preparation, such a product may be used. However, whenever dosage adjustment is necessary, the drugs should be administered separately. If combination therapy is initiated with the fixed-combination preparation, the initial dosage is 250 mg of methyldopa and 15 mg of hydrochlorothiazide given 2 or 3 times daily, or alternatively, 250 mg of methyldopa and 25 mg of hydrochlorothiazide given twice daily. Patients requiring higher dosages of the fixed-combination preparation may receive once-daily administration of 500 mg of methyldopa and 30 mg of hydrochlorothiazide, or alternatively, 500 mg of methyldopa and 50 mg of hydrochlorothiazide.138 When administered with another antihypertensive agent, dosages of hydrochlorothiazide should not exceed 50 mg daily.138
When parenteral drug therapy is indicated, the usual IV dosage of methyldopate hydrochloride in adults is 250-500 mg every 6 hours as required; the maximum dosage is 1 g every 6 hours.601
The usual IV dosage of methyldopate hydrochloride in pediatric patients is 20-40 mg/kg per 24 hours, administered in equally divided doses at 6-hour intervals.601 The maximum IV dosage in children is 65 mg/kg daily or 3 g daily, whichever is less.601 When blood pressure is controlled, oral therapy should be substituted using the same dosage as the parenteral dosage.601
Blood Pressure Monitoring and Treatment Goals
Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., ACE inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200,1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with methyldopa, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200,1216
The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,1201,1207,1209,1222 A 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults, regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200,1207 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220
Patients with impaired renal function may respond to smaller doses of methyldopa.
The most common adverse effect of methyldopa is drowsiness which occurs within the first 48-72 hours of therapy and may disappear with continued administration of the drug. Sedation commonly recurs when dosage is increased. A persistent decrease in mental acuity, including impaired ability to concentrate, lapses of memory, and difficulty in performing simple calculations, may occur and usually necessitates withdrawal of the drug. Other adverse nervous system effects which occur early in therapy include vertigo, headache, asthenia, and weakness.
Adverse CNS effects, which are less common than sedation and decreased mental acuity, include paresthesia, parkinsonism, and Bell's palsy. Involuntary choreoathetotic movements have been reported rarely in patients with severe bilateral cerebrovascular disease and are an indication for discontinuance of the drug. Psychic disturbances including nightmares and reversible mild psychoses or mental depression have also occurred.
Orthostatic hypotension with attendant dizziness, lightheadedness, and symptoms of cerebrovascular insufficiency may occur during methyldopa therapy and is an indication for dosage reduction. Orthostatic hypotension may be less pronounced with methyldopa than with guanethidine or ganglionic blocking agents but may be more severe than with reserpine, clonidine, hydralazine, propranolol, or thiazides. Syncope in older patients may be related to an increased sensitivity to methyldopa and advanced arteriosclerotic vascular disease and may be avoided by using lower dosages.
Bradycardia may occur occasionally in patients receiving methyldopa. Aggravation of angina pectoris, congestive heart failure, and prolonged carotid sinus hypersensitivity have also been reported. Following IV administration of methyldopate hydrochloride, a paradoxical pressor response has been reported. Rebound hypertension has occurred rarely following abrupt withdrawal of oral methyldopa.
Sodium retention resulting in edema and weight gain has been reported in patients receiving methyldopa and can usually be controlled by concomitant administration of a thiazide diuretic. If edema cannot be controlled by diuretics and becomes progressive or leads to congestive heart failure, methyldopa should be discontinued.
Positive direct antiglobulin (Coombs') test results have been reported in about 10-20% of patients receiving methyldopa, usually after 6-12 months of therapy. This phenomenon is dose related, with the lowest incidence in patients receiving 1 g or less of methyldopa daily. In most patients, a positive Coombs' test associated with methyldopa therapy is not clinically important. Reversal of the positive Coombs' test occurs within weeks to months after discontinuance of the drug and usually becomes negative within 6 months. Hemolytic anemia has only rarely occurred, although 2 deaths have been reported in patients with methyldopa-induced hemolytic anemia. If anemia or a positive Coombs' test occurs, appropriate laboratory studies should be performed to determine if hemolysis is present; if there is evidence of hemolytic anemia, the drug should be discontinued. (See Cautions: Precautions and Contraindications.) Discontinuance of the drug alone or initiation of corticosteroid therapy has produced remission of methyldopa-induced hemolytic anemia.
Reversible leukopenia (primarily granulocytopenia) and immune thrombocytopenia have occurred rarely during methyldopa therapy. Methyldopa may cause hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. Positive lupus and rheumatoid factor tests have been reported to result from methyldopa therapy.
