Health Canada has reviewed the potential risks of choroidal effusion (CE), acute myopia (AM), and acute angle-closure glaucoma (AACG) with the use of certain diuretics, including hydrochlorothiazide, chlorthalidone, indapamide, and acetazolamide. Health Canada has concluded that there is a link between the use of these medications and the risks of CE with AM or with AACG or with both AM and AACG; Health Canada's review also concluded that there might be a link between metolazone and the risk of these ophthalmic disorders. Health Canada is working with manufacturers to update the Canadian product safety information for these products to add a warning about these risks.
Further information may be found at https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00261.
Note: The brand name product Thalitone should not be substituted with other formulations of chlorthalidone (manufacturer’s labeling).
Calcium nephrolithiasis, prevention (off-label use):
Note: Use for patients with high urine calcium that is not due to hypercalcemia (AUA [Pearle 2014]; Curhan 2021).
Oral: Initial: 12.5 to 25 mg once daily; after several weeks, may titrate based on urinary calcium response and tolerability up to a maximum of 100 mg once daily; usual effective dose: 25 to 50 mg once daily (AUA [Pearle 2014]; Curhan 2021).
Edema, refractory (adjunctive to loop diuretic ):
Note: Typically for short-term use under close monitoring, including serum electrolytes (particularly potassium) and renal function (Brater 2021; Colucci 2020).
Oral: Initial: 12.5 to 25 mg once daily or as needed on intermittent days; adjust dose based on response and tolerability; maximum dose: 100 mg/day. Due to long half-life, diuretic effect may be more pronounced after several days when steady-state serum concentration is achieved (ACC [Hollenberg 2019]; ACCF/AHA [Yancy 2013]).
Hypertension, chronic:
Note: For patients who warrant combination therapy (blood pressure ≥20/10 mm Hg above goal or suboptimal response to initial monotherapy), may use in combination with another appropriate agent (eg, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, dihydropyridine calcium channel blocker) (ACC/AHA [Whelton 2018]). However, some experts prefer regimens that do not include thiazide diuretics for combination therapy (Mann 2021).
Oral: Usual dosage range: 12.5 to 25 mg once daily evaluate response after ~2 to 4 weeks and titrate dose, as needed; doses higher than 25 mg/day are not recommended due to greater adverse effects with minimal added antihypertensive benefit; if additional blood pressure control is needed, consider combination therapy. Patients with severe asymptomatic hypertension and no signs of acute end organ damage should be evaluated for medication titration within 1 week (ACC/AHA [Whelton 2018]; Mann 2021).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function:
CrCl ≥10 mL/minute: No dosage adjustment necessary. The diuretic effect is diminished with CrCl <30 mL/minute, but small, short-term studies suggest antihypertensive effect may be preserved (Agarwal 2012; Agarwal 2014; KDIGO 2012; KDIGO 2021; Kramer 2019; Sinha 2016). Switching to a loop diuretic may be considered if BP is no longer controlled or if management of fluid overload is required (KDIGO 2012). Alternatively, thiazides may augment diuresis when combined with a loop diuretic in patients unresponsive to monotherapy; closer monitoring of electrolytes is necessary when utilizing this approach (Dussol 2012; Fliser 1994).
CrCl <10 mL/minute: Use not recommended due to lack of efficacy (Sinha 2019; manufacturer's labeling).
Hemodialysis, intermittent (thrice weekly): Use not recommended due to lack of efficacy (Sinha 2019).
Peritoneal dialysis: Use not recommended due to lack of efficacy (Sinha 2019).
CRRT: In general, use not recommended; fluid management can be more effectively managed using CRRT ultrafiltration (expert opinion).
PIRRT (eg, sustained, low-efficiency diafiltration) : In general, use not recommended; fluid management can be more effectively managed using PIRRT ultrafiltration (expert opinion).
