Diuretics I

Objectives:-
By the end of lectures 1 and 2, The student will be given the full information
of the 5 groups of diuretics which are:
1. High efficacy diuretics
2. Moderate efficacy diuretics
3. Low efficacy diuretics
4. Osmotic diuretics
5. Carbonic anhydrase inhibitors

Diuretics are drugs that increase the volume of urine excreted. Most diuretic
agents are inhibitors of renal ion transporters that decrease the reabsorption
of Na+ at different sites in the nephron. Diuretics are most commonly used
for management of abnormal fluid retention (edema) or treatment of
hypertension. Technically, a “diuretic” is an agent that increases urine
volume, whereas a “natriuretic” causes an increase in renal sodium excretion
and an “aquaretic” increases excretion of solute-free water.

Normal regulation of fluids and electrolytes by the kidneys:-

Approximately 16% to 20% of the blood plasma entering the kidneys is
filtered from the glomerular capillaries into Bowman’s capsule. The filtrate,
although normally free of proteins and blood cells, contains most of the low
molecular weight plasma components in concentrations similar to that in the
plasma. These include glucose, sodium bicarbonate, amino acids, and other
organic solutes, as well as electrolytes, such as Na+, K+, and Cl−. The kidney
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regulates the ionic composition and volume of urine by active reabsorption or
secretion of ions and/or passive reabsorption of water at five functional zones
along the nephron:
1) The proximal convoluted tubule. 2) The descending loop of Henle.
3) The ascending loop of Henle. 4) The distal convoluted tubule. 5) The
collecting tubule and duct.

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A. Proximal convoluted tubule
In the proximal convoluted tubule located in the cortex of the kidney, almost
all the glucose, bicarbonate, amino acids, and other metabolites are
reabsorbed. Approximately two-thirds of the Na + is also reabsorbed. The
proximal tubule is the site of the organic acid and base secretory systems. The
organic acid secretory system, located in the middle-third of the proximal
tubule, secretes a variety of organic acids, such as uric acid, some antibiotics,
and diuretics, from the bloodstream into the proximal tubular lumen. Most
diuretic drugs are delivered to the tubular fluid via this system. The organic
acid secretory system is saturable, and diuretic drugs in the bloodstream
compete for transfer with endogenous organic acids such as uric acid. A
number of other interactions can also occur. For example, probenecid
interferes with penicillin secretion. The organic base secretory system,
located in the upper and middle segments of the proximal tubule, is
responsible for the secretion of creatinine and choline.

B. Descending loop of Henle

The remaining filtrate, which is isotonic, next enters the descending limb of
the loop of Henle and passes into the medulla of the kidney. The osmolarity
increases along the descending portion of the loop of Henle because of the
countercurrent mechanism that is responsible for water reabsorption. This
results in a tubular fluid with a threefold increase in salt concentration.
Osmotic diuretics exert part of their action in this region.

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C. Ascending loop of Henle
The cells of the ascending tubular epithelium are unique in being
impermeable to water. Active reabsorption of Na +, K +, and Cl −is mediated
by a Na +/K+/2Cl−cotransporter. Both Mg 2+ and Ca2+ enter the
interstitial fluid via the para-cellular pathway. The ascending loop is, thus, a
diluting region of the nephron. Approximately 25% to 30% of the tubular
sodium chloride returns to the interstitial fluid, thereby helping to maintain
high osmolarity. Because the ascending loop of Henle is a major site for salt
reabsorption, drugs affecting this site, such as loop diuretics, have the greatest
diuretic effect.

D. Distal convoluted tubule

The cells of the distal convoluted tubule are also impermeable to water. About
10% of the filtered sodium chloride is reabsorbed via a Na+/Cl−transporter
that is sensitive to thiazide diuretics. Calcium reabsorption is mediated by
passage through a channel and then transported by a Na +/Ca2+-exchanger
into the interstitial fluid. The mechanism, thus, differs from that in the loop
of Henle. Additionally, Ca2+ excretion is regulated by parathyroid hormone
in this portion of the tubule.

