Among the thiazide diuretics is chlorthalidone. Peak serum concentrations are attained 2–6 hours after oral dosing. Chlorthalidone has a half-life of roughly 42 (range 29–55) hours, which can increase to 45–60 hours after repeated administration. The half-life of chlorthalidone, however, differs greatly amongst people. The kidneys eliminate chlorthalidone unaltered. Chlorthalidone's natriuretic impact peaks at 18 hours and lasts for more than 48 hours. When chlorthalidone dosages were compared, it was found that 25 mg per day was nearly as efficacious as higher doses while carrying a lower risk of hypokalemia [1]. Magnesium hydroxide did not prevent the recurrence of calcium oxalate stones, whereas chlorthalidone did. Analyze if magnesium hydroxide or chlorthalidone is more successful at preventing the recurrence of kidney stones caused by calcium oxalate. There was a double-blind randomized assignment design, and the daily dose was either 25 or 50 mg. 1,300 or 650 mg of chlorthalidone. One of the two options: magnesium hydroxide or a similar placebo. All groups experienced a significant decrease in stone incidents when compared to pre-treatment levels. Throughout the experiment, the groups receiving low- and high-dose magnesium hydroxide demonstrated a reduction in stones of 73.9% and 62.3%, respectively (p less than 0.001 and less than 0.01), while the placebo group had 56.1% fewer stones than expected (p less than 0.01). 0.01). Treatment with chlorthalidone reduced expected rates by 90.1%, and the effects of both dosages were comparable. Chlorthalidone outperformed magnesium hydroxide or placebo when comparing treatments (p less than 0.01). The significant decreases in stone events observed in cases of placebo or inactive treatment highlight the favorable treatment bias that arises from using historical controls, and also highlight the necessity of using suitable experimental design [2].

Absorption, Distribution and Excretion
Approximately 50% of the administered dose is excreted renally in its unmetabolized form, characterized by a biphasic elimination phase, followed by a slow secretion phase. Chlorthalidone has been shown to rapidly concentrate within erythrocytes, subsequently reaching equilibrium through slow diffusion back to the serum chamber, resulting in a large volume of distribution. Biochemical studies indicate that the prolonged duration of action is due to slow gastrointestinal absorption and enterohepatic circulation. The drug is excreted unchanged via the kidneys. Most thiazide compound preparations are rapidly excreted within 3 to 6 hours. /Thiazide Compounds/ Chlorthalidone Dose-dependent urinary excretion studies. Metabolism/Metabolites Hepatic Biological Half-Life 40–50 hours

