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KIDNEY

Drugs inducing a state of increased urine flow are called

diuretics.

These agents are inhibitors of renal ion transporters that

decrease the reabsorption of Na+ at different sites in the

nephron.

As a result, Na+ and other ions, such as Cl–, enter the urine

in greater than normal amounts along with water, which is

carried passively to maintain osmotic equilibrium.

Diuretics, thus, increase the volume of urine and often

change its pH as well as the ionic composition of the urine

and blood.

INTRODUCTION

Furosemide

Torsemide

Amiloride

Triamterene

Spironolactone

Mannitol

Acetazolamide

Furosemide

Torsemide

Hydrochlorothiazide

Chlorthalidone

Indapamide

Diuretics exert their effect directly on the

kidneys. Most of them lead to electrolyte

excretion and

consequently to

osmotic excretion

of water, which

increases the

24-hr

urine volume.

The efficacy of the different classes of diuretics varies considerably, with the increase in Na+ secretion varying from less than 2 percent for the weak, potassium-sparing diuretics, to over 20 percent for the potent loop diuretics.

Moreover, there are osmotic diuretics that prevent water reabsorption as well as aldosterone antagonists and a carbonic anhydrase inhibitor.

The major clinical uses of diuretics are in managing disorders involving abnormal fluid retention (edema) or treating hypertension in which their diuretic action causes an initial decreased blood volume followed by a lowering of the peripheral resistance, leading to reduced blood pressure.

INTRODUCTION

1. To maintain urine volume ( e.g.: renal

failure)

2. To mobilize edema fluid (e.g.: heart

failure,liver failure, nephrotic syndrome)

3. To control high blood pressure

PURPOSE OF USING DIURETICS

The kidney is designed to filter large quantities of plasma,

reabsorb substances that the body must conserve, and leave

behind and/or secrete substances that must be eliminated.

The two kidneys in humans produce together ~120 mL of

ultrafiltrate per minute, yet only 1 mL/min of urine is

produced.

Therefore, >99% of the glomerular ultrafiltrate is reabsorbed

at a staggering energy cost.

The kidneys consume 7% of total-body oxygen intake despite

the fact that the kidneys make up only 0.5% of body weight.

OVERVIEW OF NEPHRON FUNCTION

Major locations of ion and water exchange in the nephron, showing sites of action of the

diuretic drugs

MAJOR SEGMENTS OF THE NEPHRON AND THEIR

FUNCTIONS

TUBULE TRANSPORT SYSTEMS AND SITES OF ACTION OF DIURETICS

GENERAL MECHANISM OF RENAL EPITHELIAL

TRANSPORT

REABSORPTION

Historically, the classification of diuretics was

based on a mosaic of ideas such as site of

action (loop diuretics), efficacy (high-ceiling

diuretics), chemical structure (thiazide

diuretics), similarity of action with other

diuretics (thiazide-like diuretics), and effects on

K+ excretion (K+-sparing diuretics). However,

since the mechanism of action of each of the

major classes of diuretics is now well

understood, a classification scheme based on

mechanism of action.

Carbonic anhydrase inhibitors

Acetazolamide inhibits carbonic

anhydrase (CA) mainly in proximal tubules.

H2O + CO2 CA

H2CO3 H2CO3– + H+

Apical membrane Na + /H + exchange (via NHE3) and bicarbonate

reabsorption in the proximal convoluted tubule cell

INHIBITORS OF CARBONIC ANHYDRASE

Although acetazolamide is used for treatment of edema, the

efficacy of carbonic anhydrase inhibitors as single agents is low,

and carbonic anhydrase inhibitors are not employed widely in this

regard.

The major indication for carbonic anhydrase inhibitors is open-

angle glaucoma. Two products developed specifically for this use

are dorzolamide (TRUSOPT, others) and brinzolamide (AZOPT),

which are available only as ophthalmic drops.

Carbonic anhydrase inhibitors also may be employed for secondary

glaucoma and preoperatively in acute angle-closure glaucoma to

lower intraocular pressure before surgery

Acetazolamide also is used for the treatment of epilepsy. The

rapid development of tolerance, however, may limit the usefulness

of carbonic anhydrase inhibitors for epilepsy.

