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POTASSIUM SPARING DIURETICS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Potassium sparing diuretics interfere with reabsorption of sodium at the distal tubule, thereby decreasing potassium secretion.

Specific Substances

    A) AMILORIDE
    1) 3,5-Diamino-N-(aminoiminomethyl)-6-chlorpyrazine
    2) carboximide
    3) Amipramidin
    4) Amipramizide
    5) Guanamprazine
    6) Molecular Formula: C6-H8-Cl-N7-O
    7) CAS 2609-46-3
    SPIRONOLACTONE
    1) 7-(Acetylthio)-17-hydroxy-3-oxo-pregn-4-ene-21-
    2) carboxylic acid
    3) SC 9420
    4) Molecular Formula: C24-H32-O4-S
    5) CAS 52-01-7
    TRIAMTERENE
    1) Molecular Formula: C12-H11-N7
    2) NSC 77625
    3) SKF 8542
    4) 6-Phenyl-2,4,7-pteridinetriamine
    5) CAS 396-01-0
    GENERAL TERMS
    1) Diuretics, potassium sparing

Available Forms Sources

    A) FORMS
    1) AMILORIDE hydrochloride is available as 5 mg tablets (Prod Info amiloride HCl oral tablets, 2009).
    2) SPIRONOLACTONE is available as 25 mg, 50 mg, and 100 mg tablets (Prod Info Aldactone(R) oral tablets, 2011).
    3) TRIAMTERENE is available as 50 mg and 100 mg capsules (Prod Info DYRENIUM(R) oral capsules, 2005).
    B) USES
    1) Potassium sparing diuretics are used as single agents to exert a weak diuretic and antihypertensive effect (Prod Info Aldactone(R) oral tablets, 2011; Prod Info amiloride HCl oral tablets, 2009).
    2) These agents may be given alone or with other diuretic agents that act more proximally in the renal tubule (Prod Info Aldactone(R) oral tablets, 2011).
    3) AMILORIDE is indicated as adjunctive treatment with thiazide diuretics or other kaliuretic diuretic agents in CHF or hypertension to help restore normal serum potassium levels in patients who develop hypokalemia on the kaliuretic diuretic; to prevent the development of hypokalemia in patients who would be exposed to particular risk if hypokalemia were to develop (eg, digitalized patients or patients with significant cardiac dysrhythmias) (Prod Info amiloride HCl oral tablets, 2009).
    4) SPIRONOLACTONE is used in the treatment of primary hyperaldosteronism and for edematous conditions (eg, CHF, cirrhosis of the liver accompanied by edema/ascites, nephrotic syndrome, essential hypertension, and severe heart failure) (Prod Info Aldactone(R) oral tablets, 2011).
    5) TRIAMTERENE is indicated in the treatment of edema associated with CHF, cirrhosis of the liver and the nephrotic syndrome; steroid-induced edema, idiopathic edema and edema due to secondary hyperaldosteronism (Prod Info DYRENIUM(R) oral capsules, 2005).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Potassium sparing diuretics are used to treat congestive heart failure, fluid retention from liver failure, and hypertension. Spironolactone is used to prevent amphotericin B-related hypokalemia in cancer patients, and in the management of neonatal chronic lung disease.
    B) PHARMACOLOGY: Amiloride acts by blocking the sodium channel in the later portion of the nephron, distal tubule, and collecting duct. Triamterene inhibits the reabsorption of sodium ions in the exchange for potassium and hydrogen ions in the segment of the distal tubule under the control of adrenal mineralocorticoids. Eplerenone and spironolactone bind to aldosterone receptors in the distal tubules and collecting duct, preventing the binding of aldosterone to its receptor. Aldosterone acts at the kidney to cause sodium and water retention and potassium loss in the urine.
    C) TOXICOLOGY: Overdose may cause dehydration due to the diuretic effect. It can also cause electrolyte abnormalities, most commonly hyperkalemia.
    D) EPIDEMIOLOGY: Adverse effects during therapeutic use are relatively common. Potassium sparing diuretic overdose is rare and deaths have not been reported.
    E) WITH THERAPEUTIC USE
    1) AMILORIDE: Hyperkalemia, headache, paresthesia, depression, loss of libido, nausea, anorexia, diarrhea, vomiting, weakness, fatigue, muscle cramps.
    2) EPLERENONE: Hyperkalemia, diarrhea, dizziness, fatigue, coughing.
    3) SPIRONOLACTONE: Hyperkalemia, acidosis, cramping, diarrhea, drowsiness, lethargy, ataxia, gynecomastia, impotence, irregular menses.
    4) TRIAMTERENE: Hyperkalemia, diarrhea, nausea, vomiting, interstitial nephritis, blood dyscrasias, nephrolithiasis, photodermatitis.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, diarrhea, mild dehydration, and hyperkalemia may develop.
    2) SEVERE TOXICITY: Severe toxicity has not been reported, but severe dehydration (tachycardia, hypotension, and possibly mental status changes) and hyperkalemia (which may cause dysrhythmias) should be expected. Acute renal failure has been reported from triamterene deposition in the renal tubules after overdose.
    0.2.20) REPRODUCTIVE
    A) AMILORIDE and EPLERENONE are classified as FDA category B. SPIRONOLACTONE, SPIRONOLACTONE/HYDROCHLOROTHIAZIDE, TRIAMTERENE, and TRIAMTERENE/HYDROCHLOROTHIAZIDE are classified as FDA category C. There are no adequate and well-controlled studies of potassium sparing diuretic use during pregnancy. In animal studies, there was no evidence of teratogenic effects in studies with AMILORIDE, EPLERENONE, SPIRONOLACTONE/HYDROCHLOROTHIAZIDE, or TRIAMTERENE/HYDROCHLOROTHIAZIDE. Embryotoxic effects in animals included decreased body weight, increased fetal resorptions, and post-implantation loss with EPLERENONE and with SPIRONOLACTONE/HYDROCHLOROTHIAZIDE, and progestational and antiandrogenic effects with SPIRONOLACTONE. Modest amounts of amiloride crossed the placental barrier following maternal AMILORIDE exposure in mice and rabbits. In human lactation studies, canrenone, a major, active metabolite of SPIRONOLACTONE, appears in human breast milk. In animal fertility studies, slowed ovarian follicle development and a reduction in circulating estrogen levels were observed in female rats following SPIRONOLACTONE exposure and there was a decreased rate in the number of mated mice that conceived, the number of implanted embryos in those that became pregnant, and a decrease in the latency period to mating in mice.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturers of amiloride/hydrochlorothiazide and triamterene do not report any carcinogenic potentials in humans. Although a causal relationship has not been established, carcinoma of the breast has been reported with spironolactone therapy.

Laboratory Monitoring

    A) Monitor serum electrolytes and ECG after overdose.
    B) Drug concentrations are not routinely available and are not used clinically to guide management following overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Serious toxicity is not expected after ingestion. Most patients will remain asymptomatic or have a mild diuresis. Oral rehydration and monitoring for hyperkalemia is sufficient in most cases.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Correct dehydration with intravenous fluids. There is a theoretical risk of hyperkalemia following overdose. Hyperkalemia is treated in the usual fashion: administer calcium chloride for dysrhythmias or wide complex rhythms. Sodium bicarbonate, insulin, glucose, and cationic exchange resins (eg, sodium polystyrene sulfonate) may also be used. Dialysis may be required for patients with impaired renal function.
    C) DECONTAMINATION
    1) PREHOSPITAL: Gastrointestinal decontamination is not indicated.
    2) HOSPITAL: Gastrointestinal decontamination should not be routinely performed following potassium sparing diuretic ingestion. Activated charcoal may be considered after extremely large ingestions or if more toxic coingestants are involved and the patient has presented early after the ingestion.
    D) AIRWAY MANAGEMENT
    1) Airway compromise is not expected following potassium sparing diuretic ingestion.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) As significant toxicity is not expected, there is no role for enhanced elimination following ingestion. Dialysis is ineffective in removing spironolactone, but may increase the clearance of triamterene.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with small, inadvertent ingestions and normal renal function can be monitored at home.
    2) OBSERVATION CRITERIA: Patients with large or deliberate ingestions or impaired renal function should be monitored for fluid status and serum electrolytes changes (particularly sodium and potassium). Monitor vital signs and ECG in symptomatic patients and those with significant electrolyte abnormalities.
    3) ADMISSION CRITERIA: Admit patients with severe electrolyte abnormalities, dehydration, or impaired renal function.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) Failure to recognize that these medications may cause hyperkalemia during therapeutic use.
    I) PHARMACOKINETICS
    1) AMILORIDE: 30% to 90% oral bioavailability. Onset of diuresis is within 2 to 3 hours of an oral dose; peak effects on electrolyte excretion occur within 6 to 10 hours. Volume of distribution is 350 to 380 liters. There is minimal metabolism and is mainly excreted unchanged in the urine, with 50% excreted in the urine and 40% fecal excretion within 72 hours after administration of a 20-mg dose. The plasma half-life is 6 to 9 hours.
    2) EPLERENONE: Absolute bioavailability is 69%. Peak plasma concentrations occur approximately 1.5 hours following oral administration. Protein binding is approximately 50% and the volume of distribution ranges from 43 to 90 liters. Primarily metabolized in the liver via cytochrome P450 3A4 enzymes. Less than 5% of dose is excreted unchanged in the urine and feces. Elimination half-life is approximately 4 to 6 hours.
    3) SPIRONOLACTONE: Spironolactone is relatively slow in onset with maximal effects usually occurring after the third day of therapeutic use of the drug, with effects persisting up to 3 days following discontinuation of the drug. Peak serum concentrations are attained 1 to 3 hours. Protein binding is more than 90%. It is rapidly and extensively metabolized to an active metabolite, canrenone. Approximately 30% of the administered dose is reported to be recovered in the urine after 5 days and 23% in the feces after 5 days. The elimination half-life is 70 hours.
    4) TRIAMTERENE: Oral bioavailability is 30% to 70%. Onset of diuresis occurs 2 to 4 hours after ingestion. Mean peak serum concentrations were 30 ng/mL at 3 hours in healthy volunteers. Primarily metabolized to the sulfate conjugate of hydroxytriamterene. Approximately 21% is recovered in the urine. Elimination half-life is 1.5 to 2.5 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Non-toxicological causes of dehydration and hyperkalemia; cardioactive steroid poisoning (eg, digoxin), ACE inhibitor intoxication.

