Chapter 41 Diuretics 1

Anatomy and Physiology Basic functional unit of the kidney: nephron Four functionally distinct regions Glomerulus Proximal convoluted tubule Loop of Henle Distal convoluted tubule 2

Anatomy and Physiology Three basic functions of diuretics Cleansing of extracellular fluid (ECF) and maintenance of ECF volume and composition Maintenance of acid-base balance Excretion of metabolic wastes and foreign substances 3

Anatomy and Physiology Physiology (cont’d) Three basic renal processes Filtration: occurs at the glomerulus Reabsorption 99% of water, electrolytes, and nutrients undergo reabsorption Active tubular secretion Proximal convoluted tubule 4

Anatomy and Physiology Physiology (cont’d) Processes of reabsorption that occur at specific sites along the nephron Proximal convoluted tubule Loop of Henle Distal convoluted tubule (early segment) Late distal convoluted tubule and collecting duct (distal nephron) Sodium-potassium exchange Regulation of urine concentration 5

Introduction to Diuretics How diuretics work Most cause the blockade of sodium and chloride reabsorption Adverse impact on extracellular fluid May cause hypovolemia Acid-base imbalance Altered electrolyte levels 6

Classification of Diuretics High-ceiling (loop) diuretics Thiazides and related diuretics Potassium-sparing diuretics Aldosterone antagonists Nonaldosterone antagonists Osmotic diuretics Carbonic anhydrase inhibitors 7

Diuretics Drugs that increase urinary output Two major applications Treatment of hypertension Mobilization of edematous fluid to prevent renal failure 8

Fig. 41–1. Schematic representation of a nephron and collecting duct. 9

Introduction to Diuretics How diuretics work—mechanism of action Blockade of sodium and chloride reabsorption Site of action Proximal tubule produces greatest diuresis Adverse effects Hypovolemia Acid-base imbalance Electrolyte imbalances 10

Fig. 41–2. Schematic diagram of a nephron showing sites of sodium absorption and diuretic action. 11

Introduction to Diuretics Classification of diuretics Four major categories High-ceiling (loop): furosemide Thiazide: hydrochlorothiazide Osmotic: mannitol Potassium-sparing: two subdivisions Aldosterone antagonists (spironolactone) Nonaldosterone antagonists (triamterene) Fifth group Carbonic anhydrase inhibitors 12

High-Ceiling (Loop) Diuretics Furosemide (Lasix): most frequently prescribed loop diuretic Mechanism of action Acts on ascending loop of Henle to block reabsorption Pharmacokinetics Rapid onset (PO 60 min; IV 5 min) Therapeutic uses Pulmonary edema Edematous states Hypertension 13

Furosemide (Lasix) Adverse effects Hyponatremia, hypochloremia, and dehydration Hypotension Loss of volume Relaxation of venous smooth muscle Hypokalemia Ototoxicity 14

Furosemide (Lasix) Adverse effects (cont’d) Ototoxicity Hyperglycemia Hyperuricemia Use in pregnancy Impact on lipids, calcium, and magnesium 15

Furosemide (Lasix) Drug interactions Digoxin Ototoxic drugs Potassium-sparing diuretics Lithium Antihypertensive agents Nonsteroidal anti-inflammatory drugs Preparations, dosage, and administration Oral Parenteral 16

Other High-Ceiling (Loop) Diuretics Ethacrynic acid (Edecrin) Bumetanide (Bumex) Torsemide (Demadex) All can cause: Ototoxicity, hypovolemia, hypotension, hypokalemia, hyperuricemia, hyperglycemia, and disruption of lipid metabolism 17

Thiazides and Related Diuretics Also known as benzothiadiazides Effects similar to those of loop diuretics Increase renal excretion of sodium, chloride, potassium, and water Elevate levels of uric acid and glucose Maximum diuresis is considerably lower than that produced by loop diuretics Not effective when urine flow is scant (unlike loop diuretics) 18

Hydrochlorothiazide (HydroDIURIL) Most widely used Action: early segment distal convoluted tubule Peaks in 4–6 hours Therapeutic uses Essential hypertension Edema Diabetes insipidus 19

Hydrochlorothiazide (HydroDIURIL) Adverse effects Hyponatremia, hypochloremia, and dehydration Hypokalemia Use in pregnancy and lactation Enters breast milk Hyperglycemia Hyperuricemia Impact on lipids, calcium, and magnesium 20

Hydrochlorothiazide (HydroDIURIL) Drug interactions Digoxin Augments effects of hypertensive medications Can reduce renal excretion of lithium (leading to accumulation) NSAIDs may blunt diuretic effect Can be combined with ototoxic agents without increased risk of hearing loss 21

Potassium-Sparing Diuretics Useful responses Modest increase in urine production Substantial decrease in potassium excretion Rarely used alone for therapy Aldosterone antagonist Spironolactone Nonaldosterone antagonists Triamterene Amiloride 22

Spironolactone (Aldactone) Mechanism of action Blocks aldosterone in the distal nephron Retention of potassium Increased excretion of sodium 23

Spironolactone (Aldactone) Therapeutic uses Hypertension Edematous states Heart failure (decreases mortality in severe failure) Primary hyperaldosteronism Premenstrual syndrome Polycystic ovary syndrome Acne in young women 24

Spironolactone (Aldactone) Adverse effects Hyperkalemia Benign and malignant tumors Endocrine effects Drug interactions Thiazide and loop diuretics Agents that raise potassium levels 25

Triamterene (Dyrenium) Mechanism of action Disrupts sodium-potassium exchange in the distal nephron Direct inhibitor of the exchange mechanism Decreases sodium reuptake Inhibits ion transport Therapeutic uses Hypertension Edema 26

Triamterene (Dyrenium) Adverse effects Hyperkalemia Leg cramps Nausea Vomiting Dizziness Blood dyscrasias (rare) 27

Amiloride (Midamor) Mechanism of action Therapeutic uses Blocks sodium-potassium exchange in the distal nephron Therapeutic uses To counteract potassium loss caused by more powerful diuretics Adverse effects Hyperkalemia Drug interaction ACE inhibitors; other drugs with hyperkalemia ACE = angiotensin-converting enzyme. 28

Osmotic Diuretic Mannitol (Osmitrol) Promotes diuresis by creating osmotic force within lumen of the nephron Pharmacokinetics Drug must be given parenterally Therapeutic uses Prophylaxis of renal failure Reduction of intracranial pressure Reduction of intraocular pressure 29

Mannitol (Osmitrol) Adverse effects Edema Headache Nausea Vomiting Fluid and electrolyte imbalance 30