Diuretics

Diuretics

Diuretics are drugs which increase sodium and water excretion

by the kidney.

The term ‘diuresis’ means increased urine flow, while the term

‘saluresis’ means increased urinary sodium excretion.

All diuretics increase the excretion of water from the body,

although each class of diuretic does so in a distinct way.

Chemically, diuretics are a diverse group of compounds that

either stimulate or inhibit various hormones that naturally occur

in the body to regulate urine production by the kidneys.

The primary therapeutic goal of diuretic use is to reduce edema by reducing the

ECF volume.

1. For this to occur, NaCl output must exceed NaCl intake.

2. Diuretics primarily prevent Na+ entry into the tubule cell.

Once a diuretic enters the tubule fluid, the nephron site at which it acts

determines its effect.

In addition, the site of action also determines which electrolytes, other than

Na+, will be affected. All diuretics except spironolactone exert their effects

from the luminal (tubule fluid) side of the nephron.

Hence, it is necessary for diuretics to get into the

tubule fluid in order to be effective.

Mannitol does this by filtration at the glomerulus, however,

all other diuretics (except spironolactone) are fairly tightly

protein bound and undergo little filtration.

They reach the urine by secretion across the proximal

tubule via the organic acid or organic base secretory

pathway.

ROLE OF THE NEPHRON1. Kidneys control the extracellular fluid (ECF) volume by

adjusting NaCl and H2O excretion.

2. Each day the kidney filters more than 22 moles of Na.

To maintain NaCl balance, approximately 3 lbs of NaCl

must be reabsorbed by the renal tubules on a daily basis.

3. The body maintains blood pressure at the expense of ECF

volume.

4. When NaCl intake > output, i.e. congestive heart failure or

renal failure, edema develops.

5. Na+ reabsorption is driven primarily by Na+/K+

adenosine triphosphatase (ATPase) located at the

basolateral (blood side) membrane of epithelial cells

throughout the nephron.

6. The Na+/K+ is an energy-requiring pump which

exchanges 1 Na+ for 2 K+, thereby keeping a low Na+

concentration and a high K+ concentration within the cell.

7. On the luminal side, cell-specific pathways exist forpassive movement of Na+ down its electrochemicalgradient from lumen to cell.

These cells form the physiologic basis of diuretic action.

Acetazolamide

N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide

Furosemide

4-Chloro-2-[(furan-2-ylmethyl)amino]-5-sulfamoylbenzoic acid

Ethacrynic acid

Carbonic Anhydrase InhibitorsMechanism of action

Bicarbonate is primarily reabsorbed in the proximal tubule. H+

ion is secreted into the lumen where it can combine with filtered

bicarbonate (HCO3-) to form H2CO3 that is then converted to

CO2 and H2O (catalyzed by carbonic anhydrase).

CO2 diffuses into the proximal tubule where it combines with

H2O to form H2CO3 (Carbonic acid) that then forms H+ and

HCO3-. HCO3- exits the proximal tubule on the blood side,

while H+ is again secreted into the tubule lumen.

If CA activity is inhibited, HCO3- reabsorption is reduced and

exits the proximal tubule in much larger amounts.

Because Na+ is the most abundant cation present in proximal

tubule fluid, it is the major cation which accompanies HCO3 -

out of the proximal tubule.

In the distal nephron, Na+ is largely reabsorbed (unlike HCO3 -)

and is exchanged for K+.

Therefore, acetazolamide primarily causes an increase in urinary

HCO3-, K+, and water excretion.

Effectiveness is reduced with continued therapy because plasma

[HCO3-] fall, reducing the amount of HCO3 - that appears in the

urine.

Structure–activity relationship Site1 Carbonic anhydrate inhibitors acetazolamide,methazolamide

1. Simple heterocyclic sulfonamides yielded the

prototypic carbonic anhydrase inhibitor

acetazolamide.

2. The sulfamoyl group is essential for the in vitro and

in vivo carbonic anhydrase activity.

3. The sulfamoyl nitrogen must remain unsubstituted

to retain both in vivo and in vitro activities.

4. Substitution of a methyl group on one of acetazolamide’s

ring nitrogen yields methazolamide retains carbonic

anhydrase inhibitory activity.

5. The moiety to which sulfamoyl group is attached must

possess aromatic character.

6. Heterocyclic sulfonamide, the derivative with highest

lipid/water partition coefficient and the lowest pKa values

has the greatest carbonic anhydrase activity and diuretic

activity.

Uses

1. 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.

