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.

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.

Methyldopa overdose reports are exceedingly rare.

Clinical manifestations include coma, hypothermia, hypotension, bradycardia, and dry mouth.

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. 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 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]

Management of drug overdose requires an interprofessional team of healthcare professionals that includes pharmacists, nurses, laboratory technologists, and several physicians in different specialties. Absent proper management, morbidity, and mortality from methyldopa overdose are high. The moment the triage nurse has admitted an 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 was correct
• Nursing should review the MAR 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.

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]