Diuretics Lecture Gurusamy Fall 2024 PDF

DIURETICS Dr. Narasimman Gurusamy Assistant Professor College of Pharmacy 954-262-1322 [email protected] LEARNING OBJECTIVES Mechanism of action, Site of action, Therapeutic uses and side effects of diuretics Diuretics used in renal insufficiency Factors that induce...

DIURETICS Dr. Narasimman Gurusamy Assistant Professor College of Pharmacy 954-262-1322 [email protected] LEARNING OBJECTIVES Mechanism of action, Site of action, Therapeutic uses and side effects of diuretics Diuretics used in renal insufficiency Factors that induce resistance to diuretic effects  DIURETIC DRUGS/AGENTS Osmotic diuretics Carbonic anhydrase inhibitors (proximal tubules) Loop diuretics (inhibitors of sodium- potassium-chloride symport at the thick ascending limb of Henle). Thiazide and thiazide-like diuretics (inhibitors of the sodium-chloride symport in the cortical portion of the thick ascending limb of Henle and the early distal convoluted tubule) Potassium sparing diuretics: Aldosterone antagonists Inhibitors of renal epithelial sodium channels at the late distal convoluted tubules and collecting ducts  Mannitol, OSMOTIC Urea, DIURETICS Glycerin and Isosorbide (Mannitol is the most commonly employed agent) These are agents are given IV or as an irrigation.  OSMOTIC DIURETICS: MECHANISM OF ACTION Freely filtered at the glomerulus. Poorly reabsorbed and not secreted by renal tubules. Action depends on the number of active particles (e.g., Mannitol) in solution Increases osmolarity of the tubular fluid in the proximal tubule and descending Loop of Henle. Draws water into the lumen by osmosis. Reduces water reabsorption and increases urine output (diuresis). Osmotic diuretics also increase vascular and extracellular volume, which increases renal blood flow and GFR.  OSMOTIC DIURETICS: INDICATIONS 3. Treatment of Acute Renal Failure (Acute Tubular Necrosis ) 1. Prophylaxis of Acute Renal Failure Reduces obstructing casts in the renal tubules. Indicated in cases of cardiovascular surgery, severe trauma, etc. Dilutes nephrotoxic substances. Maintains a high urine flow to decrease toxic Reduces tubular cell swelling, improving renal solute concentration in the kidneys. function. 2. Prophylaxis for Drug-Induced 4. Reduction of Intracranial Pressure (ICP) Nephrotoxicity Indicated in cerebral edema and neurosurgical Used in patients treated with nephrotoxic drugs procedures. (e.g., cisplatin, cyclosporin, amphotericin B). Draws fluid out of the brain tissue, lowering ICP. Promotes diuresis to minimize nephrotoxic effects. Aids in the management of toxic overdoses. 5. Reduction of Intraocular Pressure (IOP) Used in acute glaucoma or during ocular surgery. Reduces intraocular fluid volume to lower pressure within the eye. OSMOTIC DIURETICS SIDE EFFECTS: Reduced intracellular volume → Precautions: Dehydration due to water shifting from cells to extracellular space. Elderly patients: Extracellular volume expansion → Risk of pulmonary edema, especially in Risk of phlebitis and thrombosis CHF patients, from rapid fluid shifts. during IV administration. Water loss is greater than sodium loss → Higher risk of hypernatremia as Hepatic patients: osmotic diuretics cause more water than May cause ammonium sodium to be excreted. accumulation, worsening hepatic Increased magnesium loss → Osmotic encephalopathy. diuretics enhance magnesium excretion, leading to hypomagnesemia.  Acetazolamide Brinzolamide Dorzolamide CARBONIC Ethoxzolamide ANHYDRASE Methazolamide INHIBITORS Diclofenamide Zonisamide  Normal Physiological Process of NaHCO₃ Reabsorption 1. Na⁺ enters the Proximal Tubule cell via a Na⁺/H⁺ exchanger, while H⁺ is secreted into the lumen. 