Diuretics

Diuretics are a diverse class of pharmacologic agents that increase the excretion of water and electrolytes from the body by acting on various segments of the nephron. They are primarily used to manage conditions involving fluid overload or electrolyte imbalances, including hypertension, heart failure, chronic kidney disease, cirrhosis, and edema of other etiologies.

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1. Classification of Diuretics

Diuretics are categorized based on their site and mechanism of action within the nephron:

A. Thiazide and Thiazide-like Diuretics

• Act on the distal convoluted tubule

• Inhibit Na⁺/Cl⁻ symporter

B. Loop Diuretics

• Act on the thick ascending limb of Henle’s loop

• Inhibit Na⁺/K⁺/2Cl⁻ cotransporter

C. Potassium-Sparing Diuretics

• Aldosterone antagonists (spironolactone, eplerenone)

• ENaC blockers (amiloride, triamterene)

D. Carbonic Anhydrase Inhibitors

• Act on the proximal convoluted tubule

• Inhibit carbonic anhydrase (e.g., acetazolamide)

E. Osmotic Diuretics

• Filtered but not reabsorbed in the nephron

• Create osmotic gradient (e.g., mannitol)

F. Vasopressin Antagonists (Aquaretics)

• Promote water excretion without major sodium loss

• Block V2 receptors (e.g., tolvaptan, conivaptan)

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2. Mechanisms of Action by Class

Class	Nephron Site	Mechanism
Thiazides	Distal convoluted tubule	Na⁺/Cl⁻ symporter inhibition
Loop diuretics	Loop of Henle	Na⁺/K⁺/2Cl⁻ inhibition
Potassium-sparing	Collecting duct	Aldosterone antagonism or ENaC inhibition
Carbonic anhydrase inhibitors	Proximal tubule	HCO₃⁻ reabsorption blockade
Osmotic	PCT/Loop of Henle	Osmotic water loss
Vasopressin antagonists	Collecting duct	Block vasopressin-mediated water reabsorption

3. Common Generic Drug Names

Thiazide Diuretics

• Hydrochlorothiazide (HCTZ)

• Chlorthalidone

• Indapamide

• Metolazone

Loop Diuretics

• Furosemide

• Bumetanide

• Torsemide

• Ethacrynic acid

Potassium-Sparing Diuretics

• Spironolactone

• Eplerenone

• Amiloride

• Triamterene

Carbonic Anhydrase Inhibitors

• Acetazolamide

• Methazolamide

• Dorzolamide (topical)

Osmotic Diuretics

• Mannitol

• Urea

Vasopressin Antagonists

• Tolvaptan (oral)

• Conivaptan (IV)

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4. Therapeutic Indications

Condition	Preferred Diuretic Class
Hypertension	Thiazides (first-line)
Heart failure	Loop diuretics ± aldosterone antagonists
Nephrotic syndrome	Loop diuretics
Chronic kidney disease	Loop ± thiazides
Hepatic cirrhosis with ascites	Spironolactone ± furosemide
Acute pulmonary edema	IV loop diuretics
Glaucoma	Acetazolamide, dorzolamide
Mountain sickness	Acetazolamide
Intracranial hypertension	Mannitol
Hyponatremia (SIADH)	Tolvaptan, Conivaptan

5. Dosing Overview

Thiazides:

• Hydrochlorothiazide: 12.5–50 mg/day orally

• Chlorthalidone: 12.5–25 mg/day (longer acting)

Loop Diuretics:

• Furosemide: 20–80 mg orally or IV (up to 600 mg/day in renal failure)

• Bumetanide: 0.5–2 mg

• Torsemide: 10–20 mg

Potassium-Sparing:

• Spironolactone: 25–100 mg/day

• Eplerenone: 25–50 mg/day

• Amiloride/Triamterene: 5–10 mg/day

Acetazolamide:

• 250–1000 mg/day (oral or IV)

Mannitol:

• 0.25–1 g/kg IV over 30–60 minutes

Tolvaptan:

• 15–60 mg orally once daily

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6. Adverse Effects by Class

Thiazides:

• Hypokalemia, hyponatremia

• Hyperuricemia → gout

• Hyperglycemia, hyperlipidemia

• Erectile dysfunction

Loop Diuretics:

• Profound hypokalemia and hypomagnesemia

• Ototoxicity (especially with ethacrynic acid)

• Dehydration, volume depletion

• Hyperuricemia

Potassium-Sparing:

• Hyperkalemia (especially with ACEIs, ARBs)

• Spironolactone: gynecomastia, menstrual irregularities

Carbonic Anhydrase Inhibitors:

• Metabolic acidosis

• Paresthesia

• Renal stones (due to alkaline urine)

• Sulfa allergy cross-reactivity

Osmotic Diuretics:

• Initial fluid overload

• Electrolyte imbalance

• Acute kidney injury if not monitored

Vasopressin Antagonists:

• Hypernatremia

• Liver toxicity (especially with tolvaptan)

• Thirst, polyuria

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7. Contraindications

Diuretic Class	Major Contraindications
Thiazides	Anuria, sulfa allergy (relative)
Loop Diuretics	Anuria, dehydration, sulfa allergy (relative)
K⁺-sparing Diuretics	Hyperkalemia, severe renal impairment, Addison’s
Carbonic Anhydrase Inhibitors	Sulfa allergy, cirrhosis, electrolyte imbalance
Osmotic	Heart failure, active cranial bleeding, anuria
Vasopressin Antagonists	Hypovolemia, liver disease (tolvaptan risk)

8. Drug Interactions

Diuretic Class	Notable Interactions
Thiazides	Lithium (↑ levels), NSAIDs (↓ efficacy), digoxin
Loops	Aminoglycosides (ototoxicity), lithium, digoxin
K⁺-sparing	ACEIs, ARBs (↑ K⁺), potassium supplements
Acetazolamide	Salicylates (toxicity), antiepileptics
Osmotic	Monitor for interaction with other IV drugs
Vasopressin antagonists	CYP3A4 inhibitors (↑ levels of tolvaptan)

9. Monitoring Parameters

• Electrolytes: Na⁺, K⁺, Mg²⁺, Ca²⁺, bicarbonate

• Renal function: BUN, creatinine, urine output

• Volume status: weight, edema, blood pressure

• Uric acid: particularly with thiazides, loops

• Liver function tests: for tolvaptan, spironolactone

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10. Use in Special Populations

Pregnancy:

• Avoid unless clearly necessary; thiazides may reduce placental perfusion

• Spironolactone: anti-androgenic – avoid

• Loop diuretics: may be used in acute pulmonary edema

Elderly:

• Increased risk of orthostatic hypotension, electrolyte imbalances

Renal Failure:

• Loop diuretics preferred (retain efficacy at low GFR)

• Avoid thiazides and potassium-sparing agents in advanced renal failure

Liver Cirrhosis:

• Spironolactone is first-line for ascites

• Avoid acetazolamide (may precipitate hepatic encephalopathy)

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11. Comparative Efficacy

Drug Class	Natriuretic Potency	Duration	Onset
Loop diuretics	Very high	Short (6 h)	Rapid (30–60 min)
Thiazides	Moderate	Long	Slower onset
K⁺-sparing	Weak	Moderate	Variable
Acetazolamide	Weak	Moderate	Intermediate
Osmotic	High (for water loss)	Short	Rapid
Vaptans	Moderate (water only)	Long	Slow

12. Clinical Guidelines and Practice Recommendations

• Hypertension: Thiazides (chlorthalidone preferred over HCTZ)

• Volume Overload in CHF: Loop diuretics ± thiazide synergy

• Hypokalemia Risk: Consider combination with K⁺-sparing agents

• Acute Emergency (e.g., pulmonary edema): IV furosemide

• Diuretic Resistance: Combine loop + thiazide; check for NSAID use

• Monitoring: Frequent labs during titration, especially in the elderly or renal impairment