Toxicity Summary
Drug Identification: Chlorthalidone is a thiazide diuretic. It can be used alone or in combination with other antihypertensive drugs to treat hypertension. Chlorthalidone can be used as adjunctive therapy for edema associated with heart failure, cirrhosis, and corticosteroid and estrogen therapy. It can also be used to treat edema caused by various renal disorders, such as nephrotic syndrome. It can also be used to treat premenstrual tension in the presence of fluid retention. Chlorthalidone has a paradoxical antidiuretic effect in patients with diabetes insipidus. Human Exposure: Major Risks and Target Organs: Chlorthalidone is generally well tolerated during treatment. Clinical toxicity is relatively rare and may result from overdose, adverse reactions, or allergic reactions. Acute Toxicity: Major risks include hypokalemia, hyponatremia, hypotension, arrhythmias, and central nervous system damage. Target Organs: Kidneys, heart, central nervous system. Chronic toxicity and adverse reactions include: metabolic disorders, hypersensitivity reactions, worsening of renal and/or hepatic impairment, gastrointestinal disturbances, hematologic disorders, and central nervous system damage. Clinical manifestations overview: Acute toxicity: Symptoms may include: hypokalemia, hyponatremia, dehydration, hypovolemia, arrhythmias (ventricular premature beats and torsades de pointes due to hypokalemia), dizziness, drowsiness, and paresthesia. Chronic toxicity and adverse reactions: Several adverse reactions have been reported: Metabolic system: hypokalemia, hyponatremia, hyperglycemia, hyperuricemia, metabolic alkalosis, and worsening of renal impairment. Cardiovascular system: arrhythmias, enhanced effects of digitalis on the myocardium, and orthostatic hypotension. Central nervous system: dizziness, vertigo, paresthesia, headache, and xanthopsia. Gastrointestinal: Anorexia, gastric irritation, nausea, vomiting, cramps, diarrhea, constipation, jaundice due to intrahepatic cholestasis, pancreatitis, sialadenitis, dry mouth, liver dysfunction, intestinal ulcers. Allergic reactions: Purpura, intravascular immune hemolysis, pneumonia, rash, urticaria, eczema, lichen planus-like reaction; photosensitivity, similar to subacute lupus erythematosus; vasculitis; Stevens-Johnson syndrome. Hematologic system: Thrombocytopenia, granulocytopenia, leukopenia, aplastic anemia, and hemolytic anemia. Respiratory system: Acute non-cardiogenic pulmonary edema. Other: Gout attack, elevated plasma cholesterol and triglyceride levels. Uses: Chlorthalidone can prevent the formation of kidney stones in patients with hypercalciuria. Chlorthalidone can improve vertigo associated with Meniere's disease. Contraindications: Anuria, hypersensitivity to sulfonamides, hepatic encephalopathy. Precautions: Chlorthalidone should be used with caution in patients with impaired liver function, as it may increase the risk of hepatic encephalopathy. Caution should be exercised when using chlorthalidone in patients with impaired renal function, as it can further reduce renal function and induce azotemia. Drug accumulation may occur in patients with impaired renal function. Caution should also be exercised in patients receiving quinidine antiarrhythmic drugs, amiodarone, or sotalol. Chlorthalidone should be avoided in patients with gout, as it may trigger gout attacks. Close monitoring of fluid and electrolyte imbalances is necessary. Chlorthalidone may enhance the toxicity of digitalis by lowering serum potassium levels. There are reports that chlorthalidone may worsen or induce systemic lupus erythematosus. Chlorthalidone can cross the placenta; there are reports of neonatal jaundice, thrombocytopenia, and electrolyte imbalances after maternal use of chlorthalidone. Chlorthalidone can be secreted into breast milk. Treatment may suppress lactation. Caution should be exercised when using chlorthalidone in the following conditions: diabetes, hypercalcemia, hyperuricemia, history of lupus erythematosus, pancreatitis, or sympathectomy. Route of administration: Oral administration is the most common route of administration. Accidental or intentional ingestion of large doses may occur. Pharmacokinetics: Absorption via exposure route: Chlorthalidone absorption in the gastrointestinal tract is unstable. The bioavailability after oral administration is approximately 65%. Approximately 75% is bound to plasma proteins, with a plasma concentration ratio of 72.5%. Chlorthalidone can cross the