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Transcript
Diuretic Agents
Carbonic Anhydrase
Inhibitors
Carbonic Anhydrase Inhibitors





Carbonic anhydrase is in the PCT, where it
catalyzes the dehydration of H2CO3
By blocking carbonic anhydrase, drugs block
NaHCO3 reabsorption and cause diuresis
Carbonic anhydrase inhibitors are now rarely
used as diuretics
They have several specific applications
The prototypical drug is acetazolamide
Carbonic Anhydrase Inhibitors




the inhibition of enzyme causes HCO3– losses and
metabolic acidosis
the major clinical applications of acetazolamide
involve sites other than the kidney.
The ciliary body of the eye secretes HCO3– from
the blood into the aqueous humor.
formation of CSF by the choroid plexus also
involves HCO3– secretion.
Clinical Indications




Glaucoma (dorzolamide, brinzolamide)
Urinary Alkalinization

Uric acid, cystine, and other weak acids are
reabsorbed from acidic urine.

renal excretion of cystine (in cystinuria) can be
enhanced by increasing urinary pH.
Metabolic Alkalosis + Edema
Acute Mountain Sickness
Toxicity

Metabolic Acidosis

Renal Stones

Calcium salts are relatively insoluble at alkaline
pH

Renal Potassium Wasting

Drowsiness and paresthesias after large doses
Contraindications

alkalinization of the urine decreases urinary
excretion of NH4+ (converts it to rapidlyreabsorbed NH3)

in patients with cirrhosis this contributes to
hyperammonemia and hepatic
encephalopathy.
Loop diuretics
Loop Diuretics


Loop diuretics selectively inhibit NaCl
reabsorption in the TAL
Loop diuretics are the most efficacious diuretics
because:




large NaCl absorptive capacity of TAL
The two prototypical drugs of this group are
furosemide and ethacrynic acid.
bumetanide and torsemide are also loop
diuretics.
The duration of effect for loop diuretics is short.
Pharmacodynamics

Loop diuretics inhibit the Na+/K+/2Cl– transporter in
the TAL

They reduce both the reabsorption of NaCl and
lumen-positive potential that comes from K+
recycling.

This positive potential normally drives divalent cation
reabsorption in the loop

So loop diuretics cause an increase in Mg2+ and Ca2+
excretion.
Pharmacodynamics

Prolonged use can cause significant hypomagnesemia

intestinal absorption of Ca2+ can be increased and Ca2+ is
actively reabsorbed in the DCT

So loop diuretics do not generally cause hypocalcemia

in disorders that cause hypercalcemia, Ca2+ excretion can
be usefully enhanced by loop diuretics combined with
saline infusions

Both furosemide and ethacrynic acid have also been
shown to reduce pulmonary congestion and LVEDP in
heart failure before diuretic effect.
Clinical Indications

The major application of loop diuretics is in
the treatment of edematous states


heart failure, ascites, and acute pulmonary edema
They are sometimes used in hypertension if
response to thiazides is inadequate, but the
short duration of action of loop diuretics is a
disadvantage in this condition
Clinical Indications

A less common but important application is in
the treatment of severe hypercalcemia

Acute Renal Failure

They increase urine flow and enhance K+
excretion.

they can flush out pigment cast in the tubules.
Toxicity


Hypokalemic Metabolic Alkalosis

They increase salt delivery to the collecting duct.

This leads to increased secretion of K+ and H+
Ototoxicity

dose-related hearing loss may happen and is usually
reversible.

It is most common in diminished renal function or those
who are using other ototoxic drugs.
Toxicity


Hyperuricemia

They may cause hyperuricemia and precipitate
attacks of gout.

This is caused by hypovolemia-associated
enhancement of uric acid reabsorption in the PCT.
Hypomagnesemia

Occurs in dietary magnesium deficiency.

It can be reversed by oral magnesium.
Toxicity

Allergic & Other Reactions

Most of the loop diuretics are sulfonamides.

skin rash, eosinophilia, and interstitial nephritis are
occasional adverse effects.

