Medicinal Chemistry II By Dr. Mehnaz Kamal Assistant Professor, Pharmaceutical Chemistry Prince Sattam Bin Abdulaziz University

Diuretics are agents that increase the rate of urine formation and salt excretion. “Diuresis” = increased water formation, but the term is also used to indicate increased salt excretion. The primary action of most diuretics is the direct inhibition of Na + at one or more of the four major anatomical sites of the nephron where Na + reabsorption takes place. A Diuretic usually possess some combination of natriuretic, chloruretic, saluretic, kaliuretic, bicarbonaturetic, or calciuretic properties depending on whether it enhances the renal excretion of Na +, Cl -, Na + /Cl -, K +, HCO3 - or Ca 2+ respectively.

Sites of Action of Diuretics in the Nephron

Indications for Diuretics uses 1. Edema a. Congestive heart failure b. Hepatic cirrhosis with ascites c. Renal disease/nephrotic syndrome 2. Maintenance of urine flow a. Circulatory shock b. Surgical procedures c. Reduce the toxic effects of poisons filtered or secreted into the renal tubules 3. Hypertension 4. Nephrolithiasis (renal stones) 5. Hypercalcemia 6. Glaucoma

CLASSIFICATION OF DIURETICS 1. OSMOTIC DIURETICS 2. CARBONIC ANHYDRASE INHBITORS 3. ION TRANSPORT INHIBITORS: a. Thiazides and thiazides like diuretics b. Loop or high-ceiling diuretics c. Potassium sparing diuretics

1. OSMOTIC DIURETICS They are low-molecular-weight compounds that are freely filtered at the glomerulus into the renal tubules and are non reabsorbable solutes. Because of their osmotic action they prevent the reabsorption of water and impair Na + reabsorption thus causing water pass from the body into the tubule and inducing the diuretic effect. They include polyols (e.g. Glycerin, Isosorbide, Mannitol) and urea.

Mannitol D-Mannitol is a hexahydroxy alcohol and the most commonly used osmotic diuretic. It does not diffuse across the GIT membrane so it is given by I.V. route. It is a suitable alternative to a loop diuretic for Acute renal failure.

Isosorbide It is a bicyclic form of sorbitol obtained by acid dehydrogenation of the later. 1,4:3,6-Dianhydrosorbitol

It is used orally to reduce the intraocular pressure in glucoma patients. In spite of the diuretic effect its opthalmological properties are its primary value Urea It is a product of proteins metabolism, and excreted in human urine in average amounts of 30g/day. It is used by I.V. route for the reduction of intraocular pressure and control of cerebral edema.

2. CARBONIC ANHYDRASE INHBITORS Carbonic anhydrase is an ubiquitous enzyme responsible for the catalytic reversible hydration of CO 2 and dehydration of H 2 CO 3, a process critical to the transport of CO 2 in the erythrocyte and its exchange in the parenchyma of the lung. The renal tubular cells also contain substantial amount of Carbonic anhydrase and the CO 2 produced metabolically in the cells of renal tubule is converted to H 2 CO 3 by the enzyme Inhibition of Carbonic anhydrase results in increase of pH due to decrease of H + available to exchange with Na + which lead to retention of NaHCO 3 in tubules thus lead to diuretic effect.

Acetazolamide N-(5-(aminosulfonyl)-1,3,4-thiadiazole-2-yl)acetamide It was the first introduced Carbonic anhydrase inhibitors. It is orally effective diuretic with a duration of action of 8-12 hrs. Its diuretic action is limited due to the systemic acidosis. It reduces the rate of aqueous humor formation and is used to reduce the intraocular pressure in glucoma.

Methazolamide N-(5-(aminosulfonyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene)acetamide It has better penetration into the eye compared with Acetazolamide. SAR of CA inhibitors. Simple heterocyclic sulfonamide. Sulfamoyl group is essential for CA inhibitory activity and for diuresis. The sulfamoyl nitrogen should not be substituted for activity.

Thiazides and Thiazides Like Diuretics The thiazides were the first orally effective saluretic agents. They were developed from cyclization of chloraminophenamide (CA inhibitor). Thiazide and Hydrothiazide derivative

Mode and Site of Action of Thiazide Diuretics The diuretic effect of the thiazides is related to their ability to inhibit the Na + -Cl - symporter located in Distal Convoluted Tubules. They inhibit the reabsorption of Na + and Cl - ions so they are referred to as saluretics.

Chlorothiazide 6-Chloro-7-sulfamoyl-2H-1,2,4-benzothiadiazine-1,1-dioxide. The prototype of benzothiadiazine diuretics. Benzthiazide It is about 10 times as potent as chlorothiazide.

