(klor oh THYE a zide)
Management of hypertension; adjunctive treatment of edema
Guideline recommendations:
Hypertension: The 2014 guideline for the management of high blood pressure in adults (Eighth Joint National Committee [JNC 8]) recommends initiation of pharmacologic treatment to lower blood pressure for the following patients:
- Patients ≥60 years of age with systolic blood pressure (SBP) ≥150 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg. Goal of therapy is SBP <150 mm Hg and DBP <90 mm Hg.
- Patients <60 years of age with SBP ≥140 mm Hg or DBP is ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.
- Patients ≥18 years of age with diabetes and SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.
- Patients ≥18 years of age with chronic kidney disease (CKD) and SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.
Chronic kidney disease (CKD) and hypertension: Regardless of race or diabetes status, the use of an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) as initial therapy is recommended to improve kidney outcomes. In the general nonblack population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic, calcium channel blocker, ACEI, or ARB. In the general black population (without CKD), including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic or a calcium channel blocker instead of an ACEI or ARB.
Coronary artery disease (CAD) and hypertension: The American Heart Association, American College of Cardiology and American Society of Hypertension (AHA/ACC/ASH) 2015 scientific statement for the treatment of hypertension in patients with coronary artery disease (CAD) recommends the use of a thiazide (or thiazide-like diuretic) as part of a regimen in patients with hypertension and chronic stable angina. A BP target of <140/90 mm Hg is reasonable for the secondary prevention of cardiovascular events. A lower target BP (<130/80 mm Hg) may be appropriate in some individuals with CAD, previous MI, stroke or transient ischemic attack, or CAD risk equivalents (AHA/ACC/ASH [Rosendorff 2015]).
Hypersensitivity to chlorothiazide, any component of the formulation or sulfonamide-derived drugs; anuria
Note: Although the FDA approved product labeling states this medication is contraindicated with other sulfonamide-containing drug classes, the scientific basis of this statement has been challenged. See "Warnings/Precautions " � for more detail.
Note: The manufacturer states that IV and oral dosing are equivalent. Some clinicians may use lower IV doses; however, because of chlorothiazides poor oral absorption.
Hypertension: Oral: 500 to 2000 mg daily divided in 1 to 2 doses
Edema: Oral, IV: 500 to 1000 mg once or twice daily; intermittent treatment (eg, therapy on alternative days) may be appropriate for some patients
ACCF/AHA 2013 heart failure guidelines:
Oral: 250 to 500 mg once or twice daily (maximum daily dose: 1000 mg)
IV: 500 to 1000 mg once daily in combination with a loop diuretic for sequential nephron blockade
Refer to adult dosing.
Note: The manufacturer states that IV and oral dosing are equivalent. Some clinicians may use lower IV doses; however, because of chlorothiazides poor oral absorption. IV dosing in infants and children has not been well established.
Infants <6 months: Oral: 10 to 30 mg/kg/day in 2 divided doses (maximum dose: 375 mg daily)
Infants >6 months and Children: Oral: 10 to 20 mg/kg/day in 1 to 2 divided doses (maximum dose: 375 mg daily in children <2 years or 1000 mg daily in children 2 to 12 years)
Infants and Children: IV (off-label): 5 to 10 mg/kg/day in 2 divided doses (Costello, 2007)
CrCl <10 mL/minute: Avoid use. Ineffective with CrCl <30 mL/minute unless in combination with a loop diuretic (Aronoff, 2007).
No dosage adjustments provided in manufacturer 's labeling; use with caution.
Powder for injection: To reconstitute, add SWFI 18 mL to make 28 mg/mL. May be further diluted with dextrose or sodium chloride solutions.
Do not administer injection via IM or SubQ route. Administer slowly by direct IV injection or infusion; avoid extravasation of parenteral solution since it is extremely irritating to tissues.
May need to decrease sodium and calcium, may need to increase potassium, zinc, magnesium, and riboflavin in diet. Some products may contain sodium.
Powder for injection: Prior to reconstitution, store between 2 � �C to 25 � �C (36 � �F to 77 � �F). The manufacturers labeling recommends any unused reconstituted solution be discarded. 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous, as sodium [strength expressed as base]:
Sodium Diuril: 500 mg (1 ea)
Generic: 500 mg (1 ea)
Solution Reconstituted, Intravenous, as sodium [strength expressed as base, preservative free]:
Generic: 500 mg (1 ea)
Suspension, Oral:
Diuril: 250 mg/5 mL (237 mL) [contains alcohol, usp, benzoic acid, fd&c yellow #10 (quinoline yellow), methylparaben, propylparaben, saccharin sodium]
Tablet, Oral:
Generic: 250 mg, 500 mg
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 to 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 to 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.Stable in D5LR, D51/4NS, D51/2NS, D5NS, D5W, D10W, D10NS, LR, 1/2NS, NS.
