This piece of document will clarify to you the concepts of diuretic agents.

1. Pharmacology of
diuretic agents
By; Monas Kitessa
Email: Moni.kitessa8709@gmail.com

2. RENAL ANATOMY AND PHYSIOLOGY
• The basic urine-forming unit of the kidney is the
nephron, which consists of a filtering apparatus, the
glomerulus, connected to a long tubular portion that
reabsorbs and conditions the glomerular ultra-filtrate.
• Each human kidney is composed of ~1 million
nephron.
• The 2 kidneys in humans produce together ~120 mL
of ultra filtrate per minute.

3. Cont…

4. PRINCIPLES OF DIURETIC ACTION
• By definition, diuretics are drugs that increase the rate of
urine flow.
By altering how the kidney handles sodium.
• Combination of two diuretics (synergistic effect).
One nephron segment can compensate for
altered Na+ reabsorption at another nephron
segment
Therefore, blocking multiple nephron sites
significantly enhances efficacy.
• Classification is based on the mechanism and site
of action.

5.  NaCl in the body is the major determinant of extracellular
fluid volume
 most clinical applications of diuretics are directed toward
reducing extracellular fluid volume by decreasing total-
body NaCl content
 A sustained imbalance between dietary Na+ intake and
Na+ loss is incompatible with life
Monas K. 5

6. A net positive Na+ balance would result in volume
overload with pulmonary edema
 A net negative Na+ balance would result in volume
depletion and cardiovascular collapse
Although continued diuretic administration causes a
sustained net deficit in total-body Na+, the time course of
natriuresis is finite
because renal compensatory mechanisms bring Na+
excretion in line with Na+ intake, a phenomenon
known as diuretic braking
Monas K. 6

7.  These compensatory, or braking, mechanisms include
 activation of the sympathetic nervous system
 activation of the rennin–angiotensin–aldosterone axis
 decreased arterial blood pressure (which reduces
pressure natriuresis)
 renal epithelial cell hypertrophy, increased renal
epithelial transporter expression
 alterations in natriuretic hormones such as atrial
natriuretic peptide
Monas K. 7

8. Tubule transport systems and sites of
action of diuretics.
Monas K. 8

9. The classification of diuretics was based on :
 Site of action (loop diuretics)
 Efficacy (high-ceiling diuretics), medium efficacy
diuretics ,weak diuretics
 Chemical structure (thiazide diuretics), similarity of
action with other diuretics (thiazide like diuretics)
 Effects on potassium excretion (potassium-sparing
diuretics),
 Mechanism of action (carbonic anhydrase inhibitors,
osmotic diuretics) Monas K. 9

10. Carbonic Anhydrase (CA) Inhibitors:
• Example:
Acetazolamide (250 mg),
Dichlorphenamide (50 mg),
Methazolamide (50 mg)
 They are un substituted sulfonamide derivatives and were
discovered when it was found that bacteriostatic
sulfonamides caused an alkaline diuresis and metabolic
acidosis
 Acetazolamide is the prototype of this class of agents
Monas K. 10

11. Mechanism of Action
 Normally the carbonic anhydrase enzyme
facilitates the reaction between H2O + CO2 to form
carbonic acid.
CO2 + H2O CA H2 CO3 2H+ + HCO3
-
Inhibition of carbonic anhydrase reduces H+ ion
concentration in renal tubules.
As a result, there is increased excretion of
bicarbonate, sodium, water, and potassium.
Reasorption of water is decreased and urine
volume is increased.
Monas K. 11

12.  These drugs inhibits both luminal and cytoplasmic
carbonic anhydrase
 is present in many nephron sites,
but the predominant location of this enzyme is the
luminal membrane of the proximal tubule cells where it
catalyzes the dehydration of H2CO3, a critical step in the
reabsorption of bicarbonate
 By blocking carbonic anhydrase, inhibitors block sodium
bicarbonate reabsorption and cause diuresis.
Monas K. 12

13. Monas K. 13

14.  Inhibition of cytoplasmic CA limits the formation of
intracellular protons and
 Inhibition of luminal CA delays luminal carbonic acid
dehydration
 Both of which indirectly inhibit luminal Na+ -H+
exchange.
•These results in increased delivery of Na+ and
H2CO3 to nephron segments beyond the
proximal tubule.
Monas K. 14

