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Chapter 41

Diuretics

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Anatomy and Physiology Anatomy

Basic functional unit of the kidney: nephron Four functionally distinct regions

• Glomerulus• Proximal convoluted tubule• Loop of Henle• Distal convoluted tubule

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Anatomy and Physiology 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

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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

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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

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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

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Classification of Diuretics High-ceiling (loop) diuretics Thiazides and related diuretics Potassium-sparing diuretics

Aldosterone antagonists Nonaldosterone antagonists

Osmotic diuretics Carbonic anhydrase inhibitors

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Diuretics Drugs that increase urinary output Two major applications

Treatment of hypertension Mobilization of edematous fluid to prevent renal

failure

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

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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

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

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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

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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

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Furosemide (Lasix) Adverse effects

Hyponatremia, hypochloremia, and dehydration Hypotension

• Loss of volume• Relaxation of venous smooth muscle

Hypokalemia Ototoxicity

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Furosemide (Lasix) Adverse effects (cont’d)

Ototoxicity Hyperglycemia Hyperuricemia Use in pregnancy Impact on lipids, calcium, and magnesium

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Furosemide (Lasix) Drug interactions

Digoxin Ototoxic drugs Potassium-sparing diuretics Lithium Antihypertensive agents Nonsteroidal anti-inflammatory drugs

Preparations, dosage, and administration Oral Parenteral

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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

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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)

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Hydrochlorothiazide (HydroDIURIL) Hydrochlorothiazide (HydroDIURIL)

Most widely used Action: early segment distal convoluted tubule Peaks in 4–6 hours Therapeutic uses

• Essential hypertension• Edema• Diabetes insipidus

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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

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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

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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

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Spironolactone (Aldactone) Mechanism of action

Blocks aldosterone in the distal nephron Retention of potassium Increased excretion of sodium

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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

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Spironolactone (Aldactone) Adverse effects

Hyperkalemia Benign and malignant tumors Endocrine effects

Drug interactions Thiazide and loop diuretics Agents that raise potassium levels

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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

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Triamterene (Dyrenium) Adverse effects

Hyperkalemia Leg cramps Nausea Vomiting Dizziness Blood dyscrasias (rare)

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Amiloride (Midamor) Mechanism of action

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.

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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

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Mannitol (Osmitrol) Adverse effects

Edema Headache Nausea Vomiting Fluid and electrolyte imbalance