2. Secreted H⁺ combines with HCO₃⁻ in the tubular lumen to form carbonic acid H₂CO₃ 3. Carbonic anhydrase IV (CA-IV) in the lumen catalyzes the conversion of H₂CO₃ into CO₂ and H₂O. 4. CO₂ and H₂O freely diffuse back into the proximal tubule cells. 5. Inside the cell, Carbonic anhydrase-II converts CO₂ and H₂O back into H₂CO₃. 6. H₂CO₃ dissociates into H⁺ and HCO₃⁻. 7. HCO₃⁻ is reabsorbed into the bloodstream (Na⁺/HCO₃⁻ cotransporter), and the H⁺ is recycled to maintain Na⁺/H⁺ exchange.  EFFECT OF CARBONIC ANHYDRASE INHIBITORS (CAI) Carbonic anhydrase (CA) inhibitors inhibit both CA-II and CA-IV, blocking the conversion of H₂CO₃ to CO₂ and H₂O in the lumen. This prevents the reformation of H₂CO₃ inside the cell, disrupting NaHCO₃ reabsorption. Bicarbonate Loss (Lumen) Due to inhibition, NaHCO₃ is not reabsorbed and is lost in the urine, leading to bicarbonate wasting. Metabolic Effects (Blood) Loss of bicarbonate in urine leads to metabolic acidosis. Increased Na⁺ delivery to the collecting duct enhances K⁺ secretion, contributing to hypokalemia. Compensatory NH₃ Increase As a compensatory mechanism, plasma levels of NH₃ (ammonia) may increase to neutralize excess H⁺.  CARBONIC ANHYDRASE INHIBITORS: INDICATIONS 1. Edematous States: Inhibit NaHCO₃ 3. Acute Mountain Sickness: Induces reabsorption in the proximal tubule, increasing sodium, metabolic acidosis, stimulating ventilation and improving bicarbonate, and water excretion. (Causes diuresis, but oxygenation. (Higher doses required compared to other risk of metabolic acidosis limits long-term use.) uses.) 2. Glaucoma: Inhibit carbonic anhydrase in the 4. Sleep Apnea: Increases respiratory drive by ciliary body, reducing aqueous humor formation and inducing metabolic acidosis. May reduce episodes, lowering intraocular pressure (IOP). Protects the optic especially in central sleep apnea. nerve. Topical (dorzolamide, brinzolamide) or oral/parenteral. 5. Epilepsy (Petit Mal): Likely alters neuronal excitability by affecting brain pH. Secondary treatment for absence seizures. CARBONIC ANHYDRASE INHIBITORS: SIDE-EFFECTS 1. Metabolic Acidosis: Inhibits bicarbonate reabsorption, causing bicarbonate loss, leading to metabolic acidosis. 2. Hypokalemia and Hyponatremia: Increased sodium delivery to the distal nephron enhances potassium and sodium excretion, leading to hypokalemia and hyponatremia. 3. Hepatic Encephalopathy: In patients with hepatic dysfunction, bicarbonate loss can increase plasma ammonia levels, potentially triggering hepatic coma. 4. Worsened Respiratory Acidosis: In respiratory insufficiency, pre-existing CO₂ retention is exacerbated by metabolic acidosis, worsening acid-base balance.  Furosemide, Torsemide. LOOP Ethacrynic acid, DIURETICS Bumetanide and  LOOP DIURETICS: Mechanism of Action Na⁺/K⁺/2Cl⁻ Symporter (NKCC2) in the thick ascending loop of Henle simultaneously transports 1 Na⁺, 1 K⁺, and 2 Cl⁻ ions from the lumen of the nephron into the epithelial cells Lood diuretics Inhibit Na⁺/K⁺/2Cl⁻ symporter in the thick ascending loop of Henle. Prevents reabsorption of Na⁺, K⁺, and Cl⁻, leading to significant diuresis and electrolyte depletion. Results in the excretion of large amounts of Na⁺, K⁺, Cl⁻, and water, producing a strong diuretic effect. Blocks the reabsorption of 25% of filtered NaCl, a major portion of total Na⁺ reabsorption. Excess use can cause profound diuresis, water and electrolyte depletion (Na⁺, K⁺, Cl⁻), necessitating careful monitoring and individualized dosing. ROMK (renal outer medullary potassium) channels  Loop Diuretics: Mechanism of Ca²⁺ and Mg²⁺ Loss