A 61-year-old male is given acetazolamide to treat open-angle glaucoma. Upon diuresis, his urine is found to be highly alkaline. Which of the following accounts for the alkaline nature of this patient’s urine?

Inhibition of bicarbonate reabsorption in the proximal tubule

Inhibition of bicarbonate reabsorption in beta-intercalated cells

Inhibition of acid secretion in alpha-intercalated cells

Inhibition of chloride reabsorption in the distal convoluted tubule

Inhibition of chloride reabsorption in the thick ascending loop of Henle

A new drug has been shown to block epithelial sodium channels in the cortical collecting duct. Which of the following is most likely to be decreased upon drug administration?

Potassium secretion in the collecting tubules

Urea reabsorption in the collecting tubules

Hydrogen ion secretion in the collecting tubules

Sodium secretion in the collecting tubules

Sodium chloride reabsorption in the distal tubule

A 66-year-old man with congestive heart failure presents to the emergency department complaining of worsening shortness of breath. These symptoms have worsened over the last 3 days. He has a blood pressure of 126/85 mm Hg and heart rate of 82/min. Physical examination is notable for bibasilar crackles. A chest X-ray reveals bilateral pulmonary edema. His current medications include metoprolol succinate and captopril. You wish to add an additional medication targeted towards his symptoms. Of the following, which statement is correct regarding loop diuretics?

Loop diuretics inhibit the action of the Na+/K+/Cl- cotransporter

Loop diuretics can cause metabolic acidosis

Loop diuretics can cause ammonia toxicity

Loop diuretics can cause hyperlipidemia

Loop diuretics decrease sodium, magnesium, and chloride but increase calcium

A 55-year-old woman presents to the emergency room with severe abdominal pain for the past 24 hours. She has also noticed blood in her urine. She does not have any significant past medical history. Family history is significant for her mother having cholecystitis status post cholecystectomy at age 45. Her vital signs include: temperature 36.8°C (98.2°F), pulse 103/min, respiratory rate 15/min, blood pressure 105/85 mm Hg. Physical examination is significant for a woman continuously moving on the exam table in an attempt to get comfortable. Laboratory findings are significant for the following: Serum electrolytes Na 138 mEq/L N: 135–145 mEq/L K 4.0 mEq/L N: 3.5–5.0 mEq/L Cl 102 mEq/L N: 98–108 mEq/L CO2 27 mEq/L N: 22–32 mEq/L Ca 9.2 mEq/dL N: 8.4–10.2 mEq/dL PO4 3.5 mg/dL N: 3.0–4.5 mg/dL A 24-hour urine collection is performed and reveals a urinary calcium of 345 mg/day (ref: < 300 mg/day in men; < 250 mg/day in women). A non-contrast CT of the abdomen is performed and is shown in the exhibit. The patient’s symptoms pass within the next 12 hours with hydration and acetaminophen for pain management. She is prescribed a medication to prevent subsequent episodes. At which of the following parts of the nephron does this medication most likely work?

Descending limb of the loop of Henle

Thick ascending limb of the loop of Henle

An 18-year-old boy presents to the clinic with shortness of breath and fever for the last 2 days. He also has a cough for the same duration. He is asthmatic and uses inhaled albuterol for symptom relief when required. He used albuterol today 3 times at 10-minute intervals but has not had relief of his symptoms. On physical examination, his temperature is 38.3°C (101.0°F), pulse is 130/min, blood pressure is 116/80 mm Hg, and respirations are 28/min. Auscultation of the chest reveals bilateral crackles. Considering that he has already taken inhaled albuterol and has tachycardia, the physician nebulizes him with inhaled ipratropium bromide, which significantly improves his symptoms. Which of the following is the mechanism of action of this drug?

Inhibition of vagally-mediated contraction of bronchial smooth muscles

Inhibition of degranulation of mast cells

Inhibition of phosphodiesterase-4, leading to prevention of release of cytokines and chemokines

Inhibition of adenosine receptors in the respiratory tract

Stimulation of β2-adrenergic receptors in bronchial smooth muscle

An investigator studying hormone synthesis and transport uses immunocytochemical techniques to localize a carrier protein in the central nervous system of an experimental animal. The investigator finds that this protein is synthesized together with a specific hormone from a composite precursor. The protein is involved in the transport of the hormone from the supraoptic and paraventricular nuclei to its destination. The hormone transported by these carrier proteins is most likely responsible for which of the following functions?

Upregulation of renal aquaporin-2 channels

Stimulation of thyroglobulin cleavage

Hyperplasia of the adrenal zona fasciculata

Increased insulin-like growth factor 1 production

Maturation of primordial germ cells

A 32-year-old woman is admitted to the emergency department for 36 hours of intense left-sided back pain that extends into her left groin. She reports that the pain started a day after a charitable 5 km (3.1 mi) marathon. The past medical history is relevant for multiple complaints of eye dryness and dry mouth. Physical examination is unremarkable, except for intense left-sided costovertebral pain. The results from laboratory tests are shown. Laboratory test Result Serum Na+ 137 Serum Cl- 110 Serum K+ 3.0 Serum creatinine (SCr) 0.82 Arterial blood gas Result pH 7.28 pO2 98 mm Hg pCO2 28.5 mm Hg SaO2% 98% HCO3- 15 mm Hg Which of the following explains this patient’s condition?

