Digoxin & digitoxin

Cardiac Glycosides

1. Presentation: PHYTOCHEMISTRY Submitted To: Submitted By: Dr. Malik Saadullah M. Rashad (616) M. Shan (621)

2. BIOLOGICAL EVALUATION OF PLANT DERIVED DRUG MOLECULES ( DIGOXIN & DIGITOXIN)

3. Introduction: Drug evaluation may be defined as the determination of identity, purity and quality of a drug. Identity – identification of biological source of the drug. Quality – the quantity of the active constituents present. Purity – the extent of foreign organic material present in a crude drug.

4. Biological Evaluation: It is employed when the drug cannot be evaluated satisfactorily by chemical and physical methods. In this method, the response produced by the test drug on a living system is compared with that of the stranded preparation. Such an activity is represented in units as International Units (I.U).

5. Indication of Biological Evaluation: When the chemical nature of the drug is not known but is has an biological action. When chemical methods are not available. When the quantity of the drug is small and so it cannot be evaluated chemically. Drugs which have different chemical composition but same biological activity. Example: Cardiac glycosides arte evaluated by this method on cats, frogs or pigeons.

6. Cardiac G lycosides : 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 more efficiently . There are two main constituents of Digitalis plant. Digoxin is obtained from Digitalis lanata . Digitoxin is obtained from Digitalis purpurae . Compounds R1 R2 Digitoxigenin H H Digoxigenin OH H

7. 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 Solubility in water & High solubility in chloroform Glycoside with low Solubility in water & High solubility in chloroform

8. Aqueous solution Extraction with chloroform Washing with chloroform with water 2N HCl, 2N Na 2 CO 3 . Discard washing Separation of glycoside by chromatography Elution with chloroform & chloroform containing graded proportion of methanol Adjust filtrate to pH 6 Successive washing with chloroform Ether. ethanol Discard washing Into aqueous phase add Sodium sulfate to saturation Extraction with chloroform ethanol mixture Acetylation/ benzoylation of more polar glycoside KHCO 3 Separation of individual glycoside By chromatography Less polar glycoside

9. Biosynthesis of Digoxigenin & Digitoxigenin

10. SAR 1. 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 group, 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 .

11. USES: Heart failure with sinus rhythm or atrial fibrilation . Atrial flutter. Paroxysmal atrial tachcardia . Prevention of paroxysmal atrial arrythmias . Prophylactically before cardiac surgery.