Medicinal Chemistry of Diuretics

Medicinal Chemistry of Diuretics

• Diuretics are agents that increase the rate of urine formation, increasing the excretion of electrolytes and water from the body.
• They are used to treat edematous conditions and manage hypertension.
• The primary target organ for diuretics is the kidney.
• Diuretics interfere with the reabsorption of sodium and other ions in the nephrons' lumina.
• The amount of excreted ions and water depends on numerous factors.
• Understanding the normal mechanisms of urine formation and renal control is vital to grasp how diuretics work.
• Kidneys have two main functions: maintaining electrolyte and water balance and excreting metabolic byproducts.
• Urine formation happens in the nephrons.

Outline of Diuretic Classes

• Carbonic anhydrase inhibitors
• High-ceiling or loop diuretics
• Thiazide and thiazide-like diuretics
• Potassium-sparing and other diuretics

Diuretic Classification

• Diuretics are classified by their chemical class (e.g., thiazides).
• Mechanism of action (e.g., carbonic anhydrase inhibitors, osmotics).
• Site of action (e.g., loop diuretics).
• Effects on urine contents (potassium-sparing diuretics).

Efficacy and Potency

• Diuretic efficacy is measured by their ability to increase sodium ion excretion at the glomerulus.
• Potency refers to the amount of diuretic required for a specific response.

Normal Physiology of Urine Formation

• Kidney functions include maintaining electrolyte and water balance, and excreting water-soluble metabolic waste products.
• This is achieved by forming urine through nephrons.

Carbonic Anhydrase Inhibitors

• Mechanism: Inhibit the carbonic anhydrase enzyme in the proximal convoluted tubule wall, preventing H2CO3 formation. This prevents H+ ion availability for exchange with Na+ ions, thus blocking Na+ reabsorption.
• Side effects: Weak diuretics

Specific Examples of Carbonic Anhydrase Inhibitors

• Acetazolamide
• Methazolamide
• Ethoxzolamide
• Dorzolamide
• Brinzolamide

Structure-Activity Relationships (SAR) of Carbonic Anhydrase Inhibitors

• Sulfamoyl group is essential for CA inhibitory activity and diuresis, with unsubstituted sulfamoyl having the highest activity.
• Mono- and di-substitutions at the SO2NH2 group abolish activity.
• Methyl group substitution on the heterocyclic ring retains activity.
• High lipid/water partition coefficient and low pKa values correlate with increased CA inhibitory and diuretic activity.
• Benzene meta-sulphonamide derivatives have activity only when substituted with chlorine or methyl groups.

Benzothiadiazines (Thiazide Diuretics)

• Benzene disulfonamide derivatives were investigated to find more efficacious carbonic anhydrase inhibitors.
• Acylation of the amino group led to unexpected ring closure, establishing a new class: benzothiadiazines.
• Unlike carbonic anhydrase inhibitors, their diuretic activity is independent of carbonic anhydrase inhibition.
• The major site of action is in the distal convoluted tubule, where these drugs compete for the chloride binding site of the Na+/Cl– symporter.
• Blocking this symporter inhibits Na+ and Cl– reabsorption.

Structure-Activity Relationships (SAR) of Thiazide Diuretics

• Thiazide diuretics are weakly acidic with a benzothiadiazine 1,1-dioxide nucleus.
• The most acidic portions arise from the sulfone group.
• Alkyl substitutions decrease polarity, and increase diuretic duration.
• Acidic protons facilitate the formation of water-soluble salts for intravenous administration.
• The sulfamoyl groups in the 7 position is essential for diuretic activity.
• Removal or replacement of the group significantly reduces, or completely removes, diuretic activity.
• Haloalkyl, aralkyl, or thioether substitutions enhance lipid solubility, increasing potency and duration.
• Saturation of the double bond gives more active diuretics.
• Electron-withdrawing groups are necessary for diuretic activity and chloro or trifluoromethyl substitutions result in greater activity.
• If electron-releasing groups (e.g., methyl or methoxyl) are placed at position 6, then diuretic activity is reduced.

High-Ceiling or Loop Diuretics

• Characterized by their pharmacological similarities, rather than chemical ones.
• Examples include furosemide, bumetanide, torsemide, and ethacrynic acid.
• These produce a greater peak diuresis than other diuretics.
• Their main site of action is on the thick ascending limb of the loop of Henle, inhibiting the luminal Na+/K+/2Cl− symporter.
• They are also known as loop diuretics.
• Additional effects on the proximal and distal tubules are possible.
• Onset is rapid (~30 minutes), and duration is short (~6 hours).

Structure-Activity Relationships (SAR) of Furosemide

• Furosemide is a high-ceiling diuretic derived from anthranilic acid.
• A sulfamoyl group is in position 5; this is essential for high-ceiling diuretic activity.
• The activating group (X) in the 4-position can be Cl or CF3.
• Furosemide has 8-10 fold greater saluretic effect than thiazide diuretics.
• The saluretic effect is shorter (<6-8 hours) compared to thiazides.

Bumetanide

• Bumetanide is a high-ceiling loop diuretic, acting on the ascending limb of the loop of Henle.
• Its duration of action is approximately 4 hours.
• The phenoxy group replaces the chloro/trifluoromethyl substituents. (Electron withdrawing group)
• The amine group is moved to the 5 position.
• This results in 50 times more activity/potent than furosemide.

Ethacrynic Acid

• Ethacrynic acid is another high-ceiling diuretic in the phenoxyacetic acid derivative category.
• Optimal diuretic activity is attained when an oxyacetic acid group is para to an alpha, beta-unsaturated carbonyl group.
• Chloro or methyl groups at the 2- or 3-position of the phenyl ring are also important.
• Hydrogen atoms on the terminal alkene carbon increase reactivity/activity.

Potassium Sparing Diuretics

• These diuretics increase Na+ and Cl- excretion without increasing the rate of K+ excretion in the collecting duct.
• They are also known as antikaliuretic agents, and they are grouped into:
• Aldosterone antagonists
• Na+-channel blockers

Aldosterone Antagonists (e.g., Spironolactone)

• Aldosterone enhances Na+ entry into tubular cells and K+ exit.
• Competitive antagonists against mineralocorticoids (like aldosterone).
• This blocks Na+ and Cl− reabsorption, along with water.
• Useful in primary and secondary aldosteronism (e.g., adrenal adenoma, CHF, cirrhosis).
• Spironolactone is a common example and is a drug of choice for hepatic cirrhosis.

Adverse Effects of Potassium-Sparing Diuretics

• Hyperkalemia (contraindicated in renal insufficiency)
• Gynecomastia
• Hormonal disturbances due to affinity for androgen and progesterone receptors.

Na+-channel Blockers (e.g., Triamterene and Amiloride)

• Interfere with cationic exchange by blocking luminal Na+-channels in the distal convoluted tubule (DCT), which lead to blocking Na+ reabsorption and K+ secretion.
• Amiloride is the open chain analogue of triamterene, with identical mode of action.
• Side effects include kidney stones and leg cramps due to hyperkalemia.

This quiz explores the medicinal chemistry and classifications of diuretics, agents that influence urine formation and electrolyte excretion. It covers their mechanisms of action, targeting the kidneys, and various classes such as loop and thiazide diuretics. Understanding these concepts is essential for pharmacology and medicine.