2nd unit diuretics

Introduction.
General Mechanism of Action
Classification
Carbonic anhydrase inhibitors
Thiazides
Loop diuretics
Potassium sparing Diuretics
Osmotic Diuretics
SAR.
Structure , Synthesis.
Adverse Drug Reactions , Uses.
References

1. 2 nd UNIT DIURETICS Prepared by G. Nikitha, M.Pharmacy Assistant Professor Department of Pharmaceutical Chemistry Sree Dattha Institute Of Pharmacy Hyderabad 1 Subject: Medicinal Chemistry-II Year: B.Pharmacy 3 rd Year Semister: 1 st Semister

2. Contents Introduction. General Mechanism of Action Classification Carbonic anhydrase inhibitors Thiazides Loop diuretics Potassium sparing Diuretics Osmotic Diuretics SAR. Structure , Synthesis. Adverse Drug Reactions , Uses. References 2

3. Introduction Diuretics increase the rate of urine flow and sodium excretion and are used to adjust the volume of body fluids. The normal fluids filtration in human body is 180 liters about 1.5 liters of urine is formed in 24 hours. Diuretics are concerned with the maintenance of volume as well as composition of the body fluids. Hence they are indicated in the treatment of various edematous conditions like chronic heart failure, nephritic syndrome, hypertension, glaucoma, acute mountain disease, pregnancy, hepatic disease etc. 3

4. General Mechanism of Action The diuretic effect is achieved by direct action on the various segment of nephron of indirectly by altering the glomerular filtration content. 4

5. 5

6. Classification Based on Diuretic Potency a. Highly Potent /High ceiling diuretics Loop Diuretics: Furosemide, Bumetanide , Torasemide , Ethacrynic acid. b. Moderately potent (efficacious) diuretics i.Thiazide diuretics: Chlorthiazide , Hydrochlorothiazide, Hydroflumethiazide , Cyclothiazide . ii. Osmatic diuretics: Mannitol, Urea etc. c. Mioteldy Potent/ Weak diuretics: i . Carbonic anhydrase inhibitors: Acetazolamide , Methazolamide , Dichlorphenamide ii. Xanthine derivatives: Theophylline , Aminophylline iii. Potassium sparing diuretics: Spironolactone , Triamterene , Amiloride 6

7. Based on Mechanism of action a. At Proximal Convoluted tubule (PCT) i . Carbonic anhydrase inhibitors: Acetazolamide , Metazolamide , Dichlorphenamide ii. Xanthine derivatives: Theophylline , Aminophylline b. At the loop of henle (LH) i . Osmatic diuretics: Mannitol, Urea Glycerine , Isosorbide ii. Loop diuretics: Furosemide, Bumetanide , Torasemide , Ethacrynic acid. 7

8. c. At the Distal Convoluted tubule (DCT) Thiazide diuretics: Chlorthiazide , Hydrochlorothiazide Indapamide , Xapamide , Metolazone , Bendroflumethiazide , Hydroflumethiazide , Cyclothiazide d. At Collecting tubules (CT) Potassium sparing diuretics i . Aldosterone antagonist: Spironolactone ii. Inhibitors of renal epithelial Na + channels: Triamterene , Amiloride 8

9. Based on Chemical structure i . Organomercurial derivatives: 9 Name R R 1 X Chlormerodrin -NH 2 -CH 3 -Cl Mersalyl Sodium - CH 3 -OH Meralluride NaOOCCH 2 CH 2 CONH- - CH 3 -OH

10. ii. Phenoxyacetic acid: 10 Name R Ethacrynic acid Indacrinone

11. iii. Potassium Sparing Diuretics: a. Aldosterone antagonist: Spironolactone b. Aminopyrazine : Amiloride 11

12. 12 c. pteridines : Trimaterene

13. iv. Carbonic anhydrase inhibitors: Acetazolamide 13 Methazolamide Dichlorphenamide

14. v. Benzothiadiazines : a. Thiazide Diuretics: 14 Name R R 1 Chlorothiazide -Cl -H Benzthiazide -Cl Flumethiazide -CF 3 -H

15. b. Hydrothiazide Diuretics: 15 Name R R 1 R 2 Hydrochlorothiazide -H -H -Cl Bendroflumethiazide - H - CH 2 -C 6 H 5 -CF 3 Hydromethiazide -H -H -CF 3 Methylchlorthiazide - CH 3 - CH 2 Cl -Cl Polythiazide - CH 3 - CH 2 SCH 3 CF 3 -Cl Trichlormethiazide -H - CHCl 2 -Cl

