Diuretics, Potassium-sparing, and Hydrochlorothiazide (Systemic)

This monograph includes information on the following:

1) Amiloride and Hydrochlorothiazide
2) Spironolactone and Hydrochlorothiazide
3) Triamterene and Hydrochlorothiazide

VA CLASSIFICATION
Primary: CV704
Secondary: CV408; TN900

Commonly used brand name(s): Aldactazide2; Apo-Triazide3; Dyazide3; Maxzide3; Moduret1; Moduretic1; Novo-Spirozine2; Novo-Triamzide3; Spirozide2.

Another commonly used name is
Co-triamterzide [Triamterene and Hydrochlorothiazide]
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antihypertensive—

antihypokalemic—

diuretic—

Indications

Accepted

Edema (treatment)—These combinations are indicated as adjuncts in the management of edematous states such as congestive heart failure, hepatic cirrhosis, and nephrotic syndrome, as well as in corticosteroid- and estrogen-induced edema and idiopathic edema. {08} {10} {11} {53} {54}

Hypertension (treatment)—Spironolactone and hydrochlorothiazide, triamterene and hydrochlorothiazide, and amiloride and hydrochlorothiazide1 are also indicated in the treatment of hypertension, especially when a potassium-sparing diuretic effect is desired. {08} {10} {11} {51} {52} {53} {54}
—Fixed-dosage combinations are generally not recommended in initial therapy and are useful in subsequent therapy only when the proportion of the component agents corresponds to the dose of the individual agents, as determined by titration. {08}
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.

Hypokalemia (treatment)1—Amiloride and hydrochlorothiazide, {51} triamterene and hydrochlorothiazide {52}, and spironolactone and hydrochlorothiazide combinations are also indicated for treatment of diuretic-induced hypokalemia in hypertensive patients in whom other measures are inappropriate or inadequate. {10} {53}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Amiloride hydrochloride: 302.12 {55}
    Hydrochlorothiazide: 297.73 {55}
    Spironolactone: 416.58 {55}
    Triamterene: 253.27 {55}

pKa—
    Amiloride: 8.7
    Triamterene: 6.2

Mechanism of action/Effect:

Diuretic or antihypokalemic—Potassium-sparing diuretics interfere with sodium reabsorption in the distal convoluted tubule, thereby promoting excretion of sodium and water, and retention of potassium. {51} {52} Amiloride and triamterene have a direct inhibitory effect on the entry of sodium into the cells, while spironolactone competitively inhibits the action of aldosterone. {51} {52} {53} The antidiuretic effect of hydrochlorothiazide is a result of mild sodium and water depletion leading to increased reabsorption of glomerular filtrate in the proximal renal tubule and reduced delivery of tubular fluid available for excretion.

Antihypertensive—Diuretics lower blood pressure initially by reducing plasma and extracellular fluid volume; cardiac output also decreases. Eventually, the extracellular fluid volume and the cardiac output return to normal with an accompanying decrease in peripheral vascular resistance.

Aldosterone antagonist or diagnostic aid (primary hyperaldosteronism)—Spironolactone is a competitive inhibitor of aldosterone; neither amiloride nor triamterene has this effect. {53}

Absorption:

Amiloride—Incompletely (15 to 20%) absorbed from gastrointestinal tract; rate, but not necessarily extent, of absorption is increased after 4 hours of fasting.

Hydrochlorothiazide—Rapidly absorbed. {53}

Spironolactone—Well absorbed following oral administration; bioavailability is greater than 90%. Absorption is enhanced by concomitant intake of food.

Triamterene—Rapidly but incompletely (30 to 70%) absorbed from the gastrointestinal tract.

Protein binding:

Amiloride—Minimal.

Spironolactone and canrenone (active metabolite)—Very high (more than 90%). {53}

Triamterene—Moderate (67%).

Biotransformation:

Amiloride—Not metabolized. {51}

Spironolactone—Hepatic; approximately 25 to 30% converted to canrenone.

Triamterene—Hepatic.

Half-life:


Amiloride:

6 to 9 hours. {51}



Hydrochlorothiazide:

5.6 to 14.8 hours. {51}



Spironolactone:


Canrenone—

13 to 24 hours {53} (average 19 hours) when administered once or twice daily; 9 to 16 hours (average 12.5 hours) when administered 4 times daily.




Triamterene:


Elimination half-life—

Normal renal function—90 to 120 minutes; metabolites up to 12 hours.

Anuric—10 hours.



Terminal half-life—

5 to 7 hours.



Onset of action:


Diuretic:

Amiloride: Single dose—Within 2 hours. {51}

Hydrochlorothiazide: Within 2 hours. {51}

Triamterene: Within 1 hour. {52}


Time to peak concentration:

Amiloride—3 to 4 hours. {51}

Hydrochlorothiazide—2 hours. {52}

Triamterene—2 to 4 hours.

Time to peak effect:


Diuretic:

Amiloride: Single dose—6 to 10 hours. {51}

Spironolactone: Multiple doses—2 to 3 days.

