1. Ass. Prof. Dr. Naza M. Ali Lec. 11-12 G2 19 May 2019 G1 22 May 2019
Diuretic Agents
Ass. Prof. Dr. Naza M. Ali Lec G May G May 2019

2. Outlines Normal Regulation of Fluid and Electrolytes The Nephron
Major Segments of The Nephron
Diuretics and Classification
Multiple Choice Examples

3. Normal Regulation of Fluid and Electrolytes
About % of the blood plasma entering the kidneys is filtered from the glomerular capillaries into the Bowman capsule.
The filtrate, normally free of proteins and blood cells, does contain most LMWT plasma components in approximately the same concentrations as are found in the plasma.

4. Like glucose, sodium bicarbonate, amino acids, and electrolytes, such as Na+ , K+ , Cl–.
The kidney regulates the ionic composition and volume of urine by:
the active reabsorption or secretion of ions and/or the passive reabsorption of water
at five functional zones

5. The Nephron PCT The descending loop of Henle
The ascending loop of Henle
DCT
The collecting tubule and duct

6. Sites of transport of solutes and water along the nephron

7. Major Segments of the Nephron

8. Diuretics:
Any substance which increase urine and solute excretion.
It often change its pH as well as the ionic composition of the urine and blood.
Classification
1. Carbonic anhydrase inhibitors / PCT
2. Loop diuretics / TAL
3. Thiazide / DCT
4. K- sparing diuretics / CCT
5. Drugs that modify water excretion

9. Major locations of ion and water exchange in the nephron, showing sites of action of the diuretic drugs.

11. Proximal Convoluted Tubule_
HCo3 reabsorption is initiated by the action of
Na + /H +
exchange (via NHE3).
Which allow Na + to enter the cell from the tubular lumen in exchange for a proton H+ from inside the cell
Carbonic Anhydrase (CA)

12. 1. Carbonic Anhydrase Inhibitors/ CAI
Acetazolamide/ Sulfonamide derivatives
Effects:
Normally, carbonic anhydrase catalyzes the
dehydration of H2CO3 to CO2 at the luminal membrane & rehydration of CO2 to H2CO3 in the cytoplasm
The major renal effect is bicarbonate diuresis (NaHCO3 is excreted)

13. Body bicarbonate is depleted, and metabolic acidosis results.
CAI blunt NaHCO3 reabsorption and cause diuresis
are well absorbed after oral administration.
Diuresis is apparent within 30 minutes,
is maximal at 2 hours,
and persists for 12 hours after a single dose.

14. Clinical Indications Glaucoma Mountain sickness
C. Urinary Alkalinization
D. Metabolic Alkalosis
E. Other Uses

15. Glaucoma: Is to reduce the elevated intraocular pressure
Decreases the production of aqueous humor, by blocking carbonic anhydrase in the ciliary body of eye.
It is useful in the chronic treatment of glaucoma.
Topical, dorzolamide and brinzolamide
Have the advantage of not causing any systemic effects.

16. Mountain sickness:
Can be used in the prophylaxis of acute mountain sickness among healthy, physically active individuals who rapidly ascend above 10,000 feet.
Acetazolamide given nightly for 5 days before the
ascent prevents the weakness, breathlessness, dizziness, nausea, and cerebral as well as pulmonary edema characteristic of the syndrome.

17. D. Other Uses
used as adjuvants in the treatment of epilepsy
useful in treating patients with CSF leakage (By reducing the rate of CSF formation and intracranial pressure) CAI can significantly slow the rate of CSF leakage)
Protect against Acute Mountain Sickness

18. Toxicity A. Drowsiness and parasthesias B. Metabolic Acidosis C
Toxicity A. Drowsiness and parasthesias B. Metabolic Acidosis C. Renal Stone/ alkalization of urine may precipitation of calcium salts, enhanced stone formation D. Renal Potassium Wasting E. Cross-allergy

19. Thick Ascending Limb
NKCC2 is the primary transporter in the luminal membrane.
Because k+ is pumped into the cell from both the luminal & basal sides, an escape route must be provided.
This occurs into the lumen via a potassium-selective channel.
Because the potassium diffusing through these channels is not accompanied by an anion, a net positive charge is set up in lumen.
This positive potential drives the reabsorption of Ca+ ² and Mg +²
Target loop diuretics

20. 2. Loop Diuretics: Sulfonamide derivative :Furosemide, Bumetanide,
Torsemide
Not a sulfonamide derivative forms: Ethacrynic acid
Inhibit co-transport of sodium, potassuim chloride ( inhibit NKCC2)

