Polythiazide is a thiazide diuretic with actions and uses similar to those of hydrochlorothiazide. Polythiazide under brand name Rense is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Renese is indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension. The 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, but as a diuretic, polythiazide inhibits active chloride reabsorption at the early distal tubule via the thiazide-sensitive Na-Cl cotransporter (TSC), resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like polythiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of polythiazide may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle.

Methyclothiazide, a diuretic-antihypertensive agent, is a member of the benzothiadiazine (thiazide) class of drugs. Methyclothiazide has a per mg natriuretic activity approximately 100 times that of the prototype thiazide, chlorothiazide. At maximal therapeutic dosages, all thiazides are approximately equal in their diuretic/natriuretic effects. Like other benzothiadiazines, methyclothiazide also has antihypertensive properties, and may be used for this purpose either alone or to enhance the antihypertensive action of other drugs. Methyclothiazide appears to block the active reabsorption of chloride and possibly sodium in the ascending loop of Henle, altering electrolyte transfer in the proximal tubule. This results in excretion of sodium, chloride, and water and, hence, diuresis. As a diuretic, methyclothiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like methyclothiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of methyclothiazide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle. Methyclothiazide is used in the management of hypertension either as the sole therapeutic agent or to enhance the effect of other antihypertensive drugs in the more severe forms of hypertension. Also used as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.

Aminoglutethimide, marketing as Cytadren has been used in the treatment of advanced breast and prostate cancer. It was formerly used for its weak anticonvulsant properties. Cytadren is indicated for the suppression of adrenal function in selected patients with Cushing’s syndrome. Morning levels of plasma cortisol in patients with adrenal carcinoma and ectopic ACTH producing tumors were reduced on the average to about one half of the pretreatment levels, and in patients with adrenal hyperplasia to about two thirds of the pretreatment levels, during 1-3 months of therapy with Cytadren. Data available from the few patients with adrenal adenoma suggest similar reductions in plasma cortisol levels. Measurements of plasma cortisol showed reductions to at least 50% of baseline or to normal levels in one third or more of the patients studied, depending on diagnostic groups and time of measurement. Because Cytadren does not affect the underlying disease process, it is used primarily as an interim measure until more definitive therapy such as surgery can be undertaken or in cases where such therapy is not appropriate. Only small numbers of patients have been treated for longer than 3 months. A decreased effect or “escape phenomenon” seems to occur more frequently in patients with pituitary dependent Cushing’s syndrome, probably because of increasing ACTH levels in response to decreasing glucocorticoid levels. Cytadren blocks several other steps in steroid synthesis, including the C-11, C-18, and C-21 hydroxylations and the hydroxylations required for the aromatization of androgens to estrogens, mediated through the binding of Cytadren to cytochrome P-450 complexes. A decrease in adrenal secretion of cortisol is followed by an increased secretion of pituitary adrenocorticotropic hormone (ACTH), which will overcome the blockade of adrenocortical steroid synthesis by Cytadren. The compensatory increase in ACTH secretion can be suppressed by the simultaneous administration of hydrocortisone. Since Cytadren increases the rate of metabolism of dexamethasone but not that of hydrocortisone, the latter is preferred as the adrenal glucocorticoid replacement. Although Cytadren inhibits the synthesis of thyroxine by the thyroid gland, the compensatory increase in thyroid-stimulating hormone (TSH) is frequently of sufficient magnitude to overcome the inhibition of thyroid synthesis due to Cytadren. In spite of an increase in TSH, Cytadren has not been associated with increased prolactin secretion. At low doses, aminogluthethimide is only an effective inhibitor of aromatase (Cytochrome P450 11A1), but at higher doses, it effectively blocks Cytochrome P450 11A1 (P450scc) as well. Citadel was marketed previously as an anticonvulsant but was withdrawn from marketing for that indication in 1966 because of the effects on the adrenal gland.