Class: Thiazide-like Diuretics
- Diuretics, Thiazide
VA Class: CV701
CAS Number: 77-36-1
Brands:

Chlorthalidone is also contained as an ingredient in the following combinations:
Atenolol and Chlorthalidone

Medically reviewed by Drugs.com. Last updated on Jan 4, 2021.

• Uses
• Dosage
• Cautions
• Interactions
• Pharmacokinetics
• Patient advice
• Preparations

Introduction

Diuretic and antihypertensive agent, structurally and pharmacologically similar to thiazides.

Uses for Chlorthalidone

Hypertension

Used alone or in combination with other antihypertensive agents for all stages of hypertension.^{b 501 600 1200}

Classified as a thiazide-like drug with regard to management of hypertension.¹²⁰⁰

Thiazide-type diuretics are recommended as one of several preferred agents for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include ACE inhibitors, angiotensin II receptor antagonists, and calcium-channel blockers.^{501 502 503 504 1200} While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.^{501 502 504 1200 1213}

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).^{501 502 503 504 515 1200 1201}

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.¹²⁰⁰ (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP.¹²⁰⁰ However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.^{501 503 504 505 506 507 508 515 523 526 530 1200 1201 1207 1209 1222 1223 1229}

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BPs to achieve with drug therapy and/or nonpharmacologic intervention) <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.¹²⁰⁰ In addition, an SBP goal of <130 mm Hg generally is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg.¹²⁰⁰ These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.^{1200 1202 1210}

Previous hypertension guidelines have based target BP goals on age and comorbidities.^{501 504 536} Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients compared with^{501 504 536} those recommended by the 2017 ACC/AHA hypertension guideline.¹²⁰⁰

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the current ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.^{1222 1223 1224 1229}

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient’s BP treatment goal.^{1200 1220}

For decisions regarding when to initiate drug therapy (BP threshold), the current ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors.^{1200 1207} ASCVD risk assessment recommended by ACC/AHA for all adults with hypertension.¹²⁰⁰

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).¹²⁰⁰

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.¹²⁰⁰

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years of age are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg.¹²⁰⁰ Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.^{502 1200}

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP.¹²⁰⁰ Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.¹²⁰⁰

Black hypertensive patients generally tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists).^{109 501 504 1200} However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar BP lowering in black patients as in other racial groups.¹²⁰⁰

Thiazide-like diuretics may be preferred in hypertensive patients with osteoporosis. Secondary beneficial effect in hypertensive geriatric patients of reducing the risk of osteoporosis due to effect on calcium homeostasis and bone mineralization.

Edema (General)

Management of edema resulting from various causes; diagnose etiology before use.^b

Edema caused by renal disease or by corticosteroids or estrogens may be relatively resistant to treatment.^b

Ineffective in patients with S_cr or BUN concentrations greater than twice normal.^b

May be ineffective in patients with a GFR of <15–25 mL/minute; even when GFR is 25–50 mL/minute, more potent (e.g., loop) diuretics may be indicated.^b

No substantial difference in clinical effects or toxicity of comparable thiazide or thiazide-like diuretics, except metolazone may be more effective in edema with renal impairment.^b

Edema in Pregnancy

Generally responds well to thiazides except when caused by renal disease.^b

Thiazides should not be used for routine therapy in pregnant women with mild edema who are otherwise healthy.^b

Edema in Heart Failure

Management of edema associated with heart failure.^{b c}

Most experts state that all patients with symptomatic heart failure who have evidence for, or a history of, fluid retention generally should receive diuretic therapy in conjunction with moderate sodium restriction, an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., ACE inhibitor, angiotensin II receptor antagonist, angiotensin receptor-neprilysin inhibitor [ARNI]), a β-adrenergic blocking agent (β-blocker), and in selected patients, an aldosterone antagonist.⁵²⁴

Do not use diuretics as monotherapy in heart failure even if symptoms (e.g., peripheral edema, pulmonary congestion) are well controlled; diuretics alone do not prevent progression of heart failure.⁵²⁴

Diuretics produce rapid symptomatic benefits, relieving pulmonary and peripheral edema more rapidly (within hours or days) than cardiac glycosides, ACE inhibitors, or β-blockers (in weeks or months).

Once fluid retention has resolved in heart failure, diuretic therapy should be maintained to prevent recurrence of fluid retention. Ideally, diuretic therapy should be adjusted according to changes in body weight (as an indicator of fluid retention) rather than maintained at a fixed dosage.

