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Diuretics, Thiazide (Systemic)

This monograph includes information on the following:

1) Bendroflumethiazide
2) Chlorothiazide  
3) Chlorthalidone
4) Hydrochlorothiazide
5) Hydroflumethiazide  
6) Methyclothiazide
7) Metolazone
8) Polythiazide  
9) Quinethazone  
10) Trichlormethiazide  


INN:
Chlorthalidone —Chlortalidone

VA CLASSIFICATION
Primary: CV701
Secondary: CV409; GU900

Commonly used brand name(s): Apo-Chlorthalidone3; Apo-Hydro4; Aquatensen6; Diucardin5; Diuchlor H4; Diulo7; Diuril2; Duretic6; Enduron6; Esidrix4; Hydro-D4; Hydro-chlor4; HydroDIURIL4; Hydromox9; Hygroton3; Metahydrin10; Microzide4; Mykrox7; Naqua10; Naturetin1; Neo-Codema4; Novo-Hydrazide4; Novo-Thalidone3; Oretic4; Renese8; Saluron5; Thalitone3; Trichlorex10; Uridon3; Urozide4; Zaroxolyn7.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Diuretic—

antihypertensive—

antidiuretic (central and nephrogenic diabetes insipidus)—

antiurolithic (calcium calculi)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Edema (treatment)—Indications include edema associated with congestive heart failure, hepatic cirrhosis with ascites, corticosteroid and estrogen therapy, and some forms of renal function impairment including nephrotic syndrome, acute glomerulonephritis, and chronic renal failure. {04} {05} {06} {08} However, prompt metolazone tablets are not indicated for treatment of edema because a safe and effective diuretic dosage has not been established.

Hypertension (treatment)—Thiazide diuretics are indicated either alone or as adjunctive therapy {04} in the treatment of hypertension . {03} {04} {05} {06} {08}
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.

[Diabetes insipidus, central or nephrogenic (treatment)]1—Thiazide diuretics are used in the treatment of central and nephrogenic diabetes insipidus. {22}

[Renal calculi, calcium (prophylaxis) ]1—Thiazide diuretics are also used for prevention of calcium-containing renal stones. {22}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Note: Although they are not chemically the same, chlorthalidone, metolazone, and quinethazone have the same actions as the thiazide diuretics.


Physicochemical characteristics:
Molecular weight—
    Bendroflumethiazide: 421.41
    Chlorothiazide: 295.72
    Chlorthalidone: 338.76
    Hydrochlorothiazide: 297.73
    Hydroflumethiazide: 331.28
    Methyclothiazide: 360.23
    Metolazone: 365.83
    Polythiazide: 439.87
    Quinethazone: 289.74
    Trichlormethiazide: 380.65

pKa—
    Bendroflumethiazide: 8.5
    Chlorothiazide: 6.7 and 9.5
    Chlorthalidone: 9.4
    Hydrochlorothiazide: 7.9 and 9.2
    Hydroflumethiazide: 8.9 and 10.7
    Methyclothiazide: 9.4
    Metolazone: 9.7
    Quinethazone: 9.3 and 10.7
    Trichlormethiazide: 8.6

Mechanism of action/Effect:

Diuretic—Thiazide diuretics increase urinary excretion of sodium and water by inhibiting sodium reabsorption in the early distal tubules {04}. They increase the rate of delivery of tubular fluid and electrolytes to the distal sites of hydrogen and potassium ion secretion, while plasma volume contraction increases aldosterone production. The increased delivery and increase in aldosterone levels promote sodium reabsorption at the distal tubules, thus increasing the loss of potassium and hydrogen ions. {24}

Antihypertensive—Diuretics lower blood pressure initially by reducing plasma and extracellular fluid volume; cardiac output also decreases. Eventually, cardiac output returns to normal. Thiazide diuretics decrease peripheral resistance by a direct peripheral effect on blood vessels. {24} {25} {51} {52}

Antidiuretic—The antidiuretic effect of thiazide diuretics 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. {22} {50}

Antiurolithic (calcium calculi)—Thiazide diuretics decrease urinary calcium excretion by a direct action on the distal tubule, which may prevent recurrence of calcium-containing renal calculi. {22} {23}

Absorption:

Thiazide diuretics are absorbed relatively rapidly after oral administration. {03}

Metolazone—The time to peak concentration is 8 hours for extended metolazone tablets and 2 to 4 hours for prompt metolazone tablets {01}. In addition, prompt metolazone tablets have higher bioavailability {01}.

Protein binding:

Bendroflumethiazide—Very high (94%).

Chlorothiazide—Low to high (20 to 80%).

Chlorthalidone—High (75% [58% to albumin]) {05}; increased affinity to carbonic anhydrase in red blood cells. {05}

Hydroflumethiazide—High (74%).

Metolazone—Very high (95%; 50 to 70% to red blood cells).

Polythiazide—High (84%).

Elimination:
    Unchanged; almost totally via the kidneys, {04} {61} with minute quantities in the bile; metolazone undergoes some enterohepatic recycling and slightly greater amounts are excreted in the bile.


        Drug
        Half-life
        (hr)
        Diuretic Effect (hr)
        Onset
        Peak
        Duration
        Bendroflumethiazide
        8.5
        1–2
        4
        6–12
        Chlorothiazide
        1–2
        2
        4
        6–12
        Chlorthalidone
        35 to 50
        2
        2
        48–72
        Hydrochlorothiazide
        5.6–14.8
        2
        4
        6–12
        Hydroflumethiazide
        17
        1–2
        3–4
        18–24
        Methyclothiazide
          2
        6
        >24
        Metolazone
        14 {01}
        1 *
        2 *
        12–24 *
        Polythiazide
          2
        6
        24–48
        Quinethazone
          2
        6
        18–24
        Trichlormethiazide
          2
        6
        £24
*         Information on diuretic effect applies to extended metolazone tablets.

