1. Diuretic Agents

2. Learning Objectives At the end of this session, you will be able to:
Classify the diuretic agents
Describe the mechanism of diuretic agents
Demonstrate the pharmacological effects of typical diuretic agents
Propose the rational clinical application

3. Three stages of urine forming
A: Glomerular filtration
B: Reabsorption in renal tubule
C: Excretion in dismal and collecting tubule

4. Review of Kidney Function
GFR = 130 ml min-1
Glomerular Filtration Rate  130ml /min,
Normal urine production rate  1 ml/min, which indicates that 129/130 (>99%) of glomerular ultrafiltrate (filtered plasma, tubular fluid) is reabsorbed
>99% of salt is reabsorbed >99% of H2O is reabsorbed
Urine flow = 1 ml min-1

5. DIURETICS
Diuretics are drugs which increase the excretion of sodium and water from the body by an action on the kidney.
Their primary effect is to decrease the reabsorption of sodium and chloride from the filtrate, increase water loss being secondary to the increased excretion of salt.

6. Classification of Diuretic Agents
1. High-effective diuretics: Loop diuretics
2. Mid-effective diuretics: Thiazide diuretics
3. Low-effective diuretics: K+-sparing diuretics
& CAIs
According to the efficacy
Loop diuretics: furosemide, ethacrynic acid
Thiazides: hydrochlorothiazide, indapamide
K+-sparing diuretics: spironolactone, amiloride and triamterene
Carbonic anhydrase inhibitors: acetazolamide and dorzolamide
Osmotic diuretics: Mannitol

7. Loop diuretic， 12ml/min=0.72L/h
Excretion rates of typical diuretics, values observed at peak diuresis after a maximally effective dose
Loop diuretic， 12ml/min=0.72L/h
Normal urine production rate  1 ml/min

8. Nephron sites of action of diuretics

10. Mechanisms of Action: Loop diuretics
No transport systems in descending loop of Henle
Ascending loop contains Na+-K+-2Cl- cotransporter from lumen to ascending limb cells
Inhibit Na+-K+-2Cl- transport system to reduce the reabsorption of NaCl in the thick ascending limb of the loop of Henle
Inhibition of this transporter system leads to the reduction of K+ back diffusion into the tubular lumen, which reduces the lumen positive potential, and then causes an increase in Mg2+ and Ca2+ excretion

11. Loop Diuretics
Furosemide
Bumetanide
Torsemide
Ethacrynic acid

12. High efficacy diuretics
Pharmacological effects:
Diuresis
Increase Ca2+ excretion
Pharmacological kinetics:
Onset in 5 min by i.v. ; 30 min by p.o.
t 1/2=1h last for 4-6 h , even to 10h

13. CLINICAL APPLICATIONS OF LOOP DIURETICS
EDEMA due to CHF, nephrotic syndrome or cirrhosis
Acute heart failure with PULMONARY EDEMA
HYPERCALCEMIA
Accelerate the excretion of poisons

14. Adverse reaction
Ototoxicity (ethacrynic acid> lasix> bumetanide)
Disturbance of water and electrolyte
Hyperuricemia
Others toxicities: allergic reactions, nausea et al.

15. Thiazide Diuretics in the Distal Convoluted Tubule
Less reabsorption of water and electrolytes in the distal convoluted tubule than proximal tubule or loop
Thiazides block Na+-Cl- cotransporter

16. Thiazide Diuretics Hydrochlorothiazide Metolazone
PTH=Parathyroid Hormone 甲状旁腺激素

17. Pharmacol-effects & Clinical uses
Diuresis & Edema
Anti-hypertension & Hypertension
Decrease [Ca2+ ]in urine by increasing Ca2+ reabsorption & Idiopathic hypercalciuria or renal calculus
Anti-diuretic effect & Nephrogenic diabetes insipidus
- PDE , + cAMP, + permeability of H2O
+ NaCl excretion, - plasma osmotic pressure , - Thirsty feeling & drinking quantity

