1. Prof. Hanan Hagar Pharmacology Department
DIURETICS Part 1
Prof. Hanan Hagar
Pharmacology Department

2. Diuretics
Are drugs that increase renal excretion of sodium and water resulting in increase in urine volume.
Most diuretics act by interfere with the normal sodium handling by the kidney.

3. Sites of action for diuretics
Target molecules for diuretics are specific membrane transport proteins in renal tubular epithelial cells (transporters).

4. Classification of diuretics
Carbonic Anhydrase Inhibitors
Loop Diuretics
Thiazides
Potassium-Sparing Diuretics
Osmotic Diuretics

5. SITES OF ACTION OF DIURETICS

6. kidney Nephron is the unit of the kidney
It is classified structurally and functionally into different zones
Glomerulus
Proximal convoluted tubule
Descending loop of Henle
Ascending loop of Henle
Distal convoluted tubule
Collecting duct

7. FUNCTION OF THE KIDNEY
Kidney is responsible for regulation of fluids and electrolytes.
Kidney do its function through three processes
Glomerular filtration
Passive tubular re-absorption
Active tubular secretion

8. Regulation of fluids and electrolytes

9. Sites for solutions and water transport along the nephron

10. Glomerular filtration:
16-20 % of blood entering the kidney is filtered
Filtrate contains water, glucose, amino acids, sodium bicarbonates, organic solutes and electrolytes (sodium, potassium, chloride).

11. Responsible for re-absorption of all glucose, amino acids
Proximal convoluted tubules:
Responsible for re-absorption of
all glucose, amino acids
organic solutes
electrolytes as
sodium chloride (NaCl)(66% of Na)
sodium bicarbonate (NaHCO3,85%)
Potassium (K+, 66 %)

12. PCT is the site of organic acids or bases secretory systems
Proximal convoluted tubule (PCT):
HCO3- is reabsorbed by action of enzyme carbonic anhydrase (luminal membrane of proximal tubular cells).
Water (passively following salts to maintain osmolarity in tubular fluids (60%).
PCT is the site of organic acids or bases secretory systems

13. carbonic anhydrase
Lumen
Blood
Luminal membrane
Basolateral membrane

14. organic acids or bases secretory systems
Organic base secretory system responsible for secretion of bases into luminal fluid e.g. choline and creatinine
Organic acid secretory system responsible for secretion of acids into luminal tubular fluid e.g. uric acid, NSAIDs, antibiotics and diuretics.

15. Descending loop of Henle
In thin descending loop of Henle :
water is re-absorbed by osmotic
forces in hypertonic medullary
interstitium (counter current
mechanism)

17. Ascending loop of Henle
Is impermeable to water
In thick ascending loop of Henle (TAL) is responsible for active re-absorption of Na, K and Cl (25-30% Na) via transport system in luminal membrane called Na+/ K+ / 2Cl- co-transporter
TAL is called the diluting segment
Ca and Mg enter the interstitial fluid via paracellular pathway

18. Ascending loop of Henle

19. Distal convoluted tubule (DCT)
Is impermeable to water
Responsible for active re-absorption of NaCl (10%) via transport system Na/Cl transporter in luminal membrane
Ca2+ actively reabsorbed via apical Ca channel and Na+/Ca2+ exchanger in basolateral membrane

20. Distal convoluted tubules (DCT)

21. Collecting tubule
Principal cells are responsible for re-absorption of Na (in exchange for K via Na/K-ATPase) and water
Aldosterone receptors located in the principle cells influence Na re-absorption and K secretion
Intercalated cells affect H secretion
Water re-absorption (anti-diuretic hormone, ADH).

