"Diuresis"

Signifies an increase in urine volume.

"Natriuresis"
Denotes an increase in renal sodium excretion.

Because natriuretic drugs almost always also increase

water excretion, they are usually called diuretics.
Types of diuretics:

According to their natriuretic capacity

I- High efficacy:

They allow 15-25% of filtered Na to be excreted as:

Loop diuretics
II-Moderate efficacy:
They allow 5-10 % of filtered Na to be excreted as :
 Thiazides.
III-Low efficacy:
They allow less than 5 % of filtered Na to be excreted
as :
 K sparing diuretics
 Osmotic diuretics
 Carbonic anhydrase inhibitors
 Loop diuretics

 Furosemide.
 Torsemide
 Bumetanide.
 Ethacrynic acid.
Mechanism of actions:
These drugs inhibit the luminal Na+/K+/2Cl-
transporter in the thick ascending limb of loop of
Henle. So, loop diuretics lead to :
Reduce the reabsorption of NaCl.
Increase in K+ excretion.
• Increase in Mg2+ and Ca2+ excretion.
Induce (COX-2), which participates in the synthesis
of PGE 2 , from arachidonic acid.
Hemodynamic action:

 Loop diuretics stimulate renal prostaglandin

synthesis.
 These PGs participate in the renal actions of these
drugs.
 NSAIDs (eg, indomethacin) can interfere with the
actions of the loop diuretics by reducing PGs
synthesis in the kidney.
 Loop diuretics increase renal blood flow.
 Increase systemic venous capacitance.
 Reduce pulmonary congestion.
 Decrease left ventricular filling pressures in
heart failure before a measurable increase in

urinary output occurs.

Therapeutic uses:
1-Acute pulmonary edema.

2-Other edematous states as in

Cardiac, renal, or hepatic diseases,

In some cases, salt and water retention may

become severe so a combination with thiazides is
necessary.
3-Essential hypertension:
Useful in hypertensive emergency
In patients have hypertension with chronic renal
failure
4-Hyperkalemia:
It can significantly enhance urinary excretion of K+.
5-Symptomatic hypercalcemia:
It increases the urinary excretion of Ca++ but
replacement of urinary losses of Na+ and Cl- is
required.
Toxicity:
1-Hypokalemia:
Can be reversed by K+ replacement.
2-Ototoxicity:
Loop diuretics can cause dose-related hearing loss that
is usually reversible.
3-Hyperuricemia:
Loop diuretics can precipitate attacks of gout .
4-Hypomagnesemia:
Can be reversed by administration of oral magnesium
preparations.
5-Allergic Reactions:
Skin rash, eosinophilia and, less often, interstitial
nephritis
These usually disappear after drug withdrawal.
6-Hyperglycemia
7-Nephrotoxicity:
Loop diuretics can potentiate the nephrotoxicity of
cephalosporins.
 Thiazide diuretics

Chlorothiazide.
Hydrochlorothiazide.
Bendroflumethiazide
Chlorthalidone.
Indapamide.
Metolazone.
Mechanism of actions:
 Thiazides act on distal convoluted tubule.
 They block the Na+/Cl- transport system.
 So, inhibit NaCl reabsorption from the luminal
side of epithelial cells.
Thiazides Ca2+ reabsorption in the DCT:
This enhancement due to:

thiazides increase Na+/Ca2+ exchange so ,

increasing reabsorption of Ca2+.
Affect Ca2+ absorption by parathyroid hormone on
DCT.
Therapeutic uses:
1-Hypertension
Thiazides are useful in treating all patients with
essential hypertension.

Firstly, they decrease B.P by decreasing plasma

volume and COP.

During chronic therapy they decrease B.P by

vasodilator effect.
2- Heart failure:
In mild and moderate CHF.
But not useful in patients with impaired renal
function.

3-Edema due to chronic hepatic and renal

diseases.
4-Nephrolithiasis due to idiopathic

hypercalciuria

This disease can be treated with thiazide diuretics,

which enhance calcium reabsorption in the distal
convoluted tubule and thus reduce the urinary
calcium concentration.

5-Osteoporosis
6-Nephrogenic Diabetes Insipidus:
Thiazide diuretics can reduce polyuria in these
patients.
The effect is paradoxic.
By reduction in plasma volume GFR

Proximal reabsorption NaCl and water

Toxicity:
1-Hypokalemic
Can be reversed by K+ replacement.
2-Hyperuricemia
Thiazides diuretics can precipitate attacks of gout
3-Hyperlipidemia.
They increase in serum cholesterol and increased (LDL).
4-Hyperglycemia.
5-Hyponatremia.
.
6-Allergic Reactions
As photosensitivity, dermatitis, hemolytic
anemia, thrombocytopenia.

