Loop diuretics, thiazides, and other diuretic classes are summarized. Loop diuretics act in the thick ascending limb of Henle's loop by inhibiting the Na-K-2Cl transporter. Thiazides act in the distal convoluted tubule by blocking coupled Na and Cl reabsorption. Carbonic anhydrase inhibitors inhibit bicarbonate absorption in the proximal tubule. Osmotic diuretics like mannitol are filtered but not reabsorbed, drawing water out of cells. Potassium-sparing diuretics like amiloride act late in the distal nephron to inhibit Na reabsorption. Diuretic combinations can have synergistic effects.

1. DIURETICS
Sumanee prakobsuk

2. Individual classes of Diuretics
 Carbonic Anhydrase Inhibitors
 Osmotic Diuretics
 Loop Diuretics
 Thiazides and Thiazides like Diuretis
 Distal Potassium-Sparing Diuretics

4. Carbonic Anhydrase Inhibitors
 Acetazolamide (Diamox)
 Act primarily on proximal tubule cells to
inhibit bicarbonate absorption
 An additional, more modest, effect
along the distal nephron, however, is
also observed.

5. Carbonic anhydrase (CA) catalyzes inside the cell the
formation of HCO3 from H2O and CO2. This is the
result of the two-step process. Bicarbonate leaves
the cell via the Na-HCO3, cotransporter.464,465 A
second pool of carbonic anhydrase is located in the
brush border (CA). This participates in disposing of
carbonic acid, formed from filtered bicarbonate and
secreted H+. Both pools of CA are inhibited by
acetazolamide and other CA inhibitors

6. Pharmacokinetics.
 Acetazolamide (Diamox)
 Methazolamide (Neptazane)
 All of which favor penetration into aqueous
humor and cerebrospinal fluid (CSF). It has
less renal effect and, therefore, is preferred
for treatment of glaucoma.

7. ADVERSE EFFECTS
 Patients may complain of weakness,
lethargy, abnormal taste, paresthesia,
gastrointestinal distress, malaise, and
decreased libido.
 Overall, symptomatic metabolic acidosis
develops in half of glaucoma patients
treated with CAIs
Significant metabolic acidosis induced by acetazolamide. Not a rare
complication. Arch Intern Med 1985; 145:1815-1817.

8. Osmotic Diuretics
 Omsotic diuretics are substances that are freely
filtered but poorly reabsorbed.
 Mannitol is the prototypic osmotic diuretic
 Manitol is a hypertonic solute that abstracts water
from cells.
 In the water-permeable nephron segments of the
proximal nephron and the thin limbs of the loop of
Henle, fluid reabsorption concentrates filtered
mannitol sufficiently to diminish tubular fluid
reabsorption.

9.  Mannitol is recommended for management of severe
head injury.
 A trial of mannitol therapy for cerebral edema
complicating hepatic failure demonstrated a markedly
improved survival of 47%, compared with only 6% in
the control group.
Controlled trial of dexamethasone and mannitol for the cerebral
oedema of fulminant hepatic failure. Gut 1982; 23:625-629.

10. ADVERSE EFFECTS
 The osmotic abstraction of cell water initially causes
hyponatremia and hypochloremia.
 Later, when the excess ECF is excreted, the
decrease in cell water concentrates K+ and H+ within
cells, which increases the gradient for their diffusion
into the ECF, leading to hyperkalemic acidosis.
 Later, hypernatremic dehydration may develop if free
water is not provided, because urinary concentrating
ability is inhibited.

11. Loop Diuretics
 The prime action of loop diuretics
occurs from the luminal aspect of the
TAL .
 An electroneutral Na+/K+/2Cl−
cotransporter, termed NKCC2, is located
at the luminal membrane.

12. Brenner: Brenner and Rector's The Kidney, 8th ed.

13.  Loop diuretics increase the fractional
excretion of Ca2+ by up to 30%
 Loop diuretics can increase fractional
Mg2+ excretion by more than 60%
Effect of furosemide on calcium and magnesium transport in the rat nephron.
Am J Physiol 1981; 241:F340-F347.

14.  The total RBF is maintained or increased and the
GFR is little changed during administration of loop
diuretics to normal subjects.
 Furosemide increases the renal generation of
prostaglandins (PGs)
 Loop diuretics, by blocking NaCl entry into macula
densa cells, block the TGF completely.This is one
reason that loop diuretics tend to preserve GFR,
despite ECV depletion.
Effects of diuretics on inner medullary hemodynamics in the
dog. Circ Res 1982; 51:703-710.