15.  Concurrently, the decreased bicarbonate reabsorption leads
to decreased gradients for subsequent chloride and sodium
absorption and thus increases sodium chloride delivery out
of the proximal tubule.
 However, the increase in sodium concentration in the
tubular fluid may be compensated partially by increased
NaCl reabsorption in later segments of the tubule.
 Thus, the diuretic effect of the carbonic anhydrase
inhibitors is mild
Monas K. 15

16. Effect on electrolyte excretion
 CA Inhibitors primarily cause;-
– An increase in urinary HCO3
-, K+, and water
excretion.
–The fractional excretion of Na+ (5%) & K+ (70%)
– but have little or no effect on the excretion of
Ca2+ or Mg2+.
•45% of the whole kidney HCO3
- reabsorption is
inhibited.
 CA inhibitors are now rarely used as diuretics
Monas K. 16

17.  The diuretic efficacy is reduced with continued therapy
because;-
–Un catalyzed reaction between CO2 and water is
sufficient to achieve HCO3
- reabsorption.
–In addition, depletion leads to enhanced NaCl
reabsorption by the reminder of the nephron.
Monas K. 17

18. Pharmacokinetics
 Well absorbed after oral administration.
 An increase in urine pH from the bicarbonate diuresis is
apparent within 30 minutes, maximal at 2 hours, and
persists for 12 hours after a single dose.
 Excretion of the drug is by secretion in the proximal
tubule; therefore, dosing must be reduced in renal
insufficiency.
Monas K. 18

19. Clinical Indications
• Glaucoma
 The ciliary body of the eye secretes bicarbonate from the blood into the
aqueous humor.
 The reduction of aqueous humor formation by carbonic anhydrase
inhibitors decreases the intraocular pressure
 The primary indication for CA inhibitors is open angle glaucoma.
 CA Inhibitors may be used preoperatively in acute angle-closure
glaucoma to lower ocular pressure before surgery
 But these are less effective as compared to other class of drugs and
have short duration of action
Monas K. 19

20. Increased intracranial pressure
 The formation of cerebrospinal fluid by the choroid
plexus involves bicarbonate secretion into the
cerebrospinal fluid.
 Therefore; Production of CSF, is dependent on CA and
thus CA inhibitors may be used to decrease CNS pressure.
Monas K. 20

21. Acute Mountain Sickness (AMS)
 AMS occurs when people ascend to high altitude (usually >3500m)
because of lack of oxygen.
 Headache, fatigue, undue breathlessness on exertion, the sensation
of the heart beating forcibly, loss of appetite, nausea, vomiting,
dizziness, ataxia, difficulty sleeping and irregular breathing during
sleep are the common complaints.
 The only cure for mountain sickness is either acclimatization or
descent but acetazolamide can be used either for prophylaxis or
symptomatic treatment.
Monas K. 21

22. • The proposed mechanism of action of CA inhibitors use in AMS
includes;-
 Increase kidney excretion of bicarbonate and lead to decreased blood
PH.
– The decreases of blood pH stimulates extra breathing, which results
in higher oxygen levels in the blood.
– The decrease in serum pH lowers hemoglobin's affinity for oxygen,
thereby increasing oxygen delivery to the tissues.
 Acetazolamide is effective for prophylaxis and the recommended dose
is 125mg BID for 3 days before ascent to  3500m, and for two more
following day
Monas K. 22

23. Epilepsy
 Acetazolamide is used as an adjuvant in the treatment of
absence seizure when primary drugs are not fully
effective
 Potential anticonvulsant mechanism of acetazolamide is
an increase in the efficacy of GABA-mediated inhibition.
Monas K. 23

24. Metabolic Alkalosis
 Carbonic anhydrase inhibitors can be useful for correcting
a metabolic alkalosis, especially an alkalosis caused by
diuretic-induced increases in H+ excretion.
Alkaline Diuresis
 CA inhibitors can be given in conditions where urine
alkalinization is beneficial as in the case of acidic drug
overdoses to facilitate excretion.
Monas K. 24

25. Adverse Drug Reactions
Hypokalemia: Increased delivery of Na+ in the late distal
tubule and collecting duct enhances the driving force for
the reabsorption of Na+ which is linked to secretion of K+
to the lumen.
Metabolic acidosis: Metabolic acidosis develops due to
urinary loss of bicarbonate.
Renal Stones: Kidney stone formation can occur due to
precipitation of calcium phosphate salts in alkaline urine.
Monas K. 25

26. Allergic reactions
 Allergic reactions such as rash, fever, and
interstitial nephritis may occur in patients
hypersensitive to sulfonamides
 Other sulfonamide related ADR such as bone
marrow depression may rarely occur.
CNS effects
 With large doses, many patients exhibit
drowsiness
Monas K. 26

