CHLOROTHIAZIDE, CHLOROTHIAZIDE SODIUM
Chemistry - A thiazide diuretic structurally related to the sulfonamides, chlorothiazide occurs as awhite or practically white, odorless, slightly bitter-tasting, crystalline powder. It has a melting pointof approximately 355° C. and pKas of 6.7 and 9.5. It is very slightly soluble in water and slightlysoluble in alcohol. The pH of the commercially available oral suspension is from 3.2 to 4.
Chlorothiazide sodium occurs as a white powder that is very soluble in water. The commercialinjection is provided as a lyophilized powder mixed with mannitol. Sodium hydroxide is added toadjust the pH to 9.2 - 10 after reconstitution. Approximately 2.4 mEq of sodium is contained in a500 mg vial.
Chlorothiazide sodium for injection is reportedly compatible with the following IV solutions:dextrose and/or saline products for IV infusion (with the exception to many Ionosol and Normosolproducts), Ringer's injection and Lactated Ringer's, 1/6 M sodium lactate, Dextran 6% withdextrose or sodium chloride, and fructose 10%. It is also reportedly compatible with the followingdrugs: cimetidine HCl, lidocaine HCl, nafcillin sodium, and sodium bicarbonate. Chlorothiazide sodium is reportedly incompatible with the following drugs: amikacin sulfate, chlorpromazine HCl, codeine phosphate, hydralazine HCl, insulin (regular), morphine sulfate, norepinephrine bitartrate, polymyxin B sulfate, procaine HCl, prochlorperazine edisylate andmesylate, promazine HCl, promethazine HCl, streptomycin sulfate, tetracycline HCl, trifluopromazine HCl, and vancomycin HCl.
The antihypertensive effects of thiazides are well known, and these agents are used extensively inhuman medicine for treating essential hypertension. The exact mechanism of this effect has notbeen established.
Thiazides paradoxically reduce urine output in patients with diabetes insipidus (DI). They havebeen used as adjunctive therapy in patients with neurogenic DI and are the only drug therapy fornephrogenic DI.
Uses, Indications - In veterinary medicine, furosemide has largely supplanted the use of thiazidesas a general diuretic (edema treatment). Thiazides are still used for the treatment of systemic hypertension, nephrogenic diabetes insipidus, and to help prevent the recurrence of calcium oxalateuroliths in dogs.
Chlorothiazide is approved for use in dairy cattle for the treatment of post parturient udder edema.
The onset of diuretic activity occurs in 1 to 2 hours and peaks at about 4 hours. The serum half-lifeis approximately 1-2 hours and the duration of activity is from 6-12 hours. Like all thiazides, theantihypertensive effects of chlorothiazide can take several days to transpire.
Thiazides are found in the milk of lactating humans. Because of the chance of idiosyncratic orhypersensitive reactions, it is recommended that these drugs not be used in lactating females ormothers not nurse if receiving them.
Contraindications/Precautions - Thiazides are contraindicated in patients hypersensitive to anyone of these agents or to sulfonamides, and in patients with anuria. They are also contraindicated inpregnant females who are otherwise healthy and have only mild edema. Newborn human infantshave developed thrombocytopenia when their mothers received thiazides.
Thiazides should be used with extreme caution, if at all, in patients with severe renal disease orwith preexisting electrolyte or water balance abnormalities, impaired hepatic function (may precipitate hepatic coma), hyperuricemia, lupus (SLE) or diabetes mellitus. Patients with conditions that may lead to electrolyte or water balance abnormalities (e.g., vomiting, diarrhea, etc.) should be monitored carefully.
Hypochloremic alkalosis (with hypokalemia) may develop, especially if there are other causes ofpotassium and chloride loss (e.g., vomiting, diarrhea, potassium-losing nephropathies, etc.) or thepatient has cirrhotic liver disease. Dilutional hyponatremia and hypomagnesemia may also occur.
Hyperparathyroid-like effects of hypercalcemia and hypophosphatemia have been reported inhumans, but have not led to effects such as nephrolithiasis, bone resorption or peptic ulceration.
Hyperuricemia can occur, but is usually asymptomatic.
Other possible adverse effects include GI reactions (vomiting, diarrhea, etc.), hypersensitivity/dermatologic reactions, GU reactions (polyuria), hematologic toxicity, hyperglycemia, hyperlipidemias, and orthostatic hypotension.