16. C. Thiazides like diuretics: 1. Benzhydrazides Indapamide 16

17. 2. Tetrahydro Quinazolines : 17 Name R R 1 Quinethazone - C 2 H 5 -H Metalazone - CH 3

18. 3. Pthalimide Derivative: Chlorthalidone vi. High celling (Loop) Diuretics: Furosemide 18

19. Bumetanide Torsemide 19

20. vii. Miscellaneous a. Xanthene Derivatives:   20 Name R R 1 R 2 Caffeine - CH 3 - CH 3 - CH 3 Theophylline - CH 3 - CH 3 -H Theobromine -H - CH 3 - CH 3

21. b. Osmotic Diuretics Mannitol 21 Urea Isosorbide

22. Carbonic anhydrase inhibitors 22

23. Carbonic anhydrase is an enzyme found in various segments of nephron , especially in the cells of proximal convoluted tubule. Its function to catalyse the reversible reaction involved in the formation of carbonic acid from H 2 O and Co 2 and enhances the rate of reaction to many folds. The carbonic acid dissociates to form H + a nd HCO 3 ions. The carbonic anhydrase inhibitors inhibit this reaction leading to urinary excretion of Na + , K + , Ca + , and HCO 3 ions. These are heterocyclic derivatives. 23

24. Mechanism of action: 24

25. This class of diuretics inhibit carbonic anhydrase enzyme in the membrane and cytoplasm of the epithelial cells. The primary site of action is proximal tubules. These agents interfere with the reabsorption of HCO 3 − . HCO 3 − is reabsorbed in the proximal tubule and requires the activity of carbonic anhydrase. Intracellularly carbonic anhydrase converts H 2 O and CO 2 to carbonic acid (H 2 CO 3 ). H 2 CO 3 dissociates into H + and HCO 3 – . The HCO 3 – is transported across the basolateral membrane. H + is secreted into the tubular lumen in exchange for Na + . The H+ combines with a filtered HCO 3 – (using CA) to form H 2 CO 3 , which immediately dissociates into H 2 O and CO 2 that, is reabsorbed. Therefore, filtered bicarbonate is reabsorbed for every H + secreted. Carbonic anhydrase inhibitors, by blocking the enzyme, prevent the reabsorption of HCO 3 – . Accumulation of HCO 3 – in the tubular lumen subsequently inhibits Na + —H + exchange and Na + reabsorption . The increase in sodium concentration in the tubular fluid may be compensated partially by increased NaCl reabsorption in later segments of the tubule. Thus, the diuretic effect of the carbonic anhydrase inhibitors is mild. 25

26. SAR: These are heterocyclic sulphonamide and derivatives of m- disulfamoyl benzene. Both these groups are essential. Hence the SAR of carbonic anhydrase inhibitors would be studied under two headings. Heterocyclic Sulphonamide : The diuretic potency and carbonic inhibitory activity is entirely due to the sulphamoyl group present at C-5. The nitrogen atom of the sulphamoyl group should remain unsubstituted as the mono and di - substituted compound were pharmacologically inactive. The sulphamoyl group must be attached to an aromatic moiety. Substitution of methyl group at 3 rd position yielded methazolomide which exhibits carbonic anhydrase inhibitory activity. 26

27. Derivatives of m- disulpamoyl benzene: Similar to the heterocyclic sulphonamide the essential resistant for diuretic activity of m- disulphamoyl benzene derivatives is the presence of a sulphamoyl moiety in the unsubstituted form. These derivatives also possess an additional sulphamoyl group at C-3 which produced compounds with increased uretic activity. The basic structure disulphamoylbenzene is devoid any activity however substituted derivatives exhibit appreciable diuretic activity. 27

28. The replacement of additional sulphamoyl group present at C-3 with other electron withdrawing groups yield potent diuretic compound. Substitution of halogen groups like Cl, CF 3 , Br , and NO2 at C-4 has maximum activity. When an additional Chlorine atom is substituted at C-5 the analogue termed dichlorphenamide induces relatively less uretic effect. When amino group substituted at C-6 position the resulting compound induce increase excretion of Na + and Cl - ion but less inhibitory activity towards the enzyme. 28

29. Methazolamide Structure: IUPAC: N-(3-methyl-5-sulfamoyl-4,5-dihydro-1,3,4-thiadiazol -2-ylidene) acetamide Properties: White or yellow crystalline powder, slight odor, soluble in water, alcohol, acetone, dimethyl formamide. 29 Molecular formula: C 5 H 8 N 4 O 3 S 2