7-Hypercalcemia
 Potassium-Sparing Diuretics
I- Aldosterone receptors antagonist:
Spironolactone.

II-Inhibitors of Na+ influx through ion channels in

renal epithelial cells:
Amiloride.
Triamterene.
I- Aldosterone receptors antagonist:
Spironolactone.
Eplerenone.
Mechanism of action:
It antagonizes the effects of aldosterone in the
collecting tubule.

It reduces Na+ absorption.

It reduces K+ and H+ secretion.
Therapeutic uses:
1-In treatment of hypertension, usually associated with other
diuretics.

2- In states of primary hyperaldosteronism as Conn's

syndrome, ectopic ACTH production.

3-In cases of secondary aldosteronism in

 Hepatic cirrhosis.
 Nephrotic syndrome.
 Heart failure.
4-It slows the progression of albuminuria in

diabetic patients and reduces myocardial perfusion

defects after myocardial infarction.

Where low doses of eplerenone interfere with the

fibrotic and inflammatory effects of aldosterone.

Adverse effects:
1-Hyperkalemia

These drugs can cause mild, moderate, or even life-

threatening hyperkalemia.

2-Gynecomastia and menstrual irregularity.

3-Benign prostatic hyperplasia.

4-Mild GIT symptoms.

II-Inhibitors of Na+ influx through ion
channels in renal epithelial cells:
They directly interfere with Na+ entry through
the Na+channels in the apical membrane of the
collecting tubule.
K+ secretion is coupled with Na+ entry in this
segment, so, act also as potassium-sparing
diuretics.
Therapeutic uses:
 In the treatment of hypertension and Heart failure.
usually associated with other diuretics.

 By inhibiting Na+ absorption from the surfaces of

airway epithelial cells, amiloride leads to hydration of
respiratory secretions and improves mucociliary
function in cystic fibrosis.
 Amiloride also is useful for lithium-induced
nephrogenic diabetes insipidus
Adverse effects:
1-Hyperkalemia

2-Kidney Stones with Triamterene

3-Nausea, vomiting diarrhea

 Carbonic Anhydrase (CA) Inhibitors
CA inhibitors block CA enzyme, so prevent the
dehydration of H2CO3 to CO2 at the luminal
membrane and cause diuresis.

-CA inhibition causes significant HCO3− losses and

metabolic acidosis.
Clinical uses:
1- Glaucoma: The reduction of aqueous humor
formation by HCO3− losses lead to reduce in the
I.O.P.

2- Urinary Alkalinization: CA inhibitors can

increase urinary pH, so decrease uric acid stones.

3-They are used as adjuvants in the treatment of

epilepsy.
Adverse Effects:
Most adverse effects are secondary to urinary
alkalinization or metabolic acidosis, including:
1-Drowsiness.
2-Increase the absorption of ammonia from urine
into the blood leads to worsen hepatic encephalopathy,
so the drugs are contraindicated in patients with
hepatic cirrhosis.
3-Ureteral colic due to precipitation of calcium salts
in an alkaline urine.
 Osmotic Diuretics

Mannitol.

Site of action:

 Proximal tubule.
 Descending limb of Henle's loop.
Pharmacokinetics
Osmotic diuretics are characterised by:

They are poorly absorbed.

They are not metabolized and are excreted
primarily by glomerular filtration.

They are not reabsorbed by renal tubules.

They are pharmacologically inert.
Mechanism of action:
They prevent the water reabsorption in Proximal

tubule and Descending limb of the loop of Henle.

They also antagonize the action of ADH in the

collecting tubule.
The presence of mannitol prevents the normal
absorption of water by increasing the osmotic

force.

So, urine volume increases.

The increase in urine flow rate decreases Na +

reabsorption.
Therapeutic uses:
1-Prophylaxis and early treatment of acute renal
failure in cases of:

Cardiovascular operations.
Severe traumatic injury.
Hemolytic transfusion reactions.
2-Used to reduce intracranial pressure in
neurologic conditions.

3-To reduce intraocular pressure before

ophthalmologic procedures

4-Used in the treatment of

dialysis disequilibrium syndrome:

In patient with chronic renal failure

Toxicity
1-Extracellular Volume Expansion

Mannitol is rapidly distributed in the extracellular

compartment and extracts water from cells.

This effect can:

Complicate heart failure.

Produce pulmonary edema
2-Hypernatremia.

3-Dehydration.

4- Headache, nausea, and vomiting.

Diuretic Combinations
I-Loop Agents & Thiazides
the use of two drugs acting at different nephron
sites may exhibit synergy.
K+-wasting is extremely common and may require
parenteral K+ administration with careful
monitoring of fluid and electrolyte status.
II-Potassium-Sparing Diuretics & Loop
Agents.

III-Potassium-Sparing Diuretics & Thiazides.