THERAPEUTIC USES

Sedation and drowsiness; Hypersensitivity

reaction (because it contains sulfur) Acidosis

(because of decreased absorption of HCO3 ) ;

Renal stone (because of alkaline urine);

Hyperchloremia, hyponatremia and

hypokalemia

SIDE EFFECTS OF ACETAZOLAMIDE:

60–80%

Osmotic diuretics

Osmotic diuretics are agents that are freely filtered at the

glomerulus, undergo limited reabsorption by the renal tubule,

and are relatively inert pharmacologically.

Osmotic diuretics are administered in doses large enough to

increase significantly the osmolality of plasma and tubular

fluid.

Osmotic diuretics increase urinary excretion of nearly all

electrolytes, including Na+, K+, Ca2+, Mg2+, Cl–, HCO3– and

phosphate

OSMOTIC DIURETICS

Abbreviations: R, renal excretion of intact drug; M, metabolism; B, excretion of intact drug into

bile; U, unknown pathway of elimination; ID, insufficient data.

One use for mannitol is in the treatment of dialysis

disequilibrium syndrome.

By increasing the osmotic pressure of plasma, osmotic

diuretics extract water from the eye and brain.

All osmotic diuretics are used to control intraocular pressure

during acute attacks of glaucoma and for short-term

reductions in intraocular pressure both preoperatively and

postoperatively in patients who require ocular surgery.

Also, mannitol and urea are used to reduce cerebral edema

and brain mass before and after neurosurgery

THERAPEUTIC USES

Loop Diuretics

Drugs in this group of diuretics inhibit activity of the Na+-K+-2Cl– symporter in the thick ascending l imb of the loop of Henle; hence these diuretics also are referred to as loop diuretics .

The molecular mechanism by which this class of drugs blocks the Na+-K+-2Cl– symporter is unknown, but evidence suggests that these drugs attach to the Cl– binding site located in the symporter's transmembrane domain (Isenring and Forbush, 1997).

Cause a greater natriuresis than thiazides

Effective at low glomerular fi ltration rates (as occur in chronic

renal failure), where thiazides are ineffective

Increase potassium, calcium and magnesium excretion. Decrease urate excretion

INHIBITORS OF NA+-K+-2CL– SYMPORT

(LOOP DIURETICS)

Furosemide has p.o. bioavailability 65%

and t1/2 30–60 min. It acts on the ascending

limb of Henley's loop by increasing

urine excretion of Na+, Cl, Mg2+ and

Ca2+. Its diuretic effect is achieved in

20–30 min after p.o. administration

and lasts 4–6 h. Its effect after i.v.

administration begins in 3–5 min and

lasts 2 h. In low doses (5 to 10 mg p.o.)

furosemide has antihypertensive effect.

It does not disrupt GF.

Furosemide – ARs:

Hypokaliemia, skin rashes, hyperglycemia,

increased plasma levels of uric acid.

In fast i.v. administration – transient

hearing disturbances with temporary

deafness and orthostatic collapse.

Ototoxic risk is increased in co-medicaton

with aminoglycosides, cephalosporines,

polymyxins, sulfonamides or quinolones.

Ion transport pathways across the luminal and

basolateral membranes of the thick ascending limb cell.

paracellular pathway

EDEMA due to CHF, nephrotic syndrome or cirrhosis

(ascites)

Acute heart failure with PULMONARY EDEMA

HYPERCALCEMIA

not in widespread use for the treatment of

hypertension (except in a few special cases e.g.

hypertension in renal disease)

In patients with a drug overdose, loop diuretics can

be used to induce a forced diuresis to facilitate

more rapid renal elimination of the offending drug .

CLINICAL USES OF LOOP

DIURETICS

They increase equivalently Na+ and Cl - excretion (1:1) in distal renal tubules and this increases diuresis .

They lead to excretion of 5 to 10% from filtrated Na+ ions and have moderate diuretic action.

Reduce calcium and urate excretion.

Not effective at low glomerular filtration rates.

They potentiate significantly the effect of other

antihypertensive drugs.

INHIBITORS OF NA+-CL– SYMPORT (THIAZIDE AND

THIAZIDE-LIKE DIURETICS)

Thiazide diuretics are used for the treatment of edema

associated with heart (congestive heart failure), liver

(hepatic cirrhosis), and renal (nephrotic syndrome, chronic

renal failure, and acute glomerulonephritis) disease.

Thiazide diuretics are used widely for the treatment of

hypertension either alone or in combination with other

antihypertensive drugs.

Idiopathic hypercalciuria : condition characterized by

recurrent stone formation in the kidneys due to excess

calcium excretion.

