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Hydralazine and Hydrochlorothiazide (Hydralazine Hydrochloride / Hydrochlorothiazide) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Hydralazine HCl and hydrochlorothiazide is an antihypertensive-diuretic combination available as capsules for oral administration. Hydralazine HCl and hydrochlorothiazide capsules of 25 mg/25 mg contain 25 mg of Hydralazine hydrochloride USP and 25 mg of hydrochlorothiazide USP; capsules of 50 mg/50 mg contain 50 mg of hydralazine hydrochloride USP and 50 mg of hydrochlorothiazide USP; and capsules of 100 mg/50 mg contain 100 mg of hydralazine hydrochloride USP and 50 mg of hydrochlorothiazide USP.

Each capsule also contains the following inactive ingredients: Corn starch, crospovidone, gelatin, lactose monohydrate, pharmaceutical glaze, sodium starch glycolate, stearic acid, talc, and titanium dioxide. In addition, the 25 mg/25 mg capsule contains ammonium hydroxide, ethylene glycol monoethyl ether, propylene glycol and synthetic black iron oxide; the 50 mg/50 mg capsule contains FD&C Blue #1, FD&C Red #40, FD&C Yellow #6, synthetic red iron oxide and pharmaceutical shellac; and the 100 mg/50 mg capsule contains D&C Red #28, D&C Yellow #10, FD&C Blue #1,FD&C Blue #2, FD&C Red #40, propylene glycol and synthetic black iron oxide.

Hydralazine hydrochloride is 1-hydrazinophthalazine monohydrochloride, and its structural formula is:

Hydralazine hydrochloride USP is a white to off-white, odorless crystalline powder. It is soluble in water, slightly soluble in alcohol, and very slightly soluble in ether. It melts at about 275°C, with decomposition, and has a molecular weight of 196.64.

Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, and its structural formula is:

Hydrochlorothiazide USP is a white, or practically white, practically odorless crystalline powder. It is freely soluble in sodium hydroxide solution, in n -butylamine, and in dimethylformamide; sparingly soluble in methanol; slightly soluble in water; and insoluble in ether, in chloroform, and in dilute mineral acids. Its molecular weight is 297.75.

CLINICAL PHARMACOLOGY

Hydralazine

Although the precise mechanism of action of hydralazine is not fully understood, the major effects are on the cardiovascular system. Hydralazine apparently lowers blood pressure by exerting a peripheral vasodilating effect through a direct relaxation of vascular smooth muscle. Hydralazine, by altering cellular calcium metabolism, interferes with the calcium movements within the vascular smooth muscle that are responsible for initiating or maintaining the contractile state.

The peripheral vasodilating effect of hydralazine results in decreased arterial blood pressure (diastolic more than systolic); decreased peripheral vascular resistance; and an increased heart rate, stroke volume, and cardiac output. The preferential dilatation of arterioles, as compared to veins, minimizes postural hypotension and promotes the increase in cardiac output. Hydralazine usually increases renin activity in plasma, presumably as a result of increased secretion of renin by the renal juxtaglomerular cells in response to reflex sympathetic discharge. This increase in renin activity leads to the production of angiotensin II, which then causes stimulation of aldosterone and consequent sodium reabsorption. Hydralazine also maintains or increases renal and cerebral blood flow.

Hydrochlorothiazide

Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage, all thiazides are approximately equal in their diuretic potency. Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium.

The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not affect normal blood pressure.

Pharmacokinetics

Hydralazine: Hydralazine is rapidly absorbed after oral administration, and peak plasma levels are reached at 1-2 hours. Plasma levels decline with a half-life of 3-7 hours. Binding to human plasma protein is 87%. Plasma levels of hydralazine vary widely among individuals. Hydralazine is subject to polymorphic acetylation; slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of blood pressure. Hydralazine undergoes extensive hepatic metabolism; it is excreted mainly in the form of metabolites in the urine.

Administration of hydralazine with food results in higher levels of the drug in plasma.

Hydrochlorothiazide: Onset of action of thiazides occurs in 2 hours and the peak effect at about 4 hours. The action persists for approximately 6-12 hours. Hydrochlorothiazide is rapidly absorbed, as indicated by peak concentrations 1-2.5 hours after oral administration. Plasma levels of the drug are proportional to dose; the concentration in whole blood is 1.6-1.8 times higher than in plasma. Thiazides are eliminated rapidly by the kidney. After oral administration of 25 to 100 mg doses, 72-97% of the dose is excreted in the urine, indicating dose-independent absorption. Hydrochlorothiazide is eliminated from plasma in a biphasic fashion with a terminal half-life of 10-17 hours. Plasma protein binding is 67.9%. Plasma clearance is 15.9-30.0 L/hr; volume of distribution is 3.6-7.8 L/kg.

Gastrointestinal absorption of hydrochlorothiazide is enhanced when administered with food. Absorption is decreased in patients with congestive heart failure, and the pharmacokinetics are considerably different in these patients.

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