Triamterene: Multiple doses—1 day to several days.


Duration of action:


Diuretic:

Amiloride: Single dose—24 hours. {51}

Hydrochlorothiazide: 6 to 12 hours. {51}

Spironolactone: Multiple doses—2 to 3 days.

Triamterene: Single dose—7 to 9 hours.


Elimination:
    Amiloride—Renal, 20 to 50% (unchanged); fecal, 40% (unchanged). {51}
    Hydrochlorothiazide—Unchanged; almost totally via the kidneys, {51} with minute quantities in the bile.
    Spironolactone—Metabolites: Primary route, renal (less than 10% unchanged); secondary route, biliary/fecal. {53}
    Triamterene—Primary route, biliary/fecal; secondary route, renal.


Precautions to Consider

Cross-sensitivity and/or related problems

Hydrochlorothiazide—Patients sensitive to other sulfonamide-type medications, bumetanide, furosemide, or carbonic anhydrase inhibitors may be sensitive to hydrochlorothiazide also.

Carcinogenicity/Tumorigenicity


Amiloride

One study in mice at doses up to 25 times the maximum daily human dose for 92 weeks and another in male and female rats at doses up to 15 and 20 times the maximum daily human dose for 104 weeks showed no evidence of carcinogenicity or tumorigenicity. {08} {51}



Hydrochlorothiazide

No evidence of carcinogenicity was found in 2-year feeding studies in mice (doses up to 600 mg per kg of body weight [mg/kg] per day) or rats (doses up to 100 mg/kg per day). {51}



Spironolactone

Breast carcinoma has been reported in men and women taking this medication, but a direct causal relationship has not yet been established. {16}

Spironolactone has been found to have tumorigenic activity in rats, mainly in endocrine organs and the liver. {53} A statistically significant dose-related increase in benign adenomas of the thyroid and testes was found in male rats given spironolactone in doses up to 250 times the usual daily human dose of 2 mg/kg. {16} {53} In addition, a dose-related increase in proliferative liver changes was revealed in male rats. {53} Hepatocytomegaly, hyperplastic nodules, and hepatocellular carcinoma were evident at the highest dosage level of 500 mg/kg. {16} {53} In female rats, a statistically significant increase in malignant mammary tumors was seen at the mid-dose level. {16} {53}


Mutagenicity

Amiloride—In Ames tests, no evidence of mutagenicity was found. {51}

Hydrochlorothiazide—Hydrochlorothiazide was not found to be mutagenic in vitro in the Ames microbial mutation test; however, it did induce nondisjunction in Aspergillus nidulans . {51}

Pregnancy/Reproduction

Pregnancy—
Pregnant women should be advised to contact physician before taking these medications, since routine use of diuretics during normal pregnancy is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of toxemia. Diuretics are indicated only in the treatment of edema due to pathologic causes or as a short course of treatment in patients with severe hypervolemia.


Amiloride and hydrochlorothiazide combination

Adequate and well-controlled studies in humans have not been done. {51}

Teratogenicity studies in rabbits and mice at doses up to 25 times the maximum human daily dose have revealed no evidence of harmful effects to the fetus. {51} However, in rats given up to 25 times the maximum human daily dose, reduced body weight of pups at birth and at weaning was observed. {51}

FDA Pregnancy Category B. {51}



Spironolactone and hydrochlorothiazide combination

Studies have not been done with this combination.



Triamterene and hydrochlorothiazide combination

Adequate and well-controlled studies in humans have not been done. {52}

One generational study using a 1 to 1 ratio of triamterene to hydrochlorothiazide did not reveal evidence of teratogenicity at doses 15 and 30 times the maximum recommended human dose (MRHD). {52}

FDA Pregnancy Category C. {52}


Breast-feeding

Amiloride—It is not known whether amiloride is distributed into breast milk.

Hydrochlorothiazide—Hydrochlorothiazide is distributed into breast milk; the American Academy of Pediatrics recommends that nursing mothers avoid thiazide diuretics during the first month of lactation because of reports of suppression of lactation.

Spironolactone —Canrenone (active metabolite) is distributed into breast milk.

Triamterene—It is not known whether triamterene is distributed into human breast milk; triamterene is distributed into cow's milk.

Pediatrics

No information is available on the relationship of age to the effects of potassium-sparing diuretic and hydrochlorothiazide combinations in pediatric patients. Safety and efficacy have not been established. {51} {52}


Geriatrics


Although appropriate studies on the relationship of age to the effects of these medications have not been performed in the geriatric population, the elderly may be more sensitive to the hypotensive and electrolyte-depleting effects. In addition, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving these medications. {09}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.


