Each tablet contains chlorthalidone 25 mg.
Pharmacology: Chlorthalidone is an oral diuretic agent with a long duration of action and antihypertension agent, structurally and pharmacologically similar to the thiazides.
Pharmacodynamics: Mechanism of Action: Diuretic: Chlorthalidone enhance excretion of sodium, chloride, and water by interfering with the transport of sodium ions across the renal tubular epithelium. Primary site of action appears to be the cortical diluting segment of the nephron. The exact mechanism of diuretic action is unclear; however, it may act by altering metabolism of the tubular cells.
Thiazides decrease the glomerular filtration rate (GFR), but whether this results from a direct effect on renal vasculature or is secondary to the decrease in intravascular fluid volume or an increase in tubular pressure caused by the inhibition of sodium and water reabsorption is unclear. The fall in GFR is not important in the mechanism of action of the drugs, but contributes to their decreased efficacy in patients with impaired renal function. Thiazides also exhibit a carbonic anhydrase inhibiting effect.
In addition to increasing sodium and chloride excretion, thiazides affect excretion of other electrolytes. Potassium excretion is substantially increased because of the increased amount of sodium reaching the distal tubular site of sodium-potassium exchange. Long-term thiazide therapy can cause mild metabolic alkalosis associated with hypokalemia and hypochloremia.
Thiazides increase bicarbonate excretion. The diuretic efficacy of the thiazides is not affected by acid-base balance of the patient. Magnesium, phosphate, bromide, an iodide excretion are also increased. Excretion of ammonia may decrease slightly, and blood ammonia concentrations may be increased. Urinary calcium excretion may increase transiently when therapy is initiated; however, during long term administration, it is substantially decreased. The hypocalciuric effect is thought to result from a decrease in extracellular fluid (ECF) volume, although calcium reabsorption in the nephron may be increased. Thiazides also have been reported to cause slight or intermittent elevations in serum calcium concentration. The rate of excretion of uric acid is decreased, probably because of competitive inhibition of uric acid secretion or a decrease in ECF volume and a secondary increase in uric acid reabsorption. Lithium excretion may also be decreased.
Antihypertensive: Thiazides have hypotensive activity in hypertensive patients and they augment the action of other hypotensive agents. The precise mechanism of hypotensive action has not been determined, but postulated that part of this effect is caused by direct arteriolar dilation. Initially Thiazides cause appreciable decreases in ECF volume, plasma volume and cardiac output which may account for the decrease in blood pressure (BP). After several weeks of therapy, however, plasma and ECF volumes approach, but remain slightly below, normal. Cardiac output returns to normal or slightly above, and peripheral vascular resistance remains decreased. Slight decreases in plasma and ECF volumes and total body sodium during prolonged thiazide therapy are not sufficient to explain the long-term decrease in blood pressure, but may explain the efficacy of thiazides in combination with most other hypotensive agents which tend to increase sodium retention and plasma volume.
Plasma renin activity is considerably elevated during thiazide therapy, probably because of plasma volume changes. The aldosterone secretion rate is slightly but substantially increased and contribute to the hypokalemia caused by thiazides.
Diabetes insipidus: Thiazides decrease urine volume in patients with diabetes insipidus. The urine becomes less hypotonic, but not hypertonic, and thirst and water consumption are decreased. This effect is though to result mainly from the decrease in plasma volume and from sodium depletion, although other factors may play a role.
Thiazides can induce hyperglycemia, exacerbate preexisting diabetes mellitus, or precipitate diabetes in prediabetic patients. The mechanism of this action is not known, but there is evidence that the drugs act at both pancreatic and peripheral sites and that potassium depletion may decrease glucose tolerance.
Pharmacokinetics: Absorption: Chlorthalidone is absorbed relatively rapidly after oral administration, percent absorption is 64% (bioavailability may be dose dependent). The onset of diuretic action occurs within 2 to 3 hours, the peak effect occurs 2-6 hours and the duration of action is 24-72 hours.
Distribution: Thiazides are distributed in the extracellular space and cross the placenta. Thiazides also are distributed into milk. Chlorthalidone has high protein binding (75% (58% to albumin)); increased affinity to carbonic anhydrase in red blood cells.
Metabolism: No established data.
Elimination: Chlorthalidone is excreted unchanged; almost totally via kidney, with minute quantities the bile. Half-life is 35 to 50 hours. The drug is excreted by glomerular filtration and active secretion in the proximal tubule.
Edema: Chlorthalidone is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.
Chlorthalidone 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: Used alone or in combination with other classes of antihypertensive agents for all stages of hypertension.
