We’d like to introduce you to Clinical Correlations’ newest feature-Clinical Pharmacy Corner. This will be a bimonthly pharmacy themed post which will tackle both basic and complicated pharmacy issues. We will review the mechanisms of actions of various classes of medications, a worthwhile refresher for those of us who may have forgotten what we learned in pharmacology 101 in medical school. We will also answer our reader’s pharmacy questions based on actual cases. As always please send your clinical questions and feedback to firstname.lastname@example.org. What follows is our first review-the thiazide diuretics.
Thiazide and “thiazide-like” diuretics exert their pharmacological effect by being secreted into the proximal convulated tubule into the lumen of the nephron and traveling through the loop of Henle to the distal end of the nephron. In the early portion of the distal convoluted tubule, thiazides inhibit the action of the Na+/Cl- symport and inhibit water and electrolyte reabsorption. (1,3) The distal convulated tubule expresses thiazide binding sites and is the primary site of action, while the proximal convulated tubule represents a secondary site of action. The resultant electrolyte excretion includes the depletion of sodium, potassium, chloride, bicarbonate and magnesium. Calcium is not eliminated but paradoxically retained by the action of thiazide diuretics. (3) Thiazide diuretics have additional actions that potentially explain their ability to lower blood pressure beyond what is observed with loop diuretics. Thiazides may mobilize sodium and water from arterial walls, resulting in decreased luminal diameter and tone. Furthermore, thiazides may possess direct vascular smooth muscle dilatory properties. This is extrapolated from our knowledge on the mechanism of action of diazoxide; a potent arterial vasodilator structurally related to thiazide diuretics.
Hydrochlorothiazide (HydroDiuril®, HCTZ) and Chlorothiazide (Diuril®) are traditional thiazide diuretics used in clinical practice to manage hypertension and lessen edema by increasing diuresis. Other agents that are classified as “thiazide-like” and have the same mechanisn of action include, Chlorthalidone (Hygroton®), Indapamide (Lozol®), and Metolazone (Zaroxolyn®).1 The mechanism in which these agents exert their clinical effect involves their ability to reach the distal convulated tubule in the nephron. Therefore, patients with severe renal disease (CrCl < 30mL/min) severe congestive heart failure, and cirrhosis of the liver do not respond as effectively to the action of thiazide diuretics. (1, 2) Adverse reactions associated with thiazide use include the expected extracellular volume and electrolyte depletion, especially sodium and potassium. Additional adverse reactions include dysglycemias, dyslipidemias, hypercalcemia, hyperuricemia, and pancreatitis. Metabolic side effects may be limited when utilized in low doses (e.g., hydrochlorothiazide 12.5-25 mg per day). Encourage patients to monitor for signs and symptoms of electrolyte disturbances and to use sun block to avoid photosensitivity reactions. Thiazides are contraindicated in patients with a documented hypersensitivity to sulfonamides.
1.Brutnon LL, Lazo JS, Parker KL. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th Edition. McGraw Hill Medical Publishing Division. 2006
2.DrugDex® Evaluations System. Greenwood Village, Colo: 1974-2006 Thomson MICROMEDEX. Accessed April 17th 2007.
3.Thiazide Diuretics. 40:28.20. AHFS Drug Information 2007. Statref! Metropolitan New York Library Council. http://online.statref.com. Accessed April 17, 2007.
For further info on thiazide diuretics, check out Sarah Huen, PGY3 and David Goldfarb’s article on adverse metabolic side effects of the thiazide diuretics from the April 2007 issue of the American Journal of Urology
Image Courtesy Gray’s Anatomy, originally published 1918