Chlorthalidone

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.

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.

Signs and Symptoms of Overdose

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

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).

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

(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.