METHYLDOPA AND HYDROCHLOROTHIAZIDE- methyldopa and hydrochlorothiazide tablet
Mylan Pharmaceuticals Inc.
WARNING
This fixed combination drug is not indicated for initial therapy of hypertension. Hypertension requires therapy titrated to the individual patient. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management. The treatment of hypertension is not static, but must be re-evaluated as conditions in each patient warrant.
DESCRIPTION
This fixed combination product combines two antihypertensives: methyldopa and hydrochlorothiazide.
Methyldopa
Methyldopa is an antihypertensive and is the L -isomer of alpha-methyldopa. It is levo-3-(3,4-Dihydroxy-phenyl)-2-methylalanine sesquihydrate. Its molecular formula is C10 H13 NO4 �1 � H2 O with a molecular weight of 238.2. Methyldopa is a white to yellowish white, odorless fine powder and is sparingly soluble in water.
Hydrochlorothiazide
Hydrochlorothiazide is a diuretic and antihypertensive. It is the 3,4-dihydro derivative of chlorothiazide. Its chemical name is 6-Chloro-3,4-dihydro-2H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its molecular formula is C7 H8 CIN3 O4 S2 Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.75 which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
Each tablet for oral administration contains:
250 mg methyldopa and 15 mg
hydrochlorothiazide,
or
250 mg methyldopa and 25 mg
hydrochlorothiazide.
Potency for methyldopa is calculated on anhydrous basis. Each tablet also contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake, FD&C Yellow #6 Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium lauryl sulfate, titanium dioxide and triacetin.
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.
Hydrochlorothiazide
The mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide does not usually affect normal blood pressure.
Hydrochlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic 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.