Aldactide (Hydroflumethiazide_Spironolactone)

Uses

Hydroflumethiazide is a thiazide diuretic used to treat hypertension as well as edema due to congestive heart failure and liver cirrhosis.

Used as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Also 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.

Spironolactone is used for Congestive heart failure, Hepatic cirrhosis with ascites and oedema, Nephrotic syndrome, Primary hyperaldosteronism, Essential hypertension, For the treatment of patients with hypokalemia

Spironolactone is a long-acting aldosterone antagonist. Spironolactone is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium and magnesium is retained.

Aldactide (Hydroflumethiazide_Spironolactone) is also used to associated treatment for these conditions: Edema, High Blood Pressure (Hypertension)Acne, Ascites, Congestive Heart Failure (CHF), Edema, High Blood Pressure (Hypertension), Hypokalemia, Idiopathic Hirsutism, Nephrotic Syndrome, Primary Hyperaldosteronism, Secondary hyperaldosteronism, Chronic heart failure with reduced ejection fraction (NYHA Class III), Chronic heart failure with reduced ejection fraction (NYHA Class IV), Idiopathic hyperaldosteronism

How Aldactide (Hydroflumethiazide_Spironolactone) works

Hydroflumethiazide is a thiazide diuretic that inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, Hydroflumethiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

Spironolactone competitively inhibits aldosterone dependant sodium potassium exchange channels in the distal convoluted tubule. This action leads to increased sodium and water excretion, but more potassium retention. The increased excretion of water leads to diuretic and also antihypertensive effects.

Dosage

Aldactide (Hydroflumethiazide_Spironolactone) dosage

Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome): An initial daily dosage of 100 mg of Spironolactone administered in either single or divided doses is recommended, but may range from 25 to 200 mg daily. Combined therapy with other diuretics is indicated when more rapid diuresis is desired.

Primary hyperaldosteronism: After the diagnosis of hyperaldosteronism has been established, Spironolactone may be administered in doses of 100 to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, Spironolactone may be employed for long-term maintenance therapy at the lowest effective dosage determined for the individual patient.

Essential hypertension: For adults, an initial daily dosage of 50 to 100 mg of Spironolactone administered in either single or divided doses is recommended.

Hypokalemia: Spironolactone in a dosage ranging from 25 mg to 100 mg daily is useful in treating a diuretic-induced hypokalemia.

Side Effects

Gynaecomastia may develop in association with the use of Spironolactone. Other adverse reactions are: GI symptoms including cramping and diarrhoea, drowsiness, lethargy, headache, urticaria, mental confusion, impotence, irregular menses or amenorrhoea and post-menopausal bleeding.

Toxicity

Overdoses lead to diuresis, lethargy progressing to coma, with minimal cardiorespiratory depression and with or without significant serum electrolyte changes or dehydration.

Patients experiencing an overdose may present with drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Vomiting is generally induced or a gastric lavage is performed. Supportive treatment involves maintining hydration, electrolyte balance, and vital functions.

The oral LD50 in mice, rats, and rabbits is >1g/kg.

Spironolactone should be avoided in pregnancy due to reports of feminization of male fetuses in animal studies. Active metabolites of spironolactone are present in breast milk and levels that are likely inconsequential, though the long term effects have not been studied.

In animal studies, spironolactone slowed follicle development, ovulation, and implantation. Spironolactone increased the incidence of benign adenomas in the testes of male rats, benign uterine endometrial stromal polyps in female rats, and thyroid follicular cell adenomas in both sexes of rats. Spironolactone and canrenone are generally not considered to be mutagenic in tests but canrenone occasionally tests positive for mutagenicity with metabolic activation and spironolactone has occasionally tested inconclusive though slightly positive for mutagenicity.

Precaution

All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance. Hyperkalemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities, which may be fatal.

Interaction

ACE inhibitors: Concomitant administration of ACE inhibitors with potassium-sparing diuretics has been associated with severe hyperkalemia.

Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur.

Lithium: Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.

Digoxin: Spironolactone has been shown to increase the half-life of digoxin.

Volume of Distribution

Volume of distribution data is not readily available.

Elimination Route

Hydroflumethiazide is incompletely but fairly rapidly absorbed from the gastrointestinal tract

Spironolactone reaches a maximum concentration in 2.6 hours and an active metabolite (canrenone) reaches a maximum concentration in 4.3 hours. When taken with food, the bioavailability of spironolactone increases to 95.4%.

Giving spironolactone with food increases the maximum concentration from 209ng/mL to 301ng/mL. The time to maximum concentration also increases from 2.28 hours to 3.05 hours. The area under the curve varies from 2103ng/mL*hr to 4544ng/mL*hr.

Half Life

It appears to have a biphasic biological half-life with an estimated alpha-phase of about 2 hours and an estimated beta-phase of about 17 hours

1.4 hours.

Canrenone has a half life of 16.5 hours, 7-α-thiomethylspirolactone has a half life of 13.8 hours, and 6-ß-hydroxy-7-α-thiomethylspirolactone has a half life of 15 hours.

Clearance

Clearance data is not readily available.

Elimination Route

Metabolites of spironolactone are excreted 42-56% in urine, and 14.2-14.6% in the feces. No unmetabolized spironolactone is present in the urine.

Pregnancy & Breastfeeding use

Pregnancy: Spironolactone should not be used during pregnancy

Lactation: Canrenone, an active metabolite of Spironolactone, appears in breast milk. If use of the drug is deemed essential an alternative method of infant feeding should be instituted.

Contraindication

Spironolactone is contraindicated in patients with acute renal insufficiency, significant impairment of renal function, anuria, hyperkalaemia or sensitivity to Spironolactone.

Acute Overdose

Symptoms of overdosage include drowsiness, mental confusion, dizziness, diarrhea and vomiting etc. Patients should induce vomiting or evacuate the stomach by lavage during Spironolactone overdoasge.

Storage Condition

Store in a cool and dry place protected from light. Keep out of reach of children.

Innovators Monograph

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