Digitalis glycoside


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Digitalis glycoside

  1. 1. DIGITALIS GLYCOSIDE Kratika Daniel (Ph.D) Assistant professor MANDSAUR INSTITUTE OF PHARMACY, Mandsaur
  2. 2. INTRODUCTION•The genins of all cardiac glycosides are steroidal in nature, that act as cardio tonic agents.•They are characterized by their highly specific action cardiac muscle, increasing tone,excitability and contractility of this muscle, thus allowing the weakened heart to function moreefficiently. Lactone ring 12 CH3 17 11 13 1 16 R 9 14 2 15 10 8 OH 3 7 Sugar O 5 4 6All cardio active glycosides are characterized by the following structural features:1.The presence of β-OH at position C-3, which is always involved in a glycosidic linkage to amono, di, tri, OR tetra saccharide.2.The presence of another β-OH group at C-14.3.The presence of unsaturated 5 or 6- membered lactone ring at position C-17, also in the βconfiguration.4.The A/B ring junction is usually (cis), while the B/C ring junction is always (trans) and theC/D ring junction is in all cases (cis). Kratika Daniel (Ph.D)5.Additional OH groups may be present at C-5, C-11 and C-16. Assistant professor MANDSAUR INSTITUTE OF PHARMACY, Mandsaur
  3. 3. 1- Cardiac glycosides that α-β unsaturated 5-membered lactose ring in position C-17 areknown as cardenolides. These are represented by the digitalis and straphanthus group.2- Digitalis glycosides contain angular methyl group at C-10, while strophanthus glycoside arecharacterized by presence of either an aldehydic (CHO) or primary alcoholic (C`H2OH) groupat C-10. O O OH 12 CH3 17 11 13 1 16 R 9 14 2 15 10 8 OH 3 7 Sugar O 5 6 4 Cardenolides Digitalis glycosides R=CH3 Strophanthus glycosides R=CHO OR CH 2OH 3- Cardiac agents that have doubly unsaturated 6-membered lactone ring in position C-17 are referred to as Bufadienolides. 4- This group includes the squill glycosides and the toad venom, Bufotoxin. Kratika Daniel (Ph.D) Assistant professor MANDSAUR
  4. 4. 5- The glycone portion at position C-3 of cardiac glycosides may contain four monosaccharidemolecules linked in series. Thus, from a single genin one may have a monoside, a bioside, atrioside or a tetroside.6- With the exception of D-glucose and L-rhamnose, all the other sugars that are found in cardiacglycosides are uncommon deoxy-sugars e.g., Digitoxose, Cymarose, Thevetose. CHO CHO CHO C H2 C H2 HC OH C OH C OCH3 CH3 O C H C OH C OH H C OH C OH C OH H C OH CH3 CH3 CH3 Digitoxose Cyamarose Thevetose Kratika Daniel (Ph.D) Assistant professor MANDSAUR INSTITUTE OF PHARMACY, Mandsaur
  5. 5. SOURCED. purpurea, D. lanata, D. lutea and D. thapsi. Family – Scrophularaceae.The structures of the common aglycones of the digitalis group are: - O O R1 17 11 12 13 1 16 R2 9 14 2 15 10 8 OH 3 7 H O 5 4 6 Compounds R1 R2 Digitoxigenin H H Gitoxigenin H OH Digoxigenin OH H Kratika Daniel (Ph.D) Assistant professor MANDSAUR kratika
  6. 6. DX = Digitoxose, DX (AC)=Acetyldigitoxose,G = Glucose .1- Glycosides derived from Digitoxigenin: a- Lanatoside A = Digitoxigenin---DX---DX----DX(AC)---G. b- Acetyl-digitoxin = Digitoxigenin---DX---DX----DX---(AC). c- Digitoxin = Digitoxigenin------DX---DX----DX. d- Purpurea gly A = Digitoxigenin---DX---DX----DX---G2- Glycosides derived from Gitoxigenin: a- Lanatoside B = Gitoxigenin---DX---DX----DX(AC)---G. b- Acetyl-gitoxin = Gitoxigenin---DX---DX----DX---(AC). c- Gitoxin = Gitoxigenin------DX---DX----DX. d- Purpurea gly B = Gitoxigenin---DX---DX----DX---G3- Glycosides derived from Digoxigenin: a- Lanatoside C = Digoxigenin---DX---DX----DX(AC)---G. b- Acetyl-digoxin = Digoxigenin---DX---DX----DX---(AC). c- Digoxin = Digoxigenin------DX---DX----DX. d- Deslanoside = Digoxigenin---DX---DX----DX---G Kratika Daniel (Ph.D) Assistant professor MANDSAUR INSTITUTE OF PHARMACY,