Diuretics should be continued in heart failure and comorbid conditions (e.g., hypertension) where ongoing therapy with the drugs is indicated.⁵²⁴

Edema Secondary to Nephrotic Syndrome

May be useful if the patient fails to respond to corticosteroid therapy.^b

More likely to become refractory to thiazides than edema associated with heart failure, and more potent diuretics may be required.^b

Diabetes Insipidus

Has been used widely in the treatment of diabetes insipidus†.^b

Effective in both the neurohypophyseal and nephrogenic forms of the disease, decreasing urine volume by up to 50%.^b

Particularly useful in nephrogenic diabetes insipidus, since this form of the disease is unresponsive to vasopressin and chlorpropamide.^b

Useful in patients who are allergic or refractory to vasopressin and have been used in combination with one of these hormones and a low-salt diet in patients who excrete an exceptionally large volume of urine.^b

Renal Tubular Acidosis

Has been used with success in the treatment of electrolyte disturbances associated with renal tubular acidosis†.^b

Renal Calculus Formation

Has been used with success in the prophylaxis of renal calculus formation associated with hypercalciuria†.^b

Chlorthalidone Dosage and Administration

General

Monitoring and BP Treatment Goals

• Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.¹²⁰⁰

  If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.^{1200 1216}

• Assess patient’s renal function and electrolytes 2–4 weeks after initiation of diuretic therapy.¹²⁰⁰ (See Electrolyte Imbalance under Cautions.)

• If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., ACE inhibitor, angiotensin II receptor antagonist, calcium-channel blocker).^{1200 1216} Many patients will require at least 2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved, add a third drug.^{1200 1216 1220}

Administration

Administer orally.^a

Dosage

Individualize according to requirements and response.^a

If added to potent hypotensive agent regimen, initially reduce hypotensive dosage to avoid the possibility of severe hypotension.^a

For the management of fluid retention associated with heart failure, experts state that diuretics should be administered at a dosage sufficient to achieve optimal volume status and relieve congestion without inducing excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both.⁵²⁴

Pediatric Patients

Hypertension†

Oral

Children: Initially, 0.3 mg/kg once daily recommended by some experts.¹¹⁵⁰ May increase dosage every 2–4 weeks until BP controlled, maximum dosage reached (2 mg/kg [up to 50 mg] daily), or adverse effects occur.¹¹⁵⁰

Adults

Hypertension

Usual Dosage

Oral

Manufacturer recommends initial dosage of 25 mg once daily; may be increased to 50 mg once daily.⁶⁰⁰

Some experts recommend dosage of 12.5–25 mg once daily based on efficacy and tolerance demonstrated in clinical studies.^{109 1200}

Dosages >100 mg daily usually do not increase efficacy.⁶⁰⁰

Fixed-combination Therapy

Oral

Initially, administer each drug separately to adjust dosage; may use fixed combination if optimum maintenance dosage corresponds to drug ratio in combination preparation.^a

Manufacturer states that fixed-combination preparations containing chlorthalidone and atenolol should not be used for initial antihypertensive therapy;⁶⁰¹ however, some experts state that use of a fixed-combination preparation may increase patient compliance.¹²⁰⁰

Edema

Oral

Initial dosage: Usually, 50–100 mg daily in a single dose after breakfast.^a

Alternatively, initiate 100 mg every other day or 3 times a week; some patients require dosages of 150–200 mg daily or every other day.^a

Dosages >200 mg daily do not produce a greater response.^a

Maintenance dosage: Reduction of dosage to a lower level may be possible after several days or when nonedematous weight is attained.^a

Management of fluid retention associated with heart failure: Some experts recommend initiating chlorthalidone at a low dosage (e.g., 12.5–25 mg once daily) and increasing dosage until urine output increases and weight decreases, generally by 0.5–1 kg daily.⁵²⁴

Prescribing Limits

Pediatric Patients

Hypertension†

Oral

Maximum 2 mg/kg (up to 50 mg) once daily.¹¹⁵⁰

Adults

Hypertension

Oral

Dosages >100 mg daily do not produce a greater response.⁶⁰⁰

Edema

Oral

Dosages >200 mg daily do not produce a greater response.^a

Management of fluid retention in heart failure: 100 mg maximum daily dose recommended by ACCF/AHA.⁵²⁴

Special Populations

Hepatic Impairment

No specific dosage recommendations for hepatic impairment; caution because of risk of precipitating hepatic coma.^a

Renal Impairment

No specific dosage recommendations for renal impairment; caution because of risk of precipitating azotemia.^a

Cautions for Chlorthalidone

Contraindications

• Anuria.^{600 b}

• Known hypersensitivity to hydrochlorothiazide, other thiazides, or any ingredient in the formulation.^b

• Although manufacturers state allergy to other sulfonamide derivatives is a contraindication, evidence to support cross-sensitivity is limited, and history of sensitivity to sulfonamide anti-infectives (“sulfa sensitivity”) should not be considered an absolute contraindication.