Sensitivity Reactions and Hepatic Effects
A major toxic effect of methyldopa is drug-induced fever, usually occurring within 3 weeks after initiation of treatment. In some patients, fever has been associated with an influenza-like illness (i.e., generalized malaise and anorexia). Fever may also be associated with eosinophilia or abnormal liver function test results, such as increased serum concentrations of alkaline phosphatase, aminotransferases, and bilirubin and abnormal prothrombin time. Rarely, reversible jaundice, with or without fever, has been reported, usually within the first 2-3 months of therapy, but occasionally after long-term therapy. In some patients, laboratory tests and liver biopsies have been consistent with cholestasis, hepatitis, hepatocellular injury, or cirrhosis. Hepatic necrosis, which may be fatal, is rare. Hepatic changes may represent hypersensitivity reactions. Methyldopa therapy should be stopped if unexplained fever or jaundice occurs or if liver function test results are abnormal. (See Cautions: Precautions and Contraindications.) If methyldopa is the causative agent, temperature and liver function generally return to normal within a few months after the drug is discontinued.
Eosinophilia, myocarditis, pericarditis, vasculitis, and lupus-like syndrome have been reported as hypersensitivity reactions to methyldopa. Three cases of sialadenitis accompanied by fever have been reported in patients receiving methyldopa; 2 of these patients also had nasal congestion and pharyngitis.
Adverse GI effects including nausea, vomiting, diarrhea, dry mouth, distention, constipation, flatus, and sore or black tongue have been reported during methyldopa therapy. Pancreatitis has also occurred. At least one case of colitis associated with hepatitis has been reported.
Adverse dermatologic effects associated with methyldopa include rash, urticaria, eczema, ulceration of the soles of the feet, hyperkeratosis, and lichenoid eruptions. At least one case of granulomatous nodular skin lesions associated with fever, arthralgia, and myalgia has been reported. Tongue ulcerations with features of lichen planus have occurred.
Nasal congestion occurs commonly in patients receiving methyldopa. Decreased libido and impotence frequently occur in males during therapy with the drug. Breast enlargement, gynecomastia, hyperprolactinemia, lactation, and amenorrhea have been reported rarely in patients receiving the drug. At least one case of retroperitoneal fibrosis may have been caused by methyldopa. Blurred vision, nocturia, and increased BUN and serum amylase concentrations have been reported.
Precautions and Contraindications
When methyldopa is used as a fixed-combination preparation that includes hydrochlorothiazide, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with methyldopa.
When methyldopa therapy is started, hemoglobin, hematocrit, or a red blood cell count should be done and periodic blood counts should be performed during therapy to detect hemolytic anemia. Hepatic function should be determined periodically, especially during the first 6-12 weeks of therapy or whenever unexplained fever occurs. If the need for a blood transfusion occurs in patients receiving methyldopa, prior knowledge of a positive Coombs' reaction will aid in the evaluation of a cross match; therefore, a direct Coombs' test before methyldopa therapy and after 6 and 12 months of therapy may be useful. A positive direct Coombs' test prior to methyldopa therapy is not in itself a contraindication to use of the drug. Patients receiving methyldopa who need a transfusion should have both a direct and an indirect Coombs' test performed. In the absence of hemolytic anemia, usually only the direct Coombs' test will be positive; a positive direct Coombs' test alone will not interfere with typing or cross matching. If both the indirect and direct Coombs' tests are positive, problems with major cross matching may occur and the assistance of an expert in this area may be required.
If anemia or a positive Coombs' test occur during methyldopa therapy, appropriate laboratory studies should be performed to determine if hemolysis is present; if there is evidence of hemolytic anemia, the drug should be discontinued. The anemia usually remits promptly; if not, corticosteroids may be given and other causes of anemia should be considered and investigated. If the hemolytic anemia is related to methyldopa, therapy with the drug should not be reinstituted. Similarly, if unexplained fever, abnormal liver function test results, or jaundice occurs during methyldopa therapy, the drug should be discontinued; if these effects are caused by the drug, methyldopa therapy should not be reinstituted.
Patients who are receiving methyldopa and who undergo dialysis may occasionally become hypertensive after the dialysis, since the drug is dialyzable.
Patients should be warned that methyldopa may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). Rarely, involuntary choreoathetotic movements have occurred during methyldopa therapy in patients with severe bilateral cerebrovascular disease; if these effects occur, the drug should be discontinued.
Commercially available formulations of methyldopate hydrochloride may contain sulfites, which can cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.
Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction and is not recommended for use in patients with pheochromocytoma. Methyldopa is contraindicated in patients with active hepatic disease, such as acute hepatitis and active cirrhosis, and in patients in whom previous methyldopa therapy was associated with liver abnormalities or direct Coombs' positive hemolytic anemia. Methyldopa is contraindicated in patients receiving monoamine oxidase (MAO) inhibitors.123,124,125 Methyldopa is also contraindicated in patients who are hypersensitive to the drug or any ingredient in its formulation.
There have been no well-controlled studies to date using oral or IV preparations of methyldopa in pediatric patients.123,124 Dosage recommendations in children are based on published literature concerning use of methyldopa in hypertensive pediatric patients.123,124 The manufacturer states that safety and efficacy of preparations containing methyldopa in fixed combination with hydrochlorothiazide in pediatric patients have not been established.125,131 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Mutagenicity and Carcinogenicity
Methyldopa was not mutagenic in the Ames test and did not increase chromosomal aberration or sister chromatid exchanges in Chinese hamster ovary cells; the in vitro studies were performed both with and without metabolic activation.114
In a 2-year study, there was no evidence of tumorigenic effect when methyldopa was given to mice at dosages up to 1800 mg/kg daily (30 or 2.5 times the maximum human daily dosage when compared on the basis of body weight or body surface area, respectively) or to rats at dosages up to 240 mg/kg daily (4 or 0.6 times the maximum human daily dosage when compared on the basis of the body weight or body surface area, respectively).114
Pregnancy, Fertility, and Lactation
Reproduction studies in mice, rabbits, and rats using oral methyldopa in dosages of 1000, 200, and 100 mg/kg, respectively, have not revealed evidence of harm to the fetus.114 These dosages are 16.6, 3.3, and 1.7 times, respectively, the maximum daily human dosage when compared on the basis of body weight and 1.4, 1.1, and 0.2 times, respectively, the maximum daily human dosage when compared on the basis of body surface area.114
Methyldopa has been used for many years in the management of hypertension in pregnant women, and the drug is generally considered safe for mother and fetus when used in association with careful prenatal management.106,107,108,109,110,111,117,126,130,540 Uteroplacental blood flow and fetal hemodynamics have been reported to be stable during therapy with the drug. Although no teratogenic effects have been reported, the possibility that methyldopa may cause fetal injury (e.g., secondary to reduced placental blood flow or fetotoxicity) cannot be excluded.117
In neonates born to women treated with methyldopa, systolic blood pressure may be decreased during the first 2-3 days after delivery;112 in some neonates, tremors have also been reported.113 Studies to date, including a long-term follow-up study, of children born to women who received methyldopa during pregnancy have not revealed evidence of substantial adverse effects of the drug on the offspring;104,105,106,107,108,114,117,129 however, in the longest follow-up study, treatment with methyldopa was associated with a smaller head circumference (without an apparent effect on intelligence quotient) in male offspring of those women whose therapy was initiated between 16 and 20 weeks' gestation.107,114,123,125,131 At 4 years of age, the developmental delay commonly seen in children born to hypertensive mothers was less evident in those whose mothers received methyldopa during pregnancy than in those whose mothers were untreated.123,125,131 Children born to mothers receiving methyldopa scored consistently higher on indices of intellectual and motor development than children born to untreated hypertensive mothers; however, these differences were not apparent by 7.5 years of age.123,125,131
Methyldopa should be used during pregnancy only when clearly needed. In addition, excessive reduction in blood pressure should be avoided, and a conservative approach to treatment generally should be followed.117,126,130 (See Hypertension during Pregnancy under Uses: Hypertension.)
Reproduction studies in male and female rats using methyldopa dosages of 100 mg/kg daily (1.7 times or 0.2 times the maximum recommended daily human dosage when compared on the basis of body weight or body surface area, respectively) have not revealed evidence of impaired fertility.114,123,125,131 However, in male rats given 200 mg/kg daily (3.3 or 0.5 times the maximum daily human dosage when compared on the basis of body weight or body surface area, respectively) or 400 mg/kg daily (6.7 or 1 times the maximum daily human dosage on the basis of body weight or body surface area, respectively), there were decreases in sperm count, sperm motility, number of late spermatids, and male fertility index.114,123,125
Since methyldopa is distributed into milk, the drug should be used with caution in nursing women; the possibility of adverse effects on a nursing infant cannot be excluded. The extent to which methyldopa distributes into milk has not been clearly established, but the amount of drug a nursing infant would ingest is believed to be too small to be clinically important; however, if a woman receiving methyldopa breastfeeds, the infant (particularly if preterm) should be monitored for potential systemic effects of the drug (e.g., decreased respiration, blood pressure, or alertness).103
Diuretics and Hypotensive Agents
When methyldopa is administered with diuretics or other hypotensive agents, the hypotensive effect of methyldopa may be increased. This effect is usually used to therapeutic advantage, but careful adjustment of dosage is necessary when these drugs are used concomitantly.