E. Collecting tubule and duct

The principal cells of the collecting tubule and duct are responsible for
Na+,K+, and water transport, whereas the intercalated cells affect H+
secretion. Sodium enters the principal cells through channels (epithelial
sodium channels) that are inhibited by amiloride and triamterene. Once inside

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 the cell, Na+ reabsorption relies on a Na+/K+-ATPase pump to be transported
into the blood.

Thiazides and Related Agents

The thiazide diuretics were discovered in 1957, they are the most widely used
diuretics. They are sulfonamide derivatives. All thiazides affect the distal
convoluted tubule, and all have equal maximum diuretic effects, differing
only in potency. Thiazides are sometimes called “low ceiling diuretics,”
because increasing the dose above normal therapeutic doses does not promote
further diuretic response.

Thiazides
❖ Chlorothiazide was the first orally active diuretic that was capable of
affecting the severe edema often seen in hepatic cirrhosis and heart failure
with minimal side effects.
❖ Its properties are representative of the thiazide group, although
hydrochlorothiazide and chlorthalidone are now used more commonly.
❖ Hydrochlorothiazide is more potent, so the required dose is considerably
lower than that of chlorothiazide, but the efficacy is comparable to that of the
parent drug.
❖ In all other aspects, hydrochlorothiazide resembles chlorothiazide. [Note:
Chlorthalidone, indapamide, and metolazone are referred to as thiazide-like
diuretics, because they contain the sulfonamide residue in their chemical
structures, and their mechanism of action is similar. However, they are not
truly thiazides.]

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 Mechanism of action:
❖ The thiazide and thiazide-like diuretics act mainly in the cortical region of
the ascending loop of Henle and the distal convoluted tubule to decrease the
reabsorption of Na+, apparently by inhibition of a Na+/Cl−cotransporter on
the luminal membrane of the tubules .
❖ They have a lesser effect in the proximal tubule. As a result, these drugs
increase the concentration of Na+ and Cl−in the tubular fluid.
❖ [Note: Because the site of action of the thiazide derivatives is on the luminal
membrane, these drugs must be excreted into the tubular lumen to be
effective. Therefore, with decreased renal function, thiazide diuretics lose
efficacy.]
❖ The efficacy of these agents may be diminished with concomitant use of
NSAIDs, such as indomethacin, which inhibit production of renal
prostaglandins, thereby reducing renal blood flow.

Actions:
a. Increased excretion of Na+ and Cl−: Thiazide and thiazide-like diuretics
cause diuresis with increased Na+ and Cl−excretion, which can result in the
excretion of very hyperosmolar (concentrated) urine. This latter effect is
unique, as the other diuretic classes are unlikely to produce a hyperosmolar
urine. The diuretic action is not affected by the acid–base status of the body,
and hydrochlorothiazide does not change the acid–base status of the blood.
b. Loss of K+: Because thiazides increase Na+ in the filtrate arriving at the
distal tubule, more K+ is also exchanged for Na+, resulting in a continual loss
of K+ from the body with prolonged use of these drugs. Thus, serum K+

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should be measured periodically (more frequently at the beginning of therapy)
to monitor for the development of hypokalemia.
c. Loss of Mg2+: Magnesium deficiency requiring supplementation can occur
with chronic use of thiazide diuretics, particularly in elderly patients. The
mechanism for the magnesuria is not understood.
d. Decreased urinary calcium excretion: Thiazide and thiazide like
diuretics decrease the Ca2+ content of urine by promoting the reabsorption of
Ca2+ in the distal convoluted tubule where parathyroid hormone regulates
reabsorption. This effect contrasts with the loop diuretics, which increase the
Ca2+ concentration in the urine.
e. Reduced peripheral vascular resistance: An initial reduction in blood
pressure results from a decrease in blood volume and, therefore, a decrease in
cardiac output. With continued therapy, volume recovery occurs. However,
there are continued antihypertensive effects, resulting from reduced
peripheral vascular resistance caused by relaxation of arteriolar smooth
muscle. How these agents induce vasodilation is unknown.