  7. 7. 1.The primary glycosides Lanatoside A, Lanatoside B, Lanatoside C are acted by specificenzyme which split the terminal glucose, give the secondary glycosides acetyldigitoxin,acetylgitoxin and acetyldigoxin respectively.2.The deacetyl-lanatosides A, B and C can be obtained by the alkaline hydrolysis of thecorresponding lanatosides.3.Digitoxin, gitoxin and digoxin are obtained by the action of alkali on their acetyl-derivatives. Lanatoside A Alkaline Specificpurpurea gly. A Acetyldigitoxin hydrolysis enzyme Specific Alkaline Digitoxin enzyme hydrolysis Acid hydrolysis Digitoxigenin + 3 digitoxose Kratika Daniel (Ph.D) Assistant professor MANDSAUR
  8. 8. ISOLATION Digitalis powder Removal of fatty material by extraction with petroleum ether Digestion of defatted material with water Liquid discard Extracted more with several water and ethanol mixture Concentrate to small volume Distillation in vaccum Precipitation of tannin by lead hydroxide Super gel filtration Glycoside with low Glycoside with low Solubility in water & Solubility in water & High solubility in High solubility in chloroform chloroform Removal of alcohol by Kratika Daniel (Ph.D) Assistant professor MANDSAUR Vaccum distillation
  9. 9. Adjust filtrate to pH 6 Aqueous solution Successive washing with chloroform Extraction with Ether. ethanol chloroform Discard washing Washing with chloroform with water 2N HCl, 2N Na2CO3. Into aqueous phase add Sodium sulfate to saturation Discard washing Separation of glycoside by chromatography Extraction with chloroform ethanol mixture Acetylation/ benzoylation Elution with chloroform Less polar of more polar glycoside & chloroform containing graded glycoside proportion of methanol KHCO3Separation of individual glycosideBy chromatography Kratika Daniel (Ph.D) Assistant professor MANDSAUR
  10. 10. CHEMICAL TESTS1. Raymond test: - A small quantity of glycoside is dissolved in 1ml of 50% ethanol followed by addition of 0.1 ml of 1% solution of dinitrobenzene in methanol. To this solution 2 – 3 drops of 20% sodium hydroxide solution is added. Appearance of violet color changes to blue color.2. Legal test : - glycoside + few drops of pyridine and 1 drop of 2% sodium nitroprusside and a drop of 20% NaOH is added. Deep red color occur3. Tollens test: - mixture of pyridine & ammonical silver nitrate gives silver mirror on wall of test tube.4. Keller killani test: - drug + 10ml of 70% alcohol for few minute and filtered. To 5ml filtrate 10ml of hydrogen peroxide and 0.5 ml of strong solution of lead acetate is added. To this mixture 1 or 2 drop of concentrated sulphuric acid is added. Appearance of blue color confirms presence of deoxy sugar.5. Baljet test: - section of digitalis + add sodium picrate solution yellow to orange color.6. Antimony trichloride test: - solution of glycoside is heated with antimony trichloride and trichloroacetic acid to obtain blue or violet color.7. Liebermann test: - solution of glycoside in chloroform is added in acetic anhydride followed by conc. sulfuric acid gives violet to blue color. This test is for conformation of steroidal nucleus.8. Xanthohydral test: - a red color is produced by deoxy sugar when they are heated with 0.125% solution of xanthohydral in glacial acetic acid. Kratika Daniel (Ph.D) Assistant professor MANDSAUR
