Potassium sparing diuretics

Spironolactone

pironolactone (marketed under the trade names  is a diuretic and is used as an antiandrogen.

It is a synthetic 17-lactone drug that is a renal competitive aldosterone antagonist in a class ofpharmaceuticals called potassium-sparing diuretics, used primarily to treat heart failure, ascitesin 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. About one person in one hundred with hypertension has elevated levels of aldosterone; in these persons, the antihypertensive effect of spironolactone may exceed that of complex combined regimens of other antihypertensives. 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. It can also cause gynecomastia in males and should never be given with potassium supplementation for fear of the development of hyperkalemia.

Mechanism of action

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. This is because steroid pathways alter gene transcription, and it will take several days for the gene products to change (in this case the ENaC and ROMK channels will be decreased). Spironolactone has anti-androgen activity by binding to the androgen receptor and preventing it from interacting withdihydrotestosterone.

Pharmacokinetics

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 orcirrhosis can lead to secondary aldosteronism, which is one indication for treatment. Overall, spironolactone has a rather slow onset of action, requiring several days before full therapeutic effect is achieved

rtality and morbidity benefit in heart failure

Spironolactone was shown to have a significant mortality and morbidity benefit in the Randomized Aldactone Evaluation Study (RALES), which studied people with severe congestive heart failure (New York Heart Association functional class III or IV).^[2] Patients in the study arm of the trial (those receiving spironolactone) had a relative risk of death (when compared to the placebo group) equal to 0.70 or a 30% relative risk reduction. Patients in the study arm also had fewer symptoms of CHF and were hospitalized less frequently.

The mechanism of this effect is also mediated by inhibiting aldosterone, which in conjunction with heart failure leads to myocardial remodeling including fibrosis, sodium retention, and vascular dysfunction.

adverse effects and interactions

Spironolactone is associated with an increased risk of bleeding from the stomach and duodenum, but a causal relationship between the two has not been established. Because it also affects androgen receptors and other steroid receptors, it can cause gynecomastia, menstrual irregularities and testicular atrophy. Other side effects include ataxia, erectile dysfunction, drowsiness, and rashes. A carcinogenic effect has been demonstrated in rats, see below. Spironolactone has been shown to be immunosuppressive in the treatment of sarcoidosis.

Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, it is recommended that people using this drug avoid potassium supplements and salt substitutes containing potassium. Doctors usually recommend periodic screening of serum potassium levels and some patients may be advised to limit dietary consumption of potassium.

Research has also shown spironolactone can interfere with the effectiveness of antidepressant treatment. The drug is actually (among its other receptor interactions) a mineralocorticoid (MR) antagonist, and has been found to reduce the effectiveness of antidepressant drugs in the treatment of major depression, it is presumed, by interfering with normalization of the hypothalamic-pituitary-adrenal axis in patients receiving antidepressant therapy.

Carcinogenicity

Studies of spironolactone and the related compound potassium canrenoate (which, like spironolactone, metabolizes to canrenone) in rats for one- to two-year periods show an increase in carcinogenesis in the thyroid gland, testes, liver, breasts, and myelocytic leukocytes. Mammalian cells, depending on the presence of metabolic activation, show mixed results for mutagenicity in vitro.^[7] Doses relative to body weight were 10 to 150 mg per kg, which is ten to 500 times higher than normal doses for treating humans. In light of this research, Sandozhas recommended that unnecessary use of spironolactone be avoided.

Other potential benefits

It has been suggested that spironolactone can reduce the risk of Alzheimer's disease. In one study, researchers observed a reduction in the risk of Alzheimer's specifically associated with potassium-sparing diuretics. Unpublished findings from other studies, including theGothenberg Study have suggested that higher potassium levels may be associated with a lower risk of dementia.

Spironolactone may have antifibrotic properties and an NIH-sponsored randomized control trial of treatment of patients with diastolic heart failure with this drug, known as the TOPCAT Study has been planned (heart failure patients with diastolic dysfunction have evidence of active collagen metabolism and increasing fibrosis

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Eplerenone

Eplerenone is an aldosterone antagonist used as an adjunct in the management of chronic heart failure. It is similar to the diuretic spironolactone, though it may be more specific for the mineralocorticoid receptor and is specifically marketed for reducingcardiovascular risk in patients following myocardial infarction. It is marketed by Pfizer under the trade name Inspra.

Clinical use

Indications

Eplerenone is specifically indicated for the reduction of risk of cardiovascular death in patients with heart failure and left ventricular dysfunction within 3–14 days of an acute myocardial infarction, in combination with standard therapies and as treatment against hypertension.