21. Effects Selectively inhibit NaCl reabsorption in the TAL
Diuresis effects: Na+ , K+, 2Cl-, Mg+², Ca+² excretion
The diluting ability of the nephron is reduced because loop of Henle is the site of significant dilution of urine.
So Ca +2 excretion increase

22. Loop diuretics have highest efficacy in mobilizing Na+ and Cl – from the body
Loop diuretics have potent pulmonary vasodilating effects
PG are important in maintaining glomerular filtration
Drugs such as NSAIDs , which inhibit PG synthesis, the efficacy of loop diuretics decrease

23. Loop diuretics
Oral and parentéral preparation
Duration: short acting 4 hr
Clinical Indications
Acute pulmonary edema, other edematous conditions
Hypertension
Acute hypercalcemia
Hyperkalemia, acute renal failure
useful in treating toxic ingestion of bromide, fluoride & iodide which are reabsorbed in TAL

24. Toxicity
A. Hypokalemic Metabolic Alkalosis
B. Ototoxicity
C. Hyperuricemia
D. Allergic

25. Distal Convoluted Tubule
NCC is the primary sodium and chloride transporter in the luminal membrane.
Calcium is reabsorbed under control of parathyroid hormone
thus calcium must be transported via the sodium –calcium exchanger back into the blood.
(R, parathyroid hormone [PTH] receptor.)

26. Thiazide-like analogs Chlorthalidone Indapamide Metolazone
3. Thiazides
Chlorothiazide
Hydrochlorothiazide
Thiazide-like analogs
Chlorthalidone
Indapamide
Metolazone
All of them have sulfonamide group

27. The thiazide derivatives act mainly in the ascending loop of Henle and the distal tubule
to decrease the reabsorption of Na+ ,
by inhibition of a Na+ /Cl– co-transporter on the luminal membrane of the tubules

28. Oral, duration of action 6-12 h
All thiazides are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid by that system.
decrease uric acid secretion
elevate serum uric acid level

29. Effects
In full doses, thiazides produce moderate but sustained sodium and chloride diuresis.
Reduction in the transport of sodium and promote sodium –calcium exchange .
As a result reabsorption of calcium from urine is increased ( the opposite effect of loop diuretics).
Reduce blood pressure
Inhibition of renal PG synthesis will reduces the efficacy of thiazides

30. Clinical Indications (1) hypertension, (2) heart failure, (3) Primary hypercalciuria, (4) nephrogenic diabetes insipidus.

31. Toxicity A. Hypokalemic, Metabolic Alkalosis ,Hyperuricemia B
Toxicity A. Hypokalemic, Metabolic Alkalosis ,Hyperuricemia B. Hyperlipidemia C. Hyponatremia D. Allergic Reactions E. Hyperglycemia in diabetic patients due to both impaired pancreatic release of insulin and diminished tissue utilization of glucose.

32. Cortical Collecting Tubule / CCT
Final segment of nephron is
the Last tubular site for sodium reabsorption and is controlled
by Aldosterone
The reabsorption of sodium occur via channels not transporter epithelial sodium channel (ENaC)
Accompanied by equivalent loss of K+ or H+
(R, aldosterone receptor.)
Collecting tubule is the primary site of acidification of the urine and last site of potassium excretion

33. 4. Potassium – sparing diuretics
Aldosterone antagonist / Steroid derivative
Spironolactone
Eplenerone
Slow onset & offset of action h
Reduce Na + absorption

34. Aldosterone Antagonist Non-Aldosterone Antagonists
Potassium – Sparing Diuretics
Aldosterone Antagonist
(Steroid Derivative)
Non-Aldosterone Antagonists
Spironolactone
Eplenerone
Amiloride
Triamterene

35. Antagonizes aldosterone at intracellular cytoplasmic receptor sites.
Spironolactone
Antagonizes aldosterone at intracellular cytoplasmic receptor sites.
The spironolactone-receptor complex is inactive.
it prevents translocation of the receptor complex into the nucleus of the target cell, it cannot bind to DNA.
This results in a failure to produce proteins that are normally synthesized in response to aldosterone.

36. These mediator proteins normally stimulate the Na+/K+ exchange sites of the collecting tubule.
Thus, a lack of mediator proteins prevents Na+ reabsorption and, therefore, K+ and H+ secretion.
Potassium absorption (and K + secretion) at this site is regulated by aldosterone

37. Clinical Indication
Hyperaldosteronism,
Hepatic edema
Treatment of potassium wasting cause by chronic therapy with thiazide and loop diuretics
Adverse effects:
Hyperkalemia,
Spironolactone can cause endocrine abnormality
(gynecomastia and antiandrogenic effects).

