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Pronunciation:

(klor oh THYE a zide)

U.S. Brand Names:

Diuril®

Generic Available:

Yes: Tablet

Canadian Brand Names:

Diuril®

Use:

Management of mild to moderate hypertension; adjunctive treatment of edema

Pregnancy Risk Factor:

C (manufacturer); D (expert analysis)

Pregnancy Implications:

Crosses the placenta. Hypoglycemia, thrombocytopenia, hemolytic anemia, electrolyte disturbances reported. May exhibit a tocolytic effect. Generally, use of diuretics during pregnancy is avoided for pregnancy-induced hypertension due to risk of decreased placental perfusion. Use may be considered in select patients with heart disease or chronic hypertension if started prior to gestation.

Lactation:

Enters breast milk/use caution (AAP rates "compatible")

Contraindications:

Hypersensitivity to chlorothiazide, any component of the formulation, thiazides, or sulfonamide-derived drugs; anuria; renal decompensation; pregnancy (see Pregnancy Implications)

Warnings/Precautions:

Use with caution in severe renal disease. Electrolyte disturbances (hypokalemia, hypochloremic alkalosis, hyponatremia) can occur. Use with caution in severe hepatic dysfunction; hepatic encephalopathy can be caused by electrolyte disturbances. Gout can be precipitate in certain patients with a history of gout, a familial predisposition to gout, or chronic renal failure. Cautious use in diabetics; may see a change in glucose control. Can cause SLE exacerbation or activation. Use with caution in patients with moderate or high cholesterol concentrations. Photosensitization may occur. Correct hypokalemia before initiating therapy.

Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with thiazide or sulfonamide allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe.

Adverse Reactions:

Frequency not defined.

Cardiovascular: Hypotension, orthostatic hypotension, necrotizing angiitis

Central nervous system: Dizziness, headache, restlessness, vertigo

Dermatologic: Alopecia, erythema multiforme, exfoliative dermatitis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis

Endocrine & metabolic: Cholesterol increased, hypokalemia, hypomagnesemia, triglycerides increased

Gastrointestinal: Abdominal cramping, anorexia, constipation, diarrhea, gastric irritation, nausea, pancreatitis, sialadenitis, vomiting

Genitourinary: Impotence

Hematologic: Agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, thrombocytopenia

Hepatic: Jaundice

Neuromuscular & skeletal: Muscle spasm, paresthesia, weakness

Ocular: Blurred vision, xanthopsia

Renal: Azotemia, hematuria, interstitial nephritis, renal failure, renal dysfunction

Respiratory: Pneumonitis, pulmonary edema, respiratory distress

Miscellaneous: Anaphylactic reactions, systemic lupus erythematosus

Overdosage/Toxicology:

Symptoms of overdose include signs and symptoms of hypovolemia, hypermotility, diuresis, lethargy, confusion, muscle weakness, and coma. Treatment is supportive.

Drug Interactions:

ACE inhibitors: Increased hypotension if aggressively diuresed with a thiazide diuretic

Antidiabetic agents (insulin, oral agents): Dosage adjustment of antidiabetic agent may be needed.

Beta-blockers increase hyperglycemic effects of thiazides in type 2 diabetes mellitus (noninsulin dependent, NIDDM)

Corticosteroids: May increase electrolyte-depletion effects of chlorothiazide.

Cyclosporine and thiazides can increase the risk of gout or renal toxicity; avoid concurrent use

Digoxin toxicity can be exacerbated if a thiazide induces hypokalemia or hypomagnesemia.

Lithium toxicity can occur by reducing renal excretion of lithium; monitor lithium concentration and adjust as needed

Neuromuscular-blocking agents can prolong blockade; monitor serum potassium and neuromuscular status

NSAIDs can decrease the efficacy of thiazides reducing the diuretic and antihypertensive effects

Ethanol/Nutrition/Herb Interactions:

Ethanol: May increase risk of orthostatic hypotension.

Food: Chlorothiazide serum levels may be increased if taken with food.

Herb/Nutraceutical: Avoid dong quai if using for hypertension (has estrogenic activity). Avoid dong quai, St John's wort (may also cause photosensitization). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid natural licorice (due to mineralocorticoid activity). Avoid garlic (may have increased antihypertensive effect).

Stability:

Powder for injection: Prior to reconstitution, store between 2°C to 25°C (36°F to 77°F). To reconstitute, add SWFI 18 mL to make 28 mg/mL. May be further diluted with dextrose or sodium chloride solutions. Reconstituted solution is stable for 24 hours at room temperature; precipitation will occur in <24 hours in pH <7.4. Single use only, discard any unused reconstituted solution.