Diabetes insipidus

THERAPEUTIC USES

Triamterene and amiloride are the only two drugs of

this class in clinical use.

Both drugs cause small increases in NaCl excretion

and usually are employed for their antikaliuretic

actions to offset the effects of other diuretics that

increase K+ excretion.

Consequently, triamterene and amiloride, along

with spironolactone (described in the next section),

often are classified as potassium (K+)-sparing

diuretics.

INHIBITORS OF RENAL EPITHELIAL NA+

CHANNELS (K+-SPARING DIURETICS)

Because of the mild natriuresis induced by Na+-channel

inhibitors, these drugs seldom are used as sole agents in

treatment of edema or hypertension.

Rather, their major utility is in combination with other diuretics;

indeed, each is marketed in a fixed-dose combination with a

thiazide: triamterene/hydrochlorothiazide (DYAZIDE, MAXZIDE,

others), amiloride/hydrochlorothiazide (generic).

Co-administration of an Na+-channel inhibitor augments the

diuretic and antihypertensive response to thiazide and loop

diuretics. More important, the ability of Na+-channel inhibitors to

reduce K+ excretion tends to offset the kaliuretic effects of

thiazide and loop diuretics; consequently, the combination of an

Na+-channel inhibitor with a thiazide or loop diuretic tends to

result in normal plasma K+ values

THERAPEUTIC USES

Aldosterone enters the epithelial cell from the basolateral membrane and binds to MRs; the MR-aldosterone complex translocates to the nucleus, where it binds to specific sequences of DNA (hormone-responsive elements) and thereby regulates the expression of multiple gene products called aldosterone-induced proteins (AIPs).

Drugs such as spironolactone and eplerenone competitively inhibit the binding of aldosterone to the MR. Unlike the MR-aldosterone complex, the MR-spironolactone complex is not able to induce the synthesis of AIPs. Since spironolactone and eplerenone block biological effects of aldosterone, these agents also are referred to as aldosterone antagonists .

The higher the endogenous aldosterone level, the greater the effects of MR antagonists on urinary excretion.

ANTAGONISTS OF MINERALOCORTICOID RECEPTORS

(ALDOSTERONE ANTAGONISTS, K+-SPARING

DIURETICS)

Mineralocorticoids cause salt and water retention and

increase K+ and H+ excretion by binding to specific

mineralocorticoid receptors.

Epithelial cells in late distal tubule and collecting duct

contain cytosolic MRs with a high aldosterone affinity.

MRs are members of the superfamily of receptors for steroid

hormones, thyroid hormones, vitamin D, and retinoids.

ANTAGONISTS OF MINERALOCORTICOID RECEPTORS

(ALDOSTERONE ANTAGONISTS, K+-SPARING

DIURETICS)

1. Activation of membrane-bound

Na+ channels.

2. Na+ channel (ENaC) removal from

the membrane is inhibited.

3. De novo synthesis of Na+

channels.

4. Activation of membrane-bound

Na+,K+- ATPase.

5. Redistribution of Na+,K+-ATPase

from cytosol to membrane.

6. De novo synthesis of Na+,K+-

ATPase.

7. Changes in permeability of tight

junctions.

8. Increased mitochondrial

production of ATP.

AIP, aldosterone-induced proteins;

ALDO, aldosterone; MR,

mineralocorticoid receptor; CH, ion

channel; BL, basolateral membrane;

LM, luminal membrane.

As with other K+-sparing diuretics, spironolactone often is

coadministered with thiazide or loop diuretics in the

treatment of edema and hypertension, and spironolactone in

combination with hydrochlorothiazide (ALDACTAZIDE, others)

is marketed.

Combinations result in increased mobilization of edema fluid

while causing lesser perturbations of K+ homeostasis.

Spironolactone is particularly useful in the treatment of

resistant hypertension due to primary hyperaldosteronism

(adrenal adenomas or bilateral adrenal hyperplasia) and of

refractory edema associated with secondary aldosteronism

(cardiac failure, hepatic cirrhosis, nephrotic syndrome, and

severe ascites).

THERAPEUTIC USES

Hyperkalemia (some times it’s useful other wise it’s a side effect).

Hyperchloremic metabolic acidosis

Antiandrognic effects (e.g. gynecomastia: breast enlargement in males, impotence) by spironolactone.

Triametrene causes kidney stones.

SIDE EFFECTS:

THE RAA SYSTEM

Summary