30. Pharmacokinetics: Oral route of administration metabolized in liver by cytochrome enzyme, under goes the urine elimination. Adverse Drug Reactions: decreased appetite, nausea, vomiting, constipation, diarrhea, changes in taste, drowsiness, dizziness, fatigue, weakness, nervousness, tremor, headache, confusion, increased sensitivity of the skin to sunlight, worsening gout, loss of blood sugar control (if you are diabetic), ringing in your ears (tinnitus) or hearing problems, changes in vision, tingling feeling in the extremities, General feeling of being unwell (malaise), and increased urination. 30

31. Therapeutic Uses: It is a carbonic anhydrase inhibitor. It will block the protein in the body called carbonic anhydrase. Blocking these protein can help to reduce amount of fluid inside the eye. It is used to lower pressure inside the eye. It is also used as diuretic in people with congestive heart failure to reduce edema. Dose: 25 mg to 50 mg bid 31

32. Dichlorphenamide Structure: IUPAC: 5,6-dichlorobenzene-1,3-disulfonamide Properties: White or nearly white crystalline powder, slightly characteristic odor, insoluble in water, soluble in alkaline solution, sodium hydroxide, alcohol, sodium carbonate, slightly soluble in ether. 32 Molecular formula: C 6 H 6 Cl 2 N 2 O 4 S 2

33. Pharmacokinetics: Oral route of administration metabolized in liver by cytochrome enzyme, under goes the urine elimination. Adverse Drug Reactions: Numbness/tingling, change in the sense of taste,  Nausea, diarrhea, vomiting, loss of appetite weight loss, muscle spasms/twitching, tiredness,  Dizziness or drowsiness, confusion, convulsion Abdominal Pain, stomach pain, diarrhea Chest pain, cough, dry mouth, Head ache, fever, weakness, Irregular breathing Joint pain, muscle pain 33

34. Therapeutic Uses: It reduces the action of protein, Used to treat glaucoma occasional paralysis (loss of movement) caused by high or low levels of K + in blood. Dose: Initiate  dosing  at 50 mg by mouth once or twice daily. 34

35. Acetazolamide Structure: IUPAC: N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl) acetamide Properties: White crystalline powder, odorless, soluble in dilute alkali hydroxide solution, slightly soluble in water and alcohol, insoluble in chloroform, diethyl ether, carbon tetrachloride. 35 Molecular formula: C 4 H 6 N 4 O 3 S 2

36. Synthesis: Step I : 36

37. Step II : 37

38. Step III : 38

39. Step IV : 39

40. Pharmacokinetics: Acetazolamide in oral administration exhibits bioavailability of almost 100%. It has a biological half-life of about 6-9 hours and is excreted unchanged in urine. Adverse Drug Reactions: Dizziness, lightheadedness, or increased urination may occur, especially during the first few days as your body adjusts to the medication.  Blurred vision, dry mouth, drowsiness, loss of appetite,  nausea, vomiting, diarrhea, or changes in taste  Fever, skin rashes, impairment of renal function, depression of bone marrow functioning 40

41. Therapeutic Uses: Acetazolamide  is used to prevent and reduce the symptoms of altitude sickness. This medication can decrease headache, tiredness, nausea, dizziness, and shortness of breath that can occur when you climb quickly to high altitudes. It is also used in the treatment of Glaucoma, Metabolic alkalosis, epileptic seizures, edema 41

42. Dose: Usual Dose for Edema Initial dose: 250 to 375 mg orally/IV once a day Usual Dose for Acute Mountain Sickness 500 to 1000 mg orally per day in divided doses Usual Dose for Glaucoma -Immediate-release (IR) tablets: 250 to 1000 mg orally per day; amounts over 250 mg should be administered in divided doses -Extended-release (ER) capsules: 500 mg orally 2 times a day Usual Dose for Seizure Prophylaxis Initial dose: 8 to 30 mg/kg orally/IV in divided doses 42

43. Thiazides 43

44. Thiazides diuretics are group of moderately efficacious diuretics, which enjoy vast clinical applications. All the Thiazides diuretics are inhibitors of Na + Cl – symporter and their major site of action is the early segment of the distal convoluted tubule (DCT). Thiazide diuretic differs among themselves only in their duration of action and potency, with the thiazide like diuretic exhibiting longer duration of action. 44