27. II. Loop Diuretics
• Bind to Na+/2Cl-/K+ cotransporter at the chloride binding site
• inhibit the luminal Na+/K+/2Cl- transporter in the thick ascending limb
of Henle's loop and reduce the reabsorption of NaCl.
• Results in increased delivery of sodium out of the thick limb and a
decrease in the medullary interstitial osmotic gradient
• Increase renal prostaglandins, resulting in the dilation of blood vessels
and reduced peripheral vascular resistance.
• These drugs are the most efficacious diuretic agents available; due to the
large NaCl absorptive capacity of this segment
Monas K. 27

28. • Typical loop diuretic is Furosemide
•Other drugs include: -
–Bumetanide
–Torsemide
–Ethacrynic acid
–Muzolimine
–Azosemide
–Piretanide
Monas K. 28

29. Ex. Furosemide 20–80 mg
Ethacrynic acid 50–200 mg
Bumetanide 0.5–2 mg
Torsemide 2.5–20 mg
Monas K. 29

30. • Inhibitors of Na+/2Cl-/K+ symport are highly efficacious b/c
1. large solute load normally is reabsorbed by the thick ascending
limb.
2. There is minimal solute reabsorption beyond the thick ascending
limb.
• Inhibitors of Na+/2Cl-/K+ symport also inhibit Ca2+ and Mg2+
reabsorption in the thick ascending limb
• by abolishing the transepithelial potential difference
that is the dominant driving force for reabsorption of
these cations
Monas K. 30

31. •Furosemide has a weak CA inhibitor activity and increase
HCO3- excretion
•All loop diuretics increase the urinary excretion of K+ and
titratable acid (H+)
•NSAIDs (eg, indomethacin) can interfere with the actions
of the loop diuretics by reducing prostaglandin synthesis
in the kidney
•Loop agents like furosemide appear to have direct effects
on blood flow and increases renal blood flow
Monas K. 31

32. Pharmacokinetics
•Rapidly absorbed from oral
•Eliminated by tubular secretion as well as by glomerular
filtration
•Diuretic response is extremely rapid following IV
•The duration of action for furosemide is usually 2–3 hours
and that of torsemide is 4–6 hours.
•Half-life depends on renal function
Monas K. 32

33. Therapeutic uses
•Acute pulmonary edema
–Loop diuretics increase systemic venous capacitance and
thereby decrease left ventricular filling pressure.
•Chronic congestive heart failure
–To reduce extracellular fluid volume and thus reduce
venous and pulmonary edema.
•Edema in renal failure and nephrotic syndrome
•Edema of liver cirrhosis
Monas K. 33

34. b.
– Not recommended for routine use, reserved for
emergency case and when other
antihypertensive agents fail to respond.
c.
Monas K. 34

35. Monas K. 35

36. ADR Of Loop Diuretics
Hyponatremia: Occur due to excessive use and is associated
with sever volume wasting, and hypotension.
Hypokalemia: Occurs due to increased delivery of Na+ to the
late distal tubules and collecting duct and also due to
stimulation of rennin release.
– Minimized by:
1. Consuming K+-rich foods
– Dried fruits, nuts, spinach, citrus fruits, potatoes,
bananas,…
2. Taking K+ supplements
3. Using a K+-sparing diuretics
Monas K. 36

37. Metabolic alkalosis occur due to
 Increased delivery of Na+ to collecting tubule where the
reabsorption of Na+ enhances excretion of H+
 Stimulation of rennin release which further increase H+
secretion related Na+ Reabsorption
Monas K. 37

38. Hypomagnesemia and rarely hypocalcemia
• Hypocalcemia is rare because Ca++ is reabsorbed at DCT
under the influence of parathyroid hormone (PTH).
Ototoxicity
• Manifestations include reversible hearing impairment &
deafness, tinnitus, and vertigo
• Especially common with ethacrynic acid
Monas K. 38

39. Hyperuricemia
• Occurs due to hypovolemia- associated enhancement of
uric acid reabsorption
• May precipitate gout
Hyperglycemia
• Due mainly to hypokalemia (inhibit proinsulin to insulin)
• Rarely may precipitate diabetes.
Other rare ADRs
• Include allergic reactions, leukopenia or
agranulocytosis ,thrombocytopenia, pancreatitis
Monas K. 39

