This document discusses different classes of diuretic drugs, including their mechanisms of action, classifications, indications, and side effects. It covers carbonic anhydrase inhibitors, thiazide diuretics, and loop diuretics in detail. Carbonic anhydrase inhibitors work by inhibiting bicarbonate reabsorption in the kidney and are used to treat glaucoma, altitude sickness, and metabolic alkalosis. Thiazide diuretics inhibit sodium reabsorption in the distal convoluted tubule and are used to treat hypertension, heart failure, and kidney stones. Loop diuretics strongly inhibit sodium reabsorption in the thick ascending limb of Henle's loop and are used when a more potent di

1. DIURETICS
Dr. PABBA PARAMESHWAR

4. INTRODUCTION TO DIURETICS
 Diuretics are among the most commonly prescribed drugs,
and play an important role in the treatment of heart failure
and hypertension.
 They exert most of their therapeutic effects through
inhibiting the reabsorption of sodium at different sites
along the nephron of the kidney.
 Diminished reabsorption of sodium results in increased
urinary loss of both sodium and water, leading to a
reduction in plasma volume, and a reduction of blood
pressure.
 Thiazide diuretics also exert an additional vasodilator
effect on arterial smooth muscle by a still poorly
understood mechanism.

5. CLASSIFICATION
1. High efficacy diuretics (Inhibitors of Na+-K+- 2Cl¯
cotransport)
• Sulphamoyl derivatives
Furosemide, Bumetanide, Torasemide
2. Medium efficacy diuretics (Inhibitors of Na+- Cl¯
symport)
(a) Benzothiadiazines (thiazides)
Hydrochlorothiazide, Benzthiazide,
Hydroflumethiazide, Clopamide
(b) Thiazide like (related heterocyclics)
Chlorthalidone, Metolazone, Xipamide,
Indapamide.

6. 3. Weak or adjunctive diuretics
(a) Carbonic anhydrase inhibitors
Acetazolamide
(b) Potassium sparing diuretics
(i) Aldosterone antagonist: Spironolactone
(ii) Inhibitors of renal epithelial Na+ channel:
Triamterene, Amiloride.
(c) Osmotic diuretics
• Mannitol, Isosorbide, Glycerol
4. Other high ceiling diuretics, viz. ethacrynic acid and
organomercurials (mersalyl).

7. CARBONIC ANHYDRASE INHIBITORS

9. Mechanism of action of carbonic anhydrase inhibitor
Bicarbonate absorption by the proximal tubule is dependent on the
activity of carbonic anhydrase (CA) which converts bicarbonate (HCO3
-)
to CO2 and H2O.
CO2 rapidly diffuses across the cell membrane of proximal tubule cells
where it is rehydrated back to H2CO3 by carbonic anhydrase.
H2CO3 dissociates to HCO3
- and H+which are transported out of the cell on
the basolateral side by different transporters. Bicarbonate absorption is
therefore dependent on the activity of carbonic anhydrase.
Inhibition of carbonic anhydrase by acetazolamide results in an increased
urinary loss of bicarbonate. This also interferes with the reabsorption of
Na and Cl. The basolateral Na/K ATPase maintains a low intracellular Na
concentration, which is necessary for reabsorption of Na, and in the
proximal tubule also facilitates the efflux of H+ by the Na/H exchanger on
the luminal side. Increased delivery of Na to the collecting duct results in
reabsorption of Na (through epithelial Na channels) in exchange for
increased K efflux , which can cause hypokalemia.

10. • The loss of bicarbonate produces a metabolic acidosis
• Most of the fluid loss resulting from inhibition of
carbonic anhydrase is reclaimed in more distal
segments of the nephron, especially the loop of Henle.
• As a result, the diuretic efficacy of carbonic
anhydrase inhibitors is relatively low, and it becomes
further diminished with over several days of treatment
due to the development of metabolic acidosis, with an
associated reduction in bicarbonate in the glomerular
filtrate.

11. INDICATIONS
Glaucoma
• Carbonic anhydrase inhibitors decrease the formation of aqueous humor,
an effect that will produce a reduction of intraoccular pressure in the
setting of glaucoma. Carbonic anhydrase inhibitors (dorzolamide &
brinzolamide) are given by topical application to minimize systemic and
renal side effects
Acute Mountain Sickness
• Rapid ascent to high altitudes (above 3000 m) where the partial pressure
of oxygen is low can result in symptoms including dizziness, isomnia,
headache and nausea. Acetazolamide can decrease CSF formation, as well
as CSF pH by inhibiting carbonic anhydrase in the brain. This has the effect
of increasing ventilation (increasing oxygen delivery) above that
stimulated by the hypoxia of high altitude, which can reduce the
symptoms of mountain sickness
Metabolic Alkalosis
• Acetazolamide is sometimes used to treat edema in patients who have
developed a metabolic alkalosis, a condition that can occur in patients
with hypercapnic chronic lung disease

