1. SPIRONOLACTONE HISTORY
(How was Spironolactone discovered?)

The US FDA approved Spironolactone in March 1999.

2. SPIRONOLACTONE FACTS

Spironolactone belongs to a group of medications known as the potassium-sparing diuretics. It acts in the kidney to remove excess water from the blood into the urine.

Spironolactone blocks the actions of a hormone called aldosterone, which causes an increase in the removal of salts such as sodium from the blood. This removal of salts causes water to be drawn out of the blood and into the kidneys, where it is then excreted in the urine. Removing water from the blood causes a decrease in the volume of fluid circulating through the blood vessels. This drop in fluid volume decreases the effort required by the heart to pump blood around the body.

There are many conditions, which may lead to an accumulation of fluid in the body (oedema). Spironolactone is commonly used in conditions such as heart failure, where the pumping mechanism of the heart is less effective. It is used to relieve the symptoms of heart failure, such as the shortness of breath seen with fluid on the lungs.

3. ABOUT SPIRONOLACTONE MEDICATION

Spironolactone belongs to a family of drugs called diuretics. 

A diuretic helps reduce the amount of excess fluid in the body by increasing the amount of urine produced.

Diuretics prevent, treat or improve symptoms in a variety of conditions, such as:

• High blood pressure
• Congestive heart failure
• Edema
• Polycystic ovary syndrome
• Certain kidney disorders, such as kidney stones
• Diabetes insipidus
• Female hirsutism
• Osteoporosis

The potency of a diuretic is determined by its ability to result in sodium loss in the urine. This ability is measured as fractional sodium excretion. Fractional sodium excretion is the percentage of filtered sodium which is excreted in the urine. The more potent the diuretic, the greater the ability to interfere with the reabsorption of sodium from the renal tubules resulting in a larger amount of sodium remaining in the excreted urine. The greater the amount of sodium in the urine, the greater the volume of urine.

Potent diuretics include

• Furosemide (25% fractional sodium excretion)
• Ethacrynic acid (25% fractional sodium excretion)
• Moderately potent diuretics include the thiazides (10% fractional sodium excretion)

Weak diuretics include

• osmotic diuretics
• carbonic anhydrase inhibitors (5% fractional sodium excretion)
• aldosterone antagonists (2% fractional sodium excretion)

Diuretics are classified by their mechanism of action. Diuretics work at different locations within the nephron. The classes of Diuretics include:

• osmotics
• inhibitors of urinary acidification
• thiazides
• loop Diuretics
• aldosterone antagonists
• xanthines

 

STRUCTURE OF NEPHRON

(Each human kidney consists of about one million nephrons, together with a maze of blood vessels and some connective tissue.)

Osmotic Diuretics
Osmotic Diuretics include any low molecular weight substance that is freely filtered by the glomeruli but poorly reabsorbed from tubular fluid. Examples include:

• urea which is increased in blood in azotemic states acts as an endogenous diuretic
• glucose which is increased in diabetes mellitus or by exogenous administration
• mannitol which is most commonly used to reduce neuronal edema in patients with CNS signs and less commonly is used in the oliguric ARF patient.

Osmotic Diuretics cause expansion of the extracellular fluid volume by relocating intracellular fluid to the extracellular space, specifically to the plasma.

Inhibitors of Urinary Acidification

Carbon dioxide is produced in renal tubular epithelial cells or is brought to the kidneys in the blood. (1) Carbon dioxide reacts with water in the presence of carbonic anhydrase (CA) to form carbonic acid.(2) Carbonic acid spontaneously breaks down to hydrogen ion and bicarbonate.(3) This bicarbonate is reabsorbed. (3) Water in the cell ionizes to hydrogen and hydroxyl ions. Hydrogen ions from the above 2 sources exchange for sodium in the tubular fluid. The secreted hydrogen ion (4) combines with bicarbonate (5) in the tubular fluid to form carbonic acid (6) that disassociates into water and carbon dioxide (7). The carbon dioxide equilibrates across the renal tubular epithelium. The end result is that for each bicarbonate filtered into tubular fluid one bicarbonate is reabsorbed. The blue numbers on the diagram correlate with the blue numbers in the text above.

Diuretics which inhibit the enzyme carbonic anhydrase impair the reabsorption of bicarbonate from tubular fluid. Sodium and water are eliminated in urine in conjunction with the lost bicarbonate.

Acetazolamide is an example of this class of Diuretics. The bicarbonate in the tubular fluid is negatively charged and will draw positively charged ions such as potassium into the urine, enhancing the loss of potassium. Some of the sodium which normally would have been reabsorbed from tubular fluid paired with bicarbonate will be reabsorbed with chloride instead. (for each negatively charged ion reabsorbed, one positively charged ion will be reabsorbed as well.) The increased reabsorption of chloride and increased loss of potassium coupled with impaired ability to reabsorb bicarbonate can lead to hyperchloremic acidosis and hypokalemia.

Carbonic anhydrase is also found in the eye where it is involved in the production of aqueous humour. Carbonic anhydrase inhibiting Diuretics are most often used to reduce the production aqueous humour in patients with glaucoma. The diuretic effects occur in conjunction with the effects on fluid production in the eye. Therefore the side effects of acidosis, hyperchloridemia, hypokalemia and dehydration may occur in treated patients.