45. Mechanism of action: 45

46. Thiazides inhibit a Na + —Cl – symport in the luminal membrane of the epithelial cells in the distal convoluted tubule. Thus, thiazides inhibit NaCl reabsorption in the distal convoluted tubule, and may have a small effect on the NaCl reabsorption in the proximal tubule. Thiazides enhance Ca ++ reabsorption in the distal convoluted tubule by inhibiting Na + entry and thus enhancing the activity of Na + —Ca ++ exchanger in the basolateral membrane of epithelial cells. 46

47. SAR: These compounds are weakly acidic; 1. H atom at N-2 is the most acidic due to the electron-withdrawing effects of the neighboring sulfone group. 2. Sulfonamide group at C-7 provides an additional point of acidity in molecule but is less acidic than N-2 proton. A free sulfamoyl group at position 7 is essential for diuretic activity. 3. These acidic protons make possible the formation of a water-soluble sodium salt that can be used for I.V. dosing. 4. An electron-withdrawing group is essential at position 6. 47

48. 5. The diuretic activity is enhanced by substitution at position 3. 6. Replacement of 6-Cl by 6-CF 3 does not change potency but alters duration of action. 7. Replacement of 6-Cl by electron-donating groups ( e.g. CH 3 ) reduces diuretic activity. 8. Saturation of thiadiazine ring to give 3, 4-dihydro derivative and replacement replace or removal of sulfonamide group at position C-7 yields compounds with little or no diuretic activity. 48

49. Hydrochlorothiazide Structure: IUPAC: 6-chloro-1,1-dioxo-3,4-dihydro-2H-1,2,4-benzo thiadiazine -7-sulfonamide Properties: White, or practically white crystalline powder, practically odorless, slightly bitter taste, soluble in ethanol , acetone, dilute ammonia; freely soluble in sodium hydroxide solution, n- butylamine ,  dimethylformamide ; sparingly soluble in alcohol; insoluble in ether, chloroform, dilute mineral acids.   49 Molecular formula: C 7 H 8 ClN 3 O 4 S 2

50. Pharmacokinetics: Oral route of administration. Hydrochlorothiazide is not metabolized, but eliminated in the urine as unchanged hydrochlorothiazide. Adverse Drug Reactions: blood pressure that’s lower than normal (especially when standing up after sitting or lying down) dizziness, headache, weakness erectile dysfunction (trouble getting or keeping an erection) tingling in your hands, legs, and feet 50

51. Therapeutic Uses: This medication is used to treat high blood pressure. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems.  This medication also reduces extra fluid in the body (edema) caused by conditions such as heart failure, liver disease, or kidney disease. This can lessen symptoms such as shortness of breath or swelling in your ankles or feet. Dose: For oedema- 25-200 mg in 1 or 2 divided doses, orally. For hypertension- 12-25 mg in 1 or 2 divided doses, orally. 51

52. Hydroflumethiazide Structure: IUPAC: 6-( trifluoromethyl )-1,1-dioxo-4H-1,2,4 benzothiadiazine -7-sulfonamide Properties: White to cream colored, finely divided, crystalline powder, odorless, Soluble in dilute alkali but unstable in alkaline solutions, freely soluble in acetone, insoluble in acids. 52 Molecular formula: C 8 H 8 F 3 N 3 O 4 S 2

53. Pharmacokinetics: Oral route of administration, metabolized in liver, undergoes urinary excretion. Adverse Drug Reactions: Low blood sodium or potassium levels an imbalance of sodium and potassium in the blood high blood sugar, low blood pressure sun sensitive skin Nausea, vomiting Diarrhea, stomach cramps, loss of appetite sexual problems dizziness, and fatigue 53

54. Therapeutic Uses: It is used in the treatment of Hypertension, oedema. Dose: For oedema- 25-200 mg in 1 or 2 divided doses, orally. For hypertension- 12-25 mg in 1 or 2 divided doses, orally. 54

55. Cyclothiazide Structure: IUPAC: 3-{bicyclohept-5-en-2-yl}-6-chloro-1,1-dioxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide Properties: White to nearly white powder, odorless, freely soluble in acetone, ethyl acetate, methanol, insoluble in water, chloroform, water. 55 Molecular formula: C 14 H 16 ClN 3 O 4 S 2