Range Of Toxicity

    A) TOXICITY: No toxic dose for these medications has been established. An adult developed acute renal failure 3 days after ingesting 50 capsules of triamterene/hydrochlorothiazide. Two infants, ages 10 and 12 months, ingested up to 60 spironolactone tablets, with asymptomatic hyperkalemia as the only effect noted.
    B) THERAPEUTIC DOSE: AMILORIDE: ADULT: 5 to 20 mg/day orally; PEDIATRIC: 6 to 20 kg in body weight: 0.625 mg/kg/day orally. EPLERENONE: ADULT: 25 to 50 mg orally once or twice daily; PEDIATRIC: Safety and efficacy not established. SPIRONOLACTONE: ADULT: 25 to 100 mg/day orally in single or divided doses; PEDIATRIC: 1 to 3 mg/kg/day orally in 2 to 4 divided doses or once daily; MAX 200 mg/day. TRIAMTERENE: ADULT: 100 mg orally twice daily; MAX 300 mg/day; PEDIATRIC: Edema: 1 to 4 mg/kg/day orally in 2 divided doses. Hypertension: initially, 1 to 2 mg/kg/day orally in two divided doses; MAX 3 to 4 mg/kg/day, up to 300 mg/day.

Clinical Effects

Summary Of Exposure

    A) USES: Potassium sparing diuretics are used to treat congestive heart failure, fluid retention from liver failure, and hypertension. Spironolactone is used to prevent amphotericin B-related hypokalemia in cancer patients, and in the management of neonatal chronic lung disease.
    B) PHARMACOLOGY: Amiloride acts by blocking the sodium channel in the later portion of the nephron, distal tubule, and collecting duct. Triamterene inhibits the reabsorption of sodium ions in the exchange for potassium and hydrogen ions in the segment of the distal tubule under the control of adrenal mineralocorticoids. Eplerenone and spironolactone bind to aldosterone receptors in the distal tubules and collecting duct, preventing the binding of aldosterone to its receptor. Aldosterone acts at the kidney to cause sodium and water retention and potassium loss in the urine.
    C) TOXICOLOGY: Overdose may cause dehydration due to the diuretic effect. It can also cause electrolyte abnormalities, most commonly hyperkalemia.
    D) EPIDEMIOLOGY: Adverse effects during therapeutic use are relatively common. Potassium sparing diuretic overdose is rare and deaths have not been reported.
    E) WITH THERAPEUTIC USE
    1) AMILORIDE: Hyperkalemia, headache, paresthesia, depression, loss of libido, nausea, anorexia, diarrhea, vomiting, weakness, fatigue, muscle cramps.
    2) EPLERENONE: Hyperkalemia, diarrhea, dizziness, fatigue, coughing.
    3) SPIRONOLACTONE: Hyperkalemia, acidosis, cramping, diarrhea, drowsiness, lethargy, ataxia, gynecomastia, impotence, irregular menses.
    4) TRIAMTERENE: Hyperkalemia, diarrhea, nausea, vomiting, interstitial nephritis, blood dyscrasias, nephrolithiasis, photodermatitis.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, diarrhea, mild dehydration, and hyperkalemia may develop.
    2) SEVERE TOXICITY: Severe toxicity has not been reported, but severe dehydration (tachycardia, hypotension, and possibly mental status changes) and hyperkalemia (which may cause dysrhythmias) should be expected. Acute renal failure has been reported from triamterene deposition in the renal tubules after overdose.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) VISUAL DISTURBANCE: Increased ocular pressure and visual disturbances may be noted (Ellenhorn & Barceloux, 1988). Grant & Schuman (1993) reported no adverse effect on intraocular pressure in normal or glaucomatous patients (Grant & Schuman, 1993).
    2) MYOPIA: Acute transient myopia has been reported. This rare phenomenon may be an idiosyncratic reaction (Belci, 1968).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) Bradycardia may occur with hyperkalemia (Prod Info Aldactone(R) oral tablets, 2011; Prod Info amiloride HCl oral tablets, 2009).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) Tall, peaked T waves or T-wave elevations compared with previous tracings, lowered R waves, increased depth of the S wave, widening or absence of the P wave, progressive widening of the QRS complex, prolongation of the PR interval, and/or depression of ST segment have been associated with ECG changes of hyperkalemia (Prod Info amiloride HCl oral tablets, 2009).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) INFLUENZA-LIKE SYMPTOMS
    1) WITH THERAPEUTIC USE
    a) EPLERENONE: Coughing and influenzalike symptoms (2%) have been reported in patients (n=945) receiving eplerenone (Prod Info INSPRA(R) oral tablets, 2008).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) PARESTHESIA
    1) Hyperkalemia symptoms include paresthesias, weakness, areflexia, fatigue, and flaccid paralysis of the extremities (Prod Info Aldactone(R) oral tablets, 2011; Prod Info amiloride HCl oral tablets, 2009; Udezue & Harrold, 1980).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) AMILORIDE: Headaches have been reported in 3% to 8% of patients (n=837) receiving amiloride during clinical trials (Prod Info amiloride HCl oral tablets, 2009).
    b) EPLERENONE: Headache, dizziness, and fatigue have been reported in patients receiving eplerenone (Prod Info INSPRA(R) oral tablets, 2008).
    c) SPIRONOLACTONE: Mental confusion, ataxia, headache, drowsiness, and lethargy have been reported in patients receiving spironolactone (Prod Info Aldactone(R) oral tablets, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH THERAPEUTIC USE
    a) AMILORIDE: Nausea, vomiting, and diarrhea have been reported in 3% to 8% of patients (n=837) who received amiloride during clinical trials (Prod Info amiloride HCl oral tablets, 2009).
    b) EPLERENONE: Diarrhea (2%) has been reported in patients (n=945) receiving eplerenone (Prod Info INSPRA(R) oral tablets, 2008).
    c) SPIRONOLACTONE: Nausea, vomiting, diarrhea, and abdominal pain have been reported with spironolactone therapy (Prod Info Aldactone(R) oral tablets, 2011).
    d) TRIAMTERENE: Occasional reports of nausea, vomiting, and diarrhea have occurred during triamterene therapy (Prod Info DYRENIUM(R) oral capsules, 2005).
    2) WITH POISONING/EXPOSURE
    a) Nausea, vomiting, anorexia, diarrhea, abdominal pain, and GI bleeding may be noted (Ellenhorn, 1997; Farge et al, 1986).
    B) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) AMILORIDE: Loss of appetite was reported in 3% to 8% of patients (n=837) who received amiloride during clinical trials (Prod Info amiloride HCl oral tablets, 2009).
    C) GASTRIC HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) SPIRONOLACTONE use was associated with an increased risk of nonvaricose upper gastrointestinal bleed (adjusted odds ratio (OR), 2.7; 95% confidence interval (CI) 2.2 to 3.2) and an even greater risk of nonvaricose upper gastrointestinal bleed when on 100 mg doses of spironolactone (OR, 5.4; 95% CI, 3.4 to 8.6) in a large population-based case-control study involving 3652 patients with a diagnosis of serious upper gastrointestinal bleed. Age- and gender-matched controls (n=36,502) were identified by risk set sampling. In this study, 1869 (51.2%) of men met study criteria and were evaluated along with 18,672 controls. Of the 1869 men with upper gastrointestinal bleeds, 204 (5.6%) were current users of spironolactone, compared with 550 (1.5%) of the control group. The number needed to harm (NNTH) was estimated as 1 excess case per 230 person-years of treatment (95% CI, 173 to 317). Increased risk of upper gastrointestinal bleed was seen in patients on high dose spironolactone (100 mg per day) therapy and those in the 55 to 74 year old age group (OR, 13.1; 95% CI, 6.5 to 26.3). High cumulative dosing of spironolactone did not show the increased risk that was seen with high, current dosing of spironolactone. Concurrent use of antithrombotic drugs and NSAIDs did not affect risk. The study authors suggest spironolactone binds to mineralocorticosteroid receptors, an effect modulated by 11-beta-hydroxysteroid dehydrogenase enzymes, causing inhibition of the formation of fibrous tissue and as a result impairment of the healing of gastric or duodenal erosions resulting in formation of gastroduodenal ulcers, with or without bleeding (Gulmez et al, 2008).
    b) SPIRONOLACTONE: A case of a 64-year-old woman treated with 600 mg/day of spironolactone for 10 days for the treatment of alcoholic cirrhosis with hepatitis and ascites, who following 10 days of drug therapy complained of epigastric pain associated with vomiting has been reported. Following a vomiting episode in which she threw up about a liter of coffee ground material, the patient was endoscoped and found to have 2 bleeding ulcers located on the stomach's greater curvature. Discontinuation of the spironolactone resulted in healing of both ulcers as confirmed by endoscopy (Mackay & Stevenson, 1977).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) EPLERENONE: Serum alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (GGT) have been shown to increase in a dose-related manner in some patients treated with eplerenone (Prod Info INSPRA(R) oral tablets, 2008).
    B) INFLAMMATORY DISEASE OF LIVER
    1) WITH THERAPEUTIC USE
    a) SPIRONOLACTONE: A case of hepatitis in a 50-year-old woman with primary hyperaldosteronism has been reported. She was treated on 2 occasions with spironolactone 100 mg 3 times daily and twice daily. Approximately 8 weeks after the initiation of therapy, the patient developed elevated liver enzymes. During the second course of therapy, liver biopsy revealed changes consistent with mild, nonspecific hepatitis. Liver enzyme levels returned to normal approximately 6 to 8 weeks after withdrawal of spironolactone therapy. The patient was not receiving any other medications and denied alcohol ingestion, which would implicate spironolactone as the causative agent in the liver function abnormalities (Shuck et al, 1981).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) PRERENAL AZOTEMIA
    1) WITH THERAPEUTIC USE
    a) Mild azotemia may be noted, especially following chronic ingestion of therapeutic doses (Bosch et al, 1973).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 31-year-old woman developed acute renal failure 3 days after ingesting 50 capsules of Dyazide(R) with large amounts of ethyl alcohol.
