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Methyldopa


Methyldopa

Article Author:
Mohit Gupta
Article Editor:
Yasir Al Khalili
Updated:
7/10/2020 8:33:41 AM
For CME on this topic:
Methyldopa CME
PubMed Link:
Methyldopa

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 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 mainstays 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.

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.

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]

Enhancing Healthcare Team Outcomes

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]


References

[1] Molvi SN,Mir S,Rana VS,Jabeen F,Malik AR, Role of antihypertensive therapy in mild to moderate pregnancy-induced hypertension: a prospective randomized study comparing labetalol with alpha methyldopa. Archives of gynecology and obstetrics. 2012 Jun     [PubMed PMID: 22249781]
[2] Mah GT,Tejani AM,Musini VM, Methyldopa for primary hypertension. The Cochrane database of systematic reviews. 2009 Oct 7     [PubMed PMID: 19821316]
[3] Whelton PK,Carey RM,Aronow WS,Casey DE Jr,Collins KJ,Dennison Himmelfarb C,DePalma SM,Gidding S,Jamerson KA,Jones DW,MacLaughlin EJ,Muntner P,Ovbiagele B,Smith SC Jr,Spencer CC,Stafford RS,Taler SJ,Thomas RJ,Williams KA Sr,Williamson JD,Wright JT Jr, 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 (Dallas, Tex. : 1979). 2018 Jun;     [PubMed PMID: 29133356]
[4] Taler SJ, Initial Treatment of Hypertension. The New England journal of medicine. 2018 Feb 15;     [PubMed PMID: 29443671]
[5] Folic MM,Jankovic SM,Varjacic MR,Folic MD, Effects of methyldopa and nifedipine on uteroplacental and fetal hemodynamics in gestational hypertension. Hypertension in pregnancy. 2012     [PubMed PMID: 21219124]
[6] Khalil A,Muttukrishna S,Harrington K,Jauniaux E, Effect of antihypertensive therapy with alpha methyldopa on levels of angiogenic factors in pregnancies with hypertensive disorders. PloS one. 2008 Jul 23     [PubMed PMID: 18648513]
[7] Methyldopa 2012;     [PubMed PMID: 31643501]
[8] Myhre E,Rugstad HE,Hansen T, Clinical pharmacokinetics of methyldopa. Clinical pharmacokinetics. 1982 May-Jun     [PubMed PMID: 7047042]
[9] Chan TY,Gomersall CD,Cheng CA,Woo J, Overdose of methyldopa, indapamide and theophylline resulting in prolonged hypotension, marked diuresis and hypokalaemia in an elderly patient. Pharmacoepidemiology and drug safety. 2009 Oct;     [PubMed PMID: 19623566]