1. introduction to Diuretics for health science.pptx

Medicinal Chemistry II
Diuretics
Reduces the volume of fluid in the blood vessels and decreases the workload on the heart

Diuretics are often prescribed for conditions such as high blood pressure (hypertension), heart failure, and edema (fluid retention)
Types of Diuretics
Based on their site of action in the kidneys, diuretics are classified into
Thiazide Diuretics: These are often the first-line treatment for hypertension. They work by inhibiting sodium reabsorption in the distal convoluted tubule of the kidney

Loop or high-ceiling Diuretics: These are potent diuretics used for more severe fluid retention, such as in heart failure or kidney disease. They act on the loop of Henle in the kidney to block sodium reabsorption

Potassium-Sparing Diuretics: These diuretics spare potassium loss, which can be a side effect of other diuretics. They are often used in combination with other diuretics
MOA of �Diuretics
MOA of �Diuretics
Diuretics exert their effects through various mechanisms of action.
Loop diuretics, thiazides, and potassium-sparing diuretics act on different segments of the nephron
Loop diuretics specifically inhibit active chloride transport in the diluting segment
Thiazides act on the cortical diluting segment/distal tubules
Aldosterone antagonists like spironolactone target aldosterone receptors

Thiazide Diuretics
Thiazide diuretics (hydrochlorothiazide, chlorothiazide, bendroflumethiazide, cyclothiazide) inhibit sodium and chloride reabsorption via the inhibition of Na/Cl cotransporter (NCC) in the distal tubule
The structure of thiazide diuretics includes a sulfonamide group, which is essential for their activity

Thiazide Diuretics
Thiazide diuretics, like hydrochlorothiazide (HCTZ), work by inhibiting the sodium-chloride symporter in the distal convoluted tubule of the kidney
This prevents reabsorption of sodium and chloride ions, leading to increased excretion of water
Loop Diuretics
Loop or high-ceiling diuretics, including furosemide, bumetanide and torasemide reversibly inhibit the Na/K/2Cl- cotransporter (NKCC) at the luminal thick ascending limb of the loop of Henle, therefore inhibiting the reabsorption of sodium, potassium, and chloride ions
Their structure often includes a sulfonamide group, similar to thiazides.


Loop Diuretics
Loop diuretics, such as furosemide, act on the ascending loop of Henle in the kidney.
They inhibit the sodium-potassium-chloride symporter, preventing reabsorption of these ions.
Loop diuretics are potent and are often used in conditions where a strong diuretic effect is needed, like heart failure or severe edema
Loop diuretics produce relatively more urine formation and less loss of sodium and potassium than thiazides

Potassium-Sparing Diuretics�
Spironolactone work by blocking aldosterone receptors
Aldosterone is a hormone that promotes sodium and water retention in the kidneys. By blocking its effects, Spironolactone increase sodium and water excretion while retaining potassium

1. Medicinal Chemistry II Diuretics and Cardiovascular Drugs By Aklilu Samuel

2. Diuretics Diuretics are a class of medications commonly used to increase the production of urine, which helps the body get rid of excess salt (sodium) and water

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4. Diuretics Reduces the volume of fluid in the blood vessels and decreases the workload on the heart Diuretics are often prescribed for conditions such as high blood pressure (hypertension), heart failure, and edema (fluid retention) 4

5. Types of Diuretics Based on their site of action in the kidneys, diuretics are classified into Thiazide Diuretics: These are often the first-line treatment for hypertension. They work by inhibiting sodium reabsorption in the distal convoluted tubule of the kidney Loop or high-ceiling Diuretics: These are potent diuretics used for more severe fluid retention, such as in heart failure or kidney disease. They act on the loop of Henle in the kidney to block sodium reabsorption Potassium-Sparing Diuretics: These diuretics spare potassium loss, which can be a side effect of other diuretics. They are often used in combination with other diuretics 5

6. MOA of Diuretics 6

7. Diuretics exert their effects through various mechanisms of action. Loop diuretics, thiazides, and potassium-sparing diuretics act on different segments of the nephron Loop diuretics specifically inhibit active chloride transport in the diluting segment Thiazides act on the cortical diluting segment/distal tubules Aldosterone antagonists like spironolactone target aldosterone receptors 7 MOA of Diuretics

8. Thiazide diuretics (hydrochlorothiazide, chlorothiazide, bendroflumethiazide, cyclothiazide) inhibit sodium and chloride reabsorption via the inhibition of Na/Cl cotransporter (NCC) in the distal tubule The structure of thiazide diuretics includes a sulfonamide group, which is essential for their activity 8 hydrochlorothiazide chlorothiazide bendroflumethiazide cyclothiazide Thiazide Diuretics