Warnings/Precautions

Warnings

Hypotensive Agents

May potentiate effects of other hypotensive agents.⁶⁰⁰ Although additive or potentiated antihypertensive effects usually are used to therapeutic advantage,¹²⁰⁰ hypotension could occur.^b (See Interactions.)

Lupus Erythematosus

Possible exacerbation or activation of systemic lupus erythematosus.⁶⁰⁰

Sensitivity Reactions

Hypersensitivity

May occur with or without history of allergy or bronchial asthma.^{600 b}

Sulfonamide cross-sensitivity unlikely. (See Contraindications under Cautions.)

General Precautions

Electrolyte Imbalance

Monitor for fluid or electrolyte imbalance (hyponatremia, hypochloremic alkalosis, hypokalemia) prior to initiation of treatment and periodically thereafter.^{600 1200 b}

Observe for signs of electrolyte imbalance (e.g., dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, , oliguria, muscle pains, cramps, muscular fatigue, hypotension, tachycardia, nausea, vomiting).^{600 1200}

Perform periodic serum electrolyte determinations (particularly of potassium, sodium, chloride, and bicarbonate); institute measures to maintain normal serum concentrations if necessary.^{1200 b}

Serum and urinary electrolyte measurements are especially important with diabetes mellitus, vomiting, diarrhea, parenteral fluid therapy, or expectations of excessive diuresis.^{1200 b}

Weekly (or more frequent) electrolyte measurement early in treatment; possible to extend interval between measurements to ≥3 months when electrolyte response has stabilized.^b

Hypokalemia

May occur after brisk diuresis, when cirrhosis is present, or with prolonged therapy; inadequate oral electrolyte intake may contribute.^{600 z}

May cause cardiac arrhythmias, exaggerate cardiac response to cardiac glycoside toxicity (increase ventricular irritability).^b

Use potassium-sparing diuretics and/or potassium supplementation to avoid or treat hypokalemia.^b

Hypochloremia

Generally mild, usually does not require specific treatment except in renal or hepatic impairment.⁶⁰⁰

Chloride replacement may be required for metabolic acidosis.^z

Hyponatremia

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate treatment usually is water restriction rather than salt administration except when hyponatremia is life-threatening.⁶⁰⁰

In actual salt depletion, appropriate replacement is treatment of choice.⁶⁰⁰

Gout

Hyperuricemia or, rarely, precipitation of gout may occur; generally avoid or use with caution in patients with history of gout unless patient is receiving uric acid lowering therapy.^{600 502 1200}

Hyperglycemia

In diabetic patients, dosage adjustment of insulin or oral hypoglycemics may be required; hyperglycemia may occur and latent diabetes mellitus may become evident.⁶⁰⁰

Sympathectomy

Antihypertensive effect may be enhanced after sympathectomy.^b

Hypomagnesemia

May increase magnesium urinary excretion, resulting in hypomagnesemia.⁶⁰⁰

Hypercalcemia

May decrease calcium urinary excretion, cause slight intermittent serum calcium increase in absence of known calcium metabolism disorder; marked hypercalcemia may indicate hyperparathyroidism.^{600 a z}

Discontinue prior to performing parathyroid tests.^b

Hyperlipidemia

May increase cholesterol and triglyceride concentrations.^b

Clinical importance of these changes is unknown.^b Diet low in saturated fat and cholesterol usually compensates.^b

Hypotensive Effects

Orthostatic hypotension rarely occurs.^b

Specific Populations

Pregnancy

Category B.⁶⁰⁰

Diuretics are considered second-line agents for control of chronic hypertension in pregnant women;¹⁴² if initiation of antihypertensive therapy is necessary during pregnancy, other antihypertensives (i.e., methyldopa, nifedipine, labetalol) are preferred.^{142 540}

