---

Diuretics — Loop & Thiazide: Detailed Pharmacological Notes

---

I. Overview & Classification of Diuretics

---

II. LOOP DIURETICS (High-Ceiling Diuretics)

A. Drugs in Class

Key distinction: Furosemide and bumetanide contain a sulfonamide moiety. Ethacrynic acid is a phenoxyacetic acid derivative — the only loop diuretic safe to use in patients with true sulfa allergy. Torsemide is a sulfonylurea.

---

B. Mechanism of Action

1. Loop diuretics are highly protein-bound → not filtered at the glomerulus
2. They reach the tubular lumen via active secretion by the organic acid transport system (OAT1/OAT3 on basolateral membrane → MRP-4 on luminal membrane) in the proximal tubule
3. They bind the Cl⁻ binding site of the NKCC2 symporter on the luminal membrane of the TAL
4. Salt transport in the TAL is halted; downstream segments lack the capacity to compensate
5. This destroys the hypertonic medullary interstitium → loss of urinary concentrating ability

• TAL normally reabsorbs 25–30% of filtered NaCl
• The TAL is water-impermeable → salt reabsorption here creates the concentrated medullary gradient
• Downstream nephron segments cannot rescue the flood of unabsorbed solute

• Absorptive (NKCC2/BSC1): kidney-specific, apical membrane of TAL — primary drug target
• Secretory (NKCC1/BSC2): ubiquitous, basolateral in epithelia — responsible for ototoxicity at high doses

Bartter syndrome is caused by loss-of-function mutations in the NKCC2 transporter (or associated proteins), mimicking chronic loop diuretic use.

---

C. Effects on Urinary Excretion

• Below threshold → no diuresis
• Steep portion → dose-dependent diuresis
• Ceiling effect → no further diuresis above maximum

---

D. Renal Hemodynamic Effects

• Increase RBF (if volume depletion prevented) — mechanism may involve prostaglandins; NSAIDs blunt this
• Block tubuloglomerular feedback (TGF): By inhibiting NaCl transport into the macula densa, the macula densa cannot detect tubular NaCl → GFR maintained (unlike carbonic anhydrase inhibitors)
• Powerful stimulators of renin release: via macula densa pathway + sympathetic activation + baroreceptor mechanism
• Acute venodilation: Furosemide acutely increases systemic venous capacitance, reducing left ventricular filling pressure before diuresis begins — mediated by prostaglandins

---

E. Pharmacokinetics (ADME)

• Protein binding: Extensive → minimal filtration; access to tubule via proximal secretion
• Furosemide: ~65% excreted unchanged in urine; remainder glucuronidated in kidney → prolonged t½ in renal disease
• Bumetanide & torsemide: Significant hepatic metabolism → prolonged t½ in liver disease
• Oral bioavailability: Furosemide is notorious for erratic absorption (10–100%). Bumetanide and torsemide are reliably ~80%
• Short t½ → postdiuretic Na⁺ retention: As loop diuretic levels fall in tubule, Na⁺ is avidly reclaimed — overcome by sodium restriction or more frequent dosing
• IV dosing in hospitalized patients: Initial IV dose = 2–2.5× the chronic oral dose

---

F. Therapeutic Uses

1. Acute pulmonary edema — drug of choice; venodilation + brisk natriuresis rapidly reduces LV filling pressure
2. Chronic heart failure — reduce pulmonary/peripheral congestion; torsemide preferred over furosemide (more reliable absorption, fewer hospitalizations)
3. Hypertension — not first-line in normal renal function (less antihypertensive efficacy vs. thiazides); drugs of choice when GFR <30 mL/min or resistant hypertension
4. Nephrotic syndrome — often the only drugs capable of mobilizing massive edema
5. Cirrhosis with ascites — useful but risk of volume depletion and hepatic encephalopathy; spironolactone often combined
6. Hypercalcemia — saline + furosemide promotes calciuresis
7. Chronic kidney disease edema — dose-response curve is right-shifted; higher doses required
8. Hyponatremia (life-threatening) — forced diuresis
9. Drug overdose — forced diuresis to enhance renal elimination
10. Hyperkalemia — promotes kaliuresis

---

G. Adverse Effects

Ototoxicity precaution: Furosemide infusion rate must not exceed 4 mg/min. Synergistic ototoxicity with aminoglycosides, cisplatin, carboplatin.