2. However, studies indicate that the combination of acetazolamide

with diuretics that block Na+ reabsorption at more distal sites in the

nephron causes a marked response in patients who are resistant to

diuretic monotherapy.

3. Even so, the long-term usefulness of carbonic anhydrase

inhibitors often is compromised by the development of

metabolic acidosis.

Site 2 High ceiling or loop diuretics

Furosemide, Bumetanide and Ethacrynic Acid (LoopDiuretics)

Drugs in this group of diuretics inhibit the activity of the

Na+-K+-2Cl- symporter in the thick ascending limb of the

loop of Henle; hence these diuretics also are referred to as

loop diuretics.

Proximal tubule reabsorbs 65% of filtered Na+, diuretics

acting only in the proximal tubule have limited efficacy

because the thick ascending limb has a great reabsorptive

capacity and reabsorbs most of the rejectate from the

proximal tubule.

Diuretics acting predominantly at sites past the thick

ascending limb also have limited efficacy because only a

small percentage of the filtered Na+ load reaches these

more distal sites.

In contrast, inhibitors of Na+ – K+ – 2Cl– symport in the

thick ascending limb are highly efficacious, and for this

reason, they sometimes are called high-ceiling diuretics.

The efficacy of inhibitors of Na+ – K+ – 2Cl– symport in

the thick ascending limb of the loop of Henle is due to a

combination of two factors:

1. Approximately 25% of the filtered Na+ load normally is

reabsorbed by the thick ascending limb.

2. Nephron segments past the thick ascending limb do not

possess the reabsorptive capacity to rescue the flood of

rejectate exiting the thick ascending limb.

Furosemide and others act primarily in the thick ascending limb

and inhibit Na+ – K+ Cl – symport.

In the thick ascending limb, flux of Na+ – K+ and Cl- from the lumeninto the epithelial cell is mediated by Na+ – K+ 2Cl- symporter.

This symporter captures the energy in the Na+ electrochemical

gradient established by the basolateral Na+ pump and provides for

up hill transport of K+ and Cl– into the cell.

K+ channels in the luminal membrane provide a conductivepathway for the optical recycling of this cation and basolateral Cl–channels provide a basolateral exit mechanism for Cl–.

Inhibition of Na+ – K+ –2 Cl– symport binds to the Na+ – K+ – 2Cl–

symporter and blocks its function, bringing salt transport in this

segment of nephron to virtual stand still.

It is suggested that these drugs attach to the binding site of the

symporter.

The Na+ – K+– 2Cl– symporter has amino acid sequence of 1191

residues containing 12 putative membranes – spanning domains flanked

by long N and C termini in the cytoplasm.

NaCl reabsorption in thick ascending limb and mechanism of diureticaction of NaCl reabsorption in thick ascending limb and mechanism ofdiuretic action of Na+ – K+ – 2Cl– symport inhibitors. S = symporter, CH =ion channel

2-[2,3-dichloro-4-(2-methylidenebutanoyl)phenoxy]acetic acid

4-Chloro-2-[(furan-2-ylmethyl)amino]-5-sulfamoylbenzoic acid

3-butylamino-4-phenoxy-5-sulfamoyl-benzoic acid

2-chloro-5-(2H-tetrazol-5-yl)-4-[(thiophen-2-ylmethyl)amino]benzenesulfonamide

Uses

1. A major use of loop diuretics is in the treatment of acute pulmonary edema.

A rapid increase in venous capacitance in conjunction with a brisk

natriuresis reduces left ventricular filling pressures and thereby rapidly

relieves pulmonary edema.

2. Loop diuretics are also used widely for the treatment of chronic congestive

heart failure when diminution of extracellular fluid volume is desirable to

minimize venous and pulmonary congestion.

3. In this regard, a meta-analysis of randomized clinical trials demonstrates that

diuretics cause a significant reduction in mortality and the risk of worsening

heart failure, as well as an improvement in exercise capacity.

Adverse effect

Over use of these drugs can cause hyponatremia,

hypotension and circulatory collapse.

They can cause ototoxicity, vertigo. Drug interaction

may occur with aminoglycosides, propranolol,

probencid and thiazide diuretics.

Site 3 Thiazide and Thiazide like diuretics

MEDIUM EFFICACY DIURETICS

(Thiazides, Hydrothiazides and Thiazide-like Diuretics)

Chemistry

Inhibitors of Na+–Cl- symport are sulfonamides, and many are

analogues of 1, 2, 4-benzothiadiazine-1,1-dioxide.

Original inhibitors of Na+–Cl- symport were benzothiadiazine

derivatives, known as thiazide diuretics.

