The document discusses the pharmacology, indications, and uses of diuretics, which are drugs that increase urine excretion by inhibiting renal ion transporters, particularly sodium reabsorption in the nephron. It categorizes diuretics into various classes including thiazide, loop, carbonic anhydrase inhibitors, and potassium-sparing diuretics, detailing their mechanisms of action, pharmacokinetics, clinical uses, and potential side effects. The document also highlights the role of the kidneys in maintaining homeostasis and the impact of different diuretics on urine composition.

1. Diuretics:
Pharmacology,
Indications and Uses
Presenter: Dr. Suresh Pradhan
Moderator: Prof. UC Sharma

2. General organization of the kidneys and
the urinary system

3. Section of kidney showing the major vessels
that supply the blood flow to the kidney

4. Nephron
• Functional unit of Kidney
• Each kidney contains about 1million nephrons
• Contains six anatomical and functional divisions
• the renal corpuscle,
• the proximal convoluted tubule,
• the loop of Henle,
• the distal renal tubule,
• the collecting tubule, and
• the juxtaglomerular apparatus

5. Basic tubular segments of the nephron

7. Juxtraglomerular Apparatus

8. Schematic of the microcirculation of nephron

9. Physiology
• Involves
• Glomerular Filtration
• Tubular Secretion
• Tubular Reabsorption
• Micturation

10. Mechanisms of tubular secretion and reabsorption

11. Transport proteins involved in the movement of Na+ and
Cl– across the apical membranes of renal tubular cells

12. Functions of Kidneys
the kidneys serve many important homeostatic
functions:
⌐Excretion of metabolic waste products and foreign
chemicals
⌐Regulation of water and electrolyte balances
⌐Regulation of body fluid osmolality and electrolyte
concentrations
⌐Regulation of arterial pressure

13. ⌐Regulation of acid-base balance
⌐Regulation of erythrocyte production
⌐Secretion, metabolism, and excretion of hormones
⌐Gluconeogenesis

14. Overview
• 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
• Na+ and other ions, such as Cl−, enter the urine in
greater than normal amounts along with water

15. • increase the volume of urine, often change its pH
• alter the ionic composition of the urine and blood
• diuretic effect of the different classes of diuretics
varies considerably
• with the increase in Na+ secretion varying from
less than 2% for the weak potassium-sparing
diuretics to over 20% for the potent loop
diuretics

16. • in addition to the ion transport inhibitors, other
types of diuretics include osmotic diuretics,
aldosterone antagonists, and carbonic anhydrase
inhibitors
• are most commonly used for management of
· abnormal fluid retention (edema) or
· treatment of hypertension

18. Classification

19. Thiazide Diuretics
• are most often administered for long-term
treatment of essential hypertension where diuresis,
natriuresis, and vasodilation are synergistic
• Includes hydrochlorothiazide and thiazide-like
drugs, such as chlorthalidone and indapamide
• Hydrochlorothiazide is the second most frequently
prescribed antihypertensive medication

20. • are usually administered in combination with other
antihypertensives
• may also be used to mobilize edema fluid
associated with renal, hepatic, or cardiac
dysfunction
• less common uses of thiazide diuretics include
management of diabetes insipidus and treatment
of hypercalcemia

21. Pharmacokinetics and Pharmacodynamics
• inhibit the Na+-Cl− cotransporter in the cortical
portion of the ascending loop of Henle and the DCT,
inhibiting reabsorption of 5% to 10% of the filtered
sodium
• enhanced distal delivery of Na+ results in increased
excretion of potassium into the renal tubules
• resulting in an increase in the urinary excretion of
sodium, chloride, and potassium ions
• also stimulate the reabsorption of calcium in the DCT

23. • readily absorbed when administered orally
• extensively protein-bound
• eliminated unchanged in the kidney; indapamide-
metabolized by the liver
• thiazides’ effectiveness markedly decreases in
patients with renal insufficiency

24. • thiazide diuretics have a long half-life of 8 to 12
hours, allowing for a convenient once-a-day dosing
• Indapamide, xipamide, and metolazone are
structurally related to furosemide but share a
thiazide-like mechanism of action with differences
in their clinical effects