Contraindications

Eplerenone is contraindicated in patients with hyperkalaemia, severe renal impairment(creatinine Cl less than 30 ml/min), or severe hepatic impairment (Child-Pugh score C). The manufacturer of eplerenone also contraindicates ( relative C.I. ) concomitant treatment withketoconazole, itraconazole or other potassium-sparing diuretics (though the manufacturer still considers taking these drugs to be absolute C.I.) Potential benefits should be weighted against possible risks.

Adverse effects

Common adverse drug reactions (ADRs) associated with the use of eplerenone include:hyperkalaemia, hypotension, dizziness, altered renal function, and increased creatinine concentration.^[

Drug interactions

Eplerenone is primarily metabolised by the cytochrome P450 enzyme CYP3A4. Thus the potential exists for adverse drug interactions with other drugs that induce or inhibit CYP3A4. Specifically, the concomitant use of the CYP3A4 potent inhibitors ketoconazole anditraconazole is contraindicated. Other CYP3A4 inhibitors including erythromycin, saquinavir, and verapamil should be used with caution. Other drugs that increase potassium concentrations may increase the risk of hyperkalaemia associated with eplerenone therapy, including salt substitutes, potassium supplements and other potassium-sparing diuretics.

General considerations

Due to the high risk of elevated potassium levels in individuals taking eplerenone, The United States FDA suggests routine checks on the individual's potassium level to screen for hyperkalemia.

Triamterene

Triamterene (trade name Dyrenium) is a potassium-sparing diuretic used in combination withthiazide diuretics for the treatment of hypertension and edema.

Mechanism of action

Triamterene directly blocks the epithelial sodium channel^[1] (ENaC) on the lumen side of the kidney collecting tubule. Other diuretics cause a decrease in the sodium concentration of the forming urine due to the entry of sodium into the cell via the ENaC, and the concomitant exit of potassium from the principal cell into the forming urine. Blocking ENaC prevents this from happening. Amiloride works in the same way. Sodium channel blockers directly inhibit the entry of sodium into the sodium channels.

Side effects

Common side effects may include a depletion of sodium, folic acid and calcium, nausea, vomiting, diarrhea, headache, dizziness, fatigue, and dry mouth. Serious side effects may include heart palpitations, tingling/numbness, fever, chills, sore throat, rash, and back pain. Triamterene can also cause kidney stones through direct crystallization or by seeding calcium oxalate stones. Triamterene is best avoided in patients with chronic kidney disease due to the possibility of hyperkalemia. People using this drug should use salt substitute cautiously.

Triamterene may impart a blue fluorescent color to the urine.

Caution with certain disease states

Diabetes: Use with caution in patients with prediabetes or diabetes mellitus as there may be a change in glucose control.

Hepatic impairment: Use with caution in patients with severe hepatic dysfunction; in cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy.

Kidney stones: Use with caution in patients with kidney stones.

Use should be avoided if the creatinine clearance is less than 10 ml/minute.

Use in Ménière's disease

While there is a lack of randomized controlled trials evaluating the use of triamterene in the treatment of Ménière's disease, the typical treatment is 37.5 mg of triamterene with 25 mg of hydrochlorothiazide 1-2 capsules daily. This recommendation was given a grade of C (see http://www.aafp.org/afpsort.xml for information about the SORT evidence rating system).

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Amiloride

Amiloride is a potassium-sparing diuretic, first approved for use in 1967 (then known as MK 870), used in the management of hypertension and congestive heart failure.

Structure

Amiloride is a guanidinium group containing pyrazine derivative.

Mechanism of action

Amiloride works by directly blocking the epithelial sodium channel (ENaC) thereby inhibitingsodium reabsorption in the late distal convoluted tubules, connecting tubules, and collecting ducts in the kidneys (this mechanism is the same for triamterene). This promotes the loss of sodium and water from the body, but without depleting potassium. The drug is often used in conjunction with thiazide (e.g. co-amilozide) or loop diuretics (e.g. co-amilofruse). Due to its potassium-sparing capacities, hyperkalemia (high blood potassium levels) are occasionally observed in patients taking amiloride. The risk is high in concurrent use of ACE inhibitors orspironolactone. Patients are also advised not to use potassium-containing salt replacements. Amiloride also carries the risk of developing an acidosis.

A fraction of the effects of amiloride is inhibition of cyclic GMP-gated cation channels in the inner medullary collecting duct.

Amiloride has a second action on the heart, blocking Na+/H+ exchangers Sodium-hydrogen antiporter 1 or NHE-1. This minimizes reperfusion injury in ischemic attacks.

Acid-Sensing ion channels (ASICs) are also sensitive to inhibition by Amiloride. ASICs are involved in nociceptor responses to pH