Normal Physiology Na⁺/K⁺/2Cl⁻ Symporter in the thick ascending loop of Henle creates a positive luminal potential. This potential drives the paracellular reabsorption of Ca²⁺ and Mg²⁺ into the bloodstream. Effect of Loop Diuretics: Inhibition of Na⁺/K⁺/2Cl⁻ Symporter: Loop diuretics block the symporter, disrupting the luminal positive potential. Reduced driving force for the paracellular reabsorption of Ca²⁺ and Mg²⁺. Increased urinary loss of Ca²⁺ and Mg²⁺, leading to potential hypocalcemia and hypomagnesemia. ROMK (renal outer medullary potassium) channels  Distal tubule and Collecting Duct Why Hypokalemia & Metabolic Lumen Interstitium Alkalosis Occur With Loop Diuretics ENaC: Epithelial Sodium Channels Na⁺/K⁺-ATPase Pump ROMK; renal outer medullary Na⁺ reabsorption via ENaC: potassium channel) Loop diuretics increase sodium delivery to the distal tubule and collecting duct. Epithelial Sodium Channels (ENaC) in principal cells reabsorb Na⁺. This process is enhanced by aldosterone, increasing the number of ENaC channels, promoting Na⁺ reabsorption. α-Intercalated Cells K⁺ secretion by principal cells: Lumen at DCT and CT Interstitium As more Na⁺ is reabsorbed via ENaC, an electrochemical gradient forms in the lumen. This gradient drives K⁺ secretion via ROMK (Renal Outer Medullary Potassium Channels). H⁺-ATPase pumps Increased K⁺ secretion leads to hypokalemia (low potassium levels). H⁺/K⁺-ATPase exchangers Enhanced H⁺ Secretion: Increased sodium reabsorption via ENaC (electrochemical gradient) also stimulates H⁺ secretion by α-intercalated cells in the distal tubule and collecting duct. This occurs via H⁺-ATPase pumps and H⁺/K⁺ exchangers. Loss of H⁺ from the blood raises pH, causing metabolic alkalosis. β-Intercalated Cells at DCT and CT Chloride Loss and Bicarbonate Retention Loop diuretics promote chloride (Cl⁻) loss, leading to chloride depletion. This impairs the Cl⁻/HCO₃⁻ exchanger, reducing bicarbonate excretion. Cl⁻/HCO₃⁻ exchanger Bicarbonate (HCO₃⁻) retention in the blood further contributes to metabolic alkalosis. Interstitium Lumen  Pharmacokinetics and Transport Protein Binding: Loop diuretics are highly Loop Diuretics: chronic treatment may protein-bound and thus poorly filtered at the increase uric acid levels. glomerulus. Mechanisms: a) competition between uric acid and the loop diuretic for secretion Secretion: They must be secreted into the (organic acid tubular secretion) tubular lumen via organic acid secretory mechanisms in the proximal tubule. b) greater reabsorption of uric acid in the proximal tubule because Competition: Use of these organic acid of diuretic-induced volume depletion. transporters makes loop diuretics subject to competition with other substances like uric acid.  LOOP DIURETICS: INDICATIONS. Loop diuretics induce a rapid and significant loss of fluid, which can be clinically advantageous in managing severe fluid overload states. Additional Effects: Edema associated with: Venodilation: Congestive Heart Failure (CHF): Reduce fluid overload by promoting renal excretion of sodium and water, alleviating symptoms of heart o Mechanism: Primarily seen with IV furosemide, failure. mediated by increased synthesis of prostaglandins. Hepatic Cirrhosis: Reduces ascites formation by decreasing plasma volume and portal venous pressure. o Clinical benefits: Renal Disease: Effective in conditions like acute kidney injury (AKI) ▪ Rapid reduction in venous return and left or chronic kidney disease (CKD) by promoting diuresis despite impaired renal function. ventricular filling pressure, easing symptoms of acute pulmonary edema. Nephrotic Syndrome: Helps control fluid retention