Diabetes Insipidus: Thiazides have been used widely in the treatment of diabetes insipidus.
The drugs are effective in both the neurohypophyseal and nephrogenic forms of the disease, decreasing urine volume by up to 50%.
Particularly useful in nephrogenic diabetes insipidus, since this form of the disease is unresponsive to vasopressin or lypressin and chlorpropamide.
Also useful in patients who are allergic or refractory to vasopressin or lypressin and have been used in combination with one of these hormones and a low-salt diet in patients who excrete an exceptionally large volume of urine.
Recommended Dose: Dosage of chlorthalidone should be individualized according to the patient's requirements and response.
If added to potent hypotensive agent regimen, initially reduce hypotensive dosage to avoid the possibility of severe hypotension.
Edema: Usual initial adult dosage: 50-100 mg daily in a single dose after breakfast.
Alternatively, initiate 100 mg every other day or 3 times a week; some patients require dosages of 150-200 mg daily or every other day.
Dosages more than 200 mg daily do not produce a greater response.
Maintenance dosage: Reduction of dosage to a lower level may be possible after several days or when nonedematous weight is attained.
Hypertension in Adults: Usual initial dosage: 12.5 mg once daily and a target dosage of 12.5-25 mg once daily are recommended. Usual maximum dosage is 25 mg once daily.
Target dosages of antihypertensive agents generally can be achieved within 2-4 weeks, but it may take up to several months. Therapy should be titrated until goal blood pressure is achieved.
If an adequate blood pressure response is not achieved with chlorthalidone monotherapy, another antihypertensive agent with demonstrated benefit may be added. If goal blood pressure is still not achieved with optimal dosages of 2 antihypertensive agents, a third drug may be added.
In patients who experience intolerance adverse effects with chlorthalidone, dosage reduction should be considered; if adverse effects worsen or fail to resolve, it may be necessary to discontinue the diuretic and switch to another class of antihypertensive agent.
Maintenance dosage: may often be lower than initial dosages.
Hypertension in Elderly: Initial dosage: 12.5-25 mg once daily or every other day; there is little advantage to using dose >25 mg daily. Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in the elderly, initial dosage in the lower end of the usual range is recommended.
Hypertension in Pediatric Patients: Safety and efficacy have not been established.
Diabetes Insipidus: Initial dosage: 100 mg twice daily.
Maintenance dosage: 50 mg daily.
Dosage adjustment in renal impairment: CrCl ≥10 mL/minute: No dosage adjustment necessary. Use with caution because of risk of precipitating azotemia.
CrCl <10 mL/minute: Avoid use. Ineffective with low GRF.
Dosage adjustment in hepatic impairment: No dosage adjustment provided. Use with caution because of risk of precipitating hepatic coma.
Mode of Administration: Chlorthalidone is administered orally.
Overdose: In addition to diuresis and resultant dehydration, overdose of thiazides may produce lethargy, nausea, weakness, electrolyte imbalance; lethargy may progress to coma within a few hours with minimal depression of respiratory and cardiovascular function and without evidence of dehydration or serum electrolyte changes. GI irritation and hypermotility may occur, and temporary elevation of the BUN has been reported. Serum electrolyte changes (e.g., hypokalemia, hypochloremia, hyponatremia) may occur, especially in patients with impaired renal function.
Treatment: Gastric contents may be evacuated. If the patient is conscious, induction of vomiting with ipecac syrup is effective in remove the drug from the stomach. Treatment is generally supportive. Serum electrolytes and renal function should be monitored and replacement of fluid and electrolytes may be indicated. GI irritation is usually of short duration but may be treated symptomatically.
Known hypersensitivity to chlorthalidone, other sulfonamide-derivative drugs, or any component of the formulation, renal decompensation, hepatic coma or precoma, anuria.
Although allergy to other sulfonamide derivatives is a contraindication, evidence to support cross-sensitivity is limited, and a history of sensitivity to sulfonamide anti-infectives ("sulfa sensitivity") should not be considered an absolute contraindication to non-anti-infective sulfonamide such as Thiazides.
The routine use of thiazide is contraindicated in pregnant women with mild edema who are otherwise healthy.
Gout: Thiazides can increase serum uric acid concentrations. Although the drugs rarely induce acute gout, they generally should be avoid or used with caution in patients with a history of gout or elevated uric acid concentrations.
Thiazides should be used with caution in severe renal disease because the drugs decrease the Glomerular filtration rate (GFR), may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. If progressive renal impairment becomes evident, careful reappraisal of therapy with consideration given to interrupting or discontinuing therapy.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, particularly when potassium deficiency exists, because they may precipitate hepatic coma as a result of alterations in electrolyte balance. Discontinue immediately if signs of impending hepatic coma appear.