    1) Acute renal failure was reported as the result of triamterene crystal deposition in the kidney, which induced injury to the tubular cells (Farge et al, 1986).
    C) IMPOTENCE
    1) WITH THERAPEUTIC USE
    a) AMILORIDE: Impotence was reported in less than 3% of patients (n=837) who received amiloride during clinical trials (Prod Info amiloride HCl oral tablets, 2009).
    b) SPIRONOLACTONE: Impotence was reported with spironolactone therapy (Prod Info Aldactone(R) oral tablets, 2011).
    D) FINDING OF VAGINAL BLEEDING
    1) WITH THERAPEUTIC USE
    a) EPLERENONE: Abnormal vaginal bleeding (less than 1%) has occurred infrequently in patients (n=945) receiving eplerenone (Prod Info INSPRA(R) oral tablets, 2008).
    E) ALBUMINURIA
    1) WITH THERAPEUTIC USE
    a) EPLERENONE: Albuminuria (1%) has been reported in patients (n=945) receiving eplerenone (Prod Info INSPRA(R) oral tablets, 2008).
    F) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) EPLERENONE: In clinical trials, increases in serum creatinine (greater than 2 mg/dL) and blood urea nitrogen (BUN) (greater than 30 mg/dL) have occurred in 0.2% and 0.5% of patients treated with eplerenone, respectively. Serum creatinine increased in a dose-related manner (mean increases ranged from 0.01 mg/dL at 50 mg daily to 0.03 mg/dL at 400 mg daily) (Prod Info INSPRA(R) oral tablets, 2008).
    G) TOXIC NEPHROPATHY
    1) WITH THERAPEUTIC USE
    a) SPIRONOLACTONE: In one report, 4 patients with hepatic cirrhosis and ascites treated with 150 mg/day of spironolactone developed renal insufficiency characterized by elevations of plasma potassium, decreases in diuresis, natriuresis, creatinine clearance, and increases in plasma urea and creatinine. Discontinuation of the drug resulted in normalization of the plasma urea, creatinine and creatinine clearance values (Bosch et al, 1973a).
    H) KIDNEY STONE
    1) WITH THERAPEUTIC USE
    a) TRIAMTERENE has induced urinary sediment. In a crossover study, 26 patients were administered amiloride 5 mg/day and triamterene 50 mg/day, while simultaneously receiving hydrochlorothiazide 50 mg/day. A blinded uroscopist evaluated urine samples 1 month after each agent was administered. In the triamterene group, distinctive reddish-brown crystals and casts were observed in 14 of 26 patients. No sediment was seen in the amiloride group. The casts induced by triamterene may be responsible for an increased incidence of nephrolithiasis or interstitial nephritis (Spence et al, 1985).
    b) TRIAMTERENE: A 50-year-old man with essential hypertension was initially treated with hydrochlorothiazide 25 mg/day. Blood pressure was uncontrolled and the patient's regimen was changed to hydrochlorothiazide-triamterene 1 tablet/day plus methyldopa 250 mg/day. Two years later the patient complained of intermittent bilateral flank pain and passed 2 kidney stones spontaneously. Two years later the patient again complained of severe flank pain, urinary burning, frequency and hematuria. IVP revealed that a ureteral stone passed spontaneously. Chemical analysis of the stone revealed a combination of uric acid salts and a triamterene metabolite. Factors which affect the solubility and saturation levels of triamterene may influence stone formation (Patel, 1981).
    I) AMENORRHEA
    1) WITH THERAPEUTIC USE
    a) SPIRONOLACTONE: Irregular menses or amenorrhea were reported with spironolactone therapy (Prod Info Aldactone(R) oral tablets, 2011).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEPHROSIS
    a) RATS receiving 1.5 mg, 3 mg, and 4.5 mg/100 g body weight of triamterene for 3 weeks developed severe degenerative changes of renal cortical and medullary tubules resembling osmotic nephrosis (Ozegovic et al, 1981).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) SPIRONOLACTONE
    1) Reversible hyperchloremic metabolic acidosis, associated with hyperkalemia, has occurred with spironolactone therapy (Prod Info Aldactone(R) oral tablets, 2011; Wan & Lye, 1980; Gabow et al, 1979) .
    2) A case of acidosis in a 58-year-old woman treated with 25 mg 4 times daily of spironolactone for 27 days concomitantly with digoxin, ammonium chloride, potassium chloride, and methenamine mandelate has been reported (Mashford & Robertson, 1972). Subsequently, the patient developed acidosis, which presented 20 days after adding ammonium chloride. The addition of ammonium chloride resulted in reduction of the patient's plasma CO2 content to 13 mEq/L and arterial pH to 7.3. Discontinuation of the patient's drug resulted in correction of acidosis, but the patient subsequently died 2 days later due to bronchial pneumonia. In addition, it was noted that the patient's potassium level had climbed to 5.7 in the face of concomitant potassium chloride administration.
    3) Acidosis developing in a 76-year-old woman with renal disease during antihypertensive therapy with oral spironolactone 100 mg daily, has been reported (Rado, 1988). In another woman (88 years of age), probably with underlying hyporeninemia and hypoaldosteronism, severe renal tubular acidosis developed with life-threatening hyperkaliemia, caused by spironolactone (O'Connell & Colledge, 1993).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) SPIRONOLACTONE: Four cases of spironolactone-induced agranulocytosis have been reported. Patients received spironolactone 100 to 300 mg daily. Symptoms began to resolve 2 to 5 days following discontinuation of spironolactone. Several predisposing risk factors were suggested, including increased age, female gender, hepatic or renal impairment, dosage and duration, concomitant drugs (eg, furosemide), and genetic variables. Although the exact mechanism of spironolactone-induced agranulocytosis is still unclear, it appears that spironolactone may have a direct toxic effect on the bone marrow and or the drug may mediate peripheral destruction of circulating leukocytes (Whitling et al, 1997; Ferguson et al, 1993; Jivraj et al, 1987; Stricker & Oei, 1984).
    b) CASE REPORT: Agranulocytosis was associated with spironolactone therapy on 2 occasions in a 70-year-old woman (Stricker & Oei, 1984a).
    B) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) TRIAMTERENE: Transient megaloblastic anemia, hemolytic anemia, leukopenia, agranulocytosis, and thrombocytopenia have rarely been reported with triamterene (Prod Info DYRENIUM(R) oral capsules, 2005; Corcino et al, 1970).
    b) TRIAMTERENE/CASE REPORT: A 32-year-old female alcoholic with cirrhotic liver disease and ascites developed purpura with severe epistaxis during her first course of triamterene (300 mg/day for 14 days) treatment. Discontinuing the drug resulted in rapid recovery. Four months later, triamterene 400 mg/day for 8 days resulted in mucous hemorrhagic syndrome, acute pancytopenia, and bone marrow megaloblastosis. The patient was treated with folic acid and blood transfusion, but died of GI hemorrhage (Renoux et al, 1976).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) SPIRONOLACTONE/CASE REPORT: Patch test positive contact dermatitis has been reported in a factory worker with incidental skin contact with purified spironolactone powder for many years (Klijn, 1984).
    b) SPIRONOLACTONE: Facial contact dermatitis has been reported in patients who have used a cream containing 5% spironolactone for facial acne (Corazza et al, 1996; Vincenzi et al, 1993).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) EPLERENONE: Rash has been reported with eplerenone use in postmarketing surveillance (Prod Info INSPRA(R) oral tablets, 2008).
    b) SPIRONOLACTONE: In one woman who received oral spironolactone 200 mg daily for treatment of hirsutism, urticaria developed. In another woman in the same study, treated for the same condition in the same doses, scalp alopecia was observed. Both side effects disappeared after cessation of spironolactone treatment (Helfer et al, 1988).
    c) TRIAMTERENE: Isolated cases of skin rash and photosensitivity rash have been reported with triamterene (Prod Info DYRENIUM(R) oral capsules, 2005).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) AMILORIDE: Muscle cramps were reported in less than 3% of patients (n=837) who received amiloride during clinical trials (Prod Info amiloride HCl oral tablets, 2009).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) GYNECOMASTIA
    1) WITH THERAPEUTIC USE
    a) EPLERENONE: In clinical studies in patients with hypertension, gynecomastia was reported in 0.5%, 0.7%, and 1% of male patients treated with eplerenone in all controlled studies, controlled studies with a duration of 6 months or longer, and open-label, long-term studies, respectively (Prod Info INSPRA(R) oral tablets, 2008).
    b) SPIRONOLACTONE: Gynecomastia has been reported to occur in men receiving spironolactone therapy. In some cases the gynecomastia has been associated with impotence Greenblatt & Koch-Weser, 1987a (Dupont, 1985; Zarren & Black, 1975; Clark, 1965).
    c) SPIRONOLACTONE: One study reported that 91 (13%) of 699 men prescribed spironolactone alone or in association with another antihypertensive treatment, developed gynecomastia which was reversible and dose-related (Jeunemaitre et al, 1987). At daily doses of 50 mg or less the incidence was 6.9%; at daily doses of 150 mg or higher the incidence was 52.2%.
    d) CASE REPORT/SPIRONOLACTONE: Gynecomastia occurring in a 51-year-old man during spironolactone therapy resolved by substitution of potassium canrenoate 100 mg daily. Following more than 1 year of treatment, blood pressure has remained stabilized and gynecomastia subsided (4 months after withdrawal of spironolactone) (Dupont, 1985).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) EOSINOPHIL COUNT RAISED
    1) WITH THERAPEUTIC USE
    a) SPIRONOLACTONE: Erythematous macular rash and eosinophilia were associated with spironolactone therapy (Wathen et al, 1986).

