Chlorthalidone

0.85

log Kow= 0.85

1.3

Crystals from 50% acetic acid

WHITE TO YELLOWISH-WHITE CRYSTALLINE POWDER

120

12 mg/100 ml in water @ 20 °C, 27 mg/100 ml @ 37 °C; 577 mg/100 ml in 0.1 N sodium carbonate; more sol in aq soln of sodium hydroxide; sol in warm ethanol; slightly sol in ether.

Chlorthalidone is practically insoluble in water, in ether and in chloroform; soluble in methanol; slightly soluble in alcohol.

5.28e-02 g/L

239

Dec 224-226 °C. Melting point range may extend from 218 to 264 °C on slow heating.

218 - 264 °C

166.7 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

175.75 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]；174.48 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

This chemical does not meet GHS hazard criteria for 38.7% (41 of 106) of reports.

Warning

H315 (58.5%): Causes skin irritation [Warning Skin corrosion/irritation]；H319 (59.4%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]；H335 (57.5%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 106 reports by companies from 13 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Reported as not meeting GHS hazard criteria per 41 of 106 reports by companies.；There are 11 notifications provided by 65 of 106 reports by companies with hazard statement code(s).；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

IMAP assessments - Benzenesulfonamide, 2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1-yl)-: Environment tier I assessment；IMAP assessments - Benzenesulfonamide, 2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1-yl)-: Human health tier I assessment

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

CHLOROTHIAZIDE & OTHER THIAZIDE DIURETICS /INCL CHLORTHALIDONE/ ENHANCE CARDIOTOXIC & NEUROTOXIC EFFECTS OF LITHIUM...

CHLORTHALIDONE.../IS/ STRUCTURALLY RELATED TO THIAZIDE DIURETICS...SHOULD BE EXPECTED TO INTERACT WITH GUANETHIDINE /ENHANCING ITS HYPERTENSIVE ACTION/...

/CHLORTHALIDONE/...MAY...INTERACT WITH PROBENECID /ANTAGONIZING ITS URICOSURIC EFFECTS & CAUSING URIC ACID RETENTION/.

Concurrent use of thiazide diuretics with amiodarone may lead to an increased risk of arrhythmias associated with hypokalemia. /Thiazide diuretics/

For more Interactions (Complete) data for CHLORTHALIDONE (17 total), please visit the HSDB record page.

Significant adverse effects are electrolyte derangement (hypokalemia, hyponatremia, etc), hypersensitivity reaction, and precipitation of acute gout attacks. The adverse effects of chlorthalidone involve most organ systems to differing degrees and manifestations. Of significance, electrolyte derangement is a commonly reported adverse effect of this medication, which results from increased diuresis and altering of nephron physiology. Most commonly, chlorthalidone causes hypokalemia, but it may also cause hyponatremia or hypochloremia. These known derangements make monitoring serum electrolytes essential for patients receiving chlorthalidone periodically throughout hypertensive management.；Reported Adverse Effects (per the Food and Drug Administration):；* Gastrointestinal adverse effects: anorexia, gastritis, nausea, emesis, cramping, loose stools, constipation, and pancreatitis；* Neurologic reactions: paresthesias, dizziness, and headaches；* Hematologic reactions: aplastic anemia, leukopenia, agranulocytosis, and thrombocytopenia；* Cardiovascular reaction: orthostatic hypotension；* Dermatologic reactions: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (cutaneous vasculitis), Lyell syndrome (toxic epidermal necrolysis), pseudoporphyria；* Other adverse reactions include hyperglycemia, glycosuria, muscle spasm, weakness, restlessness, impotence, and hyperuricemia.；Drug-Drug Interactions；* Digitalis: Medications like digitalis can influence serum electrolyte levels, potentially leading to warning signs such as dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscle fatigue, low blood pressure, decreased urine output, rapid heart rate, and gastrointestinal issues like nausea and vomiting.；* Insulin and oral hypoglycemic agents: Chlorthalidone therapy may affect insulin needs in patients with diabetes, potentially necessitating adjustments in insulin dosage or requirements for higher doses of oral hypoglycemic agents. Additionally, latent diabetes may become apparent during treatment with chlorthalidone.；* Tubocurarine: Chlorthalidone and similar drugs can increase sensitivity to tubocurarine, affecting its action.；* Norepinephrine: Chlorthalidone may diminish arteries' responsiveness to norepinephrine, although the effect is not significant enough to render norepinephrine ineffective for therapeutic use.；* Lithium: Close monitoring of lithium levels is imperative in individuals undergoing lithium treatment due to the potential of diuretics such as chlorthalidone to diminish lithium excretion, consequently triggering lithium toxicity.