56. Pharmacokinetics: Oral route of administration, metabolized in liver, undergoes urinary excretion. Adverse Drug Reactions: Dizziness, dehydration, Salt imbalance, Anorexia, Gastric irritation, Nausea, Vomiting Cramping, Diarrhea, Jaundice, Vertigo Headache, Fever, Respiratory distress Therapeutic Uses: Cyclothiazide is used in the treatment of: Edema, Hypertension, Nephrotic Syndrome, Heart Failure Dose: For oedema- 25-200 mg in 1 or 2 divided doses, orally. For hypertension- 12-25 mg in 1 or 2 divided doses, orally. 56

57. Chlorthiazide Structure: IUPAC: 6-chloro-1,1-dioxo-4H-1,2,4-benzothiadiazine-7-sulfonamide Properties: White crystalline powder, odorless, soluble in water, freely soluble in Dimethylformamide, dimethyl sulfoxide , slightly soluble in methanol, pyridine, insoluble in ether, benzene, and chloroform. 57 Molecular formula: C 7 H 6 ClN 3 O 4 S 2

58. Synthesis: 58

59. Pharmacokinetics: Chlorothiazide is not metabolized but is eliminated rapidly by the kidney. After oral doses, 10 to 15 percent of the dose is excreted unchanged in the urine. Chlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. Adverse Drug Reactions: Dizziness, lightheadedness, headache, blurred vision, loss of appetite,  stomach upset, diarrhea, or constipation 59

60. Therapeutic Uses: This medication is used to treat high blood pressure. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems.  Chlorothiazide  is a "water pill" (diuretic) that causes you to make more urine. This helps your body get rid of extra salt and water. This medication is also used to decrease swelling (edema) caused by conditions such as cancer, congestive heart failure, liver disease, and kidney disease. This effect can help your kidneys work better and lessen symptoms such as trouble breathing and swelling in your ankles, feet, hands, or belly. Dose: For oedema- 500-1000 mg orally. For hypertension- 125-250 mg in 1 or 2 divided doses, orally. 60

61. Loop diuretics 61

62. Loop Diuretics are more potent and efficacious diuretics. In normal doses, loop diuretics are capable of inducing up to 20-30% of natriuresis and increasing the dose, up to 30-40% natriuresis can be achieved. Such an excretion is not exhibited by any other diuretics like thaizides or potassium sparing diuretics. Loop diuretics are more efficacious because their site of action is thick ascending limb of loop of henel which accounts for the reabsorption of 30-40% NaCl . 62

63. Mechanism of action: 63

64. Loop diuretics inhibit reabsorption of NaCl and KCl by inhibiting the Na + —K + —2Cl – symport in the luminal membrane of the thick ascending limb (TAL) of loop of Henle . As TAL is responsible for the reabsorption of 35% of filtered sodium, and loop diuretics are highly efficacious and are thus called high ceiling diuretics. The Na + —K + —2Cl – symport and sodium pump together generate a positive lumen potential that drives the reabsorption of Ca ++ and Mg ++ , inhibitors of the Na + -K + -2Cl – symport also inhibit reabsorption of Ca ++ and Mg ++ . Loop diuretics also have direct effects on vasculature including increase in renal blood flow, and increase in systemic venous capacitance. 64

65. SAR: They are either 5-sulphamoyl-2-amino benzoic acid or 5-sulhamoyl-3-amino benzoic acid derivatives. The carbonyl group C-1 provides optimal diuretic activity. The substitution of activating group (X) in the position 4 by Cl, alkoxy , aniline, benzyl or benzoyl group at 4 th position increases the diuretic activity. The presence of sulphamoyl group in the 5 th position is essential for activity. The two series of 5-sulphamoyl benzoic acid differ in the nature of the functional group that substituted in 2 nd and 3 rd position. The presence of furfuryl , phenyl, and thienyl methyl group at 2 nd amino group of 5-sulphomoyl. 2-amino benzoic acid gives maximum diuretic activity. The wide range of alkyl group can be substituted at 3 rd amino group of 5-sulfamoyl-3-amino benzoic acid without modifying the optimal diuretic activity. A molecule with a week acidic group to direct the drug to the kidney and alkylating moiety to react with sulphydryl groups and lipophilic groups seemed to provide the best combination of a diuretic in the class. 65

66. Ethacrynic acid Structure: IUPAC: 2-[2,3-dichloro-4-( 2-methylidenebutanoyl) phenoxy ]acetic acid Properties : White crystalline powder, odorless, soluble in alcohol, ether, chloroform, very slightly soluble in water 66 Molecular formula: C 13 H 12 Cl 2 O 4