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
(For additional information see "Chlorthalidone: Pediatric drug information")
Hypertension: Children and Adolescents: Oral: Initial: 0.3 mg/kg/dose once daily; may titrate up to a maximum daily dose: 2 mg/kg/day or 50 mg/day (NHBPEP 2004; NHLBI 2011)
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; based on experience in adult patients, use is contraindicated with anuria and considered ineffective in patients with CrCl <10 mL/minute (Aronoff 2007).
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Calcium nephrolithiasis, prevention (off-label use): Refer to adult dosing.
Edema, refractory: Refer to adult dosing.
Hypertension, chronic: Oral: Initial: 6.25 to 12.5 mg once daily or every other day; maximum: 25 mg/day (Carter 2004; SHEP 1991).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Thalitone: 15 mg
Generic: 25 mg, 50 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Generic: 50 mg, 100 mg [DSC]
Oral: Administer as a single dose in the morning with food.
Oral: Administer in the morning with food
Edema, refractory: Adjunctive treatment (eg, added to loop diuretics) of edema associated with heart failure, renal impairment, hepatic cirrhosis, or corticosteroid and estrogen therapy.
Hypertension, chronic: Management of hypertension.
Calcium nephrolithiasis, prevention
Beers Criteria: Diuretics (chlorthalidone) are identified in the Beers Criteria as potentially inappropriate medications to be used with caution in patients 65 years and older because of the potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults (Beers Criteria [AGS 2019]).
Reversible hypokalemia, hypomagnesemia, hypercalcemia, and hyponatremia may occur with chlorthalidone and may increase the risk of arrhythmias. Electrolyte disturbances may be more significant with chlorthalidone compared to hydrochlorothiazide (Ref). Development of electrolyte disturbances may be minimized when used in combination with other electrolyte sparing antihypertensives (eg, angiotensin-converting enzyme, angiotensin receptor blockers, or aldosterone inhibitors) (Ref).
Mechanism: Dose-related; related to the pharmacologic action. Thiazide diuretics block the NaCl cotransporter in the distal convoluted tubule, leading to decreased reabsorption of sodium and chloride and increased delivery of sodium to the collecting duct, which leads to increased potassium wasting. Diluting capacity of the kidney is also impaired, leading to decreased magnesium and increased calcium concentrations (Ref).
Onset: Intermittent to delayed; hypokalemia generally occurs within 2 weeks of initiation (Ref). Hyponatremia onset varies, may range from 2 weeks to 10 years after treatment initiation (Ref).
Risk factors:
• High doses (>25 mg/day) (Ref) or concurrent loop diuretic therapy (Ref)
• Hypokalemia: GI losses (ie vomiting, diarrhea) (Ref)
• Hypomagnesemia: Heart failure, poor magnesium intake, high alcohol intake (Ref)
• Hypercalcemia: Older patients, females (Ref)
• Hyponatremia: Increased water intake (Ref); older patients, females (Ref)
Chlorthalidone may cause hyperuricemia and precipitate gout or gouty arthritis in susceptible individuals (Ref).
Mechanism: Dose-related; related to the pharmacologic action. Diuretics increase reabsorption of uric acid in the proximal tubule, reducing urinary excretion, increasing the risk of hyperuricemia and gout (Ref). Volume contraction with use of diuretics may also contribute to increased uric acid (Ref).
Onset: Varied; increased uric acid and risk of gout generally occurs within first few days of treatment initiation (Ref) but may occur up to 1 year after treatment initiation (Ref).
Risk factors:
• High doses (Ref)
• Increased duration of therapy (Ref)
• Personal or family history of gout (Ref)
Hypersensitivity reactions, both immediate (urticaria, angioedema) and delayed, have been reported (Ref). Delayed hypersensitivity reactions range from maculopapular skin rash (Ref) and bullous fixed drug eruption (Ref) to rare severe cutaneous adverse reactions, including toxic epidermal necrolysis (Ref).
Mechanism:
Immediate hypersensitivity reactions: Non–dose-related; immunologic (ie, IgE-mediated, with specific antibodies formed against a drug allergen following initial exposure) (Ref).