9. Thiazide Diuretics Thiazide diuretics, like hydrochlorothiazide (HCTZ), work by inhibiting the sodium-chloride symporter in the distal convoluted tubule of the kidney This prevents reabsorption of sodium and chloride ions, leading to increased excretion of water 9

10. Loop Diuretics Loop or high-ceiling diuretics, including furosemide, bumetanide and torasemide reversibly inhibit the Na/K/2Cl- cotransporter (NKCC) at the luminal thick ascending limb of the loop of Henle, therefore inhibiting the reabsorption of sodium, potassium, and chloride ions Their structure often includes a sulfonamide group, similar to thiazides. 10 torasemide furosemide bumetanide

11. Loop Diuretics Loop diuretics, such as furosemide, act on the ascending loop of Henle in the kidney. They inhibit the sodium-potassium-chloride symporter, preventing reabsorption of these ions. Loop diuretics are potent and are often used in conditions where a strong diuretic effect is needed, like heart failure or severe edema Loop diuretics produce relatively more urine formation and less loss of sodium and potassium than thiazides 11

12. Potassium-Sparing Diuretics Potassium-sparing agents can be divided into those that antagonize aldosterone (spironolactone and eplerenone) and those that are independent of aldosterone (amiloride and triamterene). Spironolactone is a powerful potassium-sparing diuretic that inhibits the binding of aldosterone to mineralocorticoid receptors in many tissues, including epithelial cells of the distal convoluted tubule and collecting duct As a result, it increases sodium and water loss and spares potassium Another group of potassium-sparing diuretics - epithelial sodium channel (ENaC) blockers (amiloride and triamterene) - acts by inhibiting the Na/H exchanger and indirectly decreasing potassium loss 12

13. Potassium-Sparing Diuretics Spironolactone work by blocking aldosterone receptors Aldosterone is a hormone that promotes sodium and water retention in the kidneys. By blocking its effects, Spironolactone increase sodium and water excretion while retaining potassium The structure of spironolactone includes a steroid backbone, similar to aldosterone 13 Spironolactone

14. Carbonic Anhydrase Inhibitors These are less commonly used diuretics like acetazolamide, which inhibit the enzyme carbonic anhydrase in the proximal convoluted tubule. By inhibiting this enzyme, they reduce bicarbonate reabsorption, leading to increased excretion of bicarbonate, sodium, and water. Acetazolamide's structure includes a sulfonamide group Acetazolamide is a diuretic medication that treats swelling caused by heart disease1. It works by helping your body make more pee so you can lose salt and excess water from your body 14

15. Osmotic Diuretics Osmotic diuretics, like mannitol, are not often used for routine diuresis but are employed in specific situations such as reducing intracranial pressure. They work by creating an osmotic force that draws water into the renal tubules, inhibiting water reabsorption. Mannitol's structure is a sugar alcohol. 15

16. Osmotic Diuretics Osmotic diuretics inhibit Na+ and Cl- reabsorption in the thick ascending limb of the loop of Henle by competing with Cl- for its binding site on the Na+-K+-2Cl- luminal carrier protein1. With maximal effect, they can promote excretion of 15-20% of the filtered sodium load. They also increase urinary calcium and magnesium excretion1. They inhibit the Na+Cl- Symport pump at distal convoluted tubules and enhance the excretion of Na+, Cl-, K+, and Mg2+ ions and reduce the excretion of Ca22+2. They also decrease the plasma volume, ECF, cardiac output, and release of insulin2. 16

17. Discovery and Development of Diuretic Agents The chemistry of diuretics is diverse, with common features like sulfonamide groups in thiazides and loop diuretics, and a steroid backbone in spironolactone. Understanding these structures and their mechanisms of action helps in designing effective medications for conditions like hypertension, heart failure, and edema. High-throughput screening, progress in protein structure analysis and modern methods of chemical modification have opened good possibilities for identification of new promising agents for preclinical and clinical testing 17

18. Historical Perspective on Diuretic Development 1 Ancient Times Diuretic agents have been used since ancient times, with records of herbal remedies containing diuretic properties dating back to ancient Egyptian, Greek, and Chinese civilizations. 2 19th Century The discovery of mercury-based diuretics in the 19th century marked a significant milestone, paving the way for the development of more effective and safer diuretic therapies. 3 20th Century Throughout the 20th century, the introduction of loop diuretics, thiazide diuretics, and potassium-sparing diuretics revolutionized the treatment of various fluid balance disorders and cardiovascular conditions.

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