Note: In the absence of edema, negative sodium balance induced by {50} thiazide diuretics lasts for 3 days to 4 weeks {56} with chronic administration. Extracellular fluid volumes remain steady thereafter, although at a lower concentration and volume than before initiation of therapy.
The antihypertensive effects of the thiazide diuretics may be noted after 3 to 4 days of therapy, although up to 3 to 4 weeks may be required for optimal effect. Antihypertensive effects persist for up to 1 week after withdrawal of therapy.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other sulfonamide-type medications, bumetanide, furosemide, or carbonic anhydrase inhibitors may be sensitive to this medication also.

Carcinogenicity/Mutagenicity

Bendroflumethiazide—Studies have not been done in either animals or humans. {49} {59}

Chlorothiazide—Carcinogenicity studies have not been done in either animals or humans. Chlorothiazide was not found to be mutagenic in the Ames microbial mutation test, dominant lethal assay, or a test in Aspergillus nidulans . {08} {73}

Hydrochlorothiazide—Carcinogenicity studies have not been done in either animals or humans. Hydrochlorothiazide was not found to be mutagenic in vitro in the Ames microbial mutation test or on examination of urine from patients who received hydrochlorothiazide; however, it did induce nondisjunction in Aspergillus nidulans . {04} {65}

Hydroflumethiazide—Studies have not been done in either animals or humans. {03} {66}

Methyclothiazide—Studies have not been done in either animals or humans. {06} {67}

Metolazone—Studies in mice and rats for 11/2 to 2 years at doses of 2, 10, and 50 mg per kg of body weight (mg/kg) per day (100, 500, and 2500 times the maximum recommended human dose [MRHD]) found no evidence of carcinogenicity. {68}

Trichlormethiazide—Studies have not been done in either animals or humans. {72}

Pregnancy/Reproduction
Fertility—
Hydrochlorothiazide: No adverse effects on fertility were found in rats given doses up to 2 times the maximum recommended human dose of hydrochlorothiazide. {65}

Methyclothiazide: No adverse effects on fertility were found in rats given methyclothiazide in doses up to 4 mg per kg of body weight (mg/kg) per day (at least 20 times the maximum recommended human dose). {67}

Metolazone: A study in which male rats were given metolazone at doses of 2, 10, and 50 mg/kg for 127 days prior to mating with untreated female rats revealed an increase in the number of resorption sites in dams mated with males given the 50 mg/kg dose. Furthermore, decreased fetal weight and reduced pregnancy rate were observed in dams mated with males from the 10 and 50 mg/kg groups. In mice, there was no evidence that metolazone alters reproductive capacity. {68}

Pregnancy—
Thiazide diuretics cross the placenta and appear in cord blood. Although studies in humans have not been done, thiazide diuretics can cause fetal harm when given to pregnant women. Fetal or neonatal jaundice has been reported.

Pregnant women should be advised to contact their physician before taking this medication, since routine use of diuretics during normal pregnancy is inappropriate and exposes mother and fetus to unnecessary hazard. Thiazide diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of toxemia. Thiazide 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. {04} {05} Possible hazards include fetal or neonatal jaundice, thrombocytopenia, or other adverse reactions seen in adults.

Studies in animals have not shown that thiazide diuretics cause adverse effects on the fetus at several times the human dose.


Bendroflumethiazide

Adequate and well-controlled studies in humans and animals have not been done. {49}

FDA Pregnancy Category C.



Chlorothiazide

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

Studies in rabbits, mice, and rats at doses up to 500 mg/kg per day (25 times the MRHD) have not shown that chlorothiazide causes adverse effects on the fetus.

FDA Pregnancy Category B. {08}



Chlorthalidone

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

Studies in rats and rabbits at doses up to 420 times the human dose have not shown that chlorthalidone causes adverse effects on the fetus.

FDA Pregnancy Category B. {05}



Hydrochlorothiazide

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

A study in rats at dosages up to 250 mg/kg per day (62.5 times the MRHD) has not shown that hydrochlorothiazide causes adverse effects on the fetus. {04}

Studies in mice and rabbits with doses up to 100 mg/kg per day (50 times the maximum human dose) revealed no evidence of external abnormalities of the fetus. {65}

FDA Pregnancy Category B.



Hydroflumethiazide

Studies have not been done in humans.

Studies have not been done in animals.

FDA Pregnancy Category C. {66}



Methyclothiazide

Studies have not been done in humans. {67}

Studies in rats and rabbits given methyclothiazide at doses up to 4 mg/kg per day have revealed no evidence of harm to the fetus. {67}

FDA Pregnancy Category B.



Metolazone

Adequate and well-controlled studies in humans have not been done. {15}

Studies in mice, rabbits, and rats at doses up to 50 mg/kg per day (333 times the MRHD) have not shown that metolazone causes adverse effects on the fetus.

FDA Pregnancy Category B.



Trichlormethiazide

Adequate and well-controlled studies in humans have not been done. {13}

Studies in rats at doses 250 to 1250 times the recommended human daily dose have not shown that trichlormethiazide causes adverse effects on the fetus.