Drugs that are pharmacologically similar to thiazide diuretics are

called thiazide-like diuretics. The term thiazide diuretic is used here

to refer to all members of the class of inhibitors of Na+–Cl- symport.

Mechanism of action

The primary site of action of thiazide is the distal convulated tubule,

whereas the proximal tubule may represent a secondary site of

action.

In the distal convulated tubule, transport is powered by an Na+

pump in the basolateral membrane.

Cl then passively exists the basolateral membrane via a chloride

channel.

Thiazide diuretics inhibit the Na+–Cl–symporter,perhaps by competing for the chloride binding site.

The Na+ –Cl– symporter has a predicted size of 1023amino acid residues, has 12 putative membrane spanningdomains.

These domains exhibit 12 potential membrane-spanninghelices and they are flanked by long –NH2 and COOHterminal nonhydrophobic domains.

Development of thiazide and hydrothiazide diuretics

from chloraminophenamide

Structure–activity relationship

1. The SO2 group can be replaced with CO with increase in activity.

2. Saturation of 3, 4-double bond increase in activity.

3. Substitution of the ring nitrogen at position 2 with methyl increases

activity. However, at position 4 the methyl group reduces activity

with the heterocyclic ring more vulnerable to heterocyclic cleavage.

4. Substituent in the position 3, hydrophobic in character, increases

1000 times saluretic activity.

thiazide and hydrothiazide

Hydrochlorothiazide Hydroflumethiazide

ChlorothiazideBenzthiazide

5. Substituents include, –CH2Cl, –CHCl2, –CH2C6H5,

CH2CH2S-CH2C6H5. The increase in activity correlates with

the lipid solubility.

6. Substitutions in the 6 position by Cl, Br, or CF3 increase

activity, whereas H, or NH2 are weakly active.

7. A free sulfamoyl or potentially free sulfamoyl group at 7

position is essential for activity.

8. The loss of sulfamoyl group eliminated the diuretic effect, but

not the hypertensive effect.

Uses1. Thiazide diuretics are used for the treatment of the edema

associated with heart (congestive heart failure), liver

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

renal failure, and acute glomerulonephritis) disease.

2. With the possible exceptions of metolazone and

indapamide, most thiazide diuretics are ineffective when

the GFR is less than 30 to 40 ml/min.

Adverse effect

The most serious adverse effect is extracellular volumedepletion, hypotension, hyponatremia andhypochloremia.

POTASSIUM SPARING DIURETICS OR ANTI-KALIURETIC AGENTS

Inhibitors of renal epithelial Na+ channel. The body as awhole contains more K+ than Na+.

The saluretic diuretic agents also cause a concomitantincrease in K+ excretion; therefore producing hypokalemiais not desired.

Potassium-sparing diuretics produce decrease potassiumand hydrogen ions secretion.

Efforts to discover diuretics that would increase Na+excretion by inhibiting its exchange with K+ in the distalconvulated tubule produced two classes of potassiumsparing agents.

1. Direct acting anti-kaliuretic agents. 2. Aldosterone antagonist

Direct Acting Anti-KaliureticMechanism of action

These agents are used in combination with otherdiuretic agents (thiazide) for the treatment ofhypertension, edema associated with chroniccongestive heart failure or cirrhosis.

These agents inhibit active Na+ reabsorption.

The increased excretion of Na+ and Cl disrupts normalNa+ transport and produces a net change in theelectrogenic force across tubular a membrane, whichsubsequently reduces the net driving force for K+secretion.

Their action is independent of aldosterone.

Uses Because of the mild natriuresis induced by Na+-channel

inhibitors, these drugs seldom are used as sole agents inthe treatment of edema or hypertension.

Rather, their major utility is in combination with otherdiuretics. Coadministration of an Na+-channel inhibitoraugments the diuretic and antihypertensive response tothiazide and loop diuretics.

More important, the ability of Na+-channel inhibitors toreduce K+ excretion tends to offset the kaliuretic effects ofthiazide and loop diuretics; consequently, the combinationof an Na+ channel inhibitor with a thiazide or loop diuretictends to result in normal values of plasma K+.

Amiloride is also useful for lithium-inducednephrogenic diabetes insipidus because it blocks Li+transport into the cells of the collecting tubules.

Aldosterone Antagonist

Mechanism of action

Epithelial cells in the late distal tubule and collectingduct contain cytosolic MRs (mineralocorticoids) thathas a high affinity for aldosterone.

This receptor is a member of the superfamily ofreceptors for steroid hormones, thyroid hormones,vitamin D, and retinoids.