40. Drug Interactions
•Effect of loop diuretic reduced by NSAIDs
•Diuretic effect is reduced by probenecid
•Potentiate ototoxicity or nephrotoxicity of amphotericin B,
aminoglycosides
•Potentiate induction of arrhythmias by digitalis
•Potentiate hypokalemia associated with amphotericin B,
mineralocorticoids, some synthetic penicillins, many others
(that induce hypokalemia)
•Potentiate neuromuscular junction blockers
Monas K. 40

41. III. Thiazides and Thiazide like Diuretics
• Methyclothiazide, Hydrochlorothiazide, Chlorothiazide,
Hydroflumethiazide (Thiazides )
• Chlorthalidone, Indapamide, Metolazone, Mefruside (Thiazide like
Diuretics)
MOA:
• They block Na+/Cl- transporter in the distal convoluted tubule
• Thiazides enhance Ca2+ reabsorption in the distal convoluted tubule
therefore, are useful in the treatment of kidney stones caused by
hypercalceuria
Monas K. 41

42. •Like loop diuretics, the actions of thiazides can be inhibited
by NSAIDs under certain conditions.
•They compete with the secretion of uric acid in the PCT. As
a result, uric acid secretion may be reduced, with an
elevation in serum uric acid level
•Small amount of NaCl (about 5% of filtered load) is excreted
because large amount (up to 90%) is absorbed at earlier sites.
•Thus thiazides have only a medium diuretic efficacy.
•Some thiazides have weak CA inhibitory activity and
produce HCO3-excretion
Monas K. 42

43. Monas K. 43

44. Na+
Cl-
Ca2
+
K+
Na+
R PTH
Na+
Ca2+
Ca2+
H+
TRDs
Lumen-
Urine Interstitium-
Blood
TRDs= Thiazides and Thiazide related diuretics
Monas K. 44

45. Pharmacokinetics
•All thiazides and related drugs are well absorbed orally
and are administered only by this route
•They are secreted at proximal tubule by organic acid
secretary system.
•Most agents undergo little hepatic metabolism and are
excreted as such.
Monas K. 45

46. Therapeutic uses
• Treatment of mild to moderate hypertension.
– Thiazides are drugs of choice in the initial management
of HTN.
• Hypercalciuria
– They prevent Ca++ loss which may be associated with
recurrent calcium stones in kidney.
– May also be useful in osteoporosis.
• Edema
– Thiazides are preferred in mild to moderate edema for
maintenance therapy
Monas K. 46

47. ADRs of Thiazides
Fluid and Electrolyte imbalance
 Hypokalemia, Hyponatremia, Hypochloremia, Metabolic
alkalosis, Hypomagnesemia, Hypercalcemia, and
Hyperuricemia.
GIT disturbances
• Anorexia, Nausea, Vomiting, Cramping, Diarrhea
CNS disturbances
• Vertigo, headache
Monas K. 47

48. Allergic reaction
• Thiazides are sulfonamides and can cause allergic
reactions similar to other sulfonamides.
Glucose intolerance
• Hyperglycemia occurs due to impaired insulin release
and diminished glucose utilization.
Hyperlipidemia
• May increase LDL cholesterol, total cholesterol, and total
triglycerides.
Monas K. 48

49. Drug interaction
•Hypokalemia induced by thiazides potentiates digitalis
toxicity
•Probenecid reduces diuretic effect of thiazides, and
thiazides diminish its uricosuric action
•Amphotericin B and corticosteroids increase the risk of
hypokalemia induced by thiazide diuretics
Monas K. 49

50. Potassium Sparing Diuretics
• Two classes of drugs
– Aldosterone Antagonists : -
• Spironolactone, Canrenone (eplerenone), Potassium
canrenoate,
– Na+ channel Inhibitors: -
• Triamterene and Amiloride
Monas K. 50

51. • Spironolactone competitively inhibits the binding of aldosterone to its
receptor and abolishes its biological effects.
• Its metabolite canrenone has also similar effects.
• Both drugs decrease the number of open Na channels and the activity
of Na-K-ATPase pumps
Monas K. 51

52. • Amiloride and triamterene directly inhibit the sodium channel in the luminal membrane of the
late distal tubule and collecting duct
Monas K. 52

53. • Both classes of drugs decrease potassium excretion secondary to their
inhibition of the lumen-negative transepithelial potential difference
• Either mechanism produces poor diuresis when the drugs used alone.
– Since little solute reabsorption occurs in late distal tubules and
collecting duct, the drugs results in only a mild increase in the
excretion rates of Na+ and Cl-.
• However the diuretic activity increased if:
– sodium load in the body is high
– Aldosterone concentrations are high
– sodium load in tubule is high - secondary to diuresis
Monas K. 53