22. COLLECTING TUBULES (CT)

23. COLLECTING TUBULES (CT)

24. Sodium Excretion Regulation
Nephron Segment
Filtered Na+ reabsorbed
Na+ Transporter
Proximal CT
60-70%
Na+- H+ transporter
Ascending
Loop of Henle
20-30%
Na+-K+-2Cl- transporter
Distal CT
5-10%
Na+-Cl- transporter
Cortical Collecting Tubules 5%
Aldosterone
Na+ channel
ADH

25. Site of action of diuretics
transporter
Function
segment
Carbonic anhydrase inhibitors
Na/H transporter, Carbonic anhydrase enzyme
Re-absorption of 66% Na, K, Ca, Mg, 100% glucose and amino acids; 85% NaHCO3
Proximal convoluted tubules
None
Acid & base transporter
Secretion and re-absorption of organic acids and bases
Proximal
Straight Tubules
Loop diuretics
Na/K/2Cl transporter
Active reabsorption
25% Na, K, Cl
Secondary reabsorption Ca, Mg
Thick ascending loop
Thiazide diuretics
Na and Cl cotransporter
Active tubular reabsorption of 5%Na, Cl, Ca
Distal convoluted tubules
K-sparing diuretics
Na channels
K & H transporter
Na reabsorption
K & H secretion
Collecting tubules

26. Diuretics

27. Carbonic Anhydrase Inhibitors
Acetazolamide – dorzolamide
Mechanism of action:
Inhibits carbonic anhydrase (CA) enzyme in PCT thus interferes with NaHCO3 re-absorption and causes diuresis.
CA is required for reversible reaction, in which CO2 +H2O ↔ H2CO3

28. Blood
Lumen
Basolateral membrane
Luminal membrane

30. Carbonic Anhydrase Inhibitors

31. Pharmacological actions:
↑ urinary excretion of bicarbonate, sodium, potassium “alkaline diuresis”
Metabolic acidosis.
↑ urinary phosphate excretion.
Weak diuretics.
Decreases after several days (self-limiting as the blood bicarbonate falls).

32. Carbonic anhydrase inhibitors

33. Pharmacokinetics: given orally once a day.
Onset of action is rapid (30 min).
Duration of action (12 h).
Excreted by active secretion in proximal convoluted tubules forming alkaline urine

34. Therapeutic uses:
Open angle glaucoma (↓ IOP by reducing aqueous humor formation via blocking carbonic anhydrase in ciliary body of eye).
As prophylactic therapy, in acute mountain sickness (to decrease CSF and pH of brain).

35. Therapeutic uses:
Urinary alkalinization to enhance renal excretion of acidic substances (uric acid and cysteine in cystinuria).
Epilepsy (decrease cerebrospinal fluid, CSF).
Hyperphosphatemia
Metabolic alkalosis

36. Adverse effects: Hypokalemia (potassium loss). Metabolic acidosis.
Renal stone formation (calcium phosphate stones).
Hypersensitivity reactions

37. Dorzolamide
Is a carbonic anhydrase inhibitor
Used topically for treatment of increased intraocular pressure in open-angle glaucoma.
no diuretic or systemic side effects (Why?).

38. LOOP DIURETICS High Ceiling diuretics
The most efficacious diuretics
Efficacy: High 25-30% natriuresis
Drugs as
Furosemide - torsemide
Bumetanide - Ethcrynic acid

39. LOOP DIURETICS Mechanism:
inhibit Na+ / K+ / 2 Cl- co-transporter in the luminal membrane of the thick ascending loop of Henle (TAL).
inhibit Ca++ and Mg ++ re-absorption.

40. Has fast onset of action (suitable for emergency)
Pharmacokinetics
Given orally or I. V.
Has fast onset of action (suitable for emergency)
Have short duration of action.
Excreted by active tubular secretion of weak acids into urine (compete with uric acid for renal secretory system).

41. Ascending loop of Henle

42. Ascending loop of Henle

43. Pharmacological effects:
↑ urinary excretion of Na+ , K,+ Ca++ and Mg ++
↑ urine volume
↑ renal blood flow.

44. Uses: are drug of choice for emergency situations as:
Acute pulmonary edema
Edema associated with heart failure, nephrotic syndrome
Acute hyperkalaemia.
Acute hypercalcemia

45. Adverse effects :
Hypokalemia (dietary K supplementation or K-sparing diuretics).
Metabolic alkalosis.
Acute Hypovolemia, postural hypotension

46. Adverse effects :
Hyponatraemia.
Hypomagnesaemia
Hyperuricemia (increase gouty attack).
Ototoxicity (risk increased if combined with aminoglycosides)
Allergic reactions