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Chapter: Modern Medical Toxicology: Cardiovascular Poisons: Diurets, Antihypertensives and Antiarrhythmics

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Methyldopa - Sympatholytic Drug Cardiovascular Poison

Methyldopa acts centrally via an active metabolite, alpha-methyl-noradrenaline, to lower blood pressure.

SYMPATHOLYTIC DRUGS

Methyldopa

Methyldopa acts centrally via an active metabolite, alpha-methyl-noradrenaline, to lower blood pressure. It is an antihy-pertensive, whose specific mechanism of action is uncertain. Although methyldopa is an inhibitor of dopa-decarboxylase, this effect does not appear to be responsible for its antihyper-tensive effect. The major antihypertensive action appears to be on the CNS by alpha adrenergic agonist activity in the medulla and the anterior hypothalamus, in a manner similar to clonidine.

The usual dose of methyldopa as an antihypertensive is 250 mg two to three times daily. This can be gradually increased to 500 mg to 2 grams daily, up to a maximum daily dose of 3 grams. It is well absorbed orally and peak plasma levels are seen after 2 to 3 hours. Mean bioavailability is about 50%. Methyldopa crosses the blood-brain barrier where it is decar-boxylated in the CNS to active alpha-methylnoradrenaline. Protein binding is less than 15%. Approximately 50% of an oral dose is metabolised by the liver. Elimination is biphasic with a reported half-life of approximately 1.7 hours in the initial phase, with the second phase being more prolonged. It is excreted in the urine as the sulfate conjugate (50 to 70%), and as the parent drug (25%). Urinary excretion is essentially complete in 36 hours following oral doses. Plasma half-life is reported to be 105 minutes. Terminal half-life is about 7 to 16 hours.

Patients receiving therapeutic doses of methyldopa (250 to 750 mg/day) demonstrate serum methyldopa concentrations of 2 mcg/ml.

Adverse Effects and Toxic Features

·      Methyldopa may induce life-threatening effects such as haemolytic anaemia, hepatitis, pancreatitis, and myocar-ditis, apart from a myriad other lesser effects including headache, drowsiness, depression, oedema, bradycardia, nasal stuffiness, nightmares, disorders of sexual function, gynaecomastia, galactorrhoea, dryness of mouth, and night-mares. Around 20% of patients develop a positive Coombs’ test.*

·      Acute overdosage of methyldopa may result in severe hypothermia, dry mouth, nausea, vomiting, hypotension, dizziness, weakness, lethargy, coma and bradycardia. Paraesthesias, headache, weakness, involuntary move-ments, and psychic disturbances have been reported.

Treatment

·      All cases of symptomatic methyldopa overdose should be admitted to the intensive care unit and monitored for cardiovascular complications. No specific lab work (CBC, urinalysis, electrolytes) is needed unless otherwise indicated. Monitoring of blood pressure, central venous or pulmonary wedge pressure may be necessary.

·      For hypotension, infuse 10 to 20 ml/kg of isotonic fluid and place in Trendelenburg position. If hypotension persists, administer dopamine or noradrenaline. Consider central venous pressure monitoring to guide further fluid therapy.

·      Atropine can be used to treat bradycardia.

·      Although there are no published data regarding use of haemodialysis or haemoperfusion following methyldopa overdoses, data following therapeutic use suggest that these procedures may be of value following severe intoxication refractory to conventional therapy.

 

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