For all potassium-sparing diuretic and hydrochlorothiazide combinations
Allopurinol or
Colchicine or
Probenecid or
Sulfinpyrazone    (triamterene, and to a lesser extent, hydrochlorothiazide, may raise the concentration of blood uric acid; dosage adjustment of antigout medications may be necessary to control hyperuricemia and gout {17} {21})


Amantadine    (hydrochlorothiazide and triamterene may reduce the renal clearance of amantadine, resulting in increased plasma concentrations and possible amantadine toxicity {18} {38})


Amiodarone    (concurrent use of hydrochlorothiazide with amiodarone may lead to an increased risk of arrhythmias associated with hypokalemia {19})


» Angiotensin-converting enzyme (ACE) inhibitors or
Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin, or{22}
» Blood from blood bank (may contain up to 30 mEq [mmol] of potassium per liter of plasma or up to 65 mEq [mmol] per liter of whole blood when stored for more than 10 days) or
» Cyclosporine or
» Diuretics, potassium-sparing, other, or{16}
Heparin or{22}{24}
» Low-salt milk (may contain up to 60 mEq [mmol] of potassium per liter) or
» Potassium-containing medications or{25}
» Potassium supplements or substances containing high levels of potassium or{25}
Salt substitutes (most contain substantial amounts of potassium){25}    (concurrent administration with potassium-sparing diuretics tends to promote serum potassium accumulation; hyperkalemia may result, especially in patients with renal insufficiency)


» Anticoagulants, coumarin- or indandione-derivative, or{23}
» Heparin{22}    (anticoagulant effects may be decreased when these medications are used concurrently with potassium-sparing diuretics and hydrochlorothiazide combination as a result of reduction of plasma volume, leading to concentration of procoagulant factors in the blood; in addition, diuretic-induced improvement of hepatic congestion may lead to improved hepatic function, resulting in increased procoagulant factor synthesis; dosage adjustments may be necessary)


Antidiabetic agents, oral, or{20}
Insulin    (hydrochlorothiazide may raise blood glucose concentrations; for adult-onset diabetics dosage adjustment of hypoglycemic medications may be necessary during and after hydrochlorothiazide therapy; insulin requirements may be increased, decreased, or unchanged)


Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin    (may reduce the antihypertensive effects of the potassium-sparing diuretics and hydrochlorothiazide combination; indomethacin may also reduce the natriuretic and diuretic effects, possibly because of renal prostaglandin synthesis inhibition and/or sodium and fluid retention; the patient should be carefully monitored to confirm that the desired effect is being obtained)

    (concurrent use of NSAIDs with a diuretic may increase the risk of renal failure secondary to a decrease in renal blood flow caused by inhibition of renal prostaglandin synthesis)


Calcium-containing medications    (concurrent use of hydrochlorothiazide with large doses of calcium may result in hypercalcemia because of reduced calcium excretion {26})


» Cholestyramine or{27}
» Colestipol    (may inhibit gastrointestinal absorption of hydrochlorothiazide; administration of potassium-sparing diuretic and hydrochlorothiazide combinations 1 hour before or 4 hours after cholestyramine or colestipol is recommended)


Diazoxide{28}{29}    (concurrent use with hydrochlorothiazide may enhance hyperglycemic effects; monitoring of blood glucose levels and/or dosage adjustment of one or both agents may be necessary {28} {29})

    (in addition, concurrent use with hydrochlorothiazide may enhance hyperuricemic and antihypertensive effects)


Diflunisal    (concurrent use of hydrochlorothiazide with diflunisal produces significantly increased plasma concentrations of hydrochlorothiazide; in addition, the hyperuricemic effect of hydrochlorothiazide is decreased {30})


» Digitalis glycosides    (concurrent use with hydrochlorothiazide may enhance the possibility of digitalis toxicity associated with hypokalemia or hypomagnesemia {31} {32})

    (spironolactone may increase the half-life of digoxin; dosage reduction or increased dosing intervals of digoxin may be necessary and careful monitoring is recommended {16} {37})


Dopamine    (concurrent use may increase the diuretic effect of either hydrochlorothiazide or dopamine, as a result of dopamine's direct effect on dopaminergic receptors to produce vasodilation of renal vasculature and increase renal blood flow; dopamine also has a direct natriuretic effect {33} {34})


Exchange resins, sodium cycle (such as sodium polystyrene sulfonate)    (whether administered orally or rectally, these medications reduce serum potassium levels by replacing potassium with sodium; fluid retention may occur in some patients because of the increased sodium intake {17})


Hypokalemia-causing medications, other (see Appendix II )    (risk of hypokalemia due to other hypokalemia-causing medications may be increased; monitoring of serum potassium concentrations and cardiac function may be needed with concurrent use {20} {35})


Hypotension-producing medications, other (see Appendix II )    (antihypertensive and/or diuretic effects may be potentiated when these medications are used concurrently with diuretics; although some antihypertensive and/or diuretic combinations are frequently used for therapeutic advantage, dosage adjustments may be necessary during concurrent use {16})


» Lithium    (concurrent use with potassium-sparing diuretic and hydrochlorothiazide combinations is not recommended, as they may increase the risk of lithium toxicity by reducing renal clearance {17} {25} {51})