Delayed hypersensitivity reactions: Non–dose-related; immunologic (ie, involving a T-cell mediated drug-specific immune response) (Ref).
Onset:
Immediate hypersensitivity reactions: Rapid; generally occur within 1 hour of administration but may occur up to 6 hours after exposure (Ref).
Delayed hypersensitivity reactions: Varied; typically occur days to 6 weeks after drug exposure, but may occur more rapidly (usually within 1 to 4 days) upon reexposure (Ref).
Risk factors:
• Cross-reactivity: Although chlorthalidone contains the sulfonamide moiety (Ref), there are no published reports of cross-reactivity with other sulfonamides (Ref). Cross-reactivity due to antibody production (anaphylaxis) is unlikely to occur with nonantibiotic sulfonamides and antibiotic sulfonamides (Ref). Cross-reactivity among chlorthalidone and thiazide diuretics is unknown.
Sulfa derivatives such as chlorthalidone may cause acute transient myopia and acute angle-closure glaucoma which is generally reversible (Ref).
Mechanism: Non–dose-related; idiosyncratic; suggested to involve ciliochoroidal effusion and anterior rotation of the ciliary body, leading to myopic shift and angle closure (Ref).
Onset: Varied; reported to occur between 3 days and 1 week after initiation (Ref).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Frequency not defined:
Cardiovascular: Hypersensitivity angiitis, necrotizing angiitis, vasculitis
Dermatologic: Skin photosensitivity, skin rash, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Glycosuria, hyperuricemia, hypochloremic alkalosis
Gastrointestinal: Abdominal cramps, anorexia, constipation, diarrhea, gastric irritation, nausea, vomiting
Hematologic & oncologic: Aplastic anemia, leukopenia, nonthrombocytopenic purpura
Hepatic: Intrahepatic cholestatic jaundice
Nervous system: Dizziness, paresthesia, restlessness
Neuromuscular & skeletal: Asthenia, muscle spasm
Ophthalmic: Xanthopsia
Postmarketing:
Cardiovascular: Orthostatic hypotension (Juraschek 2019)
Endocrine & metabolic: Hypercalcemia (Palmer 1978), hyperglycemia (Barzilay 2006), hypokalemia (Hripcsak 2020), hyponatremia (Hripcsak 2020)
Gastrointestinal: Pancreatitis (Mallory 1980)
Genitourinary: Impotence (Hripcsak 2020)
Hematologic & oncologic: Agranulocytosis (Hripcsak 2020), anemia (Hripcsak 2020), neutropenia (Hripcsak 2020), thrombocytopenia (Hripcsak 2020)
Hypersensitivity: Angioedema (Piller 2006), fixed drug eruption (Cuervo-Pardo 2018)
Ophthalmic: Acute angle-closure glaucoma (Durai 2016), myopia (Mahesh 2007)
Nervous system: Headache (Hripcsak 2020), vertigo (Hripcsak 2020)
Neuromuscular & skeletal: Lupus-like syndrome (Vaglio 2018)
Hypersensitivity to chlorthalidone, other sulfonamide-derived drugs, or any component of the formulation; anuria
Note: Although the FDA-approved product labeling states this medication is contraindicated in patients with hypersensitivity to sulfonamide-containing drugs, the scientific basis of this cross-sensitivity has been challenged. See “Warnings/Precautions” for more detail.
Documentation of allergenic cross-reactivity for drugs thiazide-type diuretics is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Concerns related to adverse effects:
• 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 not 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/toxic epidermal necrolysis), some clinicians choose to avoid exposure to these classes.
Disease-related concerns:
• Adrenal insufficiency: Avoid use of diuretics for treatment of elevated blood pressure in patients with primary adrenal insufficiency (Addison disease). Adjustment of glucocorticoid/mineralocorticoid therapy and/or use of other antihypertensive agents is preferred to treat hypertension (Bornstein 2016; Inder 2015).