Suspension, tablets: Store at room temperature 15°C to 30°C (59°F to 86°F); protect from freezing

Compatibility:

Stable in dextran 6% in dextrose, dextran 6% in NS, D5LR, D5¹/4NS, D5¹/2NS, D5NS, D5W, D10W, D10NS, LR, ¹/2NS, NS

Compatibility when admixed: Compatible: Cimetidine, lidocaine, nafcillin, ranitidine, sodium bicarbonate. Incompatible: Amikacin, chlorpromazine, hydralazine, insulin (regular), levorphanol, morphine, multivitamins, norepinephrine, polymyxin B sulfate, procaine, prochlorperazine edisylate, prochlorperazine mesylate, promazine, promethazine, streptomycin, triflupromazine, vancomycin

Mechanism of Action:

Inhibits sodium reabsorption in the distal tubules causing increased excretion of sodium and water as well as potassium and hydrogen ions, magnesium, phosphate, calcium

Pharmacodynamics/Kinetics:

Onset of action: Diuresis: Oral: 2 hours; I.V.: 15 minutes

Duration of diuretic action: Oral: 6-12 hours; I.V.: ~2 hours

Absorption: Oral: Poor

Half-life elimination: 1-2 hours

Time to peak, serum: Oral: ~4 hours; I.V.: 30 minutes

Excretion: Urine (as unchanged drug)

Dosage:

Note: The manufacturer states that I.V. and oral dosing are equivalent. Some clinicians may use lower I.V. doses, however, because of chlorothiazide's poor oral absorption. I.V. dosing in infants and children has not been well established.

Infants <6 months:

Oral: 20-40 mg/kg/day in 2 divided doses (maximum dose: 375 mg/day)

I.V. (unlabeled): 2-8 mg/kg/day in 2 divided doses; doses up to 20 mg/kg/day have been used (anecdotal reports)

Infants >6 months and Children:

Oral: 10-20 mg/kg/day in 2 divided doses (maximum dose: 375 mg/day in children <2 years or 1 g/day in children 2-12 years)

I.V. (unlabeled): 4 mg/kg/day in 1-2 divided doses; doses up to 20 mg/kg/day have been used (anecdotal reports)

Adults:

Hypertension: Oral: 500 mg to 2 g/day divided in 1-2 doses (manufacturer labeling); doses of 125-500 mg/day have also been recommended

Edema: Oral, I.V.: 500 mg to 1 g once or twice daily. Intermittent treatment (ie, therapy on alternate days) may be appropriate for some patients.

Elderly: Oral: 500 mg once daily or 1 g 3 times/week

Administration:

Do not administer injection via I.M. or SubQ route. Administer I.V. 0.5 g over 5 minutes.

Monitoring Parameters:

Serum electrolytes, renal function, blood pressure; assess weight, I & O reports daily to determine fluid loss

Test Interactions:

Increased creatine phosphokinase [CPK] (S), ammonia (B), amylase (S), calcium (S), chloride (S), cholesterol (S), glucose, increased acid (S), decreased chloride (S), magnesium, potassium (S), sodium (S); may interfere with tests for parathyroid function

Dietary Considerations:

May need to decrease sodium and calcium, may need to increase potassium, zinc, magnesium, and riboflavin in diet. Sodium content of 500 mg injection: 57.5 mg (2 mEq).

Patient Education:

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take once-daily dose in morning or last of daily doses early in the day to avoid night-time disturbances. You may need to make dietary changes, follow dietary suggestions of prescriber. If using oral hypoglycemics, monitor glucose levels closely (this medication may reduce effect of oral hypoglycemics); contact prescriber with any major changes. May cause sensitivity to sunlight (use sunblock, wear protective clothing, and avoid direct sunlight); dizziness, weakness, or drowsiness (use caution when driving or engaging in tasks that require alertness until response to drug is known); or postural hypotension (use caution when rising from sitting or lying position or when climbing stairs). Report muscle twitching or cramps; acute loss of appetite; GI distress; severe rash, redness, or itching of skin; sexual dysfunction; chest pain or palpitations; or respiratory difficulty. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication. Consult prescriber for appropriate contraceptive measures. Consult prescriber if breast-feeding.

Nursing Implications:

Take blood pressure with patient lying down and standing; avoid extravasation of parenteral solution since it is extremely irritating to tissues

Anesthesia and Critical Care Concerns/Other Considerations:

Thiazide diuretics are effective first-line therapeutic agents in the management of hypertension and have proven to be of benefit in terms of cardiovascular outcome. If given the morning of surgery it may render the patient volume depleted and blood pressure may be labile during general anesthesia.

Cardiovascular Considerations:

Thiazide diuretics are effective first-line therapeutic agents in the management of hypertension and have proven to be of benefit in terms of cardiovascular outcome. They may act synergistically to lower blood pressure when combined with an ACE inhibitor or beta-blocker. The initial concern about thiazide diuretic-induced hypokalemia, glucose intolerance, and lipid profiles does not appear to be of substantial clinical consequence in the treatment of hypertension. The benefits of this class of agents in the treatment of hypertension is established and compares well with other first-line therapeutic agents.

Diuretics are standard therapy for the management of edema in patients with heart failure.

Dental Health: Effects on Dental Treatment:

Key adverse event(s) related to dental treatment: Orthostatic hypotension.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Mental Health: Effects on Mental Status:

May cause dizziness

Mental Health: Effects on Psychiatric Treatment:

Rare reports of agranulocytosis; use caution with clozapine and carbamazepine; thiazides decrease lithium clearance resulting in elevated serum lithium levels and potential toxicity; monitor serum lithium levels

Dosage Forms:

Injection, powder for reconstitution, as sodium: 500 mg

Suspension, oral: 250 mg/5 mL (237 mL) [contains alcohol 0.5% and benzoic acid]

Tablet: 250 mg, 500 mg

International Brand Names:

Azide® (AU); Chlorosal® (IL); Chlotride® (HK); Diuril® (CA); Diurone® (AU)

References

Chobanian AV, Bakris GL, Black HR, et al, "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report,"JAMA, 2003, 289(19):2560-72.

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