Continuing Education Activity

Methyldopa is a medication used in the management and treatment of hypertension. It is in the centrally acting anti-hypertensive class of drugs. This activity reviews the indications, actions, and contraindications for methyldopa as a valuable agent in the management of hypertension. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the inter-professional team in the management of patients with hypertension and related conditions.

Objectives:

• Identify the mechanism of action of methyldopa.
• Describe the adverse effects of methyldopa.
• Review the appropriate monitoring for toxicity of methyldopa.
• Outline inter-professional team strategies for improving care coordination and communication to advance methyldopa and improve outcomes.

Indications

Methyldopa is a centrally acting sympatholytic agent used in the treatment of hypertension. Since its introduction in 1960, the drug quickly became a leading antihypertensive, but its use has decreased markedly, replaced by better-tolerated alternatives. It is still in use in developing countries due to its low cost. This drug is also useful in pregnancy because it has no teratogenic effects.[1]

Mechanism of Action

Alpha-methyldopa is converted to methyl norepinephrine centrally to decrease the adrenergic outflow by alpha-2 agonistic action from the central nervous system, leading to reduced total peripheral resistance and decreased systemic blood pressure. Alpha-2 agonistic activity does not affect cardiac output or renal blood flow.; hence, this drug is useful in hypertensive patients with renal insufficiency.

Administration

Methyldopa is generically available as a single ingredient in 125, 250, or 500 mg tablets.[2] Fixed-dose combinations with thiazides are also on the market. The recommended dose in adults is 500 mg to 2 g daily. Clinicians should discontinue the drug if any side effects manifest in the patient.

IV infusion in the form of methyldopa hydrochloride is available. The drug gets diluted in 5% dextrose, and the required dose is added to 100 mL of 5% dextrose in water injection and administered slowly over 30 to 60 minutes. IM or subcutaneous administration is not a recommendation due to unpredictable absorption.[3][4]

Despite its popularity during the 70s, other alternatives have replaced methyldopa as a mainstay for the treatment of hypertension. Methyldopa remains a second-line treatment to be used safely during pregnancy.[5][6]

Adverse Effects

Common adverse effects include:

• Nausea
• Diarrhea
• Headache
• Dizziness
• Sedation
• Dry mouth
• Rash

Rare yet clinically fatal adverse effects include[4]:

• Hemolytic anemia (Coombs positive)
• Lupus-like syndrome
• Myocarditis
• Pancreatitis
• Hepatotoxicity
• Immune thrombocytopenia
• Reversible leukopenia
• Involuntary choreoathetotic movements
• Weight gain
• Rebound hypertension

Contraindications

• Active hepatic disease [7]
• Liver disorders due to previous therapy
• Direct Coombs positive hemolytic anemia
• Significant drug history of MAO inhibitor therapy
• Pheochromocytoma
• Known hypersensitivity to methyldopa in any form

Monitoring

Pharmacokinetics

Absorption

• 50% of the dose absorbed attains peak plasma concentrations in approximately 3 to 6 hours.
• A maximum reduction in blood pressure occurs in 4 to 6 hours following oral administration. 
• Following IV administration, hypotensive lasts for about 10 to 16 hours.

Distribution

• The drug is lipid-soluble and crosses the blood-brain barrier with weak binding to plasma proteins.
• Its primary metabolite has more plasma protein binding as compared to the drug.
• Conjugates formed after oral administration are acid labile and are delectable in small amounts after intravenous administration. 
• The apparent volume of distribution ranges between 0.19 to 0.32L/kg and the total volume of distribution between 0.41 to 0.72L/kg. 

Metabolism

• Methyldopa gets metabolized to alpha-methylnorepinephrine, the active metabolite. 
• The drug is also metabolized extensively in the liver to its sulfate conjugate.

