1. Diuretic Agents

2. Classification of diuretics
Carbonic anhydrase inhibitors
Thiazide diuretics
Loop diuretics
K+ sparing diuretics
Osmotic diuretics

4. Site and Mechanism of Action of Diuretics

5. 1. Carbonic Anhydrase Inhibitors
Acetazolamide, dorzolamide (All compounds are sulfonamides).
Mechanism of action
Inhibition of membrane-bound carbonic anhydrase (CA) in the cells of proximal tubule which leads to blockade of the reaction H2CO3 = H2O + CO2 that normally occurs in the proximal tubule lumen
Inhibition of cytoplasmic CA in the cells of proximal tubule which leads to blockade of the reaction: H2 O + CO2 = H2 CO3 that normally occurs in the cytoplasm
The final effect is a nearly complete abolition of NaHCO3 reabsorption in the proximal tubule (but NaHCO3 reabsorption by mechanisms independent from carbonic anhydrase still occur in other parts of the nephron).

7. Renal effects
Increased renal excretion of: Na+, K+, HCO3-
Decreased renal excretion of: NH4+, H+.
Urine pH: alkaline.
Acid-base balance: metabolic acidosis (acidosis is associated with hyperchloremia because Cl tend to exit from cells when H+ is high, in order to maintain electroneutrality) .
Efficacy of diuretic: low, moreover, as metabolic acidosis develops, the filtered load of HCO3- decreases, and therefore the diuretic effect undergoes a complete tolerance in 2-3 days)

8. Pharmacokinetics
90% excreted by tubular secretion.
Acetazolamide given PO, dorzolamide topical (eye drops)
Adverse effects
Paresthesias, drowsiness
Nephrolithiasis (due to precipitation of calcium phosphate salts inalkaline urine)
Hyperchloremic metabolic acidosis, Hyperuricemia, Hypokalemia
Sulfa-type allergic reactions

9. Glaucoma (50-60% reduction in aqueous humor production)
Therapeutic Uses
Edema
Glaucoma (50-60% reduction in aqueous humor production)
Epilepsy (direct inhibition of carbonic anhydrase in the CNS, which increases carbon High altitude sickness
Metabolic alkalosis
Contraindications and Precautions
Hepatic cirrhosis (alkalinization of urine decreases urinary trapping of NH 4+)
Chronic obstructive pulmonary disease (the risk of metabolic acidosis is increased)
Hypersensitivity to sulfa drugs.
Hypokalemic states
Mechanism of Action: Carbonic anhydrase is an enzyme responsible for forming hydrogen and bicarbonate ions from carbon dioxide and water. By inhibiting this enzyme, acetazolamide reduces the availability of these ions for active transport. Hydrogen ion concentrations in the renal tubule lumen are reduced by acetazolamide, leading to an alkaline urine and an increased excretion of bicarbonate, sodium, potassium, and water. A reduction in plasma bicarbonate results in metabolic acidosis, which rapidly reverses the diuretic effect. Reduced intraocular pressure (IOP) is the result of a 50—60% reduction in aqueous humor production by acetazolamide and is likely due to decreased bicarbonate ion concentrations in ocular fluid. The anticonvulsant activity of acetazolamide may depend on a direct inhibition of carbonic anhydrase in the CNS, which increases carbon dioxide tension and inhibits neuronal transmission. The successful treatment of altitude sickness involves production of respiratory and metabolic acidosis, which increases ventilation and binding of oxygen to hemoglobin. This occurs because the drug decreases carbon dioxide tension in the pulmonary alveoli, thus increasing arterial oxygen tension.
Other effects
- The blockade of CA on the ciliary body epithelium decreases the
production of the aqueous humor, which is rich in HCO3-.
- The blockade of CA in the choroid plexus decreases the production of
cerebrospinal fluid.

10. 2. Thiazide Diuretics The most commonly used diuretics
Bendroflumethiazide , Hydrochlorothiazide, Chlorothiazide, and Indapamide
All are sulfonamide
Mechanism of action
Inhibition of electroneutral Na+/Cl- cotransport located on the luminal surface of early distal convolute tubule
Slight inhibition of carbonic anhydrase.

11. Renal effects
Increased renal excretion of: Na+, K+, H+, Cl-, HCO3-,.
Decreased renal excretion of: Ca++, NH4+, urates.
Urine pH: alkaline (due to inhibition of carbonic anhydrase).
Acid-base balance: metabolic alkalosis.
Efficacy of diuretic effect: moderate
Kidney diluting capacity: decreased
Duration of diuretic effect: variable (6-48 hours).
Other effects
Decrease peripheral vascular resistance
Decreased cardiac output

12. Pharmacokinetics
Widely distributed in the body and can cross the placenta
Excreted kidney
Administration: PO, IM, IV.
Therapeutic Uses
Hypertension (first choice diuretics).
Edema and ascites associated with heart, liver and kidney disease
Calcium nephrolithiasis, idiopathic hypercalciuria.
Meniere’s disease (they can prevent the endolymphatic fluid buildup)
Nephrogenic diabetes insipidus (this seemingly paradoxical effect is likely mediated through the extracellular volume contraction which promotes proximal tubular reabsorption of Na+ and water. Therefore a reduced volume is delivered to the distal tubule)