15. Pharmacokinetic
Brenner: Brenner and Rector's The Kidney, 8th ed.

16.  Increase Organic Anion eg Uric acid,NSAID,
B-lactam,sulfonamide decrease uptake of
furosemide.
 Metabolic acidosis depolarizes the
membrane potential of Proximal tubule
cells,with decrease OA- secretion

17. Both uptake processes are inhibited by probenecid. Plasma albumin
concentration facilitates uptake and secretion by PT-S2 but inhibits
uptake and metabolism by PT-S1.
(Drawn from data in Pichette V, Geadah D, du Souich P: The influence of moderate
hypoalbuminemia on the renal metabolism and dynamics of furosemide in the rabbit. Br J
Pharmacol 119:885, 1996.)

19. Thaizides and Thiazide-like Diuretics
 The major site of action of thiazide and thiazide-like
diuretics is the distal convoluted tubule (DCT), where
they block coupled reabsorption of Na+ and Cl−
 Thiazides and thiazide-like diuretics are moderately
active drugs that increase excretion of sodium,
chloride, and potassium while reducing calcium
excretion.

20. Brenner: Brenner and Rector's
The Kidney, 8th ed.

21.  Thiazides increase potassium excretion,
their effects on K+ secretion result from
their tendency to stimu-late aldosterone
secretion, to increase distal flow.

22. Thiazides reduce Ca2+ excretion.
 Blockade of luminal NaCl entry—
 basolateral Na+/Ca2+ exchange
 Hyperpolarization increases calcium
entry via the transient receptor potential
channel subfamily V, member 5 (TRPV5)
 Third, thiazides stimulate proximal
reabsorption of Ca2+ owing to ECV
depletion
Brenner: Brenner and Rector's
The Kidney, 8th ed.

23. Mg excretion
 Diminishes TRPM6 mRNA expression
modestly .
Schlingmann KP, Weber S, Peters M, et al: Hypomagnesemia
with secondary hypocalcemia is caused by mutations in TRPM6,
a new member of the TRPM gene family. Nat
Genet 2002; 31:166-170.

25. Distal Potassium-Sparing Diuretics
 Act on the cells in the late DCT,
connecting tubule, and the cortical
collecting duct, where they inhibit
luminal Na+ entry via the ENaC .
 They depolarize the lumen-
negative transepithelial voltage,
diminishing the electrochemical
gradient for K+ and H+ secretion.

26.  Both amiloride and triamterene are organic cations
that block ENaC directly from the luminal surface.
 Spironolactone and eplerenone are competitive
antagonists of the mineralocorticoid receptor.

27. ADVERSE EFFECTS
 Hyperkalemia is the most common complication of
these drugs.
 The risk is dose-dependent and increases
considerably in patients with CKD or in those
receiving K+ supplements, angiotensin-converting
enzyme inhibitors (ACEIs), angiotensin receptor
blockers (ARBs), NSAIDs.

28. Diuretic Resistance
 Diuretic resistance implies an
inadequate clearance of edema despite
a full dose of diuretic.

29. Common Causes of Diuretic Resistance
Cause Example
Incorrect diagnosis Venous or lymphatic edema
Inappropriate NaCl intake Na+ intake > 120 mmol · d−1
Inadequate drug reaching tubule lumen in active form:
Noncompliance
Dose inadequate or too infrequent
Poor absorption Uncompensated CHF
Decreased renal blood flow CHF, cirrhosis of liver, elderly
Decreased functional renal mass AKF, CKD, elderly
Proteinuria Nephrotic syndrome
Inadequate renal response:
Low GFR AKI, CKD
Decreased effective ECV Edematous conditions
Activation of RAA axis Edematous conditions
Nephron adaptation Prolonged diuretic therapy
NSAIDs Indomethacin, aspirin

30. Dose –response relationship

32. ADAPTATION TO DIURETIC THERAPY
 Short term adaptation or Rebound
phenomenon
 Long term adaptation
or Braking phenomenon

33. Humoral and Neural Modulators of the
response to Diuretics
 Renin-Angiotensin-Aldosterone Axis .
 Catecholamines and Sympathetic
Nervous System.
 Arginine Vasopressin

34. Braking Phenomenon
 A reduced NaCl delivery to the site of furosemide
action . ( increase Angiotensin II )
 An enhanced ability of the distal tubule to
reabsorb the extra NaCl load delivered during
furosemide's upstream action.
 structural hypertrophy of the DCT, connecting
tubule , doubling of NCC expression in the distal
tubules of rats adapted to diuretics.
A micropuncture study in rats. Clin Sci 1996; 91:299-305.