IDENTIFICATION: Chlorthalidone is a thiazide diuretic. Chlorthalidone is indicated in the management of hypertension as sole therapeutic agent or in combination with other antihypertensive drugs. Chlorthalidone is used as adjunctive therapy in the treatment of edema associated with heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Chlorthalidone has also been found useful in the edema due to various forms of renal dysfunction such as nephrotic syndrome. Chlorthalidone has been used in the treatment of premenstrual tension if there is evidence of fluid retention. Chlorthalidone has a paradoxical antidiuretic effect in patients with diabetes insipidus. HUMAN EXPOSURE: Main risks and target organs: Chlorthalidone is generally well tolerated during therapeutic use. Clinical toxicity is relatively infrequent and may result from overdosage, adverse reactions or hypersensitivity. Acute toxicity: Main risks include: hypokalemia, hyponatremia, hypotension, cardiac arrhythmias and central nervous system effects. Target organs: kidney, heart, CNS. Chronic toxicity and adverse reactions include: Metabolic disturbances, hypersensitivity reactions, aggravation of renal and/or hepatic insufficiency, gastrointestinal disturbances, blood dyscrasias, and central nervous system effects. Summary of clinical effects: Acute toxicity: Symptoms may include: hypokalemia, hyponatremia, dehydration, hypovolemic, cardiac dysrhythmias (ventricular extrasystoles and torsade de pointes due to hypokalemia), dizziness, lethargy, paresthesias. Chronic toxicity and adverse reactions: Several disturbances have been reported: Metabolic: hypokalemia, hyponatremia, hyperglycemia, hyperuricemia, metabolic alkalosis, aggravation of renal insufficiency. Cardiovascular: cardiac arrhythmias, enhancing the effect of digitalis on cardiac muscle, orthostatic hypotension. Central Nervous System: dizziness, vertigo, paresthesias, headache, xanthopsia. Gastrointestinal: anorexia, gas

Signs and Symptoms of Overdose；* Nausea；* Weakness；* Dizziness due to severe hypotension；* Electrolyte disturbances such as hypokalemia, hyponatremia, and hypomagnesemia；Management of acute overdosage；* No specific antidote is available；* Gastric lavage；* Supportive management includes intravenous dextrose or normal saline for hypotension and intravenous potassium chloride for severe hypokalemia.

CHLORTHALIDONE...TESTED IN NORMAL & GLAUCOMATOUS PT IN DOSES FROM 200 TO 500 MG/DAY...FOUND TO HAVE NO TENDENCY TO RAISE OCULAR PRESSURE...RATHER IT WAS FOUND TO REDUCE PRESSURE SLIGHTLY, PARTICULARLY IN GLAUCOMATOUS EYES...

ACUTE TRANSIENT MYOPIA...HAS BEEN REPORTED FROM CHLORTHALIDONE... TYPICALLY... APPEARED WITHIN 1 TO 3 DAYS OF STARTING DRUG, & YOUNG PREGNANT WOMEN APPEAR... PARTICULARLY PRONE TO THIS SIDE EFFECT. ... IN 1 PT TRANSIENT RETINAL EDEMA... REPORTED. ... MYOPIA HAS ALWAYS BEEN PROMPTLY & COMPLETELY REVERSIBLE WHEN DRUG...STOPPED.

SYMPTOMS OF ACUTE POISONING IN MAN ARE USUALLY PRESUMED TO REFLECT FLUID & ELECTROLYTE DERANGEMENTS.

...NUMBER OF HYPERSENSITIVITY REACTIONS...REPORTED: PANCREATITIS, DEPRESSION OF FORMED ELEMENTS OF BLOOD, PURPURA, PHOTOSENSITIVE DERMATITIS, NECROTIZING VASCULITIS, HYPERGLYCEMIA, AGGRAVATION OF DIABETES MELLITUS & EXACERBATION OF RENAL &/OR HEPATIC INSUFFICIENCY.

60-YR OLD WOMAN TREATED WITH CHLORTHALIDONE FOR MILD HYPERTENSION DEVELOPED SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE (ADH). SERUM OSMOLALITY WAS 235 MOSM/KG WITH CONCOMITANT URINE OSMOLALITY OF 490 MOSM/KG.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Chlorthalidone

Ambiguous-DILI-concern

2

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

◉ Summary of Use during Lactation；Although amounts of chlorthalidone in milk are not great, its slow clearance may lead to accumulation in the infant, especially while nursing a newborn or preterm infant. It may also suppress lactation. An alternate drug may be preferred.；◉ Effects in Breastfed Infants；Relevant published information was not found as of the revision date.；◉ Effects on Lactation and Breastmilk；Chlorthalidone has been used successfully to suppress lactation by giving 200 mg orally right after delivery, followed by 100 mg daily for 3 days in conjunction with fluid restriction and breast binding. However, a comparative study found no difference between chlorthalidone 200 mg daily for 7.6 days and placebo in milk leakage and breast engorgement and pain. The added contribution of the diuretic to fluid restriction and breast binding, which are effective in suppressing lactation, has not been studied. There are no data on the effects of diuretics on established, ongoing lactation.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

C - Cardiovascular system；C03 - Diuretics；C03B - Low-ceiling diuretics, excl. thiazides；C03BA - Sulfonamides, plain；C03BA04 - Chlortalidone

QC - Cardiovascular system；QC03 - Diuretics；QC03B - Low-ceiling diuretics, excl. thiazides；QC03BA - Sulfonamides, plain；QC03BA04 - Chlortalidone