Elimination

• Excretion of 70% of the drug is via urine in the form of parent drug and metabolite.
• Unabsorbed drug is excreted in feces unchanged.
• Excretion is slow in patients with renal failure, leading to the accumulation of the drug and its metabolites.[8]

Monitoring

Information about the adverse effects and pharmacokinetic principles of the drug is crucial in therapeutic monitoring. After initiation of treatment, periodic testing of hemoglobin, hematocrit, and the red blood cell count is necessary to rule out hemolytic anemia. Direct Coombs test is reported positive, usually after 6 to 12 months of therapy, but rarely results in fatal hemolytic anemia. Discontinuance of drug reverses results within weeks to months.

Liver function tests are necessary for increased serum concentrations of alkaline phosphatase, aminotransferases, and bilirubin. Hepatic dysfunction may represent a hypersensitivity reaction. Therefore, a periodic assessment of hepatic function is important during the first 6 to 12 weeks of therapy. Abnormal liver function test results require discontinuation of the drug. The drug is contraindicated in active hepatic disease.

Toxicity

Methyldopa overdose reports are exceedingly rare. Clinical manifestations include coma, hypothermia, hypotension, bradycardia, and dry mouth. In addition, prolonged, severe hypotension, along with marked renal potassium loss necessitating IV infusion of norepinephrine and vigorous potassium replacement therapy for almost two days, was reported.

Hepatotoxicity

• Chronic use of methyldopa is associated with mild and transient elevations in serum aminotransferase levels that resolve after discontinuation of the medication.
• Hepatic injury is rather uncommon and may appear within weeks or months to years after initiation of drug therapy.
• An acute injury demonstrates elevated levels of ALT and AST (5-to 100-fold). Most patients become jaundiced with symptoms resembling those of viral hepatitis. Liver biopsy shows hepatitis-like features, and re-exposure can lead to severe hepatitis and death.
• The chronic injury clinically resembles autoimmune hepatitis with marked elevations in liver enzymes, increases in IgG, and high titers of ANA antibodies. In addition, cirrhosis and end-stage liver disease can occur if drug therapy continues. 
• Granulomatous hepatitis can also occur with methyldopa therapy associated with systemic symptoms.
• The disease resolves slowly with the discontinuation of the drug.[9]

Hematologic Effects

• Positive Coombs' test shows within a few weeks of initiation of drug therapy, which rarely leads to fatal hemolytic anemia.
• Discontinuation of the drug promptly resolves the anemia, along with the use of corticosteroids.[7]

Enhancing Healthcare Team Outcomes

Management of drug overdose requires an interprofessional team of healthcare professionals, including pharmacists, nurses, laboratory technologists, and several physicians in different specialties. Absent proper management, morbidity and mortality from methyldopa overdose are high. Therefore, the moment the triage nurse has admitted a patient with methyldopa overdose, the emergency department clinician is responsible for coordinating the care, which includes the following:

• Ordering drug level testing in the blood and/or urine.
• Monitor the patient for signs and symptoms of jaundice, fever, drowsiness or sedation, and other preexisting disorders.
• The pharmacist should check the medication record to verify dosing and administration were correct.
• Nursing should review the medicine administration record to ensure there were no administration errors.
• Performing various maneuvers to help limit the absorption of the drug in the body.
• Consult with the pharmacist about the use of activated charcoal. [Level 1]
• Obtain a consult with a toxicologist and nephrologist on further management, which may include dialysis.
• Consult with the radiologist about imaging tests to ensure that the patient has not swallowed any drug packages.
• Consultation with the intensivist about ICU care and monitoring while in hospital.

The management of methyldopa overdose does not stop in the emergency department. Following patient stabilization, one has to determine how and why the patient overdosed. Consult with a mental health counselor if this was an intentional act and assess risk factors for-self harm. Only by functioning as an interprofessional team can the morbidity of methyldopa overdose be decreased. The long-term outcomes for drug therapy include prescribing better-tolerated drugs within a therapeutic range. [Level 2]

Patients should understand the importance of informing clinicians of existing or contemplated concomitant therapy or concurrent diseases. The importance of informing clinicians about a current or planned pregnancy plays a vital role in improving outcomes. With an interprofessional team approach to methyldopa therapy, successful results with minimal adverse events are achievable. [Level 5]