12. SIDE EFFECTS
• Hypokalemic metabolic acidosis
• Inhibition of CA results in decreased
reabsorption of bicarbonate by the proximal
tubule, resulting in loss of Na bicarbonate in
the urine. The loss of base causes a metabolic
acidosis. The increased delivery of Na to the
collecting duct results in increased exchange
of Na for K, with resulting hypokalemia

13. Thiazides

14. – Thiazides are sulfonamide related organic acids that
are secreted into the proximal tubule by an organic
secretory mechanism. (Thiazides compete for the same
secretory process by which uric acid is secreted into the
proximal tubule).
– From within the lumen they act to increase the excretion
of Na & Cl by inhibiting the Na/Cl symporter in the distal
convoluted tubule. Natriuresis may be accompanied by
some loss of potassium and bicarbonate.
– Thiazides enhance Ca reabsorption in the distal convoluted
tubule, by increasing Na/Ca exchange (which makes
thiazides useful in treating the calcium-subtype of kidney
stones).
– Thiazide diuretics also reduce the urinary excretion of
Ca & therefore are employed to treat kidney stones & may
be useful for treating osteoporosis.

15. • ANTIHYPERTENSIVE:
• The mechanism for the antihypertensive effects of
thiazides is poorly understood. One hypothesis
proposed is that thiazides produce a smooth muscle
vasodilator effect initiated by a reduction in plasma Na
levels, which thereby reduce intracellular Ca levels in
vascular smooth muscle via Na/Ca exchange.
• However, other reasonable hypotheses have also been
proposed. Despite over five decades of research, the
extrarenal mechanism by which thiazides decrease
total peripheral resistance remains poorly understood.

16. • Thiazide diuretics compete for the chloride binding site on the
Na/Cl cotransporter that is selectively expressed in the distal
convoluted tubule, inhibiting its ability to transport ions.
• Inhibition of this co-transporter lowers intracellular Na, which in
turn results in a lowering of intracellular calcium mediated
by Na/Ca exchange expressed on the basolateral membrane.
This facilitates the diffusion of calcium through calcium ion
channels expressed on the lumen membrane.
• The inhibition of Na transport in this segment results in greater
delivery of sodium to the collecting duct (see inset), where
enhanced Na influx through epithelial Na channels stimulates
potassium efflux, which can result in the development of
hypokalemia

20. • Pharmacokinetics:
• All thiazides can be administered orally.
Administered once daily (some in two divided
doses).

21. SIDE EFFECTS
• dose related metabolic changes (primarily observed with doses higher than used in the current
standard of care):
• hypokalemic metabolic alkalosis
• with the low doses commonly used <25% of patients develop hypokalemia & most
cases are not severe
hyperuricemia
• Hyperuricemia can be aggrevated by treatment with thiazide diuretics, potentially
leading to the development of gout (Becker, 2016). Both thiazide and loop diuretics
interfere with different transporters involved in urate secretion
hyperglycemia
• Thiazides have a mild effect to impaire glucose tolerance. This is normally of little
clinical significance at therapeutic doses - but may increase hyperglycemia in a type
2 diabetic. There is evidence that the hyperglycemia may be related to loss of body
potassium, which may affect the ability of pancreatic beta cells to regulate the
release of insulin via ATP-sensitive K channels. Appropriate correction of
hypokalemia can typically reverse thiazide-induced hyperglycemia
hyperlipidemia
• Dyslipidemia can by produced by high doses of thiazides (not typically used). The
mechanism by which thiazides and some beta blockers affect lipid levels is still
poorly understood
hyponatremia
allergic reactions (sulfonamide related)

22. • Major drug interactions:
• Since thiazides must be secreted into the tubular lumen to inhibit
the Na/Cl symporter, their action can be reduced by drugs such as
probenecid which compete for transport into the proximal tubule.
• Hypokalemia caused by thiazide & loop diuretics can increase the
likelihood of potentially fatal polymorphic ventricular tachycardia
(torsade de pointes) if coadministered with other drugs that
prolong the QT interval (e.g. Class III antiarrhythmic, or quinidine-
like drugs).
• alcohol, barbiturates & narcotics may potentiate orthostatic
hypotension
• additive effects occur when combined with other antihypertensives
• decreased response to pressor amines
• dosage adjustment of antidiabetic drugs may be necessary.