due to hypoalbuminemia. ▪ Reduced preload on the heart, beneficial in heart Hypertension: failure management. Used alone or in combination with other antihypertensives to reduce blood pressure by lowering plasma volume and cardiac output. Preserved Efficacy in Renal Insufficiency: Other reported uses: o Moderate to severe renal insufficiency: Loop Glaucoma: By reducing intraocular pressure via fluid regulation. diuretics maintain efficacy even in reduced renal Adult Nocturia: By influencing the timing of urine production. function, though higher doses may be required to achieve diuresis. Hypercalcemia: Increases calcium excretion by inhibiting calcium reabsorption in the thick ascending limb. Elevated Intracranial Pressure: Reduces cerebrospinal fluid production.  LOOP DIURETICS: SIDE EFFECTS 2. Patients at Higher Risk of Serious Complications: 1. Electrolyte Imbalance & Fluid Loss: Certain patients require careful monitoring: Large/Repeated Doses lead to marked diuresis: Renal Insufficiency: Reduced renal clearance may intensify Excessive loss of water and electrolytes, fluid and electrolyte disturbances. resulting in: Cardiac Arrhythmias: Electrolyte imbalances, particularly Hypovolemia: hypokalemia, increase arrhythmia risk. Digoxin Users: Hypokalemia enhances the toxicity of Hyponatremia: digoxin, increasing the risk of arrhythmias. Hypochloremia: Elderly Patients: More susceptible to the adverse effects of Hypokalemia: diuretics due to reduced physiological reserve. Hepatic Patients: Greater risk of fluid-electrolyte imbalance Metabolic Alkalosis: and hepatic coma. Hypomagnesemia: 3. Additional Considerations: Hypocalcemia: Pre-Renal Azotemia: Excessive diuresis may cause reduced Small changes in electrolytes and pH are usually renal perfusion and subsequent increase in serum urea (azotemia). tolerated in otherwise healthy individuals, but can still pose risks in susceptible populations. Hepatic Coma: Loop diuretics may precipitate hepatic encephalopathy in cirrhotic patients due to electrolyte imbalances (e.g., hypokalemia and alkalosis).  Thiazides derivatives: (Hydrochlorothiazide, Benzothiadiazide, polythiazide, and others). Metolazone and quinethazone (quinazoline derivatives), THIAZIDE & Chlorthalidone (a phthalimidine derivative) THIAZIDE-LIKE DIURETICS Indapamide (an indoline) These agents have structural and pharmacological similarities to the thiazides  THIAZIDES: Site and Mechanism of Action Site of Action: Early Distal Convoluted Tubule (DCT) Cells: Mechanism of Action: Inhibition of the Na⁺/Cl⁻ Symporter by Competitively binding at the Cl⁻ site of the transporter, preventing Na⁺ and Cl⁻ reabsorption. This leads to increased excretion of sodium (Na⁺) and chloride (Cl⁻) into the urine. The reduced intracellular Na⁺ levels activate the basolateral Na⁺/Ca²⁺ exchanger, leading to increased calcium (Ca²⁺) reabsorption into the blood.  THIAZIDE DIURETICS: Pharmacological Effects: Increased Na⁺, Cl⁻, and Water Excretion: Thiazides promote moderate diuresis, with less potency THIAZIDE DIURETICS: RENAL FUNCTION & SYNERGY compared to loop diuretics. Only ~10% of filtered Na⁺ reaches the DCT, so the magnitude of sodium and chloride excretion is smaller compared to loop Limited Effectiveness at GFR < 30 diuretics. ml/min: Potassium Loss in the Collecting Duct: Thiazides are generally ineffective in patients with severely reduced glomerular filtration rate (GFR). The increased delivery of sodium to the collecting duct enhances Metolazone and indapamide can still induce diuresis at low GFR Na⁺ reabsorption via ENaC channels, leading to potassium (K⁺) levels. excretion. This results in hypokalemia (low potassium levels). Synergy with Loop Diuretics: Exhibit true synergism in combination, particularly useful for Calcium Reabsorption: treating refractory edema. By reducing Na⁺ levels intracellularly, thiazides increase the Combination of metolazone + furosemide is beneficial in patients activity of the Na⁺/Ca²⁺ exchanger on the basolateral membrane. with renal insufficiency to enhance diuretic response. This enhances the reabsorption of Ca²⁺, which is beneficial in conditions like osteoporosis or idiopathic hypercalciuria.  