Neuromuscular blocking agents, nondepolarizing    (hydrochlorothiazide may induce hypokalemia, which may enhance the blockade of nondepolarizing neuromuscular blocking agents; {51} however, this may be less likely with the potassium-sparing and hydrochlorothiazide diuretic combinations; serum potassium determinations may be necessary prior to administration of nondepolarizing neuromuscular blocking agents; careful postoperative monitoring of the patient may be necessary following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade {20} {25})


Sympathomimetics    (may reduce the antihypertensive effects of potassium-sparing diuretic and hydrochlorothiazide combinations; the patient should be carefully monitored to confirm that the desired effect is being obtained {36})


For triamterene only (in addition to those listed above)
Folic acid    (triamterene may act as a folate antagonist by inhibiting dihydrofolate reductase; most significant with high doses and/or prolonged triamterene use; leucovorin calcium must be used instead of folic acid in patients receiving triamterene {39} {40})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results

For hydrochlorothiazide:
Bentiromide test    (administration of hydrochlorothiazide during a bentiromide test period will invalidate test results since hydrochlorothiazide is also metabolized to an arylamine and will thus increase the percent of para-aminobenzoic acid [PABA] recovered; discontinuation of potassium-sparing diuretic and hydrochlorothiazide combinations at least 3 days prior to the administration of bentiromide is recommended)


For spironolactone:
Digoxin radioimmunoassay    (results may be falsely elevated)


Plasma cortisol determination by Mattingly (fluorometric) assay    (concentration may be falsely increased; withdrawal of spironolactone and hydrochlorothiazide combination 4 to 7 days prior to determinations, or substitution of Ertel, Peterson, or Norymberski method, is recommended)


For triamterene:
Fluorescent measurement of quinidine    (similar fluorescence spectra)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hyperkalemia    (potassium-sparing diuretics may further increase serum potassium concentrations)


Risk-benefit should be considered when the following medical problems exist

For all potassium-sparing diuretic and hydrochlorothiazide combinations:
» Anuria or severe renal function impairment    (potassium-sparing diuretic and hydrochlorothiazide combinations may be ineffective and may precipitate azotemia; {51} may produce cumulative effects; risk of developing hyperkalemia is increased {16} {20})


Diabetes mellitus or
Diabetes mellitus with confirmed or suspected renal insufficiency or
» Diabetic nephropathy    (hypoglycemic medication requirements may be altered {16} {20} {51} {52})


Gout, history of, or
Hyperuricemia{17}{20}    (serum uric acid concentrations may be elevated by potassium-sparing diuretic and hydrochlorothiazide combinations)


Hepatic function impairment    (risk of dehydration, which may precipitate hepatic coma and death; increased sensitivity to potential electrolyte changes; plasma half-life is unaltered {16} {17} {20})


Hypercalcemia or{20}
Hypercholesterolemia or{41} {42}{43}
Hypertriglyceridemia or{41}{42}{43}
Hyponatremia{20}    (conditions may be exacerbated by hydrochlorothiazide; hyponatremia may also be exacerbated by the potassium-sparing diuretics; onset of hyponatremia can be sudden and life-threatening {44} {45} {51})


Lupus erythematosus, history of    (exacerbation or activation by hydrochlorothiazide has been reported {20} {51})


Metabolic or respiratory acidosis, predisposition for{01}{07}    (acidosis potentiates hyperkalemic effects of potassium-sparing diuretics; potassium-sparing diuretics may potentiate acidosis)


Pancreatitis
Sensitivity to thiazide diuretics or other sulfonamide-derived medications or potassium-sparing diuretics
Sympathectomy    (antihypertensive effects may be enhanced {20})


» Caution is also required in jaundiced infants because of the risk of hyperbilirubinemia with hydrochlorothiazide.
» Caution is also required in severely ill patients and those with relatively small urine volumes who are at greater risk of developing hyperkalemia associated with potassium-sparing diuretics.
For spironolactone and hydrochlorothiazide combination only (in addition to those listed above):
Menstrual abnormalities or breast enlargement
For triamterene and hydrochlorothiazide combination only (in addition to those listed above):
Nephrolithiasis, history of    (increased risk of forming triamterene stones {17})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood pressure measurements    (recommended at periodic intervals in patients being treated for hypertension; selected patients may be taught to monitor their blood pressure at home and report the results at regular physician visits)


Blood urea nitrogen (BUN) and
Creatinine, serum, and
Glucose, blood, and
Uric acid, serum    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy)


Electrocardiogram (ECG)
Electrolyte concentrations, serum, especially serum potassium determinations    (determinations may be required at periodic intervals for patients on long-term therapy, especially if they are also taking systemic corticosteroids, or when congestive heart failure or severe cirrhosis is present)


For triamterene and hydrochlorothiazide only
Platelet count
Leukocyte count, total (with differential if appropriate)    (recommended prior to initiation of therapy and at periodic intervals during therapy, especially in patients with impaired hepatic function)