  11. 11. TLCSolvent system: - ethyl acetate : chloroform : ethanol (9 : 5 : 0.5) cyclohexane : acetone : acetic acid (49 : 49 : 2)Detecting reagent: - antimony tri chloride.PROPERTIES SOLUBILITY: - •The different cardiac glycosides show different solubilities in aqueous and organic solvents. They are usually soluble in water or aqueous alcohol and insoluble in the fat solvents with exception of chloroform and ethylacetate. •The higher number of sugar units in the molecule, the greater solubility in water but lower soluble in chloroform. •Alcohols are good solvents for both the glycosides and the aglycones. •pet.ether and ether are used for defatting process of drug. STABILITY: - •Acid hydrolysis cleavage of the glycosides into aglycones and sugar residues. •Specific enzyme usually coexist with CG in plants, which may split the primary G into G with less sugar units. Thus, CG deteriorate during drying and storage. These drugs should be stored in sealed containers over dehydrating agents. Kratika Daniel (Ph.D) Assistant professor MANDSAUR
  12. 12. •It is recommended to heat stabilize these CG, by destroying the enzymes at highertemperatures. At higher temperature, the tertiary OH gp at C-14 may split off as water,leading to formation of an inactive anhydro-form of CG O O O O 12 CH3 12 CH3 17 17 11 13 11 13 1 16 -H2O 16 R 9 14 1 R 9 14 2 15 2 15 10 8 OH 10 8 3 3 7 Sugar O 5 6 Sugar O 5 7 4 4 6•The gitoxin has in addition to tertiary OH at C-14 another secondary OH at C-16. Both OHgps split as water by the action of H2SO4 with the formation of two additional double bonds.These with the double bond of the lactone ring from a conjugated double bond system thatmakes the compound fluorescent in UV light.•The detection of gitoxin in other digitalis G is based on the above mentioned reaction.•Molecular formula – C27H44O5•Melting point – 230 – 265oC Kratika Daniel (Ph.D) Assistant professor MANDSAUR
  13. 13. BIOSYNTHESIS HO OH O2 NADPH 2 HO cholestrol HO NADPH2 O2 O O O H HO O O PREGNENLONE PROGESTRONE O O O OH O OH 5 - β − Pregnane 3,2 dione PREGNENALONE HO DIOL O O O acetyl CoA OH HO OH TRIOL 16 - β − hydroxylation oxalo acetyl CoA HO O O bufalin 12 - β − hydroxylation O C - 2 - unit O H H strophanthadin OH H OH Kratika Daniel (Ph.D) HO OH Assistant HO professor MANDSAUR gitoxigenin digitoxigenin
  14. 14. SAR1. The glycone part displays a great influence on the solubility and the rate of absorption and distribution of the glycosides to the site of action.2. Small change in the molecules such as a change of the location of the OH gp, modify the cardiac activity or even eliminate it completely.3. The saturation and/or cleavage of the lactone ring, destroys the cardiac activity.Therefore, the closely related CG, differ greatly in the rate of absorption, duration of action and their cumulative effect. Kratika Daniel (Ph.D) Assistant professor MANDSAUR
  15. 15. USES & ACTIONMain action on heart. The primary action may be divided into 3 parts 1. +ive inotropic effect on heart. 2. Partial blockade of A.V. conduction. 3. Reduction in heart rate.• Direct stimulation of myocardium & increased contractility with a resultant increase in cardiac output, reduction in heart size, improved, cardiac efficiency.• Depression of conduction, especially in A. V. node, which protects the ventricles from excessive bombardment by auricular impulses in auricular arrythmias. Due to this effect bradycardia occurs.• Increased vagal activity, which decrease the auricular refractory period with conversion of flutter to fibrillation. The delay in A. V. conduction & bradycardia is also vagal origin.• Increased in cardiac excitability makes heart more vulnerable to arrythmias• It has direct constrictor action on vascular smooth muscle. It may diminished clotting time.• GIT – it causes emetic action due to stimulation of chemoreceptor trigger zone in medulla.USES • Heart failure with sinus rhythm or atrial fibrilation. • Atrial flutter. • Paroxysmal atrial tachcardia. • Prevention of paroxysmal atrial arrythmias. Kratika Daniel (Ph.D) Assistant • Prophylactically before cardiac surgery. professor MANDSAUR INSTITUTE OF PHARMACY, Mandsaur