Hydrochlorothiazide Effective diuresis comparable to that produced by 0.5 g of chlorothiazide. Hydroflumethiazide It is potent orally administered thiazide diuretic useful in the management of edema associated with Congestive heart failure, hepatic cirrhosis, corticosteroid and estrogen therapy.

SAR The 2 position can tolerate the presence of relatively small alkyl groups such as CH 3. Substituents in the 3 position play a dominant role in determining the potency and duration of action of the thiazides. Saturation of the 3-4 double bond enhances the diuretic effect 10 times. An electron-withdrawing group at position 6 is necessary for diuretic activity. Electron-donating groups at position 6 result in reduction of diuretic activity.

The hydrogen atom at position 2 is acidic enough to form a water soluble sod. Salt for I.V. administration. The sulfamoyl group in the 7 position is essential for diuretic effect. Removal or replacement of this group result in significant reduction or complete loss of the diuretic activity.

Loop Diuretics (High Ceiling Diuretics) These diuretics produce a peak diuresis much greater than that observed with the other commonly used diuretics, hence the name high ceiling diuretics. They are characterized by a quick onset (~30 min) and short duration (~ 6 hr) of action.

Mode and Site of Action of High Ceiling Diuretics The diuretic effect of the high ceiling diuretics is attributed to inhibition the luminal Na + / K + /2Cl - symporter located in Thick Ascending Limb of Loop of Henle leading to a Na + -rich diuresis.

Furosemide/Frusemide 4-Chloro-N-furfuryl-5-sulfamoylanthranilic acid It has a saluretic effect 8-10 times that of the thiazides. 5-Sulfamoyl-2-aminobenzoic acid derivatives

SAR Substituent at the 1 position must be acidic. The carboxyl group provide optimal diuretic activity but other groups such as a tetrazole may impart respectable diuretic activity. A sulfamoyl group in the 5 position is a prerequisite for optimal high- ceiling diuretic activity. The activating group (-X) in the 4 position can be Cl - or CF 3 - as was the case with thiazide and thiazide-like diuretics. The substituents that can be tolerated on the 2 amino group are very limited and can be arranged in the following order:

Phenoxyacetic Acid derivatives Ethacrynic acid 2,3-Dichloro-4-(2-methylene-1-oxobutyl)phenoxyacetic acid Optimum diuretic activity was obtained when: - an oxyacetic acid group was positioned para to α,β- unsaturated enone. - 2,3-dichloro substituents on the phenyl ring. - Hydrogen atoms on the terminal alkene carbon. Thus a molecule with a weakly acidic group for drug direction to the kidney, an alkylating moiety and lipophilic groups seemed to provide the best combination for diuretic effect of this class of compounds. SAR

Potassium Sparing Diuretics This class of diuretics are characterized by their ability to increase Na + and Cl - excretion without a concomitant increase in the urinary excretion rate of K + in collecting duct. They are also known as antikaliuretic agents. They can be classified into 2 classes with respect to mechanism of action: 1. Aldosterone antagonists 2. Na + -channel blockers

Site of Action of Potassium Sparing Diuretics

1. Aldosterone antagonists Aldosterone enhances the passage of Na + from the luminal fluid into tubular cells and the passage of intracellular K + into the luminal fluid. A substance that antagonizes the effects of aldosterone could conceivably be a good diuretic.

Spironolactone It is a competitive antagonist to the mineralocorticoids such as aldosterone on the minralocorticoid receptor. This lead to inhibition of reabsorption of Na + and Cl - as well as the associated water. Aldosterone (Hemiacetal form) Particularly useful in primary aldosteronism (adrenal adenomas or hyperplasia) and in secondary aldosteronism (CHF, hepatic cirrhosis, ascites, nephrotic syndrome) – drug of choice in hepatic cirrhosis.

Adverse Effects of K + -Sparing Diuretics Hyperkalemia (contraindicated with renal insufficiency) Gynecomastia Hormonal disturbances due to its affinity for androgen and progestrone receptors. Metabolism

Eplerenone It is a recently approved specific aldosterone antagonist with a much lower affinity for androgen and progestrone receptors than spironolactone.

The main side effects are Kidney stones and leg cramps due to hyperkalemia. 2. Na + -channel blockers Triamterene 6-phenylpteridine-2,4,7-triamine It interferes with the process of cationic exchange by blocking luminal Na + -channel in the DCT. This lead to block the reabsorption Na + and block the secretion of K + without antagonizing the aldosterone.

Amiloride It is the open chain analog of triamterene acting with the same mode of action.