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 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.

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Metabolism / Metabolites
Liver

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Biological Half-Life
40-50 hours

Toxicity Summary
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, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice due to intrahepatic cholestasis, pancreatitis, sialoadenitis, dry mouth, hepatic insufficiency, intestinal ulceration. Hypersensitivity: purpura, intravascular immune hemolysis, pneumonitis, skin rashes, urticaria, eczema, lichen planus like reactions; photosensitivity, similar to subacute cutaneous lupus erythematosus; vasculitis; Stevens Johnson Syndrome. Hematological: thrombocytopenia, granulocytopenia, leucopenia, aplastic anemia, and hemolytic anemia. Respiratory tract: acute noncardiogenic pulmonary edema. Others: attacks of gout, increasing in plasma concentrations of cholesterol and triglycerides. Use: Chlorthalidone may prevent renal calculus formation in patients with hypercalciuria. Chlorthalidone may improve vertigo associated with Ménière disease. Contraindications: Anuria, hypersensitivity to sulfonamide-derived drugs, hepatic encephalopathy. Precautions: Chlorthalidone should be used with caution in: impaired hepatic function since it may increase the risk of hepatic encephalopathy. Renal impairment can occur since it can further reduce renal function, and precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. Patients treated with quinidine-like anti-arrhythmics, amiodarone, sotalol. Avoid use in patients with gout since it can precipitate attacks of the disease. Patients should be carefully observed for signs of fluids and electrolyte imbalance. Chlorthalidone may enhance the toxicity of digitalis glycosides by depleting serum potassium concentrations. The possibility of exacerbation or precipitation of systemic lupus erythematosus has been reported. Chlorthalidone crosses the placenta and there have been reports of neonatal jaundice, thrombocytopenia, and electrolytes imbalances following maternal treatment. Chlorthalidone is excreted in breast milk. Treatment can inhibit lactation. Chlorthalidone should be used with caution when the following medical problems exist: diabetes mellitus, hypercalcemia, hyperuricemia, history of lupus erythematosus, pancreatitis, sympathectomy. Routes of entry: The oral route is the commonest route of administration. Accidental or deliberate ingestion of large doses may occur. Kinetics: Absorption by route of exposure: Chlorthalidone is erratically absorbed from the gastrointestinal tract. Bioavailability after oral administration is approximately 65%. About 75% is bound to plasma protein and the blood-to-plasma ratio is 72.5%. Chlorthalidone crosses the placenta. Biological half-life by route of exposure: The plasma half-life is about 44 +/- 10 hours and increases with age. The terminal half-life is 35 to 54 hours. This may be due to the strong binding of chlorthalidone to red blood cells. Metabolism: Chlorthalidone probably undergoes metabolism but the metabolites have not been identified. Elimination by route of exposure: During long-term administration, 30 to 60% has been reported to be excreted unchanged in the urine. Chlorthalidone is excreted in breast milk. It has a very low milk:plasma ratio. Chlorthalidone is an oral diuretic with prolonged action and low toxicity. Most of the toxic effects are due to electrolyte imbalance including hypochloremic alkalosis, hyponatremia, hypokalemia, and hypomagnesemia. The mechanism of hypercalcemia and hypophosphatemia are unknown. Thiazides increase the concentration of cholesterol and triglycerides in plasma. Chlorthalidone may also cause hypersensitivity reactions. Pharmacodynamics: The diuretic effect of the drug occurs within two hours after an oral dose and continues for up to 72 hours. It produces copious loss of electrolytes, and consequently, of water. The site of action is the distal renal tubule. The hypotensive effect is also due to a reduction in peripheral resistance observed mainly in chronic use. Teratogenicity: Chlorthalidone crosses the placental barrier. In general, diuretics are not associated with teratogenicity. A slight association with respiratory malformation has been suggested. Interactions: Chlorthalidone may increase the toxicity of digitalis glycosides by depleting serum potassium concentrations. Due to the potassium depletion, chlorthalidone may enhance the neuromuscular blocking action of competitive muscle relaxants such as tubocurarine or gallamine triethiodide. It may increase the effect of antihypertensive agents such as guanethidine sulfate, methyldopa or ganglionic blocking agents. The postural hypotension due to thiazide diuretic therapy may be increased by concomitant ingestion of alcohol, barbiturates, or opioids. The potassium-depleting effect of thiazides may be enhanced by corticosteroids, corticotrophin, carbenoxolone, and amphotericin B. Chlorthalidone may reduce the response to pressor amines such as norepinephrine, but the clinical significance of this effect is uncertain. Concomitant administration of thiazide diuretics and lithium salts is not recommended since the blood concentration of lithium is increased. By depleting the serum potassium concentration, chlorthalidone may increase the risk of cardiac dysryhthmias (torsades de pointes). The pharmacological effects of oral hypoglycaemic agents may be reduced. Non-steroidal anti-inflammatory drugs may antagonize the diuretic actions of thiazides. The hyperglycemic, hypotensive, and hyperuricaemic effects of diazoxide may be potentiated by thiazides. Probenecid enhances excretion of calcium, magnesium, and citrate during thiazide therapy, but does not affect excretion of sodium, potassium, ammonium chloride, bicarbonate, and phosphate. Thiazides increase urinary pH and may decrease urinary excretion of amphetamines and quinidine. The effects of oral anticoagulants may be decreased when used concurrently with chlorthalidone. Pre-anesthetic and anesthetic drugs used in surgery may be potentiated when used concurrently with chlorthalidone. The effectiveness of methenamine may be decreased when used with chlorthalidone due to alkalinization of the urine. A study in two healthy subjects evidenced that chlorthalidone and acetazolamide competed for the same binding sites on blood cells. Main adverse effects: It may induce hyperglycemia and glycosuria and may aggravate pre-existing diabetes mellitus. Other side-effects include anorexia, gastric irritation, nausea, vomiting, constipation, diarrhea, headache, dizziness, postural hypotension, paraesthesia, impotence, mood and mental changes and yellow vision. Blood dyscrasias include thrombocytopenia, more rarely, granulocytopenia, leucopenia and aplastic anemia. administration of tablets containing thiazides with an enteric-coated core of potassium chloride. Chlorthalidone may cause intense diuresis leading to insomnia in the elderly, because of its long half-life. ANIMAL/PLANT STUDIES: Reproduction studies conducted with rats and rabbits at doses up to 240 times greater than the therapeutic dose have shown no evidence of impaired fertility or harm to the fetus due to chlorthalidone.

