Diupres (Reserpine / Chlorothiazide) - Description and Clinical Pharmacology

DESCRIPTION

DIUPRESRegistered trademark of MERCK & CO., Inc., COPYRIGHT © MERCK & CO., Inc., 1986 All rights reserved combines two antihypertensives: DIURIL (Chlorothiazide) and reserpine.

Chlorothiazide

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

Chlorothiazide 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.

Reserpine

The chemical name of reserpine is 11, 17α-dimethoxy-18β-[(3,4,5-trimethoxybenzoyl)oxy]-3β, 20α-yohimban-16β-carboxylic acid methyl ester. It is a crystalline alkaloid derived from Rauwolfia serpentina. Its empirical formula is C₃₃H₄₀N₂O₉ and its structural formula is:

Reserpine is a white or pale buff to slightly yellowish, odorless, crystalline powder with a molecular weight of 608.69, is insoluble in water and freely soluble in glacial acetic acid.

DIUPRES is supplied as tablets in two strengths for oral use:

DIUPRES-250, contains 250 mg of chlorothiazide and 0.125 mg of reserpine.

DIUPRES-500, contains 500 mg of chlorothiazide and 0.125 mg of reserpine,

Each tablet contains the following inactive ingredients: FD&C Red 3, gelatin, lactose, magnesium stearate, starch and talc.

CLINICAL PHARMACOLOGY

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.

Reserpine

Reserpine has antihypertensive, bradycardic, and tranquilizing properties. It lowers arterial blood pressure by depletion of catecholamines. Reserpine is beneficial in relieving anxiety, tension, and headache in the hypertensive patient. It acts at the hypothalamic level of the central nervous system to promote relaxation without hypnosis or analgesia. The sleep pattern shown by the electroencephalogram following barbiturates does not occur with this drug. In laboratory animals spontaneous activity and response to external stimuli are decreased, but confusion or difficulty of movement is not evident.

The bradycardic action of reserpine promotes relaxation and may eliminate sinus tachycardia. It is most pronounced in subjects with sinus tachycardia and usually is not prominent in persons with a normal pulse rate.

Miosis, relaxation of the nictitating membrane, ptosis, hypothermia, and increased gastrointestinal activity are noted in animals given reserpine, sometimes in subclinical doses. None of these effects, except increased gastrointestinal activity, has been found to be clinically significant in man with therapeutic doses.

Pharmacokinetics and Metabolism

Chlorothiazide

Chlorothiazide is not metabolized but is eliminated rapidly by the kidney. The plasma half-life of chlorothiazide is 45-120 minutes. After oral doses, 10-15 percent is excreted unchanged in the urine. Chlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Reserpine

Oral reserpine is rapidly absorbed from the gastrointestinal tract. Methylreserpate and trimethoxybenzoic acid are the primary metabolites which result from hydrolytic cleavage of reserpine. Maximal blood levels are achieved approximately 2 hours after the oral dosage of ³H-reserpine to six normal volunteers; within 96 hours approximately 8 percent was excreted in urine and 62 percent in feces. Reserpine appears in human breast milk. Reserpine crosses the placental barrier in guinea pigs.