Diuzid

Hydrochlorothiazide is a diuretic and antihypertensive. It is the 3,4-dihydro derivative of chlorothiazide. Its chemical name is 6-chloro-3,4-dihydro-2H-1,2,4 benzothiadiazine-7-sulfonamide 1,1 dioxide. Its empirical formula is C₇H₈ClN₃O₄S₂.

Pharmacologic Category: Diuretic.
Pharmacology: Pharmacokinetics: Thiazides are moderately potent diuretics and exert their diuretic effect by reducing the reabsorption of electrolytes from the renal tubules, thereby increasing the excretion of sodium and chloride ions, and consequently of water. They act mainly at the beginning of the distal tubules. The excretion of other electrolytes, notably potassium and magnesium, is also increased. The excretion of calcium is reduced. They also reduce carbonic-anhydrase activity so that bicarbonate excretion is increased, but this effect is generally small compared with the effect on chloride excretion and does not appreciably alter the pH of the urine. They may also reduce the glomerular filtration rate. Their hypotensive effect is probably partly due to a reduction in peripheral resistance; they also enhance the effects of other antihypertensives. Hydrochlorothiazide is fairly rapidly absorbed from the gastrointestinal tract. It is reported to have a bioavailability of about 65% to 70%. It has been estimated to have a plasma half-life of between about 5 and 15 hours and appears to be preferentially bound to red blood cells. It is excreted mainly unchanged in the urine. Hydrochlorothiazide crosses the placental barrier and is distributed into breast milk.

Hydrochlorothiazide is used in the treatment of edema associated with heart failure and with renal and hepatic disorders. It is also used in the treatment of hypertension, either alone or together with other antihypertensives such as ACE inhibitors and beta blockers.
Hydrochlorothiazide is also indicated in the treatment of edema accompanying premenstrual syndrome, prevention of water retention associated with corticosteroids and estrogens, treatment of diabetes insipidus, and prevention of renal calculus formation in patients with hypercalciuria.

Doses are usually given in the morning so that sleep is not interrupted by diuresis. Diuresis is initiated in about 2 hours following the oral administration of hydrochlorothiazide, reaches a maximum in about 4 hours, and lasts for 6 to 12 hours. Hydrochlorothiazide is given orally. In the treatment of edema, the usual dose is 25 mg to 100 mg daily, reduced to a dose of 25 mg to 50 mg daily or intermittently; in severe cases, initial dose up to 200 mg daily have been suggested. In the treatment of nephrogenic diabetes insipidus, an initial dose of up to 100mg daily may be employed. In the treatment of hypertension, the usual dose of hydrochlorothiazide is 25 mg to 50 mg daily, either alone or in conjunction with other anti-hypertensives. In some patients an initial dose of 12.5mg may be sufficient. Doses up to 100 mg have been suggested but use rarely.

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis.
In massive overdosage, treatment should be symptomatic and directed at fluid and electrolyte replacement. Use of activated charcoal should be considered if the patient presents within 1 hour of ingestion.

Hydrochlorothiazide is not effective in patients with a creatinine clearance of less than 30 mL per minute. They should not be used in patients with severe renal impairment or anuria. It is also contraindicated to patients with Addison's disease. Thiazide can reduce urinary excretion of calcium, sometimes resulting in mild hypercalcemia and is therefore contraindicated to patients with pre-existing hypercalcemia.

Hydrochlorothiazide should be used with caution in patients with renal impairment since it can further reduce renal function. It should also be used with caution in patients with existing fluid and electrolyte disturbances or who are at risk from changes in fluid and electrolyte balance such as the elderly. Hyponatremia may occur in patients with severe heart failure who are very oedematous, particularly with large doses of thiazide in conjunction with restricted salt in the diet. Patients should be carefully observed for signs of fluid and electrolyte imbalance, especially in the presence of vomiting or during parenteral fluid therapy. Thiazide may precipitate attacks of gout in susceptible patients. It may also cause hyperglycemia and aggravate or unmask diabetes mellitus. Blood glucose concentrations should be monitored in patients taking antidiabetics since requirements may change. An increased risk of non-melanoma skin cancer (NMSC), basal cell carcinoma and squamous cell carcinoma, with increasing cumulative dose of hydrochlorothiazide exposure has been observed in 2 epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism of NMSC. Patients taking Hydrochlorothiazide should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous NMSC.

