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THIAZIDES This group consists of a large number of sulfonamide derivatives containing the benzothiadiazide ring system, plus several other sulfonamide agents that lack the thiazide ring system but nevertheless have thiazide-like effects. Mechanisms. The thiazides inhibit sodium reabsorption in the early part of the distal tubule and stimulate calcium reabsorption in the same seg- ment. They also have an effect on the proximal tubule that is usually masked by increased sodium reabsorption in the ascending limb of the loop of Henle. (In the presence of loop diuretics, this compensatory mechanism is not available and a marked increase in effect -- a "high ceiling" diuresis -- is seen.) The net result of thiazide action is the presentation of more sodium to the collecting duct, which responds by secreting more potassium and hydrogen ion while attempting to recapture some of the sodium. The urine therefore contains an increased amount of sodium and potassium, and a hypochloremic metabolic alkalosis may result. (PgDn for more text) Urine calcium is reduced due to stimulation of calcium reab- sorption in the early distal tubule. Because they inhibit sodium ab- sorption in a part of the tubule that contributes to dilution of the urine, the thiazides also reduce the maximum diluting capacity of the kidney. Indications * Hypertension: Thiazides are the diuretics of choice, and often the first drugs used, in essential hypertension . * Edematous states: Congestive heart failure, cirrhosis, nephrotic syndrome. Salt restriction is often helpful, but therapy with a thiazide may be more effective because of compliance problems. * Idiopathic hypercalciuria (unlabeled): Recurrent renal stone formation may be reduced in patients with high (or normal) urine calcium excre- tion. * Nephrogenic diabetes insipidus (unlabeled): Urine osmolality may be in- creased to nearly isotonic levels in some patients with diabetes in- sipidus that is unresponsive to ADH. (PgDn for more text) Pharmacokinetics * Absorption: The thiazides are 50-100% absorbed from the gut, begin their action within 1-2 hours, and have peak effects in 2-6 hours. Their duration of action varies as indicated in . Only chlorothiazide is available for parenteral use. * Elimination: Except for indapamide, the thiazides are excreted primarily by secretion into the tubular urine and this is necessary for them to reach their site of action. Dosage may have to be reduced in severe renal disease to prevent accumulation; diuretic response is also reduced in this setting. Indapamide is excreted primarily by the liver into the bile and its dosage does not have to be adjusted in renal dis- ease. Contraindications and Warnings * Hypersensitivity to sulfonamides. * Renal failure. Do not use any diuretic in complete anuria. Reduce dosage in advanced renal disease. * Hepatic coma or precoma: metolazone is contraindicated. (PgDn for more text) Adverse Reactions * Electrolyte imbalance, hypokalemia: this predictable result of chronic thiazide usage may be minimized by restriction of sodium intake and by oral potassium supplements. The effect is dose-related and reductions in dosage may be helpful, especially if combined with dietary salt restriction. (Note: on initial exposure to thiazides, some individuals develop a severe dilutional hyponatremia, hypokalemia, and hypochloremia. See Ashraf reference, .) * GI: Nausea, gastric irritation; possibly pancreatitis. * CNS: Lightheadedness, vertigo (much more common with indapamide), weak- ness, restlessness, insomnia, fatigue. * CV: Arrhythmias in hypokalemic individuals, worsening of congestive failure if left ventricular filling pressure falls below the optimum 10-15 mm Hg. Orthostatic hypotension is uncommon but may occur, espe- cially in hypertensive patients being treated with other hypotensive agents. (PgDn for more text) * Metabolic: Hyperuricemia, hyperglycemia, and elevation of plasma lipids are not unusual with chronic therapy. These effects appear to be dose- related and are rarely symptom-producing except in individuals with pre-existing disease, eg, gout or diabetes. The long-term significance of the effects on serum lipids is under investigation. * Hypersensitivity: Purpura, Stevens-Johnson syndrome, fever, urticaria, hemolytic anemia, pulmonary edema, interstitial nephritis. Toxicity and Overdosage * Severe toxicity is uncommon. Electrolyte imbalance with hypokalemia is the most common and important effect of overdosage. Treatment is by removal of the drug and correction of electrolyte abnormalities. Interactions * Hypotensive drugs: the thiazides potentiate the action of these agents on blood pressure. * Digitalis: thiazide-induced hypokalemia facilitates digitalis arrhyth- mias. * Loop diuretics: true synergism occurs with a "high ceiling" diuresis and potentially hazardous hypovolemia and potassium wasting. (PgDn for more text) * Lithium: thiazides reduce the clearance of lithium by about 25-30%. Dosage of lithium should always be reduced in patients taking thiazides. * Nonsteroidal anti-inflammatory drugs may interfere with the action of the thiazides. * Cholesterol-binding resins may reduce the absorption of thiazides from the gut. Drugs of Special Importance. * Hydrochlorothiazide: this prototype thiazide is relatively safe, ef- fective in almost every instance in which thiazides are used, and cheap. * Metolazone: this thiazide-like diuretic is favored for use, in combina- tion with furosemide, when "high ceiling" diuresis is called for, eg, forced diuresis. Careful monitoring of hemodynamics and electrolytes is required for safe use in this setting. * Indapamide: this thiazide-like agent differs from other drugs in the group in having a greater vasodilating effect on blood vessels in hy- pertension, and in having a different route of excretion (hepatic rath- er than renal). It has a higher incidence of adverse CNS effects than the thiazides and other thiazide-like agents. (PgDn for more text) Related Drugs: * The furosemide group of loop diuretics are also chemically related to the sulfonamides. This is important in patients who develop hyper- sensitivity reactions to either group. * Diazoxide, a sulfonamide closely related in structure to the thiazides, has a sodium-retaining action. It resembles the thiazides in having hy- perglycemic and hyperuricemic effects. It is used as a vasodilator Chapter 5 . * Combination formulations containing a thiazide and another component, usually a potassium-sparing diuretic or an antihypertensive drug, are heavily promoted as being "more convenient" for the patient and safer (in the case of thiazide plus K-sparing combinations). A partial list- ing of such products is given in . (Home key to return to top of file)

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