This usually resolves rapidly after drug
withdrawal.
Thiazides

thiazides inhibit NaCl transport in the DCT.
Thiazides

All thiazides are secreted in the proximal tubule

They compete with the secretion of uric acid

So thiazides may elevate serum uric acid level.

Thiazides block the Na+/Cl– transporter (NCC).

thiazides actually enhance Ca2+ reabsorption.

thiazides may rarely cause hypercalcemia

They are useful for kidney stones caused by
hypercalciuria.
Thiazides

Clinical Indications

Hypertension

heart failure

nephrolithiasis due to idiopathic hypercalciuria
Toxicity

Hypokalemia, Metabolic Alkalosis and
Hyperuricemia

Hyperglycemia due to impaired release of insulin.

Hyperlipidemia as a 5–15% increase in total serum
cholesterol and LDL.

Allergic Reactions (the thiazides are sulfonamides).

Dilutional Hyponatremia is an important adverse
effect of thiazides
Potassium-Sparing Diuretics

Potassium-Sparing Diuretics

Spironolactone

Eplerenone

Amiloride

Triamterene
Potassium-Sparing Diuretics
Potassium-Sparing Diuretics




They antagonize the effects of aldosterone.
Inhibition may occur by:

direct antagonism of receptors (spironolactone,
eplerenone)

inhibition of Na+ influx (amiloride, triamterene).
Eplerenone is more selective so has less side
effects.
They cause metabolic acidosis.
Clinical Indications


Compensation of thiazide-induced hypokalemia
They are useful in primary and secondary
hyperaldosteronism

eplerenone has been found to reduce myocardial
perfusion defects after MI.

eplerenone reduced mortality rate by 15%
(compared with placebo) in heart failure after
MI.
Toxicity



They can cause life-threatening hyperkalemia.
This risk is greatly increased by:

renal disease

the use of drugs that inhibit renin (β blockers)

the use of drugs that inhibit angiotensin II activity
(ACEIs, angiotensin receptor blockers (ARBs)).
Combinations of K+-sparing and thiazides
ameliorate thiazide-induced hypokalemia and
alkalosis
Toxicity

Metabolic Acidosis

Gynecomastia, impotence is reported with
spironolactone but not with eplerenone.

Patients with chronic renal insufficiency are especially
vulnerable to hyperkalemia.
Agents That Alter Water Excretion

Osmotic Diuretics

Antidiuretic Hormone (ADH) Agonists

Antidiuretic Hormone (ADH) Antagonists
Osmotic Diuretics

Any osmotically active agent promotes a water
diuresis.

Such agents reduce intracranial and intraocular
pressure

The prototypic osmotic diuretic is mannitol.

Oral mannitol causes osmotic diarrhea so for systemic
effect, it is given parenterally.
Osmotic Diuretics

they also oppose the action of ADH.

They reduce Na+ as well as water reabsorption.

The natriuresis is of lesser magnitude than the
water diuresis, leading to hypernatremia.
Clinical indications

It is used to prevent anuria from large pigment loads
to the kidney.

Reduction in ICP in neurologic conditions & IOP
before ophthalmologic procedures.
Toxicity

Mannitol is rapidly distributed in the extracellular
compartment and extracts water from cells.

Prior to the diuresis, this leads to expansion of the
extracellular volume and hyponatremia.

This can complicate heart failure and may produce
pulmonary edema.
ADH Agonists
&
Antagonists
ADH Agonists

Vasopressin and desmopressin are used in
the treatment of central diabetes insipidus.

The renal action appears to be mediated
primarily via V2 receptors

They are ineffective in nephrogenic diabetes
insipidus

Treatment involves salt restriction, water restriction, thiazides and loop diuretics
ADH Antagonists




Syndrome of Inappropriate Antiduiretic Hormone
(SIADH) secretion, causes water retention.
Conivaptan is an antagonist against both V1a and
V2 ADH receptors.
Tolvaptan is an antagonist with more selectivity
for V2 ADH receptors than V1a.
Lithium & demeclocycline have anti-ADH
effects, but have many side effects and are not
used.
Clinical Indications

In SIADH when water restriction has failed.
Toxicity
Nephrogenic Diabetes Insipidus