25. Side Effects
• thiazide diuretic–induced hypokalemic,
hypochloremic, metabolic alkalosis is a common
side effect However, these side effects are usually
well tolerated at low doses
• hypokalemia may manifest as skeletal muscle
weakness and gastrointestinal ileus and may
increase the risk of developing digitalis toxicity
• depletion of sodium and magnesium ions may
accompany kaliuresis

26. • cardiac dysrhythmias may occur as the result of
diuretic-induced hypokalemia or hypomagnesemia
• hypercalcemia may result, especially in patients
receiving calcium supplements or vitamin D therapy
• can potentiate non-depolarizing neuromuscular
blockade by producing hypokalemia
• effectiveness of thiazides is decreased in patients
receiving nonsteroidal anti-inflammatory drugs

27. • may promote lithium reabsorption in the proximal
tubule by a compensatory mechanism, thereby
potentiating toxicity in patients on lithium therapy
• Inhibition of renal tubular secretion of urate by
thiazide diuretics can result in hyperuricemia in
50% of treated patients, and a small percentage of
patients might develop clinical gout
• glucose intolerance and aggravate glucose control
in diabetic patients, especially when used in
combination with β blockers

28. • thiazide-induced hypokalemia may be associated
with glucose intolerance and treating the
hypokalemia may protect from developing diabetes
• may affect cholesterol and triglyceride levels,
aggravating hyperlipidemia
• because of the structural similarities between
sulfonamide antibiotics and thiazide & loop
diuretics, it has been suggested that patients with
sulfa allergy may demonstrate cross-reactivity to
these classes of diuretics

29. Loop Diuretics
• inhibit reabsorption of sodium, potassium, and
chloride by impairing activity of the Na+-K+-2Cl−
transport protein in the medullary portions of the
thick ascending limb of the loop of Henle
• Includes
• Ethacrynic acid
• Furosemide
• Torasemide
• Azosemide
• Bumetanide

30. Pharmacokinetics and
Pharmacodynamics
• effective when administered orally or
intravenously (IV)
• an average bioavailability of 50% (10-100%)
• Protein binding is extensive, with approximately
90% of the drug bound to albumin
• Glomerular filtration and renal tubular secretion--
50% to 60% of furosemide excretion
• remaining 40% to 50% is conjugated to
glucuronide in the kidneys

31. • elimination half-life is 1 to 2
hours
• a rapid onset, 5 to 10
minutes of administration
• a peak effect at 30 minutes
• duration of action of 2 to 6
hours

32. • Torasemide is twice as potent as furosemide and
has a longer duration of action, with a plasma half-
life of 3 to 4 hours allowing for a once a day dosing
• Bumetanide has a bioavailability of 80% to 100%
after oral administration and is 40 times more
potent than furosemide
• Doses :
• I.V Furosemide 20-100mg (PO 0.75-3mg/kg,IV 0.1 -
1.0mg/ kg)
• Torsemide 10-100mg
• Bumetanide 0.5-1mg

33. Clinical Uses
• commonly used in patients with acute
exacerbation of heart failure-mobilization of
edema fluid
• hypertension as adjuncts
• evaluation of acute oliguria

34. • conversion of oliguric renal failure to non oliguric
renal failure
• treatment of hypercalcemia
• treatment of increased intracranial pressure

35. Side Effects
• manifest as abnormalities of fluid and electrolyte
balance
• hypokalemia and increase the likelihood of digitalis
toxicity
• may cause hyperuricemia
• Hyperglycemia

36. • braking phenomenon
• Hypotension may result in hypovolemic patients
exacerbating renal ischemic injury and
concentrating nephrotoxins in the renal tubules
• increases renal tissue concentrations of
aminoglycosides and enhances the possible
nephrotoxic effects of these antibiotics

37. • potentiate non-depolarizing neuromuscular
blockade
• renal clearance of lithium is decreased and plasma
concentrations of lithium may be increased
• Ototoxicity, either transient or permanent-rare,
dose-dependent

38. Carbonic Anhydrase Inhibitors
• Acetazolamide
• bind avidly to the enzyme carbonic anhydrase
• produces noncompetitive inhibition of enzyme
activity, principally in the proximal renal tubules
and the collecting ducts
• Interfere with Na+ reabsorption and H+ secretion in
PCT
• results in decreased reabsorption of Na+, HCO3
−,
and water

