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Pronunciation
(klor oh THYE a zide)
Generic Available (U.S.)
Yes: Excludes oral suspension
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of mild-to-moderate hypertension; adjunctive treatment of edema
Pregnancy Risk Factor
C
Pregnancy Considerations
Adverse events were not observed in animal reproduction studies; however, studies were not complete. Chlorothiazide crosses the placenta and is found in cord blood. Maternal use may cause may cause fetal or neonatal jaundice, thrombocytopenia, or other adverse events observed in adults. Use of thiazide diuretics during normal pregnancies is not appropriate; use may be considered when edema is due to pathologic causes (as in the nonpregnant patient); monitor.
Lactation
Enters breast milk/not recommended (AAP rates “compatible”; AAP 2001 update pending)
Contraindications
Hypersensitivity to chlorothiazide, any component of the formulation, thiazides, or sulfonamide-derived drugs; anuria
Warnings/Precautions
Concerns related to adverse effects:
• Electrolyte disturbances: Hypokalemia, hypochloremic alkalosis, hyponatremia, and hypomagnesemia can occur.
• Hypersensitivity reactions: Hypersensitivity reactions may occur.
• Photosensitivity: Photosensitization may occur.
• Sulfa allergy: 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. A risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe. Discontinue if signs of hypersensitivity are noted.
Disease-related concerns:
• Diabetes: Use with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control.
• Gout: In certain patients with a history of gout, a familial predisposition to gout, or chronic renal failure, gout can be precipitated.
• Hepatic impairment: Use with caution in patients with hepatic impairment; avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy.
• Hypercalcemia: Thiazide diuretics may decrease renal calcium excretion; consider avoiding use in patients with hypercalcemia.
• Hypercholesterolemia: Use with caution in patients with moderate or high cholesterol concentrations; increased cholesterol and triglyceride levels have been reported with thiazides.
• Hypokalemia: Use with caution in patients with hypokalemia; correct before initiating therapy.
• Renal impairment: Avoid in severe renal disease (ineffective). May precipitate azotemia; discontinue or consider withholding if renal impairment occurs.
• Systemic lupus erythematosus (SLE): Can cause SLE exacerbation or activation.
Adverse Reactions
Frequency not defined.
Cardiovascular: Hypotension, orthostatic hypotension, necrotizing angiitis
Central nervous system: Dizziness, fever, headache, restlessness, vertigo
Dermatologic: Alopecia, erythema multiforme, exfoliative dermatitis, photosensitivity, purpura, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Cholesterol increased, hyperglycemia, hyperuricemia, hypochloremic alkalosis, hypokalemia, hyponatremia, 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: Glycosuria, hematuria (I.V.), interstitial nephritis, renal failure, renal dysfunction
Respiratory: Pneumonitis, pulmonary edema, respiratory distress
Miscellaneous: Anaphylactic reactions, systemic lupus erythematosus
Drug Interactions
ACE Inhibitors: Thiazide Diuretics may enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Thiazide Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy
Allopurinol: Thiazide Diuretics may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Thiazide Diuretics may increase the serum concentration of Allopurinol. Specifically, Thiazide Diuretics may increase the concentration of Oxypurinolol, an active metabolite of Allopurinol. Risk C: Monitor therapy
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Analgesics (Opioid): May enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy
Antidiabetic Agents: Thiazide Diuretics may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Barbiturates: May enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Thiazide Diuretics. The diuretic response is likewise decreased. Risk D: Consider therapy modification
Calcium Salts: Thiazide Diuretics may decrease the excretion of Calcium Salts. Continued concomitant use can also result in metabolic alkalosis. Risk C: Monitor therapy
CarBAMazepine: Thiazide Diuretics may enhance the adverse/toxic effect of CarBAMazepine. Specifically, there may be an increased risk for hyponatremia. Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy
Dofetilide: Thiazide Diuretics may enhance the QTc-prolonging effect of Dofetilide. Thiazide Diuretics may increase the serum concentration of Dofetilide. Risk X: Avoid combination
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Licorice: May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy
Lithium: Thiazide Diuretics may decrease the excretion of Lithium. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May diminish the therapeutic effect of Thiazide Diuretics. Risk C: Monitor therapy
OXcarbazepine: Thiazide Diuretics may enhance the adverse/toxic effect of OXcarbazepine. Specifically, there may be an increased risk for hyponatremia. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, hydrate adequately and monitor fluid and renal status. Risk D: Consider therapy modification
Topiramate: Thiazide Diuretics may enhance the hypokalemic effect of Topiramate. Thiazide Diuretics may increase the serum concentration of Topiramate. Management: Monitor for increased topiramate levels/adverse effects (e.g., hypokalemia) with initiation/dose increase of a thiazide diuretic. Closely monitor serum potassium concentrations with concomitant therapy. Topiramate dose reductions may be necessary. Risk D: Consider therapy modification
Toremifene: Thiazide Diuretics may enhance the hypercalcemic effect of Toremifene. Risk C: Monitor therapy
Vitamin D Analogs: Thiazide Diuretics may enhance the hypercalcemic effect of Vitamin D Analogs. Risk C: Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
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 bayberry, blue cohosh, cayenne, ephedra, ginger, ginseng (American), kola, licorice (may worsen hypertension). Avoid black cohosh, California poppy, coleus, golden seal, hawthorn, mistletoe, periwinkle, quinine, shepherd's purse (may have increased antihypertensive effect).
Storage
Powder for injection: Prior to reconstitution, store between 2°C to 25°C (36°F to 77°F). Reconstituted solution is stable for 24 hours at room temperature; precipitation will occur in <24 hours in pH <7.4.
Suspension, tablets: Store at room temperature 15°C to 30°C (59°F to 86°F). Protect from freezing.
Reconstitution
Powder for injection: To reconstitute, add SWFI 18 mL to make 28 mg/mL. May be further diluted with dextrose or sodium chloride solutions. Single use only, discard any unused reconstituted solution.
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 and chloride reabsorption in the distal tubules causing increased excretion of sodium, chloride, and water resulting in diuresis. Loss of potassium, hydrogen ions, magnesium, phosphate, and bicarbonate also occurs.
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 (10% to 15% [oral], 96% [I.V.] 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: 10-30 mg/kg/day in 2 divided doses (maximum dose: 375 mg/day); anecdotal reports have used up to 40 mg/kg/day (unlabeled).
I.V. (unlabeled): 2-8 mg/kg/day in 2 divided doses; anecdotal reports have used up to 20 mg/kg/day
Infants >6 months and Children:
Oral: 10-20 mg/kg/day in 1-2 divided doses (maximum dose: 375 mg/day in children <2 years or 1 g/day in children 2-12 years)
I.V. (unlabeled route): 4 mg/kg/day in 1-2 divided doses; anecdotal reports have used up to 20 mg/kg/day
Adults:
Hypertension: Oral: 500-2000 mg/day divided in 1-2 doses (manufacturer labeling); doses of 125-500 mg/day have also been recommended (JNC 7)
Edema: Oral, I.V.: 500-1000 mg once or twice daily; intermittent treatment (eg, therapy on alternative days) may be appropriate for some patients
ACC/AHA 2009 Heart Failure guidelines:
Oral: 250-500 mg once or twice daily (maximum daily dose: 1000 mg)
I.V.: 500-1000 mg once or twice daily plus a loop diuretic
Dosage adjustment in renal impairment: Clcr <10 mL/minute: Avoid use. Ineffective with Clcr <30 mL/minute unless in combination with a loop diuretic (Aronoff, 2007)
Note: ACC/AHA 2009 Heart Failure guidelines suggest that thiazides lose their efficacy when Clcr <40 mL/minute
Administration: I.M.
Do not administer injection via I.M. or SubQ route.
Administration: I.V. Detail
Avoid extravasation of parenteral solution since it is extremely irritating to tissues.
pH: 9.2-10.0 (2.5% solution reconstituted with water for injection)
Monitoring Parameters
Serum electrolytes, renal function, blood pressure; assess weight, I & O reports daily to determine fluid loss
Test Interactions
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. Some products may contain sodium.
