Thiazides Domina Petric MD Introduction Thiazides inhibit Na
Thiazides Domina Petric, MD
Introduction Thiazides inhibit Na. Cl transport and their action is predominantly in the distal convoluted tubule (DCT). Some members of thiazides retain significant carbonic anhydrase inhibitory activity: CHLORTHALIDONE. The prototypical thiazide is HYDROCHLOROTHIAZIDE (HCTZ). 2 July 22, 2012 Katzung, Masters, Trevor. Basic and clinical pharmacology.
Pharmacokinetics • All of the thiazides have an unsubstituted sulfonamide group. • All of them can be administered orally. • Chlorothiazide is not very lipid-soluble nad must be given in relatively large doses. • It is the only thiazide available for parenteral administration. • HCTZ is more potent and should be used in lower doses. • Chlorthalidone is slowly absorbed and has a longer duration of action. • Indapamide is excreted primarily by the biliary system. • Enough of the active form of indapamide is cleared by the kidney to exert its diuretic effect in the DCT. 3 July 22, 2012 Katzung, Masters, Trevor. Basic and clinical pharmacology.
Pharmacokinetics All thiazides are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid. Thiazides may blunt uric acid secretion and elevate serum uric acid levels. 4 July 22, 2012 Katzung, Masters, Trevor. Basic and clinical pharmacology.
Thiazides and related diuretics 5 July 22, 2012 Drug Total daily oral dose Frequency of daily administration Bendroflumethiazide 2, 5 -10 mg Single dose Chlorothiazide 0. 5 -2 g Two divided doses Chlorthalidone 25 -50 mg Single dose Hydrochlorothiazide 25 -100 mg Single dose Hydroflumethiazide 12, 5 -50 mg Two divided doses Indapamide 2, 5 -10 mg Single dose Methyclothiazide 2, 5 -10 mg Single dose Metolazone 2, 5 -10 mg Single dose Polythiazide 1 -4 mg Single dose Quinethazone 25 -100 mg Single dose Trichlormethiazide 1 -4 mg Single dose Katzung, Masters, Trevor. Basic and clinical pharmacology.
Pharmacodynamics • Thiazides inhibit Na. Cl reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na+/Cltransporter (NCC). • These agents enhance Ca 2+ reabsorption. • In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na+ and passive Ca 2+ reabsorption. • In the DCT, lowering of intracellular Na+ by thiazideinduced blockade of Na+ entry, enhances Na+/Ca 2+ exchange in the basolateral membrane. • This increases overall reabsorption of Ca 2+. 6 July 22, 2012 Katzung, Masters, Trevor. Basic and clinical pharmacology.
Pharmacodynamics Thiazides rarely cause hypercalcemia as the result of enhanced reabsorption. They can unmask hypercalcemia due to other causes: hyperparathyroidism, carcinoma and sarcoidosis. They are useful in the treatment of kidney stones caused by hypercalciuria. The action of thiazides depends in part on renal prostaglandin production. The actions of thiazides can be inhibited by NSAIDs. 7 July 22, 2012 Katzung, Masters, Trevor. Basic and clinical pharmacology.
Clinical indications Hypertension Heart failure Nephrolithiasis due to idiopathic hypercalciuria Nephrogenic diabetes insipidus 8 July 22, 2012 Katzung, Masters, Trevor. Basic and clinical pharmacology.
Toxicity Hypokalemic metabolic alkalosis and hyperuricemia Impaired carbohydrate tolerance Hyperlipidemia Hyponatremia Allergic reactions Other 9 July 22, 2012 Katzung, Masters, Trevor. Basic and clinical pharmacology.
Impaired carbohydrate tolerance Hyperglycemia may occur in patients who are overtly diabetic or who have even mildly abnormal glucose tolerance tests. The effect is due to both impaired pancreatic release of insulin and diminished tissue utilization of glucose. Hyperglycemia may be partially reversible with correction of hypokalemia. 10 July 22, 2012 Katzung, Masters, Trevor. Basic and clinical pharmacology.
Hyperlipidemia Thiazides cause a 5 -15% increase in total serum cholesterol and low-density lipoproteins (LDLs). These levels may return toward baseline after prolonged use. 11 July 22, 2012 Katzung, Masters, Trevor. Basic and clinical pharmacology.
Hyponatremia It is caused by a combination of hypovolemia -induced elevation of ADH, reduction in the diluting capacity of the kidney and increased thirst. It can be prevented by reducing the dose of the drug or limiting water intake. 12 July 22, 2012 Katzung, Masters, Trevor. Basic and clinical pharmacology.
Allergic reactions The thiazides are sulfonamides so they share crossreactivity with other members of this chemical group. Photosensitivity and generalized dermatitis occur rarely. Serious allergic reactions are very rare: hemolytic anemia, thrombocytopenia, acute necrotizing pancreatitis. 13 July 22, 2012 Katzung, Masters, Trevor. Basic and clinical pharmacology.
Other toxicities Weakness Fatigability Paresthesias Impotence (probably related to volume depletion) 14 July 22, 2012 Katzung, Masters, Trevor. Basic and clinical pharmacology.
Contraindications Excessive use of any diuretic is dangerous in patients with hepatic cirrhosis, borderline renal failure and heart failure. 15 July 22, 2012 Katzung, Masters, Trevor. Basic and clinical pharmacology.
Literature • Katzung, Masters, Trevor. Basic and clinical pharmacology. 16 July 22, 2012 Katzung, Masters, Trevor. Basic and clinical pharmacology.
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