35.  Nephronal adaptation could underlie the
inappropriate renal Na+ retention that can
persist for up to 2 weeks after abrupt
cessation of diuretic therapy.
DeWardener HE: Idiopathic edema: Role of
diuretic abuse. Kidney Int 1981; 19:881

37. Diuretic Combination
 Diuretics acting on a separate
mechanism may be synergistic.
Ellison DH: The physiologic basis of diuretic synergism: Its role in treating
diuretic resistance [see comments]. Ann Intern Med 1991; 114:886-894.

38. Loop Diuretics and Thiazides.
 synergistic in normal subjects and in those with
edema or renal insufficiency.
 During prolonged furosemide therapy, the
responsiveness to a thiazide is augmented.Patients
with advanced CKD (GFR<30 mL/min) who are
unresponsive to thiazide alone have a marked
natriuresis when a thiazide is added to loop diuretic
therapy, probably by blockade of enhanced distal
tubular Na+ reabsorption.
Coadministration of thiazides increases the efficacy of loop diuretics even in
patients with advanced renal failure. Kidney Int 1994; 46:482-488.

39. Loop Diuretics or Thiazides
and Distal Potassium-Sparing Diuretics .
 Amiloride or triamterene increases
furosemide natriuresis only modestly
but curtails the excretion of K+ and net
acid and preserves total body K+.
Long-term metabolic effects of spironolactong and thiazides
combined with potassium-sparing agents for treatment of
essential hypertension. Am J Cardiol 1988; 62:1072-1077.

40. ADVERSE EFFECTS OF DIURETICS

41. Hyponatremia
 Thiazides, which inhibit urinary dilution, whereas
loop diuretics inhibit urinary concentration and
dilution. Indeed, thiazides are 12-fold more likely than
loop diuretics to cause hyponatremia.
Spital A: Diuretic-induced hyponatremia. Am J
Nephrol 1999; 19:447-452.

42. Hypokalemia

43. Hypomagnesemia
 Loop diuretics inhibit Mg2+ reabsorption in the
TAL by reducing the transepithelial voltage
(Tm) that drives Mg2+ and Ca2+ paracellularly
 Thiazide diminishes TRPM6 mRNA
expression

44. Hypercalcemia
 Thiazides increase the serum
concentrations of total and ionized
calcium

45. Other side effects
 Hyperglycemia.
 Thiazides impair glucose uptake into muscle and
liver.
 It has been ascribed to a diuretic-induced
reduction in cardiac output with reflex activation
of the SNS and catecholamine secretion leading to
reductions in hepatic glucose uptake, muscle
blood flow, and muscle glucose uptake
A comparison of the effects of hydrochlorothiazide and captopril on
glucose and lipid metabolism in patients with hypertension. N Engl J
Med 1989; 321:868-873.

46.  Hyperlipidemia
 Administration of loop diuretics or thiazides
increases the plasma concentrations of total
cholesterol, triglycerides, and low-density
lipoprotein (LDL) cholesterol but reduces high-
density lipoprotein (HDL) cholesterol. These
adverse changes average 5% to 20% during
initiation of therapy.The mechanism is uncertain
Ames RP: The effects of antihypertensive drugs on serum lipids and
lipoproteins. II. Non-diuretic drugs. Drugs 1986; 32:335-357.

47.  Hyperuricemia
 Prolonged thiazide therapy for
hypertension increases the serum urate
concentration by approximately 35%.
 Renal urate clearance falls because of
competition for secretion between urate
and the diuretic and because ECV deplete
induced urate reabsorption

49. END

50. Hyponatemia
Redrawn from Clark BA, Shannon RP, Rosa RM, Epstein FH:
Increased susceptibility to thiazide-induced hyponatremia in
the elderly. J Am Soc Nephrol 5:1106, 1994.