• Autosomal-dominant hypoparathyroidism: Use with caution in patients with hypoparathyroidism due to autosomal-dominant hypoparathyroidism (ADH) type 1 and ADH type 2; thiazides may further exacerbate hypokalemia (ES [Brandi 2016]; ESE [Khan 2019]).
• Bariatric surgery: Dehydration: Avoid diuretics in the immediate postoperative period after bariatric surgery; electrolyte disturbances and dehydration may occur. Diuretics may be resumed, if indicated, once oral fluid intake goals are met (Ziegler 2009).
• Diabetes: Use with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment; in progressive or severe hepatic disease, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy.
• Hypercholesterolemia: Use with caution in patients with moderate or high cholesterol concentrations; increased cholesterol and triglyceride levels have been reported with thiazide diuretics.
• Parathyroid disease: Thiazide diuretics reduce calcium excretion; pathologic changes in the parathyroid glands with hypercalcemia and hypophosphatemia have been observed with prolonged use; should be discontinued prior to testing for parathyroid function.
• Renal impairment: Cumulative effects may develop, including azotemia, in patients with impaired renal function. Avoid in severe renal disease (ineffective).
Special populations:
• Surgical patients: If given the morning of surgery, thiazide diuretics may render the patient volume depleted and blood pressure may be labile during general anesthesia.
None known.
Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the orthostatic hypotensive effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: 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. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: Thiazide and Thiazide-Like Diuretics may enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Anticholinergic Agents: May increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Antidiabetic Agents: Thiazide and Thiazide-Like Diuretics may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Arsenic Trioxide: Thiazide and Thiazide-Like Diuretics may enhance the hypotensive effect of Arsenic Trioxide. Thiazide and Thiazide-Like Diuretics may enhance the QTc-prolonging effect of Arsenic Trioxide. Management: When possible, avoid concurrent use of arsenic trioxide with drugs that can cause electrolyte abnormalities, such as the thiazide and thiazide-like diuretics. Risk D: Consider therapy modification
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Beta2-Agonists: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Thiazide and Thiazide-Like Diuretics. The diuretic response is likewise decreased. Management: Consider separating administraton of bile acid sequestrants and thiazide diuretics by at least 4 hours. Monitor for decreased therapeutic effects of thiazide diuretics if coadministered with a bile acid sequestrant. Risk D: Consider therapy modification
Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
Calcium Salts: Thiazide and Thiazide-Like Diuretics may decrease the excretion of Calcium Salts. Continued concomitant use can also result in metabolic alkalosis. Risk C: 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. Risk C: 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. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Cyclophosphamide: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, granulocytopenia may be enhanced. Risk C: Monitor therapy
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Risk C: Monitor therapy
Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Diacerein: May enhance the therapeutic effect of Diuretics. Specifically, the risk for dehydration or hypokalemia may be increased. Risk C: Monitor therapy
Diazoxide: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Diazoxide. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Dichlorphenamide: Thiazide and Thiazide-Like Diuretics may enhance the hypokalemic effect of Dichlorphenamide. Risk C: 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. Management: Although hydrochlorothiazide is specifically cited as a contraindication, the risk likely extends to all thiazide and thiazide-like diuretics and may be even greater with chlorthalidone or bendroflumethiazide. Consider alternatives when possible. Risk D: Consider therapy modification
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Herbal Products with Blood Pressure Increasing Effects: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Ipragliflozin: May enhance the adverse/toxic effect of Thiazide and Thiazide-Like Diuretics. Specifically, the risk for intravascular volume depletion may be increased. Risk C: Monitor therapy
Ivabradine: Thiazide and Thiazide-Like Diuretics may enhance the arrhythmogenic effect of Ivabradine. Risk C: Monitor therapy
Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy
Levosulpiride: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Levosulpiride. Risk X: Avoid combination