Side/Adverse Effects

Those indicating need for medical attention
    
Electrolyte imbalance, especially, hyperkalemia, hypokalemia, or hyponatremia{02}{03}{04}{05}{06} (confusion; dryness of mouth; increased thirst; irregular heartbeat; mood or mental changes; muscle cramps or pain; numbness or tingling in hands, feet, or lips; shortness of breath or difficulty breathing; unusual tiredness or weakness; weak pulse; weakness or heaviness of legs)
Incidence rare
    
Agranulocytosis (fever or chills; cough or hoarseness)
    
allergic reaction (skin rash or hives)
    
cholecystitis or pancreatitis (severe stomach pain with nausea and vomiting)
    
gout or hyperuricemia (joint pain)
    
hepatic function impairment (yellow eyes or skin)
    
thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)

Incidence rare (for triamterene and hydrochlorothiazide combination only)
    
Megaloblastosis (bright red tongue; burning, inflamed feeling in tongue; cracked corners of mouth; weakness)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (less frequent with triamterene and hydrochlorothiazide combination)
    
Anorexia (loss of appetite)
    
nausea and vomiting
    
stomach cramps and diarrhea
    
upset stomach

Incidence less frequent
    
Decreased sexual ability
    
orthostatic hypotension (dizziness or lightheadedness when getting up from a lying or sitting position)
    
headache
    
photosensitivity (increased sensitivity of skin to sunlight)

Incidence less frequent (for amiloride only)
    
Constipation

Incidence related to dose and/or duration of therapy (for spironolactone only)
    
Antiandrogenic or endocrine effects (breast tenderness in females; deepening of voice in females; enlargement of breasts in males; increased hair growth in females; irregular menstrual periods; sweating)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Recommended treatment for overdose includes: immediate evacuation of the stomach; supportive, symptomatic treatment; monitoring of serum electrolyte concentrations and renal function; immediate institution of appropriate treatment for hyperkalemia {07}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Diuretics, Potassium-sparing, and Hydrochlorothiazide (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to the potassium-sparing diuretic prescribed, hydrochlorothiazide or other thiazide diuretics, other sulfonamide-type medications, bumetanide, furosemide, or carbonic anhydrase inhibitors

Pregnancy—Diuretics not recommended for routine use





Breast-feeding—Hydrochlorothiazide distributed into breast milk; spironolactone may be distributed into breast milk





Use in the elderly—Elderly patients may be more sensitive to hypotensive and electrolyte-depleting effects
Other medications, especially angiotensin-converting enzyme inhibitors, cholestyramine, colestipol, coumarin or indandione anticoagulants, cyclosporine, digitalis glycosides, heparin, lithium, low-salt milk, other potassium-sparing diuretics, potassium-containing medications or supplements, or stored blood from a blood bank
Other medical problems, especially, diabetic nephropathy, hepatic function impairment, renal function impairment or anuria

Proper use of this medication
Diuretic effects of the medication and timing of doses to minimize inconvenience of diuresis

Getting into habit of taking at same time each day to help increase compliance

Taking with meals or milk to reduce stomach upset

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

For use as an antihypertensive
Possible need for control of weight and diet, especially sodium intake

» Patient may not experience symptoms of hypertension; importance of taking medication even if feeling well

» Does not cure, but helps control hypertension; possible need for lifelong therapy; checking with physician before discontinuing medication; serious consequences of untreated hypertension

Precautions while using this medication
Regular visits to physician to check progress

» Possibility of hypokalemia or hyperkalemia; possible need for monitoring potassium in diet; not changing diet without first checking with physician

To prevent dehydration, checking with physician if severe nausea, vomiting, or diarrhea occurs and continues

Diabetics: May increase blood sugar levels

Possible photosensitivity; avoiding too much sun; using protective clothing and sun block product; avoiding use of sunlamp, tanning bed, or tanning booth

Caution if any kind of surgery or emergency treatment is required

Caution if any laboratory tests required; possible interference with test results

For triamterene and hydrochlorothiazide combination
Not changing brands of triamterene and hydrochlorothiazide combination without checking with physician

For use an an antihypertensive
» Not taking other medications, especially nonprescription sympathomimetics, unless discussed with physician


Side/adverse effects
Signs of potential side effects, especially electrolyte imbalance, agranulocytosis, allergic reaction, cholecystitis or pancreatitis, gout or hyperuricemia, hepatic function impairment, thrombocytopenia, megaloblastosis (for triamterene)

For spironolactone
Possibility of enlargement of breasts in males and irregular menstrual periods in females; usually reversible within several months


General Dosing Information
Dosage must be adjusted to meet the individual requirements of each patient, based on clinical response. The lowest effective dosage should be utilized to minimize potential electrolyte imbalance.

Fixed-dosage combinations are generally not recommended in initial therapy and are useful in subsequent therapy only when the proportion of the component agents corresponds to the dose of the individual agents, as determined by titration.