FDA Pregnancy Category C. {33}


Breast-feeding

Thiazide diuretics are 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. {03} {04} {05} {48}

Pediatrics

Although appropriate studies on the relationship of age to the effects of thiazide diuretics have not been performed in the pediatric population, {03} {04} {05} pediatrics-specific problems that would limit the usefulness of this medication in children are not expected. However, caution is required in jaundiced infants because of the risk of hyperbilirubinemia.


Geriatrics


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

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.

Amantadine    (hydrochlorothiazide may reduce the renal clearance of amantadine, resulting in increased plasma concentrations and possible amantadine toxicity {27})


Amiodarone    (concurrent use of thiazide diuretics with amiodarone may lead to an increased risk of arrhythmias associated with hypokalemia {17})


Anticoagulants, coumarin- or indandione-derivative    (effects may be decreased when used concurrently with thiazide diuretics 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 {03} {28} {29})


Antidiabetic agents, oral or{05}
Insulin{03}{04}{05}    (thiazide diuretics may raise blood glucose concentrations; for adult-onset diabetics, dosage adjustment of hypoglycemic medications may be necessary during and after thiazide diuretic therapy; insulin requirements may be increased, decreased, or unchanged {28})


Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin{03}{04}{28}    (may antagonize the natriuresis and increase in plasma renin activity [PRA] caused by thiazide diuretics; they may also reduce the antihypertensive effect and increase in urine volume caused by thiazide diuretics, possibly by inhibiting renal prostaglandin synthesis and/or by causing sodium and fluid retention; the patient should be carefully monitored to confirm that the desired effect is being obtained {28} {47})

    (in addition, 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 thiazide diuretics with large doses of calcium may result in hypercalcemia because of reduced calcium excretion {53} {54} {55})


» Cholestyramine or{13}{28}{46}
» Colestipol{28}    (may inhibit gastrointestinal absorption of the thiazide diuretics; administration of thiazide diuretics 1 hour before or 4 hours after cholestyramine or colestipol is recommended {03})


Diazoxide{59}{63}{64}    (concurrent use with thiazide diuretics may enhance hyperglycemic effects; monitoring of blood glucose levels and/or dosage adjustment of one or both agents may be necessary {59} {63} {64})

    (in addition, concurrent use with thiazide diuretics may enhance hyperuricemic and antihypertensive effects {59})


Diflunisal    (concurrent use of hydrochlorothiazide with diflunisal produces significantly increased plasma concentrations of hydrochlorothiazide; in addition, the hyperuricemic effect of hydrochlorothiazide is decreased {18})


» Digitalis glycosides    (concurrent use with thiazide diuretics may enhance the possibility of digitalis toxicity associated with hypokalemia or hypomagnesemia {03} {04} {05} {06} {08} {29} {30} {31})


Dopamine    (concurrent use may increase the diuretic effect of either thiazide diuretics 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 {57} {58})


Hypokalemia-causing medications, other (see Appendix II )    (risk of severe hypokalemia due to other hypokalemia-causing medications may be increased; monitoring of serum potassium concentrations and cardiac function and potassium supplementation may be necessary {03} {04} {05} {32})


Hypotension-producing medications, other (see Appendix II )    (antihypertensive and/or diuretic effects may be potentiated when these medications are used concurrently with thiazide diuretics; although some antihypertensive and/or diuretic combinations are frequently used for therapeutic advantage, when used concurrently dosage adjustments may be necessary {15})


» Lithium    (concurrent use with thiazide diuretics is not recommended, as they may provoke lithium toxicity because of reduced renal clearance; in addition, lithium has nephrotoxic effects {03} {04} {05} {06} {08} {28})


Neuromuscular blocking agents, nondepolarizing    (thiazide diuretics may induce hypokalemia, which may enhance the blockade of nondepolarizing neuromuscular blocking agents; 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 {04} {06} {13} {28})


Sympathomimetics    (may antagonize the antihypertensive effect of the thiazide diuretics; the patient should be carefully monitored to confirm that the desired effect is being obtained {03} {04} {13})



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
Bentiromide    (administration of thiazide diuretics during a bentiromide test period will invalidate test results since thiazide diuretics are also metabolized to arylamines and will thus increase the percent of para-aminobenzoic acid [PABA] recovered; discontinuation of thiazide diuretics at least 3 days prior to the administration of bentiromide is recommended)


Phenolsulfonphthalein (PSP) excretion test    (bendroflumethiazide and trichlormethiazide may interfere with PSP excretion {59})


Phentolamine and tyramine tests    (bendroflumethiazide and trichlormethiazide may produce false negative results {59})

With physiology/laboratory test values
Bilirubin    (serum concentrations may be increased by displacement from albumin binding {03})


Calcium    (serum concentrations may be increased; thiazide diuretics should be discontinued before parathyroid function tests are carried out {03} {04})


Cholesterol, low-density lipoprotein, and triglyceride and
Creatinine{45}    (serum concentrations may be increased {06})


Glucose, blood and urine    (concentrations may be increased, usually only in patients with a predisposition to glucose intolerance {03})


Magnesium and
Potassium and
Sodium{03}    (serum concentrations may be decreased; serum magnesium concentrations may increase in uremic patients; a fall in sodium can be life-threatening {43} {44})


Protein-bound iodine (PBI)    (serum concentrations may be decreased {03} {04} {05} {06})


Uric acid    (serum concentrations may be increased {03})


Urinary calcium concentrations    (may be decreased {03})


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).


