Diuretics

Diuretic Drugs

Diuretic Drugs
1. Thiazide Diuretics
2. Loop Diuretics
3. Potassium-Sparing Diuretics
4. Carbonic Anhydrase Inhibitors
5. Osmotic Diuretics

Carbonic Anhydrase Inhibitors

Acetazolamide
 Inhibits the enzyme carbonic anhydrase in the proximal tubular epithelial cells.
 Carbonic anhydrase inhibitors used for other pharmacologic actions rather than for diuretic effect(less efficacious than the thiazides or loop diuretics)
Mechanism of action:
 Acetazolamide inhibits carbonic anhydrase located intracellularly (cytoplasm) and on the apical membrane of the proximal tubular epithelium.
 Carbonic anhydrase catalyzes the reaction of CO2 (carbon dioxide) and H2O, leading to H2CO3 (carbonic acid).
which spontaneously ionizes to H+ and HCO3 - (bicarbonate).
• The decreased ability to exchange Na+ for H+ in the presence of acetazolamide results in a mild diuresis. Additionally, HCO3- is retained in the lumen, with marked elevation in urinary pH.
• The loss of HCO3- causes a hyperchloremic metabolic acidosis and decreased diuretic efficacy following several days of therapy.
Therapeutic uses
1. Treatment of glaucoma (decreases the production of aqueous humor by blocking carbonic anhydrase in the ciliary body of the eye ,this lead to reducing elevated intraocular pressure).
2. Mountain sickness
Treatment of glaucoma:
• Acetazolamide decreases the production of aqueous humor, probably by blocking carbonic anhydrase in the ciliary body of the eye (reduce elevated intraocular pressure).
• It is useful in the chronic treatment of glaucoma but should not be used for an acute attack; pilocarpine is preferred for an acute attack because of its immediate action.
Topical carbonic anhydrase inhibitors, such as dorzolamide and brinzolamide, have the advantage of not causing any systemic effects.
Pharmacokinetics:
 Acetazolamide is given orally once a day.
Adverse effects
1. Metabolic acidosis (mild)
2. Potassium depletion
3. Renal stone formation
4. Drowsiness
5. Paresthesia
6. The drug should be avoided in patients with hepatic cirrhosis, because it could lead to a decreased excretion of NH4 +.
Loop or High-Ceiling Diuretics
• Bumetanide
• Furosemide
• Torsemide,
• Ethacrynic acid
• They have their major action on the ascending limb of loop of Henle.
• These drugs have highest efficacy in mobilizing Na+ and CI- from the body.
They produce copious amounts of urine.


Furosemide is the most commonly used of these drugs.
• Ethacrynic acid it shows greater side effects than those seen with the other loop diuretics, and its use is therefore limited.
• Bumetanide is much more potent than furosemide, and its use is increasing.
Mechanism of action:
1. Loop diuretics inhibit cotransport of Na+/K+/2CI- in luminal membrane in ascending limb of loop of Henle.
Therefore, reabsorption of these ions is decreased.
2. The loop diuretics are the most efficacious of the diuretic drugs

Actions of loop diuretics

• The loop diuretics act even among patients who have poor renal function or have not responded to thiazides or other diuretics.
• Loop diuretics increase the Ca2+ content of urine, whereas thiazide diuretics decrease the Ca2+ concentration of the urine.
• In patients with normal serum Ca2+ concentrations, hypocalcemia does not result, because Ca2+ is reabsorbed in the distal convoluted tubule.
However, hypomagnesemia can occur due to loss of Mg2+.
 The loop diuretics cause decreased renal vascular resistance a increased renal blood flow.
 Loop diuretics increase prostaglandin synthesis.
PGs have a role in their diuretic action, and substances such as indomethacin that interfere in PG synthesis can reduce diuretic action of these agents.
Therapeutic uses:
1. acute pulmonary edema of heart failure( drugs of choice).
Because of their rapid onset of action, particularly when given intravenously, (rapid, intense diuresis).
2. hypercalcemia, because they stimulate tubular Ca2+ excretion.
3. hyperkalemia.
Pharmacokinetics:
 administered orally or parenterally.
 Their duration of action 2-4 hours.
 secreted into the urine.
Adverse effects:
1. Ototoxicity
2. Acute hypovolemia
3. Hyperuricemia
4. Potassium depletion
5. Hypomagnesemia
Thiazides and Related Agents
 They are most widely used of diuretic drugs.
 They are sulfonamide derivatives and, as such, are related in structure to the carbonic anhydrase inhibitors.
 All thiazides affect distal tubule
 have equal maximum diuretic effects, differing only in potency
 They are called "ceiling diuretics" because increasing dose above normal does not promote a further diuretic response ( so called ceiling diuretics)
 Thiazides partly depend on renal prostaglandin synthesis
Chlorothiazide
 Active orally
 Capable of affecting the severe edema of cirrhosis and heart failure with a minimum of side effects.
Hydrochlorothiazide
 More potent, so that the required dose is considerably lower than that of chlorothiazide.
Note: Chlorthalidone, indapamide, and metolazone are referred to as thiazide-like diuretics, because they contain the sulfonamide residue in their chemical structures and their mechanism of action is similar.
Mechanism of action:
The thiazide derivatives act mainly in the distal tubule to decrease the reabsorption of Na+ apparently by inhibition of a Na+/CI- cotransporter on the luminal membrane of the distal convoluted tubule. They have a lesser effect in the proximal tubule
• These drugs increase concentration of Na+ and Cl- in the tubular fluid. The acid-base balance is not usually affected.
Note: Because the site of action of the thiazide derivatives is on luminal membrane, these drugs must be excreted into tubular lumen to be effective.
Therefore, with decreased renal function, thiazide diuretics lose efficacy.
Thiazides Actions
 Increased excretion of Na+ and CI-
 Loss of K+
 Loss of Mg2+
 Decreased urinary calcium excretion
 Reduced peripheral vascular resistance
Therapeutic uses of thiazides
1. Hypertension
2. Heart failure
3. Hypercalciuria
4. Diabetes insipidus
Pharmacokinetics:
 The drugs are effective orally.
 prolonged biologic half-life (40 hours).
 Most thiazides take 1-3 weeks to produce a stable reduction in blood pressure
 All thiazides are secreted by the organic acid secretory system of the kidney.