If a single daily dose is indicated, it is preferably taken on arising in order to minimize the effect of increased frequency of urination on sleep.

When these medications are used to promote diuresis, intermittent dosage schedules (drug-free days) may reduce the possibility of electrolyte imbalance or hyperuricemia resulting from therapy.

If anuria or signs of progressive hepatic or renal (including azotemia or hyperkalemia) dysfunction occur, it is recommended that treatment with this medication be permanently discontinued. If hyperkalemia is associated with ECG changes, prompt additional therapy with intravenous sodium bicarbonate, calcium gluconate, or calcium chloride or with oral or rectal sodium polystyrene sulfonate, or with parenteral glucose and insulin may be indicated. It is important to remember that severe hyperkalemia may occur suddenly and may not be preceded by any warning signs.

Although concurrent administration of potassium supplements may be indicated in some patients considered to be at high risk for developing hypokalemia, extreme caution in administering potassium supplements is recommended, and close monitoring of serum potassium concentrations is essential. Use of potassium supplements is not recommended in patients with renal function impairment. {07}

Recent evidence suggests that withdrawal of antihypertensive therapy prior to surgery is not desirable. However, the anesthesiologist must be aware of such therapy.

Diet/Nutrition
It is recommended that potassium-sparing diuretic and hydrochlorothiazide combinations be taken with or after meals to minimize stomach upset.

AMILORIDE AND HYDROCHLOROTHIAZIDE

Summary of Differences


For amiloride:


Pharmacology/pharmacokinetics—
Biotransformation—None; excreted unchanged.

Onset of action—Diuretic: Single dose—Within 2 hours.

Duration of action—Diuretic: Single dose—24 hours.



Side/adverse effects—
Amiloride may cause constipation. Agranulocytosis has not been reported.




Oral Dosage Forms

AMILORIDE HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE TABLETS USP

Usual adult dose
Diuretic or
Antihypertensive1
Oral, 1 or 2 tablets a day. {08} {51}


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


5 mg of amiloride hydrochloride and 50 mg of hydrochlorothiazide (Rx) [Moduretic (scored)][Generic] (may be scored)

Canada—


5 mg of amiloride hydrochloride and 50 mg of hydrochlorothiazide (Rx) [Moduret (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • Take with meals or milk.
   • Avoid overexposure to the sun or use of sunlamp.
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



SPIRONOLACTONE AND HYDROCHLOROTHIAZIDE

Summary of Differences


For spironolactone:


Pharmacology/pharmacokinetics—
Mechanism of action/effect—Aldosterone antagonist.

Protein-binding—Very high (more than 90%).

Biotransformation—Hepatic, extensive, to active metabolite (canrenone).

Duration of action—Diuretic: Multiple doses—2 to 3 days.



Precautions—
Carcinogenicity—Tumorigenic in rats and possibly associated with breast carcinoma in humans.

Drug interactions and/or related problems—May increase digoxin half-life.

Laboratory value alterations—May falsely increase plasma cortisol determinations by Mattingly (fluorometric) assay and may falsely elevate digoxin radioimmunoassays.

Medical considerations/contraindications—Menstrual abnormalities or breast enlargement.



Side/adverse effects—
Endocrine or antiandrogenic effects more common at doses exceeding 100 mg per day. May cause CNS effects and causes more frequent gastrointestinal irritation.




Additional Dosing Information
See also General Dosing Information .

When the spironolactone and hydrochlorothiazide combination is added to therapy with another diuretic or antihypertensive agent, it is recommended that the dosage of the other drug (especially ganglionic blocking agents) be reduced by at least 50% and then adjusted as required.


Oral Dosage Forms

SPIRONOLACTONE AND HYDROCHLOROTHIAZIDE TABLETS USP

Usual adult dose
Diuretic—Edema due to congestive heart failure, hepatic cirrhosis, or nephrotic syndrome:
Maintenance—Oral, 1 to 4 tablets a day, taken as a single dose or in divided doses. {53}

Antihypertensive
Maintenance: Oral, 2 to 4 tablets a day in divided doses. {10} {53}


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual pediatric dose
Diuretic
Maintenance: Oral, 1.65 to 3.3 mg of spironolactone and of hydrochlorothiazide per kg of body weight a day in divided doses. {10} {53}


Strength(s) usually available
U.S.—


25 mg of spironolactone and 25 mg of hydrochlorothiazide (Rx) [Aldactazide] [Spirozide][Generic] (may be scored)


50 mg of spironolactone and 50 mg of hydrochlorothiazide (Rx) [Aldactazide (scored)]

Canada—


25 mg of spironolactone and 25 mg of hydrochlorothiazide (Rx) [Aldactazide (scored)] [Novo-Spirozine (scored)]


50 mg of spironolactone and 50 mg of hydrochlorothiazide (Rx) [Aldactazide (scored)] [Novo-Spirozine (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. Protect from light.