THIAZIDES: INDICATIONS 1. Hypertension (HT): Thiazides are the diuretic of choice for the treatment of HT. 4. Osteoporosis (Postmenopausal Reduction in plasma volume (short-term effect) → decreases cardiac output. Women): Thiazides are useful in osteoporosis due to their Reduction in peripheral vascular resistance (long- ability to increase calcium retention. term effect) → sustained blood pressure lowering. By reducing calcium excretion, thiazides help maintain bone mineral density and lower the risk of fractures. 2. Adjunctive Therapy in Edema: Used in edema associated with Congestive Heart Failure (CHF), hepatic cirrhosis, renal disease, and nephrotic syndrome. 5. Diabetes Insipidus (DI): Thiazides are used to reduce urine volume by 30-50%, especially in nephrogenic Promotes sodium and water excretion, reducing extracellular diabetes insipidus (NDI). (Paradoxical Effect): fluid volume and improving symptoms of fluid overload. Thiazides reduce GFR, leading to increased proximal tubular sodium and water reabsorption. 3. Calcium Nephrolithiasis (Kidney Stones): They activate the renin-angiotensin-aldosterone Thiazides are effective in preventing stone formation. system (RAAS), leading to decreased water excretion. Thiazides reduce urinary calcium excretion by enhancing This effect is paradoxical, as thiazides typically calcium reabsorption in the distal convoluted tubule via promote diuresis, but in DI they reduce excessive urine activation of the Na⁺/Ca²⁺ exchanger. output. This is beneficial for preventing hypercalciuria and recurrence of calcium stones. Combination Therapy: May be used with amiloride or allopurinol in some cases.  THIAZIDES: Side Effects 1. Lithium Toxicity: Thiazides reduce sodium reabsorption in the distal convoluted tubule. 4. NSAID Interaction: This leads to increased sodium excretion, which in turn activates proximal tubular reabsorption of both sodium and lithium. NSAIDs reduce the production of prostaglandins, which are crucial for maintaining renal blood flow. Reduced lithium excretion results in higher serum lithium levels, potentially leading to toxicity. Thiazides rely on prostaglandins to exert their natriuretic (sodium excretion) and antihypertensive effects. Close monitoring of lithium levels is necessary during thiazide therapy in patients on lithium. By inhibiting prostaglandins, NSAIDs can reduce the effectiveness of thiazides. 2. Worsening of Gout: Caution should be exercised when combining thiazides with Thiazides increase serum uric acid levels by competing for the same NSAIDs, as this may lead to reduced diuretic and blood organic acid transporters in the proximal tubule that excrete uric acid. pressure-lowering efficacy. This results in reduced uric acid clearance and can precipitate or worsen 5. Hypokalemia and metabolic alkalosis: gout. Thiazides increase the delivery of Na⁺ to the distal nephron, Thiazides should be used cautiously in patients with a history of gout or enhancing Na⁺ reabsorption in exchange for K⁺ and H⁺ hyperuricemia. excretion in the collecting duct. This can result in hypokalemia and metabolic alkalosis. 