K+ Sparing Diuretics

Amiloride (10-40 mg/day) can be substituted for spironolactone in patients with tender gynecomastia. Amiloride is more expensive and less effective

Usual maximum doses of diuretic for the treatment of ascites in decompensated cirrhosis are 400 mg/day of spironolactone and 160 mg/day of furosemide.

Spironolactone is a competitive antagonist of the aldosterone receptor. Hypokalemia and hypertension in patients with primary aldosteronism can be controlled by spironolactone, 50-100 mg/d. Although spironolactone is an effective aldosterone receptor antagonist, it is not without side effects that can limit its use in the chronic treatment of this disease. The most important are anti-androgenic reactions.

Spironolactone acts as an antiandrogen by decreasing the production of testosterone by the adrenal gland and by preventing DHT (dihydrotestosterone) from binding to its androgen receptor. As a result of this, in the long run, gynecomastia occurs in more than 10% of the treated men. Impotence, loss of libido, and menstrual irregularities are also common side effects of spironolactone therapy. On the other side, these spironolactone features are the basis for its usage in the treatment of hirsutism, acne, and alopecia.

Spironolactone is also used by transsexuals in the feminizing regimen because of its anti-androgenic actions. 

Cardiac arrhythmia is not a frequent adverse reaction to spironolactone treatment, and it is seen only in the presence of significant hyperkalemia.

Dehydration is usually very mild, and can be prevented with adequate water intake.

Hyperkalemia develops in 5-10% of treated patients, especially if renal function is compromised, or the patient is diabetic, or elderly.

Also Know:

Ans. is ‘a’ i.e., Spironolactone

o Among potassium sparing diuretics, aldosterone antagonists (Spironolactone, eplerenone) reduce mortality in CHF.

Ans. is ‘b’ i.e., Distal tubule

 o Potassium sparing diuretics (Sprionolactone and triameterene) act on late distal tubule and collecting duct.

Ans. is ‘a’ i.e., Spironolactone; ‘b’ i.e., Triamterene; ‘c’ i.e., Amiloride

Potassium sparing diuretics

Aldosterone antagonists          Renal epithelial Na⁺ channel inhibitors

o Spironolactone                         o Amiloride

o Epleronone                              o Triamterene

o Canrenone

o Potassium canrenone

o Prorenone

o Mexrenone

Ans is ‘a’i.e., Eplerenone & b’i.e. Sprionolactone

o Aldosterone antagonists are spironolactone, eplerenone, canrenone, prorenone, mexrenone.

Ans. is ‘a’ i.e., Cirrhotic edema

“Although can be used in all kinds of edema, spironolactone is the drug of choice for initial management of edema of liver cirrhosis”.

Ans. is ‘c’ i.e., ACE inhibitors

o  Spironolactone is a potassium sparing diuretic, therefore, it can cause hyperkalemia decreasing the potassium diuresis.

o ACE inhibitors can also cause hyperkalemia by inhibiting the production of angiotensin I, an inmmediate precursor of angiotensin II. Angiotensin causes excretion of K^t by increasing the secretion of aldosterone (Normally aldosterone enhances absortion of Na’ in distal tubules in exhange of active secretion of Kt).

o ACE inhibitors decrease potassium excretion by inhibiting the generation of Angiotensin.

o Therefore, More pronoundced hyperkalemia can occur in patients receiving ACE inhibitors with sprironolactone.

Ans. is ‘a’ i.e., Enalapril

o More pronounced hyperkalemia can occur in patients receiving ACE inhibitors/ungiotensin receptor blockers with spironolactone.

Answer is B (Thiazide / Amiloride diuretics and salt restriction):

The treatment of Nephrogenic Diabetes Insipidus is usually achieved through a combination of thiazide / amiloride diureties and dietary salt restriction. A prostaglandin synthesis inhibitor (indomethacin) may be added.

• Thiazide diuretics and salt restriction can reduce urinary output by inducing a state of mild volume contraction thereby promoting increased proximal reabsorption of isotonic fluid and inhibiting the delivery of free water to the collecting duct. A combination of thiazide – amiloride formulation will avoid thiazide induced hypokalemia.

Addition of Indomethacin may further reduce urinary output by inhibiting prostaglanding synthesis-Harrison

• Thiazide diuretics in combination with amiloride and indomethacin are the most useful pharmacological agents in the treatment of Nephrogenic diabetes insipidus’- Pediatric Endocrinology (CDC Press) 2007/668

Desmopressin is usually ineffective in Congenital Nephrogenic Diabetes Insipidus. If renal resistance is partial, it may be overcome by ten fold higher doses of desmopressin but this treatment is too expensive and inconvenient to be useful chronically.

Ans. C: Spironolactone

• Aldosterone antagonists: Spironolactone, which is a competitive antagonist of aldosterone. Aldosterone normally adds sodium channels in the principal cells of the collecting duct and late distal tubule of the nephron. Spironolactone prevents aldosterone from entering the principal cells, preventing sodium reabsorption. A similar agent is potassium canreonate.
• Epithelial sodium channel blockers: amiloride and triamterene.