23. • Contraindications:
• The effects of loop diuretics, thiazides & K-sparing
diuretics depend on renal prostaglandin production
(involved in autoregulation of renal blood flow) & their
diuretic effects can be reduced by NSAIDs.
• This effect is not of major importance in normal subjects,
where postaglandin production is relatively low, but can be
significant in patients with underlying renal disease
• Anuria. Thiazides are ineffective when the GFR is less than
30-40 ml/min.
• Hypersensitivity to this or other sulfonamide-derived drugs.

24. Indications:
• hypertension. They are especially effective in lowering BP in elderly
& African American patients.
• heart failure (reduce blood volume, venous pressure & preload).
• treatment of kidney stones caused by hypercalciuria
• nephrogenic diabetes insipidus
– Nephrogenic Diabetes Insipidus results from renal insensitivity to the
effects of ADH, resulting in polyuria. It can be either congenital (due to
inherited genetic defects), or acquired (most commonly caused by
hypercalcemia, or chronic therapy with lithium).
– Urine output in such patients can be reduced with a low sodium diet,
NSAIDs and thiazide diuretics. Thiazide diuretics appear to exert their
effect by a combination effects, one of which is by producing a mild
hypovolemia, which causes an increase in proximal sodium and water
reabsorption, and decreased water delivery to the ADH-sensitive sites
in the collecting tubules. This results in a reduction of urine output by
up to 50% . Thiazides may also produce an increase in the expression
of Na transporters in regions surrounding the distal convoluted tubule,
which would have an “anti-diuretic” effect

25. LOOP DIURETICS

26. Furosemide (Frusemide) Prototype drug
• The development of this orally and rapidly acting highly
efficacious diuretic was a breakthrough.
• Its maximal natriuretic effect is much greater than that
of other classes.
• The diuretic response goes on increasing with
increasing dose: upto 10 L of urine may be produced in
a day.
• It is active even in patients with relatively severe renal
failure.
• The onset of action is prompt
• (i.v. 2–5 min., i.m. 10–20 min., oral 20–40 min.)
and duration short (3–6 hours).

27. • The major site of action is the thick AscLH (site II)
where furosemide inhibits Na+- K+-2Cl¯ cotransport.
• A minor component of action on PT has also been
indicated.
• It is secreted in PT by organic anion transport and
reaches AscLH where it acts from luminal side of the
membrane.
• It abolishes the corticomedullary osmotic gradient and
blocks positive as well as negative free water clearance.
• K+ excretion is increased mainly due to high Na+ load
reaching DT.
• However, at equinatriuretic doses, K+ loss is less than
that with thiazides

28. • Furosemide has weak CAse inhibitory action and
increase HCO3¯ excretion as well; urinary pH may
rise.
• furosemide causes acute changes in renal and
systemic haemodynamics.
• After 5 min of i.v. injection, renal blood flow is
transiently increased and there is redistribution
of blood flow from outer to midcortical zone;
• g.f.r. generally remains unaltered due to
compensatory mechanisms despite increased
renal blood flow.

29. • Intravenous furosemide causes prompt
increase in systemic venous capacitance and
decreases left ventricular filling pressure, even
before the saluretic response is apparent.
• This action also appears to be PG mediated
and is responsible for the quick relief it affords
in LVF and pulmonary edema.

30. • Furosemide increases Ca2+ excretion as well
as Mg2+ excretion. It tends to raise blood uric
acid level by competing with its proximal
tubular secretion as well as by increasing
reabsorption in PT which is a consequence of
reduced e.c.f. volume.

31. Molecular mechanism of action
• A glycoprotein with 12 membrane spanning domains
has been found to function as the Na+-K+-2Cl¯
cotransporter in many epithelia performing secretory/
absorbing function, including AscLH.
• Recently, distinct absorptive or secretory isoforms of
Na+-K+- 2Cl¯ cotransporter have been isolated.
• The former is exclusively expressed at the luminal
membrane of thick AscLH—furosemide attaches to
the Cl¯ binding site of this protein to inhibit its
transport function. The secretory form is expressed on
the basolateral membrane of most glandular and
epithelial cells.

34. Pharmacokinetics:
• Onset of action is relatively rapid (e.g. usually within 30 minutes
after an oral dose of ethacrynic acid or within 5 minutes after an
intravenous injection of ethacrynic acid).
• After oral use, diuresis peaks in about 2 hours and lasts about 6 to
8 hours. Most loop diuretics have a short duration of action &
require twice-daily dosing.
Side Effects:
• hypokalemic metabolic alkalosis (hypokalemia)
• ototoxicity
• hyperuricemia
• hypomagnesemia
• allergic reactions
• dehydration

35. Interactions:
• Lithium generally should not be given with diuretics
because they reduce its renal clearance and add a high
risk of lithium toxicity.
• Loop diuretics may increase the ototoxic potential of
other drugs such as aminoglycosides and some
cephalosporin antibiotics.
• NSAIDs (eg. aspirin, indomethacin) can interfere with
the actions of loop diuretics by interfering with
prostaglandin synthesis. This interference is minimal in
normal subjects, but may be significant in patients with
nephrotic syndrome or hepatic cirrhosis.