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Effects During Pregnancy and Lactation
◉ 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.

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Protein Binding
Approximately 75 percent of the drug is bound to plasma proteins, 58 percent of the drug being bound to albumin. This is caused by an increased affinity of the drug to erythrocyte carbonic anhydrase.

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Interactions
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.

[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 Agents; Diuretics, Sulfamyl
...ORALLY EFFECTIVE DIURETIC USEFUL IN TREATMENT OF EDEMA ASSOC WITH CONGESTIVE HEART FAILURE, RENAL DISEASE, HEPATIC CIRRHOSIS, PREGNANCY, OBESITY, & PREMENSTRUAL SYNDROME. DIURETIC EFFECTS START WITHIN 2 HR AFTER ADMIN, REACH PEAK IN 6 HR, & PERSIST FOR 48 TO 72 HR.
MOST OF THIAZIDES ARE GIVEN IN DIVIDED DAILY DOSES FOR TREATMENT OF HYPERTENSION, BUT SINGLE DAILY DOSE MAY BE PREFERABLE FOR MOBILIZATION OF EDEMA FLUID. ...CHLORTHALIDONE...SHOULD BE GIVEN LESS FREQUENTLY, SINCE.../IT HAS/ DURATION OF ACTION LONGER THAN 24 HR.
CHLORTHALIDONE ALSO EXERTS ANTIHYPERTENSIVE EFFECT & MAY BE ADMIN WITH OTHER AGENTS, SUCH AS RESERPINE, GANGLIONIC BLOCKING AGENTS, HYDRALAZINE, & GUANETHIDINE. SINCE.../IT/ CONTAINS SULFONAMIDE GROUP, ITS PHARMACOLOGICAL ACTIONS & MANY OF ITS UNTOWARD EFFECTS ARE SIMILAR TO THOSE OF OTHER ORALLY ADMIN DIURETICS.
For more Therapeutic Uses (Complete) data for CHLORTHALIDONE (11 total), please visit the HSDB record page.

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Drug Warnings
CHLORTHALIDONE IS CONTRAINDICATED IN PT WITH SEVERE RENAL OR HEPATIC DISEASE. PT ON THIS DRUG SHOULD BE WATCHED CLOSELY FOR SYMPTOMS OF RENAL DAMAGE OR OF ELECTROLYTE DISTURBANCE.
May suppress lactation ... /Thiazide diuretics; from table/
Many experts consider diuretics contraindicated in pregnancy except for patients with heart disease, since they do not prevent or alter course of toxemia and may decrease placental perfusion. /Chlorothiazide; from table/
Maternal Medication usually Compatible with Breast-Feeding: Chlorthalidone: Reported Sign or Symptom in Infant or Effect on Lactation: Excreted slowly. /from Table 6/
For more Drug Warnings (Complete) data for CHLORTHALIDONE (14 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.)