Chlorthalidone prevents reabsorption of sodium and chloride through inhibition of the Na+/Cl- symporter in the cortical diluting segment of the ascending limb of the loop of Henle. Reduction of sodium reabsorption subsequently reduces extracellular fluid and plasma volume via an osmotic, sodium-driven diuresis. By increasing the delivery of sodium to the distal renal tubule, Chlorthalidone indirectly increases potassium excretion via the sodium-potassium exchange mechanism. The exact mechanism of chlorthalidone's anti-hypertensive effect is under debate, however, it is thought that increased diuresis results in decreased plasma and extracellular fluid volume which therefore requires decreased cardiac output and overall lowers blood pressure. Chlorthalidone has also been shown to decrease platelet aggregation and vascular permeability, as well as promote angiogenesis in vitro, which is thought to be partly the result of reductions in carbonic anhydrase–dependent pathways. These pathways may play a role in chlorthalidone's cardiovascular risk reduction effects.

...ACT BY INHIBITING RENAL TUBULAR TRANSPORT OF VARIOUS IONS.

Decreased plasma volume and decreased extracellular fluid volume; decreased cardiac output initially, followed by decreased total peripheral resistance with normalization of cardiac output ... /from table/

...ANTIHYPERTENSIVE EFFECT OF CHLORTHALIDONE IS THOUGHT TO BE DUE TO DECR CARDIAC OUTPUT.

The exact mechanism for reduction of arterial blood pressure by diuretics is not certain. Initially the drugs decrease extracellular volume and cardiac output. However, the hypotensive effect is maintained during long-term therapy because of reduced vascular resistance ... /Diuretics/

For more Mechanism of Action (Complete) data for CHLORTHALIDONE (8 total), please visit the HSDB record page.

Q0MQD1073Q

CHLORTHALIDONE

Physiologic Effects [PE] - Increased Diuresis

Established Pharmacologic Class [EPC] - Thiazide-like Diuretic

Chlorthalidone is a Thiazide-like Diuretic. The physiologic effect of chlorthalidone is by means of Increased Diuresis.

CHLORTHALIDONE

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Agents that promote the excretion of urine through their effects on kidney function.

Agents that inhibit SODIUM CHLORIDE SYMPORTERS. They act as DIURETICS. Excess use is associated with HYPOKALEMIA.

Approximately 50% of the administered dose is excreted unmetabolized through the kidney, and excretion is characterized by biphasic elimination with a rapid phase followed by a slow secretory phase.

Chlorthalidone has been shown to rapidly concentrate within erythrocytes and subsequently equilibrate via a slow diffusion back into the serum compartment, resulting in a large volume of distribution.

BIOCHEM STUDIES SUGGEST THAT PROLONGED DURATION OF ACTION IS DUE TO SLOW GI ABSORPTION & ENTEROHEPATIC RECIRCULATION. DRUG IS EXCRETED UNCHANGED BY KIDNEY.

MOST /THIAZIDE/ COMPD ARE RAPIDLY EXCRETED WITHIN 3 TO 6 HR. /THIAZIDE COMPD/

STUDY OF DOSE-DEPENDENT URINARY EXCRETION OF CHLORTHALIDONE.

Therap cat (Vet): Diuretic

Therap cat: Diuretic, antihypertensive

... is indicated in the management of hypertension either alone or in combination with other antihypertensive drugs. Chlorthalidone is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteriod and estrogen therapy.

MEDICATION

Use (kg; approx.) in Germany (2009): >500；Use (kg) in USA (2002): 1380；Consumption (g per capita; approx.) in Germany (2009): 0.00611；Consumption (g per capita) in the USA (2002): 0.00489；Calculated removal (%): 8.8

(1977) 4.33X10+6 GRAMS (PRINCPL CUSTMS DISTS)

(1979) 7.15X10+7 GRAMS (PRINCPL CUSTMS DISTS)

(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS

(1976) PROBABLY GREATER THAN 4.54X10+5 GRAMS

Fine chemical: $100/kg, 100 tons/year; Specialty chemical: $1000/kg, 100 tons/yr

DIAZOTIZATION OF 3-AMINO-4-CHLOROBENZOPHENONE-2-CARBOXYLIC ACID, FOLLOWED BY REACTION WITH SULFUR DIOXIDE, THEN THIONYL CHLORIDE AND AMMONIA

Graf et al, Helv Chim Acta 42, 1085 (1959); US patent 3,055,904 (1962 to Geigy).

HEATING...4-CHLORO-2'-CARBOXYBENZOPHENONE-3-SULFONYL CHLORIDE WITH THIONYL CHLORIDE YIELDS 3-CHLORO-3-(3'-CHLOR OSULFONYL-4'-CHLOROPHENYL)PHTHALIDE WHICH IS ISOLATED, DISSOLVED IN CHLOROFORM, & REACTED WITH AMMONIA...IN...ETHANOL. REMOVAL OF SOLVENT & TREATMENT OF RESIDUE WITH HCL YIELDS CRUDE CHLORTHALIDONE...

DOSAGE FORMS--TABLETS USP: 50 & 100 MG.

15 or 25 mg tablets for oral use.

Usual dosage range: 12.5 to 50 mg/d.

Clinical doses range from 25 to 400 mg.