ACE Inhibitors: Thiazide and Thiazide-Like Diuretics may enhance the hypotensive effect of ACE Inhibitors. Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Monitor therapy
Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy
Alcohol (Ethyl): May enhance the orthostatic hypotensive effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Allopurinol: Thiazide and Thiazide-Like Diuretics may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Allopurinol. Specifically, Thiazide Diuretics may increase the concentration of Oxypurinol, an active metabolite of Allopurinol. Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification
Aminolevulinic Acid: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. Monitor therapy
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy
Analgesics (Opioid): May enhance the adverse/toxic effect of Diuretics. Analgesics (Opioid) may diminish the therapeutic effect of Diuretics. Monitor therapy
Anticholinergic Agents: May increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Antidiabetic Agents: Thiazide and Thiazide-Like Diuretics may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy
Barbiturates: May enhance the orthostatic hypotensive effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Beta2-Agonists: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Thiazide and Thiazide-Like Diuretics. The diuretic response is likewise decreased. Consider therapy modification
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Calcium Salts: Thiazide and Thiazide-Like Diuretics may decrease the excretion of Calcium Salts. Continued concomitant use can also result in metabolic alkalosis. Monitor therapy
CarBAMazepine: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of CarBAMazepine. Specifically, there may be an increased risk for hyponatremia. Monitor therapy
Cardiac Glycosides: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Cardiac Glycosides. Specifically, cardiac glycoside toxicity may be enhanced by the hypokalemic and hypomagnesemic effect of thiazide diuretics. Monitor therapy
Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Cyclophosphamide: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, granulocytopenia may be enhanced. Monitor therapy
Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Monitor therapy
Diazoxide: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Diazoxide. Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Dofetilide: Thiazide and Thiazide-Like Diuretics may enhance the QTc-prolonging effect of Dofetilide. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Dofetilide. Avoid combination
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy
Ivabradine: Thiazide and Thiazide-Like Diuretics may enhance the arrhythmogenic effect of Ivabradine. Monitor therapy
Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy
Levosulpiride: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Levosulpiride. Avoid combination
Licorice: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Lithium: Thiazide and Thiazide-Like Diuretics may decrease the excretion of Lithium. Consider therapy modification
Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Avoid combination
Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Multivitamins/Fluoride (with ADE): May enhance the hypercalcemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Multivitamins/Minerals (with ADEK, Folate, Iron): Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Multivitamins/Minerals (with ADEK, Folate, Iron). Monitor therapy
Multivitamins/Minerals (with AE, No Iron): Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Multivitamins/Minerals (with AE, No Iron). Specifically, thiazide diuretics may decrease the excretion of calcium, and continued concomitant use can also result in metabolic alkalosis. Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification
OXcarbazepine: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of OXcarbazepine. Specifically, there may be an increased risk for hyponatremia. Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Reboxetine: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hyponatremic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy
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. Consider therapy modification
Topiramate: Thiazide and Thiazide-Like Diuretics may enhance the hypokalemic effect of Topiramate. Thiazide and Thiazide-Like 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. Consider therapy modification
Toremifene: Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Toremifene. Monitor therapy
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy
Vitamin D Analogs: Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Vitamin D Analogs. Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy
Serum electrolytes, renal function, blood pressure; assess weight, I & O reports daily to determine fluid loss
May interfere with tests for parathyroid function
Frequency not defined.
Cardiovascular: Hypotension, necrotizing angiitis, orthostatic hypotension
Central nervous system: Dizziness, headache, paresthesia, restlessness, vertigo
Dermatologic: Alopecia, erythema multiforme, exfoliative dermatitis, skin photosensitivity, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Glycosuria, hypercalcemia, hyperglycemia, hyperuricemia, hypochloremic alkalosis, hypokalemia, hypomagnesemia, hyponatremia, increased serum cholesterol, increased serum triglycerides
Gastrointestinal: Abdominal cramps, anorexia, constipation, diarrhea, gastric irritation, nausea, pancreatitis, sialadenitis, vomiting
Genitourinary: Hematuria (IV), impotence
Hematologic & oncologic: Agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, purpura, thrombocytopenia
Hepatic: Jaundice
Hypersensitivity: Anaphylaxis
Neuromuscular & skeletal: Muscle spasm, systemic lupus erythematosus, weakness
Ophthalmic: Blurred vision, xanthopsia
Renal: Interstitial nephritis, renal failure, renal insufficiency
Respiratory: Pneumonitis, pulmonary edema, respiratory distress
Miscellaneous: Fever
Concerns related to adverse effects:
- Electrolyte disturbances: Hypercalcemia, hypokalemia, hypochloremic alkalosis, hyponatremia, and hypomagnesemia can occur.
- Hypersensitivity reactions: Hypersensitivity reactions may occur.
- Orthostatic hypotension: Concomitant ethanol use may increase the risk of orthostatic hypotension.
- Photosensitivity: Photosensitization may occur.
- Sulfonamide ( "sulfa " �) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.
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.
Special populations:
- Surgical patients: If given the morning of surgery, chlorothiazide may render the patient volume depleted and blood pressure may be labile during general anesthesia.
Dosage form specific issues:
- Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol ( ≥99 mg/kg/day) have been associated with a potentially fatal toxicity ( "gasping syndrome " �) in neonates; the "gasping syndrome " � consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP [Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer 's labeling.
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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 to treat edema during normal pregnancies is not appropriate; use may be considered when edema is due to pathologic causes (as in the nonpregnant patient); monitor. Untreated chronic maternal hypertension is associated with adverse events in the fetus, infant, and mother (ACOG, 2013). Women who required thiazide diuretics for the treatment of hypertension prior to pregnancy may continue their use (ACOG, 2013).
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.
Oral: Poor
Not metabolized
Urine (10% to 15% [oral], 96% [IV] as unchanged drug)
Diuresis: Oral: Within 2 hours; IV: 15 minutes; Peak effect: Oral: ~4 hours; IV: 30 minutes
Diuretic action: Oral: ~6 to 12 hours; IV: 2 hours
45 to 120 minutes
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience headache. Have patient report immediately to prescriber signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), severe dizziness, passing out, burning or numbness feeling, vision changes, sexual dysfunction, agitation, shortness of breath, severe loss of strength and energy, bruising, bleeding, chills, or pharyngitis (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.