Patients receiving methyldopa and phenothiazines or tricyclic antidepressants should be monitored for a possible reduction in hypotensive effect. Although methyldopa has been used with haloperidol and chlorpromazine to treat patients with schizophrenic disorder, nonschizophrenic patients have developed symptoms such as psychomotor retardation, memory impairment, and inability to concentrate when haloperidol was added to methyldopa therapy; these symptoms disappeared when haloperidol was discontinued.
Methyldopa and monoamine oxidase inhibitors are not to be used concomitantly.123,124,125
Patients receiving lithium carbonate have developed signs and symptoms of lithium toxicity when methyldopa was added to their therapy. Therefore, patients receiving the drugs concomitantly should be monitored for lithium toxicity and therapy with the drugs adjusted accordingly.
Methyldopa should be used with caution in patients receiving levodopa, since an additive hypotensive effect may occur. In addition, methyldopa can cause toxic CNS effects such as psychosis if administered concomitantly with levodopa.
Results of one cross-over study in healthy adults indicate that concomitant administration of a single oral dose of ferrous sulfate (325 mg) or ferrous gluconate (600 mg) can decrease oral absorption of methyldopa (500 mg) by 61-73%.116 In addition, concomitant administration of these oral iron preparations appears to affect metabolism of methyldopa since there was a 79-88% decrease in urinary excretion of free methyldopa and an increase in urinary excretion of the sulfate conjugate of the drug.116 When oral ferrous sulfate therapy (325 mg every 8 hours) was initiated in a group of hypertensive patients receiving chronic methyldopa therapy (250 mg 1-3 times daily or 500 mg 3 times daily), there was an increase in blood pressure during concomitant therapy and a decrease in blood pressure when the oral iron preparation was discontinued.116 Therefore, at least one manufacturer states that concomitant administration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended.138
Patients receiving methyldopa may require reduced doses of general anesthetics; if hypotension occurs during anesthesia, the manufacturers state that vasopressor drugs are usually effective. In patients receiving methyldopa, norepinephrine should be administered cautiously, beginning with small doses, since the magnitude and duration of the pressor response to norepinephrine may be enhanced. Theoretically, the effect of ephedrine may be reduced in methyldopa-treated patients, since methyldopa reduces the quantity of norepinephrine in sympathetic nerve endings and ephedrine activity is due to an indirect effect resulting in release of norepinephrine. Clinically, methyldopa treatment has decreased the mydriasis produced by topical ephedrine. Theoretically, amphetamines may increase sympathetic activity and result in a decrease in the hypotensive effect of methyldopa.
Patients receiving methyldopa may develop positive direct antiglobulin (Coombs') tests. (See Cautions: Precautions and Contraindications.)
Methyldopa may interfere with measurement of creatinine by the alkaline picrate method and AST (SGOT) by colorimetric methods. Interference with spectrophotometric methods for AST analysis has not been reported. Although methyldopa has been reported to interfere with measurement of uric acid by the phosphotungstate method, a recent study indicated that interference occurs only with concentrations of the drug that are several times higher than therapeutic concentrations.
Methyldopa causes fluorescence in urine samples at the same wavelengths as catecholamines and, therefore, may cause a false report of elevated urinary catecholamines. The drug does not interfere with measurement of vanillylmandelic acid (VMA) by methods which convert VMA to vanillin.
In the modified Watson-Schwartz test for porphobilinogen, the urine of patients receiving methyldopa produces a characteristic equal distribution of a pink or red color between the aqueous and butanol layers. Rarely, when urine is exposed to air, it may darken because of breakdown of methyldopa or its metabolites. Alkaline urine containing iron and methyldopa or its metabolites has been reported to darken immediately on exposure to air.
The oral LD50 of methyldopa exceeds 1.5 g/kg in mice and rats.114 The IV LD50 of methyldopate hydrochloride in mice is 321 mg/kg.
Overdosage with methyldopa may produce acute hypotension associated with excessive sedation, weakness, bradycardia, dizziness, lightheadedness, constipation, GI distention, flatus, diarrhea, nausea, and vomiting. A few patients have received 6 g of methyldopa daily without adverse effects.