38. B. Nonaldosterone antagonists:
Amiloride
Triamterene
Have duration 12-24h
directly interfere with Na+ entry through the epithelial Na+ channels
So block Na+ transport channel , decrease Na+ entry , decrease K+ secretion
Toxicity
A. Hyperkalemia
B. Metabolic Acidosis

39. 5. Drugs that modify water excretion
A. Osmotic diuretics
The proximal tubule and descending limb of Henle’s loop are freely permeable to water .
Mannitol
Mannitol is poorly absorbed by the GI tract,
For systemic effect, mannitol must be given IV
Mannitol is not metabolized and is excreted by glomerular filtration within 30–60 minutes

40. Clinical Indications
A. Increase of Urine Volume
B. Reduction of Intracranial and Intraocular Pressure
Mannitol can reduce brain volume and intracrainal pressure by osmotically extracting water from tissue into blood.
A similar effect occur in the eye.
Toxicity
. Extracellular Volume Expansion
. Dehydration, Hyperkalemia, and Hypernatremia
. Hyponatremia

41. B. Antidiuretic Hormone
Drugs that modify water Excretion
A. Osmotic Diuretics
B. Antidiuretic Hormone
Mannitol
Urea
ADH Agonists
Vasopressin
Desmopressin
ADH Antagonist
Conivaptan

42. B. Antidiuretic hormone Agonists & Antagonists:
ADH Agonists:
Vasopressin
Desmopressin
ADH Antagonists:
Conivaptan

43. ADH Agonists: ADH facilitates water reabsorption from the collecting
tubule by activation of V2 receptor which stimulate
adeynylyl cyclase via Gs
Increase cAMP cause insertion of additional aquaporin
AQP2 water channels into luminal membrane in this
part of the tubule.
Reduce urine volume & increase its concentration.
are used in the treatment of pituitary diabetes insipidus.
Toxicity : large water load may cause hyponatremia.

44. Collecting Duct Above, low water permeability
exists in the absence of antidiuretic hormone (ADH).
Below, in the presence of ADH, aquaporins are inserted into the apical membrane, greatly increasing water permeability.
AQP2, apical aquaporin water channel AQP3,4, basolateral aquaporin water channel
V2 , vasopressin V2 receptor.

45. ADH Antagonists: Conivaptan
ADH antagonists oppose the actions of ADH on V2 receptor
use in the syndrome of inappropriate ADH secretion, when water restriction has failed to correct the abnormality.

46. Electrolyte changes by diuretics Agents
NaCl
NaHCo3
K +
Body PH
CAI ↑
↑↑↑
Acidosis
Loop
↑↑↑↑
Alkalosis
Thiazide ↑↑
K+ sparing ↓

47. Choose the ONE best answer.
18.1  An elderly patient with a history of heart disease is brought to the emergency room with difficulty breathing. Examination reveals that she has pulmonary edema. Which treatment is indicated?
A. Acetazolamide. B. Chlorthalidone. C. Furosemide. D. Hydrochlorothiazide. E. Spironolactone.
18.2  A group of college students is planning a mountain climbing trip to the Andes. Which would be appropriate for them to take to prevent mountain sickness?
A thiazide diuretic such as hydrochlorothiazide.
An anticholinergic such as atropine.
A carbonic anhydrase inhibitor such as acetazolamide.
A loop diuretic such as furosemide.
A β-blocker such as metoprolol.

48. 18. 3 An alcoholic male has developed hepatic cirrhosis
18.3 An alcoholic male has developed hepatic cirrhosis. To control the ascites and edema, which should be prescribed? A. Acetazolamide. B. Chlorthalidone. C. Furosemide. D. Hydrochlorothiazide. E. Spironolactone A 55-year-old male with kidney stones has been placed on a diuretic to decrease calcium excretion. However, after a few weeks, he develops an attack of gout. Which diuretic was he taking? A. Furosemide. B. Hydrochlorothiazide. C. Spironolactone. D. Triamterene. E. Urea A 75-year-old woman with hypertension is being treated with a thiazide. Her blood pressure responds well and reads at 120/76 mm Hg. After several months on the medication, she complains of being tired and weak. An analysis of the blood indicates low values for which of the following? A. Calcium. B. Glucose. C. Potassium. D. Sodium. E. Uric acid.

49. Correct answer = C.
Correct answer = E.
Correct answer = B.