placenta. Biological half-life via exposure route: The plasma half-life is approximately 44 ± 10 hours, increasing with age. The terminal half-life is 35 to 54 hours. This is likely due to the strong binding affinity of chlorthalidone to erythrocytes. Metabolism: Chlorthalidone may be metabolized, but the metabolites are not yet identified. Clearance via exposure route: During prolonged use, 30% to 60% of the drug has been reported to be excreted unchanged in the urine. Chlorthalidone is excreted into breast milk, but the milk/plasma ratio is extremely low. Chlorthalidone is an oral diuretic with sustained-release action and low toxicity. Most toxic reactions are caused by electrolyte disturbances, including hypochloremic alkalosis, hyponatremia, hypokalemia, and hypomagnesemia. The mechanisms of hypercalcemia and hypophosphatemia are unclear. Thiazide drugs increase plasma cholesterol and triglyceride concentrations. Chlorthalidone may also cause allergic reactions. Pharmacodynamics: It takes effect within two hours after oral administration, and its diuretic effect can last up to 72 hours. It leads to significant electrolyte loss, resulting in dehydration. Its site of action is the distal renal tubules. The antihypertensive effect is also associated with a decrease in peripheral resistance, which is mainly seen with long-term use. Teratogenicity: Chlorthalidone can cross the placental barrier. Generally, diuretics are not associated with teratogenicity. Some studies suggest a slight association between chlorthalidone and respiratory malformations. Drug interactions: Chlorthalidone can increase the toxicity of digitalis by lowering serum potassium levels. Due to potassium depletion, chlorthalidone may enhance the neuromuscular blocking effects of competitive muscle relaxants (such as tubocurarine or gallium triiodide). It may also enhance the effects of antihypertensive drugs (such as guanethidine sulfate, methyldopa, or ganglion blockers). Orthostatic hypotension induced by thiazide diuretics may be exacerbated by concomitant use of alcohol, barbiturates, or opioids. The potassium-depleting effect of thiazide diuretics can be enhanced by corticosteroids, adrenocorticotropic hormone (ACTH), carbenone, and amphotericin B. Chlorthalidone may reduce the response to pressor amines such as norepinephrine, but the clinical significance of this effect is unclear. Concomitant use of thiazide diuretics with lithium salts is not recommended, as it increases serum lithium levels. Chlorthalidone may increase the risk of arrhythmias (torsades de pointes) by lowering serum potassium levels. The pharmacological effects of oral hypoglycemic agents may be weakened. Nonsteroidal anti-inflammatory drugs (NSAIDs) may antagonize the diuretic effect of thiazide diuretics. Thiazide diuretics may enhance the hyperglycemic, hypotensive, and hyperuricemic effects of diazoxide. Probenecid can enhance the excretion of calcium, magnesium, and citrate during thiazide therapy, but does not affect the excretion of sodium, potassium, ammonium chloride, bicarbonate, and phosphate. Thiazides can increase urine pH and may decrease the urinary excretion of amphetamines and quinidine. The efficacy of chlorthalidone may be reduced when used in combination with oral anticoagulants. The effect of chlorthalidone may be enhanced when used in combination with preoperative anesthetics and anesthetic drugs. Due to urine alkalinization, the efficacy of methylamine may be reduced when chlorthalidone is used in combination with methylamine. A study in two healthy subjects showed that chlorthalidone and acetazolamide compete for the same binding sites on blood cells. Major adverse reactions: May induce hyperglycemia and glycosuria, and may worsen pre-existing diabetes. Other side effects include anorexia, gastric irritation, nausea, vomiting, constipation, diarrhea, headache, dizziness, orthostatic hypotension, paresthesia, impotence, altered mood and mental status, and xanthopsia. Hematologic disorders include thrombocytopenia, and less commonly, granulocytopenia, leukopenia, and aplastic anemia. This product is a tablet containing a thiazide diuretic and potassium chloride enteric-coated tablets. Due to the long half-life of chlorthalidone, it may cause strong diuresis in the elderly, leading to insomnia. Animal/plant studies: Reproductive studies in rats and rabbits at doses up to 240 times the therapeutic dose have shown that chlorthalidone does not impair fertility or harm the fetus.