Treatment of methyldopa overdosage generally involves symptomatic and supportive care. If ingestion of methyldopa is recent, gastric lavage or emesis may reduce absorption. Management of overdosage includes keeping the patient supine and symptomatic treatment with monitoring of the cardiac rate and output, blood volume, electrolyte balance, GI motility, renal function, and cerebral activity. Some experts suggest that keeping the patient supine and adequately hydrated with infusion of IV fluids should reverse most of the hypotension; if these measures are inadequate, norepinephrine or dopamine may be used with caution. (See Drug Interactions: Other Drugs.) Methyldopa is dialyzable. Infusion of IV fluids may promote urinary excretion of the drug.
The mechanism of the hypotensive action of methyldopa has not been fully elucidated, but probably is predominantly due to an effect on the CNS. Methyldopa is decarboxylated to form α-methylnorepinephrine in the CNS, where it lowers arterial pressure by stimulation of central inhibitory α-adrenergic receptors. Reduction of plasma renin activity (PRA) may also contribute to the hypotensive effect of methyldopa. In one study, the drug decreased PRA and blood pressure in patients with moderate to severe hypertension and normal PRA, and in hypertensive patients with renal failure. In another study, blood pressure decreased but there was no effect on PRA in low or normal renin hypertensive patients receiving methyldopa.
Methyldopa inhibits the decarboxylation of dihydroxyphenylalanine (dopa)the precursor of norepinephrineand of 5-hydroxytryptophan (5-HTP)the precursor of serotoninin the CNS and in most peripheral tissues. Although the drug's major hypotensive effect is not attributed to decarboxylase inhibition nor to any other effect on peripheral sympathetic nerves or their mediators, some contribution by peripheral mechanisms cannot be ruled out.
Although reports are conflicting, the hypotensive effect of methyldopa is generally attributed to a decrease in total peripheral resistance with little change in cardiac output and heart rate. However, one study has shown that chronic oral administration of methyldopa reduces blood pressure mainly by decreasing cardiac output with little change in total peripheral resistance. Results of another study indicated that short-term oral administration of the drug in hypertensive patients with congestive heart failure may also decrease cardiac output. Although methyldopa has a somewhat greater hypotensive effect when the patient is standing, blood pressure is also significantly reduced in the supine position. The drug may cause postural hypotension. (See Cautions: Cardiovascular Effects.)
Renal blood flow and glomerular filtration rate are unchanged or increased in patients receiving methyldopa. Methyldopa causes sodium and water retention. Tolerance to the hypotensive effect develops during prolonged therapy, especially if a diuretic is not administered concurrently. Methyldopa increases serum prolactin concentrations.
Methyldopa is partially absorbed from the GI tract. The degree of absorption varies among individuals and in the same patient from day to day, but generally about 50% of an oral dose is absorbed. Plasma concentrations of methyldopa generally do not correlate with therapeutic effect. Following oral administration of methyldopa, peak plasma concentrations of the drug occur in approximately 3-6 hours. Mean plasma concentrations of the drug 3 hours after a 750-mg dose are approximately 3.4 mcg/mL. The maximum decrease in blood pressure occurs in 4-6 hours after oral administration of methyldopa. Once an adequate oral dosage level is attained, optimum blood pressure response occurs in 12-24 hours in most patients. After withdrawal of the drug, blood pressure usually returns to pretreatment levels within 24-48 hours.
Methyldopate hydrochloride is hydrolyzed in the body to form methyldopa; hydrolysis is somewhat delayed. The mean plasma concentration of methyldopa 60 minutes after IV administration of 250 mg of methyldopate hydrochloride is approximately 1.7 mcg/mL. After IV administration of methyldopate hydrochloride, the hypotensive effect begins in 4-6 hours and lasts 10-16 hours.
Methyldopa and its metabolites are weakly bound to plasma proteins.
Animal studies indicate that the drug crosses the blood-brain barrier. Methyldopa crosses the placenta in humans.101,102 Methyldopa is distributed into milk;101,103 peak milk concentrations of free methyldopa are approximately 20-35% of those in maternal plasma following an individual dose during continuous therapy.103 The extent of distribution of methyldopa into milk has not been clearly determined, but it is estimated that about 0.02% of a daily maternal dose of 1 g would be ingested by a nursing infant and that this amount is probably not clinically important.103
Plasma concentrations of methyldopa decline in a biphasic manner; in patients with normal renal function, 95% of the drug is eliminated during the initial phase with a plasma half-life of 1.8 hours; the second phase is much slower. Renal clearance of the drug is decreased in patients with renal insufficiency. In patients with severely impaired renal function, about 50% of the drug is excreted during the initial phase with a half-life of 3.6 hours.