18. Adverse reactions be careful when use with digitalis. Hypokalemia ---
Hyperlipidemia
Hyperuricemia
Hyperglycemia
Allergic reactions

19. Low efficacy diuretics
K+ sparing diuretics
Agent: Antisterone, Triamterene & amiloride
Action site: DCT & CT (Collecting Tubule)

20. Potassium-sparing diuretics
Two cell types in collecting tubule
Principal cells – transport Na +, K +, water
Intercalated cells – secretion of H+ and HCO3
Blocking Na+ movement in also prevents K+ movement out

21. Spironolactone/ Antisterone
Act as antagonists to aldosterone, competes with aldosterone for receptor sites in DCT
Results in decreased Na+ reabsorption in DCT
Promotes Na+ and water loss
Decreased Na+ reabsorption balanced by K+ retention at this site (and H+).
Used in combination with diuretic e.g.. frusomide

22. Clincal use
Obstinate edema
Congestive heart failure
ADR
Hyperkalemia,
sex hormone-like effects

23. Triamterene and amiloride
Take action on distal convoluted tubule and collecting tubule
Block Na+ channel to decrease the reabsorption of Na+
Secondary to inhibit the excretion of K+
Not to antagonize the aldosterone

24. Carbonic anhydrase inhibitors
CAIs work on cotransport of Na+, HCO3- and Cl- that is coupled to H+ countertransport
Acts to block carbonic anhydrase (CA),
CA converts HCO3- + H+ to H2O + CO2 in tubular lumen
CO2 diffuses into cell (water follows Na+), CA converts CO2 + H2O into HCO3- + H+
H+ now available again for countertransport with Na+, etc
Na+ and HCO3- now transported into peritubular capillary

25. Site of Action of CAIs

26. Carbonic Anhydrase Inhibitors
Carbonic anhydrase inhibitors (acetazolamide)
H2O + CO H+ + HCO3-
Na+ CA
reabsorption

27. Clinic uses: Glaucoma Cerebral edema Acute mountain sickness
Urine basification
Treatment of Metabolic Alkalosis

28. Adverse reaction Allergic reaction Metabolic Acidosis Urinary calculus
Hypokalemia
Others: drowsiness,feeling dysfunction, central nerve system toxicity,allergic reaction

29. Osmotic diuretics No interaction with transport systems
All activity depends on osmotic pressure exerted in lumen
Blocks water reabsorption in proximal tubule, descending loop, collecting duct
Results in large water loss, smaller electrolyte loss  can result in hypernatremia

30. Dehydrant agents /osmotic diuretics
Agents : Mannitol, 50% hypertonic Glucose
Characteristics:
no metabolism/freely filtrable/no reabsorpted
Pharmacological effects and clinical uses:
Hyperosmolarity Dehydration
Diuresis

31. USMLE-type questions

32. Your 60 yr male hypertensive patient who had an MI three months ago is now showing signs of CHF. You therefore add spironolactone to his drug regimen. What side effect should you warm your patient about that is associated with this drug? A. gynecomastia B. hypokalemia C. lupus syndrome D. ototoxicity E. uricemia

33. A/gynecomastia is the correct answer
A/gynecomastia is the correct answer. Spironolactone is a weak agonist at androgen receptors, as well as an aldosterone antagonist. His breasts may become slightly enlarged and tender.

34. A 70-Y-O woman is admitted to the emergency department because of a “fainting spell” at home. She appears to have suffered no trauma from her fall, but her BP is 120/60 when lying down and 60/20 when she sits up. Neurologic examination and an ECG are within normal limits when she is lying down. Questioning reveals that she has recently started taking diuretics for a heart condition. Which of the following drugs is the most likely cause of her fainting spell?
Acetazolamide
Amiloride
Furosemide
Hydrochlorothiazide
Spironolactone