Overdosage - Acute overdosage may cause electrolyte and water balance problems, CNS effects(lethargy to coma and seizures), and GI effects (hypermotility, GI distress). Transient increases in
BUN have also been reported.
Treatment consists of emptying the gut after recent oral ingestion using standard protocols. Avoidgiving concomitant cathartics as they may exacerbate the fluid and electrolyte imbalances that mayensue. Monitor and treat electrolyte and water balance abnormalities supportively. Additionally, monitor respiratory, CNS and cardiovascular status and treat supportively and symptomatically ifrequired.
Thiazide induced hypokalemia may increase the likelihood of digitalis toxicity. Tubocurarineor other nondepolarizing neuromuscular blocking agents response or duration may be increased inpatients taking thiazide diuretics. Sulfonamides may potentiate thiazide activity.
Quinidine half-life may be prolonged by thiazides (thiazides can alkalinize the urine).
Increased hyperglycemia, hyperuricemia and hypotension may occur with concurrent administration with diazoxide.
Hypercalcemia may be exacerbated if thiazides are concurrently administered with Vitamin D orcalcium salts.
Thiazides may alter the requirements of insulin or other anti-diabetic agents in diabetic patients.
Laboratory Interactions - Thiazides may decrease protein-bound iodine values.
Hydrochlorothiazide may falsely decrease total urinary estrogen when using a spectrophotometric assay; apparently, chlorothiazide does not interfere with this test.
In asymptomatic patients and those in the developmental stages of acute pancreatitis (humans), thiazides can increase serum amylase values.
Thiazides can decrease the renal excretion of cortisol.
Chlorothiazide sodium occurs as a white powder that is very soluble in water. The commercialinjection is provided as a lyophilized powder mixed with mannitol. Sodium hydroxide is added toadjust the pH to 9.2 - 10 after reconstitution. Approximately 2.4 mEq of sodium is contained in a500 mg vial.
Storage, Stability, Compatibility
The oral suspension should be protected from freezing. Theinjectable preparation is stable for 24 hours after reconstitution. If the pH of the reconstitutedsolution is less than 7.4, precipitation will occur in less than 24 hours.Chlorothiazide sodium for injection is reportedly compatible with the following IV solutions:dextrose and/or saline products for IV infusion (with the exception to many Ionosol and Normosolproducts), Ringer's injection and Lactated Ringer's, 1/6 M sodium lactate, Dextran 6% withdextrose or sodium chloride, and fructose 10%. It is also reportedly compatible with the followingdrugs: cimetidine HCl, lidocaine HCl, nafcillin sodium, and sodium bicarbonate. Chlorothiazide sodium is reportedly incompatible with the following drugs: amikacin sulfate, chlorpromazine HCl, codeine phosphate, hydralazine HCl, insulin (regular), morphine sulfate, norepinephrine bitartrate, polymyxin B sulfate, procaine HCl, prochlorperazine edisylate andmesylate, promazine HCl, promethazine HCl, streptomycin sulfate, tetracycline HCl, trifluopromazine HCl, and vancomycin HCl.
Pharmacology - CHLOROTHIAZIDE, CHLOROTHIAZIDE SODIUM
Thiazide diuretics act by interfering with the transport of sodium ions across renaltubular epithelium possibly by altering the metabolism of tubular cells. The principle site of actionis at the cortical diluting segment of the nephron. Enhanced excretion of sodium, chloride, and waterresults. Thiazides also increase the excretion of potassium, magnesium, phosphate, iodide, andbromide and decrease the glomerular filtration rate (GFR). Plasma renin and resulting aldosteronelevels are increased which contributes to the hypokalemic effects of the thiazides. Bicarbonateexcretion is increased, but effects on urine pH are usually minimal. Thiazides initially have ahypercalciuric effect, but with continued therapy, calcium excretion is significantly decreased. Uricacid excretion is also decreased by the thiazides. Thiazides can cause, or exacerbate hyperglycemiain diabetic patients, or induce diabetes mellitus in prediabetic patients.The antihypertensive effects of thiazides are well known, and these agents are used extensively inhuman medicine for treating essential hypertension. The exact mechanism of this effect has notbeen established.
Thiazides paradoxically reduce urine output in patients with diabetes insipidus (DI). They havebeen used as adjunctive therapy in patients with neurogenic DI and are the only drug therapy fornephrogenic DI.