40. Pharmacokinetics and Pharmacodynamics
• After oral administration, acetazolamide is excreted
unchanged by the kidneys
• dose should be adjusted in patients with renal
failure and the elderly
• increased excretion of HCO3
− results in an alkaline
urine and metabolic acidosis
• Natriuresis associated with carbonic anhydrase
inhibitors is modest

41. • increased delivery of Na+ to the distal tubules leads
to potassium loss
• Most of the chloride is reabsorbed in the loop of
Henle, leading to the excretion of an alkaline urine
in the presence of hyperchloremic metabolic
acidosis
• dose 200mg – 500mg orally

42. Clinical Uses
• Diuretic of choice in altitude sickness
• Correction of metabolic alkalosis in edematous
patients
• Alkalinization of urine- enhance urinary excretion of
weakly acidic compound such as uric acid
• Reduction of IOP

43. • Idiopathic intracranial hypertension
• Epilepsy : because acidosis results in decrease
seizures
• Familial periodic paralysis- drug induced metabolic
acidosis which increases the local concentration of
K+ in skeletal muscles

44. Side Effects
• high incidence of systemic side effects associated
with the use of acetazolamide
• fatigue
• decreased appetite
• depression
• paresthesias
• dose should be reduced in patients with chronic
renal insufficiency and avoided in patients with
severe chronic renal insufficiency because of the
increased risk of metabolic acidosis

45. Osmotic Diuretics
• are inert substances that do not undergo
metabolism and are filtered freely at the
glomerulus
• mannitol, urea, isosorbide, and glycerin
• administration causes increased plasma and renal
tubular fluid osmolality, with resulting osmotic
diuresis

46. • portions of the renal tubules that are highly
permeable to water-the proximal renal tubules and
more importantly, the loop of Henle, represent the
principal site of action of osmotic diuretics

47. Mannitol
• only osmotic diuretic in current use
• mannitol is a six-carbon sugar alcohol that does not
undergo metabolism
• is not absorbed from the gastrointestinal tract,
which necessitates its exclusive use by IV injection
• does not enter cells, and only means of clearance
from the plasma is by glomerular filtration

48. Pharmacokinetics and Pharmacodynamics
• is completely filtered at the glomeruli, and none of
the filtered drug is subsequently reabsorbed from
the renal tubules
• by increasing tubular fluid osmolality, it decreases
water reabsorption and promotes water diuresis

49. • sodium is diluted in the retained water in the renal
tubules, leading to less reabsorption
• Hypernatremia may result from the water diuresis
• Onset-10 to 15 minutes, with a peak effect at 30 to
45 minutes and a duration of 6 hours

50. Clinical Uses
• primarily in the acute management of elevated ICP
and in the treatment of glaucoma
• to prevent perioperative kidney failure in the
setting of acute tubular necrosis
• has free radical scavenging properties, which may
protect transplanted kidneys following reperfusion

51. Side Effects
• increase in intravascular volume with the use of
mannitol may be poorly tolerated in patients with
left ventricular dysfunction, leading to pulmonary
edema
• in patients with renal insufficiency, mannitol is not
filtered and will cause increase in the intravascular
volume
• prolonged use of mannitol may cause hypovolemia,
electrolyte disturbances with hypokalemic
hypochloremic alkalosis, and plasma
hyperosmolarity due to excessive excretion of
water and sodium

52. Potassium-Sparing Diuretics
• act on the collecting ducts
• grouped in two categories: pteridine analogs and
aldosterone receptor blockers

53. • Pteridine analogs-triamterene and amiloride
• prevent Na+ reabsorption in the cortical
collecting duct by blocking the epithelial Na+
channels independent of aldosterone
• Aldosterone receptor blockers-
spironolactone and eplerenone
• prevent the synthesis and the activation of the
aldosterone-dependent basal cell Na+-K+-ATPase
pump

54. • Both mechanisms result in decreased Na+
reabsorption without the increased K+ secretion
• do not cause substantial diuresis and are not used
as single antihypertensive therapy
• are used in conjunction with thiazide diuretics to
prevent the associated loss of potassium and
magnesium

55. Pteridine Analogs
Pharmacokinetics and Pharmacodynamics
• Oral absorption of amiloride and triamterene is
limited (25% and 50%, respectively)
• Amiloride is more potent than triamterene and is
not metabolized but excreted unchanged in the
kidneys
• Triamterene is a pteridine with a structural
resemblance to folic acid