Reproductive

    3.20.1) SUMMARY
    A) AMILORIDE and EPLERENONE are classified as FDA category B. SPIRONOLACTONE, SPIRONOLACTONE/HYDROCHLOROTHIAZIDE, TRIAMTERENE, and TRIAMTERENE/HYDROCHLOROTHIAZIDE are classified as FDA category C. There are no adequate and well-controlled studies of potassium sparing diuretic use during pregnancy. In animal studies, there was no evidence of teratogenic effects in studies with AMILORIDE, EPLERENONE, SPIRONOLACTONE/HYDROCHLOROTHIAZIDE, or TRIAMTERENE/HYDROCHLOROTHIAZIDE. Embryotoxic effects in animals included decreased body weight, increased fetal resorptions, and post-implantation loss with EPLERENONE and with SPIRONOLACTONE/HYDROCHLOROTHIAZIDE, and progestational and antiandrogenic effects with SPIRONOLACTONE. Modest amounts of amiloride crossed the placental barrier following maternal AMILORIDE exposure in mice and rabbits. In human lactation studies, canrenone, a major, active metabolite of SPIRONOLACTONE, appears in human breast milk. In animal fertility studies, slowed ovarian follicle development and a reduction in circulating estrogen levels were observed in female rats following SPIRONOLACTONE exposure and there was a decreased rate in the number of mated mice that conceived, the number of implanted embryos in those that became pregnant, and a decrease in the latency period to mating in mice.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) AMILORIDE
    a) MICE and RABBITS: There was no evidence of teratogenic effects in rabbits and mice given amiloride at 20 and 25 times the maximum human dose, respectively (Prod Info MIDAMOR(R) oral tablets, 2002).
    2) EPLERENONE
    a) RABBITS and RATS: There was no evidence of teratogenic effects in rats and rabbits given eplerenone at doses up to 32 and 31 times the human AUC for the 100-mg/day therapeutic dose, respectively (Prod Info INSPRA(R) oral tablets, 2008).
    3) SPIRONOLACTONE
    a) MICE: There were no teratogenicity in mice following a 20-mg/kg dose of spironolactone (substantially below the maximum recommended human dose) (Prod Info Aldactazide(R) oral tablets, 2006).
    4) TRIAMTERENE
    a) RATS: There was no evidence of fetal harm when triamterene was given to pregnant rats at doses as high as 20 and 6 times the maximum recommended human dose on the basis of body weight and body surface area, respectively (Prod Info Dyazide(R) oral capsules, 2009).
    3.20.3) EFFECTS IN PREGNANCY
    A) PLACENTAL BARRIER
    1) SPIRONOLACTONE
    a) Spironolactone or its metabolites may cross the placental barrier and appear in cord blood (Prod Info Aldactazide(R) oral tablets, 2006).
    B) PREGNANCY CATEGORY
    1) AMILORIDE and EPLERENONE are classified by their manufacturers as FDA pregnancy category B (Prod Info INSPRA(R) oral tablets, 2008; Prod Info MIDAMOR(R) oral tablets, 2002)
    2) SPIRONOLACTONE, SPIRONOLACTONE/HYDROCHLOROTHIAZIDE, TRIAMTERENE, and TRIAMTERENE/HYDROCHLOROTHIAZIDE are classified by their manufacturers as FDA pregnancy category C(Prod Info ALDACTONE(R) oral tablets, 2008; Prod Info Aldactazide(R) oral tablets, 2006; Prod Info DYRENIUM(R) oral capsules, 2005; Prod Info Dyazide(R) oral capsules, 2009).
    C) ANIMAL STUDIES
    1) AMILORIDE
    a) MICE and RABBITS: Modest amounts of amiloride crossed the placental barrier following maternal amiloride exposure in mice and rabbits (Prod Info MIDAMOR(R) oral tablets, 2002).
    2) EPLERENONE
    a) RABBITS and RATS: Decreased body weight in maternal rabbits, increased fetal resorptions in rabbits, and post-implantation loss were observed at the highest administered amiloride doses of 1000 mg/kg/day in rats and 300 mg/kg/day in rabbits (up to 32 and 31 times the human AUC for the 100-mg/day therapeutic dose, respectively) (Prod Info INSPRA(R) oral tablets, 2008).
    3) SPIRONOLACTONE
    a) MICE: There were no embryotoxic effects in mice following a 20-mg/kg dose of spironolactone (substantially below the maximum recommended human dose) (Prod Info Aldactazide(R) oral tablets, 2006)
    b) RATS: Progestational and antiandrogenic effects of spironolactone have been observed in animals. Feminization of male fetuses was observed in male rats given spironolactone at doses of 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development). Offspring exposed during late pregnancy to spironolactone 50 and 100 mg/kg/day exhibited reproductive tract changes including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other symptoms of endocrine dysfunction, that persisted into adulthood (Prod Info Aldactazide(R) oral tablets, 2006).
    c) RABBITS: There was an increased rate of resorption and lower number of live fetuses in rabbits following a 20-mg/kg dose of spironolactone (approximately equivalent to the maximum recommended human dose) (Prod Info Aldactazide(R) oral tablets, 2006).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) SPIRONOLACTONE
    a) A major, active metabolite of spironolactone, canrenone, appears in human breast milk (Prod Info Aldactazide(R) oral tablets, 2006).
    B) ANIMAL STUDIES
    1) EPLERENONE
    a) RATS: Preclinical data revealed that eplerenone and/or metabolites were found in rat breast milk (0.85:1 milk:plasma AUC ratio) obtained after a single oral dose. Plasma and milk peak drug levels were obtained from 0.5 to 1 hour after dosing. However, rat pups developed normally. It is unknown if eplerenone is excreted into human breast milk after oral use (Prod Info INSPRA(R) oral tablets, 2008).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) SPIRONOLACTONE
    a) RATS: There were no effects on mating or fertility in female rats after receiving dietary doses of spironolactone 15 and 50 mg/kg/day in a three-litter reproduction study. The length of the estrous cycle was increased by prolonging diestrus during treatment and inducing constant diestrus during a 2-week posttreatment observation period after female rats were injected with spironolactone 100 mg/kg/day for 7 days. These effects were associated with slowed ovarian follicle development and a reduction in circulating estrogen levels, which would be expected to impair mating, fertility and fecundity (Prod Info Aldactazide(R) oral tablets, 2006).
    b) MICE: When female mice were injected with spironolactone 100 mg/kg/day during a two week cohabitation period with untreated males, there was a decreased rate in the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation). At 200 mg/kg, the latency period to mating was increased (Prod Info Aldactazide(R) oral tablets, 2006).
    2) TRIAMTERENE
    a) There are no fertility studies of triamterene use in animals (Prod Info Dyazide(R) oral capsules, 2009).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturers of amiloride/hydrochlorothiazide and triamterene do not report any carcinogenic potentials in humans. Although a causal relationship has not been established, carcinoma of the breast has been reported with spironolactone therapy.
    3.21.3) HUMAN STUDIES
    A) SPIRONOLACTONE
    1) Carcinoma of the breast has been noted in patients receiving spironolactone therapy although a causal relationship has not been established (Prod Info Aldactone(R) oral tablets, 2011).
    3.21.4) ANIMAL STUDIES
    A) SPIRONOLACTONE
    1) RATS: Oral administration of spironolactone in rats during an 18-month dietary administration study resulted in benign adenomas of the thyroid and testes and a dose-related increase in proliferative liver changes in males following doses of 50, 150, and 500 mg/kg/day. A 24-month study in rats administered spironolactone 10, 30, 100, and 150 mg/kg/day resulted in increased hepatocellular adenomas, testicular interstitial cell tumors, increased thyroid follicular cell adenomas, and carcinomas in males and females. Although it was not dose related, an increase in benign uterine endometrial stromal polyps was also observed (Prod Info Aldactone(R) oral tablets, 2011).
    B) TRIAMTERENE
    1) MICE, RATS: Animal studies in which rats and mice were fed diets containing triamterene, there was an increased incidence of hepatocellular neoplasia, primarily adenomas, in male and female mice administered triamterene 45 and 60 mg/kg/day, respectively (approximately 7.5 and 10 times the maximum recommended human dose, respectively). During the rat study, the incidence of hepatocellular neoplasia was limited only to triamterene exposed males administered triamterene 25 mg/kg/day compared with female rats administered triamterene 30 mg/kg/day (Prod Info DYRENIUM(R) oral capsules, 2009).
    C) LACK OF EFFECT
    1) AMILORIDE/HYDROCHLOROTHIAZIDE
    a) MICE, RATS: There was no evidence of carcinogenicity in mice and rats administered hydrochlorothiazide up to 600 mg/kg/day during a feeding study of 2 years duration. There was also no evidence of carcinogenicity in male and female rats administered amiloride hydrochloride for 104 weeks at doses of 6 and 8 mg/kg/day, respectively (15 and 20 times the maximum daily recommended human dose, respectively) (Prod Info AMILORIDE HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE oral tablets, 2011).