3. Interaction with Bile Acid Sequestrants (e.g., Cholestyramine or Colestipol): 6. Increased Risk of Hyponatremia: Bile acid sequestrants bind to thiazides in the gastrointestinal tract, Due to reduced sodium reabsorption, prolonged use can result reducing their absorption and hence their efficacy. in dangerously low sodium levels. Administer thiazides at least 2 hours before or 4-6 hours after bile acid sequestrants to avoid interaction.  Epithelial Sodium Channels Inhibitors: Amiloride Triamterene K+-SPARING DIURETICS Aldosterone Antagonists: Spironolactone Eplerenone  K+-SPARING DIURETICS: Mechanism of Action 2-5% of Na⁺ is reabsorbed in the collecting duct, where K⁺-sparing diuretics exert their effects. K⁺-Sparing Diuretics are ENaC Inhibitors (Triamterene, Amiloride): Block Epithelial Sodium Channels (ENaC) in the collecting duct. Prevents Na⁺ reabsorption, reducing the electrochemical gradient that drives K⁺ secretion. Reduced Na⁺ influx leads to K⁺ retention and can cause hyperkalemia. Aldosterone Antagonists (Spironolactone, Eplerenone): Block aldosterone receptors in the collecting tubule cell. Inhibits aldosterone-mediated increases in: ENaC expression (reducing Na⁺ reabsorption). Na⁺/K⁺ ATPase expression (limiting Na⁺/K⁺ exchange). Decreased Na⁺ reabsorption, with a consequent decrease in K⁺ and H⁺ excretion, leading to hyperkalemia and a risk of acidosis.  Aldosterone and Principal Cells (Na⁺ And K⁺ Regulation) Aldosterone acts on principal cells located in the late distal convoluted tubule (DCT) and collecting duct (CD). Na⁺ reabsorption: Aldosterone upregulates the expression of Epithelial Sodium Channels (ENaC) on the luminal membrane of principal cells. This increases the influx of Na⁺ from the tubular fluid (pre-urine) into the cell. On the basolateral side, aldosterone increases the activity of the Na⁺/K⁺ ATPase pump, which pumps Na⁺ out of the cell into the interstitial fluid (and subsequently the bloodstream) in exchange for K⁺. More Na⁺ is reabsorbed into the blood, increasing sodium retention and fluid volume. K⁺ secretion: As more Na⁺ is reabsorbed, it creates a negative electrical potential in the tubular lumen. This negative charge drives the secretion of K⁺ through ROMK (Renal Outer Medullary Potassium Channels) from principal cells into the tubular lumen (pre-urine). This leads to increased K⁺ excretion in the urine, which can contribute to hypokalemia if aldosterone levels are high. Aldosterone and Intercalated Cells (H⁺ Regulation) H⁺ secretion: Aldosterone also stimulates intercalated cells, specifically α-intercalated cells, in the collecting duct. It increases the activity of H⁺-ATPase pumps on the luminal membrane of these cells, which actively secrete H⁺ ions into the tubular lumen. Additionally, the H⁺/K⁺-ATPase exchanger can secrete H⁺ in exchange for K⁺. This leads to increased H⁺ excretion, which raises blood pH and contributes to metabolic alkalosis.  K+ SPARING: CONTRAINDICATIONS 1. Elevated Serum Potassium (Hyperkalemia): 4. Renal Function Impairment (Chronic Renal Potassium-sparing diuretics (e.g., spironolactone, eplerenone, amiloride, Failure, CRF): triamterene) work by inhibiting sodium reabsorption and reducing potassium excretion in the collecting duct. In patients with renal impairment, the ability to excrete potassium is diminished. This can result in increased potassium levels in the blood, especially in individuals with pre-existing hyperkalemia. The use of potassium-sparing diuretics in these patients can exacerbate the risk of severe hyperkalemia due to reduced Avoid use in patients with hyperkalemia due to the risk of life-threatening