---

H. Drug Interactions

---

I. Contraindications

• Severe Na⁺ depletion / volume depletion
• Anuria unresponsive to a trial dose
• Sulfa allergy (for sulfonamide-based agents — use ethacrynic acid instead)
• Caution in post-menopausal osteopenic women (↑ Ca²⁺ excretion affects bone)
• Hepatic encephalopathy risk in cirrhosis

---

III. THIAZIDE DIURETICS

A. Drugs in Class

• Chlorothiazide (first orally active)
• Hydrochlorothiazide (HCTZ) — most widely used

• Chlorthalidone (~2× more potent than HCTZ; longer t½ ~45–60 h)
• Indapamide — additional direct vasodilatory effect
• Metolazone — effective even with low GFR; particularly useful for diuretic resistance

---

B. Mechanism of Action

1. Thiazides are secreted into the tubular lumen via the proximal tubule organic acid secretory system — therefore impaired renal function (↓ GFR) reduces diuretic efficacy
2. They bind the NCC on the apical membrane of DCT cells, blocking Na⁺ and Cl⁻ reabsorption
3. ↑ Na⁺ in tubular fluid → ↑ Na⁺/K⁺ exchange in collecting duct → K⁺ wasting
4. Unique calcium effect: By lowering intracellular Na⁺, the basolateral Na⁺/Ca²⁺ exchanger is enhanced → increased Ca²⁺ reabsorption (opposite to loop diuretics)
5. Long-term: reduce peripheral vascular resistance (mechanism independent of diuresis — possibly related to vascular smooth muscle effects)

NSAIDs reduce thiazide efficacy by inhibiting renal prostaglandin synthesis and reducing RBF.

---

C. Effects on Urinary Excretion

---

D. Pharmacokinetics

---

E. Therapeutic Uses

1. Hypertension — first-line therapy in most patients; antihypertensive effect is only partially dependent on diuresis; long-term reduction of peripheral vascular resistance is important
2. Edema — mild-to-moderate fluid retention (heart failure, hepatic cirrhosis, corticosteroid/estrogen therapy)
3. Chronic heart failure — adjunct for volume management; often combined with loop diuretics
4. Hypercalciuria / Calcium nephrolithiasis — Ca²⁺-retaining effect prevents stone formation
5. Nephrogenic diabetes insipidus (DI) — paradoxical antidiuretic effect: volume depletion → ↑ proximal Na⁺ reabsorption → ↓ water delivery to collecting duct → reduced urine volume
6. Osteoporosis — Ca²⁺ retention may reduce bone loss (secondary benefit)

Thiazides are ineffective when GFR <30 mL/min for diuretic purposes — switch to loop diuretics (exception: metolazone remains effective).

---

F. Adverse Effects

• Hyperglycemia
• Hyperlipidemia
• Hyperuricemia
• Hypercalcemia
• HypoKalemia, HypoMagnesemia, HypoNatremia

---

G. Drug Interactions

---

H. Contraindications

• Sulfa allergy (relative — cross-reactivity rare but possible)
• Anuria
• Severe hypokalemia/hyponatremia
• Gout (caution — hyperuricemia)
• GFR <30 mL/min for diuretic purposes (except metolazone)
• Pregnancy: avoid (associated with neonatal thrombocytopenia, electrolyte disturbances)

---

IV. KEY COMPARATIVE TABLE: Loop vs. Thiazide

---

V. DIURETIC RESISTANCE

1. Diminished oral bioavailability — especially furosemide (gut edema in heart failure)
2. Impaired proximal tubular secretion — hypoalbuminemia reduces drug delivery to lumen; NSAIDs block OAT
3. "Braking" phenomenon — chronic neurohormonal activation (RAAS, SNS, ADH) causes compensatory Na⁺ retention in distal nephron
4. Distal tubular remodeling — chronic loop diuretic use → hypertrophy of DCT cells → increased NCC expression → more downstream compensation