Thiazide Diuretics
Thiazides such as hydrochlorothiazide are moderately potent Diuretics. They inhibit carbonic anhydrase to a minor degree and more importantly, impede the reabsorption of sodium and chloride in the distal convoluted tubule and loop of Henle. The end result is increased excretion of Na, Cl, K and water. Additionally thiazide diuretics decrease renal excretion of calcium and therefore should not be given to hypercalcemic patients. Potential side effects of thiazides include hypokalemia and metabolic alkalosis. Alkalosis occurs as the sodium that is reabsorbed is absorbed primarily with bicarbonate as the reabsorption of chloride is blocked. Thiazides are used in the treatment of arterial hypertension and may have some direct relaxing effect on vascular smooth muscle in addition to the diuretic effect. Thiazide diuretics may decrease the severity of polyuria in patients with diabetes insipidus (decrease urine volume by 30-40%). It is not clear how a diuretic actually decreases urine volume in these patients

Loop diuretics include Lasix (furosemide) and ethacrynic acid. They have a rapid oral absoprtion. There is a diuretic effect within minutes which persists for 1-3 hours. The action is to strongly inhibit Cl pump in ascending loop of Henle (and subsequently Na reabsorption). They can produce hypokalemia and metabolic alkalosis.

Aldosterone antagonists

Aldosterone antagonists like Spironolactone compete with aldosterone for its physiologic binding site. Aldosterone antagonists are usually given with other, more potent, diuretics for their effect of potassium sparing. Hyperkalemia (increased levels of potassium) is a possible side effect

Xanthines

Xanthines include caffeine, theobromine, and theophylline which is a bronchodilator. Xanthines act to increase cardiac output which increases GFR (Glomerular filtration rate) resulting in a modest loss of Na, Cl, and water. Additionally a direct tubular action is suspected as their effect persists after GFR returns to normal. 

4.SPIRONOLACTONE EFFECTIVENESS
(When is Spironolactone best taken?)

Spironolactone is rapidly and extensively metabolized. Sulfur-containing products are the predominant metabolites and are thought to be primarily responsible, together with Spironolactone, for the therapeutic effects of the drug. The following pharmacokinetic data were obtained from 12 healthy volunteers following the administration of 100 mg of Spironolactone daily for 15 days. On the 15th day, Spironolactone was given immediately after a low-fat breakfast and blood was drawn thereafter.

The pharmacological activity of Spironolactone metabolites in man is not known. However, in the adrenalectomized rat the antimineralocorticoid activities of the metabolites C, T.S. and HTMS, relative to Spironolactone, were 1.10, 1.28, and 0.32, respectively. Relative to Spironolactone, their binding affinities to the aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06, respectively.

In humans the potencies of TMS and 7-alpha-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33 and 0.26, respectively, relative to Spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities.

Spironolactone and its metabolites are more than 90% bound to plasma proteins. The metabolites are excreted primarily in the urine and secondarily in bile.

The effect of food on Spironolactone absorption was assessed in a single dose study of 9 healthy, drug-free volunteers. Food increased the bioavailability of unmetabolized Spironolactone by almost 100%. The clinical importance of this finding is not known.

5.SPIRONOLACTONE EFFECTS ON SPECIAL POPULATION
(How do different people react to Spironolactone?)

Pregnancy
There are no adequate and well-controlled studies with Spironolactone dose in pregnant women. Spironolactone has known endocrine effects in animals including progestational and antiandrogenic effects. The antiandrogenic effects can result in apparent estrogenic side effects in humans, such as gynecomastia. Therefore, the use of Spironolactone dose in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the fetus.

Nursing Mothers
Canrenone, a major (and active) metabolite of Spironolactone, appears in human breast milk. Because Spironolactone has been found to be tumorigenic in rats, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted.

Pediatric Use
Safety and effectiveness in pediatric patients have not been established.

6.SPIRONOLACTONE EFFECTS ON MEDICAL CONDITIONS
(How does Spironolactone affect your existing condition/ailment?)

Spironolactone should not be used if you suffer from failure of the kidneys to produce urine (anuria).

Spironolactone should not be used if you suffer from Hyperkalemia, inadequate production of natural steroid hormones by the adrenal glands (Addison's disease) and acute renal insufficiency. 

7.OTHER/ALTERNATE USES OF SPIRONOLACTONE
(What else does Spironolactone treat?)

Spironolactone is also used to remove excess fluid associated with liver failure, as well as in the treatment of excessive levels of aldosterone (hyperaldosteronism). 

Spironolactone also reduces testosterone levels in women with polycystic ovary syndrome (PCOS).

8.ADVERSE/SIDE EFFECTS of SPIRONOLACTONE
(What are the side effects of Spironolactone?)

The following adverse reactions have been reported and within each category (body system), are listed in order of decreasing severity.

Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting.

Endocrine: Gynecomastia, inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding. Carcinoma of the breast has been reported in patients taking Spironolactone but a cause and effect relationship has not been established.

Hematologic: Agranulocytosis.

Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis.

Nervous system/psychiatric: Mental confusion, ataxia, headache, drowsiness, lethargy.

Liver/biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with Spironolactone administration.

Renal: Renal dysfunction (including renal failure).