. Therapeutic uses:
a. Hypertension: Clinically, the thiazides are a mainstay of antihypertensive
medication, because they are inexpensive, convenient to administer, and well
tolerated. They are effective in reducing blood pressure in the majority of
patients with mild to moderate essential hypertension. Blood pressure can be
maintained with a daily dose of thiazide, which causes lower peripheral
resistance without having a major diuretic effect. Some patients can be
continued for years on thiazides alone; however, many patients require
additional medication for blood pressure control .
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b. Heart failure: Loop diuretics (not thiazides) are the diuretics of choice in
reducing extracellular volume in heart failure. However, thiazide diuretics
may be added if additional diuresis is needed. When given in combination,
thiazides should be administered 30 minutes prior to loop diuretics in order
to allow the thiazide time to reach the site of action and produce effect.
c. Hypercalciuria: The thiazides can be useful in treating idiopathic
hypercalciuria, because they inhibit urinary Ca 2+ excretion. This is
particularly beneficial for patients with calcium oxalate stones in the urinary
tract.
d. Diabetes insipidus: Thiazides have the unique ability to produce a
hyperosmolar urine. Thiazides can be utilized as a treatment for nephrogenic
diabetes insipidus. The urine volume of such individuals may drop from 11
to about 3 L/d when treated with thiazides.
e. Resistant oedema – thiazides or related drugs (e.g. metolazone) are
extremely potent when combined with a loop diuretic.
f. Prevention of stones – thiazides reduce urinary calcium excretion and thus
help to prevent urinary stone formation in patients with idiopathic
hypercalciuria;
Pharmacokinetics:
The drugs are effective orally. Most thiazides take 1 to 3 weeks to produce a
stable reduction in blood pressure, and they exhibit a prolonged half-life. All
thiazides are secreted by the organic acid secretory system of the kidney

Adverse effects:
These mainly involve problems in fluid and electrolyte balance.

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a. Potassium depletion: Hypokalemia is the most frequent problem with the
thiazide diuretics, and it can predispose patients who are taking digoxin to
ventricular arrhythmias . Often, K+ can be supplemented by dietary measures
such as increasing the consumption of citrus fruits, bananas, and prunes. In
some cases, K+ supplementation may be necessary.
b. Hyponatremia: Hyponatremia may develop due to elevation of ADH as a
result of hypovolemia, as well as diminished diluting capacity of the kidney
and increased thirst. Limiting water intake and lowering the diuretic dose can
prevent hyponatremia.
c. Hyperuricemia: Thiazides increase serum uric acid by decreasing the
amount of acid excreted by the organic acid secretory system. Being
insoluble, uric acid deposits in the joints and may precipitate a gouty attack
in predisposed individuals. Therefore, thiazides should be used with caution
in patients with gout or high levels of uric acid.
d. Volume depletion: This can cause orthostatic hypotension or light-
headedness.
e. Hypercalcemia: The thiazides inhibit the secretion of Ca2+, sometimes
leading to hypercalcemia (elevated levels of Ca2+in the blood).
f. Hyperglycemia: Therapy with thiazides can lead to glucose intolerance,
possibly due to impaired release of insulin and tissue uptake of glucose.

Thiazide-like diuretics
These compounds lack the thiazide structure, but, like the thiazides, they have
the unsubstituted sulfonamide group and, therefore, share their mechanism of
action. The therapeutic uses and adverse effect profiles are similar to those of
the thiazides.
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1. Chlorthalidone: Chlorthalidone is a non thiazide derivative that behaves
pharmacologically like hydrochlorothiazide. It has a long duration of action
and, therefore, is often used once daily to treat hypertension.