• Switch to IV administration (bypasses gut absorption problem)
• Combine loop + thiazide (sequential nephron blockade — adds metolazone or HCTZ to loop diuretic = profound synergistic diuresis)
• Restrict dietary sodium (<2 g/day)
• Switch to torsemide (more reliable absorption) or bumetanide
• Consider IV albumin (in hypoalbuminemia/nephrotic syndrome)
• Ultrafiltration or dialysis if refractory

---

VI. RENAL PHARMACOLOGY: CONTEXT

Tubular Secretion of Diuretics

• Basolateral uptake via OAT1/OAT3
• Luminal efflux via MRP-4
• Any condition reducing proximal tubule secretion blunts diuretic efficacy (renal failure, probenecid competition, hypoalbuminemia)

Renin-Angiotensin System Activation

• Volume depletion → baroreceptor-mediated sympathetic activation
• Macula densa NaCl sensing → direct renin stimulation (loop diuretics, via NKCC2 block)
• This is why combining diuretics with ACE inhibitors/ARBs is rational — it blocks the compensatory RAAS activation

Electrolyte Monitoring

• Serum Na⁺, K⁺, Cl⁻, HCO₃⁻ (electrolytes)
• Mg²⁺ (often overlooked; hypomagnesemia perpetuates hypokalemia)
• Serum creatinine / BUN (volume depletion, pre-renal AKI)
• Uric acid (hyperuricemia)
• Glucose (especially in diabetics on thiazides)
• Blood pressure (orthostatic measurements)

---

• Goodman & Gilman's Pharmacological Basis of Therapeutics, 14e, Chapter 29 (Diuretics)
• Lippincott Illustrated Reviews: Pharmacology, 8e, Chapter 9 (Diuretics)
• Brenner & Rector's The Kidney, 10e
• Harrison's Principles of Internal Medicine, 21e

---

ADDENDUM: Katzung's Basic & Clinical Pharmacology, 16th Edition

---

LOOP DIURETICS — Katzung Perspective

Chemistry & Background

---

Pharmacodynamics (Katzung)

Lumen-positive potential: NKCC2 activity generates a lumen-positive transepithelial potential (driven by K⁺ recycling back into the lumen via ROMK channels). This positive potential drives divalent cation reabsorption paracellularly — particularly Mg²⁺ and Ca²⁺. By abolishing this potential, loop diuretics increase urinary Mg²⁺ and Ca²⁺ excretion. This is the mechanistic explanation for loop-diuretic-induced hypomagnesemia and calciuresis.

• NSAIDs blunt loop diuretic efficacy by blocking prostaglandin synthesis
• Loop diuretics increase renal blood flow via prostaglandin-mediated vasodilation

---

Pharmacokinetics — Key Katzung Points

• Furosemide: Mainly renally eliminated (GFR + tubular secretion); oral absorption 2–3 hours; variable bioavailability
• Torsemide: Mainly hepatically eliminated (~80%); oral absorption ~1 hour — nearly as complete as IV; duration 4–6 h; has at least one active metabolite with a longer t½ than the parent compound
• Bumetanide: 50% renal, 50% hepatic; similar kinetics to torsemide but much more potent
• Clinical implication: Because furosemide's bioavailability is variable and torsemide/bumetanide's bioavailability is more consistent, equivalent doses are unpredictable — must adjust based on renal function
• Emerging evidence (Katzung 16e): Torsemide may decrease hospitalizations and possibly reduce AKI episodes compared to furosemide in heart failure patients; however, mortality benefit has not been shown in any study to date

---

Clinical Indications (Katzung)

1. Acute pulmonary edema and edematous conditions — primary indication
2. Hypertension with renal insufficiency — loop diuretics often required when other agents fail in this setting
3. Hypercalcemia — IV saline + loop diuretic promotes calciuresis
4. Hyperkalemia — enhances urinary K⁺ excretion; if patient is hypo/euvolemic, must accompany with normal saline to maintain euvolemia and enhance K⁺ excretion
5. Acute renal failure — can increase urine flow and K⁺ excretion, but cannot prevent or shorten the duration of renal failure
   • ⚠️ Caution in myeloma/light-chain nephropathy: Increased distal Cl⁻ enhances secretion of Tamm-Horsfall protein, which aggregates with Bence Jones proteins → worsens cast nephropathy
6. Anion overdose (bromide, fluoride, iodide) — these anions are reabsorbed in the TAL; loop diuretics enhance their excretion (must replace Na⁺ with saline)
7. Autism spectrum disorder — emerging evidence that bumetanide may improve communicative and cognitive abilities (Katzung 16e novel inclusion; cytokine levels may predict responders)