Allergic reactions are most likely to occur in patients with a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Electrolyte Imbalances: Electrolyte disturbances may occur during thiazide therapy. Observe for signs of electrolyte imbalance (e.g., dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, oliguria, muscle pains, cramps, muscular fatigue, hypotension, tachycardia, nausea, vomiting).
Perform periodic determination of serum electrolyte concentrations (particularly potassium, sodium, chloride, and bicarbonate); institute measures to maintain normal serum concentrations if necessary.
Serum and urinary electrolyte measurements are especially important in patients with diabetes mellitus, vomiting, diarrhea, on parenteral fluid therapy, or expecting to undergo excessive diuresis.
Measure electrolytes weekly or more frequent early in the course of treatment; it may be possible to extend the interval between measurements to ≥3 months once electrolyte response has stabilized.
Hypokalemia: Hypokalemia may develop (with consequent weakness, cramps, cardiac dysrhythmias) during concomitant use corticosteroids, adrenocorticotropic hormone, and especially with brisk diuresis, severe liver disease or cirrhosis, vomiting or diarrhea, or after prolonged therapy.
Hypokalemia may cause cardiac arrhythmias and sensitize or exaggerate the heart's response to toxic effects of digitalis (e.g., increased ventricular irritability).
Avoid or use potassium-sparing diuretics, potassium supplements or foods with high potassium content to treat hypokalemia.
Hypochloremia: Hypochloremic alkalosis may occur with hypokalemia, especially in patients with other losses of potassium and chloride such as those with vomiting, diarrhea, GI drainage, excessive sweating or paracentesis or potassium-losing renal disease. Patients with hepatic cirrhosis who are receiving thiazide are very susceptible to hypokalemic hypochloremic alkalosis.
A chloride deficit is generally mild and usually does not require specific treatment, except under extraordinary circumstances (as in liver or renal disease). Treatment of metabolic or hypochloremic alkalosis may require chloride replacement.
Hyponatremia: Dilutional hyponatremia may occur or be aggravated during thiazide therapy and can occasionally be life-threatening.
Dilutional hyponatremia most commonly occurs in hot weather in patients with chronic congestive heart failure or hepatic disease and is usually present before diuretic therapy and is manifested by signs of edema associated with hyponatremia.
Thiazide-induced hyponatremia has been associated with death and neurologic damage in elderly patients. CNS manifestations include seizures, coma, and extensor-plantar response.
Geriatric patients, especially females who are underweight, have poor oral intake of fluid and electrolytes, and/or excessive intake of low sodium nutritional supplements may be at increased risk of dilutional hyponatremia induced by the drugs.
This is usually treated by restriction of fluid intake to about 500 mL per day and withdrawal of the diuretic. Sodium chloride should not be administered except the hyponatremia is life threatening.
Hyperuricemia: Hyperuricemia is usually asymptomatic and rarely leads to clinical gout except in patients with a history of gout, familial predisposition to gout or chronic renal failure. If therapy is required, may be treated with a uricosuric agent.
Hyperglycemia and glycosuria: Thiazides and related diuretics can produce hyperglycemia and glycosuria in diabetic patients. Insulin or oral antidiabetic agent requirements of diabetics may be altered by the thiazide. Precipitation of diabetes mellitus may occur in prediabetic patients receiving thiazides. However, the risk of developing diabetes mellitus among hypertensive patients receiving thiazides was shown to be no greater than among those receiving no drug therapy.
Abnormal glucose tolerance usually does not develop in patients receiving thiazides who previously exhibited normal glucose tolerance. Hyperglycemia and impairment of glucose tolerance are almost always reversible by discontinuance of the drugs, and correction of hypokalemia may improve glucose tolerance.
Postsympathectomy: Antihypertensive effects may be enhanced in the postsympathectomy patients.
Hypomagnesemia: Thiazide diuretics increase urinary excretion of magnesium, resulting in hypomagnesemia.
Hypercalcemia: Hypercalcemia may occur, infrequently, especially in patients receiving vitamin D or having mild hyperparathyroidism.
Hyperlipidemia: Use with caution in patients with moderate or high cholesterol concentrations and in patients with elevated triglyceride levels. Thiazides may increase concentrations of total serum cholesterol, total triglyceride, and low density lipoproteins in some patients although these appear to return to pretreatment levels with long-term therapy.
Pathologic changes in the Parathyroid gland: With hypercalcemia and hypophosphatemia, have occurred occasionally during prolonged thiazide therapy.
