Furosemide: Mechanism of Action

• Furosemide is a loop diuretic used for fluid overload conditions, such as liver cirrhosis, congestive heart failure, and renal disease.

Furosemide Mechanism of Action

• Acts on the thick ascending limb of the loop of Henle (TALH), where 25% of filtered Na+ is reabsorbed.
• Causes net water loss by disrupting the electrochemical gradient between the lumen and medullary interstitium, leading to increased urine flow and decreased plasma volume.
• Increases excretion of solutes like Na+, K+, Cl-, Ca2+, and Mg2+.
• Competes with chloride to bind to the NKCC2 cotransporter, blocking transcellular transport of Na+, K+, and Cl-.
• Decreases reabsorption of Na+, K+, and Cl-, increasing tubular solute concentration and preventing water reabsorption, thus causing diuresis.
• Reduces osmolarity in the medullary interstitium, disrupting the countercurrent multiplier system and decreasing the kidney's ability to concentrate urine.
• NKCC2 cotransporter contributes to the positive luminal potential that drives paracellular reabsorption of Ca2+ and Mg2+.
• Blocking the NKCC2 cotransporter decreases interstitial K+ levels and positive luminal potential, causing loss of force for paracellular transport of Ca2+ and Mg2+.
• Reduces reabsorption of bicarbonate, increasing urinary excretion of HCO3 and phosphate, primarily in the proximal convoluted tubules.

Metabolic Imbalances

• NKCC2 blockage prevents the transcellular reabsorption of Na+, K+, and Cl-, decreasing the osmolarity of the medullary interstitium, which lowers the interstitial osmotic gradient, thus preventing water reabsorption and increasing water excretion via urine.
• Decreased water and electrolytes reabsorption, combined with high solute concentration in the lumen, leads to reduced plasma volume and dehydration.
• Net water loss exceeds increased natriuresis, leading to a higher concentration of sodium in the extracellular fluid.
• Furosemide also decreases urea permeability in the collecting ducts, exacerbating free H₂O loss.
• NKCC2 blockage decreases K+ reabsorption, and ECF volume contraction triggers RAAS, increasing K+ excretion in the distal tubule and collecting duct.
• NKCC2 blockage decreases Cl reabsorption, increasing Cl excretion in the urine.
• NKCC2 blockage reduces solute reabsorption and the positive potential in the tubular lumen, decreasing paracellular Ca2+ reabsorption.
• Decreased force for paracellular flux of Ca2+ in the TALH, decreasing Ca2+ reabsorption.
• Decreased positive (+) potential in the tubular lumen, decreasing the force for paracellular flux of Mg2+.
• Furosemide blocks MRP4, inhibiting uric acid secretion in the proximal tubule, while diuretic-induced volume depletion increases uric acid reabsorption.

ABG Results- Metabolic Alkalosis

• Volume depletion due to inhibited reabsorption of solutes and water concentrates ECF HCO₃, resulting in the elevation of plasma pH

ABG results- Activation of RAAS

• Reduced ECF volume results in low blood pressure, leading to activation of RAAS.
• Angiotensin II stimulates vasoconstriction and Na+/H+ exchanger in the proximal convoluted tubule, increasing H+ secretion into the lumen.
• Aldosterone stimulates H+ secretion and bicarbonate reabsorption, increasing ECF pH.
• Alkalosis increases the HCO3-/H+ ratio in the renal tubular fluid, causing increased HCO₃ secretion in the tubular fluid.

Urinalysis and Electrolyte Levels

• Net effect of the Extracellular Fluid Volume Contraction (ECFB) mechanism and Carbonic Anhydrase II (CAII) inhibition where the effect of decreased ECF volume prevails over CAll inhibition
• Leads to increased water secretion at the lumen, low specific gravity and low osmolality

Glomerular Filtration Rate

• Blocked NKCC2 in thick ascending limb stimulates the constriction of afferent arteriole, decreasing GFR.
• Loop diuretics would actually result in increased GFR by causing inhibition of tubuloglomerular feedback

Other Diuretics to Counteract Furosemide

• Thiazide diuretics trigger blockage of Na+/Cl channels in the proximal segment of the distal convoluted tubule, preventing sodium from crossing the luminal membrane to increase calcium reabsorption
• Potassium-Sparing Diuretics: Prevent overexcretion of K+ ions by interfering on the Na+/K+ exchange
• Epithelial Sodium Channel (EnaC) Blockers: Reduces Nat entry through the luminal membrane, decreasing the activity of the Na+/K+ ATPase pump, inhibiting Na+/K+ exchange and retaining K+

Clinical Management

• Electrolyte-rich drinks provide benefits for the body's sodium, potassium, and chloride
• Electrolyte-rich food includes Potassium-rich: Bananas, oranges, avocados, spinach, kale, and potatoes, Chloride-rich: Tomatoes, olives, pickles, cheese, and dairy products, Magnesium-rich: Nuts.

Renal Apnea

• Hypoventilation occurs to compensate and regulate blood pH
• There is a bidirectional relationship between sleep apnea and kidney disease