Uses, Indications - In veterinary medicine, furosemide has largely supplanted the use of thiazidesas a general diuretic (edema treatment). Thiazides are still used for the treatment of systemic hypertension, nephrogenic diabetes insipidus, and to help prevent the recurrence of calcium oxalateuroliths in dogs.
Chlorothiazide is approved for use in dairy cattle for the treatment of post parturient udder edema.
Pharmacokinetics - CHLOROTHIAZIDE, CHLOROTHIAZIDE SODIUM
The pharmacokinetics of the thiazides have apparently not been studied indomestic animals. In humans, chlorothiazide is only 10 - 21% absorbed after oral administration.The onset of diuretic activity occurs in 1 to 2 hours and peaks at about 4 hours. The serum half-lifeis approximately 1-2 hours and the duration of activity is from 6-12 hours. Like all thiazides, theantihypertensive effects of chlorothiazide can take several days to transpire.
Thiazides are found in the milk of lactating humans. Because of the chance of idiosyncratic orhypersensitive reactions, it is recommended that these drugs not be used in lactating females ormothers not nurse if receiving them.
Contraindications/Precautions - Thiazides are contraindicated in patients hypersensitive to anyone of these agents or to sulfonamides, and in patients with anuria. They are also contraindicated inpregnant females who are otherwise healthy and have only mild edema. Newborn human infantshave developed thrombocytopenia when their mothers received thiazides.
Thiazides should be used with extreme caution, if at all, in patients with severe renal disease orwith preexisting electrolyte or water balance abnormalities, impaired hepatic function (may precipitate hepatic coma), hyperuricemia, lupus (SLE) or diabetes mellitus. Patients with conditions that may lead to electrolyte or water balance abnormalities (e.g., vomiting, diarrhea, etc.) should be monitored carefully.
Adverse Effects, Warnings
Hypokalemia is one of the most common adverse effects associatedwith the thiazides, but rarely causes symptoms or progresses. However, monitoring of potassium isrecommended with chronic therapy.Hypochloremic alkalosis (with hypokalemia) may develop, especially if there are other causes ofpotassium and chloride loss (e.g., vomiting, diarrhea, potassium-losing nephropathies, etc.) or thepatient has cirrhotic liver disease. Dilutional hyponatremia and hypomagnesemia may also occur.
Hyperparathyroid-like effects of hypercalcemia and hypophosphatemia have been reported inhumans, but have not led to effects such as nephrolithiasis, bone resorption or peptic ulceration.
Hyperuricemia can occur, but is usually asymptomatic.
Other possible adverse effects include GI reactions (vomiting, diarrhea, etc.), hypersensitivity/dermatologic reactions, GU reactions (polyuria), hematologic toxicity, hyperglycemia, hyperlipidemias, and orthostatic hypotension.
Overdosage - Acute overdosage may cause electrolyte and water balance problems, CNS effects(lethargy to coma and seizures), and GI effects (hypermotility, GI distress). Transient increases in
BUN have also been reported.
Treatment consists of emptying the gut after recent oral ingestion using standard protocols. Avoidgiving concomitant cathartics as they may exacerbate the fluid and electrolyte imbalances that mayensue. Monitor and treat electrolyte and water balance abnormalities supportively. Additionally, monitor respiratory, CNS and cardiovascular status and treat supportively and symptomatically ifrequired.
Drug Interactions
Thiazides used concomitantly with corticosteroids, corticotropin or amphotericin B can lead to an increased chance of hypokalemia developing.Thiazide induced hypokalemia may increase the likelihood of digitalis toxicity. Tubocurarineor other nondepolarizing neuromuscular blocking agents response or duration may be increased inpatients taking thiazide diuretics. Sulfonamides may potentiate thiazide activity.
Quinidine half-life may be prolonged by thiazides (thiazides can alkalinize the urine).
Increased hyperglycemia, hyperuricemia and hypotension may occur with concurrent administration with diazoxide.
Hypercalcemia may be exacerbated if thiazides are concurrently administered with Vitamin D orcalcium salts.
Thiazides may alter the requirements of insulin or other anti-diabetic agents in diabetic patients.
Laboratory Interactions - Thiazides may decrease protein-bound iodine values.
Hydrochlorothiazide may falsely decrease total urinary estrogen when using a spectrophotometric assay; apparently, chlorothiazide does not interfere with this test.
In asymptomatic patients and those in the developmental stages of acute pancreatitis (humans), thiazides can increase serum amylase values.
Thiazides can decrease the renal excretion of cortisol.