Use in Children: Safety and efficacy have not been established with chlorthalidone.
Use in the Elderly: Elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving thiazide diuretics.
Use in Pregnancy: Pregnancy Category B.
Thiazide diuretics cross the placenta and are found in cord blood. Maternal use may cause fetal or neonatal jaundice, thrombocytopenia or other adverse events observed in adults.
The routine use of thiazide is contraindicated in pregnant women with mild edema who are otherwise healthy.
Use in treating edema during normal pregnancies is not appropriate; use may be considered when edema is due to pathologic causes (as in non-pregnant women).
May use only when the potential benefits outweigh the possible risk to the fetus or neonate.
Thiazide diuretics may be used as second-line antihypertensive agents and may be particular useful in sodium sensitive women. If initiation of antihypertensive therapy is necessary during pregnancy (chronic hypertension with persistent severely elevated blood pressure), other antihypertensives (i.e., methyldopa, nifedipine, labetalol) are recommended.
In women who are already receiving antihypertensive therapy prior to pregnancy, treatment decisions, whether to continue or discontinue, should be individualized.
Thiazide diuretics are not recommended for prevention or management of gestational hypertension or preeclampsia.
Use in Lactation: Thiazides are excreted into breast milk. Due to the potential for serious adverse reactions in the breast-feeding infant, recommend a decision be made whether to discontinue nursing or the drug, taking into account the importance of treatment to the mother. Diuretics have the potential to decrease milk volume and suppress lactation.
The following adverse reactions have been observed: Electrolytes and metabolic Effects:
Hypokalemia, hyperuricemia, rise in blood lipid, hyponatremia, hypomagnesemia, hyperglycemia, gout, hypercalcemia, glycosuria, worsening of diabetic metabolic state, hypochloremic alkalosis.
Orthostatic hypotension, cardiac arrhythmias.
Gastrointestinal System Effects:
Anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis.
Central Nervous System Effects:
Dizziness, vertigo, paresthesias, headache, xanthopsia,
Leukopenia, hemolytic anemia, agranulocytosis, thrombocytopenia, aplastic anemia, eosinophilia.
Purpura, photosensitivity dermatitis, rash, urticaria, necrotizing angiitis (vasculitis, cutaneous vasculitis), exfoliative dermatitis/toxic epidermal necrolysis.
Other Adverse Effects:
Muscle cramp/spasm, allergic interstitial nephritis, weakness, restlessness, idiosyncratic pulmonary oedema (respiratory disorder).
Chlorthalidone may potentiate the action of other antihypertensive drugs.
The hypokalemic effect of diuretics may be potentiated by corticosteroids, corticotropin, amphotericinB.
Thiazide-induced electrolyte disturbances (principally hypokalaemia, but also hypomagnesaemia and hypercalcemia) may precipitate digitalis-induced cardiac toxicity (arrhythmias).
Chlorthalidone and related drug may increase the responsiveness to tubercurarine.
Chlorthalidone and related drug may decrease arterial responsiveness to vasopressors (e.g. norepinephrine).
Lithium renal clearance is reduced by chlorthalidone, increasing the risk of lithium toxicity.
Hyperglycemic effect of the thiazides may exacerbate diabetes mellitus, resulting in increase requirements of insulin or sulfonylurea antidiabetic agent, temporary loss of diabetic control, or secondary failure to antidiabetic agent.
The biological effects of vitamin D may be enhanced by chlorthalidone. Hypercalcemia could manifest.
Concurrent use of calcium salts may result in hypercalcemia because of renal tubular reabsorption or bone release of calcium may be amplified by exogenouse calcium.
Concurrent use of nonsteroid anti-inflammatory drugs (e.g. indomethacin) may reduce the diuretic, natriuretic, and antihypertensive effect of chlorthalidone.
Thiazide diuretics may raise blood uric acid level, dosage adjustment of anti-gout agents may be necessary.
Concurrent use of thiazide diuretics may increase the incidence of hypersensitive reaction to allopurinol, may enhance the hyperglycemic effects of diazoxide, and may reduce the anticoagulant effects of anticoagulant drugs.
Cholestyramine or colestipol resin may bind thiazides and reduce their GI absorption.
Administer thiazides at least 2 hours before the resin when used concomitantly.
Anticholinergic (e.g. atropine, beperiden) may substantially increase thiazide diuretic absorption.
C03BA04 - chlortalidone ; Belongs to the class of low-ceiling sulfonamide diuretics.
Tab 25 mg (white round with letter "B" on one side and scored onto "25" on the other side) x 10 x 10's, 50 x 10's.