Diuretics

Diuretics chemical agents that increase the rate of urine formation.

	Urinary excretion of Na⁺, K⁺, CL^-, HCO₃^-	Potency of Na⁺ excretion	Potency as Diuretic
Carbonic Anhydrase Inhibitor		+	+ (not used as a diuretic)
Thiazides	Ý , Ý , Ý , -/Ý*	++	++
Loop diuretics	Ý , Ý , Ý , -/Ý*	+++	+++
K⁺ sparing diuretics	Ý , ß , -, -	+	+
Aldosterone antagonists	Ý , ß , -, -	+	+
Mannitol		+	+

-/Ý = dependent of heritage, if a descendent of CA inhibitors Ý , if not -

Loop Diuretics

Furosemide, a.k.a. Lasix as well as Bumetanide and Ethacrynic acid

inhibit the Na⁺, K⁺, 2 Cl^- transporter on the apical membrane of the Thick Ascending Limb of the Loop of Henle. Since the TAL accounts for 25-30% of filtered NaCl and the downstream sites are not able to compensate for the increased Na⁺ load, Loop diuretics are the most efficacious of the diuretic drugs. The only other place that this membrane protein is expressed in mammals is in the Organ of Corti in the ear. This explains the temporary deafness that can occur with high dose Furosemide.

Mechanism of Action: by inhibiting the Na⁺, K⁺, 2CL^- reabsorption in the medullary portion of the Thick Ascending Limb, the loop diuretics limit the ability to generate as osmotic gradient in the medulla and consequently blunt or eliminate free water reabsorption during hydropenia. By blocking the transporter in the cortical segments the Loop diuretics decrease free water clearance. (eg urine specific gravity ~1.010) Loop diuretics enhance the urinary excretion of both Ca²⁺ and Mg²⁺.

Protein Binding: Furosemide is 96-98% bound to albumin (because it’s a weak organic acid) so very little is filtered at the glomerulus. In order to work (it’s site of action is on the luminal side) Furosemide needs to be actively secreted by the Anion transport system in the late proximal tubule. (this process can be inhibited by Probenecid).

Side Effects: Ototoxicity (with continued use), Hyperuricemia (can exacerbate gouty attacks), acute Hypovolemia (when they work too well), Hypocalcemia (Ý urinary Ca²⁺ excretion), and Potassium depletion Þ Hypokalemic alkalosis.

Clinical uses: drug of choice for reducing acute pulmonary edema of CHF. Also in the treatmentof hypercalcemia

Thiazide and Thiazide-like Diuretics

Hydrochlorothiazide and Metolazone, respectively

Mechanism of Action: All thiazides affect the Distal Tubule to decrease the reabsorption of Na⁺ by inhibition of the Na⁺/Cl^- cotransporter in the luminal membrane. Thiazides selectively bind the Cl^- site of the cotransporter.

Protein Binding: like Furosemide, a weak organic acid that needs to be actively secreted in the late proximal tubule.

Side Effects: Hypokalemia, decreased urinary Ca²⁺ excretionÞ Hypercalcemia, Hyperuricemia (gout in predisposed individuals), Volume Depletion, and Hyperglycemia (in DM patients both Furosemide and Thiazides inhibit Insulin secretion)

Clinical uses: HTN, CHF, Renal impairment, Hypercalceuria, Diabetes Insipidus (thiazides have the unique ability to produce a hyperosmolar urine and can substitute for ADH in the treatment of nephrogenic DI)

Potassium Sparing Diuretics

Amiloride, Triamterene, Spironolactone

Mechanism of Action: work in the Collecting Duct by either acting as an Aldosterone antagonist (Spironolactone) or by inhibiting the Na⁺/K⁺ exchanger that Aldosterone upregulates (Amiloride and Triamterene).

Spironoloactone: the active drug Canrenone derived from the pro-drug Spirolactone, is 98% protein bound.

Canrenone blocks the effects of Aldosterone. In disease states without Aldosterone (Addison’s disease)
Spironolactone will have no diuretic effect.

Side effects: painful gynecomastia in males, menstrual irregularities in females, hyperkalemia in both.

Clinical uses: to offset K⁺ losses in patients using Loop or Thiazide diuretics, treatment of secondary hyperaldosteronism.

Amiloride and Triamterene: both are weak bases that are actively secreted by the late proximal tubule. They bind to the collecting duct Na⁺ K⁺exchanger. Both are effective in the absence of Aldosterone.

Side effects: leg cramps, Ý BUN, Ý [K⁺], Ý [Uric acid]

Clinical uses: Like Spironolactone, Amiloride and Triamterene are not very efficacious diuretics but rather are used in combination with other diuretics for their K⁺sparing effect.

DO NOT USE POTASSIUM SUPPLEMENTS WITH K⁺ SPARING DIURETICS.

Osmotic Diuretics

Mannitol, Urea, and other simple hydrophilic compounds

A number of simple hydrophilic chemical substances filtered by the glomerulus result in some degree of diuresis. Once filtered the substance undergoes little to no reabsorption. Because they carry fluid with them into the tubular fluid osmotic diuretics increase urinary output. Because they are used to effect Ý H₂O secretion rather than Na⁺ excretion they are not useful in treating conditions where Na⁺ retention occurs.

Clinical uses: to reduce elevated intracranial pressure, to maintain urine flow following acute toxin ingestion of substances capable of producing acute renal failure, and acute renal failure due to shock or trauma.