67. Pharmacokinetics: On set of action upon oral administration is after 2-3 hours and within minutes on i.v route of administration. About 38% of the oral dose is biotransformed while the remaining fraction undergoes renal excretion in an unchanged form. Adverse Drug Reactions: It may cause frequent urination, muscle cramps Loss of hearing, liver damage On oral administration it may cause diarrhea, dry mouth, nausea, vomiting muscle pain, uneven heart beat. Loss of appetite, stomach pain, difficulty swallowing Weakness, headache, confusion 67

68. Therapeutic Uses: Ethacrynic acid is used to treat edema (fluid retention; excess fluid held in body tissues) in adults and children caused by medical problems such as cancer, heart, kidney, or liver disease. Ethacrynic acid is in a class of medications called diuretics ('water pills'). Dose: Oral: 50 to 200 mg orally per day in 1 to 2 divided doses. 50 mg (or 0.5 to 1 mg/kg) IV once; occasionally, a second dose at a new injection site may be required. 68

69. Bumetanide Structure: IUPAC: 3-butylamino-4-phenoxy-5-sulfamoylbenzoic acid Properties : White crystalline powder, insoluble in water, soluble in acetone, alcohol, dilute solutions of alkali hydroxide, slightly soluble in methylene chloride. 69 Molecular formula: C 17 H 20 N 2 O 5 S

70. Pharmacokinetics: Oral route of administration, some fraction of administered in gets metabolized in the liver while the reaming fraction undergoes urinary excretion in an unchanged form. Adverse Drug Reactions: Muscle pain, weakness, tiredness, convulsions, dizziness, drowsiness, skin rashes, vomiting, irregular heartbeat, Stomach pain, dry mouth, loss of appetite, memory problems, low blood pressure, headache, nausea 70

71. Therapeutic Uses: Bumetanide is used to treat edema (fluid retention; excess fluid held in body tissues) caused by various medical problems, including heart, kidney, and liver disease. Bumetanide is in a class of medications called diuretics ('water pills'). It works by causing the kidneys to get rid of unneeded water and salt from the body into the urine. Dose: The usual total daily dosage of Bumetanide tablets is 0.5 mg to 2 mg and in most patients is given as a single dose. 71

72. Furosemide Structure: IUPAC: 4-chloro-2-[(furan-2-ylmethyl)amino]-5-sulfamoylbenzoic acid Properties: White to off-white crystalline powder, odorless , practically tasteless, slightly soluble in water, chloroform, ether, soluble in acetone, methanol, DMF, aqueous solutions above pH 8.0, less soluble in ethanol, freely soluble in alkali hydroxide. 72 Molecular formula: C 12 H 11 ClN 2 O 5 S

73. Synthesis: Step-I : 73

74. Step-II : 74

75. Pharmacokinetics: Oral, i.v route of administration, the metabolism of furosemide occurs mainly in the kidneys and the liver, to a smaller extent. The kidneys are responsible for about 85% of total furosemide total clearance, where about 40% involves biotransformation. Two major metabolites of furosemide are furosemide glucuronide , which is pharmacologically active, and saluamine (CSA) or 4-chloro-5-sulfamoylanthranilic acid. Excreted unchanged in urine. Adverse Drug Reactions: increased urination, thirst, muscle cramps, itching or rash, weakness, dizziness,, spinning sensation, Diarrhea, stomach pain and constipation. dehydration, dark urine, clay-colored stools, nausea, vomiting, fever, jaundice (yellowing of skin or eyes), electrolyte abnormalities, Loss of appetite and rapid weight loss. Cardiac arrest can occur following i.v administration. 75

76. Therapeutic Uses: Furosemide is used in the treatment of hypertension, hypercalcaemia , acute renal failure. Furosemide is used to treat edema (fluid retention; excess fluid held in body tissues) caused by various medical problems, including heart, kidney, and liver disease. Dose: Edema The usual initial dose of Furosemide is 20 to 80 mg given as a single dose.  Hypertension The usual initial dose of Furosemide for hypertension is 80 mg, usually divided into 40 mg twice a day. 76

77. Potassium sparing Diuretics 77

78. Potassium sparing Diuretics are a class of weak diuretics whose site of actions are the distal and collecting tubules where they inhibit the reabsorption of Na + ions. Due to this, the stimulation secretion of monovalent ions i.e K + and H + are also inhibited. As these diuretics conserve K + ions, they are used along with other diuretics which have significant uretic effect. Such a combination is beneficial in maintaining the potassium homeostasis in the body. 78