Genotoxicity

    A) AMILORIDE/HYDROCHLOROTHIAZIDE
    1) There was no evidence of mutagenicity with amiloride hydrochloride in the following test: Ames test (Prod Info AMILORIDE HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE oral tablets, 2011).
    2) There was no evidence of genotoxicity with hydrochlorothiazide in the following test: Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538, in the Chinese Hamster Ovary test, or in vivo assays with mouse germinal cell chromosomes, Chinese Hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Hydrochlorothiazide tested positive for clastogenicity in the Chinese Hamster Ovary Sister Chromatic Exchange assay and for mutagenicity in the Mouse Lymphoma Cell assay (Prod Info AMILORIDE HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE oral tablets, 2011).
    B) SPIRONOLACTONE
    1) In the absence of metabolic activation, there was no evidence of mutagenicity with spironolactone in the following tests: bacteria and yeast testing, mammalian in vitro tests. In the presence of metabolic activation, some mammalian mutagenicity tests in vitro were negative; however, other mammalian tests in vitro were found to be inconclusive but slightly positive for mutagenicity (Prod Info Aldactone(R) oral tablets, 2011).
    C) TRIAMTERENE
    1) There was no evidence of mutagenicity with triamterene in the following tests: Salmonella typhimurium strains TA98. TA100, TA1535, and TA1537 (with or without metabolic activation), in vitro Chinese Hamster ovary cells. Triamterene did induce sister chromatid exchanges in Chinese Hamster ovary cells in vitro (with and without metabolic activation) (Prod Info DYRENIUM(R) oral capsules, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes and ECG after overdose.
    B) Drug concentrations are not routinely available and are not used clinically to guide management following overdose.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) BUN concentration should be monitored in patients receiving amiloride in combination with other diuretics (Prod Info amiloride HCl oral tablets, 2009).
    2) Monitor serum electrolytes after overdose
    3) Drug concentrations are not routinely available and are not used clinically to guide management following overdose.
    B) LABORATORY INTERFERENCE
    1) Triamterene will interfere with the fluorescent measurement of quinidine, due to similar fluorescence spectra between the two agents (Prod Info DYRENIUM(R) oral capsules, 2005).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Monitor ECG after overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Admit patients with severe electrolyte abnormalities, dehydration, or impaired renal function.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients with small, inadvertent ingestions and normal renal function can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with large or deliberate ingestions or impaired renal function should be monitored for fluid status and serum electrolytes changes (particularly sodium and potassium). Monitor vital signs and ECG in symptomatic patients and those with significant electrolyte abnormalities.

