Renese-R (Polythiazide / Reserpine) - Description and Clinical Pharmacology

DESCRIPTION

RENESE®-R tablets combine polythiazide and reserpine, two antihypertensive agents with complementary properties. Each blue, scored tablet of RENESE-R provides:

Renese (polythiazide).. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 2.0 mg

Reserpine. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ... .. .. .. .0.25 mg

RENESE (polythiazide) is a member of the benzothiazide (thiazide) family of diuretic/antihypertensive agents. It is designated chemically as 2H-1,2,4-Benzothiadiazine-7-sulfonamide,6-chloro-3,4-dihydro-2-methyl-3-[[2,2,2-trifluoroethyl)thio]methyl]-,1,1-dioxide with a molecular formula of C₁₁H₁₃ClF₃N₃O₄S₃ and a molecular weight of 439.87.

Polythiazide is a white crystalline substance insoluble in water, but readily soluble in alkaline solution, and has the following structural formula:

Reserpine, one of the alkaloids of Rauwolfia serpentina, has the following structural formula:

Reserpine – which is administered orally, is insoluble in water, very slightly soluble in ether, l g in about 1800 mL alcohol and about 6 mL chloroform, slightly soluble in benzene, freely soluble in acetic acid.

It has a molecular weight of 608.69 and its molecular formula is C₃₃H₄₀N₂O₉. Reserpine is chemically designated as Yohimban-16-carboxylic acid, 11,17-dimethoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-, methyl ester, (3β,16β,17α,18β,20α)-. It is a white or pale buff to slightly yellowish crystalline powder that is insoluble in water.

Inert Ingredients: FD&C Blue No. 1; dibasic calcium phosphate; lactose; magnesium stearate; polyethylene glycol; sodium lauryl sulfate; starch; vanillin.

CLINICAL PHARMACOLOGY

Polythiazide

Renese (polythiazide) alone has demonstrated clinical effectiveness in lowering elevated blood pressure in patients without visible edema as well as in edematous hypertensive patients. 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. Polythiazide is well absorbed following oral administration with diuresis beginning approximately 2 hours later. Peak human plasma concentrations occur about 5 hours after ingestion. Polythiazide 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.

Reserpine

Reserpine has several complementary actions of benefit to the hypertensive patient, including a calming effect and a slowing of the pulse rate.

Depletion of norepinephrine from tissue receptor sites is thought to be responsible for the decrease in peripheral vascular resistance and subsequent fall in blood pressure. Bradycardia is usually associated with this effect.

The tranquilizing effect of reserpine is apparently due to serotonin and catecholamine depletion in the brain.

Sympathetic inhibition produced by reserpine also may result in vasodilation and increased cutaneous blood flow with resulting flushing, feeling of warmth, or nasal congestion. Increased parasympathomimetic activity may produce increased gastrointestinal motility, increased gastric acid secretion and miosis.

Reserpine is absorbed orally and is widely distributed in body tissues, especially adipose tissue. A study in a small number of normal subjects who received a radioactively labeled 0.25 mg dose of reserpine showed a biphasic half-life of 4.5 hours during the first phase, and 11.3 days during the second phase. The full therapeutic effects of reserpine may not be seen for 2–3 weeks.

Reserpine is extensively metabolized to inactive compounds. It is slowly excreted via the urine and feces.

Reserpine crosses the blood-brain barrier and the placenta, and appears in cord blood.

Since polythiazide reduces or eliminates the sodium and fluid retention frequently associated with hypertension, it enhances the efficacy of reserpine in lowering elevated blood pressure. RENESE-R often has been found to be more effective than equivalent doses of either agent alone. Both the cardiovascular and central nervous system effects may persist following withdrawal of the drug.