79. Aldosterone Antagonists Mechanism of action: Aldosterone , by binding to its receptor in the cytoplasm of epithelial cells in collecting tubule and duct, increases expression and function of Na + channel and sodium pump, and thus enhances sodium reabsorption (see “Na + channel inhibitors” above). Spironolactone competitively inhibits binding of aldosterone to its receptor and abolishes its biological effects. 79

80. Spironolactone Structure: IUPAC: 7- acetylsulfanyl-17-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ- lactone Properties: Light cream-colored to light tan, crystalline powder, Mild mercaptan -like odor, Soluble in ethyl acetate and ethanol; slightly soluble in methanol. 80 Molecular formula: C 24 H 32 O 4 S

81. Pharmacokinetics: Oral route of administration, metabolized in liver, it gets metabolically transformed to canrenone which is active. The drug undergoes urinary excretion and some fraction is also found in bile. Adverse Drug Reactions: Drowsiness, dizziness, lightheadedness, confusion Stomach upset, diarrhea, nausea, vomiting, or headache may occur. To minimize lightheadedness, get up slowly when rising from a seated or lying position. Abdominal upset, menstrual irregularities. 81

82. Therapeutic Uses: Spironolactone  is used to treat high blood pressure and heart failure. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. It is also used to treat swelling (edema) caused by certain conditions (such as heart failure, liver disease) by removing excess fluid and improving symptoms such as breathing problems. This medication is also used to treat low potassium levels and conditions in which the body is making too much of a natural chemical ( aldosterone ). 82

83. Dose: Usual Dose for Edema: 25 to 200 mg orally per day in single or divided doses Usual Dose for Hypertension: Initial dose: 50 to 100 mg orally per day in single or divided doses Usual Dose for Congestive Heart Failure: Initial dose: 25 mg orally once a day assuming serum potassium is less than or equal to 5 mEq /L and serum creatinine is less than or equal to 2.5 mg/ dL 83

84. Na+ Channel Inhibitors Mechanism of action: Amiloride and triamterene inhibit the sodium channel in theluminal membrane of collecting tubule and collecting duct. This sodium channel is critical for Na + entry into cells down the electrochemical gradient created by sodium pump in the basolateral membrane, which pumps Na + into interstitium . This selective transepithelial transportof Na + establishes a luminal negative transepithelial potential which in turn drives secretionof K + into the tubule fluid. The luminal negative potential also facilitates H + secretion via the proton pump in the intercalated epithelial cells in collecting tubule and collecting duct. Inhibition of the sodium channel thus not only inhibits Na + reabsorption but also inhibitssecretion of K + and H + , resulting in conservation of K + and H + . 84

85. Amiloride Structure: IUPAC: 3,5-diamino-N-carbamimidoyl-6-chloropyrazine-2-carboxamide Properties : Pale yellow to greenish-yellow powder, slightly soluble in water, ethanol. 85 Molecular formula: C 6 H 8 ClN 7 O

86. Pharmacokinetics: Amiloride is partly absorbed by GIT. It has an oral bioavailability of about 15-25% and it undergoes metabolism and is excreted unchanged in urine. Adverse Drug Reactions: Headache, dizziness, nausea, vomiting, loss of appetite, stomach/abdominal pain, gas, or diarrhea  Skin rashes, emesis, hyperkalaemic . 86

87. Therapeutic Uses: Amiloride  is used with other "water pills"/diuretics (such as  furosemide , thiazide diuretics like hydrochlorothiazide) to treat high blood pressure (hypertension), heart failure, or extra fluid in the body (edema), Ascites . Amiloride also helps to treat or prevent low blood potassium levels caused by the other diuretics. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Amiloride is called a "water pill" (diuretic) and causes your body to get rid of extra salt and water while also preventing the kidneys from getting rid of too much potassium. 87

88. Dose: Usual Adult Dose for Ascites Initial dose: 5 mg orally once a day. Maintenance dose: 5-10 mg once a day. Usual Adult Dose for Congestive Heart Failure Initial dose: 5 mg orally once a day. Maintenance dose: 5-10 mg once a day. Usual Adult Dose for Edema Initial dose: 5 mg orally once a day. Maintenance dose: 5-10 mg once a day. Usual Adult Dose for Hypertension Initial dose: 5 mg orally once a day. Maintenance dose: 5-10 mg once a day. 88