Ans. C: Thiazides act by inhibiting Sodium-potassium-chloride cotransport

High Efficacy diuretics:

–  High ceiling diuretics/Loop diuretics, such as furosemide, inhibit the body’s ability to reabsorb sodium (by inhibiting sodium-potassium-chloride cotransport) at the ascending loop in the kidney which leads to a retention of water in the urine as water normally follows sodium back into the extracellular fluid (ECF). Other examples of high ceiling loop diuretics include ethacrynic acid, torasemide and bumetanide.

Medium efficacy diuretics:

– Thiazide-type diuretics such as hydrochlorothiazide, Clopamide, act on the distal convoluted tubule and inhibit the sodium-chloride symporter leading to retention of water in the urine, as water normally follows penetrating solutes. The short-term anti-hypertensive action is based on the fact that thiazides decrease preload, decreasing blood pressure. On the other hand the long-term effect is due to an unknown vasodilator effect that decreases blood pressure by decreasing resistance.

– Thiazide like diuretics includes chlorthalidone, metolazone, xipamide, indapamide

Weak/adjunctive drugs:

– Carbonic Anhydrase Inhibitors inhibit the enzyme carbonic anhydrase which is found in the proximal convoluted tubule. This results in several effects including bicarbonate retention in the urine, potassium retention in urine and decreased sodium absorption. Drugs in this class include acetazolamide and methazolamide.

– Potassium-sparing diuretics do not promote the secretion of potassium into the urine; thus, potassium is spared and not lost as much as in other diuretics. The term “potassium-sparing” refers to an effect rather than a mechanism or location; nonetheless, the term almost always refers to two specific classes that have their effect at similar locations:

• Aldosterone antagonists: spironolactone, which is a competitive antagonist of aldosterone. Aldosterone normally adds sodium channels in the principal cells of the collecting duct and late distal tubule of the nephron. Spironolactone prevents aldosterone from entering the principal cells, preventing sodium reabsorption. A similar agent is potassium canreonate.
• Epithelial sodium channel blockers: amiloride and triamterene.

Osmotic diuretics as mannitol are filtered in the glomerulus, but cannot be reabsorbed. Their presence leads to an increase in the osmolarity of the filtrate. To maintain osmotic balance, water is retained in the urine.

Ans. C: Hypertension

Spironolactone

• It is a synthetic 17-lactone drug that is a renal competitive aldosterone antagonist in a class of potassium-sparing diuretics

It used primarily to treat heart failure, ascites in patients with liver disease, low-renin hypertension, hypokalemia, secondary hyperaldosteronism (such as occurs with hepatic cirrhosis), and Conn’s syndrome (primary hyperaldosteronism).

On its own, spironolactone is only a weak diuretic because its effects target the distal nephron (collecting tubule), where urine volume can only be slightly modified; but it can be combined with other diuretics to increase efficacy.

• Due to its antiandrogen effect, it can also be used to treat hirsutism.
• It is also used for treating hair loss and acne in women, and can be used as a topical medication for treatment of male baldness.
• It is commonly used to treat symptoms of polycystic ovary syndrome (PCOS) such as excess facial hair and acne.
• Spironolactone can cause gynecomastia in males and, unless regularly monitored, should not be given with potassium supplementation for fear of development of hyperkalemia.

Spironolactone inhibits the effect of aldosterone by competing for intracellular aldosterone receptors in the cortical collecting duct.

• This decreases the reabsorption of sodium and water, while decreasing the secretion of potassium.
• Spironolactone has a fairly slow onset of action, taking several days to develop, and, so, the effect diminishes slowly.
• Spironolactone has anti-androgen activity by directly binding to and blocking androgens from interacting with the androgen receptor, by blocking androgen production, and by increasing estrogen levels.
• Production of androgens is decreased by inhibiting 17alpha-hydroxylase and 17, 20-desmolase, which are enzymes in the testosterone biosynthesis pathway.
• Estrogen levels are increased by enhancing the peripheral conversion of testosterone to estradiol and by displacing estradiol from sex hormone-binding globulin (SHBG)
• Spironolactone is a synthetic steroid that acts as a competitive antagonist to aldosterone.
• Its onset and duration of action are determined by the kinetics of the aldosterone response in the target tissue.
• Substantial inactivation of spironolactone occurs in the liver and hepatitis or cirrhosis can lead to secondary aldosteronism, which is one indication for treatment.
• Spironolactone is associated with an increased risk of bleeding from the stomach and duodenum
• Because it also affects androgen receptors and other steroid receptors, it can cause gynecomastia, menstrual irregularities and testicular atrophy.
• Spironolactone often increases serum potassium levels and can cause hyperkalemia, therefore, it is recommended that people using this drug avoid potassium supplements and salt substitutes containing potassium.
• Long-term administration of spironolactone gives the histologic characteristic of spironolactone bodies in the adrenal cortex.
• Spironolactone bodies are eosinophilic, round, concentrically laminated cytoplasmic inclusions surrounded by clear halos in preparations stained with hematoxylin and eosin.

Ans. is ‘d’ i.e., All of the above