2. Metolazone: Metolazone is more potent than the thiazides and, unlike the
thiazides, causes Na+ excretion even in advanced renal failure.
3. Indapamide: Indapamide is a lipid-soluble, non-thiazide diuretic that has
a long duration of action. At low doses, it shows significant antihypertensive
action with minimal diuretic effects.

Loop or High Ceiling Diuretics

Bumetanide, furosemide, torsemide , and ethacrynic acid have their major
diuretic action on the ascending limb of the loop of Henle . Of all the diuretics,
these drugs have the highest efficacy in mobilizing Na+ and Cl−from the
body. They produce abundant amounts of urine. Furosemide is the most
commonly used of these drugs. Bumetanide and torsemide are much more
potent than furosemide, and the use of these agents is increasing. Ethacrynic
acid is used infrequently due to its adverse effect profile.

Bumetanide, furosemide, torsemide, and ethacrynic acid

Mechanism of action:
Loop diuretics inhibit the cotransport of Na+/K+/2Cl−in the luminal
membrane in the ascending limb of the loop of Henle. Therefore, reabsorption
of these ions is decreased. These agents have the greatest diuretic effect of all
the diuretic drugs, since the ascending limb accounts for reabsorption of 25%

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to 30% of filtered NaCl, and downstream sites are unable to compensate for
the increased Na+ load.
Actions:
Loop diuretics act promptly, even in patients with poor renal function or lack
of response to other diuretics. [Note: Unlike thiazides, loop diuretics increase
the Ca2+content of urine. In patients with normal serum Ca2+concentrations,
hypocalcemia does not result, because Ca2+is reabsorbed in the distal
convoluted tubule.] The loop diuretics may increase renal blood flow,
possibly by enhancing prostaglandin synthesis. NSAIDs inhibit renal
prostaglandin synthesis and can reduce the diuretic action of loop diuretics.
Therapeutic uses: The loop diuretics are the drugs of choice for reducing
acute pulmonary edema and acute/chronic peripheral edema caused from
heart failure or renal impairment. Because of their rapid onset of action,
particularly when given intravenously, the drugs are useful in emergency
situations such as acute pulmonary edema. Loop diuretics (along with
hydration) are also useful in treating hypercalcemia, because they stimulate
tubular Ca2+excretion. They also are useful in the treatment of hyperkalemia.

Pharmacokinetics: Loop diuretics are administered orally or parenterally.

Their duration of action is relatively brief (2 to 4 hours), allowing patients to
predict the window of diuresis. They are secreted into urine.
Adverse effects:
a. Ototoxicity: Reversible or permanent hearing loss may occur with loop
diuretics, particularly when used in conjunction with other ototoxic drugs (for
example, aminoglycoside antibiotics). Ethacrynic acid is the most likely to

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cause deafness. Although less common, vestibular function may also be
affected, inducing vertigo.
b. Hyperuricemia: Furosemide and ethacrynic acid compete with uric acid
for the renal secretory systems, thus blocking its secretion and, in turn,
causing or exacerbating gouty attacks.
c. Acute hypovolemia: Loop diuretics can cause a severe and rapid reduction
in blood volume, with the possibility of hypotension, shock, and cardiac
arrhythmias.
d. Potassium depletion: The heavy load of Na+ presented to the collecting
tubule results in increased exchange of tubular Na+ for K+, leading to the
possibility of hypokalemia. The loss of K+ from cells in exchange for H+
leads to hypokalemic alkalosis. Use of potassium-sparing diuretics or
supplementation with K+ can prevent the development of hypokalemia.
e. Hypomagnesemia: Chronic use of loop diuretics combined with low
dietary intake of Mg2+can lead to hypomagnesemia, particularly in the
elderly. This can be corrected by oral supplementation

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Sources:- 1. Clinical pharmacology- Brown and Bennet 10th ed.
2. Lippincott Illustrated Reviews, Pharmacology - Whalen, Karen. 6th ed. 2015
3. Katzungs Basic & Clinical Pharmacology -12th Ed

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