DIURETICS : NCP

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DIURETICS PRESENTED BY, MEGANA.H.S 1ST M.PHARM ( ANALYSIS ) NCP UNDER THE GUIDANCE OF, Mr.B.G.GOPINATH DIURETICS PRESENTED BY, MEGANA.H.S 1ST M.PHARM ( ANALYSIS ) NCP UNDER THE GUIDANCE OF, B.GOPINATH SIR

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DEFINITION : Diuretics are the drugs used to increase the process of urine formation. HISTORY & DEVELOPMENT: From the time of Paracelus mercurous chloride had been used as diuretic. In 1920, organomercurials were introduced. Sulphonamides caused acidosis and mild diuresis. In 1950, carbonic inhibitors were developed. In 1957, first orally active diuretic developed i.e. Chlorthiazide. In 1960, Thiazide diuretics were developed. In mid of 1960, Furosemide & Ethacrynic acid were developed.

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CLASSIFICATION OF DIURETICS : 1. Carbonic anhydrase inhibitors: These act on proximal tubule. During urine formation carbonate ion ( HCO3-) is reabsorbed via H+ secretion. Secretion of H+ in the cell & its removal from tubular fluid are catalyzed by Carbonic anhydrase. These exerts their effect by inhibiting both membrane bound and cytoplasmic forms of carbonic anhydrase. Therefore leading to inhibition of H+ secretion, decrease in HCO3- absorption , so decreasing net Na+ reabsorption. H2CO3 H+ + HCO3-

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EXAMPLES: Acetazolamide, Dichlorophenamide, Ethoxazolamide, Methazolamide etc. STRUCTURES : Methazolamide Acetazolamide

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2. Loop or high ceiling diuretics : Site of action is on ascending limb of loop of Henley. Act on Na+, K+ and Cl- symporter to inhibit sodium and chloride reabsorption. Thereby prevent the urine from becoming concentrated. Ultimately result in increased renal blood flow. The onset of action is rapid. EXAMPLES : Furosemide, Ethacrynic acid, Mercaptomerine. Mersalyl etc.

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Furosemide Ethacrynic acid STRUCTURES :

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3. Thiazide and Thiazide like diuretics : Act on distal convoluted tubule. These agents act by inhibiting Na+-Cl- symporter system. This is a co-transport system that helps in movement of Na+ and Cl- into and out the cell. Na+ ion is pumped out of cell via co-transport system through bilateral membrane. Cl- exits the cell via Chloride channel. These also act as carbonic anhydrase inhibitors. EXAMPLES : Chlorthiazide, Benzthiazide, Chlorthalidone, Hydrochlorthiazide etc.

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STRUCTURES : Benzthiazide Chlorthalidone

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4. Potassium sparing diuretics : Site of action is on distal tubule. These alone are not a highly efficient diuretic. So used in causing mild diuresis. Or in conjugation with other diuretics to minimize the loss of K+ through urine. Act by inhibiting Na+ ion exchange, with K+ and H+. EXAMPLES : Amiloride, Triamterene, Spironolactone, Aldosterone etc.

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Amiloride Triamterene STRUCTURES :

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USES : To treat edema. To treat cardiac failure. To treat renal diseases like nephritis. Cirrhosis of liver. Treatment of hypertension. Treatment of Diabetes Incipidus. ADVERSE EFFECTS: Hypercalciurea. Hypokalemia Anorexia Weight loss. Weakness, GIT disorder. Photosensitivity , headache etc.

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AMILORIDE Structure : .HCl.2H2O Mol formula : C6H8ClN7O.HCl.2H2O Mol weight : 302.12g/ml Description : Yellow to greenish yellow crystalline powder which is odorless. Solubility : Freely soluble in Dimethylsulfoxide, sparingly soluble in water, very slightly in ethanol. Brand name : MIDAMOR

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METHODS OF ANALYSIS : Non – aqueous titration Thin layer chromatography UV spectroscopy HPLC IR spectroscopy

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1. Non – aqueous titration : Principle : Substances which are either too weakly basic or too weakly acidic to give sharp end point in aqueous solutions are determined by non-aqueous method. Procedure : Dissolve 450mg of sample in 100ml of glacial acetic acid Add 10ml of mercuric acetate. Add 15ml of dioxane. Titrate with 0.1N perchloric acid using crystal violet as indicator until a blue color. Blank determination is done to make necessary corrections. Each ml 0.1N perchloric acid = 26.61gm of Amiloride hydrochloride.

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Amiloride HCl

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1. Thin layer chromatography : Principle : Main principle is adsorption. Adsorbent acts as stationary phase, Mobile phase selection depend on elutropic series based upon polarity of solvents. Amiloride hydrochloride is analyzed by Normal phase TLC on silica gel by employing two solvent system ;

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UV spectroscopy : Principle : Any molecule has either η,π and σ or a combination of these electrons. Bonding (σ and π) & non-bonding (η) electrons abosorb the characteristic radiation and undergoes transition from ground state to excited state. By this characterization absorption peaks are obtained. There by the nature of electrons present and hence the molecular structure can be elucidated.

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Procedure : UV spectrum of amiloride can be determined in a solution of 0.01N aqueous hydrochloric acid. Absorption maxima is approximately at 212nm, 285nm and 362nm . Molar absorptivity of 1% drug solution in a 1cm cell is 642, 555 and 617 for the wavelengths of 212nm, 285nm and 362nm respectively.

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4. High Performance Liquid Chromatography : Principle : Amiloride is determined by Rp-HPLC method Where stationary phase is non-polar and mobile phase is polar. Procedure : Column : C-2 ( 300mm X 4.6 mm i.d) Adsorbent : Silica Gel G Particle size of adsorbent : 10μm Temp : Ambient Mobile Phase : 85% aqueous 0.01Msodium hexane sulphonate in acetonotrile Flow rate : 2ml/min Retention time : 2mins Detection : By UV at 280nm.

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5. IR spectroscopy : Principle : For any molecule to absorb IR radiation it should posses, Dipole moment Applied frequency of IR must be equal to natural frequency of radiation. IR spectra is nothing but a fingerprint of a molecule. Procedure : 1) IR spectrum in a KBr pellet was obtained using a Fourier-transform (FT IR ) spectrometer. 2) IR spectrum obtained in a mineral oil called mull ( nujol )

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IR spectral assignments : Frequency ( cm-1 ) Assignments 3250 -3500 N-H stretch ( NH2) 3150 N-H stretch (NH) 1680 C=O stretch 1640 H2 deformation mode 1600 H2 deformation mode 1240 N- (C6H6) stretch 770 C-H out of plane mode

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REFERENCES : Text book of Pharmacology by P.D Seth. Pg 292 – 303. Analytical Profiles of Drug Substances by Klaus Florey, vol 15, Pg 1 – 30. Clinical Pharmacology by P.N.Bennett and M.J.Brown. 9th edition, Pg 529 – 547. Modern Pharmacology by Charles.R.Craig and Robert.E.Stitzel,3rd edition, pg 270 – 270. The Pharmacological basis of Therapeutics by Goodmann and Gilman, 8th edition, vol 1, pg 708 – 730.

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