13. Side effects
Hypokalaemia, metabolic alkalosis, hypercalcemia, hypovolaemia and hyponatraemia
Hyperuricaemia, Hyperglycaemia, Hyperlipidaemia
Hypotension
Hypersensitivity
Deterioration of patients with hepatic or renal failure
Parethesia, drowsiness, fatigability
Impotence
Contraindications
Anuria
Sulfonamide hypersensitivity, thiazide diuretic hypersensitivity
Precautions
Hyperglycemia, Hyperuricemia, electrolyte imbalance

14. 3. Loop diuretics Mechanism of action A. Renal mechanism:
Inhibit the Na+/k+/2cl- co-transport (thick ascending limb of Henle's loop).
Increased synthesis of vasodilator prostaglandins PGE2 and PGI2.
Loop diuretics that are sulfonamide compounds also cause a slight inhibition of carbonic anhydrase.
B. Extra-renal mechanism:
Vasodilatation action mainly in the venous bed caused by PGs.

15. Renal effects
Increased renal excretion of: Na+, Cl-, K+, H+, Ca++, (sulfonamides also increase the excretion of HCO3).
Acid-base balance: metabolic alkalosis.
The diluting and concentrating capacity of the kidney are decreased.
Efficacy of diuretic effect: high, moreover the diuretic effect remains even when the GFR is less than 30 mL/min).

17. Pharmacokinetics
They are strongly bound to plasma proteins.
They have rapid onset of action
Efficacy: High
Administration: PO, IM, IV.
Therapeutic uses
Acute pulmonary edema (given IV). Heart failure.
Edema, Ascites (associated with hepatic, renal and heart disease.
Hypertension (associated with renal insufficiency or heart failure).
Hypercalcemia.
(Addition of a thiazide can cause synergistic effect when a patient become refractory to a loop diuretic alone )

18. Side Effects
Ototoxicity
Hyperuricemia, Hyperglycemia, Hyperlipidemia
Hypotension
Hypokalemia, Hypomagnesemia, hyponatraemia

20. N.B.
Loop Loose Calcium
Thiazide causes Hyper GLUC
Glycemia, Lipedemia, Uricemia, Calcemia
K+ sparing diuretics causes STAY of K+

21. 4. Potassium Sparing Diuretics
Aldosterone antagonists:
Spironolactone, Eplerenone.
Spironolactone is a steroid drug.
Direct Na+ - channel inhibitors :
Triamterene , Amiloride.
Triamterene and amiloride are organic bases.

22. Mechanism of action
Spironolactone blocks aldosterone receptors in the late distal tubule and cortical collecting tubule (the synthesis of Na+/K+ ATPase in the basolateral membrane, as well as the synthesis of protein Na+ channels in the luminal membrane are impaired).
Triamterene and amiloride directly block Na+ channels in the luminal membrane of late distal tubule and cortical collecting tubule.

23. Therapeutic uses
Most commonly used in combination with other diuretics
Absolute contraindications
Hyperkalemia
Renal failure
Precautions
Gout
Pregnancy
Acid base imbalance

24. 5. Osmotic diuretics
They include: Mannitol I.V. infusion (25%), Concentrated glucose I.V (50%), Glycerol
Mechanism of action:
These sugars are relatively inert and largely excreted without metabolic changes (they have low molecular weight).
They are filtered freely through the glomerulus.
They undergo limited reabsorption by the renal tubules.
They increase the osmolarity of the plasma and consequently increase the osmolarity of glomerular filtrate and tubular fluid . Thus, water reabsorption is decreased from all the water permeable sites

25. Therapeutic Uses:
Acute oliguric RF: to maintain adequate GFR
Acute glaucoma: to ↓ aqueous humor formation
Increase intracranial tension: to ↓ CSF formation
Side effects
Headache, nausea and vomiting are commonly observed
hypernatremia
Mannitol may cause hypersensitivity reaction.
Glycerol is metabolized and can cause hyperglycemia and glucosuria.

26. Contraindications and Precautions
Absolute
Heart Failure, dehydration, intracranial bleeding
Precautions
Electrolyte imbalance, hypovolemia, geriatiric, Pregnancy, lactation

27. Antidiuretic Hormone Antagonists
Conivaptan, tolvaptan
Mechanism of action
Competitive antagonists at vasopressin receptors (conivaptan at V1a and V2, tolvaptan at V2)
Renal effects
Increased water diuresis (these drugs are also called aquaretics)
Water diuresis increases more than salt diuresis (in this way hyponatremia is relieved).
Increased renal excretion of: Na+, K+, Ca++
Urine osmolality: decreased
Other effects
Conivaptan is a strong inhibitor of CYP3A4

28. Adverse effect
Infusion-site reactions (with conivaptan)
Nephrogenic diabetes insipidus
Postural hypotension (if hypovolemia develops)
Hypokalemia (. 9%)
Therapeutic uses
Syndrome of inappropriate ADH secretion (when water restriction failed to correct the disorder)
Chronic euvolemic hyponatremia

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