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.

Usage in Pregnancy

The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia.

Edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. Thiazides are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy (however, see Precautions/Pregnancy section). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema – including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.

General

Information for Patients

Since RENESE-R may increase urination, it is advisable to take it early during the day. If stomach upset occurs, take the drug with food or milk.

Notify your physician if muscle weakness, cramps, nausea, or dizziness occur as these may indicate the loss of too much potassium from your body.

A few people who take this medicine may be more sensitive to sunlight than they are normally. Avoid too much sun or use of a sunlamp until you see how you react.

RENESE-R may cause drowsiness. Make sure you know how you react before driving, using machinery, or performing tasks that require alertness.

Notify your physician if changes in mood or sleep patterns occur. Dizziness or lightheadedness may occur when getting up from a sitting or lying position. Getting up slowly may help. Notify your physician if the problem worsens.

Laboratory Tests

Determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Drug Interactions

Drug/Laboratory Test Interactions

Animal Tumorigenicity

Although long-term studies in animals have not been conducted with RENESE-R, rodent studies have shown that reserpine is an animal tumorigen, causing an increased incidence of mammary fibroadenomas in female mice, malignant tumors of the seminal vesicles in male mice, and malignant adrenal medullary tumors in male rats. These findings arose in 2 year studies in which the drug was administered in the feed at concentrations of 5 and 10 ppm—about 100 to 300 times the usual human dose. The breast neoplasms are thought to be related to reserpine's prolactin-elevating effect.

Several other prolactin-elevating drugs have also been associated with an increased incidence of mammary neoplasia in rodents.

The extent to which these findings indicate a risk to humans is uncertain. Tissue culture experiments show that about one-third of human breast tumors are prolactin-dependent in vitro, a factor of considerable importance if the use of the drug is contemplated in a patient with previously detected breast cancer. The possibility of an increased risk of breast cancer in reserpine users has been studied extensively; however, no firm conclusion has emerged. Although a few epidemiologic studies have suggested a slightly increased risk (less than twofold in all studies except one) in women who have used reserpine, other studies of generally similar design have not confirmed this. Epidemiologic studies conducted using other drugs (neuroleptic agents) that, like reserpine, increase prolactin levels and therefore would be considered rodent mammary carcinogens, have not shown an association between chronic administration of the drug and human mammary tumorigenesis. While long-term clinical observation has not suggested such an association, the available evidence is considered too limited to be conclusive at this time. An association of reserpine intake with pheochromocytoma or tumors of the seminal vesicles has not been explored.

Pregnancy

Nursing Mothers

Thiazides and reserpine appear in breast milk. Because of the potential for serious adverse reactions in nursing infants from RENESE-R, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in children have not been established.

Polythiazide

The most common reactions associated with polythiazide therapy are weakness and dizziness, but seldom require cessation of therapy. Weakness is reported in less than 3% of patients receiving the drug, and dizziness is reported in less than 2% of patients. These can be overcome by reducing the dose or taking measures to improve electrolytic balance.

Other reactions, reported to occur in less than 1% of patients, are:

Gastrointestinal: nausea, gastrointestinal disturbances, reversible cholestatic jaundice, necrotizing angiitis, pancreatitis.

Dermatological: maculopapular skin rash, photosensitivity.

Central Nervous System: vertigo, paresthesia, fatigue, headache.

Cardiovascular: orthostatic hypotension.

EENT: xanthopsia.

Hematological: Leukopenia (neutropenia), agranulocytosis, and aplastic anemia have been reported with the older thiazides but not with the newer compounds such as polythiazide. Purpura (with or without thrombocytopenia) has been reported with polythiazide.

Reserpine

The most common reactions associated with reserpine therapy, dizziness and drowsiness, are reported in less than 2% of patients. Reactions to reserpine are usually reversible and disappear when the drug is discontinued.

Other reactions, occurring in less than 1% of patients on reserpine are:

Gastrointestinal: hypersecretion, nausea, vomiting, diarrhea, anorexia, dry mouth.

Dermatological: rash, pruritus, purpura.

Central Nervous System: depression, nervousness, paradoxical anxiety, nightmares, headache, and rare Parkinsonian syndrome to CNS sensitization manifested by deafness, glaucoma, uveitis, and optic atrophy.

Cardiovascular: angina-like symptoms, arrhythmias particularly when used concurrently with digitalis or quinidine, flushing of the skin, and bradycardia.

EENT: nasal congestion, miosis.

Sexual Difficulties: impotence or decreased libido.

Polythiazide

An overdose of Renese may cause electrolyte imbalance, manifested by fatigue, muscle weakness, cramps, gastrointestinal disturbances, lethargy, tachycardia, and/or other arrhythmias, and hypotension.

Should overdosage with Renese occur, electrolyte balance and adequate hydration should be maintained. Gastric lavage is recommended followed by supportive treatment. Where necessary, this may include intravenous dextrose and saline with potassium and other electrolyte therapy, administered with caution as indicated by laboratory testing at appropriate intervals.

Reserpine

Signs of overdosage include CNS depression ranging from drowsiness to coma, bradycardia and hypotension, respiratory depression, hypothermia, diarrhea, vomiting, mental depression, skin flushing, miosis, and extrapyramidal signs such as stiffness and tremors. Emesis or gastric lavage to remove unabsorbed drug is of benefit in conscious patients, even if several hours have elapsed since ingestion. Treatment is symptomatic and supportive.

Parasympathomimetic side effects usually can be controlled with small doses of atropine or other anticholinergics. Evidence of motor dysfunction often can be controlled by drugs useful for parkinsonism. Avoid vasopressor drugs (except in cases of extreme hypotension) and rapid intravenous infusions because of the uncertain cardiac status.

It is not known whether dialysis would be of benefit in treating cases of overdosage of RENESE-R.