Chlorothiazide

Chlorothiazide is an antihypertensive agent belonging to Thiazide Diuretics.

Chlorothiazide is a thiazide diuretic used to treat hypertension and edema in congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.

Incompletely and variably absorbed from the GI tract. Bioavailability 9-56% (dose-dependent). Food may increase the extent of absorption. Time to peak plasma concentration: Approx 4 hours (oral); 30 min (IV). Crosses placenta and excreted in breast milk (small amounts). Chlorothiazide is not metabolized but it is eliminated rapidly by the kidney. The plasma half-life of chlorothiazide is 45-120 minutes. After oral doses, 10-15 % of the dose is excreted unchanged in the urine.

Chlorothiazide shows common side effects like Dizziness, spinning sensation, numbness or tingling, diarrhea, constipation, stomach cramps, blurred vision, muscle spasm, impotence, sexual problems, etc.

Chlorothiazide is available in the dosage form of Oral Tablets, Oral Suspension, and Intravenous Powder for Injection.

Chlorothiazide is available in India, China, the US, the UK, Switzerland, and Germany.

Chlorothiazide belonging to the Thiazide Diuretics, acts as an antihypertensive agent.

Chlorothiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like chlorothiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide-sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of chlorothiazide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in smooth muscle.

The onset of action of Chlorothiazide occurs within 2 hours (by mouth), and 15min (Intravenous) of its administration.

The Duration of Action for Chlorothiazide in the body is approximately 6-12 hours.

The Tmax was found within 4 hours (by mouth) and 30 min (Intravenous) following the administration of Chlorothiazide.

Chlorothiazide is available in the form of Oral Tablets, Oral Suspension, and Intravenous Powder for Injection.

Chlorothiazide Oral Tablet is taken by mouth. Usually once a day or twice a day.

Chlorothiazide Oral Suspension has been taken by mouth. Usually once a day or twice a day.

Chlorothiazide Powder for Injection by Intravenous once a day or twice a day.

Chlorothiazide is a thiazide diuretic used to treat hypertension and edema in congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. This medicine works by acting on the kidneys to gain the flow of urine. It is also indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension.

Chlorothiazide is an antihypertensive agent belonging to Thiazide Diuretics.

Chlorothiazide inhibits Na reabsorption in distal renal tubules resulting in increased excretion of Na+ and water, also K+ and H+ ions. Chlorothiazide is a thiazide diuretic used to treat fluid retention (edema) in people with congestive heart failure, cirrhosis of the liver, kidney disorders, or edema caused by taking steroids or estrogen.

Chlorothiazide is approved for use in the following clinical indications

• Edema

Chlorothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Chlorothiazide has also been found useful in edema due to various forms of renal dysfunction such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

• Hypertension

Chlorothiazide is indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension.

• Edema

Adult:

Oral or IV: 500 to 1000 (10 mL to 20 mL) mg once or twice a day.

Pediatric:

Infants less than 6 months:

Oral: 10 to 30 mg/kg/day in 2 divided doses

Maximum dose: 375 mg/day orally

Anecdotal reports have used up to 40 mg/kg/day (unlabeled).

IV (off-label): 2 to 8 mg/kg/day in 2 divided doses

Anecdotal reports have used up to 20 mg/kg/day

Infants greater than 6 months and Children:

Oral: 10 to 20 mg/kg/day in 1 to 2 divided doses

Maximum dose: 375 mg/day orally in children less than 2 years or 1 g/day orally in children 2 to 12 years

IV (off-label): 4 mg/kg/day in 1 to 2 divided doses

Anecdotal reports have used up to 20 mg/kg/day

• Hypertension

Adult:

Oral or IV: 500 to 1000 mg (10 mL to 20 mL) once or twice a day.

Pediatric:

Infants less than 6 months:

Oral: 10 to 30 mg/kg/day in 2 divided doses

Maximum dose: 375 mg/day orally

Anecdotal reports have used up to 40 mg/kg/day (unlabeled).

IV (off-label): 2 to 8 mg/kg/day in 2 divided doses

Anecdotal reports have used up to 20 mg/kg/day

Infants greater than 6 months and Children:

Oral: 10 to 20 mg/kg/day in 1 to 2 divided doses

Maximum dose: 375 mg/day orally in children less than 2 years or 1 g/day orally in children 2 to 12 years

IV (off-label): 4 mg/kg/day in 1 to 2 divided doses

Anecdotal reports have used up to 20 mg/kg/day

Chlorothiazide is available in various strengths as Tablets (250mg and 500mg), Oral Suspension (250mg/5ml) and Intravenous Powder for Injection (0.5 g).

Chlorothiazide is available in the form of Oral Tablets, Oral Suspensions, and Intravenous Powder for Injection.

Avoid consumption of a high-salt or high-sodium diet while taking Chlorothiazide.

Chlorothiazide is contraindicated in patients with

• Anuria
• Hypersensitivity to this product or to other sulfonamide-derived drugs

• Renal disease

Use with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

• Liver disease

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

• Allergy or bronchial asthma.

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported. Lithium generally should not be given with diuretics.

• Hypokalemia

Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmias and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may be avoided or treated by the use of potassium-sparing diuretics or potassium supplements such as foods with a high potassium content.

• Hyponatremia

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

• Hyperuricemia

Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazides.

• Hypoglycemic

In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.

• Hypomagnesemia

Thiazides have been shown to gain the urinary excretion of magnesium; this may result in hypomagnesemia.

• Hyperparathyroidism

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Consumption of alcohol is not recommended while taking this drug as it may increase the risk of orthostatic hypotension.