Auxiliary labeling:
   • Take with meals or milk.
   • Avoid overexposure to the sun or use of sunlamp.
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



TRIAMTERENE AND HYDROCHLOROTHIAZIDE

Summary of Differences


For triamterene:


Pharmacology/pharmacokinetics—
Biotransformation—Hepatic.

Onset of action—Diuretic: Single dose—Within 1 hour.

Duration of action—Diuretic: Single dose—7 to 9 hours.



Precautions—
Drug interactions and/or related problems—Use with allopurinol, colchicine, probenecid, or sulfinpyrazone may raise blood uric acid concentrations.

Laboratory value alterations—May interfere with fluorescent measurement of quinidine.

Medical considerations/contraindications—Hyperuricemia or gout; history of nephrolithiasis.



Side/adverse effects—
Nephrolithiasis; megaloblastosis. No decrease in sexual ability reported.




Additional Dosing Information
See also General Dosing Information .

Since triamterene is a weak folic acid antagonist, it may contribute to development of megaloblastosis in patients who have depleted folic acid stores (e.g., in pregnancy, hepatic cirrhosis).


Oral Dosage Forms

TRIAMTERENE AND HYDROCHLOROTHIAZIDE CAPSULES USP

Usual adult dose
Diuretic or
Antihypertensive
Oral, 1 or 2 capsules once a day, {52} as determined by individual titration with the component agents; some patients may be maintained on 1 capsule a day or every other day. {11}


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual adult prescribing limits
Up to 4 capsules daily. {11}

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


37.5 mg of triamterene and 25 mg of hydrochlorothiazide (Rx) [Dyazide (lactose)]


50 mg of triamterene and 25 mg of hydrochlorothiazide (Rx)[Generic]


75 mg of triamterene and 50 mg of hydrochlorothiazide (Rx)[Generic]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. Protect from light.

Auxiliary labeling:
   • Take with meals or milk.
   • Avoid overexposure to the sun or use of sunlamp.
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.
Capsules ( Dyazide) and tablets ( Maxzide) available in the U.S. are not bioequivalent. One product should not be substituted for the other. If patients are to be transferred from one dosage form to the other, retitration and appropriate changes in dosage may be necessary.



TRIAMTERENE AND HYDROCHLOROTHIAZIDE TABLETS USP

Usual adult dose
Antihypertensive or
Diuretic


Maxzide:
Oral, 1 tablet per day, as determined by individual titration. {11}



Apo-Triazide; Dyazide (Canada); Novotriamzide:
Oral, 1 or 2 tablets two times a day, as determined by individual titration with the component agents; some patients may be maintained on 1 tablet a day or every other day. {12}



Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


37.5 mg of triamterene and 25 mg of hydrochlorothiazide (Rx) [Maxzide (scored)]


75 mg of triamterene and 50 mg of hydrochlorothiazide (Rx) [Maxzide (scored)][Generic] (may be scored)(may contain lactose)

Canada—


50 mg of triamterene and 25 mg of hydrochlorothiazide (Rx) [Apo-Triazide (scored)] [Dyazide (scored)] [Novo-Triamzide (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. Protect from light.

Auxiliary labeling:
   • Take with meals or milk.
   • Avoid overexposure to the sun or use of sunlamp.
   • Do not take other medicines without your doctor's advice.

Note: Check refill frequency to determine compliance in hypertensive patients.
Tablets ( Maxzide) and capsules ( Dyazide) available in the U.S. are not bioequivalent. One product should not be substituted for the other. If patients are to be transferred from one dosage form to the other, retitration and appropriate changes in dosage may be necessary.




