1. Diuretics
the role of different portions of the nephron in ion exchange;
the sites of action and pharmacology of diuretics;
the therapeutic applications of diuretics

2. A diuretic -
is any drug that elevates the rate of bodily urine excretion (diuresis).
All diuretics increase the excretion of water from the body.

4. Classification /due to location of action/
1. Diuretics which increase glomerular filtration rate
/Xanthines/
Caffeine,
Theophyllinum
Euphyllinum

5. 2. Proximal convoluted tubule diuretics
2.1. Osmotic diuretic
Mannitol
2.2. Carbonic anhydrase (CA) inhibitors
Diacarbum (acetazolamide)

6. 3. Loop (of Henle) diuretics
Furosemidum
Bumetanidum
Ethacrynic acid
4. Distal convoluted tubule diuretics
/Thiazides and thiazide-like drugs/
Hydrochlorothiazidum

7. 5. Collecting duct diuretics
5.1. Antagonist of aldosterone Spironolactonum
5.2. Agents inhibit the Na+ channel in the apical membrane
Amiloridum
Triamterenum

8. Indications:
Hypertension
CHF,
Nephrotic syndrome
Poisonings

9. Proximal convoluted tubule diuretics
The proximal tubule (PT) determines the rate of Na+ and H2O delivery to the more distal portions of the nephron
A wide variety of transporters couple Na+ movement into the cell to the movement of amino acids, glucose, phosphate, and other solutes

10. Mannitol Mechanism of Action
Mannitol is a non-metabolizable osmotic diuretic and is filtered into the tubular space where it markedly increases tubular fluid osmolality.
This results in impared reabsorption of fluid with a resultant increased excretion of water (some Na+ accompanies)

12. Pharmacokinetics of Mannitol:
Given only i.v. and acts within 10 min;
if given p.o. it causes an osmotic diarrhea (not well absorbed from gut).
In pts with normal renal function t1/2 is approx. 1.2 hr.

13. Indications: Contraindications:
prophylaxis against renal dysfunction, e.g. major surgical procedure
Contraindications:
CHF,
chronic renal failure

15. Carbonic anhydrase (CA) inhibitors

17. Carbonic anhydrase (CA) inhibitors Mechanism of Action:
If CA activity is inhibited, HCO3- reabsorption is reduced and exits the proximal tubule in much larger amounts.
In the distal nephron, Na+ is largely reabsorbed (unlike HCO3-) and is exchanged for K+. Therefore acetazolamide primarily causes an increase in urinary HCO3-, K+, and water excretion.

18. CA Inhibitors: Adverse Side Effects
hypokalemia
metabolic acidosis

19. Loop Diuretics

20. Loop Diuretics: Mechanism of Action
block the Na+/K+/Cl- co-transporter in the apical membrane of the thick ascending limb of Henle's loop. Therefore, loop diuretics increase urinary water, ions excretion.
cause dilation of the venous system and renal vasodilation - effects that may be mediated by prostaglandins.

22. Loop diuretics: Pharmacokinetics
- act within 20 min and t1/2 is approx hr.
- are rapidly absorbed from the gut and can be given i.v.
- are the most potent available and can cause excretion of up to 20% of the filtered Na+.

23. Clinical uses of loop diuretics
acute pulmonary oedema
chronic heart failure
cirrhosis of the liver complicated by ascites
nephrotic syndrome
renal failure.

24. Loop diuretics Adverse Side Effects
hypokalemia
metabolic alkalosis
hypomagnesemia
hyperuricemia
dehydration (hypovolemia), leading to hypotension
dose-related hearing loss (ototoxicity)

25. Thiazides: Mechanism of Action
They inhibit Na+ and Cl- transport in the cortical thick ascending limb and early distal tubule.
They have a milder diuretic action than do the loop diuretics because this nephron site reabsorbs less Na+ than the thick ascending limb.

26. Thiazides

27. Thiazides: Pharmacokinetics
All are well absorbed from the gut. Onset of action is within approx. 1 hr;
effects can be long lasting but vary with the drug used (6-48 hr).

28. Clinical uses of thiazide diuretics
Hypertension.
Mild heart failure (loop diuretics are usually preferred).
Severe resistant oedema (together with loop diuretics).

29. Thiazides have a week antihypertensive
effect because reduce arterial wall sensitivity
to NA (noradrenaline) and AT (Angiotensin).
They potentiate significantly the effect
of other antihypertensive drugs.

30. Thiazide Adverse Side Effects
hypokalemia
metabolic alkalosis
dehydration (hypovolemia), leading to hypotension
hyponatremia
hyperglycemia in diabetics
hyperuricemia (at low doses)
Erectile dysfunction

31. Symptoms of hypokalemia
muscle weakness
paralysis
arrhythmia

32. Potassium sparing diuretics
These agents are often given to avoid the hypokalemia
They should never be given in the setting of hyperkalemia
(diabetes mellitus, multiple myeloma, renal insufficiency)

33. Spironolactone Mechanism of Action
It is a competitive antagonist of aldosterone.
Therefore it blocks aldosterone-stimulated Na+ reabsorption and K+ and H+ excretion in the late distal tubule and collecting duct.

34. Potassium sparing diuretics

36. Spironolactone Pharmacokinetics:
Given orally, spironolactone takes up to 2 days to be effective with a t1/2 approx. 20 hr.

37. Amiloride and triamterene Mechanism of Action
inhibit the Na+ channel in the apical membrane of the late distal tubule and collecting duct.
Because K+ and H+ secretion in this nephron segment are driven by the electrochemical gradient generated by Na+ reabsorption, K+ and H+ transport into the urine is reduced.

39. Clinical uses of potassium-sparing diuretics (e. g
Clinical uses of potassium-sparing diuretics (e.g. amiloride, spironolactone)
in heart failure, where either of these improves survival
in primary hyperaldosteronism (Conn's syndrome)
in resistant essential hypertension (especially low-renin hypertension)
in secondary hyperaldosteronism caused by hepatic cirrhosis complicated by ascites.

40. K+-sparing diuretics Adverse Side Effects
hyperkalemia
metabolic acidosis
gynecomastia (aldosterone antagonists)
gastric problems including peptic ulcer

42. Arctostaphylos uva-ursi L. (Bearberry)

43. Stipites
Cerasorum
(Cherry)

44. Equisetum arvense (Common horsetail) Contains silicates with diuretic
and urolitholytic effects.