Licorice: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Lithium: Thiazide and Thiazide-Like Diuretics may decrease the excretion of Lithium. Management: Reduce the lithium dose if coadministered with thiazide or thiazide-like diuretics. Monitor serum lithium levels during coadministration with thiazide and thiazide-like diuretics. Risk D: Consider therapy modification
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Mecamylamine: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Mecamylamine. Management: Consider avoiding the use of mecamylamine and thiazide diuretics. If combined, mecamylamine prescribing information suggests reducing the mecamylamine dose by 50% in order to avoid excessive hypotension. Risk D: Consider therapy modification
Methenamine: Thiazide and Thiazide-Like Diuretics may diminish the therapeutic effect of Methenamine. Risk C: Monitor therapy
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Multivitamins/Fluoride (with ADE): May enhance the hypercalcemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: 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). Risk C: 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. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Neuromuscular-Blocking Agents (Nondepolarizing): Thiazide and Thiazide-Like Diuretics may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: 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. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. Risk C: 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. Risk D: Consider therapy modification
Opioid Agonists: May enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy
OXcarbazepine: Thiazide and Thiazide-Like 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 Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Promazine: Thiazide and Thiazide-Like Diuretics may enhance the QTc-prolonging effect of Promazine. Risk X: Avoid combination
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Reboxetine: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hyponatremic effect of Thiazide and Thiazide-Like Diuretics. Risk C: 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. Risk D: 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 (eg, 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 and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Toremifene. Risk C: Monitor therapy
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Vitamin D Analogs: Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Vitamin D Analogs. Risk C: Monitor therapy
Chlorthalidone crosses the placenta and can be detected in cord blood (Mulley 1978).
Maternal use may cause fetal or neonatal jaundice, thrombocytopenia, hypoglycemia, and electrolyte abnormalities.
Chronic maternal hypertension is associated with adverse events in the fetus/infant. The risk of birth defects, low birth weight, premature delivery, stillbirth, and neonatal death may be increased with chronic hypertension in pregnancy. Actual risks may be related to duration and severity of maternal hypertension. Diuretics are considered second-line therapy for treating chronic hypertension in pregnancy (ACOG 203 2019).
The treatment of edema associated with chronic heart failure during pregnancy is similar to that of nonpregnant patients. Use of thiazide diuretics may be considered but use with caution due to the potential reduction in placental blood flow. Patients diagnosed after delivery can be treated according to heart failure guidelines (ESC [Bauersachs 2016]; ESC [Regitz-Zagrosek 2018]).
Chlorthalidone is present in breast milk (Mulley 1978).
Due to the potential for serious adverse reactions in the breastfeeding infant, breastfeeding is not recommended by the manufacturer. In general, thiazide diuretics have the potential to decrease milk volume and suppress lactation; use should be avoided when possible (ACOG 203 2019; WHO 2002).
Monitor weight, intake and output (I and O) records daily to determine fluid loss; blood pressure, serum electrolytes, renal function.
Hypertension: The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults (ACC/AHA [Whelton 2018]):
Confirmed hypertension and known cardiovascular disease or 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥10%: Target blood pressure <130/80 mm Hg is recommended.
Confirmed hypertension without markers of increased ASCVD risk: Target blood pressure <130/80 mm Hg may be reasonable.
Sulfonamide-derived diuretic that inhibits sodium and chloride reabsorption in the distal convoluted tubule (Gamba 2005; Moes 2014; Rose 1991).
Onset of action: ~2.6 hours; Peak effect: 2 to 6 hours (Carter 2004)
Bioavailability: Brand name Thalitone tablet bioavailability is slightly greater (104% to 116%) relative to an oral solution of chlorthalidone.
Duration: Single dose: 24 to 48 hours; Long-term dosing: 48 to 72 hours (Carter 2004)
Protein binding: ~75% (58% to albumin)
Metabolism: Hepatic
Half-life elimination: Single dose: 40 hours; Long-term dosing: 45 to 60 hours (Carter 2004); may be prolonged with renal impairment
Excretion: Urine (primarily as unchanged drug)
Tablets (Chlorthalidone Oral)
25 mg (per each): $1.21 - $2.62
50 mg (per each): $1.48 - $1.49
Tablets (Thalitone Oral)
15 mg (per each): $4.44
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