Adverse effects
1. Potassium depletion
2. Hyponatremia
3. Hyperuricemia
4. Volume depletion
5. Hypercalcemia
6. Hyperglycemia
7. Hyperlipidemia
8. Hypersensitivity

Thiazide-like analogs

Chlorthalidone:
• Has a very long duration of action
• Used to treat hypertension. It is given once per day for this indication.
Metolazone: Metolazone is more potent than the thiazides.

Indapamide:

 lipid-soluble
 Has a long duration of action. At low doses, it shows significant antihypertensive action with minimal diuretic effects.
 It is metabolized and excreted by the gastrointestinal tract and the kidneys.
It is therefore less likely to accumulate in patients with renal failure, and may be useful in their treatment.


Potassium-sparing Diuretics
 They act in the collecting tubule to inhibit Na+ reabsorption and K+ excretion.
 Potassium-sparing diuretics are used alone primarily when aldosterone is present in excess.
 The major use of potassium-sparing agents is in the treatment of hypertension, most often in combination with a thiazide.
 The patients who are treated with potassiumsparing diuretic need monitoring for potassium levels.
 If the patients take supplementation is usually discontinued when potassium-sparing diuretic therapy is instituted.

Spironolactone

Mechanism of action
 Antagonizes aldosterone at intracellular cytoplasmic receptor sites.
 Prevents Na+ reabsorption and, therefore, K+ and H+ secretion
Actions:
• In most edematous states, spironolactone is given to a patient with elevated circulating levels of aldosterone, the drug antagonizes the activity of the hormone, resulting in retention of K+ and excretion of Na+.

Therapeutic uses:

1.Diuretic:
 Spironolactone has a low efficacy in mobilizing Na+ from the body in comparison with the other drugs. Spironolactone has the useful property of causing the retention of K+.
 It is the diuretic of choice in patients with hepatic cirrhosis.

2. Secondary hyperaldosteronism: spironolactone is the only potassium-sparing iuretic that is routinely used alone to induce a net negative salt balance.
It is particularly effective in clinical situations associated with secondary hyperaldosteronism.


3. Heart failure: Spironolactone prevents the remodeling that occurs as compensation for the progressive failure of the heart.
Pharmacokinetics
 Spironolactone
 Absorbed orally
 Strongly bound to proteins
 Converted to an active metabolite
 The action of spironolactone is largely due to the effect of its active metaboliets, which has mineralocorticoid-blocking activity.
Spironolactone is enzyme inducer

Adverse effects

1. Gastric upsets and can cause peptic ulcers.
2. Because it chemically resembles some of the sex steroids, spironolactone may act at receptors in other organs to induce gynecomastia in males and menstrual irregularities in females

Triamterene and amiloride

• Triamterene and amiloride block Na+ transport channels, resulting in a decrease in Na+/K+ exchange.
Although they have a K+-sparing diuretic action similar to that of spironolactone, their ability to block the Na+/K+-exchange site in the collecting tubule does not depend on the presence of aldosterone.
• Thus, they have diuretic activity even in individuals with Addison disease.
Triamterene and amiloride
• The side effects of triamterene are leg cramps and the possibility of increased blood urea nitrogen, as well as uric acid and K+ retention.

Osmotic Diuretics

Mannitol and urea
 Mannitol is not absorbed when given orally, and should only be given intravenously.
 They have ability to carry water with them into the tubular fluid and will cause an increase in urinary output.
 Used to increased water excretion rather than Na+ excretion


END