Risk-benefit should be considered when the following medical problems exist
» Anuria or severe renal function impairment    (ineffective; may precipitate azotemia; may produce cumulative effects {03} {04} {05})


Diabetes mellitus    (hypoglycemic medication requirements may be altered {03} {04})


Gout, history of or{03}{04}{05}
Hyperuricemia{03}{04}{05}    (serum uric acid concentrations may be elevated)


Hepatic function impairment    (risk of dehydration which may precipitate hepatic coma and death; plasma half-life is unaltered {04} {05})


Hypercalcemia or{04}
Hypercholesterolemia or{34}{35}{36}
Hypertriglyceridemia or{34}{35}{36}
Hyponatremia{03}    (conditions may be exacerbated; onset of hyponatremia can be sudden and life-threatening {43} {44})


Lupus erythematosus, history of    (exacerbation or activation by thiazide diuretics has been reported {04})


Pancreatitis
Sensitivity to thiazide diuretics or other sulfonamide-derived medications{59}
Sympathectomy    (antihypertensive effects may be enhanced {03} {04} {05})


» Caution is required also in jaundiced infants because of the risk of hyperbilirubinemia.

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 glucose and
Blood urea nitrogen (BUN) and
Creatinine, serum and{03}{37}
Uric acid, serum{03}    (determinations recommended prior to initiation of therapy and if clinical signs of a significant increase occur)


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


Cholesterol, serum and
Triglycerides, serum    (determinations recommended after 6 months of therapy and annually thereafter {06} {38})


Electrolyte, serum, concentrations{03}{04}{05}    (determinations may be required for patients on long-term therapy, especially if they are also taking cardiac glycosides or systemic steroids, or when severe cirrhosis is present)




Side/Adverse Effects

Note: Most side effects are dose-related.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Electrolyte imbalance such as hyponatremia (confusion; convulsions; decreased mentation; fatigue; irritability; muscle cramps), hypochloremic alkalosis, and hypokalemia{04}{05} (dryness of mouth; increased thirst; irregular heartbeat; mood or mental changes; muscle cramps or pain; nausea or vomiting; unusual tiredness or weakness; weak pulse)

Note: Hyponatremia as a complication is rare, but constitutes a medical emergency as onset may be rapid. {43} {44}


Incidence rare
    
Agranulocytosis (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination){03}{04}{05}
    
allergic reaction (skin rash or hives)
    
cholecystitis or{03} pancreatitis (severe stomach pain with nausea and vomiting)
    
gout or{03}{04}{05} hyperuricemia (joint pain, lower back or side pain)
    
hepatic function impairment (yellow eyes or skin){04}{05}
    
thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin){03}{04}{05}



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Anorexia (loss of appetite){03}{04}{05}
    
decreased sexual ability{05}
    
diarrhea{03}{04}{05}
    
orthostatic hypotension (dizziness or lightheadedness when getting up from a lying or sitting position){03}{04}{05}
    
photosensitivity (increased sensitivity of skin to sunlight){03}{04}{05}
    
upset stomach{03}{04}{05}





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
Thiazide diuretic overdose should be treated by immediate evacuation of the stomach followed by supportive, symptomatic treatment and monitoring of serum electrolyte concentrations and renal function. {03} {04}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Diuretics, Thiazide (Systemic) .

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

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

Pregnancy—Not recommended for routine use; may cause jaundice, thrombocytopenia, hypokalemia in infant





Breast-feeding—Distributed into breast milk; recommended that nursing mothers avoid thiazides during first month of breast-feeding because of reports of suppression of lactation





Use in children—Caution if giving to infants with jaundice






Use in the elderly—Elderly patients may be more sensitive to hypotensive and electrolyte effects
Other medications, especially cholestyramine, colestipol, digitalis glycosides, or lithium
Other medical problems, especially anuria or severe renal function impairment or infants with jaundice

Proper use of this medication
Diuretic effects of the medication and timing of doses to minimize inconvenience of diuresis (except in diabetes insipidus)

Compliance with therapy; taking medication at the same time each day to maintain the therapeutic effect

Proper administration of concentrated oral hydrochlorothiazide solution: Taking orally; special dropper to be used for accurate measuring

» 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
Importance of diet; possible need for sodium restriction and/or weight reduction

» 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
Making regular visits to physician to check progress

» Possibility of hypokalemia; possible need for additional 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 unprotected exposure to sun; using protective clothing and sun block product; avoiding use of sunlamp, tanning bed, or tanning booth

For use as 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, pancreatitis, hepatic function impairment, hyperuricemia, gout, and thrombocytopenia


General Dosing Information
The lowest effective dosage should be utilized to minimize potential electrolyte imbalance and the reflex increase in renin and aldosterone levels.

A single daily dose is preferably taken on arising in order to minimize the effect of increased frequency of urination on sleep. When used to promote diuresis, intermittent dosage schedules (drug-free days) may reduce the possibility of electrolyte imbalance or hyperuricemia resulting from therapy.

Concurrent administration of potassium supplements or potassium-sparing diuretics may be indicated in patients considered to be at higher risk for developing hypokalemia. Caution in administering potassium supplements is recommended, however, since loss of potassium is not clinically significant in most patients, and supplementation leads to a risk of development of hyperkalemia.

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

For hypertension
Low dose thiazide therapy has been found to be effective in the treatment of hypertension. {39} {40} {41} {42}

BENDROFLUMETHIAZIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Protein binding—Very high.

Half-life—Normal: 8.5 hours.

Onset of action—Diuretic: 1 to 2 hours.