Methyldopa is extensively metabolized mainly to the conjugate, methyldopa mono- O -sulfate, probably in the GI tract and the liver. Conjugation occurs to a greater extent when the drug is given orally than when it is given IV. The sulfate conjugate of methyldopa may be therapeutically active. There is wide interindividual difference in the ratio of free to conjugated methyldopa in the plasma. The rate of conjugation of methyldopa is decreased in patients with renal insufficiency. Unchanged methyldopa and its conjugates are the major constituents found in plasma and urine, but small amounts of decarboxylated derivatives have also been identified.
Methyldopa is excreted in urine largely by glomerular filtration, primarily unchanged and as the mono- O -sulfate conjugate. Delayed excretion and accumulation of this metabolite occur in patients with renal insufficiency and may cause an increased hypotensive effect during methyldopa therapy. Unabsorbed methyldopa is excreted in the feces unchanged. Methyldopa is removed by hemodialysis and peritoneal dialysis.
Methyldopa is a hypotensive agent that is structurally related to the catecholamines and their precursors. Methyldopa occurs as a white to yellowish white, fine powder that may contain friable lumps and is sparingly soluble in water and slightly soluble in alcohol.
Methyldopate hydrochloride, the ethyl ester of the hydrochloride salt of methyldopa, occurs as a white or practically white, odorless or practically odorless, crystalline powder and is freely soluble in water and in alcohol. Methyldopate hydrochloride injection is a sterile solution of the drug in water for injection. Sodium hydroxide is used to adjust the pH of the commercially available injection to 3-4.2. Methyldopate hydrochloride imparts some buffer capacity to IV solutions. When methyldopate hydrochloride injection is diluted with most IV infusion fluids, the resulting solutions generally have a pH of 7 or less, even when alkaline solutions are used.
Methyldopa is decomposed by oxidizing agents. Methyldopa tablets should be stored in tight, light-resistant containers at 15-30°C unless otherwise directed by the manufacturer. Methyldopate hydrochloride injection should be stored at a temperature less than 30°C, preferably at 15-30°C; freezing should be avoided.
Methyldopate hydrochloride injection is stable at pH 3.5-6 for 24 hours in most IV infusion fluids. Exposure to air may accelerate decomposition. Methyldopate hydrochloride should be mixed cautiously with drugs that are poorly soluble in an acidic medium (e.g., sodium salts of barbiturates and sulfonamides) and with drugs that are acid labile. Methyldopate hydrochloride injection has been reported to be physically incompatible with other drugs, but compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific information.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Tablets, film-coated | 250 mg* | ||
500 mg* | Methyldopa Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Tablets, film-coated | 250 mg with Hydrochlorothiazide 15 mg* | ||
250 mg with Hydrochlorothiazide 25 mg* | Methyldopa and Hydrochlorothiazide Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Parenteral | Injection | 50 mg/mL* |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions April 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
101. Jones HMR, Cummings AJ. A study of the transfer of α-methyldopa to the human foetus and newborn infant. Br J Clin Pharmacol . 1978; 6:432-4. [PubMed 728288][PubMedCentral]
102. Jones HMR, Cummings AJ, Setchell KDR et al. A study of the disposition of α-methyldopa in newborn infants following its administration to the mother for the treatment of hypertension during pregnancy. Br J Clin Pharmacol . 1979; 8:433-40. [PubMed 508547][PubMedCentral]
103. White WB, Andreoli JW, Cohn RD. Alpha-methyldopa disposition in mothers with hypertension and in their breast-fed infants. Clin Pharmacol Ther . 1985; 37:387-90. [PubMed 3838502]
104. Kincaid-Smith P, Bullen M, Mills J. Prolonged use of methyldopa in severe hypertension in pregnancy. Br Med J . 1966; 1:274-6. [PubMed 5948099][PubMedCentral]
105. Leather HM, Humphreys DM, Baker P et al. A controlled trial of hypotensive agents in hypertension in pregnancy. Lancet . 1968; 2:488-90. [PubMed 4174507]
106. Redman CWG, Beilin LJ, Bonnar J et al. Fetal outcome in trial of antihypertensive treatment in pregnancy. Lancet . 1976; 2:753-6. [PubMed 61439]
107. Cockburn J, Moar VA, Ounsted M et al. Final report of study on hypertension during pregnancy: the effects of specific treatment on the growth and development of the children. Lancet . 1982; 1:647-9. [PubMed 6121965]
108. Fidler J, Smith V, Fayers P et al. Randomised controlled comparative study of methyldopa and oxprenolol in treatment of hypertension in pregnancy. BMJ . 1983; 286:1927-30. [PubMed 6407638][PubMedCentral]
109. Anon. Treatment of hypertension in pregnancy. Drug Ther Bull . 1982; 20:1-3. [PubMed 7056146]
110. de Swiet M. Antihypertensive drugs in pregnancy. BMJ . 1985; 291:365-6. [PubMed 2861881][PubMedCentral]
111. Lindheimer MD, Katz AI. Current concepts: hypertension in pregnancy. N Engl J Med . 1985; 313:675-80. [PubMed 3894964]
112. Whitelaw A. Maternal methyldopa treatment and neonatal blood pressure. BMJ . 1981; 283:471. [PubMed 6790020][PubMedCentral]
113. Bodis J, Sulyok E, Ertl T et al. Methyldopa in pregnancy hypertension and the newborn. Lancet . 1982; 2:498-9. [PubMed 6125663]
114. Merck & Company. Aldomet® (methyldopa) tablets and oral suspension prescribing information. West Point, PA; 1991 Dec.