36. • Contraindications:
• anuria. If increasing electrolyte imbalance, azotemia, and/
or oliguria occur during treatment of severe, progressive
renal disease, the diuretic should be discontinued.
• The effects of loop diuretics, thiazides & K-sparing
diuretics depend on renal prostaglandin production
(involved in autoregulation of renal blood flow) & their
diuretic effects can be reduced by NSAIDs.
• This effect is not of major importance in normal subjects,
where postaglandin production is relatively low, but can be
significant in patients with underlying renal disease
• Prostaglandins also exert some effect on Na transport in
various segments of the nephron

37. Indications:
• Loop diuretics produce a more potent diuresis & less vasodilation than
thiazide diuretics. Therefore they are less effective in lowering BP than
thiazide diuretics .
• Loop diuretics are drugs of choice for patients with severe edema where a
potent diuresis is needed, including:
– congestive heart failure, cirrhosis of the liver, and renal disease (e.g. GFR <30
ml/min), including the nephrotic syndrome.
– Short-term management of ascites due to malignancy, idiopathic edema, and
lymphedema.
– Short-term management of hospitalized pediatric patients, other than infants,
with congenital heart disease or the nephrotic syndrome.
• where a rapid onset of diuresis is desired, e.g., in acute pulmonary edema,
or when gastrointestinal absorption is impaired or oral medication is not
practicable.
• by reducing the lumen voltage gradient that drives cation reabsorption in
the loop, loop diuretics increase the excretion of divalent cations (Ca &
Mg) & this can be useful in treating disorders causing
hypercalcemia (Note: this is an effect opposite from that caused by thiazide
diuretics).

39. • It is a steroid, chemically related to the mineralocorticoid
aldosterone.
• Aldosterone acts on the late DT and CD cells by combining
with an intracellular mineralocorticoid receptor
• Aldosterone induces the formation of ‘aldosterone-
induced proteins’ (AIPs) which promote Na+ reabsorption
by a number of mechanisms and K+ secretion.
• Spironolactone acts from the interstitial side of the
tubular cell, combines with the mineralocorticoid
receptor and inhibits the formation of AIPs in a
competitive manner. It has no effect on Na+ and K+
transport in the absence of aldosterone, while under
normal circumstances, it ncreases Na+ and decreases K+
excretion.

42. • SIDE EFFECTS
• Gynecomastia
• Spironolactone can cause gynecomastia
(enlargement of glandular tissue in the male
breast) due to effects on estrogen steroid
receptors. Due to its greater selectivity for
mineralocorticoid receptors,
• Eplerenone has not been associated with this
side effect.

43. INDICATIONS
• Used by themselves, potassium-sparing diuretics exert only a mild
diuretic effect because the collecting duct reabsorbs only 2-5% of
filtered sodium. They are occasionally used to counteract the
potassium-wasting effects of thiazides.
• Hyperaldosteronism
• Mineralocorticoid receptor antagonists are useful in blunting the
symptoms produced by states of mineralocorticoid excess
(hyperaldosteronism) due to primary or secondary causes (including
heart failure).
• Hypokalemia
• For correction of excessive potassium loss.
• Drug-resistant Hypertension
• Treatment-resistant hypertension is often caused by excessive Na
retention. A recent clinical trial found spironolactone to be superior
to non-diuretic add-on drugs at lowering blood pressure

51. Mannitol
• Mannitol is a nonelectrolyte of low molecular weight (182) that is
pharmacologically inert— can be given in large quantities sufficient to
raise osmolarity of plasma and tubular fluid.
• It is not metabolized in the body; freely filtered at the glomerulus and
undergoes limited reabsorption: therefore excellently suited to be used as
osmotic diuretic.
• Mannitol appears to limit tubular water and electrolyte reabsorption in a
variety of ways:
 Retains water iso osmotically in PT— dilutes luminal fluid which opposes
NaCl reabsorption.
 Inhibits transport processes in the thick AscLH by an unknown
mechanism. Quantitatively this appears to be the most important cause
of diuresis.
 Expands extracellular fluid volume (because it does not enter cells,
mannitol draws water from the intracellular compartment)—increases
g.f.r. and inhibits renin release.
 Increases renal blood flow, especially to the medulla—medullary
hypertonicity is reduced— corticomedullary osmotic gradient is
dissipated—passive salt reabsorption is reduced.