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Minizide (Prazosin Hydrochloride / Polythiazide) - Description and Clinical Pharmacology

 
 



MINIZIDE® CAPSULES
(prazosin hydrochloride/polythiazide)

FOR ORAL ADMINISTRATION

DESCRIPTION

MINIZIDE® is a combination of MINIPRESS® (prazosin hydrochloride) plus RENESE® (polythiazide).

MINIPRESS (prazosin hydrochloride), a quinazoline derivative, is the first of that chemical class of antihypertensives. It is the hydrochloride salt of 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furoyl) piperazine and its structural formula is:

It is a white, crystalline substance, slightly soluble in water and isotonic saline, and has a molecular weight of 419.87. Each 1 mg capsule of MINIPRESS (prazosin hydrochloride) contains drug equivalent to 1 mg free base.

RENESE (polythiazide) is an orally effective, non-mercurial diuretic, saluretic, and antihypertensive agent.

It is designated chemically as 2 H -1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2-methyl-3-[[(2,2,2-trifluoroethyl)thio]methyl]-,1,1-dioxide, and has the following structural formula:

It is a white, crystalline substance insoluble in water, but readily soluble in alkaline solution.

Inert ingredients in the formulations are: hard gelatin capsules (which may contain Blue 1, Green 3, Red 3 and other inert ingredients); magnesium stearate; sodium lauryl sulfate; starch; sucrose.

CLINICAL PHARMACOLOGY

MINIZIDE (prazosin hydrochloride/polythiazide)

MINIZIDE produces a more pronounced antihypertensive response than occurs after either prazosin hydrochloride or polythiazide alone in equivalent doses.

MINIPRESS (prazosin hydrochloride)

The exact mechanism of the hypotensive action of prazosin is unknown. Prazosin causes a decrease in total peripheral resistance and was originally thought to have a direct relaxant action on vascular smooth muscle. Recent animal studies, however, have suggested that the vasodilator effect of prazosin is also related to blockade of postsynaptic alpha -adrenoceptors. The results of dog forelimb experiments demonstrate that the peripheral vasodilator effect of prazosin is confined mainly to the level of the resistance vessels (arterioles). Unlike conventional alpha -blockers, the antihypertensive action of prazosin is usually not accompanied by a reflex tachycardia. Tolerance has not been observed to develop in long term therapy.

Hemodynamic studies have been carried out in man following acute single dose administration and during the course of long term maintenance therapy. The results confirm that the therapeutic effect is a fall in blood pressure unaccompanied by a clinically significant change in cardiac output, heart rate, renal blood flow, and glomerular filtration rate. There is no measurable negative chronotropic effect.

In clinical studies to date, MINIPRESS has not increased plasma renin activity.

In man, blood pressure is lowered in both the supine and standing positions. This effect is most pronounced on the diastolic blood pressure.

Following oral administration, human plasma concentrations reach a peak at about three hours with a plasma half-life of two to three hours. The drug is highly bound to plasma protein. Bioavailability studies have demonstrated that the total absorption relative to the drug in a 20% alcoholic solution is 90%, resulting in peak levels approximately 65% of that of the drug in solution. Animal studies indicate that MINIPRESS is extensively metabolized, primarily by demethylation and conjugation, and excreted mainly via bile and feces. Less extensive human studies suggest similar metabolism and excretion in man.

MINIPRESS has been administered without any adverse drug interaction in limited clinical experience to date with the following: (1) cardiac glycosides—digitalis and digoxin; (2) hypoglycemics—insulin, chlorpropamide, phenformin, tolazamide, and tolbutamide; (3) tranquilizers and sedatives—chlordiazepoxide, diazepam, and phenobarbital; (4) antigout—allopurinol, colchicine, and probenecid; (5) antiarrhythmics—procainamide, propranolol (see WARNINGS however), and quinidine; and (6) analgesics, antipyretics and anti-inflammatories—propoxyphene, aspirin, indomethacin, and phenylbutazone.

RENESE (polythiazide)

RENESE is a member of the benzothiadiazine (thiazide) family of diuretic/antihypertensive agents. Its mechanism of action results in an interference with the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic potency. The mechanism whereby thiazides function in the control of hypertension is unknown. Renese is well absorbed, giving peak human plasma concentrations about 5 hours after oral administration. Drug is removed slowly thereafter with a plasma elimination half-life of approximately 27 hours. One fifth of the drug is recovered unchanged in human urine; the remainder is cleared via feces and as metabolites. Animal studies indicate metabolism occurs by rupture of the thiadiazine ring and loss of the side chain.

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