Methyldopa

Methyldopa is an aromatic-amino-acid decarboxylase inhibitor in animals and in man. Although themechanism of action has yet to be conclusively demonstrated, the antihypertensive effect of methyldopaprobably is due to its metabolism to alpha-methylnorepinephrine, which then lowers arterial pressure bystimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction ofplasma renin activity. Methyldopa has been shown to cause a net reduction in the tissue concentration ofserotonin, dopamine, norepinephrine, and epinephrineOnly methyldopa, the L-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase andto deplete animal tissues of norepinephrine. In man, the antihypertensive activity appears to be due solelyto the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equalantihypertensive effect.

Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtrationrate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiacacceleration. 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 effectivelowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotensionand diurnal blood pressure variations rarely occur.

Hydrochlorothiazide: The mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide does notusually affect normal blood pressure.Hydrochlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximaltherapeutic dosage all thiazides are approximately equal in their diuretic efficacy.Hydrochlorothiazide 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. Once aneffective dosage level is attained, a smooth blood pressure response occurs in most patients in 12 to 24hours. After withdrawal, blood pressure usually returns to pretreatment levels within 24-48 hours.Methyldopa is extensively metabolized. The known urinary metabolites are: α-methyldopa mono-0-sulfate; 3-0-methyl-α-methyldopa; 3,4-dihydroxyphenylacetone; α-methyldopamine; 3-0-methyl-α-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 diminishedin 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.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours.

Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.