Methyldopa injection clinical pharmacology

Methyldopa
Methyldopa tablet® FDA Package Insert
Indications and Usage
Dosage and Administration
Contraindications
Warnings
Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Overdosage
Description
Clinical Pharmacology
Nonclinical Toxicology
How Supplied/Storage and Handling
Labels and Packages
Methyldopa injection® FDA Package Insert
Indications and Usage
Dosage and Administration
Contraindications
Warnings
Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Overdosage
Description
Clinical Pharmacology
Nonclinical Toxicology
How Supplied/Storage and Handling
Labels and Packages
Clinical Trials on Methyldopa
ClinicalTrials.gov

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Abdurahman Khalil, M.D. [2]

CLINICAL PHARMACOLOGY

Methyldopate, an antihypertensive agent, is an aromatic-amino-acid decarboxylase inhibitor in animals and in man. Although the mechanism of action has yet to be conclusively demonstrated, the antihypertensive effect of methyldopa probably is due to its metabolism to alpha-methyl-norepinephrine, which then lowers arterial pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activity. Methyldopa has been shown to cause a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine.

Only methyldopa, the L-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase and to deplete animal tissues of norepinephrine. In man, the antihypertensive activity appears to be due solely to the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equal antihypertensive effect.

Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed.

Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy.

Methyldopa reduces both supine and standing blood pressure. It usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.

Pharmacokinetics and Metabolism

Methyldopate hydrochloride is the ethyl ester of methyldopa hydrochloride and possesses the same pharmacologic attributes.

Methyldopa is extensively metabolized. The known urinary metabolites are ∝-methyldopa mono-0-sulfate; 3-0-methyl-∝-methyldopa; 3,4-dihydroxyphenylacetone; ∝-methyldopamine; 3-0-methyl-∝-methyldopamine and their conjugates.

Following intravenous administration of methyldopate hydrochloride a decrease in blood pressure may occur in four to six hours and last 10 to 16 hours.

Approximately 49 percent of the dose of methyldopate hydrochloride is excreted in the urine as methyldopa and its mono-0-sulfate. The renal clearance of methyldopa following methyldopate hydrochloride is about 156 mL/min in normal subjects and is diminished in renal insufficiency. Following methyldopate hydrochloride injection the plasma half-life of methyldopa is 90-127 minutes. Approximately 17 percent of a dose of methyldopate hydrochloride given to normal subjects appears in plasma as free methyldopa.

Methyldopa crosses the placental barrier, appears in cord blood, and appears in breast milk.