Diureticos - Hernán Monteiro

Introduction to Diuretics and Renal System

Overview of the Renal System

• Hernán Monteiro introduces himself and outlines the topic: pharmacology of diuretics.

• The renal system's structure is discussed, focusing on the proximal convoluted tubule, which is highly permeable to sodium and water, facilitating significant sodium reabsorption.

Functionality of the Nephron

• The loop of Henle is described; its descending limb is permeable to water but impermeable to solutes like sodium and urea.

• The ascending limb becomes permeable to solutes while remaining impermeable to water, crucial for creating a hyperosmolar interstitium necessary for water reabsorption in distal nephron segments.

Role of Macula Densa

• In the thick ascending limb, macula densa cells play a critical role in feedback mechanisms that regulate glomerular filtration rate (GFR).

• High sodium concentrations trigger vasodilation of the afferent arteriole, increasing GFR; low concentrations cause vasoconstriction and renin production to enhance sodium reabsorption.

Classification of Diuretics

Major Groups of Diuretics

• Five main groups are identified: loop diuretics, thiazide diuretics (including thiazides and thiazide-like), potassium-sparing diuretics (hormonal or non-hormonal), carbonic anhydrase inhibitors, and osmotic diuretics.

• Loop diuretics are emphasized as particularly important, with furosemide being highlighted as the most relevant drug in this category.

Pharmacodynamics of Loop Diuretics

Mechanism of Action

• Loop diuretics act primarily on the thick ascending limb by inhibiting the Na-K-Cl co-transporter.

• These drugs are secreted by organic acid transporters into tubular fluid where they bind to their target channel, preventing sodium reabsorption.

Effects on Electrolyte Reabsorption

• Inhibition leads to decreased reabsorption not only of sodium but also chloride and potassium; this disrupts magnesium and calcium reabsorption due to loss of medullary interstitial tonicity.

Clinical Implications

Compensatory Mechanisms

• As loop diuretics inhibit sodium entry into cells, macula densa senses lower sodium levels leading to increased renin production from juxtaglomerular cells.

Indications for Use

Pharmacological Effects of Diuretics

Overview of Pharmacological Effects

• The pharmacological effects of diuretics include increased sodium, potassium, proton, calcium, and magnesium excretion. They also enhance venous capacitance, which is beneficial for patients with dyspnea.

• Renin release is stimulated by these medications. Diuretics can be administered orally or intravenously; the latter is preferred in cases of sudden dyspnea with pulmonary edema.

Pharmacokinetics of Loop Diuretics

• Loop diuretics require secretion via organic acid transporters in the kidneys to function effectively. Some drugs are eliminated unchanged while others are metabolized through glucuronidation.

Adverse Effects

• Major adverse effects relate to electrolyte homeostasis disruption. Hypovolemia from potent diuretic action can lead to acute renal failure.

• Electrolyte imbalances such as hyponatremia, hypocalcemia, hypokalemia, and hypomagnesemia may occur. Hypocalcemia can cause tetany; low magnesium and sodium levels increase arrhythmia risk.

• Metabolic alkalosis (hypochloremic) may develop due to increased chloride excretion and proton expression.

Ototoxicity and Allergic Reactions

• Autotoxicity manifests as tinnitus, vertigo, and hearing loss primarily associated with rapid intravenous administration.

• Patients with sulfa allergies may experience hypersensitivity reactions due to the sulfonamide derivatives like furosemide.

Drug Interactions with Loop Diuretics

Pharmacokinetic Interactions

• Food intake can reduce absorption of loop diuretics. Competing substances like uric acid or beta-lactam antibiotics may decrease renal secretion efficiency.

Impact on Lithium Levels

• Lithium elimination depends on sodium reabsorption; loop diuretics can elevate lithium levels due to altered sodium handling.

Synergistic Effects with Other Drugs

• Combining loop diuretics with thiazide diuretics enhances their effect but increases ototoxicity risk when used alongside other ototoxic agents (e.g., platinum compounds).

Thiazide Diuretics: Mechanism and Effects

Types of Thiazide Diuretics

• Thiazides include chlorothiazide and hydrochlorothiazide as well as thiazide-like drugs such as chlorthalidone.

Mechanism of Action

• Thiazides act at the distal convoluted tubule by inhibiting the sodium-chloride transporter after being secreted by organic acid transporters.

Differences from Loop Diuretics

• Unlike loop diuretics that target higher concentrations in the Henle's loop, thiazides manage lower sodium amounts at their site of action.

Pharmacological Actions of Thiazides

Key Actions

Pharmacokinetics and Pharmacodynamics of Diuretics

Thiazide Diuretics

• Thiazide diuretics are well absorbed orally, with variable plasma protein binding. Indapamide and chlorthalidone undergo hepatic metabolism and renal elimination.

• Hydrochlorothiazide is eliminated unchanged, but thiazides can cause electrolyte disturbances such as hyponatremia, hypokalemia, metabolic alkalosis, hypochloremia, hypomagnesemia, and hypercalcemia.

• They may also lead to insulin secretion alterations due to potassium dependency in the mechanism, potentially causing hyperglycemia.

Potassium-Sparing Diuretics

• Potassium-sparing diuretics include non-hormonal (amiloride, triamterene) and hormonal types (spironolactone, eplerenone), which prevent sodium reabsorption in the collecting duct.

• Loop diuretics activate the renin-aldosterone system leading to increased sodium reabsorption; potassium-sparing diuretics counter this by reducing potassium excretion.

• These diuretics help mitigate hypokalemia caused by other diuretic classes while also decreasing proton and calcium excretion.

Mechanism of Action

• Non-steroidal potassium-sparing agents are secreted into the lumen where they block ENaC channels preventing sodium re-entry into cells.

• Steroidal agents like spironolactone act as competitive antagonists at mineralocorticoid receptors in the cytoplasm of collecting duct cells.

Pharmacokinetics of Potassium-Sparing Diuretics

• Hormonal potassium-sparing diuretics have higher oral bioavailability and are metabolized hepatically with renal elimination.

• Adverse effects include hyperkalemia, hyponatremia, gastrointestinal issues (nausea, vomiting), metabolic acidosis due to decreased proton elimination, gynecomastia in men, menstrual irregularities in women, and reduced libido.

Carbonic Anhydrase Inhibitors

• Carbonic anhydrase inhibitors catalyze carbonic acid formation which leads to bicarbonate anion expression resulting in urine alkalinization useful for treating metabolic alkalosis.

Osmotic Diuretics