Time to peak effect—Diuretic: 4 hours. {49}

Duration of action—Diuretic: 6 to 12 hours. {49}



Laboratory value alterations:
May produce false-negative results in phentolamine, phenolsulfonphthalein, and tyramine tests.



Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

BENDROFLUMETHIAZIDE TABLETS USP

Usual adult dose
Diuretic or
[Antidiuretic (central or nephrogenic diabetes insipidus)]1
Initial: Oral, 2.5 to 10 mg one or two times a day, once every other day, or once a day for three to five days a week. {10}

Maintenance: Oral, 2.5 to 5 mg once a day, once every other day, or once a day for three to five days a week. {10}

Antihypertensive
Oral, 2.5 to 20 mg per day, as a single dose or in two divided daily doses, the dosage being adjusted according to response. {10} {59}


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


Usual pediatric dose
Diuretic or
[Antidiuretic (central or nephrogenic diabetes insipidus)]1
Initial: Oral, up to 400 mcg (0.4 mg) per kg of body weight or 12 mg per square meter of body surface a day, as a single dose or in two divided daily doses. {26}

Maintenance: Oral, 50 to 100 mcg (0.05 to 0.1 mg) per kg of body weight or 1.5 to 3 mg per square meter of body surface once a day. {26}

Antihypertensive
Oral, 50 to 400 mcg (0.05 to 0.4 mg) per kg of body weight or 1.5 to 12 mg per square meter of body surface per day, as a single dose or in two divided daily doses, the dosage being adjusted according to response. {26}


Strength(s) usually available
U.S.—


5 mg (Rx) [Naturetin (scored) (lactose)]


10 mg (Rx) [Naturetin (scored) (lactose)]

Canada—


5 mg (Rx) [Naturetin (scored) (tartrazine)]

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.

Auxiliary labeling:
   • 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.



CHLOROTHIAZIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Protein binding—Low to high.

Half-life—Normal: 13 hours.

Onset of action—Diuretic: 2 hours.

Time to peak effect—Diuretic: 4 hours.

Duration of action—Diuretic: 6 to 12 hours.



Additional Dosing Information
See also General Dosing Information.
For parenteral dosage forms only

   • Care must be taken to avoid extravasation during intravenous administration.
   • Chlorothiazide should not be administered intramuscularly or subcutaneously.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CHLOROTHIAZIDE ORAL SUSPENSION USP

Usual adult dose
Diuretic or
[Antidiuretic (central or nephrogenic diabetes insipidus)]
Oral, 250 mg every six to twelve hours. {08}

Antihypertensive
Oral, 250 mg to 1 gram per day, as a single dose or in divided daily doses, the dosage being adjusted according to response. {08}


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


Usual pediatric dose
Children up to 6 months of age—Oral, 10 to 30 mg per kg of body weight per day, as a single dose or in two divided daily doses, the dosage being adjusted according to response. {08}

Children 6 months of age and over—Oral, 10 to 20 mg per kg of body weight per day, as a single dose or in two divided daily doses, the dosage being adjusted according to response. {08}

Strength(s) usually available
U.S.—


50 mg per mL (Rx) [Diuril (alcohol 0.5%) (glycerin) (methylparaben 0.12%) (sodium saccharin) (sucrose)]

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 freezing.

Auxiliary labeling:
   • Shake well.
   • 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.



CHLOROTHIAZIDE TABLETS USP

Usual adult dose
Diuretic or
[Antidiuretic (central or nephrogenic diabetes insipidus)]
Oral, 250 mg every six to twelve hours. {08}

Antihypertensive
Oral, 250 mg to 1 gram per day, as a single dose or in divided daily doses, the dosage being adjusted according to response. {08}


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


Usual pediatric dose
Children up to 6 months of age—Oral, 10 to 30 mg per kg of body weight per day, as a single dose or in two divided daily doses, the dosage being adjusted according to response. {08}

Children 6 months of age and over—Oral, 10 to 20 mg per kg of body weight per day, as a single dose or in two divided daily doses, the dosage being adjusted according to response. {08}

Strength(s) usually available
U.S.—


250 mg (Rx) [Diuril (scored)][Generic] (may be scored)


500 mg (Rx) [Diuril (scored)][Generic] (may be scored)

Canada—
Not commercially available.

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

Auxiliary labeling:
   • 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.




Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CHLOROTHIAZIDE SODIUM FOR INJECTION USP

Usual adult dose
Diuretic or
[Antidiuretic (central or nephrogenic diabetes insipidus)]
Intravenous, 250 mg (base) every six to twelve hours. {20}

Antihypertensive
Intravenous, 500 mg to 1 gram (base) of chlorothiazide a day, as a single dose or in two divided daily doses. {20}


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


Usual pediatric dose
Safety and efficacy have not been established.

Size(s) usually available:
U.S.—


500 mg (base) (Rx) [Diuril (mannitol 250 mg)]

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.

Stability:
Reconstituted solution may be stored at room temperature for 24 hours, after which it must be discarded. {20}

Incompatibilities:
Solutions of chlorothiazide are not compatible with whole blood or its derivatives. {20}

Additional information:
Chlorothiazide Sodium for Injection USP is reconstituted for intravenous administration by adding no less than 18 mL of sterile water for injection to the vial and shaking to dissolve, producing a solution containing 25 mg (base) per mL. {21}

Reconstituted solutions may be further diluted with dextrose injection or 0.9% sodium chloride injection for administration by intravenous infusion. {21}


CHLORTHALIDONE

Summary of Differences


Pharmacology/pharmacokinetics:
Although not chemically the same, chlorthalidone has the same actions as the thiazide diuretics.