Monitoring

    A) Monitor serum electrolytes and ECG after overdose.
    B) Drug concentrations are not routinely available and are not used clinically to guide management following overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not indicated.
    6.5.2) PREVENTION OF ABSORPTION
    A) Gastrointestinal decontamination should not be routinely performed following potassium sparing diuretic ingestion. Activated charcoal may be considered after extremely large ingestions or if more toxic coingestants are involved and the patient has presented early after the ingestion.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) There is no specific antidote. Treatment is symptomatic and supportive. Monitor patients for signs of fluid and electrolyte abnormalities, particularly sodium and potassium.
    B) MONITORING OF PATIENT
    1) Monitor serum electrolytes and ECG after overdose.
    2) Drug concentrations are not routinely available and are not used clinically to guide management following overdose.
    C) HYPERKALEMIA
    1) Treat severe hyperkalemia (associated dysrhythmias, QRS widening) aggressively. Monitor ECG continuously during and after therapy.
    2) CALCIUM CHLORIDE
    a) Intravenous calcium has no effect on circulating potassium levels, but it antagonizes cardiac toxicity in patients demonstrating cardiac signs and/or symptoms of hyperkalemia.
    b) Use 10% calcium chloride.
    c) ADULT DOSE: 5 to 10 mL (500 to 1000 mg) IV over 1 to 5 minutes; may repeat after 10 minutes (Saxena, 1989; Anon, 2000).
    d) PEDIATRIC DOSE: 0.2 mL/kg (20 to 30 mg/kg per dose up to a maximum single dose of 5 mL (500 mg) IV over 5 to 10 minutes, repeated up to 4 times or until serum calcium increases (Barkin, 1986; Anon, 2000).
    e) CALCIUM FOR INJECTION is available as 3 salts; calcium chloride, calcium gluconate, and calcium gluceptate.
    1) While the other salts may be used, calcium chloride is the preferred salt for resuscitation since it directly delivers ionized calcium, whereas the other salts must be hepatically metabolized to release ionized calcium (Chameides, 1988).
    2) Calcium chloride is very irritating, and should only be given via a central venous catheter. It may cause hypotension and bradycardia. Calcium salts are incompatible with bicarbonate (Chameides, 1988; Saxena, 1989; Anon, 2000).
    3) SODIUM BICARBONATE
    a) Administer IV sodium bicarbonate to shift potassium intracellularly. Expect 0.5 to 1 mEq/L reduction in serum potassium for each 0.1 unit rise in blood pH.
    b) A standard syringe contains 50 mL of 8.4% solution, 1 mEq/mL (total: 50 mEq/syringe).
    c) ADULT DOSE: 50 mL (50 mEq) IV over 5 minutes, repeated at 20 to 30 minute intervals (Saxena, 1989).
    d) PEDIATRIC DOSE: 1 to 2 mL/kg/dose (1 to 2 mEq/kg/dose) IV every 2 to 4 hours or as required by pH (Barkin, 1986). The onset is 15 minutes, the duration of action 1 to 2 hours (Ellenhorn & Barceloux, 1997).
    4) INSULIN/DEXTROSE
    a) Insulin enhances intracellular potassium shift.
    b) ADULT DOSE: Administer 25 g of dextrose (250 mL of a 10% solution) IV over 30 minutes, and then continue the infusion at a slower rate.
    1) Ten units of regular insulin are given subQ or added to the infusion.
    c) ALTERNATIVE DOSE: 50 mL of a 50% dextrose solution with 5 to 10 units of regular insulin may be administered IV over 5 minutes.
    1) Typically, this regimen will lower serum potassium by 1 to 2 mEq/L within 30 to 60 minutes with the decrease lasting for several hours (Saxena, 1989).
    d) PEDIATRIC DOSE: 0.5 to 1 g/kg/dose followed by 1 unit of regular insulin IV for every 4 grams of glucose infused; may repeat every 10 to 30 minutes (Barkin, 1986).
    e) HYPEROSMOLARITY: It must be remembered that 50% dextrose, and even 25% dextrose, are very hyperosmolar and may be sclerosing to peripheral veins (Chameides, 1988); administration of hypertonic solutions via central lines is preferred, if possible.
    5) SODIUM POLYSTYRENE SULFONATE
    a) SUMMARY
    1) Sodium polystyrene sulfonate, a cationic exchange resin, has been used to treat severe hyperkalemia.
    b) ADULT DOSE
    1) ORAL: Average daily adult dose is 15 g to 60 g. The dose is usually administered as a 15 g resin 1 to 4 times per day as needed in a small (20 mL to 100 mL) slurry of water or syrup (to increase palatability) (Prod Info KAYEXALATE(R) oral powder for suspension rectal powder for suspension, 2010).
    2) RECTAL: It may be given as a retention enema, although this method is less effective than oral administration. DOSE: 30 g to 50 g resin as a retention enema every 6 hours. Dilute each dose as a warm emulsion (body temperature) in 100 mL of an aqueous vehicle (eg 20% Dextrose in Water). Gently, agitate the solution during administration. The enema should be retained as long as possible; followed by a cleansing enema (Prod Info KAYEXALATE(R) oral powder for suspension rectal powder for suspension, 2010).
    c) PEDIATRIC DOSE
    1) SUMMARY: The effectiveness of sodium polystyrene sulfonate has not been established in pediatric patients (Prod Info KAYEXALATE(R) oral powder for suspension rectal powder for suspension, 2010).
    2) ORAL: INFANTS and SMALLER CHILDREN: Use lower doses than adults; consider utilizing the exchange rate of 1 milliequivalent of excess potassium per gram of resin as the basis for the calculation. NEONATES: Sodium polystyrene sulfonate should NOT be given by the oral route to neonates (Prod Info KAYEXALATE(R) oral suspension, rectal suspension, 2003).
    3) RECTAL: INFANTS and SMALLER CHILDREN: Use lower doses than adults; consider utilizing the exchange rate of 1 milliequivalent of potassium per gram of resin as the basis for the calculation. NEONATES and CHILDREN: Rectal administration should be performed with caution, as excessive dosage or inadequate dilution could result in impaction of the resin (Prod Info KAYEXALATE(R) oral suspension, rectal suspension, 2003).
    d) MONITORING PARAMETERS
    1) Monitor serum electrolytes, particularly potassium and sodium concentrations.
    2) Monitor ECG for conduction disturbances, dysrhythmias.
    e) ADVERSE EFFECTS
    1) Nausea, vomiting, gastric irritation, anorexia and constipation can develop. Diarrhea may occur infrequently. Electrolyte abnormalities such as hypocalcemia, hypokalemia, hypomagnesemia and sodium overload are also possible (Prod Info KAYEXALATE(R) oral powder for suspension rectal powder for suspension, 2010). Large doses in the elderly may cause fecal impaction, and rarely colonic necrosis (Lillemoe et al, 1987).
    2) The combined use of sorbitol and sodium polystyrene sulfonate have produced intestinal necrosis, which can be fatal. Concomitant use is not recommended (Prod Info KAYEXALATE(R) oral powder for suspension rectal powder for suspension, 2010).
    3) Intestinal obstruction from aluminum hydroxide concretions has occurred when administered in combination with sodium polystyrene sulfonate (Townsend et al, 1973).
    D) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Monitor serum electrolytes and fluid status. Administer 0.9% saline as needed

Enhanced Elimination

    A) HEMODIALYSIS
    1) As significant toxicity is not expected, there is no role for enhanced elimination following ingestion. Dialysis is ineffective in removing spironolactone, but may increase the clearance of triamterene.

Abstracts

Case Reports

    A) PEDIATRIC
    1) INFANT
    a) Two children, aged 10 and 12 months, were reported to ingest up to 60 spironolactone tablets. Gastric lavage was performed 1.5 hours postingestion, with production of pill fragments.
    1) Potassium levels were done every 6 to 10 hours and showed peak levels of 5.5 and 6 mEq/L at 24 and 32 hours, respectively. Neither child was symptomatic at any time (Kirk et al, 1989).

Range Of Toxicity

Summary

    A) TOXICITY: No toxic dose for these medications has been established. An adult developed acute renal failure 3 days after ingesting 50 capsules of triamterene/hydrochlorothiazide. Two infants, ages 10 and 12 months, ingested up to 60 spironolactone tablets, with asymptomatic hyperkalemia as the only effect noted.
    B) THERAPEUTIC DOSE: AMILORIDE: ADULT: 5 to 20 mg/day orally; PEDIATRIC: 6 to 20 kg in body weight: 0.625 mg/kg/day orally. EPLERENONE: ADULT: 25 to 50 mg orally once or twice daily; PEDIATRIC: Safety and efficacy not established. SPIRONOLACTONE: ADULT: 25 to 100 mg/day orally in single or divided doses; PEDIATRIC: 1 to 3 mg/kg/day orally in 2 to 4 divided doses or once daily; MAX 200 mg/day. TRIAMTERENE: ADULT: 100 mg orally twice daily; MAX 300 mg/day; PEDIATRIC: Edema: 1 to 4 mg/kg/day orally in 2 divided doses. Hypertension: initially, 1 to 2 mg/kg/day orally in two divided doses; MAX 3 to 4 mg/kg/day, up to 300 mg/day.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) AMILORIDE: 5 to 10 mg/day orally is the usual therapeutic dose; the dose may be increased to 20 mg/day as necessary with close monitoring of electrolytes (Prod Info amiloride HCl oral tablets, 2009).
    2) EPLERENONE: For hypertension, oral doses of 50 mg once to twice daily have been recommended. In patients receiving a weak CYP3A4 inhibitor (eg, erythromycin, saquinavir, verapamil, fluconazole), the initial starting dose should be reduced to 25 mg/day. For heart failure complicating acute myocardial infarction, an initial dose of 25 mg/day and then titrated to the target dose of 50 mg/day, preferably within 4 weeks as tolerated (Prod Info INSPRA(R) oral tablets, 2008).
    3) SPIRONOLACTONE: For essential hypertension, edema, CHF the usual therapeutic dose can range from 25 to 100 mg/day orally in single or divided doses. Doses up to 200 mg daily have been used (Prod Info Aldactone(R) oral tablets, 2011).
    4) TRIAMTERENE: Usual therapeutic dose is 100 mg orally twice daily after meals; maximum daily dose: 300 mg (Prod Info DYRENIUM(R) oral capsules, 2005).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) AMILORIDE
    a) According to the manufacturer, safety and efficacy in pediatric patients have not been established (Prod Info amiloride HCl oral tablets, 2009).
    b) DIURESIS: An oral dose of 0.625 mg/kg//24 hours in patients weighing 6 to 20 kg has been recommended; in adolescents, the suggested oral dose is 5 to 20 mg/24 hours up to a maximum of 40 mg/24 hours is recommended (Wells, 1990).
    2) EPLERENONE
    a) LACK OF EFFECT/HYPERTENSION: In a 10-week study of 304 hypertensive pediatric patients (age 4 to 17 years) treated with eplerenone up to 100 mg/day it did not lower blood pressure effectively. In this study and in a 1-year pediatric safety study in 149 patients, the incidence of reported adverse events was similar to that of adults. Eplerenone has not been studied in hypertensive patients less than 4 years due to the lack of effectiveness observed in older children (Prod Info INSPRA(R) oral tablets, 2008).
    3) SPIRONOLACTONE
    a) Usual dose: 1 to 3 mg/kg/day orally in 2 divided doses or once daily (range: divided every 6 to 12 hours); Maximum: 200 mg/day (van der Vorst et al, 2006; Buck, 2005; Lowrie, 2000; Venugopalan et al, 2000; Hobbins et al, 1981).
    4) TRIAMTERENE
    a) EDEMA: The recommended dosages for diuretics in children are 1 to 4 milligrams/kilogram/day in 2 divided doses (van der Vorst et al, 2006a).
    b) HYPERTENSION: For treatment of hypertension, initial doses of triamterene 1 to 2 mg/kg/day given in 2 divided doses are recommended in children 1 to 17 years old. The maximum recommended dose is 3 to 4 mg/kg/day, not to exceed 300 mg/day (National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents, 2004).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) A 64-year-old male chronic alcoholic with ascites developed: hyperkalemia (9 milliequivalents/liter), hyperchloremic acidosis (chloride 111 milliequivalents/liter) with normal anion gap, and intractable ventricular fibrillation. This was associated with spironolactone (300 mg/day) and hydrochlorothiazide (50 mg/day) of four months duration (Feinfeld & Carvounis, 1978).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) PEDIATRIC: Two children, aged 10 and 12 months, ingested as much as 60 tablets of spironolactone. Asymptomatic hyperkalemia was the only effect noted (Kirk et al, 1989).
    2) ADULT: A 31-year-old woman developed acute renal failure 3 days after ingesting 50 capsules of a combination product containing 50 mg triamterene and 25 mg hydrochlorothiazide, along with consuming large amounts of ethyl alcohol. Acute renal failure was reported as the result of triamterene crystal deposition in the kidney, which induced injury to the tubular cells (Farge et al, 1986).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) AMILORIDE
    1) LD50- (ORAL)MOUSE:
    a) 56 mg/kg (Prod Info amiloride HCl oral tablets, 2009)
    2) LD50- (ORAL)RAT:
    a) 36 to 85 mg/kg (Prod Info amiloride HCl oral tablets, 2009)
    B) SPIRONOLACTONE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 260 mg/kg (RTECS , 2002)
    2) LD50- (ORAL)MOUSE:
    a) >1 g/kg (Prod Info Aldactone(R) oral tablets, 2011)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 277 mg/kg (RTECS , 2002)
    4) LD50- (ORAL)RAT:
    a) >1 g/kg (Prod Info Aldactone(R) oral tablets, 2011)
    C) TRIAMTERENE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 249 mg/kg (RTECS , 2002)
    2) LD50- (ORAL)MOUSE:
    a) 380 mg/kg (Prod Info DYRENIUM(R) oral capsules, 2005)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 620 mg/kg (RTECS , 2002)
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 200 mg/kg (RTECS , 2002)
    5) LD50- (ORAL)RAT:
    a) 400 mg/kg (RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Amiloride acts by blocking the sodium channel in the later portion of the nephron, distal tubule, and collecting duct. Triamterene inhibits the reabsorption of sodium ions in the exchange for potassium and hydrogen ions in the segment of the distal tubule under the control of adrenal mineralocorticoids (Prod Info amiloride HCl oral tablets, 2009; Prod Info DYRENIUM(R) oral capsules, 2005).
    B) Eplerenone and spironolactone bind to aldosterone receptors in the distal tubules and collecting duct, preventing the binding of aldosterone to its receptor. Aldosterone acts at the kidney to cause sodium and water retention and potassium loss in the urine (Prod Info Aldactone(R) oral tablets, 2011; Prod Info INSPRA(R) oral tablets, 2008).