56. • metabolism of triamterene by the liver is extensive,
and its metabolite, secreted into the renal tubule,
has diuretic activity
• Accordingly, both kidney and liver disease will
affect the pharmacokinetics of triamterene
• the elimination half-time for triamterene is 4 hours
and for amiloride is about 20 hours

57. Clinical Uses
• are most often used in combination with loop
diuretics or thiazide diuretics to augment diuresis
and limit renal loss of potassium
• are rarely used as monotherapy
• cystic fibrosis is associated with increased sodium
absorption across airway epithelium, aerosolized
amiloride has been investigated in patients with
cystic fibrosis

58. Side Effects
• Hyperkalemia is the principal side effect of therapy
with potassium-sparing diuretics
• especially when combined with angiotensin-converting
enzyme inhibitors or angiotensin II receptor blockers or
in presence of nonsteroidal anti-inflammatory drugs
• although triamterene is a weak folic acid
antagonist, it rarely causes megaloblastic anemia
except in patients already at risk for folic acid
deficiency

59. Aldosterone Antagonists
• synthetic steroid analog and a nonspecific
mineralocorticoid receptor antagonist
• Spironolactone
• binds to the cytoplasmic mineralocorticoid
receptors in the collecting ducts, preventing Na+
reabsorption via the Na+-K+ pump
• Eplerenone-selective aldosterone receptor blocker,
has less affinity for other mineralocorticoid
receptors, and is less potent than spironolactone

60. • previously believed that spironolactone effects
were solely the result of competitive antagonism of
aldosterone binding to the mineralocorticoid
receptors--it has been shown to block the effects of
other ligands, such as cortisol

61. Pharmacokinetics and Pharmacodynamics
• exert their effect on the aldosterone receptor of
the tubular cell
• reach the tubular cells from the plasma, not from
the tubular fluid
• only diuretics that do not need to reach the renal
tubule to exert their effect

62. • competitive blockade of epithelial aldosterone
receptors in the distal tubule and the collecting
duct, preventing Na+-K+-ATPase activation and
resulting in
• decreased sodium reabsorption and in
• decreased potassium excretion
• Oral absorption of spironolactone approaches 70%
of the administered dose

63. • Spironolactone undergoes extensive hepatic first-
pass metabolism with multiple active metabolites,
which account for spironolactone’s long half-life of
20 hours
• Spironolactone and its metabolites are extensively
bound to plasma proteins and excreted by the
kidneys
• Eplerenone undergoes hepatic metabolism and its
half-life is prolonged in the presence of CYTP3A4
inhibitors, such as ketoconazole and verapamil

64. Clinical Uses
• treatment of essential hypertension, in combination
with thiazides, particularly in patients with a low
renin state or patients with metabolic syndrome
• used in patients with refractory hypertension
• combination with a thiazide diuretic results in
improved diuresis and blood pressure control
• used to promote diuresis in patients with edema and
fluid overload associated with hyperaldosteronism,
such as liver cirrhosis, nephrotic syndrome, and
heart failure

65. Side Effects
• Hyperkalemia, especially in the presence of
impaired renal function
• nonspecific mineralocorticoid receptor antagonist--
can block androgen and progesterone receptors,
leading to gynecomastia and breast tenderness

66. Other Diuretics
• Dopamine Receptor Agonists
• dopamine and fenoldopam
• Natriuretic Peptides
• nesiritide, a recombinant brain natriuretic peptide
• Vasopressin Receptor Antagonists (V2)
• tolvaptan
• Neprilysin Antagonists
• Aquaporin Modulators

69. THANK YOU!!!

70. Effects Of Diuretics On Urine Composition
Volume
(ml/min)
pH
Na+
(mEq/L)
K+
(mEq/L)
Cl-
(mEq/L)
HCO3
-
No Drug 1 6.4 50 15 60 1
Thiazide diuretics 13 7.4 150 25 150 25
Loop Diuretics 8 6.0 140 25 155 1
Osmotic Diuretics 10 6.5 90 15 110 4
Potassium-sparing
diuretics
3 7.2 130 10 120 15
Carbonic anhydrase
Inhibitors
3 8.2 70 60 15 120

71. Reabsorption of filtered water and solutes from the
tubular lumen across the tubular epithelial cells