Revised: 08/03/1994



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Amiloride and Hydrochlorothiazide package insert (Moduretic, MSD—US), 10/85.
  1. Br Med J 1984 Sep 15; 289: 659.
  1. J Neurol, Neurosurg, Psych 1984 Aug; 47: 886.
  1. JAMA 1984 Jul 20; 252: 389.
  1. Br J Pharm Practice 1986 Apr; 8: 101-2.
  1. Br Med J 1984 Jun 30; 288: 1962.
  1. Panel comments, 7/87.
  1. Amiloride and Hydrochlorothiazide product information (Moduretic, MSD—US), Rev 88, Rec 3/89.
  1. Open.
  1. Spironolactone and Hydrochlorothiazide product information (Aldactazide, Searle—US), Rev 9/87, Rec 1/89.
  1. Triamterene and Hydrochlorothiazide product information (Maxzide, Lederle—US), Rev 8/88, Rec 12/88.
  1. Apo-Triazide product information. In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 27th ed. Ottawa: Canadian Pharmaceutical Association, 1992.
  1. International Olympic Committee (IOC) Medical Commission Doping classes, Methods and Restrictions, 1991.
  1. United States Olympic Committee, Drug Education Handbook 1989 to 1992.
  1. The National Collegiate Athletic Association (NCAA) Drug Testing/Education Programs 1990/1991.
  1. Spironolactone package insert (Aldactone, Searle—US), Rev 1/91, Rec 4/92.
  1. Triamterene package insert (Dyrenium, SKF—US), Rev 5/89, Rec 5/92.
  1. Canadian Med Assoc J 1983 Nov 1; 129: 974-5.
  1. Cordarone product information (Wyeth—US), Rev 5/88, Rec 4/89.
  1. Hydrodiuril package insert (Merck—US), Rev 10/87, Rec 2/92.
  1. Manufacturer comment, 1991 revision cycle.
  1. Saxena K. Clinical features and management of poisoning due to potassium chloride. Med Toxicol Adv Drug Exp 1989; 4(6): 429-43.
  1. O'Reilly R. Spironolactone and warfarin interaction. Clin Pharmacol Ther 1980; 27(2): 198-201.
  1. Busch E, Ventura H, Lavie C. Heparin-induced hyperkalemia. South Med J 1987; 80(11): 1450-1.
  1. Hansten PD, Horn JR. Drug interactions. 6th ed. Philadelphia: Lea & Febiger, 1990.
  1. Gora M, et al. Milk-alkali syndrome associated with use of chlorothiazide and calcium carbonate. Clin Pharm 1989; 8: 227-9.
  1. Hunninghake D, Hibbard D. Influence of time intervals for cholestyramine dosing on the absorption of hydrochlorothiazide. Clin Pharmacol Ther 1986; 39: 329-34.
  1. Tatro DS, editor. Drug interaction facts. St Louis: Facts and Comparisons, 1990: 246.
  1. Hansten PD, Horn JR. Drug interactions. 6th ed. Philadelphia: Lea & Febiger, 1990: 187.
  1. Dolobid product information (MSD—US), Rev 1988.
  1. Dyckner T, Webster P. Intracellular magnesium loss after diuretic administration. Drugs 1984; 28(suppl 1): 161-6.
  1. Whang R, Oli T, Watanabe A. Frequency of hypomagnesemia in hospitalized patients receiving digitalis. Arch Intern Med 1985; 145: 655-6.
  1. Panel comment, 1991 revision.
  1. Dopamine product information (Astra—US), Rev 11/87, Rec 1/89.
  1. Stanaszek W, Romankiewicz J. Current approaches to management of potassium deficiency. DICP 1985; 19: 176-83.
  1. Epinephrine product information (IMS—Canada), Rev 1/88, Rec 11/88.
  1. Paladino J, Davidson K, McCall B. Influence of spironolactone on serum digoxin concentration. JAMA 1984; 251(4): 470-1.
  1. Wilson T, Rajput A. Amantidine-dyazide interaction. Can Med Assoc 1983; 129: 974-5.
  1. Olin BR, editor. Drug facts and comparisons. St. Louis: Facts and Comparisons Inc, 1989: 78.
  1. Butterworth C, Tamura T. Folic acid safety and toxicity: a brief review. Am J Clin Nutr 1989; 50: 353-8.
  1. Grimm R, Leon A, Hunninghake D, Lenz K, Hanman P, Blackburn H. Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive patients. Ann Intern Med 1981; 94: 7-11.
  1. Lardinois C, Neuman S. The effects of antihypertensive agents on serum lipids and lipoproteins. Arch Intern Med 1988; 148: 1280-8.
  1. Pollare T, Lithell H, Berne C. A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Eng J Med 1989; 321(13): 868-73.
  1. Panel comment, 1990 revision cycle.
  1. Friedman E, Shadel M, Halkin H, Forfel Z. Thiazide-induced hyponatremia. Ann Intern Med 1989; 110(1): 24-30.
  1. Am Academy of Pediatrics. The transfer of drugs and other chemicals into human breast milk. Pediatr 1983; 72(3): 375-83.
  1. Spironolactone and Hydrochlorothiazide package insert (Aldactazide, Searle—US), 7/6/84.
  1. Spironolactone and Hydrochlorothiazide package insert (Parke-Davis—US), 10/82.
  1. Triamterene and Hydrochlorothiazide package insert (Dyazide, SKF—US), 2/86.
  1. Triamterene and Hydrochlorothiazide package insert (Maxzide Lederle—US), 11/85.
  1. Amiloride and Hydrochlorothiazide package insert (Moduretic, Merck—US), Rev 5/93, Rec 3/94.
  1. Triamterene and Hydrochlorothiazide package insert (Dyazide, SmithKline-Beecham—US), Rev 10/93, Rec 4/94.
  1. Spironolactone and Hydrochlorothiazide package insert (Aldactazide, Searle—US), Rev 10/92, Rec 4/94.
  1. Spironolactone and Hydrochlorothiazide product monograph (Searle—Canada), Rev 7/93, Rec 8/93.
  1. Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1993: 42, 328, 617, 684.
  1. Red book 1993. Montvale, NJ: Medical Economics Data, 1993.
  1. Triamterene and Hydrochlorothiazide (Maxide, Lederle—US) product information. In: PDR Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company, 1994: 1168.
  1. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993; 153(2): 154-83.
Hide
(web3)