116. Campbell N, Paddock V, Sundaram R. Alteration of methyldopa absorption, metabolism, and blood pressure control caused by ferrous sulfate and ferrous gluconate. Clin Pharmacol Ther . 1988; 43:381-6. [PubMed 3356082]
117. National High Blood Pressure Education Program Working Group. National High Blood Pressure Education Program Working Group report on high blood pressure in pregnancy. Am J Obstet Gynecol . 1990; 163:1689-1712.
119. National Heart, Lung, and Blood Institute. NHLBI panel reviews safety of calcium channel blockers. Rockville, MD; 1995 Aug 31. Press release.
120. National Heart, Lung, and Blood Institute. New analysis regarding the safety of calcium-channel blockers: a statement for health professionals from the National Heart, Lung, and Blood Institute. Rockville, MD; 1995 Sep 1.
121. Psaty BM, Heckbert SR, Koepsell TD et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA . 1995; 274:620-5. [PubMed 7637142]
122. Yusuf S. Calcium antagonists in coronary artery disease and hypertension: time for reevaluation? Circulation . 1995; 92:1079-82. Editorial.
123. Merck. Aldomet® (methyldopa) tablets and oral suspension prescribing information. West Point, PA; 1997 Feb.
124. Merck. Aldomet® Ester HCL (methyldopate hydrochloride) injection prescribing information. West Point, PA; 1997 Feb.
125. Merck. Aldoril® (methyldopa-hydrochlorothiazide) tablets prescribing information. West Point, PA; 1997 Feb.
126. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98-4080.)
127. Kaplan NM. Choice of initial therapy for hypertension. JAMA . 1996; 275:1577-80. [PubMed 8622249]
128. Psaty BM, Smith NL, Siscovich DS et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA . 1997; 277:739-45. [PubMed 9042847]
129. Rey E, LeLorier J, Burgess E et al. Report of the Canadian Hypertension Society consensus conference: 3. pharmacologic treatment of hypertensive disorders in pregnancy. CMAJ . 1997; 157:1245-54. [PubMed 9361646][PubMedCentral]
130. ACOG task force on hypertension in pregnancy: hypertension in pregnancy. Washington, DC: American College of Obstetricians and Gynecologists; 2013.
131. Merck & Co. Aldoclor®(methyldopa-chlorothiazide) tablets prescribing information (dated 1996 Oct). In: Physicians' desk reference. 52nd ed. Montvale, NJ: Medical Economics Company Inc; 1998:1590-2.
132. Merck & Co. Aldoclor®(methyldopa-chlorothiazide) tablets prescribing information (dated 1997 Feb). In: Physicians' desk reference. 52nd ed. Montvale, NJ: Medical Economics Company Inc; 1998(Suppl A):A204.
133. Whelton PK, Appel LJ, Espeland MA et al for the TONE Collaborative Research Group. Sodium reduction and weight loss int he treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). JAMA . 1998; 279:839-46. [PubMed 9515998]
134. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension . 2000; 35:1021-4. [PubMed 10818056]
135. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension . 2000; 35:1019-20. [PubMed 10818055]
136. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis . 2000; 36:646-61. [PubMed 10977801]
137. Hansson L, Zanchetti A, Carruthers SG et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet . 1998; 351:1755-62. [PubMed 9635947]
138. Food and Drug Administration. Aldoril (methyldopa/hydrochlorothiazide) tablets [July 23, 1999: Merck]. MedWatch drug labeling changes. Rockville, MD; July 1999. From FDA website ([Web]).
141. Appel LJ. The verdict from ALLHATthiazide diuretics are the preferred initial therapy for hypertension. JAMA . 2002; 288:3039-60. [PubMed 12479770]
142. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA . 2002; 288:2981-97. [PubMed 12479763]
143. National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Report of the National High Blood Pressure Education Program Working Group on high blood pressure in pregnancy. Am J Obstet Gynecol . 2000; 183:S1-22.