Physicochemical

Physical Characteristics

    A) AMILORIDE: yellow to green-yellow powder (S Sweetman , 2002)
    B) SPIRONOLACTONE: light cream to light tan crystals with mild mercaptan-like odor (S Sweetman , 2002)
    C) TRIAMTERENE: yellow, odorless crystalline powder (S Sweetman , 2002)

Molecular Weight

    A) AMILORIDE: 229.63 (S Budavari , 2001)
    B) SPIRONOLACTONE: 416.58 (S Budavari , 2001)
    C) TRIAMTERENE: 253.26 (S Budavari , 2001)

References

General Bibliography

    1) Abshagen U: Influence of enterohepatic circulation on pharmacokinetics of spironolactone in man. Naunym Schmiedeberg Arch Pharmacol 1977; 297(Suppl II):R62.
    2) Anon: American Heart Association/International Liaison Committee on Resuscitation: Guidelines 2000 for Cardiopulmonary Resuscitation and emergency Cardiovascular Care: an international consensus on science. Circulation 2000; 102:I1-I384.
    3) Barkin RM: Emergency Pediatrics, 2nd ed, CV Mosby Co, St. Louis, MO, 1986.
    4) Belci C: Transitory myopia in the course of treatment with diuretics. Boll Oculist 1968; 47:24-31.
    5) Bosch J, Arroyo V, & Rodes J: Renal insufficiency induced by diuretics in hepatic cirrhosis patients with ascites. Rev Clin Esp 1973; 131:375.
    6) Bosch J, Arroyo V, Rodes J, et al: Renal insufficiency induced by diuretics in hepatic cirrhosis patients with ascites. Rev Clin Esp 1973a; 131:375.
    7) Buck ML: Clinical experience with spironolactone in pediatrics. Ann Pharmacother 2005; 39(5):823-828.
    8) Chameides L: Textbook of Pediatric Advanced Life Support, American Heart Association, Dallas, TX, 1988.
    9) Chiu TF, Bullard MJ, Chen JC, et al: Rapid life-threatening hyperkalemia after addition of amiloride HCl-hydrochlorothiazide to angiotensin-converting enzyme inhibitor therapy. Ann Emerg Med 1997; 30(5):612-615.
    10) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    11) Clark E: Spironolactone therapy and gynecomastia. JAMA 1965; 193:163-164.
    12) Corazza M, Strumia R, Lombardi AR, et al: Allergic contact dermatitis from spironolactone. Contact Derm 1996; 35:365-366.
    13) Corcino J, Waxman S, & Herbert V: Mechanism of triamterene-induced megalobastosis. Ann Intern Med 1970; 73:419.
    14) Dupont A: Disappearance of spironolactone-induced gynaecomastia during treatment with potassium canrenoate. Lancet 1985; 2:731.
    15) Ellenhorn MJ & Barceloux DG: Medical Toxicology: Diagnosis and Treatment of Human Poisoning, Elsevier, New York, NY, 1988.
    16) Ellenhorn MJ: Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning, 2nd ed, Williams & Wilkins, Baltimore, MD, 1997.
    17) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    18) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    19) Farge D, Turner MW, & Roy DR: Dyazide-induced reversible acute renal failure associated with intracellular crystal deposition. Am J Kidney Dis 1986; 8:445-449.
    20) Feinfeld DA & Carvounis CP: Fatal hyperkalemia and hyperchloremic acidosis. JAMA 1978; 240:1516.
    21) Ferguson I, Fogg C, & Baughan P: Spironolactone induced agranulocytosis (letter). Med J Aust 1993; 159:837.
    22) Frazier HS & Yager H: The clinical use of diuretics (2 Parts). N Engl J Med 1973; 288:246&455.
    23) Gabow PA, Moore S, & Schrier RW: Spironolactone-induced hyperchloremic acidosis in cirrhosis. Ann Intern Med 1979; 90:338-340.
    24) Gardiner P, Schrode K, Quinlad D, et al: Spironolactone metabolism: Steady-state serum levels of the sulfur-containing metabolites. J Clin Pharmacol 1989; 29:342-347.
    25) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    26) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    27) Grant WM & Schuman RS: Toxicology of the Eye, 4th ed, Charles C Thomas, Springfield, IL, 1993.
    28) Greenblatt DJ & Koch-Weser J: Adverse reactions to spironolactone. A report from the Collaborative Drug Surveillance Program. JAMA 1973; 225:40-43.
    29) Gulmez SE, Lassen AT, Aalykke C, et al: Spironolactone use and the risk of upper gastrointestinal bleeding: a population-based case-control study. Br J Clin Pharmacol 2008; Epub:--.
    30) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    31) Helfer EL, Miller JL, & Rose LI: Side effects of spironolactone therapy in the hirsute woman. J Clin End Metab 1988; 66:208-211.
    32) Hobbins SM, Fowler RS, Rowe RD, et al: Spironolactone therapy in infants with congestive heart failure secondary to congenital heart disease. Arch Dis Child 1981; 56(12):934-938.
    33) Huffman DH, Kampmann JP, & Hignite CE: Gynecomastia induced in normal males by spironolactone. Clin Pharmacol Ther 1978; 24:465-473.
    34) Jeunemaitre X, Chatellier G, Kreft-Jais C, et al: Efficacy and tolerance of spironolactone in essential hypertension. Am J Cardiol 1987; 60:820-825.
    35) Jivraj KT, Noseworthy TW, Friesen EG, et al: Spironolactone-induced agranulocytosis. Drug Intell Clin Pharm 1987; 21:974-975.
    36) Karim A, Zagarella J, & Hribar J: Spironolactone I. Disposition and metabolism. Clin Pharmacol Ther 1976a; 19:158.
    37) Karim A, Zagarella J, & Hutsell TC: Spironolactone II. Bioavailability. Clin Pharmacol Ther 1976b; 19:170-176.
    38) Karim A, Zangarella J, & Hutsell TC: Spironolactone III. Canrenone-maximum and minimum steady-state plasma levels. Clin Pharmacol Ther 1976c; 19:177.
    39) Kirk MA, Kulig K, & Rumack BH: Acute Aldactone overdose resulting in hyperkalemia (Abstract 163). Vet Hum Toxicol 1989; 31:370.
    40) Klijn J: Contact dermatitis from spironolactone. Contact Dermatitis 1984; 10:105.
    41) Lant AF, Smith AF, & Wilson GM: Clinical evaluation of amiloride, a potassium-sparing diuretic. Clin Pharmacol Ther 1969; 10:50-63.
    42) Lillemoe KD, Romolo JL, & Hamilton SR: Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and experimental support of the hypothesis. Surgery 1987; 101:267-272.
    43) Lowrie L: Diuretic therapy of heart failure in infants and children. Prog Pediatr Cardiol 2000; 12(1):45-55.
    44) Macfie HL, Colvin CL, & Anderson PO: Amiloride (Midamor(R) - Merck Sharp & Dohme). Drug Intell Clin Pharm 1981; 15:94-98.
    45) Mackay A & Stevenson RD: Gastric ulceration induced by spironolactone. Lancet 1977; 1:481.
    46) Maddox WR, Arnold WS, & Dewell WM Jr: Extreme hyperkalemia associated with amiloride (letter). South Med J 1985; 78:365.
    47) Mashford ML & Robertson MB: Spironolactone and ammonium and potassium chloride. Br Med J 1972; 4:298-299.
    48) Mutschler E, Gilfrich HJ, Knauf H, et al: Pharmacokinetics of triamterene. Clin Exper Hyper-theory Pract 1983; A5:249-269.
    49) National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents: The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004; 114(2):555-576.