Decreased renal excretion of hydrogen ions (H+)

Decreased bicarbonate renal absorption

Decreased synthesis of ammonia (NH3)

Decreased excretion of nonvolatile acids

Diuretic mechanisms of action for USMLE Step 2 CK: High-Yield Physiology Lessons

Diuretic Classes & Nephron Sites - The Great Water Escape

Nephron diagram: Diuretic sites of action

Diuretics primarily work by inhibiting Na+ reabsorption at distinct sites along the nephron, which in turn increases water excretion (diuresis). The site of action determines the diuretic's efficacy and side effect profile.

Proximal Tubule: Carbonic Anhydrase Inhibitors
Thick Ascending Limb: Loop Diuretics
Distal Tubule: Thiazides
Collecting Duct: K+-Sparing Diuretics

⭐ Loop diuretics are the most potent ("high-ceiling"), blocking the Na-K-2Cl cotransporter in the thick ascending limb, a site responsible for reabsorbing ~25% of filtered sodium.

Carbonic Anhydrase Inhibitors - Fizzle Out the Bicarb

Nephron: Diuretic Mechanisms & Associated Syndromes

Mechanism: Blocks carbonic anhydrase in the Proximal Convoluted Tubule (PCT), preventing reabsorption of sodium bicarbonate.
Key Drug: Acetazolamide.
Effect: ↑ excretion of $HCO₃⁻$, leading to alkaline urine and a mild hyperchloremic metabolic acidosis.
- $H₂O + CO₂ \leftrightarrow H₂CO₃ \leftrightarrow H⁺ + HCO₃⁻$
📌 Mnemonic: "ACID"-azolamide causes metabolic ACIDosis.

⭐ Used to treat glaucoma, metabolic alkalosis, and acute mountain sickness.

Loop Diuretics - Powerhouse Pump Blockers

Mechanism: Inhibit the $Na⁺/K⁺/2Cl⁻$ cotransporter in the thick ascending limb of the Loop of Henle. This powerful action disrupts the generation of the corticomedullary gradient.
Key Drugs: Furosemide, Bumetanide, Torsemide.
Efficacy: Highest efficacy among all diuretic classes (“high-ceiling” diuretics).
Electrolyte Wasting: Causes significant loss of $Na⁺$, $K⁺$, $Cl⁻$, $Mg²⁺$, and $Ca²⁺$.
- 📌 Mnemonic: Loops Lose Ca²⁺.

⭐ Exam Favorite: Can precipitate gout by causing hyperuricemia due to competition for the same organic acid transporter in the PCT.

Diuretic mechanisms of action on nephron cotransporters

Thiazide Diuretics - The Calcium Keepers

Mechanism: Inhibit the Na⁺/Cl⁻ cotransporter in the early Distal Convoluted Tubule (DCT), leading to ↓ NaCl reabsorption and diuresis.
Key Drugs: Hydrochlorothiazide (HCTZ), Chlorthalidone.
Key Effects:
- ↑ Excretion of Na⁺, K⁺.
- ↑ Reabsorption of Ca²⁺ (hypercalcemia). 📌 'Thiazides Treasure Ca²⁺'.

⭐ Exam Favorite: Thiazides are used to treat recurrent calcium-containing kidney stones (nephrolithiasis) by reducing urinary Ca²⁺ excretion.

Thiazide Diuretic Mechanism in DCT and Calcium Reabsorption

Potassium-Sparing Diuretics - The Potassium Protectors

Site of Action: Late Distal Convoluted Tubule (DCT) & Collecting Duct.
Mechanism & Drugs:
- Aldosterone Antagonists: Spironolactone, Eplerenone
  - Inhibit the mineralocorticoid receptor, reducing ENaC and Na+/K+ pump synthesis.
- ENaC Blockers: Amiloride, Triamterene
  - Directly block the Epithelial Sodium Channel (ENaC).
Effect: ↓ Na+ reabsorption, ↓ K+ excretion → potential for ⚠️ hyperkalemia.

⭐ Spironolactone can cause painful gynecomastia due to its anti-androgenic effects. Eplerenone is a more selective antagonist with fewer endocrine side effects.

High‑Yield Points - ⚡ Biggest Takeaways

Carbonic anhydrase inhibitors (Acetazolamide) act on the PCT, causing metabolic acidosis.

Loop diuretics (Furosemide) inhibit the Na-K-2Cl cotransporter in the thick ascending limb, causing significant electrolyte loss.

Thiazides (HCTZ) block the Na-Cl symporter in the DCT, uniquely causing hypercalcemia.

K+-sparing diuretics (Spironolactone, Amiloride) act on the collecting duct to prevent K+ loss.

Spironolactone is an aldosterone antagonist; Amiloride blocks ENaC channels.

Mannitol is an osmotic diuretic working at the PCT and descending limb.

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