147. The Guidelines Subcommittee of the WHO/ISH Mild Hypertension Liaison Committee. 1999 guidelines for the management of hypertension. J Hypertension . 1999; 17:392-403.
149. Carter B for the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High blood Pressure (JNC). Personal Communication.
501. James PA, Oparil S, Carter BL et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA . 2014; 311:507-20. [PubMed 24352797]
502. Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens . 2013; 31:1281-357. [PubMed 23817082]
503. Go AS, Bauman MA, Coleman King SM et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension . 2014; 63:878-85. [PubMed 24243703]
504. Weber MA, Schiffrin EL, White WB et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) . 2014; 16:14-26. [PubMed 24341872]
505. Wright JT, Fine LJ, Lackland DT et al. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med . 2014; 160:499-503. [PubMed 24424788]
506. Mitka M. Groups spar over new hypertension guidelines. JAMA . 2014; 311:663-4. [PubMed 24549531]
507. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: what are the right goals and purposes?. JAMA . 2014; 311:474-6. [PubMed 24352710]
508. Bauchner H, Fontanarosa PB, Golub RM. Updated guidelines for management of high blood pressure: recommendations, review, and responsibility. JAMA . 2014; 311:477-8. [PubMed 24352759]
515. Thomas G, Shishehbor M, Brill D et al. New hypertension guidelines: one size fits most?. Cleve Clin J Med . 2014; 81:178-88. [PubMed 24591473]
523. Fihn SD, Gardin JM, Abrams J et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation . 2012; 126:e354-471.
526. Kernan WN, Ovbiagele B, Black HR et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke . 2014; :. [PubMed 24788967]
530. Myers MG, Tobe SW. A Canadian perspective on the Eighth Joint National Committee (JNC 8) hypertension guidelines. J Clin Hypertens (Greenwich) . 2014; 16:246-8. [PubMed 24641124]
536. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl . 2012: 2: 337-414.
540. Magee LA, Pels A, Helewa M et al., for the Canadian Hypertensive Disorders of Pregnancy (HDP) Working Group. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. Pregnancy Hypertens . 2014; 4:105-45. [PubMed 26104418]
542. Marik PE, Varon J. Hypertensive crises: challenges and management. Chest . 2007; 131:1949-62. [PubMed 17565029]
600. Mylan. Methyldopa tablets prescribing information. Morgantown, WV; 2015 May.
601. American Regent. Methyldopate hydrochloride prescribing information. Shirley, NY; 2005 Nov.
1200. Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension . 2018; 71:el13-e115. [PubMed 29133356]
1201. Bakris G, Sorrentino M. Redefining hypertension - assessing the new blood-pressure guidelines. N Engl J Med . 2018; 378:497-499. [PubMed 29341841]
1202. Carey RM, Whelton PK, 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association hypertension guideline. Ann Intern Med . 2018; 168:351-358. [PubMed 29357392]
1207. Burnier M, Oparil S, Narkiewicz K et al. New 2017 American Heart Association and American College of Cardiology guideline for hypertension in the adults: major paradigm shifts, but will they help to fight against the hypertension disease burden?. Blood Press . 2018; 27:62-65. [PubMed 29447001]
1209. Qaseem A, Wilt TJ, Rich R et al. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med . 2017; 166:430-437. [PubMed 28135725]
1210. SPRINT Research Group, Wright JT, Williamson JD et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med . 2015; 373:2103-16. [PubMed 26551272]
1216. Taler SJ. Initial treatment of hypertension. N Engl J Med . 2018; 378:636-644. [PubMed 29443671]
1220. Cifu AS, Davis AM. Prevention, detection, evaluation, and management of high blood pressure in adults. JAMA . 2017; 318:2132-2134. [PubMed 29159416]
1222. Bell KJL, Doust J, Glasziou P. Incremental benefits and harms of the 2017 American College of Cardiology/American Heart Association high blood pressure guideline. JAMA Intern Med . 2018; 178:755-7. [PubMed 29710197]
1223. LeFevre M. ACC/AHA hypertension guideline: what is new? what do we do?. Am Fam Physician . 2018; 97(6):372-3. [PubMed 29671534]
1224. Brett AS. New hypertension guideline is released. From NEJM Journal Watch website. Accessed 2018 Jun 18. [Web]
1229. Ioannidis JPA. Diagnosis and treatment of hypertension in the 2017 ACC/AHA guidelines and in the real world. JAMA . 2018; 319(2):115-6. [PubMed 29242891]