54. Clinical Uses
• In combination with other diuretics for treatment of edema,
hypertension and CHF
– All potassium sparing diuretics are not used alone either in the
treatment of edema or hypertension.
– Used in combination with loop and thiazide diuretics mainly to
avoid hypokalemia and also to enhance diuretic efficacy.
• Hyperaldosteronism
– Spironolactone is used in primary hyperaldosteronism (e.g. adrenal
tumour) and also secondary hyperaldosteronism resulting from
congestive heart failure, nephritic syndrome, hepatic cirrhosis, etc
Monas K. 54

55. ADRs
•Hyperkalemia
–The risk of hyperkalemia is increased in renal disease, and
if used together with other drugs that decrease
aldosterone activity (Beta blockers, NSAIDs, ACE
inhibitors).
–Oral K+ supplementation should be discontinued if K+
sparing diuretics are used.
•Metabolic Acidosis
–Due to decrease secretion of H+
Monas K. 55

56. •Endocrine abnormalities
–Spironolactone may produce adrenal and sex hormone
effects with long term use due to its steroidal structure.
•Gynecomastia, impotence, decreased libido, hirsutism,
deepening of the voice, and menstrual irregularities.
•mediated by nonselective binding to estrogen and
progesterone receptors
•GI effects
–Spironolactone also may induce diarrhea, gastritis, gastric
bleeding, and peptic ulcers; it is contraindicated
Monas K. 56

57. Pharmacokinetics
•Spironlacotone has good oral bioavalability (75%).
•It is highly bound to plasma proteins and is extensively
metabolized
•Its metabolites are active, the most important of which is
Canrenone (responsible for ½ - 2/3 of the activity)
•It has a short half-life (approximately 1.4 hours). However
canrenone, has a half-life of approximately 16.5 hours,
which prolongs its pharmacological effects.
Monas K. 57

58. Drug interactions
• Dangerous hyperkalemia with KCl supplements
• Risk of hyperkalemia increases with Beta blockers, NSAIDs,
ACE inhibitors
• Salicylates, block spironolactone action by inhibiting
secretion of canrenone
Monas K. 58

59. Osmotic Diuretics
 The prototype osmotic agent is mannitol.
 Other drugs include: -
– Glycerin, Isosorbide, and urea.
 Osmotic diuretics
 freely filtered at the glomerulus
 undergo limited reabsorption by the renal tubule and
increase tubular tonicity.
 Thus they prevent passive water reabsorption both in the
proximal tubule and the loop of Henle
Monas K. 59

60. •The thin descending limb appears to be the major site of
action
•Na+ reabsorption may be slightly reduced due to increased
rate of urine flow or because luminal retention of water
opposes Na+ reabsorption.
•In general osmotic diuretics increase the urinary excretion of
nearly all electrolytes including Na+, K+, Ca2+, Mg2+ , Cl-,
HCO3
-, and phosphate.
Monas K. 60

61. Pharmacokinetics
• Mannitol and urea are poorly absorbed and are not
effective orally. Thus must be given intravenously
• Glycerin and isosorbide can be given orally
• Eliminated renally via glomerular filtration, except
gylcerin.
Monas K. 61

62. Clinical Uses
Reduction of intracranial and intraocular pressure
• Osmotic agents encourage movement of water from CSF
and Aqueous humor by increasing osmotic pressure of the
plasma
• Used to control IOP and ICP both preoperatively and
postoperatively
Acute Renal failure
• Osmotic agents are used in acute renal failure where kidney
is incapable of forming urine. They maintain GFR and
urine flow
Monas K. 62

63. ADRs
ECF fluid volume expansion
• Extract water from intracellular compartment and increase ECF
volume.
 Thus they produce pulmonary edema and aggravate congestive heart
failure
• Initially osmotic agents may cause hyponatremia which could explain
common side effects such as headache, nausea and vomiting.
Dehydration and Hypernatremia
• Excessive use leads to free water loss, severe dehydration and
hypernatremia.
Monas K. 63

64.  Urea should not be administered to patients with impaired
liver function because of the risk of elevation of blood
ammonia levels
 Glycerin is metabolized and can cause hyperglycemia.
Contraindication
 Pulmonary edema
 acute left ventricular failure, CHF
 Cerebral hemorrhage
 Acute tubular necrosis
Monas K. 64

65. Monas K. 65

66. Reading assignment
• Antidiuretic Hormone Agonists & Antag
onists