89. Triamterene Structure: IUPAC: 6-phenylpteridine-2,4,7-triamine Properties: Yellow crystalline powder, odorless, slightly soluble in water,  ethanol, chloroform, soluble in formic acid, dilute ammonia, dilute aqueous sodium hydroxide, and  dimethyl formamide, sparingly soluble in  methoxyethanol , methanol, very slightly soluble in acetic acid, dilute mineral acids ,  benzene, chloroform, ether, and dilute alkali hydroxides, alcohol 89 Molecular formula: C 12 H 11 N 7

90. Pharmacokinetics: Oral route of administration, undergoes hepatic metabolism to yield an active metabolite, undergoes urinary elimination. Adverse Drug Reactions: congestive heart failure, low blood pressure headache, light sensitivity rash, yellowing of eyes and skin (jaundice), severe allergic reaction (anaphylaxis) diarrhea, nausea, vomiting, gastrointestinal upset, dry mouth uric acid in the blood, kidney damage, kidney stones, kidney inflammation, acute kidney failure low platelets in the blood folic acid antagonism, high blood potassium level, megaloblastic  anemia liver enzyme abnormalities 90

91. Therapeutic Uses: This drug is used to treat high blood pressure. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. This medication is a combination of two "water pills" (diuretics):  triamterene  and hydrochlorothiazide. This combination is used by people who have developed or are at risk for having low potassium levels on hydrochlorothiazide. It causes you to make more urine, which helps your body get rid of extra salt and water. This medication also reduces extra fluid in the body (edema) caused by conditions such as heart failure, liver disease, or kidney disease. This can lessen symptoms such as shortness of breath or swelling in your ankles or feet. 91

92. Dose: Edema Adults 100-300 mg/day orally each day or divided every 12 hours Geriatric 50-300 mg/day orally each day or divided every 12 hours Hypertension Adults 100-300 mg/day orally each day or divided every 12 hours Geriatric 50-300 mg/day orally each day or divided every 12 hours 92

93. Osmotic Diuretics 93

94. Osmotic diuretics exert their diuretic effect indirectly by altering the contents of the tubular lumen. These agents are pharmacologically inert, enhance the osmolatility of plasma and tubular fluids and are filtered freely by the Bowman’s capsule. In addition, these are not metabolized and are reabsorbed partially or completely by the various segment of the nephron which ultimately reduces the tubular water reabsorption . 94

95. Mechanism of action: Osmotic diuretics are substances to which the tubule epithelial cell membrane has limited permeability. When administered (often in a large dosage), osmotic diuretics significantly increase the osmolarity of plasma and tubular fluid. The osmotic force thus generated prevents water reabsorption , and also extracts water from the intracellular compartment, expands extracellular fluid volume and increases renal blood flow resulting in reduced medulla tonicity. The primary sites of action for osmotic diuretics are the Loop of Henle and the proximal tubule where the membrane is most permeable to water. 95

96. Mannitol Structure: IUPAC: Hexane-1,2,3,4,5,6-hexol Properties : White crystalline powder or freely flowing granules, odorless, sweet taste, soluble in pyridine, aniline, alkalies , water, insoluble in ether. 96 Molecular formula: C 6 H 14 O 6

97. Pharmacokinetics: Oral, i.v route of administration. The preferred route of administered is i.v as its absorption via the oral route is poor. Upon administration Mannitol, is not metabolized but undergoes glomerular filteration (without being effectively reabsorbed), with an hour of its administration. It is rapidly excreted in the urine. Adverse Drug Reactions: headache, nausea, vomiting, dry mouth, thirst, dizziness, diarrhea, dehydration, blurred vision, runny nose, arm pain, chills, hives, chest pain low blood pressure (hypotension), irregular heart beat Electrolyte imbalance and irritation/pain/swelling at the injection site. Thrombophlebitis (inflammation of the walls veins). This may subsequently leads to local tissue death. 97

98. Therapeutic Uses: Used to treat edema formation due heart failure, kidney failure. Used in the treatment of high blood pressure, liver cirrhosis. Dose: The usual adult dosage ranges from 50 to 200 g in a 24-hour period 98

99. Reference books Text book of Medicinal chemistry volume-1-3 rd edition by V.Alagarasamy. Text book of Medicinal chemistry volume-2-3 rd edition by V.Alagarasamy. Medicinal chemistry by Rama Rao Nadendla. Faye’s Principles of Medicinal Chemistry- 7 th edition by Thoms L.Lemke , Victoria F.Roche , S. Willam Zito . Medicinal Chemistry- 4 th edition by Ashutosh Kar Medicinal and Pharmaceutical Chemistry by Harkishan Singh, V.K Kapoor . 99

100. Thank you 100