Patient Education
Take once-daily dose in morning or last of daily doses early in the day to avoid night-time disturbances. If using oral hypoglycemics, monitor glucose levels closely (this medication may reduce effect of oral hypoglycemics). May cause sensitivity to sunlight, dizziness, weakness, drowsiness, or postural hypotension. Report muscle twitching or cramps; acute loss of appetite; GI distress; severe rash, redness, or itching of skin; chest pain or palpitations; or respiratory difficulty.
Geriatric Considerations
Chlorothiazide is minimally effective in patients with a Clcr <30 mL/minute. This may limit the usefulness of chlorothiazide in the elderly.
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
Heart Failure: Diuretics are standard therapy for the management of edema in patients with heart failure. Thiazide diuretics may be preferred in hypertensive heart failure patients with mild fluid retention. Thiazides lose their effectiveness in patients with impaired renal function. Loop diuretics may be the preferred diuretic in heart failure because of their greater ability to increase sodium excretion.
Hypertension: 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. The ALLHAT study (ALLHAT Collaborative Group, 2002) compared CV outcomes of lisinopril, amlodipine, or chlorthalidone in hypertensive patients having at least one other risk factor for coronary heart disease. Investigators found no difference between the groups on the primary outcome of fatal coronary disease or nonfatal MI. The JNC 7 recommends diuretics for the treatment of hypertension with concurrent heart failure where diuresis is also required (loop diuretics may more frequently be required), high coronary disease risk (as in the ALLHAT trial), diabetes (beneficial in reducing CVD and stroke incidence), and recurrent stroke prevention (in combination with an ACE inhibitor). Thiazides are useful in slowing demineralization in osteoporosis, but need to be used cautiously in gout and in patients with significant history of hyponatremia.
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
Nursing: Physical Assessment/Monitoring
Assess allergy history prior to beginning therapy. Monitor blood pressure, fluid status, and electrolyte balance on a regular basis throughout therapy.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution, as sodium [strength expressed as base]: 500 mg
Sodium Diuril®: 0.5 g
Suspension, oral:
Diuril®: 250 mg/5 mL (237 mL) [contains benzoic acid, ethanol 0.5%]
Tablet, oral: 250 mg, 500 mg
Pricing: U.S. (www.drugstore.com)
Suspension (Diuril)
250 mg/5 mL (237): $29.99
Tablets (Chlorothiazide)
250 mg (30): $13.99
500 mg (30): $14.99
Extemporaneously Prepared
A 50 mg/mL oral suspension may be made with tablets. Crush ten 500 mg chlorothiazide tablets in a mortar and reduce to a fine powder; mix with a small amount of glycerin to form a uniform paste. Add 2 g carboxymethylcellulose gel (mix 2 g carboxymethylcellulose with 5-10 mL water to form a paste; add 40 mL water and heat to 60°C with moderate stirring until dissolution occurs; cool and allow to stand for 1-2 hours to form a clear gel). Dissolve 500 mg citric acid in 5 mL water and add to chlorothiazide carboxymethylcellulose mixture with 0.1% parabens. Add a quantity of purified water sufficient to make 100 mL (Nahata, 2004). Label "shake well" and "refrigerate". Stable for 30 days.
Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.
References
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, "Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)," JAMA, 2002, 288(23):2981-97.
American Academy of Pediatrics Committee on Drugs, "Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics, 2001, 108(3):776-89.
Aronoff G, Brier M, Berns J, et al, The Renal Drug Book, online edition, 2002. Available at http://www.kdp-baptist.louisville.edu/renalbook. Last accessed September 20, 2005.
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.
Hunt SA, Abraham WT, Chin MH, et al, “2009 Focused Update Incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation,” J Am Coll Cardiol, 2009, 53(15):e1-e90.
Lindenfeld J, Albert NM, Boehmer JP, et al, “HFSA 2010 Comprehensive Heart Failure Practice Guideline,” J Card Fail, 2010, 16(6):e1-194.
Werthmann MW Jr and Krees SV, "Excretion of Chlorothiazide in Human Breast Milk," J Pediatr, 1972, 81(4):781-3.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
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