renal clearance of potassium. cardiac arrhythmias. Avoid use in patients with chronic renal failure or severely 2. Concomitant Potassium Supplementation or Salt reduced renal function (eGFR < 30 mL/min). Substitutes: Many salt substitutes contain potassium chloride, which can further raise 5. Concurrent Use with ACE Inhibitors or ARBs: serum potassium levels. ACE inhibitors (e.g., lisinopril) and ARBs (e.g., losartan) In combination with potassium-sparing diuretics, this can significantly increase decrease aldosterone production, which reduces potassium the risk of hyperkalemia. excretion. Avoid combining potassium-sparing diuretics with potassium supplements or When combined with potassium-sparing diuretics, these potassium-based salt substitutes. medications can lead to cumulative effects on potassium retention, further increasing the risk of hyperkalemia. 3. Concurrent Use of Other Potassium-Sparing Diuretics: Monitor potassium levels closely when using potassium-sparing Co-administration of multiple potassium-sparing agents (e.g., spironolactone + diuretics with ACE inhibitors or ARBs. amiloride) can result in excessive retention of potassium, significantly raising the risk of hyperkalemia. Avoid combining two or more potassium-sparing diuretics to prevent potassium overload. Factors influencing DIURETIC RESISTANCE (DR) Intra-Nephron Diuretic Resistance Mechanisms: Pre-Nephron Diuretic Resistance Factors: Pre-Loop of Henle DR: Reduced Nephron Number: Fewer nephrons (e.g., in chronic kidney disease) lead to decreased response to diuretics. Cardio-Renal Dynamics: Reduced GFR: Decreased kidney filtration limits drug delivery Impaired interaction between the heart and kidneys (e.g., to the nephron’s action sites. heart failure) reduces renal blood flow, limiting diuretic delivery to the kidneys. Organic Anion Competition: Increased organic anions (e.g., uremic toxins) compete with diuretics for transporter entry into Renal Blood Flow: the nephron, reducing their secretion and activity. Decreased blood flow to the kidneys reduces the glomerular filtration rate (GFR), impairing diuretic Albuminuria: Protein in urine binds diuretics, reducing their efficacy. efficacy. Hypoalbuminemia: Loop of Henle DR: Low serum albumin reduces drug binding and distribution, leading to altered pharmacokinetics and Altered Loop Response: Changes in the loop of Henle, reduced diuretic delivery. such as cell adaptations or improper dosing, may limit the natriuretic response. Sodium/Fluid Intake: High sodium or fluid intake can counteract the diuretic’s Post-Loop of Henle DR: effects by increasing fluid retention, reducing efficacy. Distal Tubule Hypertrophy/Hyperfunction: Adaptation of distal tubule cells can enhance sodium reabsorption, reducing the overall diuretic effect.  DIURETIC RESISTANCE PHARMACOKINETIC Changes: PHARMACODYNAMIC Factors: Reduced Bioavailability: Receptor Downregulation: Gastrointestinal absorption issues (e.g., ascites) Reduced number of diuretic receptors at target decrease the amount of drug entering circulation. sites diminishes drug effect. Altered Distribution: Decreased Sensitivity: Changes in volume of distribution (e.g., in severe edema) reduce the concentration of diuretics at Even with the presence of the diuretic, reduced their target sites. receptor response leads to decreased drug action. Impaired Renal Excretion: In renal impairment, the clearance of diuretics is Hypertrophy of Nephron Segments: reduced, decreasing their concentration at the Hypertrophy of nephron segments not targeted site of action. by diuretics increases sodium reabsorption, weakening the diuretic response.