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Aldoclor (Methyldopa / Chlorothiazide) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ALDOCLOR * (Methyldopa-Chlorothiazide) combines two antihypertensives: methyldopa and chlorothiazide.

Methyldopa

Methyldopa is an antihypertensive and is the L - isomer of alpha-methyldopa. It is levo-3-(3,4-dihydroxyphenyl)-2- methylalanine. Its empirical formula is C10H13NO4, with a molecular weight of 211.22, and its structural formula is:

Methyldopa is a white to yellowish white, odorless fine powder, and is soluble in water.

Chlorothiazide

Chlorothiazide is a diuretic and antihypertensive. It is 6-chloro-2 H -1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide. Its empirical formula is C7H6ClN3O4S2 and its structural formula is:

It is a white, or practically white crystalline powder with a molecular weight of 295.73, which is very slightly soluble in water, but readily soluble in dilute aqueous sodium hydroxide. It is soluble in urine to the extent of about 150 mg per 100 mL at pH 7.

ALDOCLOR is supplied as tablets for oral use, each containing 250 mg of methyldopa and 250 mg of chlorothiazide.

Each tablet contains the following inactive ingredients: calcium disodium edetate, cellulose, citric acid, D&C Yellow 10 aluminum lake, ethylcellulose, FD&C Yellow 6 aluminum lake, gelatin, glycerin, guar gum, hydroxypropyl methylcellulose, magnesium stearate, starch, talc, titanium dioxide, and FD&C Blue 2 aluminum lake.


*Registered trademark of MERCK & CO., INC.

CLINICAL PHARMACOLOGY

Methyldopa

Methyldopa 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-methylnorepinephrine, 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.

Chlorothiazide

The mechanism of the antihypertensive effect of thiazides is unknown. Chlorothiazide does not usually affect normal blood pressure.

Chlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic efficacy.

Chlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.

After oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

Pharmacokinetics and Metabolism

Methyldopa

The maximum decrease in blood pressure occurs four to six hours after oral dosage. After withdrawal, blood pressure usually returns to pretreatment levels within 24-48 hours.

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

Approximately 70 percent of the drug which is absorbed is excreted in the urine as methyldopa and its mono-0-sulfate conjugate. The renal clearance is about 130 mL/min in normal subjects and is diminished in renal insufficiency. The plasma half-life of methyldopa is 105 minutes. After oral doses, excretion is essentially complete in 36 hours.

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

Chlorothiazide

Chlorothiazide is not metabolized but is eliminated rapidly by the kidney. The plasma half-life is 45-120 minutes. After oral doses, 20-24 percent of the dose is excreted unchanged in the urine. Chlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

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