---

Toxicity (Katzung)

• Hyponatremia: Less common than with thiazides; loop diuretics are generally protective against hyponatremia, but patients who increase water intake in response to thirst can become hyponatremic
• Secondary hyperparathyroidism: Chronic hypercalciuria → mild hypocalcemia → ↑ PTH
• Pseudoporphyria (furosemide — reported)
• Thiamine (Vitamin B₁) deficiency worsening in heart failure patients on long-term loop diuretics
• Increased fracture risk with chronic furosemide
• Bumetanide IV: Superficial skin tenderness at injection site; continuous infusion → generalized musculoskeletal pain (38% in one study) — resolves on cessation

• Sulfa cross-reactivity (furosemide, bumetanide, torsemide) — though appears very rare
• Overzealous use in hepatic cirrhosis, borderline renal failure, or heart failure is dangerous

---

THIAZIDE DIURETICS — Katzung Perspective

History & Chemistry

Full Katzung Dosing Table (Table 15-6)

Pharmacokinetics — Katzung Highlights

• All thiazides secreted by the organic acid secretory system in the proximal tubule → compete with uric acid secretion → hyperuricemia
• Chlorothiazide: Not lipid-soluble; large doses required; only thiazide available for parenteral use
• Chlorthalidone: Slowly absorbed; longest duration of action → preferred in hypertension
• Indapamide: Primarily biliary excretion; enough active drug excreted renally to act on DCT; useful in patients with mild-to-moderate renal impairment
• Bendroflumethiazide: Likely least prescribed

Pharmacodynamics — Katzung's Ca²⁺ Mechanism (Detailed)

1. Proximal tubule effect: Thiazide-induced volume depletion → enhanced proximal Na⁺ reabsorption → passive Ca²⁺ reabsorption follows
2. DCT effect: Blockade of NCC lowers intracellular Na⁺ → basolateral Na⁺/Ca²⁺ exchanger (NCX) works harder to extrude Na⁺, exchanging it for Ca²⁺ → net Ca²⁺ reabsorption increased

Although thiazides alone rarely cause frank hypercalcemia, they can unmask hypercalcemia from other causes (primary hyperparathyroidism, malignancy, sarcoidosis). Clinically useful for calcium-containing nephrolithiasis prevention and may modestly reduce osteoporotic fracture risk.

---

Clinical Indications (Katzung — Table 15-6 summary)

1. Hypertension — first-line; antihypertensive effect has both a diuretic and a non-diuretic vascular component
2. Heart failure — volume management
3. Nephrolithiasis due to idiopathic hypercalciuria — Ca²⁺-retaining effect reduces urinary Ca²⁺ and stone formation
4. Nephrogenic diabetes insipidus — paradoxical antidiuresis via volume depletion and enhanced proximal reabsorption
5. Osteoporosis — shown to increase bone mineral density in women; however, not strong enough evidence to recommend solely for this purpose (Katzung caveat)

---

Toxicity — Katzung Additions

• Weakness, fatigue, paresthesias (similar to CA inhibitors)
• Impotence (likely volume-depletion-related)
• Acute angle-closure glaucoma (hyponatremia-induced)
• Hypomagnesemia — more likely with thiazides than with loop diuretics; typically appears after >1 year of use
• Rare: systemic lupus, ARDS, Merkel cell carcinoma, choroidal effusion

---

Katzung: Combined Use — Loop + Thiazide ("Sequential Nephron Blockade")

Combining a loop diuretic with a thiazide-like agent (e.g., metolazone) synergistically blocks Na⁺ reabsorption at two sequential nephron sites — the TAL and the DCT — producing profound diuresis in diuretic-resistant states. Potassium-sparing diuretics should be considered alongside to prevent severe hypokalemia.

---

Summary Comparison Table — Updated with Katzung

---

• Goodman & Gilman's Pharmacological Basis of Therapeutics, 14e
• Lippincott Illustrated Reviews: Pharmacology, 8e
• Brenner & Rector's The Kidney, 10e
• Harrison's Principles of Internal Medicine, 21e