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Although chlorthalidone is present in low concentrations in breast milk, its slow clearance may lead to accumulation in the infant, especially in breastfed newborns or premature infants. It may also inhibit lactation. In such cases, alternative medications should be considered.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
Chlorthalidone has been successfully used to suppress lactation by administering 200 mg orally immediately after delivery, followed by 100 mg daily for 3 days, while restricting fluid intake and using a breast binder. However, a comparative study found no difference in milk leakage or breast engorgement between daily 200 mg chlorthalidone for 7.6 days and placebo. The additional effects of diuretics on fluid restriction and breast binders (both effective in suppressing lactation) have not been investigated. There are currently no data on the effects of diuretics on established, sustained lactation.
Protein Binding
Approximately 75% of the drug binds to plasma proteins, with 58% binding to albumin. This is due to the increased affinity of the drug for erythrocyte carbonic anhydrase.

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Interactions
Chlorothiazine and other thiazide diuretics (including chlorothiazide) enhance the cardiotoxicity and neurotoxicity of lithium…
Chlorothiazine…is structurally related to thiazide diuretics…and is expected to interact with guanethidine (enhancing its hypotensive effect)…
Chlorothiazine…may…interact with probenecid (antagonizing its uricosuric effect and leading to uric acid retention).
Concomitant use of thiazide diuretics with amiodarone may increase the risk of the following: arrhythmias associated with hypokalemia. /Thiazide Diuretics/
For more (complete) data on interactions of chlorothiazide (17 in total), please visit the HSDB record page.

[1]. Barrios V, et al. Which thiazide to choose as add-on therapy for hypertension? Integr Blood Press Control. 2014 Jul 30;7:35-47.
[2]. Ettinger B, et al. Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not. J Urol. 1988 Apr;139(4):679-84.

Therapeutic Uses
Antihypertensive drugs; diuretics, sulfamethoxazole… An effective oral diuretic, used to treat edema caused by congestive heart failure, kidney disease, cirrhosis, pregnancy, obesity, and premenstrual syndrome. The diuretic effect begins within 2 hours of administration, peaks at 6 hours, and lasts for 48 to 72 hours. Most thiazide diuretics are used to treat hypertension and are taken in divided doses, but once-daily administration may be better to promote the drainage of edema fluid. Chlorthalidone should be administered less frequently because its duration of action exceeds 24 hours. Chlorthalidone also has antihypertensive effects and can be used in combination with other drugs, such as rivaroxaban, ganglion blockers, hydralazine, and guanethidine. Because it contains a sulfonamide group, its pharmacological effects and many adverse reactions are similar to other oral diuretics. For more complete data on the therapeutic uses of chlorthalidone (11 in total), please visit the HSDB record page.

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Drug Warnings
Chlorothiazine is contraindicated in patients with severe kidney or liver disease. Patients taking this medication should be closely monitored for signs of kidney damage or electrolyte disturbances.
May inhibit lactation…/Thiazide diuretics; from table/
Many experts believe that diuretics are contraindicated during pregnancy, except in patients with heart disease, because they do not prevent or alter the course of preeclampsia and may reduce placental perfusion. /Chlorothiazine; from table/
Maternal use generally compatible with breastfeeding: Chlorothiazine: Signs or symptoms reported by the infant or effects on lactation: Slow excretion. /From Table 6/
For more complete data on drug warnings for chlorothiazine (14 in total), please visit the HSDB record page.

C14H11CLN2O4S

338.76

338.012

77-36-1

Chlorthalidone-d4;1794941-44-8

2732

Crystals from 50% acetic acid
WHITE TO YELLOWISH-WHITE CRYSTALLINE POWDER

1.6±0.1 g/cm3

265-267ºC (dec.)

1.694

-0.74

3

5

2

22

564

0

ClC1C([H])=C([H])C(=C([H])C=1S(N([H])[H])(=O)=O)C1(C2=C([H])C([H])=C([H])C([H])=C2C(N1[H])=O)O[H]

JIVPVXMEBJLZRO-UHFFFAOYSA-N

InChI=1S/C14H11ClN2O4S/c15-11-6-5-8(7-12(11)22(16,20)21)14(19)10-4-2-1-3-9(10)13(18)17-14/h1-7,19H,(H,17,18)(H2,16,20,21)

2-chloro-5-(1-hydroxy-3-oxo-2H-isoindol-1-yl)benzenesulfonamide

Thalitone Chlorthalidone Chlorphthalidolone Phthalamodine OxodolineChlortalidone Phthalamudine Hygroton Phthalamudine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 41 mg/mL (~121.03 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.14 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (6.14 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)