Protein binding—Very high to carbonic anhydrase in red blood cells.

Half-life—Normal: 35 to 50 hours.

Onset of action—Diuretic: 2 hours.

Time to peak effect—Diuretic: 2 hours.

Duration of action—Diuretic: 48 to 72 hours.



Oral Dosage Forms

CHLORTHALIDONE TABLETS USP

Usual adult dose
Diuretic
Oral, 25 to 100 mg once a day, or 100 to 200 mg once every other day, {05} or once a day for three days a week.

Antihypertensive
Oral, 25 to 100 mg once a day, the dosage being adjusted according to response. {05} {61}


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


Usual pediatric dose
Oral, 2 mg per kg of body weight or 60 mg per square meter of body surface once a day for three days a week, the dosage being adjusted according to response. {26}

Strength(s) usually available
U.S.—


25 mg (Rx) [Hygroton] [Thalitone][Generic] (may be scored)


50 mg (Rx) [Hygroton][Generic] (may be scored)


100 mg (Rx) [Hygroton (scored)][Generic] (may be scored)

Canada—


50 mg (Rx) [Apo-Chlorthalidone (scored)] [Hygroton (scored)] [Novo-Thalidone (scored)] [Uridon (scored)]


100 mg (Rx) [Apo-Chlorthalidone (scored)] [Hygroton (scored)] [Novo-Thalidone (scored)] [Uridon (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:
   • 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.



HYDROCHLOROTHIAZIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Half-life—Normal: 15 hours.

Onset of action—Diuretic: 2 hours.

Time to peak effect—Diuretic: 4 hours.

Duration of action—Diuretic: 6 to 12 hours.



Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

HYDROCHLOROTHIAZIDE CAPSULES

Usual adult dose
Antihypertensive
Oral, initially, 12.5 once a day, administered alone or in combination with other antihypertensive agents. {77}

Note: This lower-dose product is recommended for patients in whom the development of hyperkalemia cannot be risked, including patients taking angiotensin-converting enzyme (ACE) inhibitors {77}.



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


Usual pediatric dose
See Hydrochlorothiazide Oral Solution .

Strength(s) usually available
U.S.—


12.5 mg (Rx) [Microzide]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F). Store in a well-closed container. Protect from light, moisture, and freezing. {77}

Auxiliary labeling:
   • 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.



HYDROCHLOROTHIAZIDE ORAL SOLUTION

Usual adult dose
Diuretic or
[Antidiuretic (central or nephrogenic diabetes insipidus)]
Oral, 25 to 100 mg one or two times a day, once every other day, {04} or once a day for three to five days a week.

Antihypertensive
Oral, 25 to 100 mg a day, as a single dose or in two divided daily doses, the dosage being adjusted according to response. {04}


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


Usual pediatric dose
Oral, 1 to 2 mg per kg of body weight {04} or 30 to 60 mg per square meter of body surface per day, as a single dose or in two divided daily doses, the dosage being adjusted according to response. {26}

Note: Infants under 6 months of age may receive up to 3 mg per kg of body weight per day. {04} {19}


Strength(s) usually available
U.S.—


10 mg per mL (Rx)[Generic]


100 mg per mL (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), in a well-closed container, unless otherwise specified by manufacturer. Protect from freezing.

Auxiliary labeling:
   • 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.
Be careful not to confuse oral solution with concentrated oral solution.
Make sure patient understands how to measure dose of concentrated oral solution with calibrated dropper.



HYDROCHLOROTHIAZIDE TABLETS USP

Usual adult dose
Diuretic or
[Antidiuretic (central or nephrogenic diabetes insipidus)]1
Oral, 25 to 100 mg one or two times a day, once every other day, {04} or once a day for three to five days a week.

Antihypertensive
Oral, 25 to 100 mg a day, as a single dose or in two divided daily doses, the dosage being adjusted according to response. {04}


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


Usual pediatric dose
Oral, 1 to 2 mg per kg of body weight {04} or 30 to 60 mg per square meter of body surface per day, as a single dose or in two divided daily doses, the dosage being adjusted according to response. {26}

Note: Infants under 6 months of age may receive up to 3 mg per kg of body weight per day. {04} {19}


Strength(s) usually available
U.S.—


25 mg (Rx) [Esidrix (scored)] [HydroDIURIL (scored)] [Oretic (scored)][Generic] (scored)


50 mg (Rx) [Esidrix (scored)] [Hydro-chlor] [Hydro-D] [HydroDIURIL (scored)] [Oretic (scored)][Generic] (scored)


100 mg (Rx) [Esidrix (scored)] [HydroDIURIL (scored)][Generic] (scored)

Canada—


25 mg (Rx) [Apo-Hydro (scored)] [HydroDIURIL (scored)] [Neo-Codema (scored)] [Novo-Hydrazide (scored)] [Urozide (scored)]


50 mg (Rx) [Apo-Hydro (scored)] [Diuchlor H (scored)] [HydroDIURIL (scored)] [Neo-Codema (scored)] [Novo-Hydrazide (scored)] [Urozide (scored)]


100 mg (Rx) [Apo-Hydro (scored)] [HydroDIURIL (scored)] [Urozide (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:
   • 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.



HYDROFLUMETHIAZIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Protein binding—High.

Onset of action—Diuretic: 1 to 2 hours.

Time to peak effect—Diuretic: 3 to 4 hours.

Duration of action—Diuretic: 18 to 24 hours.



Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

HYDROFLUMETHIAZIDE TABLETS USP

Usual adult dose
Diuretic or
[Antidiuretic (central or nephrogenic diabetes insipidus)]
Oral, 25 to 100 mg one or two times a day, {03} {66} once every other day, or once a day for three to five days a week.

Antihypertensive
Oral, 50 to 100 mg per day, {03} {66} as a single dose or in two divided daily doses, the dosage being adjusted according to response.


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


Usual adult prescribing limits
Up to 200 mg per day in divided doses.

Usual pediatric dose
Oral, 1 mg per kg of body weight or 30 mg per square meter of body surface once a day, the dosage adjusted according to response. {26}

Strength(s) usually available
U.S.—


50 mg (Rx) [Diucardin (scored)] [Saluron (scored)][Generic] (may be scored)

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.

Auxiliary labeling:
   • 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.



METHYCLOTHIAZIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Onset of action—Diuretic: 2 hours.

Time to peak effect—Diuretic: 6 hours.

Duration of action—Diuretic: More than 24 hours.



Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

METHYCLOTHIAZIDE TABLETS USP

Usual adult dose
Diuretic or
[Antidiuretic (central or nephrogenic diabetes insipidus)]1
Oral, 2.5 to 10 mg once a day, {06} once every other day, or once a day for three to five days a week.

Antihypertensive
Oral, 2.5 to 5 mg once a day, the dosage being adjusted according to response. {67}

Note: Doses beyond 5 mg once a day will usually not result in further lowering of blood pressure.



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


Usual pediatric dose
Oral, 50 to 200 mcg (0.05 to 0.2 mg) per kg of body weight or 1.5 to 6 mg per square meter of body surface once a day, the dosage being adjusted according to response. {26}

Strength(s) usually available
U.S.—


2.5 mg (Rx) [Enduron][Generic] (may be scored)


5 mg (Rx) [Aquatensen] [Enduron][Generic] (may be scored)

Canada—


5 mg (Rx) [Duretic]

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:
   • 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.



METOLAZONE

Summary of Differences


Pharmacology/pharmacokinetics:
Although not chemically the same, metolazone has actions similar to the thiazide diuretics.

Absorption—More rapid and more complete with prompt metolazone tablets than with extended metolazone tablets.

Protein binding—Very high (50 to 70% to red blood cells).

Half-life—Normal: 8 hours.

Onset of action—Diuretic: 1 hour.

Time to peak effect—Diuretic: 2 hours.

Duration of action—Diuretic: 12 to 24 hours.

Elimination—Metolazone undergoes some enterohepatic recycling, and slightly greater amounts are excreted in the bile.



Additional Dosing Information
Extended metolazone tablets and prompt metolazone tablets should not be substituted for one another because of significant differences in rate of absorption and bioavailability.

Absorption of metolazone after oral administration is reduced in patients with cardiac disease (65% in normal subjects as compared with 40% in cardiac disease patients).

Plasma clearance of metolazone is 20 mL per minute in patients with renal failure as compared with 110 mL per minute in healthy subjects.

Duration of diuretic effect is dose-related.

Metolazone may be more effective as a diuretic than other thiazides in patients with severe renal failure. Because of this, metolazone has been added to furosemide therapy in resistant patients; however, caution is necessary because of the risk of severe electrolyte imbalance.


Oral Dosage Forms

EXTENDED METOLAZONE TABLETS

Usual adult dose
Diuretic
Oral, 5 to 20 mg once a day. {15} {68}

Antihypertensive
Oral, 2.5 to 5 mg once a day, the dosage being adjusted according to response. {15} {68}


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.—


2.5 mg (Rx) [Diulo] [Zaroxolyn]


5 mg (Rx) [Diulo] [Zaroxolyn]


10 mg (Rx) [Diulo] [Zaroxolyn]

Canada—


2.5 mg (Rx) [Zaroxolyn]


5 mg (Rx) [Zaroxolyn]


10 mg (Rx) [Zaroxolyn]

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

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

Note: Extended and prompt metolazone tablets are not bioequivalent. One product should not be substituted for the other. If patients are to be transferred from one to the other, retitration and appropriate changes in dosage may be necessary. {15}
Check refill frequency to determine compliance in hypertensive patients.



PROMPT METOLAZONE TABLETS

Usual adult dose
Antihypertensive
Initial: Oral, 500 mcg (0.5 mg) once a day, the dosage being adjusted according to response. {21}

Maintenance: Oral, 500 mcg (0.5 mg) to 1 mg once a day. {21}


Usual adult prescribing limits
Up to 1 mg per day.

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


500 mcg (0.5 mg) (Rx) [Mykrox]

Canada—
Not commercially available.

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

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

Note: Extended and prompt metolazone tablets are not bioequivalent. One product should not be substituted for the other. If patients are to be transferred from one to the other, retitration and appropriate changes in dosage may be necessary.
Check refill frequency to determine compliance in hypertensive patients.



POLYTHIAZIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Protein binding—High.

Onset of action—Diuretic: 2 hours.

Time to peak effect—Diuretic: 6 hours.

Duration of action—Diuretic: 24 to 48 hours.



Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

POLYTHIAZIDE TABLETS USP

Usual adult dose
Diuretic or
[Antidiuretic (central or nephrogenic diabetes insipidus)]
Oral, 1 to 4 mg once a day, once every other day, or once a day for three to five days a week. {14} {70}

Antihypertensive
Oral, 2 to 4 mg once a day, the dosage being adjusted according to response. {14} {70}


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


Usual pediatric dose
Oral, 20 to 80 mcg (0.02 to 0.08 mg) per kg of body weight or 500 mcg (0.5 mg) to 2.5 mg per square meter of body surface once a day, the dosage being adjusted according to response. {26}

Strength(s) usually available
U.S.—


1 mg (Rx) [Renese (scored) (lactose)]


2 mg (Rx) [Renese (scored) (lactose)]


4 mg (Rx) [Renese (scored) (lactose)]

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, light-resistant container.

Auxiliary labeling:
   • 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.



QUINETHAZONE

Summary of Differences


Pharmacology/pharmacokinetics:
Although not chemically the same, quinethazone has the same actions as the thiazide diuretics.

Onset of action—Diuretic: 2 hours.

Time to peak effect—Diuretic: 6 hours.

Duration of action—Diuretic: 18 to 24 hours.



Oral Dosage Forms

QUINETHAZONE TABLETS USP

Usual adult dose
Diuretic or
Antihypertensive
Oral, 50 to 200 mg per day, as a single dose or in two divided daily doses, adjusted according to response. {16}


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


Usual adult prescribing limits
Up to 200 mg daily in divided doses. {16}

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg (Rx) [Hydromox (scored)]

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.

Auxiliary labeling:
   • 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.



TRICHLORMETHIAZIDE

Summary of Differences


Pharmacology/pharmacokinetics:
Onset of action—Diuretic: 2 hours.

Time to peak effect—Diuretic: 6 hours.

Duration of action—Diuretic: Up to 24 hours.



Laboratory value alterations:
May produce false-negative results in phentolamine, phenolsulfonphthalein, and tyramine tests.



Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

TRICHLORMETHIAZIDE TABLETS USP

Usual adult dose
Diuretic or
[Antidiuretic (central or nephrogenic diabetes insipidus)]
Oral, 1 to 4 mg once a day, once every other day, or once a day for three to five days a week.

Antihypertensive
Oral, 2 to 4 mg once a day, the dosage being adjusted according to response.


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


Usual pediatric dose
For children over 6 months of age—Oral, 70 mcg (0.07 mg) per kg of body weight or 2 mg per square meter of body surface per day, as a single dose or in two divided daily doses, the dosage being adjusted according to response. {26}

Strength(s) usually available
U.S.—


2 mg (Rx) [Metahydrin] [Naqua (scored)][Generic]


4 mg (Rx) [Metahydrin] [Naqua (scored)] [Trichlorex][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.

Auxiliary labeling:
   • 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.




Revised: 07/01/1998



References
  1. Microx package insert (Pennwalt), 8/87.
  1. Arch Intern Med 1984 May; 144: 1045-57.
  1. Saluron product information (Bristol Labs), Rev 12/88, Rec 11/89, U.S.
  1. Esidrex product information (CIBA—US), Rec 1/89, Rev 11/87.
  1. Chlorthalidone product information (US), Rec 1/89, Rev 10/87.
  1. Enduron product information (US), 1990 PDR.
  1. Aquatensen product information (US), 1990 PDR.
  1. Diuril product information (US), 1990 PDR.
  1. Diucardin product information (Ayerst—US), Rec 7/89, Rev 7/88.
  1. Naturetin product information (Squibb—Canada).
  1. Naqua product information (Schering—US), Rec 7/89, Rev 1/88.
  1. Renese product information (Pfizer—US), 1990 PDR.
  1. Zaroxolyn product information (Fisons—US), Rec 6/89, Rev 11/88.
  1. Hydromox product information (Lederle—US), 1990 PDR.
  1. Cordarone product information (Wyeth—US), Rec 4/89, Rev 5/88.
  1. Dolobid product information (MSD), Rev 1988.
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  1. Diuril injectable product information (MSD—US), 1990 PDR.
  1. Mykrox product information (Fisons—US), 1990 PDR.
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  1. Goodman & Gilman's Pharmacological Basis of Therapeutics, 7th Edition, 1985.
  1. Aranda P, Novales E. Diuretics and the treatment of systemic hypertension. Am J of Cardiol 1990; 65: 72H-76H.
  1. Lant A. Diuretic drugs. Drugs 1986; 31(suppl 4): 40-55.
  1. Shirkey H. Pediatric dosage handbook, 1980.
  1. Canadian Med Assoc J, 11/1/83, 129: 974-5.
  1. Hansten's Drug Interactions, 6th Edition.
  1. Drug Information Facts, 1990 Edition.
  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.
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  1. Menhydrinate product information (Merrell Dow—US), Rec 2/88, Rev 7/86.
  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 consensus, 1990 revision cycle.
  1. Panel comments, 1990 revision cycle.
  1. Curry C, Janda S, Harris R, MacKay J, Nugent C, Ryan J, Schnaper H, et al. Clinical studies of a new, low-dose formulation of metolazone for the treatment of hypertension. Clin Ther 1986; 9[1]: 47-62.
  1. Moser M. Low-dose diuretic therapy for hypertension. Clin Ther 1986; 8[5]: 554-61.
  1. Korduner I, Kabin I, Hagbarth G. Low-dose chlorthalidone treatment in previously untreated hypertension. Current Ther Res 1981; 29[1]: 208-15.
  1. McKenney J, Goodman R, Wright J, Rifai N, Aycock D, King M. The effect of low-dose hydrochlorothiazide on blood pressure, serum potassium, and lipoproteins. Pharmacotherapy 1986; 6[4]: 179-84.
  1. Panelist comment, 1990 revision cycle.
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