Edema associated with pregnancy generally responds well to thiazides except when caused by renal disease; however, do not use as routine therapy in pregnant women with mild edema who are otherwise healthy.^b

Diuretics are not recommended for prevention or management of gestational hypertension or preeclampsia.^{141 539 540}

Lactation

Distributed into milk.^{141 600 h} Manufacturer states to discontinue nursing or the drug;⁶⁰⁰ however, considered to be compatible with breast-feeding.¹⁴¹

Pediatric Use

Safety and efficacy not established.⁶⁰⁰

Geriatric Use

Elderly may be at increased risk of dilutional hyponatremia, especially underweight females with poor oral fluid and electrolyte intake or excessive low-sodium nutritional supplement intake.^b (See Hyponatremia under Cautions.)

Hepatic Impairment

Use with caution in hepatic impairment or progressive liver disease (particularly with associated potassium deficiency); electrolyte imbalance may precipitate hepatic coma.^{600 b}

Discontinue immediately if signs of impending hepatic coma appear.^b

Renal Impairment

Use with caution in severe renal impairment; thiazides decrease GFR and may precipitate azotemia.^{600 b} Effects may be cumulative in impaired renal function.^{600 b}

Common Adverse Effects

Potassium depletion, hyperuricemia (usually asymptomatic; rarely leading to gout).^b Hypochloremic alkalosis in patients at risk (e.g., hypokalemic patients).^b Hyperglycemia and glycosuria in diabetics.^b

Interactions for Chlorthalidone

Specific Drugs and Laboratory Tests

Chlorthalidone Pharmacokinetics

Absorption

Bioavailability

Absorbed from the GI tract.

Onset

Diuretic action begins around 2.6 hours after dosing.⁶⁰⁰

Duration

Up to 72 hours.⁶⁰⁰

Distribution

Plasma Protein Binding

About 75%; 58% is bound to albumin.⁶⁰⁰

Elimination

Elimination Route

30–60% excreted unchanged in urine.^a

Half-life

40–60 hours.^{600 a}

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 20–25°C.⁶⁰⁰

Actions

• Exact mechanism of diuretic action is unclear; may act by altering metabolism of the tubular cells.^b

• Enhances excretion of sodium, chloride, and water by interfering with the transport of sodium ions across the renal tubular epithelium.^b

• Primary site of diuretic action appears to be the cortical diluting segment of the nephron.^b

• GFR decreases, but unclear whether secondary to a direct effect on renal vasculature or to the decrease in intravascular fluid volume or an increase in tubular pressure caused by the inhibition of sodium and water reabsorption.^b The fall in GFR is not important in the mechanism of action.^b

• Enhances urinary excretion of potassium secondary to increased amount of sodium at distal tubular site of sodium-potassium exchange.^b

• Increases urinary bicarbonate excretion (although to a lesser extent than chloride excretion) but change in urinary pH is usually minimal; diuretic efficacy is not affected by the acid-base balance of the patient.^b

• Hypocalciuric effect is thought to result from a decrease in extracellular fluid (ECF) volume, although calcium reabsorption in the nephron may be increased; also, slight or intermittent elevations in serum calcium concentration.^b

• Rate of uric acid excretion is decreased, probably because of competitive inhibition of uric acid secretion or a decrease in ECF volume and a secondary increase in uric acid reabsorption.^b

• Hypotensive activity in hypertensive patients; also augments the action of other hypotensive agents.^b Precise mechanism of hypotensive action has not been determined, but postulated that part of this effect is caused by direct arteriolar dilation.^b

Advice to Patients

• Advise patient of signs of electrolyte imbalance (e.g., dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, oliguria, muscle pains or cramps, muscular fatigue, hypotension, tachycardia, GI disturbances such as nausea and vomiting).^b

• Advise patients of importance of compliance with scheduled determinations of serum electrolyte concentrations (particularly potassium, sodium, chloride, and bicarbonate).^b

• Advise hypertensive patients of importance of continuing lifestyle/behavioral modifications that include weight reduction (for those who are overweight or obese), dietary changes to include foods that are rich in potassium and calcium and moderately restricted in sodium (adoption of the Dietary Approaches to Stop Hypertension [DASH] eating plan), increased physical activity, smoking cessation, and moderation of alcohol intake.¹²⁰⁰

  Advise that lifestyle/behavioral modifications reduce BP, enhance antihypertensive drug efficacy, and decrease cardiovascular risk and remain an indispensable part of the management of hypertension.¹²⁰⁰

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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