    50) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    51) O'Connell JE & Colledge NR: Type IV renal tubular acidosis and spironolactone therapy in the elderly. Postgrad Med J 1993; 69:887-889.
    52) Overdiek HWPM & Merkus FWHM: Influence of food on the bioavailability of spironolactone. Clin Pharmacol Ther 1986; 40:531-536.
    53) Overdiek JWPM, Hermens WAJJ, & Merkus FWHM: New insights into the pharmacokinetics of spironolactone. Clin Pharmacol Ther 1985; 38:468-474.
    54) Ozegovic B, Milkovic S, & Rode B: Nephrotic changes in the rat induced by overdosage of triamterene. Arzneim Forsch Drug Res 1981; 31:1257-1260.
    55) Patel KM: Triamterene nephrolithiasis complicating diazide therapy. J Urol 1981; 126:230.
    56) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    57) Product Information: ALDACTONE(R) oral tablets, spironolactone oral tablets. Pfizer, Inc, New York, NY, 2008.
    58) Product Information: AMILORIDE HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE oral tablets, amiloride hydrochloride and hydrochlorothiazide oral tablets. Mylan Pharmaceuticals, Inc. (per DailyMed), Morgantown, WV, 2011.
    59) Product Information: Aldactazide(R) oral tablets, spironolactone and hydrochlorothiazide oral tablets. G.D. Searle LLC, New York, NY, 2006.
    60) Product Information: Aldactone(R) oral tablets, spironolactone oral tablets. G.D. Searle (per Manufacturer), New York, NY, 2011.
    61) Product Information: DYRENIUM(R) oral capsules, triamterene oral capsules. Wellspring Pharmaceutical Corporation, Ontario, Canada, 2005.
    62) Product Information: DYRENIUM(R) oral capsules, triamterene oral capsules. WellSpring Pharmaceutical Corporation (Per FDA), Sarasota, FL, 2009.
    63) Product Information: Dyazide(R) oral capsules, hydrochlorothiazide/triamterene oral capsules. GlaxoSmithKline, Research Triangle Park, NC, 2009.
    64) Product Information: INSPRA(R) oral tablets, eplerenone oral tablets. GD Searle LLC, New York, NY, 2008.
    65) Product Information: KAYEXALATE(R) oral powder for suspension rectal powder for suspension, sodium polystyrene sulfonate oral powder for suspension rectal powder for suspension. Sanofi-Aventis, US, LLC, Bridgewater, NJ, 2010.
    66) Product Information: KAYEXALATE(R) oral suspension, rectal suspension, sodium polystyrene sulfonate oral suspension, rectal suspension. Sanofi-Synthelabo Inc, New York, NY, 2003.
    67) Product Information: MAXZIDE(R) oral tablet, MAXZIDE(R)-25 MG oral tablet, hydrochlorothiazide/triamterene . Bertek Pharmaceuticals Inc, Sugar Land, TX, 1996.
    68) Product Information: MAXZIDE(R)-25 oral tablets, triamterene and hydrochlorothiazide oral tablets. Mylan Pharmaceuticals Inc, Morgantown, WV, 2011.
    69) Product Information: MIDAMOR(R) oral tablets, amiloride hcl oral tablets. Merck & Co.,Inc., Whitehouse Station, NJ, 2002.
    70) Product Information: amiloride HCl oral tablets, amiloride HCl oral tablets. Par Pharmaceutical, Inc (per DailyMed), Spring Valley, NY, 2009.
    71) Pruitt AW, Winkel JS, & Dayton PG: Variations in the fate of triamterene. Clin Pharmacol Ther 1977; 21:610.
    72) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 8/31/2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    73) Rado JP: Successful treatment of hyperkalemic quadriplegia associated with spironolactone. Int J Clin Pharmacol Ther Tox 1988; 26:339-345.
    74) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    75) Renoux M, Bernard JF, Amar M, et al: Acute pancytopenia and bone marrow megaloblastosis in a cirrhotic treated with triamterene. Nouv Presse Med 1976; 5:641.
    76) S Budavari : The Merck Index, 13th ed. (CD-ROM version). Merck & Co, Inc. Whitehouse Station, NJ. 2001.
    77) S Sweetman : Martindale: The Complete Drug Reference (electronic version). The Pharmaceutical Press. London, UK (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    78) Sadee W, Schroder R, & von Leitner E at al: Multiple dose kinetics of spironolactone and canrenoate-potassium in cardiac and hepatic failure. Eur J Clin Pharmacol 1974; 7:195-200.
    79) Saxena K: Clinical features and management of poisoning due to potassium chloride. Med Toxicol Adv Drug Exp 1989; 4:429-443.
    80) Shuck J, Shen S, Owensby L, et al: Spironolactone hepatitis in primary hyperaldosteronism. Ann Intern Med 1981; 95:708-710.
    81) Spark RF, O'Hare CM, & Regan RM: Low-renin hypertension. Arch Intern Med 1974; 133:205.
    82) Spence JD, Wong DG, & Lindsay RM: Effects of triamterene and amiloride on urinary sediment in hypertensive patients taking hydrochlorothiazide. Lancet 1985; 2(8446):73-75.
    83) Stricker BH & Oei TT: Agranulocytosis caused by spironolactone. Br Med J 1984; 289:731.
    84) Stricker BHC & Oei TT: Agranulocytosis caused by spironolactone. Br Med J 1984a; 22:731.
    85) Townsend CM, Remmers AR Jr, & Sarles HE: Intestinal obstruction from medication bezoar in patients with renal failure. N Engl J Med 1973; 288:1058.
    86) Udezue EO & Harrold BP: Hyperkalaemic paralysis due to spironolactone. Postgrad Med J 1980; 56:254-255.
    87) Venugopalan P , Agarwal AK , & Worthing EA : Chronic cardiac failure in children due to dilated cardiomyopathy: diagnostic approach, pathophysiology and management. Eur J Pediatr 2000; 159(11):803-810.
    88) Vidt DG: Mechanism of action, pharmacokinetics, adverse effects, and therapeutic uses of amiloride hydrochloride, a new potassium-sparing diuretic. Pharmacotherapy 1981; 1:179-187.
    89) Vincenzi C, Trevisi P, Farina P, et al: Facial contact dermatitis due to spironolactone in an anti-acne cream. Con Derm 1993; 29:277-278.
    90) Wan HH & Lye MDW: Moduretic-induced metabolic acidosis and hyperkalemia. Postgrad Med J 1980; 56:348-350.
    91) Wathen CG, MacDonald T, Wise LA, et al: Eosinophilia associated with spironolactone. Lancet 1986; 1:919-920.
    92) Wells TG: The pharmacology and therapeutics of diuretics in the pediatric patient. Fluid Electro Ther 1990; 37:463-504.
    93) Whitling AM, Pergola PE, Sang JL, et al: Spironolactone-induced agranulocytosis. Ann Pharmacother 1997; 31:582-585.
    94) Zarren HS & Black PM: Unilateral gynecomastia and impotence during low-dose spironolactone administration in men. Milit Med 1975; 140:417.
    95) van der Vorst MM, Kist JE, van der Heijden AJ, et al: Diuretics in pediatrics : current knowledge and future prospects. Paediatr Drugs 2006; 8(4):245-264.
    96) van der Vorst MM, Kist JE, van der Heijden AJ, et al: Diuretics in pediatrics : current knowledge and future prospects. Paediatr Drugs 2006a; 8(4):245-264.