Because of the potential for serious adverse reactions in nursing infants from Chlorothiazide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Teratogenic Effects: Pregnancy Category C: Although reproduction studies performed with the chlorothiazide doses of 50 mg/kg/day in rabbits, 60 mg/kg/day in rats, and 500 mg/kg/day in mice revealed no external abnormalities in the fetus or impairment of growth and survival of fetus due to chlorothiazide, such studies did not include complete examinations for visceral and skeletal abnormalities. It is not known whether chlorothiazide can cause fetal harm when administered to a pregnant woman; however, thiazides cross the placental barrier and appear in cord blood. Chlorothiazide should be used during pregnancy only if clearly needed.

Avoid consumption of a high-salt or high-sodium diet while taking Chlorothiazide.

• Common Adverse effects

Hypotension, dizziness, fever, headache, restlessness, vertigo, alopecia, photosensitivity, purpura, rash, toxic epidermal necrolysis, urticaria, increase in cholesterol and triglycerides, electrolyte disturbances, (e.g. hypercalcemia, hypokalaemia), hyperglycemia, hyperuricemia, abdominal cramping, anorexia, constipation, diarrhea, gastric irritation, nausea, pancreatitis, sialadenitis, vomiting, impotence, aplastic anemia, renal failure, pneumonitis, pulmonary edema, resp distress, anaphylactic reactions.

• Rare Adverse effects

Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, hemolytic anemia, leukopenia, thrombocytopenia, jaundice, muscle spasm, paraesthesia, weakness, blurred vision, xanthopsia, glycosuria, haematuria, interstitial nephritis, agranulocytosis, necrotizing angiitis.

• Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur.

• Antidiabetic drugs (oral agents and insulin) - dosage adjustment of the antidiabetic drug may be required.

• Other antihypertensive drugs - additive effect or potentiation.

• Cholestyramine and colestipol resins - Both cholestyramine and colestipol resins have the potential of binding thiazide diuretics and reduce diuretic absorption from the gastrointestinal tract.

• Corticosteroids, ACTH - intensified electrolyte depletion, particularly hypokalemia.

• Pressor amines (e.g., norepinephrine) - possible decreased response to pressor amines but not sufficient to preclude their use.

• Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) - possible increased responsiveness to the muscle relaxant.

• Lithium - generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with Chlorothiazide.
  

• Non-steroidal Anti-inflammatory Drugs Including Selective Cyclooxygenase-2 (COX-2) Inhibitors - In some patients, the administration of a non-steroidal anti-inflammatory agent including a selective COX-2 inhibitor can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Therefore, when Chlorothiazide and non-steroidal anti-inflammatory agents or selective COX-2 inhibitors are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

The common side of Chlorothiazide includes the following:

• Common
  

Dizziness, spinning sensation, numbness or tingling, diarrhea, constipation, stomach cramps, blurred vision, muscle spasm, impotence, and sexual problems.

• Rare

Hyperparathyroidism, Gout, Hypercalcemia, Haemolytic Anaemia, Bone marrow failure, Purpura, Leukopenia, Near-sightedness, Hepatitis, Interstitial Nephritis, Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome, Skin Rash With Sloughing, Anaphylaxis, Jaundice, Choroidal Effusion.

• Pregnancy

Teratogenic Effects - Pregnancy Category C: Although reproduction studies performed with chlorothiazide doses of 50 mg/kg/day in rabbits, 60 mg/kg/day in rats and 500 mg/kg/day in mice revealed no external abnormalities of the fetus or impairment of growth and survival of the fetus due to chlorothiazide, such studies did not include complete examinations for visceral and skeletal abnormalities. It is not known whether chlorothiazide can cause fetal harm when administered to a pregnant woman; however, thiazides cross the placental barrier and appear in cord blood. Chlorothiazide should be used during pregnancy only if clearly needed.

• Nursing Mothers

Because of the potential for serious adverse reactions in nursing infants from Chlorothiazide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

• Pediatric Use

There are no well-controlled clinical trials in pediatric patients. Information on dosing in this age group is supported by evidence from empiric use in pediatric patients and published literature regarding the treatment of hypertension in such patients.

• Geriatric Use

Clinical studies of Chlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

• The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.
• In the event of overdosage, symptomatic and supportive measures should be employed. Emesis should be induced or gastric lavage performed. Correct dehydration, electrolyte imbalance, hepatic coma, and hypotension by established procedures. If required, give oxygen or artificial respiration for respiratory impairment.
• The degree to which chlorothiazide sodium is removed by hemodialysis has not been established.

Pharmacodynamic:

Like other thiazides, chlorothiazide promotes water loss from the body (diuretics). It inhibits Na⁺/Cl^- reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue. Chlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosages, all thiazides are approximately equal in their diuretic efficacy. Chlorothiazide increases the excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. After oral doses, 10-15 percent of the dose is excreted unchanged in the urine. Chlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Pharmacokinetics:

• Absorption

Incompletely and variably absorbed from the GI tract. Bioavailability 9-56% (dose-dependent). Food may increase the extent of absorption. Time to peak plasma concentration: Approx 4 hr (oral); 30 min (IV).

• Distribution

Crosses placenta and excreted in breast milk (small amounts).

• Metabolism and Excretion

Chlorothiazide is not metabolized but is eliminated rapidly by the kidney. The plasma half-life of chlorothiazide is 45-120 minutes. After oral doses, 10-15 percent of the dose is excreted unchanged in the urine.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/011870s040lbl.pdf
• https://www.rxlist.com/diuril-drug.htm#description
• https://www.mims.com/philippines/drug/info/chlorothiazide?mtype=generic
• https://go.drugbank.com/drugs/DB00880
• https://www.drugs.com/dosage/chlorothiazide.html