Hydrochlorothiazide must not be given to pregnant women because it crosses the placenta and is distributed in breast milk. Neonatal jaundice, thrombocytopenia and electrolyte imbalance have been reported following maternal treatment. Reductions in maternal blood volume could also adversely affect placental perfusion. Treatment with large doses of thiazide diuretics can inhibit lactation.

Hydrochlorothiazide and other thiazide diuretics may cause a number of metabolic disturbances especially at high doses. They may provoke hyperglycemia and glycosuria in diabetic and other susceptible patients. They may cause hyperuricaemia and precipitate attacks of gout in some patients. Administration of hydrochlorothiazide may be associated with electrolyte imbalances including hypochloraemic alkalosis, hyponatremia and hypokalemia. Hypokalemia intensifies the effect of digitalis on cardiac muscle and administration of digitalis or its glycosides may be temporarily suspended. Patients with cirrhosis of the liver are particularly at risk from hypokalemia, Hyponatremia may occur in patients with severe heart failure who are very edematous, particularly with large doses in conjunction with restricted salt in diet. The urinary excretion of calcium is reduced. Hypomagnesemia has also occurred. Adverse changes in plasma lipids have also been noted but their clinical significance is unclear.
Signs of electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain and cramps, seizures, oliguria, hypotension, and gastrointestinal disturbances.
Other side effects include anorexia, gastric irritation, nausea, vomiting, constipation, diarrhea, sialadenitis, headache, dizziness, photosensitivity reactions, orthostatic hypotension, paraesthesia, impotence, and yellow vision. Hypersensitivity reactions include skin rashes, fever, pulmonary edema, pneumonitis, anaphylaxis, and toxic epidermal necrolysis. Cholestatic jaundice, pancreatitis, and blood dyscrasias including thrombocytopenia, and more rarely, granulocytopenia, leucopenia, and aplastic and haemolytic anemia have been reported.

Many of the interactions of hydrochlorothiazide are due to their effects on fluid and electrolyte imbalance. Diuretic-induced hypokalemia may enhance the toxicity of digitalis glycosides, and may also increase the risk of arrhythmias with drugs that prolong the QT interval such as astemizole, terfenadine, halofantrine, pimozide and sotalol. Thiazide may enhance the neuromuscular blocking action of competitive muscle relaxants probably by their hypokalaemic effect. The potassium-depleting effect of diuretics may be enhanced by corticosteroids, corticotropin, β2 agonists such as salbutamol, carbenoxolone, amphotericin B, or reboxetine. Diuretics may enhance the effect of other antihypertensives particularly the first-dose hypotension that occurs with α blockers or ACE inhibitors. Orthostatic hypotension associated with diuretic therapy may be enhanced by concomitant ingestion of alcohol, barbiturates or opioids. The antihypertensive effects of diuretics may be antagonized by drugs that cause fluid retention, such as corticosteroids, NSAIDS, or carbenoxolone. Thiazides have been reported to diminish the response to pressor amines, such as noradrenaline (norepinephrine), but the clinical significance of this effect is uncertain. Thiazide diuretics should not usually be used with lithium salts since the association may lead to toxic blood concentration of lithium. Other drugs which increased toxicity had been reported when given with thiazides include allopurinol and tetracyclines. Thiazide may alter the requirement for hypoglycemic in diabetic patients.

Diuretics

C03AA03 - hydrochlorothiazide ; Belongs to the class of low-ceiling thiazide diuretics.

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